Heartbeat – Apr 2002 Triumph of the trials Triumph of the trials: ACC 2002 Valentin Fuster MD...
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Transcript of Heartbeat – Apr 2002 Triumph of the trials Triumph of the trials: ACC 2002 Valentin Fuster MD...
Heartbeat – Apr 2002
Triumph of the trials
Triumph of the trials: ACC 2002
Valentin Fuster MDDirector, Cardiovascular InstituteMount Sinai Medical CenterNew York, New York
Christopher Cannon MDCardiologistBrigham and Women's HospitalBoston, Massachusetts
James Ferguson MDAssociate Director, CardiologySt Luke's Episcopal Hospital and Texas Heart InstituteHouston, Texas
Michael Weber MDProfessor of MedicineSUNY Downstate College of MedicineBrooklyn, New York
Heartbeat – Apr 2002
Triumph of the trials
MADIT IIICDs for post-MI patients
with low EF
Atrial fibrillationRate vs rhythm
Coated stentsThe end of restenosis?
Subjects
Heartbeat – Apr 2002
Triumph of the trials
MADIT II
Multicenter Automatic Defibrillator Implantation Trial II
1232 post-MI patients with moderate LV dysfunction (EF 30%) randomized to ICD or conventional medical therapy
Arrhythmia was not an inclusion criteria, did not require previous EP testing
Heartbeat – Apr 2002
Triumph of the trials
Moss et al. N Engl J Med 2002;346(12):877-83.
MADIT II: All-cause mortality
0%
5%
10%
15%
20%
25%
ICD Medical therapy
14.2%
19.8%P=0.016
Heartbeat – Apr 2002
Triumph of the trials
HospitalizationsICD group had more
hospitalizations
Drug treatmentThe patients received the
proper drug regimen
CostDo we put ICDs in everyone?
MADIT II: Additional discussion
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Diverging curves
5-46283 years
Time
4-46282 years
-47-20121 year
Nominal 95% CI
Percent reduction in rate of death on
ICD therapy
Moss et al. N Engl J Med 2002;346(12):877-83.
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Increased hospitalizations
Patient group
11.3148 (19.9%)Defibrillator group
9.473 (14.9%)Conventional therapy group
# patients hospitalized/1000
hours follow-up# patients
hospitalized
Moss et al. N Engl J Med 2002;346(12):877-83.
Nominal p=0.09
"If you save lives in sick people, they are going to require more hospital resources."
Ferguson
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Medications
64%67%Statins
Medication at last contact
70%70%Beta-blockers
72%68%ACE-inhibitors
Medical therapy (n=490)
ICD (n=742)
81%72%Diuretics
Moss et al. N Engl J Med 2002;346(12):877-83.
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Performance
We don't yet have details on how often the ICDs actually fired in the patients.
VENTAK PRIZM 2 ICDSource: Guidant
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Mortality by event
46 (9.4%)27 (3.6%)Arrhythmic
Cause of death
6774Cardiac
2026Noncardiac
Medical therapy (n=490)
ICD (n=742)
1841Nonarrhythmic
Moss et al. N Engl J Med 2002;346(12):877-83.
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Fuster's hypothesis
"I bet that what is happening is the group that otherwise might have been induced into ventricular tachycardia is the group that has benefit."
Fuster
VENTAK PRIZM 2 ICDSource: Guidant
Heartbeat – Apr 2002
Triumph of the trials
• EF < 40% • CAD • spontaneous nonsustained ventricular tachycardia (VT-NS)
MADIT-II: MUSTT
Mortality at 5 years
ICDs (n=161)
Drug therapy (n=153)
P value
Total mortality 24% 55% <0.001
Buxton et al. N Engl J Med 1999;341(25):1882-90.
Entry Criteria
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: The patient
Patient with low EF, previous MI, and the patient asked for a defibrillator ICDs cost $25-35,000
Found a normal result on signal-averaging, so I sent him home
FusterVENTAK PRIZM 2 ICDSource: Guidant
Heartbeat – Apr 2002
Triumph of the trials
"The idea of risk stratification to try and identify those who benefit most has become absolute dogma in clinical practice in acute coronary syndromes."
