Heartbeat – Aug 2003 Polypill The Polypill: Therapy of the future? Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New

Heartbeat – Aug 2003

Polypill

The Polypill: Therapy of the future?

Valentin Fuster MDDirector, Cardiovascular InstituteMount Sinai Medical CenterNew York, New York

Eric Topol MDProvost and Chief Academic OfficerThe Cleveland Clinic FoundationCleveland, Ohio

Harlan Krumholz MDProfessor of Medicine (Cardiology) Yale University School of MedicineNew Haven, Connecticut

Johnathan Sackner-Bernstein MDDirector of Clinical Research North Shore University HospitalLong Island, New York


Polypill

The "Polypill" proposal

"A strategy to reduce cardiovascular disease by more than 80%." A single pill combining:

•A statin (10-mg atorvastatin or 40-mg simvastatin or lovastatin)

•Three BP-lowering drugs, at half-standard dose (thiazide, beta blocker, and ACE inhibitor)

•0.8-mg folic acid

•75-mg aspirin Wald NJ and Law MR. British Medical Journal 2003 Jun 28; 2002; 326:1419


Polypill

The idea

Wald and Law claim this approach:

•Would not be expensive

•Would not cause significant side effects

Polypill should be given to

•Patients with cardiovascular disease

•Patients >55 years of age

Fuster


Polypill

Radical approach

A combination pill used to make compliance easier (one pill instead of three) has been proposed before

The Polypill is being proposed as a means of prevention across a huge population

"I think that this is not related to the compliance of the patient and therefore is a very radical approach."

Fuster


Polypill

Theoretically provocative

Topol

Radical and provocative population-based strategy

"To think everyone over age 55 would be taking a pill on a daily basis with these six drugs is a bit removed from what we had been expecting how the field would go."

"I don't even know if such a pill could be produced without any chemical incompatibility."


Polypill

Promotion

Krumholz

The Polypill article directs attention to the fact there have been effective interventions in heart disease that are still not fully applied

Ward and Law are trademarking the name "Polypill" and are promoting it heavily

Problem in promoting the notion that the Polypill is almost a vaccine or magic bullet for heart disease


Polypill

Way ahead of themselves

Krumholz

"I think that they get way ahead of themselves in terms of the evidence."

They extrapolate very far from observational studies

No proof that three BP pills at half dose will have the effect they say

If a patient develops intolerance to a pill with six drugs, how can you tell what they aren't tolerating?


Polypill

Not unreasonable

Sackner-Bernstein

This is radical, but not unreasonable

Using these medicines more widely is based on sound data

"We've gotten so caught up with how to treat populations and how to be cost-effective that we've forgotten about the fact that we're supposed to be treating patients and describing what the risk-benefit ratio is for them."


Polypill

Individualizing medicines

Sackner-Bernstein

Use medicines like these, but individualize them

Everyone is a candidate, but not everyone should be treated the same way

The targets as they exist in the treatment guidelines are a little too lax

Patients need to be looked at individually, and optimal blood pressure and optimal LDL levels are the way to reduce risk


Polypill

Western population

Fuster

JNC 7 suggests hypertension is a graded effect, starting from 115/75 mm Hg, with a gradually increasing risk

HPS suggested any patient with a coronary-like disease should be put on a statin regardless of cholesterol level

"It seems to me that the concept of approaching a Western population aggressively is not an unreasonable one."


Polypill

Aggressive approach

An aggressive treatment such as the Polypill might make sense for someone with known risk

This strategy goes against the move toward individualized medicine

The idea of treating more widely may be appropriate, but a lot of patients don't need all six drugs

Topol


Polypill

Dumbed-up strategy

"This is a dumbed-up strategy for everybody. I just don't agree that we have to be so dumb."

It might be cost-effective, but it doesn't take into account any individualization

Topol


Polypill

Best approach

Ward and Law claim this is the best approach for decreasing CV events

Look at the Finnish success in reducing cholesterol and CV events by changing food production

Governments' ability to change food production, pressure the tobacco industry, and make populationwide approaches could be a far more effective approach

Fuster


Polypill

Lifestyle changes

Sackner-Bernstein

In the West, stamping out tobacco and changing the food industry are not likely

Meaningful lifestyle changes are extremely difficult for patients

Pragmatically, for a patient with a BP in the 130s, a pill can bring them down below 115 if they can't change their lifestyle


Polypill

Social engineering

Krumholz

Social engineering approaches are important and should be supported

•Food supply

•Exercise and lifestyle change

•Community development

All approaches should not be medicalized

Lifestyle changes should not be discounted


Polypill

Blood pressure agents

Krumholz

Must disentangle what is in this Polypill and what is meant by optimal treatment

Statins have such strong evidence supporting them that they are an obvious choice to offer patients at risk

For blood pressure drugs there are no good treatment studies saying we reduce risk by bringing someone from systolic 130 to 115


Polypill

Blood pressure reduction

Treatment of hypertension usually needs multiple drugs

According to Ward and Law's meta-analysis, a half dose of three drugs would reduce:

•Systolic BP 20 mm Hg, diastolic 11 mm Hg

•Stroke by 63%

• Ischemic heart disease events at ages 60-69 by 46%

Wald NJ et al British Medical Journal 2003 Jun 28; 2002; 326:1427


Polypill

The general population

Previous blood pressure trials were not on patients with low or normal blood pressure

"I don't think you can transfer all these data on the antihypertensives in a hypertensive population into an overall population over 55."

