Thursday July 19 2012
Can a £1 pill containing four drugs prevent thousands of deaths?
“Four-in-one pill to save 200,000 lives a year,” reports the Metro, with many other media sources making similar claims.
This news is based on research into a ‘polypill’, a single tablet that contains a combination of four different medicines that are designed to lower cholesterol and blood pressure.
The researchers concluded that giving the polypill to individuals over the age of 50 who have no history of cardiovascular disease could significantly reduce their risk of developing cardiovascular disease. Cardiovascular disease can lead to a heart attack or stroke.
But the many headlines on this story predicting that “thousands of lives would be saved” are premature.
First, the study was small – looking at only 84 people – which makes it difficult to generalise the results to a wider population. Additionally, the study did not look into the safety and side effects associated with using the polypill as a preventative medication. Larger studies will be needed to check if widespread and long-term use of the medication is associated with severe side effects in a low-risk population. Similarly, it is still unclear whether everyone who took the polypill would benefit.
Second, it is far from certain whether large sections of the population would be willing to take a medication if they were not actually unwell.
Some news sources did report a sensible note of caution from a spokesman for the British Heart Foundation who pointed out that “However interesting this potential new pill is, medicines are not a substitute for living a healthy lifestyle”.
Where did the story come from?
The study was carried out by researchers from the Wolfson Institute of Preventative Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of London. It was funded by the pharmaceutical company Cipla, and Barts and the London Charity. One of the study authors holds the European and Canadian patent for the polypill.
The study was published in the peer-reviewed journal PLoS ONE.
This research was covered well by the media. BBC News, the Daily Mail, the Metro and The Daily Telegraph all reported on the reductions seen during the trial and the potential benefits of the drug, and also discussed critics’ concerns over the mass prescription of four cardiovascular drugs based on age alone. But many of the headlines used by the media were unduly optimistic given the current status of the research.
Several news outlets also reported on the potential conflict of interest that arises from the author’s holding of the polypill patent.
What kind of research was this?
This was a randomised placebo-controlled crossover trial that examined the effect of the polypill on blood pressure and low density lipoprotein (LDL) or ‘bad’ cholesterol. Crossover trials are similar to the more common parallel group randomised controlled trials in that they randomise participants to receive either the drug or a placebo. Unlike parallel group trials, however, instead of splitting participants into two distinct groups based on treatment, all participants receive the drug for a certain period of time and then switch – or crossover – to the placebo treatment. Participants are randomised to the order in which they will receive treatments, and not to a single treatment group.
Crossover trials have several advantages. Each participant essentially acts as his or her own control, and changes seen in a participant during the treatment phase can be directly compared to changes seen during the placebo phase. This means that if fewer participants are included the results remain statistically significant.
This study design can also reduce bias that may occur as participants drop out of the study. If a person drops out, they are removed from both the treatment and comparator groups, and do not create an imbalance during data analysis.
There are limitations to crossover trials, however, that need to be taken into account during the study design. As all participants receive both the treatment and placebo, researchers need to consider whether there will be residual treatment effects that may carry forward into the next phase of the study. For instance, among participants who receive the polypill first and placebo second, there is a chance that after they stop taking the polypill, there are residual effects in terms of blood pressure or cholesterol levels that lead to inaccurate measurements during the placebo phase. In order to adjust for this, researchers generally introduce a washout period during the treatment phases to ensure that residual treatment effects are kept to a minimum.
What did the research involve?
The researchers recruited 86 individuals over the age of 50 living in London, who were taking a statin and blood-pressure lowering drugs as part of a cardiovascular disease prevention programme. The participants had no history of cardiovascular disease, and were recruited based on age alone. The participants were randomised to receive placebo or the polypill, which contained half the standard doses of blood-pressure lowering drugs amlodipine, losartan, hydrochlorothiazide and a full 40mg dose of the cholesterol-controlling drug simvastatin. After 12 weeks of taking the assigned drug, the participants crossed over to the alternative treatment option – those initially receiving placebo began taking the polypill for 12 weeks, and those receiving the polypill switched over to taking the placebo. Neither the patients nor the researchers were aware of the order in which they took the pills.
