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From Heartwire
Polypill for Primary Prevention: Largest-Yet Reductions in BP, Cholesterol in Small UK Trial
Lisa Nainggolan
July 19, 2012 (London, United Kingdom) — Results of the first trial to look at the effects of a polypill given to people solely on the basis of age for the primary prevention of CVD have shown the largest reductions in blood pressure and cholesterol levels of any polypill study to date [1].
On average, participants--who were aged >50--experienced a 12% reduction in BP and 39% fall in LDL cholesterol during the 12-week study, achieving levels typical of people aged 20, says lead author Dr David S Wald (Wolfson Institute of Preventive Medicine, London, UK), who together with colleagues, report the findings in PLoS One. "The health implications of our results are large. If people took the polypill long term from age 50, an estimated 28% would avoid or delay a heart attack or stroke during their lifetime and gain, on average, 11 years of life free of cardiovascular events," he told heartwire .
If people took the polypill long term from age 50, an estimated 28% would avoid or delay a heart attack or stroke during their lifetime.
Wald says the vision of his group at the Wolfson Institute is that everyone over a certain age, say 50 or 55 years, will take the polypill without necessarily having to see a doctor. They hope to file for UK regulatory approval for this use of their polypill, manufactured by the Indian company Cipla, within a year or so, once two further ongoing trials in India are completed.
The notion of a polypill for CVD prevention has been much debated since it was first proposed by Drs Nicholas Wald (a coauthor of the current study) and Malcolm Law (Wolfson Institute of Preventive Medicine) in 2003. A number of different formulations have been tested, in both primary and secondary prevention populations, and there are a handful of groups working on this concept worldwide. The idea is not without its detractors, however, with some arguing that the approach to give a polypill to all, as suggested by Wald et al, is far too radical. Many others working in the field believe the polypill is best placed as a treatment for secondary prevention, because those people would already be taking the individual components of a polypill. But critics feel that the global polypill approach is altogether misplaced and argue that individual risk assessment and reduction are the cornerstones of preventive cardiology.
Unique Crossover Design Gives the Most Accurate Results to Date
Wald says the polypill used in their study is three-layered and "easy to swallow"; it contains three BP-lowering medications--a calcium channel blocker, amlodipine 2.5 mg; an angiotensin-receptor blocker, losartan 25 mg; and a diuretic, hydrochlorothiazide 12.5 mg--along with the lipid-lowering simvastatin 40 mg.
Inventors Have Patents, Would License Polypill
Wald says there are four main groups working on the polypill worldwide, including his in London. The others are groups led by Dr Salim Yusuf (McMaster University, Hamilton, ON), who are working with another Indian company, Cadila Pharmaceuticals; an Australian consortium led by Dr Anthony Rodgers (George Institute for Global Health, Sydney, Australia), who are developing the red heart pill with a third Indian firm, Dr Reddy's Laboratories; and a Spanish team, led by Dr Valentin Fuster (Mount Sinai Medical Center, New York, NY), who are working with the Spanish company Ferrer Pharmaceuticals.
The inventors of the polypill, Nicholas Wald and Law, have a patent granted in Europe and Canada, and one pending in the US, that covers all formulations currently being tested by other groups, says David Wald.
"So, in terms of approvals and marketing, any other polypill would need to seek a license from us or they would be infringing the patent in those markets," he explains. "But in all other countries, there is freedom to operate, and that was always our intention, that the intellectual property would remain free to developing countries." He told heartwire that he and Nicholas Wald have invested in development of the polypill and would hope to recover that investment, "but our overwhelming motivation is the public health objective."
Wald explains why aspirin was not included in their formulation: "We took a decision to leave aspirin out of a CVD prevention polypill because it is the only component that runs a reasonable chance of serious harm. Of course it's also useful in preventing heart attacks and strokes, but once you have achieved the large BP and cholesterol reductions that we have shown in our trial, the residual benefit you get from aspirin does not justify its risk in CVD prevention."
Aspirin is the only component of a polypill that runs a reasonable chance of serious harm.
In total, 86 participants who were already enrolled in a CVD-prevention program at the Wolfson Institute and had previously been taking the individual components of the polypill were randomized to the polypill or placebo for 12 weeks. They then crossed over and took the other treatment. Mean within-person differences in BP and LDL cholesterol at the end of each 12-week period were determined, and 84 of 86 participants completed the study.
The mean systolic BP reduction was 17.9 mm Hg, diastolic BP fell by 9.8 mm Hg, and LDL was cut by 1.4 mmol/L; these results are almost identical to those predicted when the polypill was first proposed by Wald and Law, say the researchers.
Although the trial was too short to assess the impact on CV events, sustained reductions in BP and cholesterol of this magnitude would reduce ischemic heart disease events by 72% and stroke by 64%, they estimate.
The fact that this is the only crossover trial of a polypill is an important design issue, says Wald, "because it has allowed us to produce highly accurate estimates of effectiveness, with a relatively small number of participants." Previous trials that used a parallel-group design have shown smaller effects, he notes, with as many as a quarter of participants in such trials not adhering to the allocated treatment. "We believe that our results are the most accurate, direct, observations of the use of a polypill to date," he notes.
We believe that our results are the most accurate, direct, observations of the use of a polypill to date.
However, the trial design also means there are some limitations, he says. First, the high adherence rate observed (98%) is likely a result of those in the trial previously having taken the individual components of the polypill and, as such, this adherence rate cannot be used to estimate compliance in the general population. Second, "the results on tolerability cannot be used to estimate the prevalence of side effects in people who have not previously taken polypill components," he says.
Side effects were more frequent with the polypill than placebo (29% vs 13%, p=0.01), although none were serious enough to cause discontinuation. Myalgia was more common with the polypill compared with placebo (11% vs 1.2%, respectively).
'No-Fuss' Approach Starting to Be Embraced by Medics
"Scientifically, age is the dominant risk factor in predicting whether somebody will or won't have a heart attack or stroke, so it makes sense to use it in the selection of people who are offered the polypill," Wald commented. "Information on a person's BP and cholesterol adds very little extra information and is not worth the cost and complexity."
I do not believe that everybody would choose to take [the polypill], but it's really up to the regulatory agencies to make it clinically available and the medical profession.
The idea that a polypill could be an acceptable treatment offered purely on the basis of age "is one that was initially rejected by the medical community, but now it is starting to be embraced," he notes. "People like the idea of a no-fuss approach to having access to preventive treatment that does not necessarily involve going to your doctor and certainly does not involve being labeled as a patient."
"I do not believe that everybody would choose to take [the polypill], but it's really up to the regulatory agencies to make it generally available, and the medical profession to provide people with the information on its effectiveness and the possibility of its side effects, then let individuals choose for themselves," he concludes.
Nicholas Wald jointly holds European and Canadian patents (EU1272220 priority date April 10, 2000) for a combination pill for CVD prevention (pending in the USA) and, together with David Wald, has an interest in its development. Cipla provided the pills used in their crossover trial free of charge.
References
1. Wald DS, Morris JK, Wald NJ. Randomized polypill crossover trial in people aged 50 and over. PLoS ONE 2012; 7:e41297. Available here.
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