Rationale For Raas Blockade
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RationaleRationale for RA for RAAAS blockade S blockade in in
secondary stroke preventionsecondary stroke prevention
RationaleRationale for RA for RAAAS blockade S blockade in in
secondary stroke preventionsecondary stroke prevention
PPrevention revention RRegimen egimen FFor or EEffectively avoiding ffectively avoiding SSecond econd SStrokestrokes
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American Stroke Association,’06 I-A-tp dopo la fase iperacuta
I-A-efficacia diuretici ±ACE- I
II-B-tp sia ipertesi che normotesi
II-B-target tp individualizzato
(almeno riduzione 10/5 mmHg)
II-C-tener conto comorbidità
SPREAD ‘05
B – trattamento ipertesi
in fase post acuta
B – efficacia ACE- I,
Diuretici,
Ca-antagonisti
Linee guida disponibili sul trattamento antipertensivo nella prevenzione secondaria dell’ictus
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Revisione sistematica di 7 RCT in soggetti con precedente ictus: 15527 soggetti (Rashid et al, 2003)
Studio LIFE, ’02 losartan + idroclortiazide vs atenololo+ idroclortiazide, sottogruppo 728 soggetti (segmento prev. secondaria)
Studio MOSES, ‘05 eprosartan vs nitrendipina, 1405 soggetti
►Carter, ’70 Thiazide diureticmg_methyldopa(750 mg); control 99 pts
►HSCGS, ‘74 Deserpidine 1 mg and methylclothiazide 10 mg; placebo
452 pts
►Dutch TIA, ‘93 Atenolol (50 g);placebo 1473 pts
►TEST, ‘95 Atenolol ? mg; placebo 720 pts
►PATS,’95 Indapamide (2.5 mg); placebo 5665 pts Due terzi
dei dati
riconducibili
ai trial PAT e PROGRESS
►PROGRESS, 01
Perindopril 4 mg;placebo
Perindopril 4 mg _ indapamide 2.5mg; double-placebo
2561 pts
3544 pts
►HOPE, ‘00
►segmento prev. secondaria
Ramipril; placebo 1013 pts
Fonti di informazione nella stesura delle linee guida nella prevenzione secondaria dell’ictus attraverso l’uso di antipertensivi
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Content
►Stroke: the scope of the problem
– Incidence
– Consequences
– Risk factors
► study: therapeutic rationale
– Angiotensin receptor blockade
– Antiplatelet therapy
►The study
– Study design
– Treatment arms
– Patients and outcomes
►Conclusions
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Risk factors for stroke
0 1 2 3 4 5 6 7 8 9 10
Hyperlipidaemia 27%
Smoking 27%
Obesity 18%
Inactivity 27%
Carotid stenosis 4%
Hypertension 35%
Relative risk
Percentages indicate
prevalence
2%Atrial fibrillation
Alberts. Curr Med Res Opin 2003;19:438–441
Risk vs prevalence
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High blood pressure increasesthe risk of stroke
70 80 90 100 110
4.0
2.0
1.0
0.5
0.25
Usual DBP (mmHg)
Rela
tive r
isk
of
stro
ke
Law et al. Health Technol Assess 2003;7:1–106DBP=diastolic blood pressure
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Effect of reducing blood pressure on risk of stroke
► Relative reduction in risk from a 5 mmHg decrease in DBP
-60
-50
-40
-30
-20
-10
0
Ris
k re
duct
ion (
%)
No history ofCVD
Previous stroke
Law et al. Health Technol Assess 2003;7:1–106.
