The Polypill - Coming Soon
The Polypill - Coming Soon
Last year, 2 British researchers, N. J. Wald and M. R. Law, put forward the idea of a "polypill," a combination of 3 or more drugs in a single pill for the prevention of cardiovascular disease (CVD). Based on theoretical considerations, they projected that such a pharmaceutical product should enable the world's healthcare systems to decrease the incidence of CVD by "more than 80%." Although the initial publication was met with a degree of skepticism, it appears that the concept was prescient and that over the next 10 years, many different versions of the polypill will become available. In fact, according to a presentation by Anthony Rodgers, MD, PhD (Clinical Trials Research Unit, University of Auckland, Auckland, New Zealand) given at the just-concluded biannual meeting of the International Society of Hypertension, in São Paulo, Brazil, the polypill may eventually become regarded as background therapy for the primary prevention of CVD. Dr Rodgers based his prediction on a review of the advantages and disadvantages of the polypill, whose basic ingredients will be, Dr Rodgers believes, a cholesterol-lowering drug, 2 low-dose blood pressure-lowering agents, and low-dose aspirin, with various other drugs added for different formulations.
Dr Rodgers believes that the polypill concept represents huge preventive potential. It has the advantage of simplicity, and should improve compliance. It will free up physicians' time to concentrate on other important prevention measures, such as smoking cessation and nutrition advice. Importantly, especially for developing countries with limited healthcare budgets, the polypill is potentially very affordable, as all the drugs in it would be off patent. The individual ingredients need only cost a few dollars per month, Dr Rodgers pointed out.
For people with vascular disease, the polypill represents "plain common sense," he said, stressing that for the "tens of millions" of patients who currently receive little or nothing, it is essential. Nonetheless, he does not believe that everyone with hypertension should take the polypill, or any drugs at all, necessarily. For these individuals, large-scale demonstration projects and clinical trials are needed to assess benefits vs risks of taking the polypill. In any case, "we are virtually all hypertensive, if hypertension is defined as the capacity to benefit from blood pressure lowering, he pointed out. Increasingly, the decision to treat within ranges such as 115/70 mm Hg through 170/100 mm Hg will be based on an individual's cardiovascular risk, he predicts. He also foresees that the definition of "hypertension" will undergo many changes and may eventually even fall out of use within 10-20 years.
Ingredients
In an era where the aim is to effectively reduce cardiovascular risk rather than risk factors, statins are the obvious first-line therapy and should be first choice for the polypill, according to Dr Rodgers. Statins have very few side effects and, in contrast to blood pressure-lowering drugs, they are extremely effective at major risk factor reduction, with a 50% reduction in cholesterol considered not an unreasonable expectation.
Two low-dose, or possibly 3 half-dose, blood pressure-lowering drugs, should also be included. These drugs would have additive effects. The Blood Pressure Lowering Trialists Collaboration has shown that there is almost no difference between the various classes of antihypertensive drugs in terms of their protection again major cardiovascular events, Dr Rodgers noted. The choice of these drugs should be based on cost, convenience, and side effects. The effects in all blood pressure-lowering trials (drug vs placebo, drug vs drug, more vs less) and cholesterol lowering (statin, dietary, fibrate) trials are mostly or all explained by the amount of the reduction in blood pressure or cholesterol, respectively. Any other benefits are very small in comparison, so, in Dr Rodgers' opinion, the choice of agent is not very important.
Low-dose aspirin would be the third basic ingredient of the polypill. Different drug classes such as vitamins (eg, folic acid) and glucose-lowering agents (eg, metformin) would be added for different versions of the polypill.
Risk-Reduction Benefits
Extrapolating from currently available evidence, the likely net benefits of taking the polypill would be a 55% to 75% risk reduction, Dr Rodgers believes. To date, there is no direct randomized evidence of combination therapy, but this will eventually come, he hopes. In the meantime, there is very convincing evidence documenting the benefits of combination therapy from consistency of effects seen in studies such as the Heart Protection Study (HPS), which demonstrated reduction of vascular events with a statin and the Perindopril Against Recurrent Stroke Study (PROGRESS), which demonstrated reduction of stroke with ACE inhibitor with/without a diuretic. Such large trials showed similar relative risk reduction in the presence or absence of other therapies, with no important interaction in terms of clinical event reduction.
The best estimate of combined effects is the mathematical product of the relative risks, according to Dr Rodgers. If each of 3 interventions separately reduced relative risk by approximately 25%, the net effect would be 1- (0.75×0.75×0.75) = 0.58, or 58% relative risk reduction. After 1-2 years, however, risk reduction might be over 70%, since the full effects of the statin would only then be seen. Even conservative estimates with 3 drugs that each only reduced relative risk by 20% would result in an approximate 50% reduction in risk.
