Optimizing primary PCI for ST Elevation Myocardial Infarction · 3 Optimizing primary PCI for ST...
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Optimizing primary PCI for ST Elevation Myocardial Infarction Yahya Berkahanto Juwana
Transcript of Optimizing primary PCI for ST Elevation Myocardial Infarction · 3 Optimizing primary PCI for ST...
Optimizing primary PCI for ST Elevation Myocardial
Infarction
Yahya Berkahanto Juwana
2
Printed by: Gildeprint drukkerijen, Enschede
The printing of this thesis was financially supported by Diagram Research Organisation BV,
Biosensors, TOP medical, Boston Scientific, Medtronic
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Optimizing primary PCI for ST Elevation
Myocardial Infarction
Een wetenschappelijke proeve op het gebied van de Medische Wetenschappen
Proefschrift
ter verkrijging van de graad van doctor
aan de Radboud Universiteit Nijmegen
op gezag van de rector magnificus, prof. mr. S.C.J.J. Kortmann
volgens besluit van het college van decanen
in het openbaar te verdedigen op woensdag 20 april 2011
om 13.00 uur precies
door
Yahya Berkahanto Juwana
geboren op 16 Februari 1969
te Blora, Indonesië
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Promotoren: Prof. dr H. Suryapranata
Prof. dr M.J. de Boer
Copromotor: Dr J.P. Ottervanger (Isala Klinieken, Zwolle)
Manuscriptcommissie: Prof. dr. J.W.M. van der Meer (voorzitter)
Prof. dr. Budhi Setianto (University Indonesia, Jakarta)
Prof. dr. F. Zijlstra (Erasmus Universiteit, Rotterdam)
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CONTENTS
Abbreviations
1. Introduction and outline
2. Modern treatment of ST elevation Myocardial Infarction –
a review
3. Tirofiban for myocardial infarction. J Expert Opinion on
Pharmacotherapy 2010 Apr;11(5):861-6.
4. Impact of stenting on Mortality in Patients undergoing
Primary PCI for ST Elevation Myocardial Infarction.Y.B.
Juwana, et al, Treatment Strategies, ESC congress
review 2009:58-63.
5. Randomized comparison of Rapamycin and Paclitaxel-
eluting stents in patients with primary PCI for ST
elevation Myocardial Infarction. Y.B. Juwana, et al. Am J
Cardiol 2009;104:205-9.
6. Differences between Rapamacyin and Paclitaxel-eluting
stents: a meta-analysis of all randomized trials. Y.B.
Juwana, et al, J Invasive Cardiol 2010;22:312-6.
7. Routine Use of a new endothelial progenitor cells
antibody-coated stent in patients with primary PCI for ST
elevation Myocardial infarction: A prospective registry.
Y.B. Juwana, et al, submitted.
Page
9
17
39
55
73
91
113
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8. First experience of Primary PCI in a starting Indonesian
heart center. Y.B. Juwana, et al, submitted.
9. Primary coronary intervention for ST elevation myocardial
infarction in Indonesia: comparison with Europe.Y.B.
Juwana, et al, Neth Heart J 2009 Nov;17(11):418-21.
10. Summary and conclusions
11. Nederlandse samenvatting en conclusies
12. Abstrak dan kesimpulan dalam bahasa Indonesia
13. List of presentations and publications
14. Acknowledgements
15. Curriculum vitae
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Abbreviations
CABG Coronary Artery Bypass Surgery
DES Drug Eluting Stent
EPC Endothelial Progenitor Cell
IABP Intra Aortic Balloon Pumping
IRV Infarct Related Vessel
LVEF Left Ventricular Ejection Fraction
MACE Major Adverse Cardiac Events
MOHRI Ministry of Health Republic Indonesia
PCI Percutaneous Coronary Intervention
PES Paclitaxel-eluting Stent
QCA Quantitative Coronary Angiography
RES Rapamycin-eluting stent
STEMI ST Elevation Myocardial Infarction
TIMI Thrombolysis in Myocardial Infarction
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Chapter 1
Introduction and outline
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Indonesia is the largest archipelago in the world, with an estimated total of 17,504
islands, of which only about 6,000 are inhabited. The five main islands are Sumatra,
Java/Madura, Kalimantan, Sulawesi and Papua. Indonesia consists of more than 300
ethnic groups, hundreds of native languages and several religions spreading out
throughout the islands. All people are united in one country, one nation and one
language, Indonesia. It is not surprising that the national motto is ―Bhinneka Tunggal
Ika‖, meaning ―Unity in Diversity‖. Administratively, Indonesia has been divided into
33 provinces (figure 1).
Figure 1
The total population of Indonesia is about 220 million. Data on medical statistics are
collected by several institutions, including the division of Medical Care of the Ministry
of Health Republic Indonesia (MOHRI) and the Badan Pusat Statistik (BPS-Statistics
Indonesia), a Non-Departmental Government Institution directly responsible to the
president, collecting general statistics, including demographics, at both the national
12
and provincial level. Also the World Health Organization (WHO) collects data since
Indonesia joined this organization in 1950. The Indonesian health care providers
represent a mix of public and private institutions, with in 2007 approximately 1300
general hospitals, roughly half of them owned by private investors, Source: DG of
Medical Care Ministry of Health Republic Indonesia (MOHRI). Although there is an
increasing number of insurance-based financial schemes in the health sector, the
majority of Indonesians are still paying out-of pocket for their health care.
The burden of cardiovascular disease
As in many Western countries, atherosclerosis, particularly of the coronary arteries, is
a major cause of morbidity and mortality in Indonesia nowadays. However, although
substantial progress has been made in the understanding of the pathophysiology of
atherosclerosis and treatment has significantly improved over the last decades, in
2002 ischaemic heart disease was still the most common cause of death in Indonesia
(14% of all causes) and accounted for an average of 8 life years lost (Source: Death
and DALY estimates by cause, 2002;
http://www.who.int/entity/healthinfo/statistics/bodgbddeathdalyestimates.xls). The
age-standardized mortality rate by ischaemic heart disease in Indonesia and several
other countries are depicted in figure 2, showing the high death rate in Indonesia.
Figure 2
13
There are several explanations for the high mortality rate due to ischaemic heart
disease in Indonesia. First, the prevalence of smoking, diabetes and hypertension is
high in Indonesia. Second, many patients with either diabetes or hypertension have
sub-optimal treatment. Third, treatment options for several clinical presentations of
ischaemic heart disease are not available everywhere in Indonesia. This may be
caused both by limitations of the health care system, lack of awareness of patients
and doctors, including recognition of symptoms, and lack of financial resources.
Although primary prevention of coronary artery disease is of key importance, we have
to deal with the fact that in the next decades an increasing number of patients with
clinical manifestations will be presented. The broad goals of treatment for patients
with coronary artery disease are improvement in survival and a reduction in the risk
of myocardial infarction and symptoms of coronary disease.
One of the most important and dangerous complications of coronary atherosclerosis
is ST-elevation Myocardial Infarction (STEMI). In the majority of cases, it is caused
by a ruptured atherosclerotic plaque resulting in subsequent acute closure of one of
the large epicardial vessels, and if untreated, mortality is very high. The most
important goal in the treatment of patients with STEMI is to achieve rapid, complete
and sustained reperfusion of the infarct related vessel and the myocardial tissue it
supplies. Compared to medical treatment by fibrinolysis, percutaneous coronary
intervention (PCI) in patients with STEMI (―primary PCI‖) is more effective in re-
opening the occluded vessel and is associated with reduced infarct size and a lower
incidence of death and re-infarction. For these reasons, primary PCI has become the
preferred therapy of patients with STEMI, provided the procedure is performed in a
timely manner by experienced operators.
Although primary balloon angioplasty is very effective in restoration of coronary blood
flow, there are still several limitations. Recurrent ischemia occurs in 10 to 15% after
initially successful PCI, and silent or clinically apparent reocclusion of the infarct
related vessel (IRV) occurs in 5 to 10%, whereas angiographic restenosis is
observed in 30 to 50%. As a result, the need for subsequent target vessel
revascularization (TVR) in the first 6 months remains disappointingly high. Although
stenting has been shown to be superior to balloon angioplasty in reducing restenosis
14
and the need for TVR, there is also a risk of acute closure of the stent (sub-acute
stent occlusion), which is associated with high mortality.
Furthermore, although the beneficial effects of primary PCI for STEMI has been
demonstrated in a number of trials, most studies were conducted in the western
countries. Experience, logistics and patient characteristics may differ in other parts of
the world, and the effects of primary PCI should also be evaluated in these countries.
This thesis
Primary PCI has been introduced after randomised controlled trials demonstrated its
superiority over other reperfusion modalities in thebeginning of the nineties of the last
century. Since then a number of studies have been performed, increasing our
insights about important subjects as concomitant medication, thrombosuction and
treatment after primary PCI.
The main objective of the studies presented in this thesis is to investigate the most
optimal strategy for performing primary PCI. The studies were performed in close
collaboration between Klinik Kardiovaskular, Hospital Cinere, Jakarta and the
department of cardiology, Isala Klinieken, Zwolle, the Netherlands.
Main issues addressed in this thesis are:
1. Does the use of stents during primary PCI improves survival?
2. Are there differences in outcome between different drug eluting stents, used
during primary PCI?
3. Are endothelial progenitor cells capturing stents safe during primary PCI in
patients with STEMI?
4. Can primary PCI be performed safely, with good outcome in a starting
heartcenter in Jakarta, Indonesia?
5. Are there major differences between primary PCI performed in Europe, as
compared to Indonesia?
In the second chapter a brief review on current treatment of STEMI is given. After
immediate reperfusion therapy, secondary prevention is very import to decrease
death and risk of recurrent myocardial infarction. In chapter 3, use of the IIb/IIIa
inhibitor tirofiban in myocardial infarction is discussed in more detail.
15
In the fourth chapter, balloon angioplasty is compared to coronary stenting. Although
a number of randomised controlled trials has shown that stenting during primary PCI
may decrease target vessel revascularization and recurrent myocardial infarction,
there was no clear decrease of mortality after stenting. Moreover, the randomised
trials excluded many patients, and many had a limited sample size. Furthermore,
interpretation of results is difficult because of many cross-overs. To assess the
potential association between mortality and stenting in patients undergoing primary
PCI, analyses of a prospective registry was performed, with particular focus on
mortality differences between patients with and without stenting.
Although a clinical benefit of drug eluting stents, as compared to bare metal stents,
has been shown in several trials, it is still not clear which drug eluting stent has the
most benefit. In chapter 5 and 6, a randomised controlled clinical trial and a meta-
analysis of two different coated stents for use in patients with STEMI are compared.
Stents have clear benefits in reducing the risk of restenosis and can immediately
treat dissection(s) during and after (balloon) PCI. However, they have also limitations,
such as acute or late stent thrombosis. In chapter 7 a concept of a new stent, coated
with endothelial progenitor cells, is presented. Previously, the use of this stent for the
treatment of STEMI was only reported in very small studies. We did an analysis of a
large data-base of patients treated with primary PCI using this new stent.
Chapter 8 gives some data about the first experience with primary PCI in a starting
Indonesian heart center (Klinik Kardiovaskular, Hospital Cinere). In particular
attention is paid to short-term outcome and success of reperfusion. A very important
chapter is the comparison of primary PCI between Indonesia and The Netherlands,
and these results are presented in chapter 9. Not only potential differences in
performing PCI, but also potential differences in baseline characteristics and logistics
were studied.
In chapter 10 the studies are summarized and some conclusions are made.
Furthermore, some future directions are explored.
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CHAPTER 2
Modern treatment of ST-elevation myocardial
infarction (STEMI): a review
18
19
Summary
Among the clinical presentations of coronary artery disease, ST segment elevation
myocardial infarction (STEMI) has a high mortality and morbidity with increased risk
of heart failure and cardiac arrhythmias, if treated not adequate. However, if treated
well, most patients with STEMI have a very good prognosis. Timely and sustained
restoration of infarct vessel patency is the major goal of initial treatment. If primary
PCI is performed, (drug-eluting) stents may reduce restenosis, but effects on
mortality are less obvious. Concomitant administration of aspirin, heparin, clopidogrel
and glycoprotein IIb/IIIa antagonists should be considered, whereas possibly in the
future bivalirudin may replace heparin and glycoprotein IIb/IIIa antagonists.
Beta-adrenergic blockers, angiotensin-converting–enzyme inhibitors and statins
should be initiated in all patients with STEMI and may reduce mortality and risk of
heart failure or recurrent infarction. There is also some evidence about beneficial
effects of aldosterone antagonists in patients with signs of heart failure. Patients with
multi vessel coronary artery disease should receive revascularisation if ischemia is
documented by non-invasive imaging. High-risk patients, particularly those with low
ejection fraction, should receive an Implantable Cardioverter Defibrillator after 30
days, although it is not clear whether patients after primary PCI also have benefits.
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Introduction
Although during the past decades knowledge increased and therapeutic possibilities
improved, the prevalence of coronary artery disease is still high. The clinical
presentations of coronary artery disease include stable angina, heart failure,
arrhythmias and the acute coronary syndrome (ACS).
Of the patients with an ACS, particularly those with ST elevation myocardial infarction
(STEMI) should be treated fast and aggressive, because if they are not treated or
treated insufficiently, they may have a very bad prognosis. Treatment has been
changed during the last decades, and prognosis has improved subsequently during
this time period (figure 1). We review in this chapter the current treatment of STEMI.
Figure 1 - Hospital mortality in patients admitted for myocardial infarction in Zwolle in
different time periods.
Diagnosis
All patients with suspected myocardial infarction should have rapid ECG recording
and interpretation. There is a strong association between time delay and mortality in
patients with STEMI treated by primary PCI (1). Also, the choice for reperfusion
therapy is dependent on the durations of symptoms (2). All steps should be
considered for improvement, including the patient‘s ability to recognize their
symptoms and to promptly contact the medical system, the time necessary to
0
5
10
15
20
25
30
1950-60 1960-70 1980-90 1990-2000 2001-20051950-1960
Bed-rest
1960-1970
1st CCU
1980-1990
Fibrinolysis
1990-2000
Primary
PCI
2000-2005
Beyond
TIMI 3
Hospital mortality (%)
25
15
5
21
transport the patient to the hospital, the decision process on arrival, and the requisite
time to implement the reperfusion strategy. If a diagnosis of STEMI is made,
treatment with aspirin, heparin and (less clear) clopidogrel, beta blockers and GP IIa
IIIb inhibitors should be initiated, and the patient should be transferred to a hospital,
preferably a PCI center.
Reperfusion therapy
Reperfusion therapy (either mechanical or pharmacologic) is indicated for patients
with chest pain with a duration of 12 hours or less in association with ST-segment
elevation greater than 0.1 mV in two or more contiguous electrocardiographic leads
or a new (or presumed new) left bundle-branch block.
Fibrinolytic therapy
In comparison with conservative management (medical treatment without reperfusion
therapy), fibrinolytic therapy improves left ventricular systolic function and survival in
patients with myocardial infarction associated with either ST-segment elevation or left
bundle-branch block. Nowadays, fibrinolytic therapy can be considered in patients
whose first medical contact occurs less than 1 hour after the onset of symptoms (in
whom the therapy may abort the infarction) (3) and those with a history of
anaphylaxis due to radiographic contrast material. However, primary PCI should be
the first choice in the majority of patients. When primary PCI is not readily available,
efficient prehospital treatment with (t-PA-based) fibrinolytic agents may reduce
mortality when administered promptly (4). Rescue PCI should be considered for
patients in whom reperfusion fails to occur after fibrinolytic therapy (5, 6). Small
studies suggested beneficial effects of GP IIb/IIIa inhibitors in patients undergoing
rescue PCI after failed thrombolysis, without a significant increase in bleeding or
vascular complications (7, 8). Facilitated primary PCI is defined as the administration
of fibrinolytic therapy to minimize myocardial ischemia time while waiting for PCI.
Several studies have also assessed the combination of GP IIb/IIIa inhibitors with
thrombolysis, using either standard doses of thrombolytic agents (TAMI 8, IMPACT-
AMI, GUSTO V and PARADIGM) or reduced dosages of thrombolytic agents (TIMI
14, FINESSE and SPEED) for combination therapy. However, benefits were not clear
and there was an increased risk of bleeding, suggesting that facilitated PCI cannot be
recommended outside of experimental protocols at this time (9).
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Primary PCI
Primary PCI has a number of benefits over fibrinolysis. First, it can be offered to
patients with contraindications for fibrinolysis. But more important, primary PCI
restores angiographically normal flow, including optimal (TIMI) flow and blush, in the
previously occluded artery in more than 90% of patients (10-12), whereas fibrinolytic
therapy does so in only 50 to 60% of such patients.
Primary PCI causes also less frequently (intracranial) bleeding. Furthermore, about a
quarter of patients receiving fibrinolytic therapy has reocclusion of the infarct-related
artery within 3 months after the myocardial infarction, with a recurrent infarction (13).
Therefore, primary PCI may be preferable, even if the "door-to-balloon" interval
exceeds 90 minutes in patients with a contraindication to fibrinolytic therapy (14) a
high risk of bleeding with fibrinolytic therapy (15), with clinical findings as tachycardia,
hypotension, or pulmonary congestion suggesting a high risk of an infarct-related
complicated medical course or death (16), and those with cardiogenic shock (17).
There is a continuing controversy about the acceptable time-window for primary PCI.
Recent American and European guidelines recommend primary PCI if the delay in
performing PCI instead of administering fibrinolysis (PCI-related delay) is <60 min
and the presentation delay is more than 3 hours.
Where primary PCI leads to an improved left ventricular systolic function, less
complications (ie. stroke) and higher survival, the benefits of stenting are almost
entirely due to a significantly lower need for repeat ischemia-driven revascularization.
Among other studies, the CADILLAC study showed that the composite end points
(death, reinfarction, disabling stroke, or ischemia-driven revascularization of the
target vessel) were significantly lower with stenting compared to balloon angioplasty
in patients with STEMI (18). As a result, stenting of the infarct-related artery may be
preferred. As compared with bare-metal stents, drug-eluting stents may further
reduce restenosis within 12 months after primary PCI (19-21). Among the drug-
eluting stents, several studies have compared Sirolimus (SES) and paclitaxel (PES)
eluting stents in patients with STEMI. In general, it seems to be that RES, compared
to PES, significantly reduces the risk of reintervention and stent thrombosis with a
trend toward a lower risk of MI without affecting mortality (22). In addition, another
'olimus (everolimus) eluting stent has been shown to be superior to PES (23).
If drug-eluting stents are used in this setting, dual antiplatelet therapy (aspirin and
clopidogrel) should be given for at least 12 months to decrease the incidence of
23
subacute stent thrombosis. A number of studies have investigated potential benefits
of GP IIb/IIIa inhibitors in patients with primary PCI for STEMI, including a significant
reduction of the combined endpoint of death and recurrent myocardial infarction (24,
25). An alternative for heparin is bivalirudin, a direct thrombin inhibitor (26). The
Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial
Infarction (HORIZONS-AMI) trial demonstrated a significantly lower mortality and
bleeding event rate after on year in favor of bivalirudin monotherapy (with provisional
GP IIb/IIIa receptor blockade) in comparison with unfractionated heparin plus GP
IIb/IIIa blockade in patients undergoing primary PCI for STEMI (27), However,
bivalirudin monotherapy was associated with a highly significant greater incidence of
acute stent thrombosis. More randomized trials should confirm these observations,
and also potential benefits of bivalirudin given in the ambulance. Distal embolization
after primary PCI is related to more extensive myocardial damage and a poor
prognosis (28, 29). Risk factors of distal embolization include infarct location,
thrombus composition and size and diabetes (30). Thrombus aspiration before
primary PCI may lead to better myocardial reperfusion and has been associated with
lower enzyme release, and a lower risk of distal embolization and no-reflow (31).The
Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial
infarction Study (TAPAS) demonstrated even a reduction in cardiac death and the
combination of cardiac death an recurrent myocardial infarction after one year (32).
Coronary artery bypass graft surgery
Coronary artery bypass graft surgery (CABG) is infrequently performed in patients
with STEMI, but may be life saving in patients with failed primary PCI, particularly in
patients with a large size of myocardium at risk. Also patients with left main or three-
vessel disease but with restoration of blood flow either spontaneous or after balloon
PCI may benefit of short-term CABG. Despite the higher surgical mortality rate after
urgent CABG, a favorable long-term clinical outcome can be expected if the patients
survive (33).
Intensive cardiac care
Several patients with STEMI are critically ill during the acute phase, with a very high
risk of death. These patients include those after cardiac arrest, those with sustained
ventricular arrhythmias and those with (progressive) heart failure.
24
Mortality remains high in STEMI patients presenting with heart failure and particularly
cardiogenic shock (34). Mechanical complications of myocardial infarction, as
ventricular septal or mitral chorda rupture should be excluded or when diagnosed
treated. Heart failure should be aggressive treated by inotropic drugs and avoiding
negative intotropic drugs. Respiratory failure can be treated by (mechanical)
ventilation (35). In patients with acute kidney injury following cardiogenic shock, renal
replacement therapy should be considered (36). Intra-aortic balloon counterpulsation
(IABP) in patients with cardiogenic shock is strongly recommended (class IB) in the
current guidelines. However, a recent systematic review and meta-analysis showed
that there is insufficient evidence endorsing the current guideline recommendation for
the use of IABP therapy in the setting of STEMI complicated by cardiogenic shock
(37). Also a recently published trial failed to show benefits of IABP in patients with
cardiogenic shock complicating myocardial infarction (38). If available, left ventricular
assist devices may improve prognosis in patients with severe heart failure (39),
although also then prognosis remains poor.
A special type of heart failure is right ventricular dysfunction. It has been shown that
RV dysfunction as assessed by echocardiography is an independent predictor for
long-term mortality (40). Right ventricle heart failure should be treated by extra fluid
and if necessary inotropics. It has been suggested that levosimendan is more
effective than dobutamine for right ventricle dysfunction (41), but this should be
confirmed by additional trials.
In patients with STEMI and cardiac arrest, conventional cooling methods to induce
mild therapeutic hypothermia seem to improve survival and neurologic outcome after
cardiac arrest (42, 43).
Sustained VT/VF remains a significant complication associated with an increased risk
of in-hospital mortality (44). Early mortality is reduced after successful percutaneous
coronary intervention, but remains elevated in this high-risk group (45).
Medication after reperfusion therapy
Beta-adrenergic blockers (46, 47) and angiotensin-converting–enzyme inhibitors (48)
should be initiated in all patients, provided that the patient has no contraindications
and is stable hemodynamically. Beta-blockers have indisputably been demonstrated
to be clinically useful in the setting of acute Myocardial Infarction (MI) (49). Especially
early metroprolol administration during acute coronary occlusion increases
25
myocardial salvage (50). A meta-analysis of randomised trials could not demonstrate
a short-term survival benefit of treatment with beta-blockers, but this was probably
because of a negative effect in patients with heart failure (51). Patients with
obstructive lung disease may receive less often beta blockers (52). However,
although these patients should be treated with caution, the majority of these patients
can safe use beta blockers (53).
In addition to aspirin, all patients should be treated with clopidogrel for 12 months
(54), although in the future prasugrel may be an alternative, since it has been shown
that prasugrel is more effective than clopidogrel for prevention of ischaemic events,
without an apparent excess in bleeding in patients with STEMI (55).
Chronic therapy with an ACE inhibitor (unless contraindicated) for all patients after an
STEMI is recommend. Angiotensin II receptor blocker (ARB) may be an alternative
for patients unable to tolerate an ACE inhibitor, usually due to cough. ACE
inhibitors/ARBs are most important in patients with heart failure, an LVEF less than
40 percent, diabetes, or hypertension. The optimal approach is less clear in
asymptomatic, normotensive, nondiabetic patients with no or minimal impairment in
left ventricular function. Statin therapy at discharge is associated with a significant
reduction in 1-year mortality after primary angioplasty for STEMI and is
recommended for all patients with acute myocardial infarction (56, 57). Patients with
signs of heart failure may benefit of aldosterone antagonists (58).
Rehabilitation
Although most studies are before the primary PCI erea, a trend is suggested towards
decreased mortality with early mobilisaton after infarction (59). The identification of
major modifiable risk factors for coronary heart disease (dyslipidemia, hypertension,
smoking, obesity, inactivity, and diabetes) is a prerequisite to the implementation of
rehabilitation and preventative interventions. Risk factor modification by therapeutic
lifestyle changes, as well as drug therapies can decrease morbidity and mortality in
such patients. Home and centre based forms of cardiac rehabilitation seem to be
equally effective in improving clinical and health related quality of life outcomes in
patients with a low risk of further events after myocardial infarction or
revascularisation (60). Psychological interventions may reduce total cholesterol and
standardized mean anxiety scores, interventions with behavioral components may be
effective in reducing all-cause mortality and nonfatal myocardial infarction, and
26
interventions with behavioral and/or cognitive components have been associated with
reduced standardized mean depression scores (61).
Also exercise-based cardiac rehabilitation may be effective in reducing cardiac
deaths, although it is less clear whether exercise only or a comprehensive cardiac
rehabilitation intervention is more beneficial (62).
