Heartbeat – Aug 2003 Polypill The Polypill: Therapy of the future? Valentin Fuster MD Director,...
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Transcript of Heartbeat – Aug 2003 Polypill The Polypill: Therapy of the future? Valentin Fuster MD Director,...
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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."
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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?
Heartbeat – Aug 2003
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."
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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."
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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."
Heartbeat – Aug 2003
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."
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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."
Heartbeat – Aug 2003
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.
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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.
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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."
Heartbeat – Aug 2003
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."
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
Polypill
Conclusions on the Polypill
Krumholz
Fuster: Too radical
Topol: Too radical
Krumholz: Unreasonable
Sackner-Bernstein: Not unreasonable
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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?
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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."
Heartbeat – Aug 2003
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."
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
Heartbeat – Aug 2003
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
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