Side Effects
Side effects with the polypill are likely to be rare, with most coming from the low-dose aspirin, Dr Rodgers predicts. Only 1 or 2 per 100 patients may not tolerate the low-dose blood pressure-lowering drugs. Fatal or life-threatening risks would be less than 1 in 10,000. This would compare with a 1 in 25 chance of suffering a major cardiovascular event per year. Dr Rodgers believes that major side effects are overattributed to polypills or even blood pressure-lowering drugs by themselves. Most adverse events are not due to treatment, which can be seen in clinical trials, where withdrawals due to side effects are similar in the active treatment and placebo groups. However, the benefits and risks of the polypill cannot be balanced on the basis of individual experience, since no one knows when a stroke or heart attack is prevented ("the prevention paradox"), Dr Rodgers pointed out.
Tailoring
One of greatest reservations of physicians about the polypill is that they feel that tailoring might not be easy. This may well be the case, Dr Rodgers admitted, but tailoring is becoming less important, he maintains, for 10 reasons:
Practical issues that have to be addressed with the polypill will include the clinical trials, the commercial incentive -- the polypill will be a high-volume, low-margin product -- regulatory approval, and clinician and patient acceptance. Dr Rodgers foresees wide debates surrounding all of these issues, but the real challenges will be more philosophical, he believes. CVD is seen as a "natural" cause of death, and there will be skepticism that a risk reduction of more than 70% (predicted by epidemiologists such as Dr Rodgers himself) can be achieved. The perceptions that "drugs are bad" for public health and that physicians should tailor treatments to each individual will have to be overcome. Financial issues, such as commercial profit from the polypill and the lack of government funding for low-cost interventions, also have to be dealt with. Nevertheless, Dr Rodgers maintains, the polypill is the most important therapy doctors can use to prevent CVD.
References
Last year, 2 British researchers, N. J. Wald and M. R. Law, put forward the idea of a "polypill," a combination of 3 or more drugs in a single pill for the prevention of cardiovascular disease (CVD). Based on theoretical considerations, they projected that such a pharmaceutical product should enable the world's healthcare systems to decrease the incidence of CVD by "more than 80%." Although the initial publication was met with a degree of skepticism, it appears that the concept was prescient and that over the next 10 years, many different versions of the polypill will become available. In fact, according to a presentation by Anthony Rodgers, MD, PhD (Clinical Trials Research Unit, University of Auckland, Auckland, New Zealand) given at the just-concluded biannual meeting of the International Society of Hypertension, in São Paulo, Brazil, the polypill may eventually become regarded as background therapy for the primary prevention of CVD. Dr Rodgers based his prediction on a review of the advantages and disadvantages of the polypill, whose basic ingredients will be, Dr Rodgers believes, a cholesterol-lowering drug, 2 low-dose blood pressure-lowering agents, and low-dose aspirin, with various other drugs added for different formulations.
Dr Rodgers believes that the polypill concept represents huge preventive potential. It has the advantage of simplicity, and should improve compliance. It will free up physicians' time to concentrate on other important prevention measures, such as smoking cessation and nutrition advice. Importantly, especially for developing countries with limited healthcare budgets, the polypill is potentially very affordable, as all the drugs in it would be off patent. The individual ingredients need only cost a few dollars per month, Dr Rodgers pointed out.
For people with vascular disease, the polypill represents "plain common sense," he said, stressing that for the "tens of millions" of patients who currently receive little or nothing, it is essential. Nonetheless, he does not believe that everyone with hypertension should take the polypill, or any drugs at all, necessarily. For these individuals, large-scale demonstration projects and clinical trials are needed to assess benefits vs risks of taking the polypill. In any case, "we are virtually all hypertensive, if hypertension is defined as the capacity to benefit from blood pressure lowering, he pointed out. Increasingly, the decision to treat within ranges such as 115/70 mm Hg through 170/100 mm Hg will be based on an individual's cardiovascular risk, he predicts. He also foresees that the definition of "hypertension" will undergo many changes and may eventually even fall out of use within 10-20 years.
Ingredients
In an era where the aim is to effectively reduce cardiovascular risk rather than risk factors, statins are the obvious first-line therapy and should be first choice for the polypill, according to Dr Rodgers. Statins have very few side effects and, in contrast to blood pressure-lowering drugs, they are extremely effective at major risk factor reduction, with a 50% reduction in cholesterol considered not an unreasonable expectation.
Two low-dose, or possibly 3 half-dose, blood pressure-lowering drugs, should also be included. These drugs would have additive effects. The Blood Pressure Lowering Trialists Collaboration has shown that there is almost no difference between the various classes of antihypertensive drugs in terms of their protection again major cardiovascular events, Dr Rodgers noted. The choice of these drugs should be based on cost, convenience, and side effects. The effects in all blood pressure-lowering trials (drug vs placebo, drug vs drug, more vs less) and cholesterol lowering (statin, dietary, fibrate) trials are mostly or all explained by the amount of the reduction in blood pressure or cholesterol, respectively. Any other benefits are very small in comparison, so, in Dr Rodgers' opinion, the choice of agent is not very important.
