The Polypill: Therapy of the future?

1. The Polypill: Therapy of the future? Valentin Fuster MD Director, Cardiovascular Institute Mount Sinai Medical Center New York, New York Eric Topol MD Provost and Chief Academic Officer The Cleveland Clinic Foundation Cleveland, Ohio Harlan Krumholz MD Professor of Medicine (Cardiology) Yale University School of Medicine New Haven, Connecticut Johnathan Sackner-Bernstein MD Director of Clinical Research North Shore University Hospital Long Island, New York

2. 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

3. 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

4. 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

5. Theoretically provocative 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." Topol

6. Promotion 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 Krumholz

7. Way ahead of themselves "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? Krumholz

8. Not unreasonable 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." Sackner-Bernstein

9. Individualizing medicines 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 Sackner-Bernstein

10. Western population 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." Fuster

11. 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

12. 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

13. 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

14. Lifestyle changes 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 Sackner-Bernstein

15. Social engineering • 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 Krumholz

16. Blood pressure agents 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 Krumholz

17. 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

18. 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

19. Extrapolations • "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 Topol

20. Special populations "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." Topol

21. No systematic approach 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." Krumholz

22. Statins and ischemic events BMJ 2003 Jun 28; 2002; 326:1423

23. Statins for everyone 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." Sackner-Bernstein

24. Risk/benefit of aspirin Hayden M et al. Ann Intern Med 2002; 136:161-72.

25. 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

26. 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

27. 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

28. The Physicians Study 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.

29. Vitamin E meta-analysis Lancet 2003; 361:2017-2023

30. 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

31. Beta-carotene meta-analysis Lancet 2003; 361:2017-2023

32. 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

33. Decisions on strategy 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." Fuster

34. Reasonable 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." Fuster

35. Pravastatin/aspirin pill 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 Topol

36. Unreasonable 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 Krumholz

37. Conclusions on the Polypill Fuster: Too radical Topol: Too radical Krumholz: Unreasonable Sackner-Bernstein: Not unreasonable Krumholz

38. 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

39. 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

40. Risk perception 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 Sackner-Bernstein

41. Absolute benefits • 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 Krumholz

42. 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

43. Simplistic approach • 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 Topol

44. Ideal for developing countries • 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? Fuster

45. Burden of proof "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 Krumholz

46. 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

47. 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

48. A new model 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." Topol

49. The future of drug companies 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." Topol

50. Creating a new system "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 Krumholz