Fuster


Polypill

Extrapolations

Topol

"I think there are lots of assumptions and extrapolations here that are hard to fully accept."

•No one has tested the effectiveness of antihypertensive drugs in normotensive patients

•No proof half-doses will have a significant effect

•Unproven assumption each drug is having an independent benefit


Polypill

Special populations

Topol

"What does a half dose of ACE inhibitor and beta blocker do for African Americans? Does it do anything? Has it ever been tested? I mean, the full doses don't look so great, so I don't know about half doses."

"This simplistic notion of treating every 55-year-old and beyond the same is a little simplistic."


Polypill

No systematic approach

Krumholz

No systematic approach to learn from all the people currently on medications in this country

"50% of the people with risk factors or with cardiovascular disease should be in some sort of trial at any given time."

"A lot of these regimens are being used all the time, and we're really not sure because they're just being used with an N of 1."


Polypill

BMJ 2003 Jun 28; 2002; 326:1423

Statins and ischemic events

0102030405060708090

Reducti

on in

ischem

ic e

vents

(%

)

1.4 1.8 2.2

Reduction in LDL (mmol/ L)

50 years old 60 years old 70 years old


Polypill

Statins for everyone

Sackner-Bernstein

Data show that once someone is 50, they have a 75% to 80% chance of having fat-laden plaques in the proximal coronary arteries

These are the vulnerable lesions

"I tend to be pretty aggressive with statins and I think the data are probably the strongest with the statins for widespread use of any of these six components."


Polypill

Risk/benefit of aspirin

Type of eventBaseline risk of coronary disease over 5 years

1% 3% 5%

Nonfatal AMI and fatal CHD

1-4 avoided

4-12 avoided

6-20 avoided

Hemorrhagic strokes

0-2 caused 0-2 caused 0-2 caused

Major GI bleeds

2-4 caused 2-4 caused 2-4 caused

Hayden M et al. Ann Intern Med 2002; 136:161-72.


Polypill

Low-risk people

Are you taking a statin and an aspirin?

•Topol: "I'm not taking aspirin, although I am taking a statin."

•Krumholz: "I'm not taking either of them."

The question is whether people at very low risk should be on any of these drugs


Polypill

Aspirin's importance

Anyone at >1% a year risk gets a significant benefit from aspirin, especially for MI or stroke

Statin benefit has mostly been in secondary prevention

"I would assert that aspirin is the most important of the six, maybe statins being second."

Topol


Polypill

Aspirin

Guidelines say that at a 10-year risk of 3% or less (0.3% a year) aspirin is no longer favorable

Anyone over age 55 already exceeds this level of risk

"In that age group, I would advocate 75-80 mg of aspirin"

Sackner-Bernstein


Polypill

The Physicians Study

EventAspirin vs placebo

Relative risk 95% CI P

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-month average follow-up

N Engl J Med 1989; 321:129-35.


Polypill

Lancet 2003; 361:2017-2023

Vitamin E meta-analysis

0

2

4

6

8

10

12

Events

(%

)

Death CV death Cerebral event

Control Vitamin E


Polypill

Folic acid

Folic acid has not been proven in a wide population

"I guess the philosophy here of Wald and Law was that 'Oh, it can't hurt anybody and it may help some.'"

Vitamin supplements have been a bust

Topol


Polypill

Lancet 2003; 361:2017-2023

Beta-carotene meta-analysis

0

1

2

3

4

5

6

7

8

Events

(%

)

Death CV death

Control Beta-carotene


Polypill

Insufficient evidence

"The USPSTF could not determine the balance of benefits and harms of routine use of supplements of vitamins A, C, or E, multivitamins with folic acid, or antioxidant combinations for the prevention of cancer or cardiovascular disease."

US Preventive Services Task Force

Ann Intern Med 2003 Jul 1; 139(1):51-70


Polypill

Decisions on strategy

Fuster

Wald and Law acknowledge their approach is radical but insist the data are suggestive

"Maybe in medicine or in anything a radical approach has some truth . . . but it seems to me that we are all in agreement that maybe the approach is too radical."


Polypill

Reasonable

Fuster

The approach is radical but not unreasonable

They've raised awareness and forced us to "go back and think about what we would consider the data to point to as the optimal preventive strategy."