No history of CVD
Previous stroke
High blood pressureAverage blood pressure
CVD=cardiovascular disease
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Content
►Stroke: the scope of the problem
– Incidence
– Consequences
– Risk factors
► study: therapeutic rationale
– Angiotensin receptor blockade
– Antiplatelet therapy
►The study
– Study design
– Treatment arms
– Patients and outcomes
►Conclusions
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Potential benefits of angiotensin receptor blockers
Neuronal/Glial Sensitivity to ischaemia
Stroke volumeInflammation
Regenerative mechanisms
Vascular/Haemodynamic Endothelial factors
AtherosclerosisThrombosis
Brain perfusion
CardiacAtrial fibrillation
Stroke:risk andoutcome
Modified after Unger Th. 2003
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Angiotensin blockade in stroke risk reduction
► Angiotensin receptor blockers (ARBs) reduce blood pressure by interrupting the renin–angiotensin–aldosterone system (RAAS)
► Angiotensin AT1 receptor blockade may also provide stroke protection beyond blood pressure lowering
– Clinical and non-clinical studies show that ARBs reduce factors associated with increased risk of stroke
Fournier et al. J Am Coll Cardiol 2004;43:1343–1347.
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Angiotensin II
Angiotensin II
Death
Glomerular filtration rateProteinuria/albuminuriaGlomerulosclerosis
Aldosterone release
Renal failure
LVHFibrosisRemodellingApoptosis
VasoconstrictionVascular hypertrophyEndothelial dysfunctionAtherosclerosis
Stroke
HypertensionThrombosis
ArrhythmiaHeart failureMI
AT1
receptor
Vascularremodelling
Direct and indirect effects in target-organ damage
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Renin–angiotensin system in the brain
AT1-receptor mediated
► Blood pressure control
► Vasopressin secretion
► Sympathetic modulation
► ACTH secretion
► Thirst
► Oxidative stress
► Endothelial dysfunction
► Pathological remodelling
AT2-receptor mediated
► Neuroplasticity?
► Regeneration?
► Apoptosis?
AT1/AT2 receptors
► Protection against stroke?
► Protection against post-stroke events?
Modified after Unger Th. 2003.
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0
10
20
30
40
50
Non-fatal stroke All stroke All stroke
Reduct
ion in r
ela
tive
risk
of
stro
ke
ARBs reduce risk of first stroke
► 4,964 hypertensives for mean 3.7 years
► Blood pressure reduction (SBP/DBP mmHg) was 21.7/10.8 and 18.5/9.2 in the Candesartan and placebo arms, respectively
All patients Patients with ISH
Lithell et al. J Hypertens 2003;21:875–886.Papademetriou et al. Presented at the American Heart Association Annual Meeting, 10 November 2003.
p = 0.04p = ns
p = 0.05
SCOPE study: Candesartan vs placebo
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ARBs reduce risk of first stroke
► 9,193 hypertensives for mean 4.8 years
► Blood pressure reduction (SBP/DBP mmHg) was 30/17 and 29/17 in the Losartan and Atenolol arms, respectively
Favoursatenolol
Favourslosartan
Primarycompositeendpoint
Cardiovascularmortality
Stroke Myocardialinfarction
Dahlöf et al. Lancet 2002;359:995–1003
LIFE study: Losartan vs AtenololA
dju
sted h
aza
rd r
ati
o
(95
% C
I)
0.6
0.8
1.0
1.2
1.4
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Preventing second stroke
► Meta-analysis of 7 randomized clinical trials
► Much of the inter-class differences are due to blood pressure reduction
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
Odds
rati
o
-agonists ACE inhibitors
Rashid et al. Stroke 2003;34:2741–2749.
Diuretics Diuretics +ACE inhibitors
Effect of different antihypertensive classes
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Preventing second stroke
0
5
10
15
20
25
30
35
40
45
50 Non-hypertensives
Hypertensives
Reduct
ion in r
ela
tive
risk
of
recu
rrent
stro
ke (
%)
Blood pressure reduction (SBP/DBP, mmHg) 5/3 12/5
Perindopril 4 mg alone
(n = 1,281)
Perindopril 4 mg + Indapamide 2.5 mg
(n = 1,770)
PROGRESS Collaborative Group. Lancet 2001;358:1033–1041.