Additional revascularisation
After either primary PCI or fibrinolysis, (additional) revascularisation should be
considered if ischemia is documented by non-invasive imaging. The ACC/AHA
guidelines recommend exercise stress with imaging using radionuclide myocardial
perfusion imaging (MPI) or echocardiography for patients who are able to exercise
and vasodilator (adenosine or dipyridamole) MPI or dobutamine echocardiography
for patients who cannot. Routine PCI of an occluded infarct artery three to 28 days
after myocardial infarction will probably not reduce the occurrence of the death, re-
MI, and New York Heart Association class IV heart failure in comparison with patients
assigned to optimal medical therapy alone (63).
Re-stenosis rates of the infarct related vessel are considerably higher in more
complex lesion subsets, such as small vessels, long lesions, and bifurcations, and
these patients should be monitored intensively, to detect myocardial ischemia.
Patients with multivessel disease, have often an unfavorable clinical outcome, with
also less improvement of LV function after the infarction. Additional revascularisation
may be of benefit in these patients, with probably no mortality difference between
patients treated by PCI or CABG during long-term follow-up (64, 65).
Various single center registries also reported the efficacy of DES for multivessel
disease (66, 67). Because restenosis was the determining factor favoring surgery in
previous randomized clinical trials comparing PCI to CABG, PCI with DES may be
the first choice in many patients in the future, but randomized trials should confirm
this approach. However, CABG is compelling for patients with left main disease or
more diffuse coronary artery disease or specific high-risk patient subgroups (ie,
multivessel disease with left ventricular dysfunction and diabetics), whereas patients
with less diffuse disease and focal lesions are good candidates for PCI (68, 69).
ICD implantation
27
Primary prevention of sudden cardiac death after myocardial infarction by an
Implantable Cardioverter Defibrillator (ICD) was particularly studied in MADIT II and
DINAMIT (70, 71). MADIT II demonstrated that in patients with a history of
myocardial infarction who had reduced LV function (ejection fraction lower than 30%)
there was a significant mortality reduction after implantation of an ICD. In DINAMIT,
patients were randomised 6-40 days after myocardial infarction, in those with signs of
reduced LV function and impaired autonomic tone. Although in DINAMIT a significant
reduction of arrhythmogenic death was observed in patients randomised to ICD (HR
0.42, 95% CI 0.22-0.83), risk of non-arrhythmogenic death was increased in these
patients, resulting no significant mortality difference between the treatment groups.
Current guidelines advice to implant an ICD after 30 days in those patients who have
an ejection fraction lower than 30%.
In the more recently published IRIS trial, benefit of ICD after STEMI was studied in
patients with a reduced left ventricular ejection fraction (< or = 40%) and a heart rate
of 90 or more beats per minute on the first available electrocardiogram (ECG)
(criterion 1: 602 patients), nonsustained ventricular tachycardia (> or = 150 beats per
minute) during Holter monitoring (criterion 2: 208 patients), or both criteria (88
patients). In this study, prophylactic ICD therapy did not reduce overall mortality (72).
The ongoing DAPA trial, will assess benefit of ICD in patients after primary PCI and
TIMI flow less than 3 or left ventricular ejection fraction lower than 30% as measured
short after admission for the index MI (73). Patients will be randomized between 30
and 60 days after their MI.
The future
Although treatment of STEMI has improved during the last decades, in several fields
additional improvement should be achieved. Strategies should be applied for
reducing time to diagnosis, reducing time from diagnosis to arrival in a PCI center
and decreasing door-to-balloon time in all patients. Randomized trials should
demonstrate the most optimal combination of medical treatment given before arrival
in the hospital. In patients with primary PCI, bleeding should be further decrease,
possibly by use of newer agents as bivalirudin rather than heparin combined with GP
2B/3A inhibitors. It should be clarified for how long agents as clopidogrel must be
used to prevent risk of stent thrombosis, particularly in patients with drug eluting
stents. After reperfusion therapy, much more patients should receive appropriate
28
medication, including beta blockers, ACE inhibitors and statins. Before discharge,
more intensive strategies for long-term life style modification should be initiated,
including smoking cessation and weight reduction by both diet and physical exercise.
Finally, additional studies should make clear which patients when should be treated
with (prophylactic) ICD (74).
29
Abbreviations and acronyms:
ACS: Acute Coronary Syndromes
CABG: Coronary Artery Bypass Graft
CHD: Coronary Heart Disease
CVD: cardiovascular disease
IABP: Intra-aortic balloon counterpulsation
MI: Myocardial Infarction
MPI: Myocardial Perfusion Imaging
MVD: Multi Vessel Disease
PCI: percutaneous coronary intervention
STEMI: ST-segment elevated myocardial infarction
TIMI: Thrombolysis in Myocardial Infarction trial
TLR: Target Lesion Revascularization
30
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39
CHAPTER 3
Tirofiban for myocardial infarction
J Expert Opinion on Pharmacotherapy 2010;11:861-6
40
41
ABSTRACT
Importance of the field: Inhibition of platelet aggregation plays a key role in treatment
of coronary artery disease.
Areas covered in this review: Studies on the effects of tirofiban in patients with either
ST elevation or non-ST elevation myocardial infarction are reviewed.
Main findings: Tirofiban is a small molecule glycoprotein IIb/IIIa receptor inhibitor. If
discontinued, the action of tirofiban is faster reversed as abciximab. The dose varied
between low (bolus of 0.4 μg/kg administered over 30 minutes followed by an
infusion of 0.10 μg/kg/min), intermediate (bolus of 10 μg/kg administered over
3minutes followed by an infusion of 0.15μg/kg/min) and high (bolus of 25 μg/kg
administered over 3 minutes followed by an infusion of 0.15μg/kg/min). Especially the
high dose administration, may be beneficial in patients with ST Elevation Myocardial
Infarction undergoing primary PCI. There is no indication for tirofiban in patients
treated with thrombolysis. Patients with Non-ST Elevation Myocardial Infarction
requiring PCI are most likely to achieve benefit from tirofiban, when they have
ongoing ischemia and/or dynamic ECG changes. The risk of serious bleeding, with
tirofiban is low and there is a very low risk of thrombocytopenia.
Take home message: Use of tirofiban for myocardial infarction, is effective and has
an acceptable safety profile.
42
DRUG SUMMARY BOX
Drug name Tirofiban hydrochloride
Phase Launched
Launched indication Myocardial infarction Unstable angina Acute coronary syndrome
Pharmacology description GPIIb IIIa receptor antagonist Platelet aggregation antagonist
Route of administration Parenteral, intravenous
Chemical structure
Pivotal trial(s) ON-TIME2 shows effects of high-dose
tirofiban in ST elevation infarction treated with primary PCI PRISM-PLUS shows effects of tirofiban in non-ST elevation myocardial infarction COMPARE trial shows the importance of pharmacodynamics of the different GP IIb/IIIa inhibitors, including tirofiban
43
1. MYOCARDIAL INFARCTION
Cardiovascular disease still generates a substantial burden of illness in many parts of
the world. Acute coronary syndrome (ACS) is the umbrella term for the clinical signs
and symptoms of acute myocardial ischemia resulting in unstable angina, non-ST-
segment elevation myocardial infarction (non-STEMI) or ST-segment elevation
myocardial infarction (STEMI). It is the clinical manifestation of severe myocardial
ischemia due to an acute atherothrombotic coronary obstruction developed on the
surface of a ruptured atheromatous plaque or as a consequence of endothelial
erosion. Reperfusion therapy (either mechanical or pharmacologic) is indicated for
patients with chest pain with a duration of 12 hours or less in association with ST-
segment elevation with 1 mm of ST change (0.1 mV) in at least 2 contiguous limb
leads (II, III, AVF, I,AVL), or 2 mm of ST change in at least 2 contiguous chest leads
(V1-V6) or a new (or presumed new) left bundle-branch block. In comparison with
conservative management (medical treatment without reperfusion therapy),
fibrinolytic therapy improves left ventricular systolic function and survival in patients
with myocardial infarction associated with either ST-segment elevation or left bundle-
branch block. However, primary percutaneous coronary intervention (PCI) restores
angiographically normal flow, including optimal TIMI 3 flow and blush, in the
previously occluded artery in more than 90% of patients, whereas fibrinolytic therapy
does so in only 50 to 70% of such patients. Therefore, primary PCI should be a
preferred therapy in the majority of STEMI patients.
2. GLYCOPROTEIN IIB/IIIA INHIBITORS
Platelet thrombus formation has been shown to play an important role in the
pathogenesis of ACS, and it is therefore not surprising that antiplatelet medication
has become very important in the treatment of patients with ACS. Many trials have
shown that oral antiplatelet treatment with aspirin and clopidogrel in these patients is
not enough. A number of studies have investigated potential benefits of GP IIb/IIIa
inhibitors in patients with primary PCI for STEMI, including a significant reduction of
the combined endpoint of death and recurrent myocardial infarction (1).
3. TIROFIBAN
Tirofiban is an intravenously administered nonpeptide tyrosine derivative that causes
competitive GP IIb/IIIa receptor inhibition. It has a reversible, high specifici affinity for
44
the GP IIb/IIIa receptor. The platelet aggregation inhibition of tirofiban is immediate,
extensive, and additive to oral treatment with aspirin and clopdiogrel. In a study
among 100 patients with non-STEMI, it was demonstrated that tirofiban provided
consistent and effective inhibition of platelet aggregation at the time of immediate or
very early invasive therapy in contrast to only the combination of aspirin and
clopidogrel (2). It was also shown that low-risk patients according to clinical
presentation who had poor responsiveness to standard oral platelet inhibitors (aspirin
and clopidogrel) as measured by a point-of-care assay, intensified platelet inhibition
with tirofiban lowered the incidence of myocardial infarction after elective coronary
intervention (3). There are probably no major differences in platelet inhibition
between tirofiban and abciximab during PCI, although it was suggested that tirofiban
has a greater inhibition in patients with diabetes (4). Probably, tirofiban also
decreases the inflammatory reactions in patients with acute coronary syndrome (5),
but not in patients with PCI for stable angina (6).
The dose of tirofiban varied between low (bolus of 0.4 μg/kg administered over 30
minutes followed by an infusion of 0.10 μg/kg/min), intermediate (bolus of 10 μg/kg
administered over 3minutes followed by an infusion of 0.15μg/kg/min) and high
(bolus of 25 μg/kg administered over 3 minutes followed by an infusion of
0.15μg/kg/min). The half-life of tirofiban is 2–4 hours, and therefore adenosine
diphosphate (ADP)-induced platelet aggregation returns to near-baseline levels
within 4 to 8 hours after cessation of a tirofiban infusion. Tirofiban is renally cleared
and thus must have dosage adjustment if used in patients with renal insufficiency.
Half-dose tirofiban is recommended in patients with creatinin clearance < 30 ml/min.
4. ADVERSE REACTIONS TO TIROFIBAN
Tirofiban is generally well tolerated. Bleeding complications are the most commonly
reported events associated with tirofiban in clinical trials, but the rate of major
bleeding in tirofiban recipients was not significantly different from that reported with
heparin. Thrombocytopenia (platelet count < 90,000 cells/microliter) can be caused
by all GP IIb/IIIa inhibitors, but occur with tirofiban less frequently than with abciximab
(7). The underlying mechanism of glycoprotein IIb/IIIa inhibitor-induced
thrombocytopenia is probably an immune-mediated reaction, with the presence of
circulating antibodies against IIb/IIIa antagonists (8).
45
5. TIROFIBAN FOR ST-ELEVATION MYOCARDIAL INFARCTION
The initial beneficial effects of GP IIb/IIIa inhibitors in patients with primary PCI for
STEMI were demonstrated with abciximab. Although some trials failed to
demonstrate improvement (9), meta-analyses have shown clearly their benefits (10).
Another meta-analyses showed that among STEMI patients undergoing primary PCI
similar results can be observed between abciximab and small molecules (tirofiban,
eptifibatide) in terms of angiographic, electrocardiographic, and clinical outcome (9,
10). Although early studies with low or intermediate dose tirofiban showed less clear
results (13), more recent studies, using high-dose bolus tirofiban, support its
beneficial effects in patients with STEMI undergoing primary PCI (14, 15). In the
MULTISTRATEGY randomized trial, including 745 patients with STEMI undergoing
percutaneous coronary intervention, compared with abciximab, high-dose tirofiban
therapy was associated with noninferior resolution of ST-segment elevation at 90
minutes following coronary intervention (16). An early ischemic hazard disfavoring
tirofiban was suggested when compared with abciximab in studies based on 10 but
not 25 microg/kg tirofiban bolus regimen (17).
Early administration of GP IIb/IIIa inhibitors (during transport to the hospital) seems
even more attractive for the potential benefits expected from early recanalisation,
which might overcome any potential delay to mechanical reperfusion. A meta-
analysis published in 2008 showed that early administration of GP IIb/IIIa inhibitors is
associated with significant benefits in terms of preprocedural epicardial
recanalisation, improved myocardial perfusion and less distal embolisation but not
into significant benefits in survival (18). The On-Time 2 study investigated the effect
of high-dose tirofiban as administered in the ambulance as compared to high-dose
tirofiban given in the hospital (19). At the time of arrival to the PCI centre, patients
treated with tirofiban had significantly lower cumulative residual ST-segment
deviation than those who received placebo (10.9– 9.2mmvs 12.1– 9.4mm; p= 0.028).
ST-segment resolution prior to PCI (aborted infarction) occurred significantly more
often in the tirofiban arm (p = 0.041 for trend), resulting in a better net clinical
outcome. The cumulative residual ST-segment deviation 1 hour post-PCI (primary
endpoint) was 3.6 – 4.6mm for the tirofiban group versus 4.8 – 6.3mm in the placebo
group (p = 0.003). Furthermore, the percentage of patients with more than 3mm
residual ST-segment deviation was significantly lower in the tirofiban than the
placebo arm (36.6% vs 44.3%; p = 0.026). Also significant reduction in stent
46
thrombosis has been shown after prehospital administration of tirofiban, as compared
to placebo (20). These results confirm the On-Time-1 randomized trial (21), that has
shown that early administration of tirofiban is associated with a better patency (TIMI 2
or 3 flow), a lower prevalence of thrombus or fresh occlusion and a better myocardial
perfusion in the infarct-related region pre-PCI, as compared to late administration of
tirofiban. In contrast, the potential beneficial effects of only bail out administration of
GP IIb/IIIa inhibitors in patients with STEMI (indicated by suboptimal flow, distal
embolisation or side branch occlusion) is less clear (22). In conclusion, in patients
undergoing primary PCI for STEMI, tirofiban should be given early after symptom-
onset (either at home or in the ambulance) rather than upon cathlab arrival. Since it
has been shown that prasugrel is more effective than clopidogrel for prevention of
ischaemic events, without an apparent excess in bleeding in patients with STEMI
(23), it should be assessed whether GP IIb/IIIa inhibitors in patients pretreated with
pasugrel are still of additive benefit.
Several studies have assessed the combination of GP IIb/IIIa inhibitors with
thrombolysis, using either standard doses of thrombolytic agents (TAMI 8, IMPACT-
AMI, GUSTO V and PARADIGM) or reduced dosages of thrombolytic agents (TIMI
14, FINESSE and SPEED) for combination therapy. In the BRAVE study, early
administration of reteplase plus abciximab did not lead to a reduction of infarct size
compared with abciximab alone in patients with acute STEMI referred for PCI (24).
Although most studies were performed with abciximab, some were done with tirofiban
(25) or eptifibatide (26). One of the concepts of the combination of thrombolytics and
GP IIb/IIIa inhibitors was to have an optimal pharmacological combination for
facilitated (primary) PCI. However, current evidence does not support the routine use
of combination of reduced-dose thrombolytic and GP IIbIIIa inhibitor therapy-
facilitated PCI for the treatment of STEMI. In addition, this combined therapy has
been shown to be associated with an increased risk of major bleeding complications.
Small studies suggested beneficial effects of GP IIb/IIIa inhibitors in patients
undergoing rescue PCI after failed thrombolysis, without a significant increase in
bleeding or vascular complications (27,28).
The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial
Infarction (HORIZONS-AMI) trial demonstrated a significantly lower mortality and
bleeding event rate after on year in favor of bivalirudin monotherapy (with provisional
GP IIb/IIIa receptor blockade) in comparison with unfractionated heparin plus GP
47
IIb/IIIa blockade in patients undergoing primary PCI for STEMI (29), However,
bivalirudin monotherapy was associated with a highly significant greater incidence of
acute stent thrombosis. More randomized trials should confirm these observations,
and also potential benefits of bivalirudin given in the ambulance.
6. TIROFIBAN FOR NON ST-ELEVATION MYOCARDIAL INFARCTION
Glycoprotein IIb/IIIa inhibitors reduce the occurrence of death or myocardial infarction
in patients with acute coronary syndromes, with the greatest event reduction in
patients at high risk of thrombotic complications (20). Therefore, current practice
guidelines recommend administering a platelet glycoprotein IIb/IIIa inhibitor, in
conjunction with aspirin and heparin, for patients with non-ST segment elevation
myocardial infarction for whom an early invasive management strategy is indicated.
Although there was no benefit of abciximab in GUSTO-IV ACS, this was probably
caused by the variable recovery of platelet aggregation with continued (24-48 hours)
abciximab infusion before PCI as was performed in this trial (31). The negative
results of the GUSTO IV-ACS trial may be also explained by the lack of access to
timely revascularization which is in keeping with the results of several other trials
based on the use of GPIIb/IIIa inhibitors. Also a more recent trial, among high-risk
patients with an elevated troponin level, found that the incidence of events was
significantly lower with concurrently administered clopidogrel and abciximab (13.1%)
than clopidogrel and placebo (18.3%) (32), making clear that results of GUSTO IV-
ACS should be interpreted cautiously.
In PRISM-PLUS, a study involving 1915 patients with unstable angina/non-Q-
wave MI, administration of intravenous tirofiban (0.4 microgram/kg/min loading dose
for 30 minutes followed by a 0.10 microgram/kg/min infusion) with heparin for at least
48 (mean 71.3) hours reduced the 7-day risk of the composite end-point of MI, death
and refractory ischemia by 32% compared with heparin alone (33). There haven
been discussion about the optimal dose of tirofiban in patients with non-STEMI. In
vitro studies show clearly more complete platelet aggregation inhibition with higher
doses tirofiban (34). Contrary, tirofiban does not achieve >80% platelet aggregation
inhibition at the time of PCI at a dose of 10 microg/kg bolus plus 0.15 microg/kg/min
infusion, and at a dose of 0.4 lg/kg/min loading infusion for 30 minutes plus 0.1
microg/kg/min maintenance infusion, the target value is only reached after 18 h (35,
48
36). These pharmacodynamic observations may explain the excess periprocedural
thrombotic events reported with the low dose tirofiban regimen compared with
abciximab in TARGET (37). This may be also an explanation of the beneficial effects
of tirofiban in patients with non-STEMI if PCI is delayed until 4 to 48 hours after drug
initiation (38).
There has also been debate about the optimal timing of glycoprotein IIb/IIIa inhibitor
administration in patients with non-STEMI: 'upstream' in the coronary care unit or
'downstream' when the patient goes to the catheterization laboratory, although this
may have been influenced by too low loading doses. Results of the EVEREST pilot
study, a mechanistic study evaluating epicardial and tissue level perfusion and
cardiac troponin I release, significantly favored upstream administration of tirofiban
over downstream glycoprotein IIb/IIIa inhibitor for high-risk patients with NSTE ACS
undergoing PCI (39). Moreover, high bolus dose tirofiban or abciximab administered
just before PCI produced similar effects on angiographic outcome and cardiac
troponin I release in this study. However, the EARLY-ACS study demonstrated that
glycoprotein IIb/IIIa inhibitors should be initiated at the time of angiography and that
their routine administration 12 to 24 hours before the procedure can cause an
increased risk of bleeding and no improvement in outcome (38). Previously, this was
also observed in the ACUITY trial (41).
EXPERTS OPINION
Administration of tirofiban in patients with myocardial infarction, either with or without
ST elevation, is effective if an invasive approach is followed. The earlier tirofiban is
administered after symptom onset, the more clear the beneficial effects in patients
with STEMI. For this reason, we recommend that for patients with STEMI, tirofiban
should be given early, before hospital arrival, either at home, in the ambulance, or in
the referral hospital. Because the results of the high-dose tirofiban administration
(bolus of 25 μg/kg administered over 3 minutes followed by an infusion of
0.15μg/kg/min) are more effective, without significant bleeding complications, we
recommend to use the high dose. However, although existing results are promising,
there are less trial data with high-dose tirofiban compared to other GP IIb/IIIa
inhibitors, and results of initial trials should be confirmed. In patients treated with
thrombolysis, there is no additional value for GP IIb/IIIa inhibitors. In non-STEMI,
timing of administration of tirofiban, either at the coronary care unit or just before
49
angiography is less clear, but with the high dose regimen, administration just before
angiography may become the choice.
CONFLICTS OF INTEREST
The authors declare that they have not received support in the form of sponsorship,
grants or materials of the manufacturer of tirofiban or the manufacturer of another GP
IIb/IIIa inhibitor.
50
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55
CHAPTER 4
Impact of stenting on Mortality in Patients
undergoing Primary PCI for ST-Elevation
Myocardial Infarction
ESC congress review 2009:58-63
56
57
Abstract
Purpose: Although in patients with primary percutaneous coronary intervention (PCI)
for ST elevation Myocardial Infarction (STEMI), stenting seems to be associated with
a reduced risk of reinfarction and target vessel revascularization, it is less clear
whether stenting reduces mortality when compared to balloon angioplasty. To assess
the potential association between mortality and stenting in primary PCI in daily
practise, analyses of a prospective registry were performed.
Methods: A large scale, prospective, observational study was performed between
1991 and 2004 of all consecutive STEMI patients who underwent primary PCI.
Results: Primary PCI was performed in 4299 patients, of whom 2571 patients
(59.8%) were treated by (bare metal) stenting. There were no differences in age,
gender, infarct location or diabetes between the two groups. Patients in the balloon
group had more often previous myocardial infarction and multi vessel disease, and
had a longer duration between symptom start and admission. The combined end-
point of death or re-infarction after 30 days was 7.2% in the balloon group vs 5.6% in
the stent group (p=0.03). After one year follow-up, mortality in the balloon group was
7.9%, compared to 5.8% in the stent group (p=0.007). After adjusting for differences
in age, gender, previous myocardial infarction, patient delay and multi vessel
disease, use of a stent was still associated with a decreased risk of one-year
mortality, with OR 0.77, 95% CI 0.61 – 0.98.
Conclusion: In patients undergoing primary PCI for STEMI, use of stents in daily
practise is associated with a decreased mortality.
Introduction
Primary percutaneous coronary intervention (PCI) is very effective in restoration of
coronary blood flow in the infarct related vessel of patients with ST elevation
myocardial infarction (STEMI). However, recurrent ischemia occurs in a substantial
part of patients, resulting in silent or clinically apparent reocclusion of the infarct
related vessel and the need for subsequent target vessel revascularization. To treat
the significant risk of coronary flow-limiting dissections and restenosis during the first
six months following a PCI, two main studies comparing percutaneous transluminal
coronary angioplasty and coronary stenting (STRESS and BENESTENT) performed
in 1994 showed a significant reduction in restenosis after using stents (1, 2).
58
Although a number of randomised controlled trials has shown that stenting during
primary PCI may decrease target vessel revascularization and recurrent myocardial
infarction, there was no clear decrease of mortality after stenting (3, 4). Moreover, the
randomised trials excluded many patients, most had a limited sample size, and
interpreting results was difficult because of cross-over. To assess the potential
association between mortality and stenting in patients undergoing primary PCI,
analyses of a prospective registry were performed.
Methods
Population
From January 1991 to December 2004, individual patient data from all patients with
diagnosis of STEMI who were admitted for primary PCI at the Isala klinieken (Zwolle,
the Netherlands) were prospectively recorded. To avoid double inclusion of patients,
only the first recorded admission for STEMI during the study period was used. Before
angiography all patients received 300-500 mg of aspirin intravenously. Till 1999, a
bolus of 10.000 IU intravenous unfractionated heparin (high dose UFH group) was
given as adjunctive therapy. Since then, the total bolus of intravenous UFH was
decreased to 5.000 IU (low dose UFH group). In addition to aspirin and heparin,
clopidogrel was given 300mg orally since 1999. Primary PCI was performed with
standard techniques if the coronary anatomy was suitable for angioplasty. Success of
the PCI was determined by the classification system of the Thrombolysis in
Myocardial Infarction (TIMI) trial, in which a grade 3 blood flow indicates normal flow
within the vessel, in combination with a myocardial blush grade 2 or 3. Additional
treatment with stents was left to the discretion of the treating cardiologist. All patients
were treated with optimised drug-therapy including angiotensin-converting enzyme
inhibitors, β-blockers and lipid-lowering drugs where appropriate.
Measurements (end points, definitions)
Patients were diagnosed with STEMI if they had chest pain of > 30 minutes duration
and ECG changes with ST segment elevation > 2 mm in at least 2 precordial and > 1
mm in the limb leads. Recurrent myocardial infarction was diagnosed when there was
a 50 percent decrease of creatine kinase-muscle-brain fraction (CK-MB) from a
previous peak value, followed by a subsequent rise to a level exceeding the upper
limit of normal.
