“A new 10p-a-day ‘polypill’ containing aspirin and statins halves the risk of heart disease and stroke, according to the world’s first international trial of the drug,” reported The Daily Telegraph.
The news story is based on a randomised controlled trial of a polypill in 378 people who all had a slightly increased risk of vascular disease. The researchers found that people who took the polypill had improvements in their blood pressure and levels of “bad” LDL cholesterol (equivalent to a 46% reduction in cardiovascular risk) over 12 weeks, compared to those who took a dummy pill.
Other trials of polypills have reported reductions in risk factors for heart disease and stroke. However, the authors of this study say that theirs is the first to test rigorously for the risk of side effects. It also found the polypill to be effective for people who were only at a slightly increased risk of a heart attack or stroke, and who wouldn’t ordinarily be prescribed any of the single components of the combination pill.
The trial provides useful data on adverse effects and reinforces the value of considering all risk factors together. Longer trials enrolling more people will be needed if improvements in survival and other important outcomes are to be measured. One large trial of this polypill (called the Red Heart Pill) in 2,000 people was started in May 2010. The trial will be completed in 2013 and if the results are positive it is likely that approval of this drug will not be far away. This pill will not replace the need to maintain a healthy lifestyle through exercise, eating well and remaining smoke-free.
Where did the story come from?
The study was carried out by members of the PILL collaborative group, an international group of researchers based in Australia, New Zealand, Brazil, the Netherlands, India, the UK and the US. It was funded by a range of organisations including The Wellcome Trust, the Health Research Council of New Zealand, the National Heart Foundation of New Zealand, the National Health and Medical Research Council of Australia, the Brazilian Ministry of Health (Projeto Hospitais de Excelencia) and the British Heart Foundation.
The polypill itself is called the Red Heart Pill and was manufactured and provided free of charge by Dr. Reddy’s Laboratories in India.
The study was published in the peer-reviewed medical journal PLoS One .
The newspapers all cover this study accurately and address the importance of its findings. Some headlines might seem overstated for a small short study. These headlines might be best reserved for a larger and longer trial, if one is conducted, which does show the direct saving of lives.
What kind of research was this?
This was a randomised controlled trial of a polypill (a pill combining several drugs), containing four ingredients already known to reduce the main risk factors for vascular disease:
- aspirin (75 mg), for thinning the blood
- lisinopril (10 mg), for reducing blood pressure
- hydrochlorothiazide (12.5 mg), also for reducing blood pressure
- simvastatin (20 mg), for reducing “bad” LDL cholesterol
The researchers explain that although there has been widespread interest in the potential of this sort of combination pill in reducing rates of cardiovascular disease, there have been few reliable placebo-controlled trials testing how well they work and how well they are tolerated. They say that it would not be possible to carry out placebo-controlled trials in people who already meet the criteria for being treated with the individual drugs in the polypill, as giving a placebo drug in this situation would not be ethical. They therefore chose people who had an estimated five-year cardiovascular disease risk over 7.5% (slightly elevated risk) when all risk factors were considered, but who were not such a high risk that they would have been eligible for the separate drugs outside of the trial.
A randomised controlled trial is an appropriate way to answer a question such as this.
What did the research involve?
The researchers say that as far back as 2002 the World Health Organization (WHO) highlighted the potentially substantial public health impact and cost-effectiveness of scaling up access to this sort of combination treatment. It has been estimated that a four-component combination pill could reduce cardiovascular risk by about 75% among people with vascular disease. However, until this research, the polypill hadn’t been tested as a preventative treatment in people without vascular disease.
The researchers calculated that their trial would need about 400 people to detect important differences in risk factor levels between the treatment and placebo groups. They mainly recruited people with a calculated cardiovascular disease (CVD) risk over five years of at least 7.5% using standard assessment tools (the Framingham risk function). All the participants were over 18 and none of them had any indications of contraindications that would prevent them taking any of the component medicines in the polypill.
The researchers recruited from seven countries (Australia, Brazil, India, the Netherlands, New Zealand, the UK and the US) between October 2008 and December 2009.
Of the 859 people who were registered for the study, 351 were excluded because their risk was too low and 35 because they had individual risk factors that were too high. Others were excluded if they did not complete the baseline forms. This left 378 eligible participants who were randomly allocated to one of two groups by computer. One group was given the polypill, the other an identical dummy pill.
