British researchers say everyone over 55 should take their six-drugs-in-one "polypill" to prevent CV disease

Shelley Wood

June 26, 2003

London, UK - Two British doctors have what they are calling a radical proposal for preventing cardiovascular disease. They believe the "polypill"a still-hypothetical combination of six medications in one pillcould slash risk of cardiovascular events by 80% or more and benefit one in three people if everyone over the age of 55 were to take the pill. Only 8% to 15% of people taking the pill would have side effects, they calculate.

"It would be acceptably safe and with widespread use would have a greater impact on the prevention of disease in the Western world than any other single intervention," Drs Nicholas J Wald and Malcolm R Law (University of London, UK) write in the June 26, 2003 issue of BMJ. Wald also discussed the strategy at a press conference at the Wolfson Institute of Preventive Medicine, University of London.

 
[The polypill] would be acceptably safe and . . . would have a greater impact on the prevention of disease in the Western world than any other single intervention.
 

Within hours of the press conference, the American Heart Association had released its own press statement from AHA president Dr Robert O Bonow. "The usefulness of the 'polypill' is purely speculative at this pointit would have to be tested in the real world before any conclusions could be drawn," Bonow commented. "There is no evidence that giving an entire population over the age of 55 a 'magic pill' would significantly reduce cardiovascular diseases."

The researchers say that drug treatments to prevent ischemic heart disease (IHD) events typically target single risk factors with the aim of reducing them to "average" population values, a strategy that can achieve "only modest reductions" in the number of people dying from or disabled by CHD. "A large preventive effect would require intervention in everyone at increased risk irrespective of the risk-factor levels; intervention on several reversible causal risk factors together; and reducing these risk factors by as much as possible," they write.

To cure all that ails

The solution? They propose a pill combining drugs and/or vitamins that would collectively modify cholesterol levels, blood pressure, homocysteine, and platelet function. To determine the ideal combination, Wald and Law reviewed 750 drug trials (representing 400 000 participants) to identify agents that substantially modified these risk factors.

They settled, ultimately, on a hypothetical pill combining a statin (either 10-mg atorvastatin or 40-mg simvastatin or lovastatin); three blood-pressure-lowering drugs, each at a half standard dose (potentially a thiazide, beta blocker, and ACE inhibitor); 0.8-mg folic acid; and 75-mg aspirin. This combination would likely reduce ischemic heart disease events by 88% and stroke by 80% and would benefit one third of all people over age 55 if all people in this age bracket were taking the polypill combo, they calculated.

Support for the polypill in accompanying publications

Two additional papers by Wald, Law, and colleagues also appear in the June 26, 2003 issue of BMJ, both providing data in support of components of their polypill strategy. In the first, Wald et al conducted three meta-analyses to determine the degree to which statins reduced LDL concentrations and the incidence of cardiovascular events, according to drug, dose, and treatment duration[2]. They conclude, ultimately, that statins can lower LDL cholesterol concentration by an average of 1.8 mmol/L, which reduces the risk of IHD events by about 60% and stroke by 17%. Since adverse events are dose related, moderate doses of statins may be preferable to high doses for general use, the authors note. As well, both simvastatin and lovastatin are off patent or soon to be off patent and could lower LDL cholesterol by 1.8 mmol/L and reduce IHD events at age 60 years by 61% at doses of 40 mg/day, at a considerably lower cost than statins still on patent, they note.

In a second paper, Wald, Law, and colleagues conducted a meta-analysis of 354 randomized double-blind placebo controlled trials of thiazides, beta blockers, ACE inhibitors, angiotensin II receptor antagonists, and calcium channel blockers in a fixed dose to determine average reductions in blood pressure, prevalence of adverse effects, and reduction in risk of stroke and IHD events produced by these agents according to dose, singly and in combination[3].

They report that all drug classes produced similar BP reductions and that the BP-lowering effects were additive. Side effects in people taking thiazides, beta blockers, and calcium channel blockers were dose related, whereas side effects with ACE inhibitors showed no dose dependence. ARBs "caused no excess symptoms."

They conclude that a combination of three drugs at half-standard doses would have a low incidence of side effects while lowering BP by 20 mm Hg systolic and 11 mm Hg diastolic, reductions that would translate into a stroke risk reduction of 63% and a reduction in IHD events of 46% at ages 60 to 69.

-SW

Adverse effects?