p = ns
p = ns
p < 0.05p < 0.05
PROGRESS: Perindopril +/- Indapamide
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Preventing second stroke
0
2
4
6
8
10
12
14
16
18
Cerebrovacular Cardiovascular Total
Eve
nt
rate
per
10
0 p
atie
nt-
year
s
NitrendipineEprosartan
Schrader. Presented at XXVI ESC, 30 August 2004, Munich, Germany
*
*
* P<0.05 vs Nitrendipine† Includes recurrent events
MOSES: Candesartan vs Nitrendipine
† † †
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ARBs – safety post-stroke
► 342 patients with ischaemic stroke and high blood pressure
► Candesartan cilexetil 4 mg/day or placebo for 7 days post-stroke
► Followed by Candesartan cilexetil and other antihypertensive treatment as required for 1 year
► Trial stopped early due to an imbalance in endpoints
► Cumulative 12-month mortality and number of vascular events significantly favoured candesartan (OR 0.48, 95% CI 0.25–0.90)
Schrader et al. Stroke 2003;34:1699–1703.
ACCESS study
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Antiplatelets in reducing the risk of stroke
► Antiplatelet agents reduce the risk of thrombosis, a major cause of stroke
► Three antiplatelet agents are commonly used
– Acetylsalicylic acid (ASA, Aspirin)
– Extended-release dipyridamole (ER-DP), usually combined with ASA
– Clopidogrel
► Each has a different mechanism of action
O’Rourke et al. JAMC 2004;170:1123–1133
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ER-DP*: Mode of action beyond platelet inhibition
Platelet inhibition/thrombinreceptor reduction
Eisert. in Platelets (Academic Press) 2002:803–815; Aktas. Stroke 2003;34:764–769.Eisert. Am J Therapeutics. 2001;8:443–449; Biaggioni J Investig Med. 2003;51:S370.
Malinin. HeartDrug 2002;2:93–104; Weyrich et al. Abstract P134. ESC 2003.
►Additive to NO increase ►Anti-inflammatory►Antioxidant►Cell membrane protection
►Antiproliferative►Tissue conditioning
Additional effects atthe vessel wall:
Antithromboticproperties
* Extended-release dipyridamole
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Summary: current therapeutic evidence
► Hypertension is a major risk factor for stroke
► The risk of stroke is highest in the early morning, at a time when blood pressure surges
► Antihypertensive therapy reduces the risk of first and second stroke
► ARBs likely to have beneficial effects beyond reducing blood pressure (based on MOSES)
► Antiplatelet agents reduce the risk of stroke
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Unanswered clinical questions
► Do ARBs reduce the risk of second stroke?
– Are ARBs effective in patients with normal blood pressure?
► Should hypertension be treated in the acute phase of stroke?
– Which antihypertensive should be used to treat hypertension after stroke?
► Are ARBs cerebroprotective?
► Which is superior in second stroke: ER-DP + ASA* or Clopidogrel?