The researchers measured cardiovascular risk factors at the beginning of the study, including:
- blood pressure
- blood cholesterol profile
- fasting sugar
- body mass index
- kidney function
- family history of premature coronary heart disease
Blood pressure and cholesterol were again measured at 2, 6 and 12 weeks after the participants were randomised into each group, with a final appointment at 16 weeks. The researchers also looked at how regularly the participants took the drugs (adherence), the tolerability of the drugs and any adverse events.
What were the basic results?
Most patients were aged between 50 and 70 years old. Overall, 22% of the participants had a five-year cardiovascular risk of 5% to 7.5% according to the Framingham scale and 3% had a five-year cardiovascular risk of more than 20% (equivalent to the risk faced by those with previous vascular disease events).
At the start of the study, the participants’ average blood pressure was below the level usually treated with drugs (BP was 134/81 mmHg and mean LDL-cholesterol was 3.7 mmol/L).
After 12 weeks, the polypill group had an average reduction in systolic blood pressure (the top reading) of 9.9 mmHg (95% confidence interval [CI] 7.7 to 12.1). LDL-cholesterol was reduced by 0.8 (95% CI 0.6 to 0.9) mmol/L. These reductions in risk factors translate to a 46% (about half) reduction in risk of future vascular events (such as heart disease, ischaemic stroke, haemorrhagic stroke or major extra-cranial bleed).
Although the majority of participants (98.7%) attended the follow-up sessions and completed the trial, the number of people who stopped taking the drugs were high in both the polypill and the placebo group. The discontinuation rates between the groups were similar however: 23% of people in the polypill group discontinued compared to 18% in the placebo group (RR 1.33, 95% CI 0.89 to 2.00, p = 0.2).
As expected, there were also more recognised side effects from the component medicines in the polypill compared with the placebo (58% vs 42% in the placebo group, p = 0.001). These mostly happened in the first few weeks and the side effects usually did not warrant an end to taking the polypill.
How did the researchers interpret the results?
The researchers say that the polypill achieved sizeable reductions in blood pressure and cholesterol, but caused side effects in about one in eight people. They do say that their study found the benefits of the polypill were not as great as previous studies had found (about half), and that the incidence of side effects was greater. However, the balance of effects are still in favour of the polypill.
The researchers say that 80% of the global burden of cardiovascular disease occurs in low- and middle-income countries and that very few people who need these sorts of medicines receive them. They say that access to this highly cost-effective strategy [the polypill for prevention of vascular disease] could achieve most of WHO’s goals for reducing non-communicable disease.
This was a carefully designed and well-conducted study that found the polypill to have a beneficial effect in reducing cardiovascular risk factors in people who were at minimal risk. Although side effects of the polypill did occur, it seems that the balance is still in favour of the benefits of this treatment. The researchers make the following points:
- The randomised groups in this study were well balanced across a range of characteristics at study entry, suggesting that the two groups were comparable and the randomisation was effective.
- The risk factor reductions seen in the current trial were about half the size predicted by previous studies because those studies were in people who were estimated to be at a greater cardiovascular risk. Those studies were also in polypills that were made up of stronger statins and blood pressure-lowering agents. The researchers point out that the reduction in predicted heart attacks and strokes in this study (46%) is still very reasonable. This is reassuring as it means that lower doses of these drugs used together can still achieve useful reductions in risk.
- The researchers point out that among patients who have already had a heart attack or stroke, further evidence for the individual medication classes is not required, as trials involving tens of thousands of patients have already shown them to be of benefit. All major cross-disciplinary guidelines now recommend these three drug types.
- The 42% of people (79 individuals) who experienced an adverse effect to the placebo pill is of interest, and although these effects were all mild, it suggests that this group of people may have had high expectations of side effects. For example, 7% of people in both active and placebo groups reported muscle pain or weakness, a symptom that is commonly reported.
- Gastric irritation (indigestion) was a common side effect of the pill and formulations that reduce this could be considered.
Overall, this study provides useful data on the adverse events and modelled benefits of the polypill in terms of reductions in risk factors for heart disease and stroke. It adds to the growing body of evidence that a new approach to reducing vascular risk based on several commonly used drugs will be simple, cheap and effective. It may even become the standard of care.
Among people at this level of heart disease risk, smoking cessation, dietary change and physical activity will also be beneficial, with or without the polypill.