59
Protocol-specified blood sampling for creatine kinase (CK) and its muscle-brain
fraction (CK-MB) levels was performed at baseline and at 8 hours, 16 hours and 24
hours after PCI. Measurement of serum total CK and CK-MB levels was performed
according to local hospital standards. Left ventricular ejection fraction was measured
before discharge by radionuclide ventriculography or by echocardiography if the
patient had atrial fibrillation. Radionuclide ventriculography was performed by using
the multiple gated equilibrium method following the labelling of red blood cells of the
patient with 99mTc-pertechnate. A General Electric 300 gamma camera with a low-
energy all-purpose parallel-hole collimator was used. Global ejection fraction was
calculated by a General Electric Star View computer using the fully automatic PAGE
program. In patients with atrial fibrillation, standard 2-dimensional and Doppler
imaging was performed and stored in cineloop format by well-trained
echocardiographists and reviewed by experienced cardiologists who estimated the
ejection fraction by visual assessment.
Data collection and follow-up
We collected the following variables from the patient files: age, gender, history of
hypertension, diabetes, hyperlipidemia, smoking, previous myocardial infarction, Killip
class on admission, angiographic variables, laboratory measurements, major- and
minor bleeding, pre-discharge LV function and discharge medication. Follow-up
information was obtained from the patient's general physician or by direct telephone
interview with the patient. Study approval was obtained from the medical ethic
committee of our hospital.
Statistical Analysis
Statistical analysis was performed with the Statistical Package for the Social
Sciences (SPSS Inc., Chicago, IL, USA) version 15.0.1. Continuous data were
expressed as mean ± standard deviation and categorical data as percentage, unless
otherwise denoted. Differences between continuous data were performed by
student‘s t test and the chi-square or Fisher‘s exact test was used as appropriate for
dichotomous data. Multivariable logistic regression analysis was performed to test the
independent association between one year mortality and use of a stent. Significant
variables analyzed are reported with their respective odd ratios and 95% confidence
intervals. Cox proportional-hazards regression models were used to estimate hazard
60
ratios of patients with a stent with regard to survival at one year. Survival was
represented by Kaplan-Meier curves. For all analyses, statistical significance was
assumed when the two-tailed probability value was < 0.05.
Results
Baseline characteristics
During the study period, 5030 patients were admitted with STEMI (figure 1). After
excluding patients who were not treated by primary PCI, and those with missing data,
a total of 4299 patients were included in the analysis, of whom 2571 patients (59.8%)
were treated by (bare metal) stenting.
Baseline characteristics of the study population are summarized in table 1. There
were no differences in age, gender, infarct location or diabetes between the two
groups. Patients in the balloon group had more often previous myocardial infarction
and multi vessel disease, and had a longer duration between symptom-onset and
admission. Use of glycoprotein IIb/IIIa inhibitors was comparable between the two
groups.
End points
The combined end-point of death or re-infarction after 30 days was 7.2% in the
balloon group vs 5.6% in the stent group (p=0.03). After one year follow-up, mortality
in the balloon group was 7.9%, compared to 5.8% in the stent group (p=0.007). The
combined end point of dead, myocardial infarction or re-intervention after one year
was 22.6% in the balloon group compared to 20.0% in the stent group (p=0.04).
After adjusting for differences in age, gender, previous myocardial infarction, patient
delay and multi vessel disease, use of a stent was still associated with a decreased
risk of one-year mortality, with OR 0.77, 95% CI 0.61 – 0.98.
Discussion
In this prospective registry of patients treated with primary PCI for STEMI, we found
that use of a stent was independently associated with a lower one-year mortality rate.
Also the one-year combined end point of death, recurrent myocardial infarction and
recurrent revascularisation was lower after stenting, as compared to balloon group.
61
The first randomised trials demonstrating the benefits of primary PCI for STEMI as
compared to thrombolysis were published in the early 90s (5-7). Balloon angioplasty
was the principal mode of performing PCI in these first years. Nowadays, stent
implantation is mostly performed. A total of 13 randomised trials have been
performed comparing balloon with stent for STEMI (4). Although stenting was not
associated with a significant reduction in 30-day or 1-year mortality (5.1% versus
5.2%, p=0.81), as compared to balloon angioplasty, stenting was associated with
benefits in terms of target vessel revascularisation at both 30-day and 6 to 12
months.
In general, stent implantation is effective in both the management of (iatrogenic)
coronary dissection during PCI and reduces restenosis. The immediate effective
treatment of dissections and occlusion after balloon coronary angioplasty by stents
has reduced the need for emergent bypass surgery (8, 9).
Although randomised trials have shown that stenting in patients with STEMI were
particularly associated with a decreased risk of target vessel revascularisation, the
mortality rate in our study was also lower in the stent group, as compared to balloon
angioplasty. Compared to randomised trials, the mortality benefit after stenting in our
study could be explained as follows: First, in the randomised trials, many patients in
the balloon group had cross-over to stent. Secondly, in the randomised trials several
(high-risk) groups were excluded. Finally, most trials had only a limited number of
patients and were not powered to demonstrate mortality differences.
Innovations after bare metal stents
After the introduction of stents, several efforts have been made to further reduce the
incidence of re-stenosis. Beta and gamma intracoronary brachytherapy has been
shown to be more efficacious than placebo in reducing death, myocardial infarction,
and target vessel revascularization at long-term follow up of patients with in-stent
restenosis (10). However, limitations of brachytherapy include forming of aneurysms
and late stent occlusion (11, 12). Aloso ,increased late lumen loss at the stent edges,
also known as the "candy wrapper" phenomenon, may occur (13).
An important advantage in interventional cardiology was the introduction of drug
eluting stents. Benefits of drug eluting stents in reducing restenosis have clearly been
shown in many randomized trials. An epidemiological study has also shown that after
62
the widespread adoption of drug-eluting stents into routine practice, a decline in the
need for repeat revascularization procedures could be observed (14). However, the
effects on major adverse cardiac events (death, myocardial infarction) are less clear
(15). Another limitation of drug eluting stents is that they are associated with an
increased risk of stent thrombosis as compared to bare metal stents (16). This
increased risk may also exist after one year of implantation (17). However, also in the
setting of STEMI, several prospective randomised trials and meta-analyses have
shown the superiority of drug eluting stents as compared to bare metal stents in
terms of target vessel revascularisation, with similar rates of death, reinfarction, and
stent thrombosis (18, 19).
Limitations of the current analysis
Although this study included a large cohort of all comers undergoing primary PCI for
STEMI, it concerned a non-randomised registry in patients treated by bare-metal
stents only. Therefore the results should be interpreted with this in mind.
Furthermore, we had no data on medication during follow-up. Particularly aggressive
cholesterol lowering drugs may be associated with less restenosis. There may have
been a difference between patients with and without a stent regarding use of
clopidogrel. Possibly, patients with a stent had (longer) treatment with clopidogrel,
which could have introduced bias.
Conclusions
After multivariable analyses, the use of stent for STEMI in daily practise is associated
with a decreased risk of one-year mortality.
63
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Initial results with a balloon-expandable, stainless steel design. Circulation.
1993 Nov;88(5 Pt 1):2086-96.
9. Roy P, de Labriolle A, Hanna N, et al. Requirement for emergent coronary
artery bypass surgery following percutaneous coronary intervention in the
stent era. Am J Cardiol. 2009;103:950-3.
10. Saleem MA, Aronow WS, Ravipati G, et al. Intracoronary brachytherapy for
treatment of in-stent restenosis. Cardiol Rev. 2005;13:139-41.
11. Bal ET, Plokker T, van den Berg EMJ, Ernst SMPG, Mast EG, Gin RMTJ et al.
Predictability and prognosis of PTCA-induced coronary aneurysms. Cathet
Cardiovasc Diagn 1991;22:85-88.
12. Costa M, Sabaté M, van der Giessen WJ, Kay IP, Cervinka P, Ligthart JM et
al. Late coronary occlusion after intracoronary brachytherapy. Circulation
1999;100:789-92.
13. Serruys PW, Kay IP. I like the candy, I hate the wrapper: the (32)P radioactive
stent. Circulation 2000;101:3-7.
14. Malenka DJ, Kaplan AV, Lucas FL, Sharp SM, Skinner JS. Outcomes
following coronary stenting in the era of bare-metal vs the era of drug-eluting
stents. JAMA. 2008;299:2868-76.
15. Al Suwaidi J, Holmes DR Jr, Salam AM, Lennon R, Berger PB. Impact of
coronary artery stents on mortality and nonfatal myocardial infarction: meta-
analysis of randomized trials comparing a strategy of routine stenting with that
of balloon angioplasty. Am Heart J. 2004;147:815-22.
65
16. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus- and
paclitaxel-eluting coronary stents. N Engl J Med. 2007;356:998-1008.
17. Bavry AA, Kumbhani DJ, Helton TJ, Borek PP, Mood GR, Bhatt DL. Late
thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials.
Am J Med. 2006;119:1056-61.
18. Mauri L, Silbaugh TS, Garg P, et al. Drug-eluting or bare-metal stents for
acute myocardial infarction. N Engl J Med. 2008;359:1330-42.
19. De Luca G, Valgimigli M, Spaulding C, Menichelli M, Rocca HP, van der
Hoeven BL, Di Lorenzo E, de la Llera LS, Pasceri V, Pittl U, Percoco G, Violini
R, Stone GW. Short and long-term benefits of sirolimus-eluting stent in ST-
segment elevation myocardial infarction: a meta-analysis of randomized trials.
J Thromb Thrombolysis. 2009 Feb 4. [Epub ahead of print]
66
Acronyms and Abbreviations: MI: myocardial infarction; LMWH: low-molecular-
weight heparin; PCI: percutaneous coronary intervention; STEMI: ST-segment
elevated myocardial infarction;
Legend of figures
Figure 1: Flow chart of analysis
Figure 2: Effects of use of stents vs balloon on different end points
Figure 3: One year mortality curves of stent (- - - - - ) versus
balloon ( __________ )
67
Figure 1
68
Figure 2
0
5
10
15
20
25
30
30-day
MI/death
1-yr mortality 1-yr
mortality/MI or
re-intervention
%
Balloon
Stent
P=0.007
P=0.03
P=0.04
69
Figure 3
70
Table I: General characteristics according to use of stent in 4299 patients who were treated by primary PCI for ST-elevation MI
Balloon
N = 1728
Stent
N =2571
P value
% or mean SD % or mean SD
Age (years) 61.4 11.7 60.9 11.9 0.15
Female gender 25.3 23.2 0.11
History of:
Myocardial Infarction 14.9 9.4 <0.001
Coronary Bypass Surgery 2.9 2.3 0.21
Stroke 3.6 3.2 0.47
Hypertension 29.5 29.4 0.94
Diabetes 10.8 10.6 0.81
Hypercholesterolaemia 22.5 21.9 0.67
Family history of coronary
artery
disease
42.1 42.6 0.76
Anterior location 49.6 48.8 0.62
Ischemic time (hours) 4.1 5.4 3.7 4.4 0.003
Admission glucose (mmol/L) 9.7 3.7 9.6 3.6 0.65
Admission CK (U/L) 709 1225 690 1158 0.61
Multi Vessel Disease 57.3 49.3 <0.001
Use of Glycoprotein IIb/IIIa
inhibitor
57 60 0.26
71
Table II: Outcome according to use of stent in 4299 patients who were treated by primary PCI for ST-elevation MI
Balloon
N = 1728
Stent
N =2571
P value
% or mean SD % or mean SD
TIMI 3 flow post PCI 86.4 90.7 <0.001
Peak creatine kinase (IU/L) 2445 3042 2627 2376 >0.001
Left Ventricular Ejection
Fraction 44.7 11.6 45.1 12.2
0.38
Mortality
30 days 5.0 3.3 0.05
One year 7.9 5.8 0.007
Death/recurrent infarction
30 days 7.2 5.6 0.03
One year 11.7 10.0 0.08
Death/recurrent infarction/
recurrent
PCI within one year
22.6 20.0 0.04
72
73
CHAPTER 5
Comparison of Rapamycin and Paclitaxel Eluting Stents in Patients
Undergoing Primary Percutaneous Coronary Intervention for ST
Elevation Myocardial Infarction
Best coated stent for STEMI
Am J Cardiol 2009;104:205-9
74
75
Abstract
As compared to Bare Metal Stent, Sirolimus (SES) and paclitaxel (PES) eluting
stents have been shown to improve angiographic and clinical outcomes after
percutaneous coronary intervention (PCI) in elective and ST elevation Myocardial
Infarction (STEMI) patients. Aim of the current study was to compare SES to PES
among STEMI patients undergoing primary PCI. Patients with STEMI were
randomized 1:1 to receive the SES (n=196) or PES (n=201). Primary end point was
late lumen loss at 9 months follow-up by quantitative coronary angiography.
Secondary end points were major adverse cardiac clinical events (death, re-
infarction, target vessel revascularization) at 1, 9 and 12 months. A total of 397
patients with STEMI were randomized. The two groups had comparable baseline
clinical and angiographic characteristics. Mortality was low, 1.5% after 30 days, 2.3 %
after 9 months and 3.1% after one year. There was no difference in any clinical
outcome at any follow-up period between the two treatment groups. Follow-up
angiography was completed in 272 of 397 patients (69 percent). The mean (SD) in-
stent late loss was 0.01 (0.42) mm in the sirolimus group vs 0.21 (0.50) mm in the
paclitaxel group (difference, −0.20 mm, P 0.001). In conclusion: In patients with
STEMI, primary PCI with SES results in less late loss compared to paclitaxel eluting
stents. However, these benefits did not translate into significant reduction in MACE at
one-year follow-up.
Keywords: drug-eluting stents, infarction
76
Benefits of primary percutaneous coronary intervention (PCI) for ST elevation
myocardial infarction (STEMI) have been demonstrated (1-3). However, recurrent
ischemia occurs in 10 to 15% after initially successful PCI, and silent or clinically
apparent reocclusion of the infarct related vessel (IRV) occurs in 5 to 10%, whereas
angiographic restenosis is observed in 30 to 50% (4). As a result, the need for
subsequent target vessel revascularization (TVR) in the first 6 months remains
disappointingly high. Although stents may decrease restenosis and TVR (5-7), in-
stent restenosis, after initially successful stenting remains to be 20% to 50%,
depending upon a number of risk factors and lesion characteristics. Drug-eluting
stents reduce angiographic and clinical measures of restenosis compared with bare-
metal stents (8,9) in elective and STEMI patients. Sirolimus-eluting stents (SES) have
been shown to be superior to paclitaxel-eluting stents (PES) in several trials in
elective patients. However, only few data have been reported in primary PCI for
STEMI. The aim of the current study is to compare SES and PES in patients
undergoing primary PCI for STEMI.
METHODS
It concerns a prospective, single-centre (Isala klinieken, Zwolle, Netherlands),
randomized controlled study involving 397 patients with STEMI, comparing the
Sirolimus coated Cypher stent with the Paclitaxel coated Taxus stent. Patients were
followed for a period of 12 months for evaluation of continued vessel patency, and
the incidence of complications. There was no industry involvement in the design,
conduct or analysis of the study. The study was approved by the local ethics
committee. The study was registered, with number ISRCTN90526229. Written
informed consent was obtained from all patients.
All patients with STEMI, presenting within 6 hours after symptom-onset, or those
presenting between 6 and 24 hours if they had persisting chest pain associated with
clinical evidence of on-going ischemia, were eligible if they had the culprit lesion in a
native coronary artery, suitable for stenting, with a lesion length of < 30 mm and a
vessel diameter > 2.5 mm. Exclusion criteria were women of child-bearing potential,
severe hepatic or renal disease, previous participation in the study, life expectancy of
< 1 year, factors making follow-up difficult, pre-treatment with thrombolysis,
unprotected left main disease or single remaining vessel, target lesion in a bifurcation
with a large side-branch, known sensitivity to aspirin, clopidogrel or coumarin, or
77
patients who were unable to provide informed consent. All patients were pretreated
with aspirin, a loading dose of clopidogrel and intravenous nitroglycerin and heparin.
Treatment with glycoprotein IIB/IIIA inhibitors was left to the discretion of the
physicians. Stenting of target lesion were performed using standard interventional
techniques, without routinely post dilating the stents. After the primary PCI all patients
were treated with current guidelines provided medication, including statins and beta-
blockers. All patients received clopidogrel for at least 6 months.
Angiography of the IRV was performed according to the standard acquisition
procedures for QCA analysis. An independent angiographic core laboratory
(DIAGRAM BV, Zwolle, the Netherlands) analyzed all preprocedural, periprocedural,
and postprocedural angiographic images using edge detection techniques.
Quantitative angiography was done in at least 2 orthogonal views. Intracoronary
nitroglycerin was given prior to each series of angiograms if the patient was
hemodynamic stable. The PCI procedure was considered completed once the
guiding catheter was removed. Follow-up angiography at 9 months was performed
corresponding to those settings used during the stenting procedure. Quantitative
coronary angiography (QCA) was analyzed using the CAAS II system. Late lumen
loss was defined as the minimal lumen diameter (MLD) immediately post PCI – the
MLD at follow-up angiography.
Primary endpoint was the late lumen loss at 9 months follow-up by quantitative
coronary angiography. Secondary end points were major adverse cardiac clinical
events (death, re-infarction, target vessel revascularization) at 1, 9 and 12 months.
The study was designed to demonstrate superiority of the Cypher stent based on the
assumption that at follow-up angiography the late loss was at least 0.15 mm smaller
than the mean late loss when the Taxus stent was used. It was expected that in the
Sirolimus eluting stent group the mean late loss would be 0.15 mm with a standard
deviation of 0.50 mm. In a one-way ANOVA study, sample sizes of 176 patients per
group were needed, resulting in a total sample of 352 subjects achieving 80% power
to detect differences among the means versus the alternative of equal means using a
F test with a 0.05 significance level. Distinction was made between the end points
occurring during the procedure, early or late. Procedural events were defined as
events occurring in the time interval between insertion of the arterial sheath and
withdrawal of the sheath out of the patient. Early events were defined as events
occurring between sheath removal and 1 month. Late events were defined as events
78
occurring after 1 month. All other adverse events and malfunctions of stent and
delivery system were reported descriptively. Reinfarction was defined by the
presence of recurrent ischemic symptoms or electrocardiographic changes
accompanied by a creatine kinase level that was more than twice the upper limit of
the normal range (with an elevated MB isoform level) or more than 50 percent higher
than the previous value obtained during hospitalization with or without stent
thrombosis or development of Q waves. Stent thrombosis was defined as acute
ischemic symptoms (typical chest pain with duration more than 20 min) accompanied
by occlusion of the infarct related vessel, originating in the peri-stent region.
Restenosis was defined as at least 50% reduction in diameter when compared to
reference luminal diameter assessed by QCA in 2 orthogonal views. Repeat target
lesion revascularization was performed if symptoms of angina and/or objective
evidence of ischemia were documented.
Clinical and angiographic data were analyzed both according to the principle of intent
to treat and evaluable group analyses. Comparability of treatment groups with
respect to demographic and pre-treatment population characteristics were assessed
using a one-way ANOVA F- or Wilcoxon Rank Sums Scores test, a chi-square test
for two-way contingency tables, and a chi-square test for homogeneity of proportions,
respectively. End-point variables were presented by 95% confidence intervals for the
mean difference for quantitative results. An estimate of the relative risk for the
treatment groups and the 95% confidence interval of the risk were provided for 9-
month restenosis rate and each of the adverse event parameters.
The actuarial life table method was used for analyzing the occurrence of adverse
events and target revascularization during the one-year follow-up period. Patients
who died or who were lost to follow-up were censored at their last follow-up
according to their clinical status at that time. In case appropriate P values for testing
differences in survival curves were computed by means of the Wilcoxon as well the
log rank test.
RESULTS
Patients were included between January 2005 and October 2007. A total of 397
patients were included in the study. The baseline characteristics of the patients were
comparable in the two randomized groups (table 1). Mean age was 61 years and
8.6% of patients had diabetes. Baseline angiographic data are summarized in table
79
2. Again, the variables were well matched between the two treatment groups, with in
the sirolimus group a trend to more often use of only 1 stent. Due to technical
reasons, we could not implant stents in 4 patients (3 in PES group and 1 in SES
group).
The occurrence of clinical events up to one year is summarized in table 3. In the total
group, the cumulative incidence of MACE (death, re-MI or target vessel
revascularization) at 30 days, 9 months and one year was 5.8%, 8.2% and 9.8%
respectively. Mortality was low, 1.5% after 30 days, 2.3% after 9 months and 3.1%
after one year. There was no difference in any clinical outcome at any follow-up
period between the two treatment groups. Particularly TVR was comparable in the
two groups. Also the incidence of stent thrombosis was not different between the two
groups during different follow-up periods.
Follow-up angiography was completed in 272 of 397 patients (69%), after 324 (SD
88) days in the SES group and after 317 (SD 92) days in the PES group. Follow-up
angiography was more often performed in males (58% no angiography, 78%
angiography) and in younger patients. The mean (SD) in-stent late loss was 0.01
(0.42) mm in the SES group vs 0.21 (0.50) mm in the PES group (difference, −0.20
mm; 95% CI, P .001). The mean diameter stenosis at the follow-up angiography was
higher in the PES group (table 4). However, no difference was observed in restenosis
and TVR between the 2 groups.
DISCUSSION
In this randomized trial of SES versus PES in STEMI patients, we demonstrated a
lower late loss after use of SES as compared to PES. However, there were no
significant differences between the two stents regarding the incidence of MACE
during follow-up, with similar low occurrence of stent thrombosis.
Several prospective randomized trials in primary PCI for STEMI and meta-analyzes
(7, 9, 10) have shown the superiority of drug eluting stents as compared to bare
metal stents in terms of TVR, with similar rates of death, reinfarction, and stent
thrombosis. There were also several studies published comparing SES with PES in
elective patients (11). SIRTAX compared SES with PES in 1012 patients undergoing
PCI, and included both stable and unstable patients (12). The primary end point of
that study was a composite of MACE (death from cardiac causes, myocardial
infarction, and ischemia-driven revascularization of the target lesion) by nine months.
80
Follow-up angiography was completed in 53 percent. A total of 227 patients with
STEMI were included, but it is unclear whether these were treated with primary PCI.
They found fewer MACE after SES, primarily by decreasing the rates of clinical and
angiographic restenosis. The ISAR-DESIRE study randomizing 300 patients with
angiographically significant in-stent restenosis to SES, PES, or balloon angioplasty
found that both SES and PES were better than balloon angioplasty, and that SES
was superior to PES (13). Other randomized studies comparing SES with PES were
Reality, Sort Out II and Spirit III (14-16).
Few data have been reported so far on the comparison between these 2 stents in
primary PCI. The PROSIT trial randomized 308 STEMI patients to SES and PES
(17). Primary end point was MACE including death, reinfarction, stent thrombosis,
and target lesion revascularization at 12 months. This study found no differences
between the two stents. However, it must be remarked that angiographic follow-up
was performed relatively early (6 months) in this study and this might have
contributed to underestimate the benefits with SES in terms of late loss. Furthermore,
the study was underpowered to show potential differences in the primary end point.
Use of SES and PES in patients with STEMI was also compared in the RESEARCH
and T-SEARCH Registries (18). In this relatively small consecutive patient cohort,
without routine follow-up angiography, the incidence of MACE, and particularly TVR
was comparable between sirolimus and paclitaxel eluting stents.
In our study, the largest trial so far conducted in primary PCI for STEMI, SES was
associated with a significant reduction in late loss as compared to PES. However,
these beneficial effects did not translate into clinical benefits, with a similar low
incidence of stent thrombosis.
The differences of late loss between the sirolimus and paclitaxel stent may be caused
by several mechanisms, including the stent itself and the eluting drug. Although both
sirolimus and paclitaxel inhibit cell proliferation and other cellular processes, the
working mechanism is different. An in-vitro study suggested that sirolimus reduces
neointimal hyperplasia through a cytostatic mechanism while paclitaxel produces
apoptotic cell death (19). A study in diabetic patients using intravascular ultrasound
suggested that sirolimus inhibits neointimal hyperplasia more effectively (20).
Our sample size was too small to perform subgroup analyses. Furthermore, our trial
was underpowered to detect differences in the incidence of clinical events during a
relatively short (1-year) follow-up. Another limitation is that we had only follow-up
81
angiography in 69% of patients. We had also no information on medical treatment
during follow-up, in particular not on changes of the use and dosage of statin therapy.
Moreover, it was a single centre trial, with the primary PCI performed by an
experienced team.