Muir. BMJ 2004;328:–297–298.Albers, Amarenco. Stroke 2001;32:2948–2949.* Extended-release dipyridamole + aspirin
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Content
►Stroke: the scope of the problem
– Incidence
– Consequences
– Risk factors
► study: therapeutic rationale
– Angiotensin receptor blockade
– Antiplatelet therapy
►The study
– Study design
– Treatment arms
– Patients and outcomes
►Conclusions
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The study
► Two primary analyses:
– Telmisartan added to standard antiplatelet therapy versus standard antiplatelet therapy alone
– ER-DP + ASA* compared with Clopidogrel
► Diuretic, -blocker and/or calcium channel blocker as needed to control blood pressure
► Treatment period up to 4 years
► The world’s largest secondary stroke prevention trial
– 15,500 patients at around 600 centres in 32 countries
* Extended-release dipyridamole + aspirin
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Study design – 2 x 2 factorial
Clopidogrel (75 mg) qd
Extended-release dipyridamole (200 mg)
+ ASA (25 mg) bid
Telmisartan (80 mg) qd Placebo qd
n = 7,750n = 7,750TOTAL
n = 15,500
Telmisartan+
ER-DP + ASA
n = 3,875
Telmisartan+
ER-DP + ASA
n = 3,875
Placebo+
ER-DP + ASA
n = 3,875
Placebo+
ER-DP + ASA
n = 3,875
Telmisartan+
Clopidogrel
n = 3,875
Telmisartan+
Clopidogrel
n = 3,875
Placebo+
Clopidogrel
n = 3,875
Placebo+
Clopidogrel
n = 3,875
ER-DP = Extended-release dipyridamole
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Telmisartan summary
► An effective antihypertensive
► With once-daily morning dosing, provides efficacy even in the risky, early morning hours due to long duration of action
► Provides long-acting, insurmountable blockade of AT1 receptor
– Associated with target-organ protection
► Crosses the blood–brain barrier
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ER-DP + ASA*
► 6,602 patients with transient ischaemic attack or stroke within preceding 3 months
► Treated for 2 years with either:
– Placebo
– ASA (50 mg daily) alone
– ER-DP (400 mg daily) alone
– Combination ER-DP + ASA
► 2 x 2 factorial design
► Primary endpoints: stroke, death and stroke/death composite
Diener et al. J Neurological Sci 1996;143:1–13.
European Stroke Prevention Study 2 (ESPS-2)
* Extended-release dipyridamole + aspirin
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ER-DP + ASA*
► ER-DP+ASA is twice as effective for secondary stroke prevention as either ASA or ER-DP alone
Diener et al. J Neurological Sci 1996;143:1–13.
ER-DP + ASA vs Placebo 37.0% <0.001
ER-DP vs Placebo 16.3% 0.039
ASA vs Placebo 18.1% 0.013
ER-DP + ASA vs ASA 23.1% 0.006
European Stroke Prevention Study 2 (ESPS-2)
Pairwise comparisons Relative risk p valuereduction
* Extended-release dipyridamole + aspirin
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Antiplatelet summary
► Extended-release dipyridamole, Clopidogrel and ASA have complementary mechanisms of action
► The combination of ER-DP plus ASA is more effective than the components in preventing second stroke
► Adding ASA to Clopidogrel increases the risk of adverse events without increasing efficacy
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Content
►Stroke: the scope of the problem
– Incidence
– Consequences
– Risk factors
► study: therapeutic rationale
– Angiotensin receptor blockade
– Antiplatelet therapy
►The study
– Study design
– Treatment arms
– Patients and outcomes
►Conclusions
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Inclusion criteria
► Age ≥55 years AND ischaemic stroke within 90 days prior to study entry
OR
► Age >50 years AND ischaemic stroke within 120 days prior to study entry AND at least two of the following risk factors:
– Diabetes mellitus– Hypertension (SBP 140 or DBP 90 mmHg)– Smoker at time of qualifying stroke– Obesity (BMI >30)– Vascular damage (stroke, myocardial infarction, or peripheral artery
disease) prior to qualifying stroke– End-organ damage (retinopathy, left-ventricular hypertrophy or
microalbuminuria).
