Aspirin, ICDs, and MRA

Heartbeat – Feb 2002

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



AspirinNew questions about an old drug

MADIT-IIICDs for post-MI patients

with low EF

MRINon-invasive assessment of coronary arteries

Subjects



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



Baigent C et al. BMJ 2002; 324:71-86.

BMJ meta-analysis

Reprinted with permission from BMJ



Aspirin for angina?

60.2-month follow-up of 333 patients with angina and no prior MI from Physicians Health Study

Aspirin vs placebo

Aspirin vs placebo controlling for other CV risk

Relative risk of MI(95% CI)

0.30(0.14 - 0.63)

0.13 (0.04 - 0.42)

P-value 0.003 <0.001

Ridker PM et al. Ann Intern Med 1991; 114:835-9.

Aspirin group: n=178, alternate-day 325mg dosePlacebo group: n=155



SAPAT

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.




BMJ meta-analysis

Reprinted with permission from BMJ



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



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




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



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



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.



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.



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



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.



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



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



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



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



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



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



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



“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



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



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”



“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?



“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



•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



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



Mortality in MADIT-II

30% total reduction of mortality

0

5

10

15

20

25

ICD

Medical therapy

Perc

en

t m

ort

ality



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



Mortality in MADIT-II

30% total reduction of mortality

0

5

10

15

20

25

ICD

Medical therapy

Perc

en

t m

ort

ality



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



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



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



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



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.



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



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



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



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.



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



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



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



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



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



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



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




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

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Aspirin, ICDs, and MRA

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