Cannon
MADIT II: Risk stratification
•Inducibility makes sense as a good marker of the risk of arrhythmic death
•How recent is the MI?
•Arrhythmic burden might be useful
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: True costs
• We will eventually have to have risk stratification
• What is cost/quality of year of life saved?
• We need data extending out for 2-3 years
Weber
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Science takes its course
Weber
"The truth is that whenever we do anything that prolongs life we are going to be rewarded by horrifying increases in cost. And if we save them completely from heart disease they are going to get cancer."
"In a way it's a futile and frustrating discussion."
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Extending the boundaries
What we're doing is defining the boundaries of where ICDs work and don't work
"What MADIT II has done is take the stake and move it a little farther out in terms of post-MI patients with low ejection fraction."
Ferguson
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Drilling into the data
We will find a population that benefits and a population that does not
Inducible VT is a completely reasonable hypothesis for defining the benefit population
Putting ICDs in everyone who qualifies for MADIT is "potentially backbreaking"
Ferguson
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Signal-averaging
Used signal-averaging because it was a strong predictor of high-risk in MUSTT
At this point in time, don't put an ICD in patients who qualify for MADIT II who have normal signal-averaging
"We have to face these patients today."
Fuster
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: QRS interval
QRS interval Hazard ratio
Moss et al. N Engl J Med 2002;346(12):877-83.
0.2 0.4 0.6 0.8 1.0 1.2
< 0.12 sec
0.12-0.15 sec
>0.15 sec
Defibrillator better
Conventional therapy better
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Assessing patients
Weber
We don't have enough information to predict who will benefit most
"Seat of the pants indicators" such as QRS intervals or the number of extra systoles should be helpful for now
VENTAK PRIZM 2 ICDSource: Guidant
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Fundamental approach
"The fundamental approach that one takes with these patients is 'are they guilty until proven innocent' or are they 'innocent until proven guilty'?"
"Am I going to put a defibrillator in this guy unless there is a reason not to or do I require a reason to put a defibrillator in this individual?"
Ferguson
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Reasons to put an ICD in
"I still need a reason to put a defibrillator in an individual."
• Signal-averaged ECG
• Frequency of VPDs
• Heart-rate variability is a possibility
• Probably would not take someone to provocative EP testing
Ferguson
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Cost
MADIT II entry criteria would lead to an additional 300,000 patients for ICDs, a $9 billion market
ICDs cost $25-35,000
"When you have something good, industry competes and costs go down."
Fuster
VENTAK PRIZM 2 ICDSource: Guidant
Heartbeat – Apr 2002
Triumph of the trials
As demand grows, costs should drop
These ICDs are the "BMW 7-series" versions, with all the hi-tech bells and whistles
Cheaper, simpler ICDs could be used in patients with uncomplicated arrhythmic history
Cannon
MADIT II: Cheaper ICDs
Heartbeat – Apr 2002
Triumph of the trials
MADIT II: Lay press concerns
Extending Life, Defibrillators Can Prolong Death
Could we unintentionally torture patients with ICDs?