82
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86
Table 1 – Baseline characteristics
Variable Total
(N=397)
Rapamycin eluting
stent
(N=196)
Paclitaxel
eluting stent
(N=201)
Age (years) 61 11 61 12 61 11
Men 72% 69% 74%
Current smoker 50% 50% 55%
Anterior wall infarct location 43% 44% 41%
Diabetes mellitus 8.6% 10.7% 6.5%
Previous Hypertension 30% 27% 33%
Previous
Hypercholesterolemia
19% 19% 19%
Previous Myocardial Infarction 6.0% 6.1% 6.0%
Previous Percutaneous
Coronary Intervention
6.3% 6.6% 6.0%
Previous Coronary Bypass
Surgery
1.3% 1.0% 1.5%
Previous stroke 2.5% 2.0% 3.0%
Systolic blood pressure on
admission (mm Hg)
132 23 132 24 133 24
Diastolic blood pressure on
admission (mm Hg)
80 16 79 15 80 16
Heart rate on admission
(beats/min)
74 16 73 15
74 16
Heart Failure on admission,
Killip III or IV
1.0% 0.5% 1.5%
TIMI risk score > 3 26% 27% 25%
87
Table 2 - Baseline angiographic characteristics
Variable Rapamycin eluting
stent
(N=196)
Paclitaxel eluting
stent
(N=201)
P
value
Multi vessel coronary disease
(%) 38% 31%
0.15
Target lesion coronary artery
Left Anterior Descending
Artery 44% 41%
0.53
Left Circumflex Artery 14.8% 16.9% 0.56
Right Coronary Artery 41% 42% 0.84
Thrombus Aspiration before
PCI
1.0% 1.5% 1.0
PCI immediately after
angiography
99% 99% 1.0
Stent not placed 1% 1.5% 0.62
Direct stenting 32% 35% 0.46
> 1 stent 13% 21% 0.04
Pre-dilatation balloon size
(mm)
2.90 0.42 2.85 0.37 0.39
Highest pressure (mm Hg) 11.79 3.61 11.42 3.15 0.58
Stent diameter (mm) 3.20 0.33 3.19 0.36 0.22
Total stent length (mm) 22.66 8.82 23.81 10.18 0.43
Use of additional devices 6% 6% 0.80
Use of Glycoprotein IIb/IIIa
inhibitors
28% 33% 0.23
88
Table 3 - Clinical Outcomes up to 1 year after randomization
Variable Rapamycin coated
stent
(N=196)
Paclitaxel coated
stent
(N=201)
P value
Events until 30 days
Death 1.5% 1.5% 1.00
Re-MI 1.5% 1.5% 1.00
Target vessel
revascularization
4.1% 4.0% 0.96
Major Adverse Clinical Event* 5.6% 6.0% 0.88
(Sub) acute stent thrombosis 2.1% 2.0% 1.00
Events until 9 months
Death 2.6% 2.0% 0.75
Re-MI 3.1% 2.6% 0.74
Major Adverse Clinical Event* 8.3% 8.2% 0.96
Late stent thrombosis 1.1% 0.5% 0.62
Events until 1 year
Death 3.6% 2.6% 0.54
Re-MI 3.1% 3.1% 0.98
Target vessel
revascularization (%)
5.7% 6.7% 0.70
Major Adverse Clinical Event* 9.9% 9.7% 0.96
* Major Adverse Clinical Event (MACE) included death, re-MI or target vessel
revascularization
89
Table 4 - Results of quantitative coronary angiography at follow-up
Variable Rapamycin coated
stent (N=133)
Paclitaxel coated
stent (N=139)
P
value
Minimal Lumen Diameter at
follow-up (mm)
Mean SD 2.42 ± 0.53 2.26 0.62 0.038
Median (Q1-Q3) 2.4 (2.16-2.77) 2.32 (1.90-2.72)
Diameter stenosis at follow-up
(%)
Mean SD 9.58 ± 17.7 16.68 19.45 0.001
Median (Q1-Q3) 8.0 (-0.5-18.5) 13 (6-23)
Late loss (mm)
Mean SD 0.01 0.42 0.21 0.50 0.001
Median (Q1-Q3) -0.04 (-0.25 – 0.19) 0.12 (-0.12 – 0.44) 0.001
Restenosis > 50% 3.0% 4.3% 0.75
90
91
CHAPTER 6
Efficacy and safety of Rapamycin as compared to
Paclitaxel-eluting stents: a meta-analysis
Rapamycin vs Paclitaxel-eluting stents in STEMI
J Invasive Cardiol 2010 Jul;22(7):312-6.
92
93
Abstract
Objectives: To compare the efficacy of Rapamycin eluting stents (RES) and
paclitaxel eluting stents (PES) in patients undergo percutaneous coronary
intervention.
Background: RES and PES differ importantly with respect to polymer coating and
antiproliferative drugs. It is not yet clear whether there are any differences between
RES and PES with regard to clinical outcome.
Methods: Systematic searches were conducted of randomised controlled trials
(RCTs) comparing RES with PES in MEDLINE and the Cochrane Database of
systematic reviews. A meta-analysis was done of all available randomised studies
comparing PES with RES. Information on study design, inclusion and exclusion
criteria, number of patients, and clinical outcome was extracted by two investigators.
Disagreements were resolved by consensus. The primary outcome was re-
intervention, target lesion revascularisation (TLR) and target vessel revascularization
(TVR). Stent re-stenosis, myocardial infarction (MI) and all cause mortality were
secondary end points.
Results: Twenty one RCTs of RES versus PES with a total number of 10,147 patients
were included in this meta-analysis. Indication for angioplasty was either acute
coronary syndrome or stable angina. Mean follow-up period ranged from 6 to 24
months. Rates of TLR were 4.9% vs. 7.0%; p=0.0009 and rates of TVR were 5.1 vs.
8.3%; p<0.001 for RES vs. PES, respectively. The incidence of stent re-stenosis was
3.9% for RES vs. 5.3% for PES; p=0.004. Rates of MI and all cause mortality were
comparable.
Conclusions: This meta-analysis demonstrates that, as compared to PES, RES
seems to be associated with a lower risk of re-intervention and stent re-stenosis. The
risk of myocardial infarction and all cause death were similar between the 2 stents.
Key Words: Angioplasty • Drug-eluting stents • Re-intervention, Stent re-stenosis.
94
Introduction
In patients with percutaneous coronary intervention (PCI), compared to balloon
angioplasty and bare metal stenting, use of drug-eluting stents are associated with
less restenosis and less need for recurrent revascularisation. There is, however,
uncertainty about the most effective and safety between the two currently approved
and most used drug-eluting stents i.e. Rapamycin-eluting stents (RES, Cypher,
Cordis), and paclitaxel-eluting stents (PES, Taxus, Boston Scientific).
RES and PES differ importantly with respect to polymer coating and antiproliferative
drugs [1]. A number of large randomised studies have demonstrated that both
rapamycin- and paclitaxel-eluting stents significantly decrease restenosis rates in a
variety of lesion types [2-17]. A recent meta-analysis of 16 randomised trials [1]
showed that RES, compared to PES, significantly reduced the risk of reintervention
and stent thrombosis and a trend toward a lower risk of MI without affecting mortality.
However, since then several new randomised trials are conducted, presented and
published, and their results were not included in that meta-analyses. The purpose of
the present study was to compare both stents in a large series of patients with
coronary artery lesions at high risk for restenosis.
Methods
Literature review
We obtained results from all randomised trials on RES (Cypher, Cordis, Johnson &
Johnson, Miami Lakes, Florida) and PES (TAXUS, Boston Scientific Corp,
Natick, Massachusetts). The literature was scanned by formal searches of electronic
databases (MEDLINE, CENTRAL, EMBASE, and The Cochrane Central Register of
Controlled trials, http://www.mrw.interscience.wiley.com/cochrane), to October 2008,
the scientific session abstracts in Circulation, Journal of College of Cardiology,
European Heart Journal and American Journal of Cardiology from January 1990 to
October 2008. Furthermore, oral presentations and/or expert slide presentations
were included, searched on the transcatheter coronary therapeutics (TCT,
www.tctmd.com), EuroPCR (www.europcr.com), ACC (American College of
Cardiology; www.acc.org), AHA (American Heart Association; www.aha.org), and
ESC (European Society of Cardiology; www.escardio.org) websites to October 2008.
95
The websites http://clinicaltrials. gov. and www.tctmd.com were also assessed in an
attempt to locate unpublished studies. Information on study design, inclusion and
exclusion criteria, number of patients, and clinical outcome was extracted by two
investigators. Disagreements were resolved by consensus. In case of incomplete or
unclear data, authors, where possible, were contacted. Finally, all co-authors had full
access to all of the data in the study and take responsibility for the integrity of the
data and the accuracy of the data analysis.
Endpoints/data abstraction
The primary clinical endpoint was re-intervention; target lesion revascularization
(defined as re-intervention for stenosis within the stent or its 5-mm borders), target
vessel revascularization(defined as re-intervention driven by a lesion in the same
epicardial vessel as initially treated). Secondary endpoints were, stent re-stenosis,
myocardial infarction all cause death.
Statistical analysis
For clinical outcomes, we used the intention-to-treat analysis, so that the
denominator of the incidence was the total number of patients randomised to a given
therapy. There were generally fewer patients available for the determination of
several outcomes; therefore, to determine the incidence of these outcomes more
accurately, we used the treatment-received (or protocol) analysis. Mantel–Haenszel
model was used to construct random effects summary odds ratios (ORs) and risk
differences. Potential publication bias was examined by constructing a ‗funnel plot‘, in
which sample size was plotted against ORs (for incidence of target lesion
revascularisation, if available from a study).
Clinical data were initially analysed among all the studies. All outcomes were
analysed at the maximal extent of clinical follow-up. All P-values were two-tailed, with
statistical significance set at 0.05, and confidence intervals (CI) were calculated at
the 95% level. All analyses were performed using SPSS 16.
Results
A total of 21 randomised trials including 10,147 patients were analysed (Table 1).
The indications for PCI included the whole clinical spectrum of coronary artery
96
disease. As shown in figures 1-4, not every study mentioned all the outcomes that we
planned to analyse. We performed analysis on available data.
TLR occurred in 189/3864 (4.9%) vs. 266/3812 (7.0%) in the RES and PES groups,
respectively. Allocation to the RES group was associated with an OR of 0.66 (95%
confidence interval (CI) 0.51 to 0.84, p =0.0009), (Fig. 1A). TVR occurred in
147/2900 (5.1%) vs.237/2850 (8.3%) in the RES and PES groups, respectively.
Allocation to the RES group was associated with an OR of 0.53 (95% CI 0.39-0.73, p
<0.0001) for TVR (Fig. 1B). No potential publication bias was observed by analysis of
the funnel plot (Fig 2).
Stent re-stenosis, occurred in 196/4993 patients in the RES group (3.9%) versus
259/4918 patients in the PES group (5.3%). Allocation to the RES group was
associated with an odds ratio (OR) for stent thrombosis of 0.68 (95% CI 0.52-0.88, p
=0.004) (figure 3).
Myocardial infarction occurred in 168/4605 patients (3.6%)in the RES group versus
194/4546 (4.3%) patients in the PES group. Allocation to the RES group was
associated with an OR for MI of 0.84 (95% CI 0.68 to 1.04, p=0.12) (figure 4).
All cause mortality occurred in 110/4600 in RES group (2.4%) versus 115 patients in
the PES group (2.5%). Allocation to the RES group was associated with an OR for all
cause mortality of 0.94 (95% CI 0.72-1.24, p=0.68) (figure 5).
Discussion
In this meta-analysis we compared the clinical outcomes after implantation of
rapamycin eluting stent (RES) versus paclitaxel eluting stent (PES) in a large patient
population, representative of the whole clinical spectrum of coronary artery disease.
Re-intervention was clinically driven in 3 studies[2,8,17] and two additional studies
mentioned clinically as well as angiographic ally driven re-intervention [13,14]. In all
the other studies re-intervention was angiographically driven.
RES, as compared to PES, was associated with a lower need for re-intervention, less
often stent re-stenosis and a trend towards lower risk of myocardial infarction, without
affecting the risk of all cause mortality. These results confirm a previous meta-
analysis of 16 randomised trials [1]. In the current Meta-Analysis, compared with the
previous one, we add results of five additional more recent trials [18-22] and data of
two trials that are recently fully published [16-17]. Furthermore, we analysed rates of
TLR and TVR separately.
97
Use of drug-eluting stents
Because the incidence of stent thrombosis may be higher in patients with drug eluting
stents than in bare metal stents, and also the incidence of stent thrombosis may be
higher in patients undergo PCI [23], there have been concerns about using
drug eluting stents. However, various registries, randomised trials, and recent meta-
analyses on patients undergoing primary PCI have demonstrated that use of DES is
safe and is associated with significantly reduced rates of restenosis and repeat
intervention without an increased risk of myocardial infarction or stent thrombosis at
intermediate-term follow-up [24-26]. Additional large trials with hard clinical end
points and longer follow-up are needed before routine DES use can be
recommended in more patients undergoing primary PCI.
Mechanisms
Delayed healing characterized by persistent fibrin deposition, poorer
endothelialization, and local hypersensitivity reaction may explain the late occurrence
of thrombosis-related events with drug eluting stents [27]. Previous reports showed
that these phenomena are more pronounced with PES than RES [28].
Although both sirolimus and paclitaxel inhibit cell proliferation and other cellular
processes, the working mechanism is different. Sirolimus induces G1 cell cycle
inhibition, and paclitaxel mainly induces M-phase arrest. An in-vitro study suggested
that sirolimus reduces neointimal hyperplasia through a cytostatic mechanism while
paclitaxel produces apoptotic cell death [29]. A study in diabetic patients using
intravascular ultrasound suggested that sirolimus inhibits neointimal hyperplasia
more effectively [30]. Three studies compared RES with PES in patients with
diabetes showed that in these patients RES are more effective[4,19,20].
Furthermore, differences in the early systemic inflammatory response after PCI may
partially explain the differences in clinical outcome after RES and PES implantation.
A recent study showed that implantation of both types of DES induce an
acute inflammatory response, as assessed by CRP and IL-6 plasma concentrations,
where RES implantation resulted in lower inflammatory responses compared with
PES implantation. This may be of clinical relevance since this difference was
associated with the degree of re-stenosis at 8-months follow-up [31].
98
In addition, another 'olimus (everolimus) eluting stent shown to be superior to PES.
The SPIRIT III trial demonstrated a significant reduction in the in-segment late loss
with everolimus eluting stent (EES) compared with PES. at 8 months and non-
inferiority to PES for the clinical endpoint of target vessel failure at 1 year and
resulted in a significant reduction in major adverse cardiac event [32,33]. The Spirit
IV trial, that presented during the 2009 annual Transcatheter Cardiovascular
Therapeutics (TCT), showed a 2.6% absolute difference in the rate of target lesion
failure between the two stents, statistically favoring the EES [34]. Furthermore, the
COMPARE trial [35] showd that use of EES vs. PES in real worl patients was
associated with 31 relative risk reduction (RR) in the composite of safety and efficacy
(all-cause mortality, myocardial infarction, and TVR) within 12 months. The difference
was driven by lower rate, of: early stent thrombosis, 0.7 vs. 2.5% (RRR 74%); fewer
myocardial infarctions, 2.8% versus 5.3%;and fewer target-lesion revascularisations,
2.3% versus 6.0%. Based on our meta-analysis and the above mentioned studies,
RES might be preferred above PES.
Limitations
This meta-analysis was not performed on individual patient data, caution should be
exercised in the interpretation of the results, given the potential clinical heterogeneity
among trials, due to varying patient population, and varying definition of variables.
The results of our meta-analysis may only be applied for patients fulfil the criteria of
these studies and may not be applied for registries. Furthermore, the meta-analysis is
limited by the design of the original studies, with particularly the short follow-up period
of several studies.
Conclusions
This meta-analyses show that use of RES, as compared to PES, is associated with a
significantly lower need for re-intervention and less often stent occlusion, without
affecting the risk of myocardial infarction or all cause mortality.
99
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104
Figure legend:
Figure 1A: Target lesion revascularisation
Figure 1B: Target vessel revascularisation
Figure 2: Funnel plot of the studies included in the meta-analysis. Sample size of
each study was plotted against the odds ratio for target lesion revascularization. No
skewed distribution was observed, suggesting no publication bias
Figure 3: Stent re-stenosis during follow-up
Figure 4: Myocardial Infarction during follow-up
Figure 5: All cause mortality during follow-up
Table 1: General characteristics of the trials
Study Publication
year
No. of
patients
Mean age
(yrs)
Patient profile Primary end point Mandated follow-up
angiography
Mean length of follow-
up (months)
TAXI [2] 2005 202 64 Unselected Death, MI, reintervention no 7
ISAR-DESIRE [3] 2005 200 64 In-stent restenosis Angiographic restenosis yes 12
ISAR-DIABETES [4] 2005 250 68 Diabetic Angiographic late loss yes 9
CORPAL [5] 2005 515 61 Unselected Angiographic restenosis and clinical outcome yes 6
Di Lorenzo et al [6] 2005 120 64 Acute MI Death, MI, reintervention no 6
SIRTAX [7] 2005 1,012 62 Unselected Death, MI, reintervention yes 9
Basket [8] 2005 545 64 Unselected patients Cost-effectiveness based on the composite of death, MI or reintervention no 6
Cervinka et al [9] 2006 70 56 Complex lesion and patients Neointimal volume in intravascular ultrasound assessment
yes 6
Han at al [10] 2006 416 NA Multivessel disease Death, MI, reintervention no 20
ISAR-SMART [11] 2006 360 67 Small vessel, non diabetic Angiographic late loss yes 12
LONG DES II [12] 2006 500 61 Long lesions Angiographic restenosis yes 9
REALITY [13] 2006 1,353 63 Relatively unselected patients Angiographic restenosis yes 12
Zhang et al [14] 2006 449 64 Unselected patients Death, MI, reintervention no 12
Petronio e al [15] 2007 85 63 Complex lesion Neointimal area in intravascular ultrasound assessment yes 9
PROSIT [16] 2008 308 62 Acute MI Cardiac death, reinfarction, stent thrombosis or target lesion revascularization yes 12
SORT OUT II 17 2008 2,098 64 Unselected patients Death, mi or reintervention no 9
Wessely, et al [18] 2008 91 67 Stable or unstable angina In-stent late lumen loss yes 9
Lee SW et al [19] 2008 400 61 Diabetic In segment restenosis yes 9
Kim MH et al [20] 2008 169 62 Diabetic Angiographic and clinical outcome yes 6
ISAR LM 21 2008 607 69 Symptomatic left main disease Death, MI, or repeat revascularization yes 24
CEZAR 22 2009 397 61 AMI Late lumen loss yes 12
106
Figure 1A : Target lesion revascularisation
Study or Subgroup Cervinka et al 2006 CORPAL 2005 ISAR LM 2009 ISAR-DIABETES 2005 Kim MH et al 2008 Lee SW 2008 LONG-DES II 2006 Petronio et al 2007 PROSIT 2008 REALITY 2006 SIRTAX 2005 SORT-OUT II 2008 TAXI 2005 Wessely et al 2008
Total (95% CI) Total events Heterogeneity: Tau² = 0.04; Chi² = 16.72, df = 13 (P = 0.21); I² = 22% Test for overall effect: Z = 3.31 (P = 0.0009)
Events 1
12 32 8 2 4 6 1 4
41 24 48 2 4
189
Total 37 26
1 305 125 95 20
0 250 42 15
4 684 503 106
5 102 41
3864
Events 1
18 28 15 4 15 18 1 10 41 42 61 1 11
266
Total 37 25
4 302 125 95 20
0 250 43 15
4 669 509 103
3 100 41
3812
Weight 0.8
% 8.3% 13.5
% 6.3% 2.0% 4.3% 5.8% 0.8% 3.9% 16.6
% 14.0% 19.2% 1.0% 3.6%
100.0%
M-H, Random, 95% CI 1.00 [0.06,
16.61] 0.63 [0.30, 1.34] 1.15 [0.67, 1.96] 0.50 [0.20, 1.23] 0.49 [0.09, 2.74] 0.25 [0.08, 0.77] 0.32 [0.12, 0.81] 1.02 [0.06,
16.93] 0.38 [0.12, 1.25] 0.98 [0.62, 1.53] 0.56 [0.33, 0.93] 0.75 [0.51, 1.11] 1.98 [0.18,
22.19] 0.29 [0.09, 1.02] 0.66 [0.51, 0.84]
RES
PES
Odds Ratio
Odds Ratio M-H, Random, 95% CI
0.005
0.1
1 10
200 RES beter
PES beter
107
Figure 1B: Target vessel revascularisation
Study or Subgroup Basket 2005 Cervinka et al 2006 Cezar 2009 Di Lorenzo 2005 Han et al 2006 Isar Smart 3 Isar-Desire 2005 KIm MH 2008 Lee SW 2008 Long-DesII Sort-Out II2008 Zhang at el 2006
Total (95% CI) Total events Heterogeneity: Tau² = 0.09; Chi² = 16.67, df = 11 (P = 0.12); I² = 34% Test for overall effect: Z = 3.96 (P < 0.0001)
Events 8 1 4 0 9
13 8 8 4 8
70 14
147
Total 264 37 196 60 210
198 100 95 200
250 1065 225
2900
Events 17 2 20 1 11 30 19 6 15 19 81 16
237
Total 281 33 201 60 206
204 100 95 200
250 1033 187
2850
Weight 9.0% 1.5% 6.3% 0.9% 8.3% 11.9% 8.7% 6.2% 6.0% 9.1% 21.2%
10.7%
100.0%
M-H, Random, 95% CI 0.49 [0.21, 1.14] 0.43 [0.04, 4.98] 0.19 [0.06, 0.56] 0.33 [0.01, 8.21] 0.79 [0.32, 1.96] 0.41 [0.21, 0.81] 0.37 [0.15, 0.89] 1.36 [0.45, 4.09] 0.25 [0.08, 0.77] 0.40 [0.17, 0.94] 0.83 [0.59, 1.15] 0.71 [0.34, 1.49]
0.53 [0.39, 0.73]
RES
PES
Odds Ratio Odds Ratio M-H, Random, 95% CI
0.005 0.1 1 10 200 RES beter
PES beter
108
Figure 2: Funnel plot of the studies included in the meta-analysis. Sample size of each study was plotted against the odds ratio for target lesion revascularization. No skewed distribution was observed, suggesting no publication bias
109
Figure 3: Stent re-stenosis during follow-up
0.005
0.1
1 10
200 RES beter
PES beter
Study or Subgroup Basket 2005 Cervinka 2006 Cezar 2009 Corpal 2005 Han et al. 2006 Isar Desire 2005 Isar Diabetes ISAR LM 2009 ISAR-SMART 3 2006 Kim MH 2008 Lee SW 2008 LONG-DES II 2006 Petronio et al 2007 PORSIT 2008 REALITY 2006 Sirtax 2005 SORT-OUT II 2008 Taxi 2005 Wessely 2008 Zhang et al 2006 Total (95% CI) Total events Heterogeneity: Tau² = 0.08; Chi² = 25.44, df = 19 (P = 0.15); I² = 25% Test for overall effect: Z = 2.89 (P = 0.004)
Events 3 2 6
32 9
10 5
59 14 2 1 2 1 0 5
10 28 1 4 2
196
Total 26
4 37 196 261 210 91 102 305 176 85 200 250 42 154 684 503 1065 102 41 225
4993
Events 3 3 9
48 11 17 14 48 26 5 0 0 4 2
13 8
30 0
15 3
259
Total 28
1 33 201 254 206 92 103 302 174 84 200 250 43 154 669 509 1033 102 41 187
4918
Weight 2.4
% 1.9% 5.0% 13.1
% 6.3% 6.9% 4.9% 14.8
% 9.1% 2.3% 0.7% 0.7% 1.3% 0.7% 5.1% 5.9% 12.3
% 0.7% 4.0% 2.0%
100.0%
M-H, Random, 95% CI 1.07 [0.21,
5.32] 0.57 [0.09, 3.65] 0.67 [0.24, 1.93] 0.60 [0.37, 0.97] 0.79 [0.32, 1.96] 0.54 [0.23, 1.26] 0.33 [0.11, 0.95] 1.27 [0.83, 1.93] 0.49 [0.25, 0.98] 0.38 [0.07, 2.02] 3.02 [0.12,
74.46] 5.04 [0.24, 105.52] 0.24 [0.03,
2.22] 0.20 [0.01, 4.15] 0.37 [0.13, 1.05] 1.27 [0.50, 3.25] 0.90 [0.54, 1.52] 3.03 [0.12,
75.25] 0.19 [0.06, 0.63] 0.55 [0.09, 3.33] 0.68 [0.52, 0.88]
RES PES Odds Ratio
Odds Ratio M-H, Random, 95%
CI
110
Figure 4: Myocardial Infarction during follow-up
Study or Subgroup Basket 2005 Cezar 2009 Han et al. 2006 Isar Desire 2005 Isar Diabetes ISAR LM 2009 ISAR-SMART 3 2006 Kim MH 2008 Lee SW 2008 LONG-DES II 2006 Petronio et al 2007 REALITY 2006 Sirtax 2005 SORT-OUT II 2008 Taxi 2005 Wessely 2008 Zhang et al 2006 Total (95% CI) Total events Heterogeneity: Tau² = 0.00; Chi² = 2.62, df = 16 (P = 1.00); I² = 0% Test for overall effect: Z = 1.57 (P = 0.12)
Events 6
5 2 1 5
14 6 1 1
22 1 35 14 45 2 1 7
168
Total 264 196 210 100 125 305 198 95 20
0 250 42 68
4 503 106
5 102 41 22
5 4605
Events 6
5 3 2 3
15 7 1 1
27 1 40 18 53 3 0 9
194
Total 281 201 206 100 125 302 204 95 20
0 250 43 66
9 509 103
3 100 41 18
7 4546
Weight 3.4% 2.9% 1.4% 0.8% 2.1% 8.1% 3.7% 0.6% 0.6% 12.8
% 0.6% 20.7
% 8.9% 27.2
% 1.4% 0.4% 4.4%
100.0%
M-H, Random, 95% CI 1.07 [0.34, 3.35] 1.03 [0.29, 3.60] 0.65 [0.11, 3.93] 0.49 [0.04, 5.55] 1.69 [0.40, 7.25] 0.92 [0.44, 1.94] 0.88 [0.29, 2.66] 1.00 [0.06,
16.22] 1.00 [0.06, 16.10] 0.80 [0.44, 1.44] 1.02 [0.06,
16.93] 0.85 [0.53, 1.35] 0.78 [0.38, 1.59] 0.82 [0.54, 1.23] 0.65 [0.11, 3.95] 3.07 [0.12,
77.69] 0.64 [0.23, 1.74] 0.84 [0.68, 1.04]
RES
PES
Odds Ratio Odds Ratio M-H, Random, 95% CI
0.005
0.1
1 10
200 RES
beter PES beter
111
Figure 5: All cause mortality during follow-up
Study or Subgroup Basket 2005 Cezar 2009 Corpal 2005 Han et al. 2006 Isar Desire 2005 Isar Diabetes ISAR LM 2009 ISAR-SMART 3 2006 Kim MH 2008 Lee SW 2008 LONG-DES II 2006 PORSIT 2008 REALITY 2006 Sirtax 2005 SORT-OUT II 2008
Total (95% CI) Total events Heterogeneity: Tau² = 0.00; Chi² = 8.42, df = 14 (P = 0.87); I² = 0% Test for overall effect: Z = 0.42 (P = 0.68)
Events 5
7 1 3 2 4
15 3 1 0 2 5
16 5 41
110
Total 264 196 261 210 100 125 305 198 85 20
0 250 154 684 503 106
5 4600
Events 7
5 2 4 1 6
15 4 1 1 0 9 9
11 40
115
Total 281 201 254 206 100 125 302 204 84 20
0 250 154 669 509 103
3 4572
Weight 5.4% 5.4% 1.3% 3.2% 1.2% 4.4% 13.5
% 3.2% 0.9% 0.7% 0.8% 5.8% 10.7
% 6.4% 36.9
% 100.0%
M-H, Random, 95% CI 0.76 [0.24, 2.41] 1.45 [0.45, 4.65] 0.48 [0.04, 5.38] 0.73 [0.16, 3.31] 2.02 [0.18,
22.65] 0.66 [0.18, 2.38] 0.99 [0.47, 2.06] 0.77 [0.17, 3.48] 0.99 [0.06,
16.06] 0.33 [0.01, 8.19] 5.04 [0.24,
105.52] 0.54 [0.18, 1.65] 1.76 [0.77, 4.00] 0.45 [0.16, 1.32] 0.99 [0.64, 1.55] 0.94 [0.72, 1.24]
RES
PES
Odds Ratio Odds Ratio M-H, Random, 95% CI
0.005
0.1
1 10
200 RES
beter PES beter
113
CHAPTER 7
Routine Use of a new endothelial progenitor cells antibody-coated
stent in patients undergoing primary PCI for ST-segment elevation
Myocardial infarction: A prospective registry in all-comers
Submitted for publication
114
115
ABSTRACT
Aims - To assess the safety of routine use of a new endothelial progenitor cells
antibody-coated stent in patients with primary PCI for ST elevation Myocardial
Infarction (STEMI).