Polypill

Pravastatin/aspirin pill

Topol

Pravastatin/aspirin pill received FDA approval in June 2003

Available in six formulations: 20-mg, 40-mg, and 80-mg doses of pravastatin, each available with either 81 mg or 325 mg of aspirin


Polypill

Unreasonable

Krumholz

The "Polypill" proposal is unreasonable, instead we need a two-pronged approach

We need to bring patients in alignment with our guidelines

We need to have an individualized discussion between physicians and patients about how to approach their goals of therapy


Polypill

Conclusions on the Polypill

Krumholz

Fuster: Too radical

Topol: Too radical

Krumholz: Unreasonable

Sackner-Bernstein: Not unreasonable


Polypill

Don't need risk factors?

Is it time to discard the view that risk factors need to be measured?

Is Western society itself a risk factor?

A lot of truth in this view

"The fact that you start putting people on pills without measuring anything, I frankly think this is also too radical."

Fuster


Polypill

Smarter medicine

"I'm hoping that we're in a transition to a much smarter medicine."

Need to get to the biologic basis of diseases and risk

Questions remain on all the surrogate measures we currently use

Topol


Polypill

Risk perception

Sackner-Bernstein

Treating without measuring is too radical

It is important to emphasize that being in Western society is a risk factor

A relatively healthy 52-year-old still has a 6% risk of an MI over the next 10 years

Saying this patient is at "low risk" and is adequately treated is doing him a disservice


Polypill

Absolute benefits

Krumholz

There is still a great heterogeneity in risk, even in Western society

"We ought to be tying our interventions to the overall absolute benefit that is likely to be gained from the intervention."

•Must assess underlying risk and make therapeutic decisions from that


Polypill

Isn't simple

There is much to gain and little to lose from the widespread use of these drugs

What is the cost to manufacture a pill like this?

How difficult is it to make a single pill with six drugs?

What side effects will you see on people at low risk?

Fuster


Polypill

Simplistic approach

Topol

The approach is simplistic

•Potentially exaggerates the benefit

•There remain many unknowns

It might work well in a third-world environment where more couldn't be done


Polypill

Ideal for developing countries

Fuster

Authors conclude that there is no other preventive method that would have greater impact than this one

Editorial suggests that this approach is ideal for developing countries

• Is there a difference in the usefulness of a Polypill for Western countries and the developing world?


Polypill

Burden of proof

Krumholz

"The burden of proof still lies with the people who are promoting this idea to demonstrate what exactly can be achieved through this strategy."

This should not be implemented in any society without some sort of evidence of the risks and benefits


Polypill

Burden of disease

The burden of cardiovascular disease is different in different areas

There is much to gain and little to lose in looking at individual patients and wondering how to lower their risk

"Using this as a standard strategy broadly is rife with problems."

Sackner-Bernstein


Polypill

How do we move to the future?

On one hand, individualized medicine is the future. On the other, there is a problem in the field of prevention

Recent editorial in Science says that the current system cannot meet today's needs; how can advances such as postgenomic medicine be incorporated?

Fuster


Polypill

A new model

Topol

The model today is to develop a drug for an entire population, even though less than 10 in 100 patients actually derive benefit from the drug

A different model is to develop drugs for smaller populations defined by specific genes or proteins

"But we're not there yet, it's theoretical, and that's postgenomic medicine."


Polypill

The future of drug companies

Topol

The patients don't want to take all these pills, but they would take a pill tailored to them

Practically, the current model for drug companies would not support the pharmacogenetic model

"Big Pharma hasn't gotten it yet, and whether they're going to accept this notion remains to be seen."


Polypill

Creating a new system

Krumholz

"How do we create a system in which we can adopt innovations quickly and appropriately and ensure that all patients are getting the very best care for them?"

There are still too many patients not getting the interventions we already know are effective

The challenge will be bringing the innovations to the patients


Polypill

Compromise

Perhaps in the coronary patient some kind of combination pill could be developed and used while the genetic understanding moves ahead

"In a simplistic way we might begin to distinguish populations where drugs should be given and drugs should not be given."

Fuster


Polypill

Practical approach

Some sort of compromise is the optimal approach, using optimal drug therapy while genomic medicine is developed

There are millions of people who are willing to take multiple medicines, and these people should be treated as aggressively as we believe is appropriate while we wait for genomic therapy

Sackner-Bernstein


Polypill

The Polypill: Therapy of the future?

Valentin Fuster MDDirector, Cardiovascular InstituteMount Sinai Medical CenterNew York, New York

Eric Topol MDProvost and Chief Academic OfficerThe Cleveland Clinic FoundationCleveland, Ohio

Harlan Krumholz MDProfessor of Medicine (Cardiology) Yale University School of MedicineNew Haven, Connecticut

Johnathan Sackner-Bernstein MDDirector of Clinical Research North Shore University HospitalLong Island, New York

Documents

Heartbeat – Aug 2003 Polypill The Polypill: Therapy of the future? Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New