Heartbeat – Feb 2002 Aspirin, ICDs, and MRA Aspirin, ICDs, and MRA Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, New York Christopher Cannon MD Cardiologist Brigham and Women's Hospital Boston, Massachusetts James Ferguson MD Associate Director, Cardiology St Luke's Episcopal Hospital and Texas Heart Institute Houston, Texas Michael Weber MD Professor of Medicine SUNY Downstate College of Medicine Brooklyn, New York
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Heartbeat – Feb 2002 Aspirin, ICDs, and MRA Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, New York Christopher.
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Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Aspirin, ICDs, and MRA
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 – Feb 2002
Aspirin, ICDs, and MRA
AspirinNew questions about an old drug
MADIT-IIICDs for post-MI patients
with low EF
MRINon-invasive assessment of coronary arteries
Subjects
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
3 things we know about aspirin
It benefits patients with AMI and unstable angina
It is protective in the long-term for patients with prior MI or stroke
Optimal daily dose is 75 — 325 mg
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Baigent C et al. BMJ 2002; 324:71-86.
BMJ meta-analysis
Reprinted with permission from BMJ
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Aspirin for angina?
60.2-month follow-up of 333 patients with angina and no prior MI from Physicians Health Study
Swedish Angina Pectoris Aspirin Trial 2035 patients randomized to aspirin (75 mg daily) or placebo
Aspirin vs placebo
Risk reduction of MI or sudden death(95% CI)
34%(24% – 49%)
P-value 0.003
Juul-Moller S et al. Lancet 1992; 340:1421-5.
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Baigent C et al. BMJ 2002; 324:71-86.
BMJ meta-analysis
Reprinted with permission from BMJ
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Underlying diagnoses
The Oxford group has resisted stratifying patients by underlying diagnoses
•They prefer to talk about atherosclerotic or occlusive arterial disease
• In any circumstance, the use of aspirin is protective
•They get a little hostile if you start subdividing
Weber
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Acute stroke and PAD
Proportional reduction of vascular events
Acute stroke PAD
Percent reduction in vascular events
11 23
P-value 0.0001 0.004
Baigent C et al. BMJ 2002; 324:71-86.
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
A continuum of disease
"The argument that the whole group made […] was that we shouldn't think of vascular disease as regional, but peripheral arterial disease is part of the same continuum."
Weber
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Meta-analyses
You must focus on the event rates that you are trying to impact.
"That's why I think it's valuable to look at the data from these sort of meta-analyses, to tease out things we might not see in individual trials."
Ferguson
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
The Physicians study
EventAspirin vs placebo
Relative Risk 95% CI P-value
MI 0.56 0.45-0.70 <0.00001
Stroke 2.14 0.96-4.77 0.06
Total mortality
0.96 0.60-1.54 NS
Effect of aspirin on MI and stroke for 22,071 patients with 60.2 months average follow-up
N Engl J Med 1989; 321:129-35.
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Benefit of aspirin
Type of event
Baseline risk of coronary disease over 5 years
1% 3% 5%
Total mortality
No effect No effect No effect
Nonfatal AMI and fatal
CHD
1-4 avoided
4-12 avoided
6-20 avoided
Estimates of benefit of aspirin for patients with various levels of baseline risk for coronary heart disease
Hayden M et al. Ann Intern Med 2002; 136:161-72.
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Targeting
"You have to look at the mechanistic process that you're targeting, and what you are trying to prevent"
• In primary prevention population event rate is low, but the benefit of preventing disease progression may be profound
•Risk stratification must be thought about long and hard
Ferguson
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Weighing the risks of aspirin
Type of event
Baseline risk of coronary disease over 5 years
1% 3% 5%
Hemorrhagic strokes
0-2 caused
0-2 caused
0-2 caused
Nonfatal AMI and fatal
CHD
1-4 avoided
4-12 avoided
6-20 avoided
Estimates of benefit and harm of aspirin for patients with various levels of baseline risk for coronary heart disease
Hayden M et al. Ann Intern Med 2002; 136:161-72.