Background - Although endothelial progenitor cell (EPC) capture stents may be safe
and may potentially prevent stent thrombosis and restenosis, there are only limited
data on it‘s use in primary PCI.
Methods - Data on consecutive patients with STEMI treated with the endothelial
progenitor cells antibody-coated stent (Genous Bio-Engineered R Stent) were
collected in a prospective registry. Clinical follow-up was performed at 30-days and at
1-year. MACE was defined as the combined end point of death, recurrent MI, stent
thrombosis or additional revascularisation by either PCI or CABG.
Results – From January to September 2008, a total of 430 consecutive STEMI
patients were included in the registry. Of these, 9% had diabetes and 35% had
anterior infarction. At angiography, 55% of the patients had TIMI 0 flow before PCI.
More than one stent was necessary in 20.2% of patients. TIMI 3 flow was achieved in
94% of patients. Acute stent thrombosis occurred in 1.2%. The incidence of events
after one year follow-up was low, with a total mortality of 3.7% and the incidence of
late stent thrombosis 0.8%. Predictors of MACE up to one year were higher age, not-
smoking, small stent diameter, no TIMI 3 flow after PCI and use of an intra-aortic
balloon pump.
Conclusions – Use of the endothelial progenitor cells antibody-coated Genous stent
is safe and associated with a low event rate. Longer follow-up studies are necessary
to confirm its long-term efficacy.
116
INTRODUCTION
Although the use of stents in general is safe during percutaneous coronary
intervention (PCI), concerns remain with regard to safety of stenting in patients
with ST-elevation Myocardial Infarction (STEMI), particularly because of an
increased risk of stent thrombosis . This may be related to the fact that healing is
impaired after stenting of a ruptured plaque, leaving uncovered stent struts as
substrate for thrombosis.
To address this issue, a new type of stent has been developed (Genous stent),
which is coated with murine monoclonal antihuman CD34 antibodies designed to
attract circulating endothelial progenitor cells (EPC). EPCs are bone-marrow
derived cells that are present in circulating blood, and have the ability to
differentiate into mature endothelial cells, which may potentially accelerate the
healing process, protect against thrombus, and minimize re-stenosis. There have
been several published studies on the clinical use of EPC capturing stents (1-5).
A small study in 16 patients demonstrated a nine-month composite major adverse
cardiac and cerebrovascular events of 6.3% as a result of a symptom-driven
target vessel revascularization in a single patient (1). In this study, at six-month
follow-up, mean angiographic late luminal loss was 0.63 mm, and percent stent
volume obstruction by intravascular ultrasound analysis was 27 %. In a cohort of
80 consecutive patients with high-risk angiographic and/or clinical features, it was
shown that the EPC capturing stent is safe and effective, with satisfactory
immediate results and mid-term outcome, without evidence of stent thrombosis
(2).
Although EPC capture stent may be in theory safe and even may prevent stent
thrombosis and restenosis, there are only limited data on its use in primary PCI
for STEMI. Most published studies have a very small sample size (3, 4). We
report the results of a prospective study of all comers with STEMI who were
treated with a Genous stent.
METHODS
Population and procedures
From January to September 2008, individual patient data from all patients with
admission diagnosis of STEMI treated with primary PCI and the endothelial
117
progenitor cell capture stent (Genous Bio-Engineered R Stent) at the Isala
klinieken (Zwolle, the Netherlands) were prospectively recorded in a registry. To
avoid double inclusion of patients, only the first recorded admission for STEMI
during the study period was used. Patients were diagnosed with STEMI if they
had chest pain of > 30 minutes duration and ECG changes with ST segment
elevation > 2 mm in at least 2 precordials and > 1 mm in the limb leads. Before
the primary PCI procedure all patients received 300 mg of aspirin and 5.000 IU
heparin intravenously. In addition to aspirin and heparin, clopidogrel 600 mg was
given orally, and continued with 75 mg daily during one year. Primary PCI was
performed with standard techniques if the coronary anatomy was suitable for
angioplasty, and if possible a Genous stent was placed. The Genous stent
comprises a covalently coupled polysaccharide matrix coating with monoclonal
murine anti-human CD34+ antibodies on the adluminal stent surface, attached to
a 316L stainless steel stent (Genous Bio-engineered R stent™, OrbusNeich
Medical Technologies, Fort Lauderdale, FL, USA). The Genous stent received CE
mark on 11 August 2005. PCI success was determined by the classification
system of the Thrombolysis in Myocardial Infarction (TIMI) trial, in which a grade 3
blood flow indicates normal flow within the vessel, in combination with a
myocardial blush grade 2 or 3. Additional treatment with glycoprotein IIb/IIIa
inhibitors or stents was left to the discretion of the treating cardiologist. All
patients were treated with optimised drug-therapy including angiotensin-
converting enzyme inhibitors, β-blockers and lipid-lowering drugs where
appropriate.
Measurements (definitions, end points)
Reinfarction was defined by the presence of recurrent ischemic symptoms or
electrocardiographic changes accompanied by a creatine kinase level that was
more than twice the upper limit of the normal range (with an elevated MB isoform
level) or more than 50 percent higher than the previous value obtained during
hospitalization with or without stent thrombosis or development of Q waves. Stent
thrombosis was defined as acute ischemic symptoms (typical chest pain with
duration more than 20 min) accompanied by occlusion of the infarct related
vessel, originating in the peri-stent region. Acute stent thrombosis was defined as
the occurrence of stent thrombosis within 24 hours after stent implantation,
118
subacute stent thrombosis as the occurrence of stent thrombosis more than 24
hours but less than 30 days after stent implantation and late stent thrombosis if
stent thrombosis was observed after 30 days. Major bleeding was defined as
either intracranial bleeding or overt bleeding with a decrease in hemoglobin ≥5
g/dl (≥ 3.1 mmol/L) or a decrease in hematocrit ≥15% within 48 hours after
admission. Major adverse cardiac clinical events (MACE) at one year were
defined as the combined end point of death, recurrent MI, PCI of the culprit lesion,
urgent bypass surgery or stent trombosis
Data collection and follow-up
Follow-up information was obtained from the patient's general physician or by
direct telephone interview with the patient up to 1 year after admission. Study
approval was obtained from the medical ethics committee of our hospital and all
patients gave written informed consent for the collection of data. MACE at one
year was defined as the combined end point of death, recurrent MI or additional
revascularisation by either PCI or CABG.
Statistical Analysis
Statistical analysis was performed with the Statistical Package for the Social
Sciences (SPSS Inc., Chicago, IL, USA) version 15.0.1. Continuous data were
expressed as mean ± standard deviation and categorical data as percentage,
unless otherwise denoted. Differences between continuous data were performed
by students t test and the chi-square or Fisher‘s exact test were used as
appropriate for dichotomous data. Multivariable logistic regression analysis was
performed to test the independent association between baseline characteristics
and MACE at on year. Significant variables analyzed are reported with their
respective odd ratios and 95% confidence intervals. Kaplan-Meier method was
used for survival rate. For all analyses, statistical significance was assumed when
the two-tailed probability value was < 0.05.
RESULTS
During the study period, a total of 430 patients were included in this prospective
registry. Mean age was 60 years, and 76.9% was male. General characteristics of
119
the patients are summarized in Table 1. The majority of patients were
hemodynamically stable on admission (89% Killip class 1).
Angiography
The findings of angiography are listed in table 2. The majority of patients had
single vessel disease. The LAD was the most common infarct related vessel. On
the initial angiography, TIMI 0 in the infarct related vessel was observed in 55% of
the patients. Approximately 95% of the patients had TIMI 3 flow after PCI.
Follow-up
All patients had one-year follow-up. The incidence of acute stent thrombosis was
1/.2%. The occurrence of events up to one year is listed in Table 3. The event
rate was low, with total mortality at one year of 3.7%. The incidence of stent
thrombosis at 1 year was 3.4%. Patients with stent thrombosis up to 1 year were
older (66 years versus 61 years, p 0.20) and had more often a history of
hypertension (64% vs 39%, p = 0.12). Stent diameter (3.2 mm without stent
thrombosis vs 3.1 mm in those with stent thrombosis) was not different, but mean
stent length was (not significant
Table 4 shows differences between patients with and without MACE as recorded
up to one year follow-up. Independent predictors of MACE up to one year were
higher age, not-smoking, small stent diameter, no TIMI 3 flow after PCI and use of
an intra-aortic balloon pump.
DISCUSSION
This largest registry of STEMI patients treated with a Genous stent showed
favorable mid-term results with a low incidence of events. Predictors of MACE up
to one year were higher age, not-smoking, small stent diameter, no TIMI 3 flow
after PCI and use of an intra-aortic balloon pump.
Mechanism of EPC capturing by the Genous stent
EPCs were isolated primarily in 1997 as CD34+ haematopoietic progenitors from
peripheral Blood (6). EPCs share common properties and function, and they can
proliferate and differentiate in vitro to mature endothelial cells. EPCs are
120
mobilized from bone marrow into peripheral blood and recruited to the foci of
pathophysiological neovascularization and reendothelialization, thereby
contributing to vascular regeneration. Severe EPC dysfunction is an indicator of
poor prognosis and severe endothelial dysfunction. The number of circulating and
functional activities of EPCs is reduced in smokers (7) and the eldery (8). In a
study with 120 individuals (43 control subjects, 44 patients with stable coronary
artery disease, and 33 patients with acute coronary syndromes), reduced levels of
circulating EPCs independently predicted atherosclerotic disease progression (9).
Also in a larger study, with patients with coronary artery disease as confirmed on
angiography, the level of circulating CD34+KDR+ endothelial progenitor cells
predicted the occurrence of cardiovascular events and death from cardiovascular
causes after 12 months (10).
Therefore, the aim of the EPC capture stent was to improve the formation of a
confluent endothelial layer on the stent. In an in-vivo study, at 1 h after
deployment of the EPC capture stent, more than 90% cell coverage was shown,
while the bare stainless steel stents were still almost completely devoid of cells
(11).
Stent thrombosis
Despite combined antiplatelet therapy, stent thrombosis persists at a rate of
0.5%–2% in elective interventions, and up to 6% in patients with acute coronary
syndromes (12), and is associated with a worse prognosis (13). The incidence of
stent thrombosis in our ―all comers‖ population was relatively low, and
comparable to the selected patients reported in randomized trials (14). However,
the incidence of stent thrombosis in our analysis was higher than the report of Lee
et al, who observed in 321 patients with primary PCI only one patient who
developed acute stent thrombosis, another two with subacute stent thromboses,
and no late thrombosis (15).
Several clinical and angiographic predictors of stent thrombosis have been
identified, including a poor post-procedural result such as inadequate stent
expansion, residual dissection, and inappropriate platelet aggregation inhibition
(16, 17). Clopidogrel is the thienopyridine of choice for dual antiplatelet therapy
after PCI, but the efficacy is limited because clopidogrel‘s antiplatelet activity is
delayed since the drug needs to be metabolized into its active form and there is
121
strong variability in patient response to clopidogrel. To overcome shortcomings of
clopidogrel, new more potent oral platelet aggregation inhibitors have been
introduced as prasugrel and cangrelor. The TRITON-TIMI 38 (TRial to assess
Improvement in Therapeutic Outcomes by optimizing platelet inhibition with
prasugrel) found that in patients with acute coronary syndromes scheduled for
PCI, prasugrel (60 mg loading dose and a 10 mg daily maintenance dose),
compared with approved doses of clopidogrel (300 mg loading dose and a 75 mg
daily maintenance dose), resulted in significantly reduced rates of ischemic
events (18). Also a sub-analysis of this study of patients with primary PCI for
STEMI showed after 15 months decreased myocardial infarction and stent
thrombosis (19).
Further directions
There have been several published studies on the clinical use of EPC capturing
stents (1-5). Although in a small study (n=11) by Kaul et al, a high rate of
restenosis was observed, this should be confirmed in larger studies. A
randomized trial in patients with lesions carrying a high risk of restenosis, showed
that use of the Genous stent was associated with more repeat revascularizations
as compared with the Taxus stent (20). In this study, however, there were four
stent thromboses with Taxus stent, but none with the Genous stent. Theoretically,
the enhanced endothelialization may also cause unwanted angiogenesis which
may favour neoplasia progression and paradoxically atherosclerotic plaque
expansion and complications in some patients. A balloon catheter coated with
Paclitaxel has recently been developed to reduce restenosis, and have been used
routinely to prevent in-stent restenosis (21, 22). Whether a combination of EPC
capture stent and drug eluting balloon may be beneficial should further be
explored.
Another subject to be explored is the use of EPC capture stents in patients with
acute stent thrombosis. Acute stent thrombosis is associated with high morbidity
and mortality, and the incidence of recurrent acute stent thrombosis is high in
these patients (23). Whether EPC capture stents will decrease this risk in these
patients should be assessed in randomised controlled clinical trials. Another
opportunity for EPC capture stents consist of patients requiring surgical
122
procedures early after coronary stent placement, since antiplatelet drug can
possibly more safe discontinued after PCI using EPC capture stents (24).
Limitations and strengths
Our study had several limitations. It concerned a non-randomized registry with
inclusion of patients in only one hospital with high experience with primary PCI.
However, this is a real world registry of all-comers with STEMI, treated with a
EPC capture stent. We did not perform routine control angiography after 6 or 9
months, and no EPC count was obtained. However, this registry reflects daily
practice and was not limited by exclusion criteria.
Conclusion
Use of the endothelial progenitor cells antibody-coated Genous stent in a large
unselected cohort of STEMI patients was safe, and associated with a low event
rate at mid-term follow up. Longer follow-up studies are necessary to confirm
long-term efficacy.
123
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TABLE 1 – General characteristics in 446 patients, treated with endothelial progenitor cells
antibody-coated stent for ST elevation Myocardial Infarction
% or mean SD
Age (years) 60 12.4
Age > 75 years 17.5
Male gender 76.9
Current smoker 39.5
Anterior infarct location 35.2
Diabetes mellitus 9.4
Hypertension 35.0
Known hypercholesterolemia 16.3
Family history 31.9
Previous MI 4.4
Previous PCI 4.0
Previous CABG 0.9
Previous stroke 1.6
Systolic blood pressure on admission (mm Hg) 134 25
Diastolic blood pressure on admission (mm Hg) 82 16
Heart rate on admission (beats/min) 75 17
Killip 1 on admission 88.8
127
TABLE 2 - Angiographic characteristics in 430 patients with STEMI treated with endothelial
progenitor cells antibody-coated stent
% or mean SD
Vessel disease
Single vessel disease 58.9
Two vessel disease 30.2
Three vessel disease or Left Main 10.9
No collaterals 61.5
Target lesion coronary artery
LAD (%) 44.8
RCX (%) 14.9
RCA (%) 39.7
One stent placed (%) 79.8
Balloon size 2.9 0.44
Highest pressure 12.7 3.7
Stent diameter (mm) 3.18 0.34
Total stent length (mm) 23.8 9.6
Use of additional devices, as thrombosuction 22.6
Intra Aortic Balloon Pumping 6.7
TIMI 3 flow after PCI 94.2
Blush 3 after PCI 55.2
128
Table 3 – Events recorded during follow-up in 430 patients with STEMI treated with
endothelial progenitor cells antibody-coated stent
Events until 30 days %
death 2.8 recurrent myocardial infarction 0.9 additional PCI 7.2
coronary bypass surgery 2.1 (sub) acute stent thrombose 2.6
Acute 1.2 Subacute 1.4 Major bleeding 1.4
Bleeding 3.0 MACE* 6.5
Events until 1 year death 3.7 re-MI 2.3
additional PCI 14.5 coronary bypass surgery 4.6
stent trombosis 3.4 Major bleeding 2.5
Bleeding 5.2 MACE* 12.3
* Combination of death, recurrent MI, PCI of culprit lesion, urgent bypass surgery or stent
trombosis
129
Table 4 – Differences between patients with and without MACE* recorded up to one
year in 430 patients with STEMI treated with endothelial progenitor cells antibody-
coated stent
Without MACE** N = 402
With MACE** N = 28
P value
% or mean SD % or mean SD
Age (years) 61.24 12.69 67.91 13.64 0.008
Age > 75 years 16.0 35.7 0.016 Male 77.1 71.4 0.491 Hypertension 36.9 55.6 0.053 Diabetes mellitus 10.7 7.4 1.000 Previous Myocardial Infarction 5.3 11.1 0.188 Previous CABG 1.2 0 1.000 Previous PCI 5.2 3/27 (11.1%) 0.185 Hypercholesterolaemia 19.0 18.5 0.946 Smoking 44.1 22.2 0.026 Positive family history 38.9 37.0 0.847 Killip class ≥ 2 on admission 5.5 10.7 0.217 LAD the infarct related vessel 44.2 55.6 0.252 TIMI 0 before PCI 54.6 70.4 0.111 Multivessel disease 41.1 57.7 0.097 Direct stenting 37.0 22.2 0.122 Stent diameter (mm) 3.19 0.33 3.03 0.38 0.017
Stent length (mm) 23.56 9.85 24.37 10.01 0.678
Highest pressure (mm Hg) 12.49 3.78 12.56 3.79 0.926
TIMI < 3 after procedure 4.5 30.8 < 0.001 Intra Aortic Balloon Pumping 5.1 30.8 < 0.001
* Combination of death, recurrent MI, PCI of culprit lesion, urgent bypass surgery or stent
trombosis
130
131
CHAPTER 8
Primary coronary intervention for ST elevation myocardial
infarction in a starting heart center in Indonesia:
the first 100 patients
Submitted for publication
132
133
Summary
Background: The benefits of Primary percutaneous coronary intervention (PCI) for
ST elevation myocardial infarction (STEMI) have been demonstrated, but most
studies were conducted in experienced centres in western world. Experience,
logistics and patient characteristics may differ in other parts of the world, particularly
in a starting center.
Methods: Data on all consecutive STEMI patients treated with primary PCI in Cinere
hospital, Jakarta, Indonesia were collected in a prospective database.
Results:,Between July 2006 and December 2008, a total of 100 patients with STEMI
were treated by primary PCI. Mean age was 56.9 10.4 years (range 37-82), 88%
was male. Mean time between onset of chest pain and admission was 369 388
minutes. The mean time between admission and balloon inflation was 258 minutes.
Before PCI, 50% of patients had TIMI 0 flow. After primary PCI 94% of patients had
TIMI 2/3 flow. There were no deaths in the catheterisation room, and no emergency
coronary bypass surgery was needed as a result of PCI complications. Mean left
ventricular ejection fraction as measured by echocardiography after 1 day was 48
12 %.
Conclusions: Outcome after primary PCI at a starting center is excellent in this
series. Primary PCI was effective in restoration of TIMI flow, without complications.
Time delay between symptom onset, admission and balloon inflation was long and all
efforts should be encouraged to shorten this.
134
Introduction
Randomized controlled trials, involving more than 7500 patients with ST elevation
Myocardial Infarction (STEMI), have demonstrated the superiority of primary
percutaneous coronary intervention (PCI) compared to fibrinolytic therapy (1), with
the greatest absolute mortality advantage of primary PCI in high-risk patients such as
those with cardiogenic shock (2, 3). However, almost all these trials were performed
in the United States or Western Europe in highly experienced centers. Also because
success and complications of PCI are dependent of the experience of the operator
and the hospital, it is mandatory to monitor the results of primary PCI in a new
starting hospital.
In the South Asia region, including Indonesia, both morbidity and mortality due to
cardiovascular disease is high and it is expected that this will increase even more (4).
Main causes are the high prevalence of diabetes (5), hypertension (6) and smoking
(7, 8).
To assess the results of primary PCI, as well as hospital mortality after the procedure
in a new hospital in Jakarta, Indonesia, we performed a prospective registry.
Patients and Methods
All data on the first 100 consecutive patients treated with primary PCI for STEMI in
Klinik Kardiovaskular - Cinere Hospital, Jakarta, Indonesia between August 2006 and
October 2008 were registered in a dedicated database. Cinere Hospital, Jakarta
started in 2006 with PCI program. They have a close collaboration with the Isala
klinieken, Zwolle, the Netherlands, and there is always an experienced consultant
cardiologist from Netherlands in Jakarta.
There was no industry involvement in the design, conduct or analysis of this study.
All patients with STEMI, presenting within 6 hours after symptom-onset, or those
presenting between 6 and 24 hours if they had persisting chest pain associated with
clinical evidence of on-going ischemia, were eligible for primary PCI and inclusion in
the registry.
All patients were pretreated with aspirin, a loading dose of clopidogrel and
intravenous nitroglycerin and heparin. Treatment with glycoprotein IIb/IIIa inhibitors
was left to the discretion of the physicians. Stenting of target lesion were performed
135
using standard interventional techniques. After the primary PCI all patients were
treated with guidelines provided medication, including statins and beta-blockers. All
patients received clopidogrel for at least 6 months.
Statistical Analysis
Statistical analysis were performed with the Statistical Package for the Social
Sciences (SPSS Inc., Chicago, IL, USA) version 15.0. Continuous data were
expressed as mean ± standard deviation and categorical data as percentage, unless
otherwise denoted. Differences between continuous data were performed by
students t test and the chi-square or Fisher‘s exact test were used as appropriate for
dichotomous data. For all analyses, statistical significance is assumed when the two-
tailed probability value is < 0.05.
RESULTS
Data were collected from 100 patients. Mean age was 56.9 10.4 years (range 37-
82), 88% was male. The mean time between onset of chest pain and admission was
369 388 minutes. Females were older, 66.3 9.7 years compared to males, 55.6
9.9 (p=0.001). The time between symptom onset and admission was longer in
females, 412 462 minutes compared to males 362 380 minutes, but this was not
statistically significant (p=0.7).
Baseline characteristics of the patients are listed in table 1. The prevalence of
diabetes, high lipids and smoking was high. Males were more frequently smokers
(56%) compared to females (8%, p=0.002). Diabetes was more common in females
(50%) than in males (28%), but this difference was not statistically significant
(p=0.11). There were many patients with signs of heart failure on admission, 10%
had heart failure Killip class 3 and 13% had Killip class 4.
In table 2 angiographic findings are summarized. The mean time between admission
and balloon inflation was 258 minutes with a median time of 163 minutes. Time
between admission and balloon inflation was significant longer in females, 553 675
minutes as compared to males, 219 217 minutes (p=0.004).
Of the 100 patients, 33% had multivessel disease. This was (not significant) more
often observed in males (37%) compared to females (13%, p=0.18). The prevalence
136
of multivessel disease was comparable in smokers (39%) and non-smokers (32%)
and in patients with (33%) and without (35%) diabetes.