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Main exclusion criteria
► Haemorrhagic stroke
► Unstable angina
► Patients bedridden, with dementia or unable to give informed consent
► Carotid endarterectomy
► History of thrombocytopenia
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Primary and secondary outcomes
Primary outcome
► Time to recurrent stroke (target is 2,280 strokes)
Secondary outcomes
► Vascular events
– composite of time to first stroke, myocardial infarction or vascular death
► Vascular events or congestive heart failure
► New-onset diabetes
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Tertiary outcomes
► Stroke or major haemorrhagic event
► Major haemorrhagic events
► Minor haemorrhagic events
► Other designated vascular events
► Death
► New or worsening congestive heart failure
► Thrombotic thrombocytopenic purpura
► Neutropenia
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Patient follow-up
► Baseline visit and on discharge from hospital or Day 7 (whichever soonest)
► Visits at Month 1, Month 3 and Month 6
► Visits every 6 months thereafter
► Telephone contact every 3 months
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Content
►Stroke: the scope of the problem
– Incidence
– Consequences
– Risk factors
► study: therapeutic rationale
– Angiotensin receptor blockade
– Antiplatelet therapy
►The study
– Study design
– Treatment arms
– Patients and outcomes
►Conclusions
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Global trial
Europe17 countries
Africa and Middle East2 countries
Asia8 countries
South America1 country
North America3 countries
Australia
32 countries, 600 study centres
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Academicrepresentatives
Sponsorrepresentatives
(non-voting)
Sponsor
DSMB
Adjudication &AssessmentCommitteeEurope
CML/NCEuropeCML/NC
North Am.CML/NC
North Am.CML/NC
South Am.CML/NC
South Am.CML/NC
AfricaCML/NCAfricaCML/NC
AsiaCML/NCAsia
CML/NC
Steering Committee
Trial Management Committee
Publications Committee
DSMB = Data and Safety Monitoring Board; CML = Local Clinical Monitor for country; NC = National Co-ordinator for country
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Site 1Site 2Site 3Site 4
etc
Study organization
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Telmisartan
Beyondblood pressure
2003–2006 2007 and beyond
Protection inProtection inthe early the early
morning/24-hour morning/24-hour efficacyefficacy
Life saving
Efficacy vs Efficacy vs ACE inhibitorsACE inhibitors
and other ARBsand other ARBs
Heart Heart protection/protection/
LVH reductionLVH reduction
Renoprotection Renoprotection in diabeticsin diabetics
Antihypertensive Antihypertensive efficacy in efficacy in
special patient special patient populationspopulations
Phase III and IV programme rationale
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Major Phase IV trials of Telmisartan
In high-risk individuals
Blood pressure
Stroke endpoint
15,500 patients for up to 4 years
History of stroke
Normo- and hypertensives
Stroke is the primary endpoint
31,546 patients for up to 5.5 years
History of stroke or recent ischaemic attack, coronary artery disease, peripheral vascular disease, diabetes mellitus with target-organ damage
Normo- and hypertensives
Stroke is part of the primary combined endpoint
Outcome trials of Telmisartan
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Enrollment by country
Country N Country N Country N
Argentina 534 Hong Kong 250 South Africa 79
Australia 276 India 1620 South Korea 626
Austria 277 Ireland 30 Spain 130
Belgium 418 Israel 449 Sweden 503
Brazil 300 Italy 419 Taiwan 926
Canada 1549 Japan 210 Thailand 219
China 2130 Malaysia 112 The Netherlands 485
Denmark 231 Mexico 222 Turkey 62
Finland 216 Norway 152 UK 502
France 125 Portugal 280 Ukraine 560
Germany 1287 Russia 1353 USA 3408
Greece 30 Singapore 363
Total number of Countries or Regions = 35 (20 in ESA)
Total number of Randomized Patients = 20,333
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PRoFESS Enrollment - Italy
PRoFESS EnrollmentCountry = Italy
Goal N=660 in two yearsReduced goal N=400 by 31 March 2006
0
100
200
300
400
500
600
700
11/1
/200
3
12/1
/200
3
1/1/
2004
2/1/
2004
3/1/
2004
4/1/
2004
5/1/
2004
6/1/
2004
7/1/
2004
8/1/
2004
9/1/
2004
10/1
/200
4
11/1
/200
4
12/1
/200
4
1/1/
2005
2/1/
2005
3/1/
2005
4/1/
2005
5/1/
2005
6/1/
2005
7/1/
2005
8/1/
2005
9/1/
2005
10/1
/200
5
11/1
/200
5
12/1
/200
5
1/1/
2006
2/1/
2006
3/1/
2006
4/1/
2006
5/1/
2006
6/1/
2006
Nu
mb
er o
f P
atie
nts
Italy
Italy Original Projection
Italy Adapted Projection
Italy Projection with Extended Enrollment
419 pts
Enrollment End = 31 May 2006
Goal 400
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Thank You!!