Low-dose aspirin would be the third basic ingredient of the polypill. Different drug classes such as vitamins (eg, folic acid) and glucose-lowering agents (eg, metformin) would be added for different versions of the polypill.
Risk-Reduction Benefits
Extrapolating from currently available evidence, the likely net benefits of taking the polypill would be a 55% to 75% risk reduction, Dr Rodgers believes. To date, there is no direct randomized evidence of combination therapy, but this will eventually come, he hopes. In the meantime, there is very convincing evidence documenting the benefits of combination therapy from consistency of effects seen in studies such as the Heart Protection Study (HPS), which demonstrated reduction of vascular events with a statin and the Perindopril Against Recurrent Stroke Study (PROGRESS), which demonstrated reduction of stroke with ACE inhibitor with/without a diuretic. Such large trials showed similar relative risk reduction in the presence or absence of other therapies, with no important interaction in terms of clinical event reduction.
The best estimate of combined effects is the mathematical product of the relative risks, according to Dr Rodgers. If each of 3 interventions separately reduced relative risk by approximately 25%, the net effect would be 1- (0.75×0.75×0.75) = 0.58, or 58% relative risk reduction. After 1-2 years, however, risk reduction might be over 70%, since the full effects of the statin would only then be seen. Even conservative estimates with 3 drugs that each only reduced relative risk by 20% would result in an approximate 50% reduction in risk.
Side Effects
Side effects with the polypill are likely to be rare, with most coming from the low-dose aspirin, Dr Rodgers predicts. Only 1 or 2 per 100 patients may not tolerate the low-dose blood pressure-lowering drugs. Fatal or life-threatening risks would be less than 1 in 10,000. This would compare with a 1 in 25 chance of suffering a major cardiovascular event per year. Dr Rodgers believes that major side effects are overattributed to polypills or even blood pressure-lowering drugs by themselves. Most adverse events are not due to treatment, which can be seen in clinical trials, where withdrawals due to side effects are similar in the active treatment and placebo groups. However, the benefits and risks of the polypill cannot be balanced on the basis of individual experience, since no one knows when a stroke or heart attack is prevented ("the prevention paradox"), Dr Rodgers pointed out.
Tailoring
One of greatest reservations of physicians about the polypill is that they feel that tailoring might not be easy. This may well be the case, Dr Rodgers admitted, but tailoring is becoming less important, he maintains, for 10 reasons:
Philosophically, how much benefit do you want? Additional changes will be marginal. Try smoking cessation and exercise next.
The goal posts have changed -- systolic blood pressure (SBP) 135 mm Hg is not control. Thresholds are almost arbitrary. Closer to SBP 115 mm Hg is better, but the majority of patients will not be able to reach that.
There are better uses for your time; tailoring is time consuming.
There are better uses for the country's money.
Individuals vary in their responses to medications (measurement error and biological variation day to day, month to month).
There are no great diagnostic challenges now. Everything works in everyone at high risk.
The long-term adherence is the key issue. How can doctors and patients put faith in 5 pills with several dosing changes? Psychology is important: patients feel that the benefits of 5 individual drugs might not be very great. It is much different, psychologically, giving them 1 pill and telling them to take it for the rest of their life.
The reason for stopping treatment is rarely due to pharmacology.
Tailoring has usually meant undertreatment.
Personalized treatment is key to the doctor-patient relationship, but medications are only a small part of this relationship. There are many other roles, such as advising on other ways to reduce cardiovascular disease.
Practical issues that have to be addressed with the polypill will include the clinical trials, the commercial incentive -- the polypill will be a high-volume, low-margin product -- regulatory approval, and clinician and patient acceptance. Dr Rodgers foresees wide debates surrounding all of these issues, but the real challenges will be more philosophical, he believes. CVD is seen as a "natural" cause of death, and there will be skepticism that a risk reduction of more than 70% (predicted by epidemiologists such as Dr Rodgers himself) can be achieved. The perceptions that "drugs are bad" for public health and that physicians should tailor treatments to each individual will have to be overcome. Financial issues, such as commercial profit from the polypill and the lack of government funding for low-cost interventions, also have to be dealt with. Nevertheless, Dr Rodgers maintains, the polypill is the most important therapy doctors can use to prevent CVD.
References
Wald, NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003;326:1419-1423.
Rodgers A. The polypill – evidence for and against. Lecture. Hypertension 2004 – 20th Scientific Meeting of the International Society of Hypertension, February 15-19, 2004; São Paulo, Brazil.
New Zealand Guidelines Group. The assessment and management of cardiovascular risk. New Zealand Guidelines Group: Wellington; 2003. Available at
http://www.nzgg.org.nz. Accessed March 4, 2004.
Blood Pressure Lowering Treatment Trialists Collaboration. Effects of different blood-pressure lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362:1527-1535.
PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood pressure lowering regimen among 6105 individuals with previous stroke or transient ischemic attack., Lancet. 2001;358:1033-1041.
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.