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Take home message
"[In primary prevention] we need to be a little bit more circumspect before we widely prescribe something that may be associated with some adverse side effects."
Ferguson
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Aspirin vs statins
•Statins: not just preventing acute events, but preventing progression of a remorseless underlying disease
•Aspirin: focused on a short-term prevention of acute events
Weber
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
3 strategies
3 processes in acute events as targets
• In preventive strategy, you aim to reduce likelihood of plaque rupture
• If rupture takes place, you try to enhance normal endothelial function
• If endothelium is overwhelmed, you focus on aggressive antiplatelet therapy
Ferguson
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Aspirin responsiveness
Aspirin is not effective in 10-20% of the population according to platelet aggregation studies.
"We have a large population that we are not really protecting."
Fuster
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
COX inhibitor history
•Cox 1 inhibitors block thromboxane release, but can also cause stomach problems
•Cox 2 inhibitors protect the stomach, but may block prostacyclin and therefore may be prothrombotic
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Cyclo-oxygenase inhibitors and MI
August 2001: MI significantly higher in patients taking either rofecoxib or celecoxib than in placebo patients
-Mukherjee D et al. JAMA 2001; 286:954-959
November 2001: Higher rate of CV events in rofecoxib patients likely the result of the antiplatelet effects of naproxen
-Konstam MA et al. Circulation 2001;104:2280-8
January 2002: no evidence that the NSAID, naproxen, is cardioprotective
-Ray WA et al. Lancet 2002;359:118-23
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Relative risk of APTC endpoint in patients taking rofecoxib in comparison to other anti-inflammatory
drugs
Comparator Relative risk 95% CI
Vs placebo 0.84 0.51, 1.38
Vs non-naproxen NSAIDs
0.79 0.40, 1.55
Vs naproxen 1.69 1.07, 2.69
Konstam MA et al. Circulation 2001; 104(19):2280-8.
Rofecoxib vs naproxen
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
“The lesson is that if you are going to put someone on a cox-2 inhibitor, for goodness sake if that patient deserves to be on low-dose aspirin, they must continue on that treatment.”
Weber
Cox 2 inhibitors and aspirin
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Q - “I’m going to take ibuprofen because I know it affects the platelets and maybe it's helping. I cannot take aspirin . . . what would you say?
-Fuster
A - “I would not recommend ibuprofen if they can’t tolerate aspirin, they’re going to get into trouble with that as well. Ibuprofen is not a solution for that problem.
-Weber
Ibuprofen vs aspirin
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Ibuprofen - transient levels of platelet inhibition, peaks and troughs throughout the day
Naproxen - much longer half-life, much higher steady level of platelet inhibition
Diclofenac - least potent, in terms of its cox-1 inhibition
Cannon
The “drug level thing”
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
“Certainly the lessons from the IIb/IIIa realm is that dose and level of effective platelet inhibition seem to be important to have clinical efficacy.”
Cannon
GP IIb/IIIa Lessons?
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
“I think it would be really alarmist and totally unwarranted to equate ibuprofen with the oral IIb/IIIa blockers. I think ibuprofen is a great anti-inflammatory drug, but it is not a sustained anti-platelet drug and it may potentially interfere with the anti-platelet effects of aspirin.”
Ferguson
Anti-inflammatory vs anti-platelet
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
•Need clinical data on clinical events in patients on aspirin with and without cox 2 inhibitors
•Cox 1 effects of aspirin are about 170x greater than their very weak cox 2 effects
Ferguson
Aspirin effects
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
MADIT-II
Multicenter Automatic Defibrillator Implantation Trial II
1232 post-MI patients with moderate LV dysfunction (EF 30%) randomized to ICD or medical therapy
Arrhythmia was not an inclusion criteria
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Mortality in MADIT-II
30% total reduction of mortality
0
5
10
15
20
25
ICD
Medical therapy
Perc
en
t m
ort
ality
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Economic impact
MADIT-II entry criteria would lead to an additional 300,000 patients for ICDs, a $9 billion market
ICDs cost $25-35,000
"We are dealing with an issue that could have incredible economic implications"
Fuster
VENTAK PRIZM 2 ICDSource: Guidant
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Mortality in MADIT-II
30% total reduction of mortality
0
5
10
15
20
25
ICD
Medical therapy
Perc
en
t m
ort
ality
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Risk stratification:MADIT II
Can we find subgroups that have greater or lesser benefit, so that there is some form of risk-stratification?