Rare, but not impossible
Heartbeat – Apr 2002
Triumph of the trials
Atrial fibrillation : Quality of Life
While making guidelines, everyone said that AFFIRM and RACE would give all the answers
"I was disappointed"
The issue is quality of life, not mortality, but that wasn't studied
Heartbeat – Apr 2002
Triumph of the trials
Atrial fibrillation : AFFIRM design
Atrial Fibrillation Follow-up Investigation of Rhythm Management
Conducted at 213 centers in the US and Canada
Randomized 4060 patients to rate control therapy or to rhythm control therapy
All patients enrolled in the trial were able to tolerate either rate or rhythm control therapy at baseline
Heartbeat – Apr 2002
Triumph of the trials
Atrial Fibrillation: AFFIRM results
P value Endpoint
8479Stroke
356306Mortality
Rhythm Control
Rate control
0.058
NS
Wyse DG, ACC 2002
Heartbeat – Apr 2002
Triumph of the trials
Atrial Fibrillation: RACE design
RAte Control vs Electrical cardioversion for persistent atrial fibrillation (RACE)
522 patients randomized to medical rate control (n=256) or electrical cardioversion rhythm control (n=266)
3 years follow-up
Primary endpoints: morbidity and mortality
Secondary endpoints: quality of life and cost of therapy
Heartbeat – Apr 2002
Triumph of the trials
Atrial Fibrillation: RACE results
Endpoint
6.7%7.0%
22.6%17.2%Combined mortality and morbidity*
Rhythm Control (n=266)
Rate control (n=256)
*cardiovascular death, hospitalization for heart failure, thromboembolic complications, severe bleeding, pacemaker implantation, or severe drug side effects
Cardiovascular mortality
Heartbeat – Apr 2002
Triumph of the trials
Atrial fibrillation : No answers
My original question wasn't answered
Patients with systolic or diastolic dysfunction who don't have atrial kick weren't included in the study
Fuster
Heartbeat – Apr 2002
Triumph of the trials
Atrial fibrillation : Disappointing
"I'm not an electrophysiologist, so I've been waiting for guidelines to tell me what to do for some time."
"It's a little disappointing that […] those people who might have benefited probably didn't even get into the study."
Weber
Heartbeat – Apr 2002
Triumph of the trials
Atrial fibrillation : AFFIRM drugs
Rhythm control
• amiodarone (39%)
• sotalol (33%)
• propafenone (10%)
Ablation and pacemakers were given in the rhythm arm, if necessary
Heartbeat – Apr 2002
Triumph of the trials
Atrial fibrillation : AFFIRM drugs
Rate control
• digoxin (51%)
• beta-blockers (49%)
• calcium-channel blockers (41%)
There was no specific drug regimen
Heartbeat – Apr 2002
Triumph of the trials
Atrial fibrillation : Drug safety
"At least the drugs that maintained normal sinus rhythm didn't kill the patients."
Maybe amiodarone is protective
Fuster
It could be that the fact these were patients with atrial fibrillation played a role
Ferguson
Heartbeat – Apr 2002
Triumph of the trials
Atrial Fibrillation: Low mortality
Patients who need atrial kick are the toughest atrial fibrillation patients to work with
The good news is mortality favored rate control slightly – this looks pretty safe
Cannon
Heartbeat – Apr 2002
Triumph of the trials
"I came away with the notion that A-Fib and coumadin are very good partners."
Most strokes in AFFIRM occurred in patients who either stopped warfarin or had an INR below 2.0
The idea you should convert A-Fib patients so they can get off anti-coagulation doesn't hold up
Atrial Fibrillation: Warfarin
Cannon
Heartbeat – Apr 2002
Triumph of the trials
"The concept that you convert to normal sinus rhythm and therefore off of anticoagulants is really a dream."
I do Holter monitoring 3 months later because most patients you can see there are still a few beats of atrial fibrillation
Atrial fibrillation : Anticoagulation
Fuster
Heartbeat – Apr 2002
Triumph of the trials
Atrial fibrillation developing after cardiac surgery often reverses itself
You should still follow up patients with a Holter to document that the patient has stable sinus rhythm
Atrial Fibrillation: Anticoagulation
Cannon
Heartbeat – Apr 2002
Triumph of the trials
The guidelines urge great caution about discontinuing anticoagulants
You should continue anticoagulation unless something convinces you otherwiseACC/AHA/ESC GUIDELINES FOR THE MANAGEMENT OF
PATIENTS WITH ATRIAL FIBRILLATIONJ Am Coll Cardiol 2001;38:1266i-1xx
Atrial Fibrillation: Guidelines
Fuster
Heartbeat – Apr 2002
Triumph of the trials
"The big winner in this seemed to be coumadin. Because if you want to use rhythm control because you think you are reducing the need for anticoagulation you're probably making a mistake."
Atrial fibrillation: Anticoagulation
Ferguson
Heartbeat – Apr 2002
Triumph of the trials
Coated stents: FIM
Measurement at 24 months
Fast release formula
Slow release formula
Late loss 0.32 mm -0.09 mm
Restenosis rate 0% 0%
Heartbeat – Apr 2002
Triumph of the trials
Coated stents: RAVEL
Measurement at 12 months
Sirolimus (n=??)