The observed TIMI flow in the infarct related vessel before and after PCI is
summarized in figure 1. The frequency of TIMI flow 0 (occluded vessel) was (not-
significant) more often observed in males (52%) compared to females (42%, p =
0.49), and in patients with anterior location (54%) as compared to inferior location
(43%) but comparable between patients with (47%) and without diabetes (52%).
Mean age of patients with TIMI 0 flow before PCI was 56 10 years compared to 58
11 years of patients with TIMI 1-3 flow before PCI (p =0.58).
TIMI 2 or 3 flow in the infarct related vessel was achieved in 94% of patients.
Achieved TIMI 2 or 3 flow was slightly more common in males (95%) than in females
(83%, p =0.10). Mean age of patients with TIMI 2/3 flow after PCI was 57 11 years
compared to 54 5 years of patients with TIMI 2/3 flow after PCI (p =0.61). TIMI flow
2/3 was significant less often observed in patients who had TIMI flow 0 before PCI
(88%) than in patients with TIMI flow 1-3 before PCI (100%, p =0.01).
There were no deaths in the catheterisation room. Also, no patients required transfer
for emergency coronary bypass surgery as a result of PCI complications. Mean left
ventricular ejection fraction as measured by echocardiography after 1 day was 48
12 %. Mean LV ejection fraction of patients with anterior wall infarction was lower,
46% 12% compared to 52% 13% in patients with inferior wall myocardial
infarction PCI (p =0.05).
DISCUSSION
We describe a high-risk group of patients with STEMI with more than 10% Killip class
4 on admission. In these first 100 patients with STEMI treated by primary PCI in our
hospital, it was demonstrated that primary PCI was effective, resulting in restoration
of TIMI 2/3 flow in more than 90%. Delay between onset of symptoms, admission
and first balloon inflation was long.
Our results suggest that primary PCI in a starting heart center in Indonesia is safe
and is effective in achieving reperfusion. However, our results were achieved in the
setting of a close collaboration with an experienced center. Possibly, this may
influence the favourable results. Our results confirm the PAMI-No SOS study, that
137
showed that primary PCI in high-risk STEMI patients in hospitals without on-site
cardiac surgery is safe and effective (9). Also other studies in both Western world
and Asia reported that primary PCI can be safely performed in hospitals without on
site cardiac surgery (10, 11). However, it is important to monitor results of PCI,
particularly primary PCI, in small hospitals, since correlation between operator and
hospital volume and PCI outcomes has been described (12). But, with modern
techniques, this correlation may be less pronounce, (13). It has also been suggested
that expertise and experience of the whole professional team, rather than just of the
individual operator, play a major role (14).
The prevalence of risk factors in our patients was very high, with diabetes 30%, and
smoking, hypertension or high lipids in almost 50% of patients. Cardiac rehabilitation
should be an essential part of the contemporary care of these patients after the acute
phase. Risk factor modification should be achieved by encouraging exercise,
education, life stile change, counselling, support, and strategies aimed at targeting
traditional risk factors for cardiovascular disease. Intensive programs for smoking
cessation should already be started during hospital admission (15). The high
prevalence of diabetes in our study may be associated with the high prevalence of
diabetes in the general population in Indonesia.
In our study, there was a long time interval between symptom onset, hospital
admission and balloon inflation. All these intervals should be shorter. Education in
the general population should make people more aware of potential cardiac
symptoms and the importance to seek fast medical care. Ambulance transport should
be improved, possibly by regional approaches round hospitals with PCI facilities and
prehospital ECGs transmitted to an emergency department or relying on ambulance-
based paramedics trained to diagnosis STEMI and to determine which patients
should be transported directly to specialized PCI centers (16). In-hospital delay was
in our study mainly because of financial considerations and patient delay because of
fear for the procedure. General population, government and insurance companies
should be informed that costs of primary PCI, particularly if performed with only
balloon, is lower than conservative treatment.
Limitations
138
We studied only patients in one hospital, involving only few patients, and we could
therefore not perform subgroup analyses. Furthermore, selection bias may occur as
only survivors of STEMI undergoing primary PCI were included in this registry. We
had no data on patients who had STEMI but were not treated with primary PCI, or
who were not admitted in the hospital at all. Finally, we had no follow-up data, mainly
because many patients went back to their referring hospital the day after the primary
PCI.
Conclusions
Primary PCI for ST elevation Myocardial Infarction is safe and effective at a starting
heart center in Indonesia, if performed by an experienced team. However,
prehospital and in-hospital time delay is high, and therefore all efforts should be
aimed towards reduction in total ischemic time, by developing regional logistics with
pre-hospital triage and fast track facilities in dedicated PCI centers.
139
References
1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous
thrombolytic therapy for acute myocardial infarction : a quantitative review
of 23 randomised trial . Lancet 2003; 361:13-20.
2. Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley JD,
Buller CE, Jacobs AK, Slater JN, Col J, McKinlay SM, LeJemtel TH. Early
revascularization in acute myocardial infarction complicated by cardiogenic
shock. N Engl J Med. 1999;341:625– 34.
3. Zahn R, Schiele R, Schneider S, Gitt AK, Wienbergen H, Seidl K,
Voigtlander T, Gottwik M, Berg G, Altmann E, Rosahl W, Senges J.
Primary angioplasty versus intravenous thrombolysis in acute myocardial
infarction: can we define subgroups of patients benefiting most from
primary angioplasty? J Am Coll Cardiol 2001;37:1827–35.
4. Gupta M,Singh N, Verma S. South Asian and Cardiovascular Risk, What
Clinicians Should Know. Circulation. 2006; 113:e924-9.
5. Santoso T. Prevention of cardiovascular disease in diabetes mellitus: by
stressing the CARDS study. Acta Med Indones. 2006;38:97-102.
6. Martiniuk AL, Lee CM, Lawes CM, Ueshima H, Suh I, Lam TH, Gu D,
Feigin V, Jamrozik K, Ohkubo T, Woodward M; Asia-Pacific Cohort Studies
Collaboration. Hypertension: its prevalence and population-attributable
fraction for mortality from cardiovascular disease in the Asia-Pacific region.
J Hypertens. 2007;1:73-9.
7. Martiniuk AL, Lee CM, Lam TH, Huxley R, Suh I, Jamrozik K, Gu DF,
Woodward M; Asia Pacific Cohort Studies Collaboration. The fraction of
ischaemic heart disease and stroke attributable to smoking in the WHO
Western Pacific and South-East Asian regions. Tob Control 2006;15:181-8.
8. Woodward M, Lam TH, Barzi F, Patel A, Gu D, Rodgers A, Suh I; Asia
Pacific Cohort Studies Collaboration. Smoking, quitting, and the risk of
cardiovascular disease among women and men in the Asia-Pacific region.
Int J Epidemiol. 2005;34:1036-45.
9. Wharton TP Jr, Grines LL, Turco MA, Johnston JD, Souther J, Lew DC,et
al. Primary angioplasty in acute myocardial infarction at hospitals with no
140
surgery on-site (the PAMI-No SOS Study) versus transfer to surgical
centers for primary angioplasty. J Am Coll Cardiol 2004;43:1943-50.
10. Wennberg DE, Lucas FL, Siewers AE, Kellett MA, Malenka DJ. Outcomes
of percutaneous coronary interventions performed at centers without and
with onsite coronary artery bypass graft surgery. JAMA 2004;292:1961-8.
11. Ong SH, LIM, VYT, Chang BC, et al. Three-Year Experience of Primary
Percutaneous Coronary Intervention for Acute ST-Segment Elevation
Myocardial Infarction in a Hospital without On-site Cardiac Surgery. Ann
Acad Med Singapore 2009;38:1085-9.
12. McGrath PD, Wennberg DE, Dickens JD Jr, et al. Relation between
operator and hospital volume and outcomes following percutaneous
coronary interventions in the era of the coronary stent. JAMA.
2000;284:3139-44.
13. Moscucci M, Share D, Smith D, O'Donnell MJ, et al. Relationship between
operator volume and adverse outcome in contemporary percutaneous
coronary intervention practice: an analysis of a quality-controlled
multicenter percutaneous coronary intervention clinical database. J Am
Coll Cardiol. 2005;46:625-32.
14. Politi A, Galli M, Zerboni S, Michi R, De Marco F, Llambro M, Ferrari G.
Operator volume and outcomes of primary angioplasty for acute
myocardial infarction in a single high-volume centre. J Cardiovasc Med
(Hagerstown). 2006;10:761-7.
15. Smith PM, Burgess E. Smoking cessation initiated during hospital stay for
patients with coronary artery disease: a randomized controlled trial. CMAJ.
2009 Jun 23;180(13):1297-303.
16. Stone GW. Angioplasty strategies in ST-segment–elevation myocardial
infarction. Part I: primary percutaneous coronary intervention. Circulation
2008;118:538-51.
141
Table 1 – General characteristics of 100 patients treated with primary PCI for STEMI
in Klinik Kardiovaskular, Cinere hospital, Jakarta
N = 100
% or mean SD
Age (years) 56.9 10.4 Male 88 Diabetes 30 High lipids 56 Hypertension 49 Smoking 48 Previous MI 28 Previous PCI 8 Previous Coronary Bypass Surgery 2 Anterior location 60 Admission Creatinin (mg/dl) 1.24 1.09 Killip ≥ 2 on admission 46 Ventricular Fibrillation before angiography 11 Time between onset chest pain and admission (minutes)
369 388
142
Table 2 – Angiographic findings in 100 patients treated with primary PCI for STEMI in
Klinik Kardiovaskular Cinere hospital, Jakarta.
N = 100
% or mean SD Time between admission and balloon inflation (minutes)
258 317 Multi vessel disease 33 TIMI 0 before angioplasty 50 Bare metal stent 49 Drug Eluting stent 24 TIMI 2/3 flow after angioplasty 94
143
Figure 1 - TIMI flow in the infarct related vessel before and after primary PCI in 100
patients
144
145
CHAPTER 9
Primary coronary intervention for ST elevation myocardial
infarction in Indonesia and the Netherlands: a comparison
Neth Heart J 2009 Nov;17(11):418-2
146
147
Abstract
Background: Although the beneficial effects of primary percutaneous coronary
intervention (PCI) for ST elevation myocardial infarction (STEMI) has been
demonstrated in a number of trials, most studies were conducted in the western
countries. Experience, logistics and patient characteristics may differ in other parts of
the world.
Methods: Consecutive patients treated between January 2008 and October 2008
with primary PCI in hospital Cinere, Jakarta, Indonesia were compared with those
treated in the Isala klinieken, Zwolle, the Netherlands
Results: During the study period, a total of 596 patients were treated by primary PCI,
568 in Zwolle and 28 in Jakarta. Patients in Indonesia were younger (54 vs 63 years),
more often had diabetes (36% vs 12%) and high lipids and were more often smokers
(68% vs 31%). Time delay between symptom onset and admission was longer in
Indonesia. Patients from Indonesia had more often signs of heart failure at
admission. The time between admission and balloon inflation was longer in
Indonesia. At angiography, patients from Indonesia had more often multi vessel
disease. There was no difference in percentage of restoration of TIMI 3 flow by
primary PCI between the two hospitals.
Conclusions: Patients with STEMI in Indonesia have a higher risk profile compared to
the Netherlands, according to prevalence of coronary risk factors, signs of heart
failure, multivessel disease and patient delay. Time delay between admission and
balloon inflation was much longer in Indonesia, because of both logistic and financial
reasons.
Keywords: developping countries, Asia, Infarction
148
Introduction
The most important therapeutic goal in the treatment of patients with ST elevation
Myocardial Infarction (STEMI) is achievement of early and complete reperfusion of
the infarct-related vessel. Effective reperfusion can be achieved by either fibrinolytic
therapy or primary percutaneous coronary intervention (PCI) without antecedent
fibrinolysis. A total of 23 randomized controlled trials, involving more than 7500
patients have demonstrated the superiority of primary PCI over fibrinolytic therapy
(1), with the absolute mortality advantage of primary PCI greatest in high-risk patients
such as those with cardiogenic shock (2, 3). However, almost all these trials were
performed in the United States or Western Europe. The situation and the efficacy of
primary PCI may differ in other parts of the world, with regards to logistics,
experience of PCI centres and patient characteristics. More insights in potential
differences between these regions and the western world are important to estimate
whether primary PCI will also be effective in these countries.
It is expected that the cardiovascular mortality will increase in the South East Asian
region (4). Also in Indonesia, both morbidity and mortality due to coronary artery
disease is high. This may be caused by a high prevalence of diabetes (5),
hypertension (6), and smoking (7, 8). In a developing country like Indonesia, probably
only a minority of patients with STEMI is treated with primary PCI. But procedures as
well as patients who are treated with primary PCI may also differ from the Western
world. To compare treatment with primary PCI in Europe (the Netherlands) and
Indonesia, we performed a prospective registry in two hospitals.
Patients and methods
All consecutive patients treated with primary PCI for STEMI in either hospital Cinere,
Jakarta, Indonesia or the Isala klinieken, Zwolle, the Netherlands between January
and October 2008 were registered in a dedicated database. The Isala klinieken,
Zwolle is a hospital with a long experience with primary PCI. Hospital Cinere, Jakarta
started in 2006 with PCI, but has a close collaboration with the Isala klinieken,
Zwolle, and there is always an experienced consultant cardiologist and nursing staff
from Zwolle working in Jakarta.
There was no industry involvement in the design, conduct or analysis of the study.
149
All patients with STEMI, presenting within 6 hours after symptom-onset, or those
presenting between 6 and 24 hours if they had persisting chest pain associated with
clinical evidence of on-going ischemia, were considered eligible for primary PCI and
inclusion in the registry.
All patients were pretreated with aspirin, a loading dose of clopidogrel and
intravenous nitroglycerin and heparin. Treatment with glycoprotein IIB/IIIA inhibitors
was left to the discretion of the physicians. Stenting of target lesion was performed
using standard interventional techniques. After the primary PCI all patients were
treated with guidelines provided medication, including statins and beta-blockers. All
patients received clopidogrel for at least 6 months.
Statistical analysis
Statistical analysis was performed with the Statistical Package for the Social
Sciences (SPSS Inc., Chicago, IL, USA) version 15.0. Continuous data were
expressed as mean ± standard deviation and categorical data as percentage, unless
otherwise denoted. Differences between continuous data were performed by
students t test and the chi-square or Fisher‘s exact test were used as appropriate for
dichotomous data. For all analyses, statistical significance was assumed when the
two-tailed probability value was < 0.05.
Results
Data were collected in 596 consecutive patients. The mean age was 62.5 years
(range 28-96) and 75% were male. The mean time between onset of chest pain and
admission was 225 ( 215) minutes. Females were older, 66.2 ( 13.1) years
compared to males, 61.2 ( 12.6). The time between symptom onset and admission
was comparable in females (230 217 minutes) and males (223 214 minutes).
During the study period, a total of 568 patients in Zwolle and 28 patients in hospital
Cinere were treated with primary PCI for STEMI. Baseline characteristics of the
patients are listed in table 1. Patients from Indonesia were younger, with a trend to
more males. The prevalence of diabetes, high lipids and smoking was higher in
Indonesian patients. Time between symptom onset and hospital admission was
longer in Indonesian patients. In table 2 angiographic measurements are
summarized. Time from hospital admission to balloon inflation was much longer in
150
Indonesia. Furthermore, more patients from Indonesia had multi vessel disease. The
other angiographic characteristics were not different between patients from the
Netherlands and Indonesia. Death within 30 days after admission was observed in 24
patients in the Netherlands (4.2%) and in 1 patient (3.6%) in Indonesia (NS).
Discussion
We found important differences between patients treated with primary PCI for STEMI
in Indonesia and the Netherlands. Patients in Indonesia had a higher risk profile
compared to the Netherlands, with regards to prevalence of coronary risk factors,
signs of heart failure and patient delay. Although primary PCI was effective in
restoration of TIMI 3 flow in both countries, time delay between admission and
balloon inflation was longer in Indonesia.
Clinical Implications
Our results suggest that many factors can be improved to reduce morbidity and
mortality due to STEMI in Indonesia. First, both health care professionals and
politicians should still focus on primary prevention. The high prevalence of
unfavourable risk factors in our Indonesian patients was also observed in the
Indonesian general population previously (9). Patients from Indonesia had a twofold
prevalence of smoking in our study. The prevalence of smoking is still high in
Indonesia, although there have been campaigns against smoking, particularly
because it has been shown that there are no ethnic differences in the benefits of
quitting smoking (10). The Indonesian Ministry of Health makes already use of
traditional media such as the wayang kulit (shadow puppet theatre) and warnings
about the harmful effects of (passive) smoking. Also the Indonesian Heart
Foundation and several foundations as the Foundation's No-Smoking Leaders Group
(Lembaga Menanggulangi Masalah Merokok, known as Lembaga M3) and the
Wanita Indonesia Tanpa Tembakau (WITT) or Indonesian Women Without Tobacco
are fighting against smoking. Probably,even more aggressive public health efforts to
limit tobacco use are urgently needed in Indonesia now. Also, the prevalence of
diabetes was high in our study. This may be related to a high prevalence of diabetes
in the general population in Indonesia, which may be in part associated with the
metabolic syndrome. Studies of people living in rural areas of East Java and Bali
show an increasing prevalence of 1.5% in 1982 to 5.7% in 1995 among the urban
151
population. Comparative studies indicate that metabolic responses to obesity may be
greater in South and East Asians than their western counterparts at given Body Mass
Indexes (11,12) It was previously suggested that early detection of asymptomatic
diabetes in Indonesia should be encouraged, either at the hospital or doctor's private
office (13). Furthermore, it has been demonstrated that the management of type 2
diabetes in the Western Pacific Region varies widely, with often untreated
hypertension and microalbuminuria (14).
A second important goal in the treatment of patients with STEMI in Indonesia should
be to reduce the time between symptom onset and first balloon inflation. There is a
strong association between time delay and mortality in patients with STEMI treated
by primary PCI (15). This can be separated in delay between symptom onset and
hospital admission and in delay between admission and balloon inflation. There can
be several strategies to decrease time delays (16). All steps should be considered for
improvement, including the patient‘s ability to recognize their symptoms and to
promptly contact the medical system, the time necessary to transport the patient to
the hospital, the decision process on arrival, and the requisite time to implement the
reperfusion strategy. Possibly, in Indonesia particularly ambulance transport systems
can be improved, with regional approaches round hospitals with PCI facilities and
prehospital ECGs transmitted to an emergency department or relying on ambulance-
based paramedics trained to diagnosis STEMI and to determine which patients
should be transported directly to specialized PCI centers (17).
More importantly, in Indonesia much delay and even the impossibility to offer primary
PCI to patients with STEMI may be influenced by financial considerations. About 80
percent of the Indonesian population has no health insurance coverage. Although the
insurance scheme for civil servants (Askes) may have had a strongly positive impact
on access of poor patients to medical care (18), access to especially all hospital
services is still low for the middle and low-income patients (19). This is difficult to
solve on the short time, but should be an effort of government, insurance companies,
medical professionals and aid from the Western world. It should be kept in mind that
the costs of primary PCI, particularly if performed with "stand-alone" balloon-
angioplasty, may be lower than conservative treatment or thrombolysis (20).
Limitations
152
We studied only patients in two hospitals. Particularly in Indonesia, a very large
country, the results may have been different in other regions or hospitals..
Geographical variation may be of importance, due to differences in ethnics, race,
culture and lifestyle. Moreover, we included only few patients from Indonesia, and we
could therefore not perform subgroup analyses. Finally and maybe most importantly,
health economics differ greatly between Indonesia and the Netherlands. This may
have introduced confounding factors that cannot be detected by this survey. Because
of this selection bias, we are now scheduling a larger, prospective registry, with also
patients from the university hospital in Jakarta. However, also then financial reasons
may still cause (additional) selection bias, since only selected patients with
myocardial infarction are admitted to a hospital, and of those only happy few may be
treated by primary PCI.
Conclusions
Patients with STEMI in Indonesia have a higher risk profile compared to Netherlands,
according to prevalence of coronary risk factors, signs of heart failure and patient
delay. Although primary PCI was effective in both countries with regard to restoring
TIMI 3 flow, time delay between admission and balloon inflation was longer in
Indonesia. Treatment of STEMI can be improved in Indonesia and this should be a
combined effort of both government and health care professionals.
153
References
17. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous
thrombolytic therapy for acute myocardial infarction: a quantitative review
of 23 randomised trial. Lancet 2003;361:13-20.
18. Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley JD, et
al. Early revascularization in acute myocardial infarction complicated by
cardiogenic shock. N Engl J Med 1999;341:625-34.
19. Zahn R, Schiele R, Schneider S, Gitt AK, Wienbergen H, Seidl K, et al.
Primary angioplasty versus intravenous thrombolysis in acute myocardial
infarction: can we define subgroups of patients benefiting most from
primary angioplasty? J Am Coll Cardiol 2001;37:1827-35.
20. Gupta M, Singh N, Verma S. South Asian and cardiovascular risk, what
clinicians should know. Circulation 2006;113:e924-9.
21. Santoso T. Prevention of cardiovascular disease in diabetes mellitus: by
stressing the CARDS study. Acta Med Indones 2006;38:97-102.
22. Martiniuk AL, Lee CM, Lawes CM, Ueshima H, Suh I, Lam TH, et al; Asia-
Pacific Cohort Studies Collaboration. Hypertension: its prevalence and
population-attributable fraction for mortality from cardiovascular disease in
the Asia-Pacific region. J Hypertens 2007;1:73-9.
23. Martiniuk AL, Lee CM, Lam TH, Huxley R, Suh I, Jamrozik K, et al; Asia
Pacific Cohort Studies Collaboration. The fraction of ischaemic heart
disease and stroke attributable to smoking in the WHO Western Pacific
and South-East Asian regions. Tob Control 2006;15:181-8.
24. Woodward M, Lam TH, Barzi F, Patel A, Gu D, Rodgers A, et al; Asia
Pacific Cohort Studies Collaboration. Smoking, quitting, and the risk of
154
cardiovascular disease among women and men in the Asia-Pacific region.
Int J Epidemiol 2005;34:1036-45.
25. Boedhi-Darmojo R, Setianto B, Sutedjo, Kusmana D, Andradi, Supari F, et
al. A study of baseline risk factors for coronary heart disease: results of
population screening in a developing country. Rev Epidemiol Sante
Publique 1990;38:487-91.
26. Critchley JA, Capewell S. Mortality risk reduction associated with smoking
cessation in patients with coronary heart disease: a systematic review.
JAMA 2003;290:86-97.
27. Yoon KH, Lee JH, Kim JW, Cho JH, Choi YH, Ko SH, et al. Epidemic
obesity and type 2 diabetes in Asia. Lancet 2006;368:1681-8.
28. Pan WH, Yeh WT, Weng LC. Epidemiology of metabolic syndrome in Asia.
Asia Pac J Clin Nutr 2008;17 Suppl 1:37-42.
29. Adam FM, Adam JM, Pandeleki N, Mappangara I. Asymptomatic diabetes:
the difference between population-based and office-based screening. Acta
Med Indones 2006;38:67-71.
30. Eppens MC, Craig ME, Jones TW, Silink M, Ong S, Ping YJ; The
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156
Table 1 – Differences between patients treated with primary PCI for STEMI in
hospital Cinere, Jakarta and Isala klinieken, Zwolle
Isala klinieken,
Zwolle, N = 568
Hospital Cinere,
Jakarta, N = 28
P value
% or mean SD % or mean SD
Age (years) 62.9 12.8 53.8 11.6 0.001
Male 75 86 0.19
Diabetes 12 36 0.001
Family history of heart disease 37 32 0.64
High lipids 19 46 0.001
Hypertension 42 46 0.65
Smoking 31 68 0.01
Previous MI 11 18 0.27
Anterior location 39 54 0.13
Killip ≥ 2 on admission 8 52 0.001
Time between onset chest pain
and admission (minutes)
214 202 413 325 0.001
Systolic blood pressure on
admission (mm Hg)
133 26 117 23 0.002
Diastolic blood pressure on
admission
81 17 76 14 0.12
Heart rate on admission (beats
per minute)
76.8 19.6 83.4 27.3 0.09
157
Table 2 – Angiographic findings in patients treated with primary PCI for STEMI in
hospital Cinere, Jakarta or Isala klinieken, Zwolle
Isala klinieken,
Zwolle, N = 568
Hospital Cinere,
Jakarta, N = 28
P value
% or mean SD % or mean SD
Time between admission and
balloon inflation (minutes)
49 33 189 127 0.001
Multi vessel disease 51 75 0.01
Infarct related vessel:
LAD 39 46 0.40
RCA 39 39 0.99
TIMI 0 before PCI 59 68 0.34
Stenting 73 71 0.82
Only one stent used 80 75 0.62
TIMI 3 flow after PCI 93 85 0.15
158
159
CHAPTER 10
Summary & conclusions
160
161
In Indonesia, every year thousands of people have a heart attack and thousands of
people will die because of this heart attack, many because they are too late for
medical care or because medical care is sub optimal.
In the current thesis, several aspects of optimising treatment of a heart attack, ST
elevation Myocardial Infarction (STEMI) are discussed and assessed, with particular
attention for improvement of treatment in Indonesia.