"Does this have to do with presence of previous bypass surgery? Number of previous infarcts? Or extent of disease?"
Ferguson
VENTAK PRIZM 2 ICDSource: Guidant
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Steps to implementation
Vice President Dick CheneySource: GWU hospital
First people need to see the data
Guidelines for selecting patient populations
Incorporation into clinical practice
Cannon
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Reduced cost in the future
"The hope is that with supply and demand, if there is all of a sudden a huge number of patients eligible for the therapy, the cost will come way down."
Cannon
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Cost issues"The pharmaceutical industry and the device industry are very different from the world of Bell Telephone which was broken up as a monopoly. I would be surprised if the prices on these things plummet precipitously."
Ferguson
Bx-Velocity StentSource: Cordis
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Cheap ICDs alternative
"For some patients, a sophisticated ICD that could be used to treat comorbidities and monitor a variety of physiological functions may be indicated, whereas in others, an inexpensive ICD in the $10,000 to $15,000 range might be preferable."
ZipesDr Douglas ZipesSource: Indiana University School of Medicine
Zipes DP, Circulation 2001; 103:1372-4.
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
How long are you prolonging life?
In these sick patients, how much life are we giving them?
"Statistically, we are used to comparing over a short period of time 'A is better than B.' But I think we are going to talk more and more about how much we prolong the life of this individual."
Fuster
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
SCD-HeFT
2500 patients with either ischemic heart failure or dilated cardiomyopathy in proportions of roughly 50-50, EF 35%
Randomized to 3 arms: ICD, amiodarone, or placebo
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Medical Resonance Angiography
Non-invasive MRI for assessing high-risk patient•MRI of the blood•No contrast agent •A recent study of
109 patientsSource: Radiological Society of North America
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Coronary MRA results for left main or 3-vessel disease
Result % 95% CI
Sensitivity 100 97-100
Specificity 85 78-92
Accuracy 87 81-93
Kim WY et al. N Engl J Med 2001; 345:1863-9.
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Limitations of MRA
Couldn't adequately image 16% of proximal segments
"I have some concerns about that and I am not going to turn all of our cath labs into MRI suites."
Ferguson
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Straight to the OR?
Q - “If you were to go [MRA] and you found major stenotic lesions… would you now feel bold enough to go straight to the operating room?
-Weber
A - “Personally I would not, because the technique does not image your distal targets all that well.
"If they were my coronary arteries I would want to know what the distal vessels look like that I would be tying into.
-Ferguson
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Other imaging technology
MRA technology is advancing rapidly.
"I don't think this technology, regardless of the method you use, is prime time. I think what is very fascinating though, is to see the
resolution of this technology just in the last 2-3 years."
Fuster
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
AspirinWill always be a discussion
MADIT-IIWe have a fantastic therapy,
what do we do with it?
MRINew diagnostic imaging
technologies are evolving rapidly
Questions raised
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Applying the evidence
"I'm looking forward to trying to apply all of this evidence, bringing the therapies such as defibrillators […] and aspirin to all the patients who are eligible. I think it can translate into big- time benefits clinically.
Cannon
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Risk stratification
"We need to be selective to some extent in what we use and how we use it. We ultimately, with all of the different modalities that we've been coming back to, have come back to issues of risk stratification."
Ferguson
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Final thoughts on aspirin
"Low-dose aspirin is the way to go with aspirin, in all likelihood for most of our patients."
But you can't give aspirin just because a person reaches a certain milestone age
Weber
Heartbeat – Feb 2002
Aspirin, ICDs, and MRA
Aspirin, ICDs, and MRA
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