Control (n=??)
Event-free survival
94.2% 71.2%
Late loss -0.01 + 0.33 0.80 + 0.53
Restenosis rate 0% 26%
Heartbeat – Apr 2002
Triumph of the trials
"[Ending restenosis] is an idea people have been looking for, and stopping cell growth locally looks like a real winner."
Coated stents: Stopping cell growth
Cannon
Heartbeat – Apr 2002
Triumph of the trials
"It's probably a victory for vascular biologists everywhere to say the shotgun approach or crude approaches we've used in the past have not worked."
Not all coated stents will work, we need to look long at hard at the data
We need to look at the SIRIUS trial
Coated stents: Stopping cell growth
Ferguson
Heartbeat – Apr 2002
Triumph of the trials
Brazil data makes you believe the subsequent pathology is determined at the time of procedure
"I assume most of the value of the coated stent is a local effect that takes place soon after the stent is put in."
Coated stents: Early pathology
Weber
Heartbeat – Apr 2002
Triumph of the trials
Coated stents: New study
>2000 pts
Diabetics with multi-vessel disease lesions (15-30 mm long, 2.5-3.5 mm diameter)
Randomized to sirolimus stent or CABG
This study has been submitted to NIH and is under consideration
Heartbeat – Apr 2002
Triumph of the trials
Finding clinical effect on high-risk patients is the most important study to do
• BARI used balloon angioplasty without antiplatelet therapy
• Can diabetics with multi-vessel disease be stented or must they use surgery?
• It even raises questions about stenting patients with stable angina
Coated stents: End of CABG?
Cannon
Heartbeat – Apr 2002
Triumph of the trials
Coated stents: 6-month QCA in diabetics
Measurement Sirolimus (n=19)
Control (n=25) P value
Mean luminal diameter
2.31 mm 1.56 mm <0.0001
Late loss 0.08 0.82 <0.0001
Diameter stenosis
16% 38% <0.0001
Restenosis rate 0% 42% <0.0001
Heartbeat – Apr 2002
Triumph of the trials
Coated stents: Patient
What do you do with this patient?
• Had 3 previous PCIs in the circumflex artery
• Currently has a 1.5-cm lesion in the circumflex artery
Do you send him to Europe to get the sirolimus-coated stent or do you use radiation?
Heartbeat – Apr 2002
Triumph of the trials
I would go with beta-radiation therapy
• Reduces in-stent restenosis by about 50%
• Coated stents have not shown favorable results for in-stent restenosis
Coated stents: Radiation advantage
Cannon
Heartbeat – Apr 2002
Triumph of the trials
Some issues still need to be answered with radiation therapy
"What are you doing to the biology of the vessels and do you change how they are going to respond in the future if in fact you don't prevent restenosis?"
Coated stents: Radiation questions
Ferguson
Heartbeat – Apr 2002
Triumph of the trials
MADIT IIICDs for post-MI patients
with low EF
Atrial fibrillationQuantity and quality of life
Coated stentsThe end of restenosis?
Conclusions: Subjects
Heartbeat – Apr 2002
Triumph of the trials
Coated stentsMarrying mechanical approachand an understanding biology
Atrial fibrillationRhythm control doesn't mean you stop anticoagulation
ICDsPoint out our need to apply techniques of risk stratification
Conclusions: Ferguson
Ferguson
Heartbeat – Apr 2002
Triumph of the trials
Conclusions: Weber
Weber
Coated stentsIt won't be long before thecoated stent is the only way to go
Atrial fibrillationOne word: coumadin
ICDsWe still need to learn moreabout which patients are the best subjects
Heartbeat – Apr 2002
Triumph of the trials
Conclusions: Cannon
Cannon
A triumph for trials guiding appropriate therapy
Ventricular tachycardia: Devices
Coronary stenosis: Devices and medicine married together
Atrial fibrillation: Medicine is the right answer
Heartbeat – Apr 2002
Triumph of the trials
It's an exciting time, but how much could we accomplish if we could move forward even more in primary prevention?
Conclusions: Fuster
Fuster