In chapter 1, a brief introduction about the subject and the background of the thesis
is given. From data from the WHO, it is shown that the incidence of cardiovascular
disease in Indonesia is very high. This may be caused by the high prevalence of
smoking and (not or not well treated) diabetes, hypertension and elevated cholesterol
levels. Based on the increasing prevalence of these unfavourable risk factors, the
burden of cardiovascular disease is a big problem in Indonesia.
In chapter 2, modern treatment of STEMI is summarized. Treatment starts with a fast
and good diagnosis and if possible medical treatment in the ambulance. The next
goal in the treatment is timely, complete and sustained reperfusion of the infarct
related vessel. Although thrombolytics can be considered in selected patients and if
percutaneous coronary intervention (PCI) is not available, in the majority of patients
primary PCI should be the first choice. After reperfusion therapy, patients should be
treated with antiplatelet medication, beta-blocker, lipid lowering drugs and ACE-
inhibitors in selected patients. Cardiac rehabilitation should be offered to all patients
and focus on life style modification, including smoking cessation.
In chapter 3, the glycoprotein (GP) IIb/IIIa inhibitor tirofiban for use in patients with
myocardial infarction is discussed in more detail. Tirofiban is a small molecule GP
IIb/IIIa receptor inhibitor. If discontinued, the action of tirofiban is faster reversed as
abciximab, another GP IIb/IIIa inhibitor. The dose of tirofiban varies between low
(bolus of 0.4 μg/kg administered over 30 minutes followed by an infusion of 0.10
μg/kg/min), intermediate (bolus of 10 μg/kg administered over 3minutes followed by
an infusion of 0.15μg/kg/min) and high (bolus of 25 μg/kg administered over 3
minutes followed by an infusion of 0.15μg/kg/min). Especially the high dose
administration may be beneficial in patients with STEMI undergoing primary PCI.
There is no indication for tirofiban in patients treated with thrombolysis. Patients with
Non-ST Elevation Myocardial Infarction requiring PCI are most likely to achieve
162
benefit from tirofiban, when they have ongoing ischemia and/or dynamic ECG
changes. It is stated that the risk of serious bleeding with tirofiban is low and there is
a very low risk of thrombocytopenia.
In chapter 4, the potential benefits of use of stents in primary PCI are assessed.
Although in previous studies in patients with primary PCI stenting was associated
with a reduced risk of reinfarction and target vessel revascularization, it was less
clear whether stenting reduced also mortality when compared to balloon angioplasty.
To assess the potential association between mortality and stenting in primary PCI in
daily practise, analyses of a prospective registry from Zwolle, the Netherlands, were
performed. Primary PCI was performed in 4299 patients, of whom 2571 patients
(60%) were treated by (bare metal) stenting. There were no differences in age,
gender, infarct location or diabetes between the two groups, but patients in the
balloon group had more often previous myocardial infarction and multi vessel
disease, and had a longer duration between symptom start and admission. The
combined end-point of death or re-infarction after 30 days was 7.2% in the balloon
group vs 5.6% in the stent group (p=0.03). After one year follow-up, mortality in the
balloon group was 7.9%, compared to 5.8% in the stent group (p=0.007). After
adjusting for differences in age, gender, previous myocardial infarction, patient delay
and multi vessel disease, use of a stent was still associated with a decreased risk of
one-year mortality, with OR 0.77, 95% CI 0.61 – 0.98. It was concluded that in
patients undergoing primary PCI for STEMI, use of stents in daily practise is
associated with a decreased mortality.
In chapter 5, two different drug-eluting stents are compared in patients with primary
PCI. As compared to bare metal stent, both Sirolimus (SES) and paclitaxel (PES)
eluting stents have been shown to improve angiographic and clinical outcomes after
PCI in elective procedures and patients with STEMI. Aim of the current study was to
compare SES to PES among STEMI patients undergoing primary PCI. Patients with
STEMI were randomized 1:1 to receive the SES (n=196) or PES (n=201). Primary
end point was late lumen loss at 9 months follow-up by quantitative coronary
angiography. Secondary end points were major adverse cardiac clinical events
(death, re-infarction, target vessel revascularization) at 1, 9 and 12 months. A total of
397 patients with STEMI were randomized. The two groups had comparable baseline
163
clinical and angiographic characteristics. Mortality was low, 1.5% after 30 days, 2.3
% after 9 months and 3.1% after one year. There was no difference in any clinical
outcome at any follow-up period between the two treatment groups. Follow-up
angiography was completed in 272 of 397 patients (69 percent). The mean (SD) in-
stent late loss was 0.01 (0.42) mm in the sirolimus group vs 0.21 (0.50) mm in the
paclitaxel group (difference, −0.20 mm, P 0.001).
It was concluded that in patients with STEMI, primary PCI with SES results in less
late loss compared to paclitaxel eluting stents. However, these benefits did not
translate into significant reduction in MACE at one-year follow-up.
In chapter 6, a meta-analysis is presented of all trials comparing Rapamycin eluting
stents (RES) and paclitaxel eluting stents (PES) in patients undergo percutaneous
coronary intervention. Because many individual studies are small, it is not yet clear
whether there are any differences between RES and PES with regard to clinical
outcome. Systematic searches were conducted of randomised controlled trials
(RCTs) comparing RES with PES in MEDLINE and the Cochrane Database of
systematic reviews. Information on study design, inclusion and exclusion criteria,
number of patients, and clinical outcome was extracted by two investigators.
Disagreements were resolved by consensus. The primary outcome was re-
intervention, target lesion revascularisation (TLR) and target vessel revascularization
(TVR). Stent re-stenosis, myocardial infarction (MI) and all cause mortality were
secondary end points. Twenty one RCTs of RES versus PES with a total number of
10,147 patients were included in this meta-analysis. Indication for angioplasty was
either acute coronary syndrome or stable angina. Mean follow-up period ranged from
6 to 24 months. Rates of TLR were 4.9% vs. 7.0%; p=0.0009 and rates of TVR were
5.1 vs. 8.3%; p<0.001 for RES vs. PES, respectively. The incidence of stent re-
stenosis was 3.9% for RES vs. 5.3% for PES; p=0.004. Rates of MI and all cause
mortality were comparable. It was concluded that, as compared to PES, RES seems
to be associated with a lower risk of re-intervention and stent re-stenosis. The risk of
myocardial infarction and all cause death were similar between the 2 stents.
The safety of the routine use of a new endothelial progenitor cells antibody-coated
stent in patients with primary PCI is assessed in chapter 7. Although endothelial
progenitor cell (EPC) capture stents may be safe and may potentially prevent stent
164
thrombosis and restenosis, there are only limited data on its use in primary PCI. Data
on consecutive patients with STEMI treated with the endothelial progenitor cells
antibody-coated stent (Genous Bio-Engineered R Stent) were collected in a
prospective registry. Clinical follow-up was performed at 30-days and at 1-year.
MACE was defined as the combined end point of death, recurrent MI, stent
thrombosis or additional revascularisation by either PCI or CABG. From January to
September 2008, a total of 430 consecutive STEMI patients were included in the
registry. Of these, 9% had diabetes and 35% had anterior infarction. At angiography,
55% of the patients had TIMI 0 flow before PCI. More than one stent was necessary
in 20.2% of patients. TIMI 3 flow was achieved in 94% of patients. Acute stent
thrombosis occurred in 1.2%. The incidence of events after one year follow-up was
low, with a total mortality of 3.7% and the incidence of late stent thrombosis 0.8%.
Predictors of MACE up to one year were higher age, not-smoking, small stent
diameter, no TIMI 3 flow after PCI and use of an intra-aortic balloon pump.
It was concluded that use of the endothelial progenitor cells antibody-coated Genous
stent is safe and associated with a low event rate. Longer follow-up studies are
necessary to confirm its long-term efficacy.
In chapter 8, the first 100 patients treated with primary PCI in Klinik Kardiovaskular
hospital Cinere are described. Primary PCI may be very effective, but most studies
were conducted in experienced centres in western world. Experience, logistics and
patient characteristics may differ in other parts of the world, particularly in a starting
center. Data on all 100 consecutive patients treated with primary PCI in Cinere
hospital, Jakarta, Indonesia were collected in a prospective database between July
2006 and December 2008. Mean age was 57 years (range 37-82), 88% was male.
Mean time between onset of chest pain and admission was 369 minutes. The mean
time between admission and balloon inflation was 258 minutes. Before PCI, 50% of
patients had TIMI 0 flow. After primary PCI, 94% of patients had TIMI 2/3 flow. There
were no patients dying in the catheterisation room. Also, no patients required transfer
for emergency coronary bypass surgery as a result of PCI complications. Mean left
ventricular ejection fraction as measured by echocardiography after 1 day was 48 %.
It was concluded that primary PCI was effective in restoration of TIMI flow, without
complications. Time delay between symptom onset, admission and balloon inflation
was long and all efforts should be encouraged to shorten this.
165
In chapter 9, consecutive patients treated between January 2008 and October 2008
with primary PCI in hospital Cinere, Jakarta, Indonesia were compared with those
treated in the same period in the Isala klinieken, Zwolle, the Netherlands. During the
study period, a total of 596 patients were treated by primary PCI, 568 in Zwolle and
28 in Jakarta. Patients in Indonesia were younger (54 vs 63 years), more often had
diabetes (36% vs 12%) and high lipids and were more often smokers (68% vs 31%).
Time delay between symptom onset and admission was longer in Indonesia. Patients
from Indonesia had more often signs of heart failure at admission. The time between
admission and balloon inflation was longer in Indonesia. At angiography, patients
from Indonesia had more often multi vessel disease. There was no difference in
percentage of restoration of TIMI 3 flow by primary PCI between the two hospitals.
It is concluded that patients with STEMI in Indonesia have a higher risk profile
compared to the Netherlands, according to prevalence of coronary risk factors, signs
of heart failure, multivessel disease and patient delay. Time delay between
admission and balloon inflation was much longer in Indonesia, because of both
logistic and financial reasons.
166
167
CHAPTER 11
Samenvatting & conclusies
168
169
In Indonesië sterven ieder jaar duizenden mensen tengevolge van een hartinfarct
(myocardinfarct), velen doordat de behandeling te laat komt of onvoldoende is.
In dit proefschrift worden verschillende aspecten onderzocht om de behandeling van
een ST-elevatie myocardinfarct (STEMI) te verbeteren, met in het bijzonder aandacht
voor het verbeteren van de behandeling in Indonesië.
In hoofdstuk 1, wordt een korte inleiding over het onderwerp gegeven en enkele
achtergronden geschetst. Gegevens van de Wereld Gezondheids Organisatie
(WHO) tonen aan dat de incidentie van cardiovasculaire ziekten in Indonesië hoog is.
Dit wordt onder andere veroorzaakt door de hoge prevalentie van roken, (niet
optimaal behandelde) diabetes, hypertensie en verhoogd cholesterol. Door deze
hoge (en nog toenemende) prevalentie van risicofactoren, is de omvang van
cardiovasculaire ziekten in Indonesië een groot probleem.
In hoofdstuk 2, wordt de huidige behandeling van een ST Elevatie Myocardinfarct
beschreven en samengevat. De behandeling begint met een snelle en goede
diagnose, en behandeling in de ambulance. Het volgende doel is het afgesloten
infarct vat snel, compleet en blijvend te openen. Hoewel in geselecteerde patiënten
thrombolyse van waarde kan zijn, met name als een primaire Percutane Coronaire
Interventie (PCI) niet mogelijk is, is voor de meeste patiënten met een STEMI een
primaire PCI de beste keus. Na reperfusie therapie, zal optimale medicatie moeten
worden gegeven: thrombocyten aggregatie remmers (aspirine, clopidogrel),
bètablokkers, lipiden verlagende middelen (statinen) en ACE inhibitors. Alle patiënten
zullen een revalidatie traject moeten krijgen, met focus op levensstijl aanpassingen,
inclusief stoppen met roken.
In hoofdstuk 3, wordt het gebruik van de glycoprotein (GP) IIb/IIIa inhibitor tirofiban
bij patiënten met een hartinfarct meer in detail beschreven. Tirofiban is een laag
moleculaire GP IIb/IIIa receptor inhibitor. Na staken van tirofiban is de werking sneller
verdwenen dan van abciximab, een andere GP IIb/IIIa inhibitor, en dit kan gunstig
zijn bij het optreden van een bloeding of als een patiënt een operatie moet
ondergaan. De dosering van tirofiban varieert tussen laag (bolus van 0.4 μg/kg
toegediend gedurende 30 minuten gevolgd door een infuus van 0.10 μg/kg/min),
170
gemiddeld (bolus van 10 μg/kg gedurende 3 minuten, gevolgd door een infuus van
0.15μg/kg/min) and hoog (bolus van 25 μg/kg gedurende 3 minutes gevolgd door een
infuus van 0.15μg/kg/min).
Vooral de hoge dosis kan gunstig zijn bij patiënten met STEMI die een primaire PCI
ondergaan. Er is geen indicatie voor tirofiban bij patiënten die behandeld worden met
trombolyse. Patiënten met non-ST elevatie myocardinfarct bij wie een PCI nodig is,
hebben waarschijnlijk het meest profijt van tirofiban, wanneer zij de langdurige
ischemie en / of dynamische ECG-veranderingen hebben. Het risico van ernstige
bloedingen met tirofiban is laag en er is een zeer laag risico van trombocytopenie.
In hoofdstuk 4 worden de potentiële voordelen van het gebruik van stents in
primaire PCI bestudeerd. Hoewel in eerdere studies bij patiënten met primaire PCI
het gebruik van een stent was geassocieerd met een verlaagd risico van re-infarct en
revascularisatie, was het minder duidelijk of stenting ook mortaliteit in vergelijking
met ballondilatatie vermindert. Voor het beoordelen van de mogelijke associatie
tussen sterfte en stenting in primaire PCI in de dagelijkse praktijk, werden de
analyses van een prospectieve registratie uit Zwolle, Nederland, uitgevoerd. Primaire
PCI werd uitgevoerd in 4299 patiënten, van wie 2571 patiënten (60%) werden
behandeld door (bare metal) stent. Er waren geen verschillen in leeftijd, geslacht,
infarctplaats of diabetes tussen de twee groepen, maar de patiënten in de ballon
groep had vaker een eerder myocardinfarct en meertakslijden, en hadden een
langere duur tussen start van symptomen en opname. Het gecombineerde eindpunt
van overlijden of een nieuw infarct na 30 dagen was 7,2% in de ballon groep versus
5,6% in de stent-groep (p = 0,03). Na een jaar follow-up was de sterfte in de ballon
groep 7,9%, tegenover 5,8% in de stent-groep (p = 0,007). Na correctie voor
verschillen in leeftijd, geslacht, doorgemaakt myocardinfarct, tijd tussen klachten en
opname en meertakslijden, was het gebruik van een stent nog steeds geassocieerd
met een verminderd risico van 1-jaarsterfte, met OR 0,77, 95% CI 0,61 - 0,98. Er
werd geconcludeerd dat bij patiënten die een primaire PCI STEMI ondergaan, het
gebruik van stents in de dagelijkse praktijk geassocieerd is met een verminderde
mortaliteit.
In hoofdstuk 5 worden twee verschillende drug-eluting stents vergeleken bij
patiënten die wegens STEMI worden behandeld met primaire PCI. In vergelijking met
171
bare metal stents, is van zowel de sirolimus (SES) als de paclitaxel (PES) eluting
stents aangetoond dat angiografische en klinische resultaten verbeteren na een PCI
bij electieve procedures en patiënten met STEMI. Doel van de huidige studie was om
SES te vergelijken met PES bij STEMI-patiënten die primaire PCI ondergaan.
Patiënten met STEMI werden 1:1 gerandomiseerd naar de SES (n = 196) of PES (n
= 201). Primaire eindpunt was lumen reductie na 9 maanden follow-up, gemeten met
behulp van kwantitatieve coronaire angiografie. Secundaire eindpunten waren
belangrijke cardiovasculaire klinische eindpunten (overlijden, re-infarct,
revascularisatie van het infarctvat) na 1, 9 en 12 maanden. Een totaal van 397
patiënten met STEMI werden gerandomiseerd. De twee groepen hadden
vergelijkbare klinische en angiografische kenmerken. De sterfte was laag, 1,5% na
30 dagen, 2,3% na 9 maanden en 3,1% na een jaar. Er was geen verschil in
klinische uitkomst op elk follow-up moment tussen de twee behandelingsgroepen.
Follow-up angiografie werd voltooid in 272 van 397 patiënten (69 procent). De
gemiddelde (SD) in-stent lumen reductie was 0,01 (0.42) mm in de sirolimus groep
versus 0,21 (0,50) mm in de paclitaxel-groep (verschil -0,20 mm, P 0,001).
Geconcludeerd werd dat bij patiënten met STEMI, primaire PCI met SES resulteert in
minder lumen reductie, in vergelijking met paclitaxel eluting stents. Echter, deze
voordelen leidden niet tot aanzienlijke vermindering van MACE na een jaar follow-up.
In hoofdstuk 6 wordt een meta-analyse gepresenteerd van alle onderzoeken die
Rapamycin stents (RES) en paclitaxel-eluting stents (PES) vergelijken bij patiënten
die een primaire PCI ondergingen wegens een STEMI. Omdat veel afzonderlijke
studies klein zijn, was het nog niet duidelijk of er verschillen zijn tussen de RES en
PES met betrekking tot de klinische uitkomst. Een systematische onderzoek werd
uitgevoerd van alle gerandomiseerde gecontroleerde studies (RCTs) die RES met
PES vergeleken en gepubliceerd waren in MEDLINE of de Cochrane Database van
systematische reviews. Informatie over de onderzoeksopzet, inclusie en exclusie
criteria, het aantal patiënten, en het klinische resultaat werd geëxtraheerd door twee
onderzoekers. Meningsverschillen werden opgelost door consensus. De primaire
uitkomstmaat was hernieuwde revascularisatie van het infarctvat (TLR). Stent re-
stenose, myocardinfarct (MI) en mortaliteit door alle oorzaken waren secundaire
eindpunten. Eenentwintig RCT's van SES ten opzichte van PES met een totaal
aantal van 10.147 patiënten werden opgenomen in deze meta-analyse. Indicatie voor
172
angioplastiek was ofwel acuut coronair syndroom of stabiele angina pectoris. De
follow-up periode varieerde van 6 tot 24 maanden. Het voorkomen van TLR was
4,9% vs 7,0%, p = 0,0009 en van TVR 5,1 vs 8,3%; p <0,001 voor RES vs PES,
respectievelijk. De incidentie van stent re-stenose was 3,9% voor RES versus 5,3%
voor PES, p = 0,004. De incidentie van MI en mortaliteit door alle oorzaken waren
vergelijkbaar. Geconcludeerd werd dat, in vergelijking met PES, RES lijkt te zijn
geassocieerd met een lager risico van re-interventie en re-stent stenose. Het risico
van myocardinfarct en overlijden ongeacht oorzaak waren vergelijkbaar tussen de 2
stents.
De veiligheid van het routinematig gebruik van een nieuwe endotheliale
voorlopercellen antilichaam-gecoate stent bij patiënten met primaire PCI is
onderzocht in hoofdstuk 7. Hoewel door endotheliale voorlopercellen (EPC) af te
vangen stents voordeel kunnen bieden en mogelijk stent trombose en restenose
voorkomen, zijn er slechts gegevens beperkt bij het gebruik ervan bij de primaire
PCI. Gegevens over opeenvolgende patiënten met STEMI behandeld met de
endotheliale voorlopercellen antilichaam-gecoate stent (Genous Bio-engineered R
stent) werden verzameld in een prospectieve registratie. Klinische follow-up werd
uitgevoerd na 30-dagen en na 1-jaar. MACE werd gedefinieerd als het
gecombineerde eindpunt van overlijden, recidiverend MI, stent trombose of
aanvullende revascularisatie door een PCI of CABG. Van januari tot september 2008
werden in totaal 430 opeenvolgende STEMI-patiënten opgenomen in de registratie.
Van deze patiënten had 9% diabetes en 35% had anterior infarct. Bij angiografie,
bleek 55% van de patiënten TIMI 0 flow vóór PCI te hebben. Meer dan 1 stent was
nodig bij 20,2% van de patiënten. TIMI 3 flow werd bereikt bij 94% van de patiënten.
Acute stent trombose werd waargenomen bij 1,2%. De incidentie van gebeurtenissen
na een jaar follow-up was laag, met een totale mortaliteit van 3,7% en de incidentie
van late stent trombose 0,8%. Voorspellers van MACE na een jaar waren hogere
leeftijd, niet-rokers, kleine stent diameter, geen TIMI 3 flow na PCI en het gebruik van
een intra-aortale ballonpomp.
Geconcludeerd werd dat het gebruik van de endotheliale voorlopercellen
antilichaam-gecoate stent Genous veilig is en geassocieerd met een lage incidentie
van MACE tijdens 1 jaar follow-up. Langere follow-up studies zijn nodig om de
werkzaamheid op lange termijn te bevestigen.
173
In hoofdstuk 8 worden de eerste 100 patiënten die behandeld werd middels primaire
PCI in Klinik Kardiovaskular ziekenhuis Cinere, Jakarta, Indonesie, beschreven.
Primaire PCI zou zeer effectief kunnen zijn, maar de meeste studies werden
uitgevoerd in ervaren centra in de westerse wereld. Ervaring, logistiek en patiënt
kenmerken kunnen verschillen in andere delen van de wereld, met name in een
beginnende centrum. Gegevens over alle eerste 100 opeenvolgende patiënten
behandeld met primaire PCI in Cinere ziekenhuis, Jakarta, Indonesië werden
verzameld in een prospectieve database tussen juli 2006 en december 2008. De
gemiddelde leeftijd was 57 jaar (variërend tussen 37 en 82), 88% was man.
Gemiddelde tijd tussen begin van de pijn op de borst en opname was 369 minuten.
De gemiddelde tijd tussen opname en opblazen van de ballon was 258 minuten.
Voor de PCI had 50% van de patiënten TIMI 0 flow. Na de primaire PCI, 94% van de
patiënten had TIMI 2 / 3 flow. Er stierven geen patiënten in de katheterisatie kamer.
Ook geen van de patiënten behoefden een spoed coronaire bypass-operatie als
gevolg van een PCI-complicatie. De gemiddelde linker ventrikel ejectiefractie zoals
gemeten door middel van echocardiografie na 1 dag was 48%.
Geconcludeerd werd dat ook in een beginnend hartcentrum in Indonesië, primaire
PCI effectief was in het herstel van de TIMI flow in het infarctvat, zonder
complicaties. Tijdvertraging tussen aanvang van de symptomen, de
ziekenhuisopname en opblazen van de ballon was lang en alle inspanningen moeten
worden aangemoedigd om dit te verkorten.
In hoofdstuk 9 werden opeenvolgende patiënten, behandeld tussen januari 2008 en
oktober 2008 met primaire PCI in het ziekenhuis Cinere, Jakarta, Indonesië
vergeleken met degenen die behandeld werden in dezelfde periode in de Isala
klinieken, Zwolle, Nederland. Gedurende de studie periode werden in totaal 596
patiënten behandeld met primaire PCI, 568 in Zwolle en 28 in Jakarta. Patiënten in
Indonesië waren jonger (54 vs 63 jaar), hadden vaker diabetes (36% vs 12%), vaker
verhoogde lipiden en waren vaker rokers (68% vs 31%). Tijd tussen aanvang van de
symptomen en opname was langer in Indonesië. Patiënten uit Indonesië, hadden
vaker tekenen van hartfalen bij opname. De tijd tussen opname en opblazen van de
ballon was langer in Indonesië. Bij angiografie, patiënten uit Indonesië, hadden vaker
meertakslijden. Er was geen verschil in percentage van de restauratie van TIMI 3
flow door primaire PCI tussen de twee ziekenhuizen.
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Geconcludeerd wordt dat patiënten met STEMI in Indonesië een hoger risicoprofiel
hebben ten opzichte van Nederland, wat betreft de prevalentie van coronaire
risicofactoren, tekenen van hartfalen, meervatslijden ziekte, en lange tijd tussen
klachten en behandeling. Tijd tussen opname en opblazen van de ballon was veel
langer in Indonesië, zowel vanwege logistieke en financiële redenen.
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Chapter 12
Abstrak dan kesimpulan dalam bahasa
Indonesia
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Di Indonesia, setiap tahun puluhan ribu orang meninggal oleh karena serangan
jantung, kebanyakan kematian ini disebabkan oleh keterlambatan pelayanan
kesehatan atau pelayanan kesehatan yang belum memadai.
Disertasi ini membahas beberapa aspek untuk mengoptimalkan penanganan
serangan jantung akut atau ST-segmen Elevasi Miocard Infark (STEMI) terutama
dalam rangka memperbaiki penanganan di Indonesia.
Dalam bab 1, diberikan pendahuluan singkat tentang tema dan latar belakang
disertasi ini. Data WHO menunjukkan bahwa insiden penyakit kardiovaskular di
Indonesia tinggi. Hal ini dapat disebabkan oleh tingginya prevalensi merokok dan
(tidak atau kurang baiknya penanganan) diabetes, hipertensi dan kadar kolesterol
yang tinggi. Berdasarkan tingginya faktor risiko ini, beban penyakit kardiovaskular
menjadi masalah besar di Indonesia.