Wald and Law also considered adverse-event rates, noting that if the least expensive antihypertensive drugs were chosennamely a thiazide, beta blocker, ACE inhibitor combinationan adverse-effect rate of 15% could be expected. By contrast, if a combination of the agents with the lowest adverse-event rates were useda thiazide/angiotensin II receptor blocker/calcium channel blocker combinationthe event rate would fall to 8%. Indeed, the polypill component with the greatest potential for producing adverse effects is aspirin, they note, but say the risk of hemorrhagic stroke is overshadowed by the reduction in risk of thrombotic stroke.

Bonow, however, disagrees, stating, "Studies have shown that administering aspirin . . . to a large population of apparently healthy people does not save lives, because the number who are saved from fewer heart attacks and stroke is offset by the number who die from bleeding complications."

Bonow also argues that when it comes to antihypertensive agents and statins, a "one-size-fits-all" approach would inevitably lead to patients getting inappropriate doses. "People would be undertreated and would not achieve the appropriate degree of blood pressure or cholesterol lowering. Others who are at very low risk would have a higher likelihood of drug-related side effects over the long term, compared with any potential benefit," says Bonow.

 
Use of BP medications in people who might not need them has never been tested and could be dangerous.
 

Commenting on the study for heartwire , Dr Lee Goldman (University of California, San Francisco) observed that putting patients on a fixed-dose, combination regimen would "be good for adherence but requires that you know that people don't have contraindications to any of the components."

In the case of blood-pressure-lowering drugs, Goldman notes, no research has been done testing their effects in people with normal blood pressure. "Use of BP medications in people who might not need them has never been tested and could be dangerous. For the other agents, there are at least some data that treating all of us is probably as good as not treating us, if not better."

No need to measure risk factors

The boldest assertion that Wald and Law make is that everyone older than 55 should take the pill, regardless of whether they have CHD symptoms or not. The polypill should also be taken by everyone with a history of MI or cerebral thrombosis and "probably" by anyone with angina, TIA, peripheral arterial disease, and diabetes. "There is no need to measure the four risk factors before starting treatment, because intervention is effective whatever the initial levels of the risk factors, nor to monitor the effect of the treatment, because fluctuations within individuals tend to mask variations between individuals in the systematic effects of the interventions."

In an editorial accompanying Wald and Law's paper, Dr Anthony Rodgers (University of Auckland, New Zealand) calls this notion of treating everyone over age 55 "controversial . . . although this debate should not detract from the size and certainty of net benefits in those with vascular disease"[4].

Rodgers points out, however, that age is really a proxy for "exposure to life" and "life in developed countries at present almost inescapably entails long-term exposure to major risks, such as excess intake of salt and saturated fat." Whether or not this justifies the use of a strategy like the polypill in asymptomatic people will require wider debate, he says.

Enormous potential

Rodgers points out that a pill like the one proposed by Wald and Law could theoretically be made quite cheaply with off-patent components but questions whether it would be cheap enough to reach non-Western populations. The polypill strategy has an even greater potential for preventing cardiovascular events in developing countries, where people receive minimal preventive care despite exploding CHD rates, Rodgers notes. He states that a major challenge with such a therapy would be to ensure that it reaches high-risk people in underdeveloped countries.

"So is Wald and Law's bold claim justified?" Rodgers asks. "Quite possibly," he says. "Only large reductions in smoking or a few other leading health risks could achieve so much health gain. Realizing this enormous potential should be a major goal, especially for developing countries."

 
So is Wald and Law's bold claim justified? Quite possibly.
 

Bonow, however, believes that just the sheer number of people implied by Ward and Law's approach would make the strategy "prohibitively expensive," particularly in developing countries. The money would be better spent with community-based, culturally sensitive educational programs, he says, adding, "Treatment with medications and with lifestyle should be tailored to an individual's specific risk factors and medical history."

Goldman, too, raised the issue of a populationwide price tag. "Whether this is a half-way decent idea would depend dramatically on the cost."

Elsewhere, aspirin/statin combo approved for US market

In the US this week, the FDA has approved the first statin/aspirin therapy combination. Almost a year has passed since the FDA's Cardiovascular and Renal Drugs Advisory Committee voted to recommend approval of the combination, as reported by heartwire . At that time, the committee reversed their earlier rejection of PravigardTM (Bristol-Myers-Squibb) after the company returned to the FDA with dosing options. The combination approved this week offers 20, 40, or 80 mg of pravastatin (Pravachol®) packaged with either 81 mg or 325 mg of buffered aspirin.

Unlike the polypill proposed by Ward and Law, the Pravigard contains two separate pills packaged side-by-side.

-SW

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