At the end of each 12-week trial phase, the researchers measured systolic and diastolic blood pressure, as well as LDL cholesterol. They then assessed, for each participant, the average difference between blood pressure and cholesterol measurements obtained at the end of placebo treatment and those obtained at the end of polypill treatment.
What were the basic results?
In all, 84 participants completed the trial and were included in the data analysis. Compared with placebo, polypill treatment led to:
- an average reduction in systolic blood pressure of 17.9mmHg (95% confidence interval [CI] -20.1 to -15.7mmHg, p<0.001), which is a 12% reduction from placebo levels (p<0.001)
- an average reduction in diastolic blood pressure of 9.8mmHg (95% CI -11.5 to -8.1mmHg, p<0.001), which is an 11% reduction from placebo levels (p<0.001)
- an average reduction in LDL cholesterol of 1.4mmol/L (95% CI -1.6 to -1.2mmol/L, p<0.001), which is a 39% reduction from placebo levels (p<0.001)
These reductions were similar to those expected based on the performance of each individual drug, as assessed by previous research.
The researchers used the data on blood pressure and LDL cholesterol reductions, as well as existing evidence on the relationship between these risk factors and cardiovascular disease, to predict the effect of polypill treatment in terms of cardiac events and strokes.
They estimated that if the reductions seen in this trial were sustained over a long period of time, polypill use could lead to a 72% reduction in ischaemic heart disease events (heart attacks) and a 64% reduction in strokes.
How did the researchers interpret the results?
The researchers concluded that the polypill “has considerable potential for the prevention of cardiovascular disease”.
This study suggests that daily treatment with a polypill led to significant reductions in blood pressure and LDL (or ‘bad’) cholesterol in over-50s with no history of cardiovascular disease. Whether this translated into actual reductions in cardiovascular disease was not assessed.
The attraction of a polypill lies in its simple dosing schedule, which may improve how easy it is to take regularly. By offering it to all people over 50 years who can take it, the regular monitoring of blood pressure and cholesterol might become largely unnecessary.
This could be an important development in the prevention of cardiovascular disease, which is the leading cause of death in the UK. However, there are several limitations to the study that should be noted before policies are introduced regarding the widescale use of a polypill for all individuals over the age of 50 (as has been mentioned in several news stories):
- The authors report that this is the first randomised trial to assess the efficacy of a polypill in participants selected solely on age, though four other trials of the pill have been reported.
- Participants were drawn from individuals already on statins or blood-pressure lowering medication as a preventative measure. It is unclear if the same reductions in blood pressure and cholesterol would be seen in all over 50s, despite risk and medication status.
- This trial assessed changes in two cardiovascular disease risk factors, not cardiac events themselves. Further large-scale research would be necessary to see whether the reductions in blood pressure and cholesterol translate into reductions in heart attacks and strokes as projected.
- While the safety profile of these drugs has been previously studied, and these drugs are often prescribed separately, whether the risk–benefit trade off is acceptable for all healthy people over 50 years without ‘non-age’ risk factors is still unclear.
- The trial did not include a distinct washout phase, but the researchers report that the length of each treatment phase (12 weeks) should be sufficient time for the polypill treatment effects to have subsided.
Overall, this study indicates that we are closer to a single pill that combines several heart disease medications. Before a polypill is used as a widespread primary prevention policy, several questions will need to be considered, including:
- whether this trial’s results will hold in the entire over-50 (low risk) population
- what exactly is the most suitable role of a polypill in preventing heart disease (especially when combined with lifestyle changes that can also reduce risk)
- what is the patient view of what is an acceptable risk–benefit profile of the drugs for prevention, as opposed to treatment, of cardiovascular disease risk factors
Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on twitter.