Dalam bab 2, diringkas tentang penanganan mutakhir ST-segmen Elevasi Miokard
Infark. Penanganan dimulai dengan penegakan diagnosa yang cepat dan baik dan
bila memungkinkan pengobatan diawali di ambulans. Tujuan berikutnya dalam
pengobatan adalah, reperfusi yang cepat, lengkap dan patensi yang baik pada
pembuluh yang menyebabkan infark. Walaupun trombolitik dapat dipertimbangkan
pada pasien tertentu dan bila Intervensi Koroner Perkutan (IKP) tidak tersedia, untuk
sebagian besar pasien, IKP primer harus menjadi pilihan pertama. Setelah
penanganan reperfusi, pasien harus diberi pengobatan antiplatelet, penyekat beta,
obat penurun lipid dan pada pasien tertentu, penyekat Enzim Konversi Angiotensin
(EKA). Rehabilitasi jantung sebaiknya dianjurkan kepada seluruh pasien dengan
memperhatikan perubahan pola hidup, termasuk berhenti merokok.
Dalam bab 3, dibahas lebih mendetail tentang Penyekat Glikoprotein (PG) IIb/IIIa,
penggunaan tirofiban pada pasien dengan infark miokard. Tirofiban merupakan
molekul kecil PG IIb/IIIa. Bila pemberian dihentikan, kerja tirofiban kembali lebih
cepat dibandingkan abciximab, yaitu jenis PG IIb/IIIa lainnya. Dosis tirofiban
beragam dari dosis kecil (bolus 0,4 µg/kg bb diberikan selama 3 menit diikuti dengan
pemberian melalui infus 0,10 µg/kg bb/menit), dosis sedang (bolus 10 µg/kg bb
diberikan selama 3 menit diikuti dengan pemberian melalui infus 0,15 µg/kg
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bb/menit) dan dosis tinggi (bolus 25 µg/kg bb diberikan selama 3 menit diikuti dengan
pemberian melalui infus 0,15 µg/kg bb/menit),
Pemberian dosis tinggi, dapat memberi manfaat pada pasien dengan STEMI yang
menjalani IKP primer. Tidak ada indikasi pemberian tirofiban pada pasien yang
sudah ditangani dengan pemberian trombolisis. Pasien Non ST Elevation Myocard
Infarction (NSTEMI) yang membutuhkan IKP memperoleh manfaat dari tirofiban ini,
terutama bila pasien menderita iskemik yang terus-menerus dan/atau mengalami
perubahan dinamik EKG. Seperti yang dijelaskan bahwa dengan penggunaan
tirofiban dapat memberi komplikasi perdarahan yang serius dan mempunyai risiko
rendah untuk terjadinya trombositopenia.
Dalam bab 4, dikaji manfaat potensial penggunaan stent pada IKP primer. Walaupun
pada penelitian sebelumnya pemasangan stent pada pasien yang menjalani IKP
primer berhubungan dengan penurunan risiko infark berulang dan revaskularisasi
pembuluh target, namun tidak begitu jelas apakah pemasangan stent dapat juga
menurunkan angka kematian bila dibandingkan dengan angioplasti balon. Untuk
menilai adanya hubungan potensial antara kematian dan pemasangan stent pada
IKP primer dalam praktik sehari-hari, kami menggunakan analisa registri prospektif
dari Zwolle, Belanda. IKP primer dilakukan pada 4299 pasien dimana 2571 pasien
(60%) ditangani dengan pemasangan stent (metal polos). Tidak ada perbedaan pada
usia, jenis kelamin, lokasi infark atau diabetes diantara kedua kelompok, tetapi
kelompok pasien yang menggunakan balon mempunyai riwayat infark miokard
sebelumnya lebih sering dan penyakit pembuluh darah yang multipel dan
mempunyai waktu yang lebih lama dari mulai timbulnya gejala sampai dengan
masuk rumah sakit. Hasil akhir dari kombinasi dari kematian dan infark berulang
setelah 30 hari adalah 7,2% pada kelompok balon dibanding 5,6% pada kelompok
stent (p=0,03). Setelah satu tahun pengamatan, kematian pada kelompok balon
sebanyak 7,9% dibanding 5,8% dalam kelompok stent (p=0,007). Setelah
penyesuaian perbedaan umur, jenis kelamin, infark miokard sebelumnya,
keterlambatan pasien dan penyakit pembuluh koroner multipel, penggunaan stent
tetap menunjukkan penurunan risiko kematian 1 tahun, dengan RO 0,77, IK 95%
0,61-0,98. Penelitian ini menyimpulkan bahwa penggunaan stent pada praktik sehari-
hari berhubungan dengan penurunan kematian.
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Dalam bab 5, dibandingkan dua jenis stent selaput obat pada pasien yang menjalani
IKP primer. Dibanding dengan stent metal polos, baik stent selaput Sirolimus (SSS)
dan stent selaput paclitaxel (SSP) menunjukan hasil akhir perbaikan angiografi dan
klinis setelah prosedur IKP elektif dan pasien dengan STEMI. Tujuan penelitian ini
yaitu membandingkan SSS terhadap SSP pada pasien dengan STEMI. Pasien
dengan STEMI dilakukan randomisasi 1:1 menerima SSS (n=196) atau SSP
(n=201). Titik akhir primer adalah kehilangan lumen secara lambat (KLL) pada bulan
ke 9 dengan pemantauan angiografi koroner kwantitatif. Titik akhir sekunder adalah
dampak kejadian utama klinis jantung yang merugikan (KUKJM) (kematian, infark
ulangan, revaskularisasi pembuluh target) pada bulan pertama (1), sembilan (9) dan
dua belas (12). Penelitian acak dilakukan kepada 397 pasien dengan STEMI.
Kedua kelompok mempunyai klinis dasar dan karakteristik angiografik yang
sebanding. Angka kematian serendah 1,5% setelah 30 hari, 2,3% setelah 9 bulan
dan 3,1% setelah satu tahun. Tidak ada perbedaan hasil klinis pada setiap waktu
pengamatan antara kedua kelompok yang ditangani. Pengamatan angiografi
dilakukan pada 272 pasien dari 397 (69%). Rerata kehilangan lambat di dalam stent
adalah 0,01 (0,42) mm dalam kelompok sirolimus dibanding 0,21 (0,50) mm
dikelompok paclitaxel (perbedaan -0,20 mm, P=0,001). Disimpulkan bahwa pada
pasien STEMI dengan IKP primer, SSS mengakibatkan kehilangan lambat yang lebih
sedikit bila dibandingkan dengan PSS. Namun demikian, manfaat ini tidak dapat
diterjemahkan adanya penurunan yang bermakna KUKJM dalam 1 tahun
pengamatan.
Dalam bab 6, disajikan penelitian meta-analisa dari seluruh penelitian yang
membandingkan stent selaput Rapamycin (SSR) dengan stent selaput Paclitaxel
(SSP) pada pasien yang menjalani intervensi koroner perkutan. Oleh karena banyak
penelitian individu yang kecil, maka tidak jelas apakah ada perbedaan antara SSR
dan SSP untuk hasil akhir klinis. Pencarian secara sistematis dilakukan pada
penelitian randomisasi terkontrol (PRT) yang membandingkan SSR dengan SSP di
MEDLINE dan Database Cochrane secara sistematis. Informasi mengenai desain,
kriteria eksklusi dan inklusi, jumlah pasien, dan hasil klinis dirangkum oleh 2 peneliti.
Perbedaan pendapat diselesaikan secara konsensus. Hasil akhir primer adalah
intervensi ulangan, revaskularisasi lesi target (RLT) dan revaskularisasi pembuluh
target (RPT). Penyempitan berulang pada stent, infark miokard (IM) dan semua
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penyebab kematian merupakan titik akhir sekunder. Dua puluh satu PRT yang
membandingkan SSR dengan SSP berjumlah 10.147 pasien dimasukan dalam
meta-analisis ini. Indikasi angioplasti baik sindrom koroner akut atau angina stabil.
Rerata periode pengamatan berkisar antara 6 - 24 bulan. Laju RLT 4,9% banding
7,0%, p=0,0009 dan laju RPT 5,1% banding 8,3%; p<0,001 untuk SSR banding SSP
secara respektif. Kejadian penyempitan kembali pada stent 3,9% untuk SSR
dibanding 5,3% untuk SSP; p=0,004. Laju IM dan semua penyebab kematian
sebanding. Disimpulkan bahwa dibanding SSP, SSR menunjukkan risiko yang lebih
rendah untuk intervensi ulangan dan stenosis berulang. Risiko IM dan seluruh
penyebab kematian sama antara kedua stent.
Keamanan penggunaan rutin stent baru selaput antibodi sel progenitor endotelial
pada pasien dengan IKP primer dikaji dalam Bab 7. Walaupun stent penangkap sel
progenitor endothelial (SPE) mungkin aman dan secara potensial dapat mencegah
trombosis dan stenosis berulang pada stent, data yang ada dalam penggunaanya
pada IKP primer sangat terbatas. Data pasien konsekutif dengan STEMI yang
ditangani dengan stent selaput-antibodi sel progenitor endotelial (Genous Bio-
Engineered R stent ) dihimpun dalam registri prospektif. Pemantauan klinis
dilakukan pada hari ke 30 dan 1 tahun. Kejadian utama klinis jantung yang
merugikan (KUKJM) didefinisikan sebagai kombinasi dari titik akhir kematian, IM
ulangan, trombosis stent atau revaskularisasi tambahan, baik dengan IKP atau
CABG. Dari Januari- September 2008, sejumlah 430 pasien STEMI konsekutif
dimasukkan dalam registri. Dari semua pasien ini: 9% menderita diabetes dan 35%
dengan infark anterior. Pada angiografi, 55% pasien mempunyai aliran TIMI 0,
sebelum IKP. Lebih dari 1 stent diperlukan pada 20,2% pasien. Aliran TIMI 3
tercapai sebesar 94% pasien. Trombosis stent akut terjadi pada 1,2%. Ditemukan
rendahnya insiden kejadian setelah 1 tahun pengamatan dengan angka kematian
seluruhnya 3,7% dan insiden trombosis stent yang lambat sebesar 0,8%. Prediktor
KUKJM sampai dengan 1 tahun adalah kelompok usia yang lebih tua, tidak
merokok, diameter stent yang lebih kecil, tidak didapatkan TIMI 3 setelah IKP dan
penggunaan pompa balon intra aorta.
Disimpulkan bahwa penggunaan stent Genous yang berlapis sel antibodi progenitor
endotelial ini aman dan berhubungan dengan laju kejadian yang rendah.
Pengamatan lebih lama diperlukan untuk konfirmasi manfaat jangka panjang.
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Dalam bab 8, dijelaskan tentang 100 pasien yang ditangani dengan IKP primer di
Klinik Kardiovaskular Hospital Cinere. IKP primer mungkin sangat efektif, tetapi
sebagian besar penelitian dilakukan pada pusat yang berpengalaman di dunia barat.
Pengalaman, logistik dan karakteristik pasien berbeda pada belahan dunia lain,
terutama pada pusat jantung yang baru berdiri. Data dari seluruh 100 pasien
konsekutif yang ditangani dengan IKP primer di rumah sakit Cinere, Jakarta,
Indonesia dihimpun secara prospektif dari suatu database selama bulan Juli 2006
sampai dengan Desember 2008. Rerata umur adalah 57 Tahun (kisaran 37-82), 88%
adalah pria. Rerata waktu antara onset sakit dada dan masuk rumah sakit adalah
369 menit. Rerata waktu antara masuk dan inflasi balon adalah 258 menit. Sebelum
IKP, 50% pasien mempunyai aliran TIMI 0. Setelah IKP, 94% dari pasien mempunyai
aliran TIMI 2/3. Tidak ada pasien yang meninggal di ruang kateterisasi. Tidak ada
pasien yang membutuhkan rujukan untuk bedah pintas koroner darurat sebagai
komplikasi dari IKP. Rerata fraksi ejeksi ventrikel kiri yang diukur dengan
ekokardiografi setelah 1 hari adalah 48%. Disimpulkan bahwa IKP primer efektif
dalam memperbaiki aliran TIMI, tanpa komplikasi. Keterlambatan waktu antara onset
keluhan, saat masuk dan pengembangan balon cukup lama dan harus dilakukan
seluruh usaha untuk memperbaiki masalah ini.
Dalam Bab 9, pasien konsekutif yang ditangani antara Januari - Oktober 2008
dengan IKP primer di rumah sakit Cinere, Jakarta, Indonesia dibandingkan dengan
waktu yang sama di Isala Klinieken, Zwolle, Belanda. Selama periode penelitian,
sejumlah 596 pasien yang ditangani IKP primer, 568 pasien di Zwolle, dan 28 pasien
di Cinere, Jakarta. Pasien di Indonesia lebih muda (54 tahun dibanding 63 tahun),
lebih banyak menderita diabetes (36% dibanding 12%) dan lipid yang tinggi dan
sebagian besar merokok (68% dibanding 31%). Keterlambatan waktu antara onset
keluhan dan masuk rumah sakit lebih lama di Indonesia. Pasien dari Indonesia lebih
sering memiliki tanda gagal jantung saat masuk. Waktu antara masuk rumah sakit
dan inflasi balon lebih lama di Indonesia. Pada pemerikasaan angiografi, pasien
Indonesia lebih sering mempunyai penyakit pembuluh darah multipel. Tidak ada
perbedaan persentase perbaikan aliran TIMI 3 dengan IPK primer antara kedua
rumah sakit.
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Disimpulkan bahwa pasien dengan STEMI di Indonesia mempunyai profil risiko lebih
tinggi dibandingkan di Belanda, menurut prevalensi faktor risiko koroner, tanda gagal
jantung, penyakit pembuluh darah multipel dan keterlambatan pasien. Keterlambatan
waktu antara masuk rumah sakit dan pengembangan balon lebih lama di Indonesia,
oleh karena masalah logistik dan finansial.
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Chapter 13
List of presentations and publications
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ORAL PRESENTATIONS
"Biventricular Pacing in patients with severe Congestive Heart Failure: The
Indonesian experience". Presented at XII World Congress on Cardiac Pacing and
Electrophysiology held in Hong Kong, February 19 - 22, 2003.
"Anatomical Variants in Double Outlet Right Ventricle: National Cardiovascular
Center Harapan Kita experience in 5 years, presented at 4 th THIC (The Heart
Institute for Children), International symposium in Pediatric Cardiology held in Bali,
June 28 – 30, 2002.
In-hospital mortality of elective PCI, comparison of different risk scores. Dutch Yearly
Cardiology Meeting, September 2008, Amsterdam, Netherlands
Primary coronary intervention for ST elevation myocardial infarction in
Indonesia: comparison with Europe. TCT Asia Pacific 2009, Seoul, Korea, April 2009
Routine Use of a new endothelial progenitor cells antibody-coated stent in
patients with primary PCI for ST elevation Myocardial infarction: A prospective
registry. TCT Asia Pacific 2009, Seoul, Korea, April 2009
First experience of Primary PCI in a starting Indonesian heart center. SCAI's Global
Interventional Summit in Istanbul, Turkey, October 2010
PUBLICATIONS
Juwana YB, Wirianta J, Suryapranata H, de Boer MJ. Left main coronary artery
stenosis undetected by 64- slice computed tomography : a word of caution.
Netherlands Heart Journal 2007:15:255-6.
Juwana YB, Suryapranata H, Ottervanger JP, et al. Comparison of Rapamycin and
Paclitaxel Eluting Stents in Patients Undergoing Primary Percutaneous Coronary
Intervention for ST Elevation Myocardial Infarction. Am J Cardiol 2009 Jul
15;104(2):205-9.
186
Juwana YB, Wirianta J, Ottervanger JP, et al. Primary coronary intervention for ST
elevation myocardial infarction in Indonesia: comparison with Europe. Neth Heart J
2009 Nov;17(11):418-21.
Juwana YB, Rasoul S, Ottervanger JP, Suryapranata H. Efficacy and safety of
Rapamycin as compared to Paclitaxel-eluting stents: a meta-analysis. J Invasive
Cardiolo 2010Jul;22(7):312-6.
Juwana YB, Suryapranata H, Ottervanger JP, Hof AW van´t. Tirofiban for myocardial
infarction. J Expert Opinion on Pharmacotherapy 2010 Apr;11(5):861-6.
Juwana YB, Ottervanger JP, Dambrink JHD, De Boer MJ, Hoorntje, JCA, Van ‗t Hof
AWJ, Gosselink MA, Suryapranata HS. Impact of stenting on Mortality in Patients
undergoing Primary PCI for ST-Elevation Myocardial Infarction. Treatment
Strategies, ESC congress review 2009: 58-63.
187
Chapter 14
Acknowledgements
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The kindness of the Lord almighty has guided me to meet respectful teachers,
supporting friends and a wonderful family to whom I am indebted for my life, career
and today‘s achievements.
First of all and foremost, I am grateful to my promotor Prof. Dr. Harry Suryapranata
for trusting in me for over the years. You have pushed me to go beyond my own
expectations. I really appreciate your never-ending supports and encouragements.
Without your consistent and persistent encouragement and supervision the
completion of this dissertation would not have happened. All the discussions and the
important points of your teaching have enlightened me on how to optimize the
interventional procedure. Your vision and drive to enhance the tie between the
Indonesian and the Netherlands cardiology, and as the liaison officer between the
two countries, is remarkable. For all that, I would like to express my profound
gratitude. You have made me what I am now as cardiologist.
To my promotor Prof Menko Jan de Boer, I would like to express my gratitude for all
your supports and the wise advises for me. You shared your experiences with me,
which were very valuable for this dissertation and myself. The precious discussion
you brought is always inspiring for any research. Your encouragement for my
presentation during the NVVC meeting has motivated me to present research results
in other cardiology meetings. Thank you very much for teaching a child how to walk.
Most of all, I am very much indebted to my co-promotor Jan Paul Ottervanger for
guiding me through the whole process of this PhD program. I learned many things of
the a to z in conducting, writing articles, presenting before distinguished and
scholarly forum and writing a thesis. Without your help it would not have been
possible to complete this dissertation. Your understanding and patience for your
students like myself have made you a wise teacher in our eyes and a respectful
person. You have become not only a teacher, but also a close colleague to your
students. Your continuing efforts to try to speak the Indonesian language, we
sometimes are able to understand, teached me to not give up my dream too easily.
Terima kasih banyak.
190
To Prof. Budhi Setianto, thank you for your endless motivation, teaching and
philosophy discussions since my cardiology training. Your positive energy has
provided fresh air to my perspective and research. All of the discussions and your
guidance enhance this dissertation. I appreciated your efforts to make it possible to
defend the dissertation in Indonesia. It is a great honour for me, that you can join the
promotion committee in the Netherlands.
I would like to express my gratitude to Prof. Dr. Jos van de Meer and Prof. Dr. Felix
Zijlstra, members of the reading committee, for the kind assistance and guidance to
review this dissertation.
My sincere gratitude to the maatschap cardiology Zwolle and Diagram B.V. Zwolle for
their continuing support and for giving me the opportunity to work with their research
data.
Dr Jan Hoorntje, thank you for reminding me not to forget the physiology and
biological aspects in the treatment of coronary artery disease. Your wise remarks
during the morning rounds were of great value, but also your advices during my golf
games, significantly increased my insights.
Dr. Jan-Henk Dambrink, the first database for the registry you created in Cinere
initiated research, conducted in Cinere cardiovascular clinic. Your teaching of
statistics for predictors of outcome is one of the most important basic learning. Thank
you very much for this ―pearl‖.
Dr. Arnoud van‘t Hof, you have encouraged me to conduct studies in Cinere. One of
your studies, the On-time study, triggered the study in Cinere, which you helped to
initiate. I will never forget your advice in Manado, to finish my PhD program.
To Dr. Winahyo, thank you for trusting in me since the first time I entered the Cinere
hospital and I will never forget the first interview. Your support and encouragement
have brought me this far. Your vision for Cinere cardiovascular clinic is beyond the
expectation of most people. Thank you for sharing your vision with me.
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To Dr. Parmono, as my senior cardiologist you have shown me not just to be a good
cardiologist but also how to be a humble person. I will always remember your
understanding and endless supports.
Dr. Anand Ramdat Misier and Dr.Arif Elvan, thank you for the discussion of the
electrophysiology aspects and your continuing support for our Cinere cardiac center.
You have widened my horizon of treating the heart also from the electrophysiologic
point of view. You both have always been supportive and good friends.
Dr. Ed de Kluiver, thank you for all your technical support for the Cinere clinic and
myself. You have taught me an important lesson when treating a heart. It is not
simply medical treatment, but equally importantly we need to have a good
organization of all the people involved.
To my paranymph Saman Rasoul, thank you very much for joining in writing the
meta-analysis and assisting, supporting and helping me on technical issues in
completing this dissertation.
I would like to express my gratitude to Prof. J.W. Jukema, Dr. P.V. Oemrawsingh,
Prof. E.E. van der Wall, Prof. M.J. Schalij and Dr. D.E. Atsma, I owe you my debt: I
would never have been in this position without my interventional cardiology training in
the University Medical Center Leiden (UMCL). You taught me interventional
cardiology from basics to complex procedures. Your understanding, patience, critical
remarks and wisdom has built me. Wouter, you always comforted me when the
situation was down and motivated me at the same time. I will not forget your way of
teaching. Pranobe, thank you very much for pushing me, and let me realize that I can
reach my upper limit.
To my colleagues in Cinere cardiovascular clinic, Dr. Jeffrey, Dr. Dini, Dr. Wiwik, Dr.
Hoyi, Dr. Faris, Dr. Bona, Sita and Dr. Yudi I convey my humble gratitude. You have
helped me all these years, working together shoulder- to shoulder as a great team in
treating all the patients in Cinere. You are like brothers and sisters whom I respect
working together with. Thank you guys.
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To my fellow colleagues at Leiden, Hazem, Navin and Gabija, thank you for all your
help during the interventional training. The time we shared together was a
memorable one
Dr. Utojo thank you for your glowing recommendation, which allowed me to start
interventional cardiology training immediately after my cardiology training.
To nurse consultant: Helmich, Petra and Peter: Bedankt. Thank you for your help and
cooperation all these years to organize the cardiology department in Cinere.
To the Cath lab staff: Yono, Beti, Herma, Nurul, Rini, Trisda, Neva, Gina and
Sharma. I appreciate your help in filling the registry and helping the papers for the
research, you are always there when my hands are full, thank you.
Cinere Nursing department and staff, thank you for your cooperation to all of you.
I would also like to express my gratitude to the Department of Cardiology University
of Indonesia and Harapan Kita hospital, Indonesian Heart Association, and the
faculty of Medicine YARSI
To My Family:
To my brothers and sisters: Brantas, Hikmahanto, Nani, Nana, Iin and their spouses,
thank you for all support, in particular at times of difficulties. You are always there
when I needed you. All your advises and motivations have a very big impact on me. I
am very proud to have you as brothers and sisters.
To my beloved wife, Denny, I could not have been this far without your support. You
have sacrificed a lot of things to back up my career although you yourself have also
had your own. You always understand my situations and always try to find ways for
solutions. Your patience for me is enormous with your love and kindness so I can
become a better person.
193
To my wonderful daughter, Safira and my amazing son, Adam. Thank you for your
understanding and your love to daddy. My apology to both of you for not always
being there when you needed me. Your understanding of daddy‘s schedules of
working and studying is highly appreciated. You are great children; you have become
the source of motivation for daddy to be a better person. Papa sayang kalian.
Finally, I would like to express my sincere gratitude to my beloved parents. To my
mother Aisah who raised her 6 children with care, love and endless pray for success
in life and career. The encouragement you have given over the years and years to
come has become gift to us, your children.
To my father Juwana, thank you for your guidance, support and endless pray, day
and night over the years and I believe in the years to come. You have supported my
decision to become a medical doctor on an early age, even though there were many
obstacles. You believe that education is the best investment for the children. You
have supported and guided all the children to obtain quality education and have
made what we become today. The discipline, commitment and professionalism to
work and caring of the family that you have exemplified and showed are my biggest
motivation to conquer challenges and achieve success.
I cannot thank my parents enough with thousands words or luxury goods as I know
that is not what they need. But to show my profound gratitude of having parents like
them let me give today‘s procession as a tribute to my parents and I can only pray
that the Lord almighty will return their good deeds. I am blessed by the Lord to have
you both as my parents.
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Chapter 15
Curriculum vitae
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Personality
Name : Yahya Berkahanto Juwana
Born, place/date : Blora, 16 Februari 1969
Religion : Islam
Status : Maried
Wife : Syukrini Bahri Padang, 10 April 1966.
Childeren : Safira, Jakarta, !7 Agustus 1995
: Adam, Jakarta, 13 Januari 1998
Father : Juwana, Blora 10 September 1936
Mother : Siti Aisa , Malang 9 October 1938
Working place
Klinik Kardiovaskular, Hospital Cinere, Jakarta, Indonesia
Qualifications :
Graduated as General Practitioner, Medicine Faculty, University of YARSI, Jakarta,
Indonesia.
Post Graduate study in Cardiology at Medicine Faculty, University of Indonesia/
National Cardiovascular Center "Harapan Kita", Jakarta, Indonesia.
2004 - 2005 Interventional Cardiology Training, Leiden University Medical Centre,
Leiden, Netherlands
Experiences :
1995 -1998 Head of the Public Health Community (Puskesmas) Kesumadadi,
Lampung, Sumatera.
1998 Medical Doctor in Department of Emergency, Persahabatan Hospital, Jakarta.
2003 - Cardiologist, at Klinik Kardiovaskular RS. Hospital Cinere, Jakarta, Indonesia,
head of Cath lab