.. to all our investigators and study coordinators
060717
Our goal of 20,000 patients from 720 sites in 35 countries was achieved 2 days early.
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How does PRoFESS compare with similar antiplatelet trials?
Trial No. patients Mean follow-up
(months) Study drug
termination for any reason (%)
ESPS 2,500 24 30 ESPS-2 6,602 24 26 MATCH 7,599 18 CAPRIE 19,185 19 21 ESPRIT - DP+ASA -ASA
1363 1376
42 42
34 13
PRoFESS <20,000 11 15.9
8
20,333 16
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Strategies that PRoFESS sites use to successfully rechallenge patients:
95%
40%35% 35%
20%
80%
0%
20%
40%
60%
80%
100%
Frequentcommunication
Highlightbenefits of
participation
Prevention:(discuss side
effects/efficacy)
Titrate med’s Family support Establish trustrelationship
Per
cen
t
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Focus on rechallenging patients
Total n pt ever off drug
n (%)
successfully rechallenged
n (%)
Global 18,983 5,273
28%
1,642
31%
AAJ 5,904 1,899
32%
529
28%
ESA 7,186 2,093
29%
717
34%
Asia 5,893 1,281
22%
396
31%
31% of patients BACK ON MED’S
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Message: A patient can always rechallenge!
As long as it is medically acceptable
• Irrespective of how much time has passed
• Irrespective of the number of times that the patient has discontinued the study med
31% of patients have already successfully rechallenged!
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How does PRoFESS compare with similar antiplatelet trials?
Trial Mean follow-up (months)
LTFU %
ESPS 24 0.3 ESPS-2 24 0.6 MATCH 18 4.0 CAPRIE 19 0.2 ESPRIT 42 4.0 PRoFESS – missed 2 consecutive visits
11
4.0%
4.2
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N. Randomizzati in Italia
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Proportion of patients who have missed two consecutive visits, ESA Region
0%
5%
10%
15%
20%
Austri
a
Belgium
Denmar
k
Finlan
d
Franc
e
Germ
any
Greec
e
Irelan
d
Israel
Italy
Nether
lands
Norway
Portu
gal
Russia
S Afri
caSpa
in
Sweden
Turke
y
Ukrain
eUK
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Proportion of patients who have missed their last visit and two consecutive visits, ESA region
0%
5%
10%
15%
20%
Austri
a
Belgium
Denmar
k
Finlan
d
Franc
e
Germ
any
Greec
e
Irelan
d
Israel
Italy
Nether
lands
Norway
Portu
gal
Russia
S Afri
caSpa
in
Sweden
Turke
y
Ukrain
eUK
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Summary
► Compliance and Retention rates vary:
– Across regions
– Across countries within regions, and
– Across sites within countries
THEREFORE WE HAVE AN OPPORTUNITY!
► It is never too late to rechallenge study medication
► All sites will be asked to make contact with POTENTIALLY lost patients
► Compliance and Retention are important both to the patients, and to the PRoFESS Trial
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AREE GRIGIE
• Effetti specifici sui sottotipi patogenetici di ictus
• Selezione del target terapeutico in tutta la popolazione e nei soggetti anziani
• Epoca di inizio del trattamento
• Atteggiamento nella ostruzione carotidea
• Comorbilità cardiaca & renale
ed antipertensivi
ONTARGETARBs vs ACE-I vs combinazioneProtezione cardiovascolare in soggetti ad alto rischio
•Recidive di ictus•Anziani•Comorbilità
PROFESSTelmisartan nella prevenzione secondaria dell`ictus ischemico
•Sottotipi di ictus (TOAST)•Epoca di inizio del trattamento•Anziani •Comorbilità
Trattamento antipertensivo nella prevenzione secondaria