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6th April 2009
The Indian Polycap Study (TIPS), a short term, phase II study, suggests that a combination capsule which includes five active ingredients has similar effects on cardiovascular (CV)-related physiological parameters (disease-oriented outcomes, DOOs) as its component ingredients and similar risk of side effects. Despite reports in the lay media indicating reductions in “heart attacks”, this short term study was unable to report patient-oriented outcomes (POOs) such as rates of MI, stroke or death from CV causes. Similarly, long term safety data could not be determined given the nature of this research.
Action
This study is a necessary step in the development of the polypill approach. However, no action is required or possible at present. Introduction of a polypill is still some years from clinical practice. Policy issues such as the appropriate level of cardiovascular risk at which this approach is utilised, the medicalisation of a significant proportion of the adult population over the age of 55 years, and the abandonment of personalising treatment will need to be resolved, before its appropriate place, if any, in therapy can be identified.
What is the background to this?
The idea of polypill was first suggested more than five years ago. The idea was to formulate a single daily medication which would contain a cocktail of cardiovascular (CV) medicines, which would be taken by everyone over the age of 55, regardless of previous CV disease or CV risk factors. The original proponents of this strategy estimated that the combination they proposed would reduce the relative risk of stroke by about 80% and of ischaemic heart disease (IHD) by 88%. This projection was based on two assumptions: firstly that the combination would produce similar effects on physiological parameters (blood pressure [BP], lipid levels, etc) in people with population average levels as the single drugs did in trials, and secondly that these effects on CV-related physiological parameters (disease-oriented outcomes, DOOs) would translate into beneficial effects on patient-oriented outcomes (POOs) such as rates of myocardial infarction (MI), stroke or death from CV causes. In addition, the reduction in absolute risk of CV events would have to outweigh the risk of unacceptable side effects.
The possible benefits of the original polypill were estimated by mathematical modelling. In this study, researchers took a step further by testing a modified recipe for the polypill (the Polycap) in a relatively small number of people, and examined the effects on DOOs.
What does this study claim?
People without CV disease but with one CV risk factor were randomised to receive the Polycap daily (containing hydrochlorthiazide 12.5mg, atenolol 50mg, ramipril 5mg [2.5mg for the first 7 days], simvastatin 20mg and aspirin 100mg), or one of eight other regimens: aspirin alone, simvastatin alone, hydrochlorthiazide alone, three combinations of two of the BP-lowering drugs, all three BP-lowering drugs alone, or the three BP-lowering drugs plus aspirin. There were 412 people in the Polycap group and about 200 people in each of the comparator groups. Participants received the treatment for 12 weeks and were followed up for 16 weeks.
The Polycap was non-inferior to its individual constituents in lowering blood pressure and heart rate. It lowered LDL-cholesterol and urinary 11-dehydrothromboxane B2 (an indicator of antiplatelet activity) slightly less effectively than simvastatin or aspirin did alone (respectively). The authors model a more modest, but still substantial relative reduction in risk of IHD and stroke than the originators of the polypill idea: 62% and 48% compared with 88% and 80%, respectively.
Nearly 15% (1 in 7) of participants overall stopped treatment early; this was because of drug-specific reasons in a quarter of those who stopped treatment, or 1 in 26 of all participants. Rates of side effects and discontinuations in the Polycap group were similar to the comparator groups, but these could be significant for individuals: for example, 4.4% of participants who took the Polycap had serum potassium levels >5.5mmol/L, 2.9% had a doubling of ALT and 8.5% experienced an increase of >50% in serum creatinine.
So what?
These results are interesting, but of course this data cannot show whether the DOOs reported will translate into POOs. The individual ingredients of the Polycap have been shown to reduce rates of CV outcomes (MI, stroke, CV death, etc) in some populations, but not all have been shown to reduce rates in all populations. For example, in the POPADAD study, aspirin was found not to reduce the risk of CV events in patients with diabetes and asymptomatic peripheral arterial disease. Beta-blockers including atenolol have been shown to be beneficial in patients who have had an MI, and are recommended as a core treatment in NICE guidance on secondary prevention of MI. However, beta-blockers have been found to be less effective in reducing CV events, especially stroke, than other drugs in people with hypertension. Beta-blockers are therefore a fourth line treatment when initiating drug management hypertension in the NICE hypertension guidance and the NICE guidance on management of type 2 diabetes.
This highlights the ethical problem identified by some opponents of the polypill idea. Although all the ingredients of the Indian Polycap are available for prescription separately, prescribers would normally tailor treatment to the individual patient. Although rates of side effects and tolerability did not seem to differ greatly between the participants taking the Polycap and those taking either single drugs or simpler combinations, these side effects could be significant for some individuals. To reformulate a polypill for an individual person which would not contain a drug that that person could not tolerate or which was unnecessary for them (e.g. a beta-blocker because they had not had an MI) would negate the essential idea behind the polypill. On the other hand, as the accompanying editorial comments, a simple, low-cost treatment could be attractive to areas of the world with limited resources for healthcare, and could potentially improve adherence in countries where resources for healthcare are more available yet people with CV risk factors do not take treatment. However, adherence rates in practice with a polypill will remain in the domain of speculation for some time.
In the meantime, those who wish to consider non-drug interventions to reduce their cardiovascular risk could review the polymeal – an evidence based recipe including wine, fish, dark chocolate, fruits, vegetables, garlic, and almonds. In this alternative modelling study, data from the Framingham heart study and the Framingham offspring study were used to build life tables to estimate the benefits of the polymeal in the general population from age 50. The authors estimated that combining the ingredients of the polymeal would reduce cardiovascular disease events by an impressive 76%. For men, taking the polymeal daily would represent an increase in total life expectancy of 6.6 years, an increase in life expectancy free from cardiovascular disease of 9.0 years, and a decrease in life expectancy with cardiovascular disease of 2.4 years. The corresponding differences for women were 4.8, 8.1, and 3.3 years. Whilst the real world adherence rate to the polymeal remains as uncertain as the polypill, it seems possible that the side effect profile of the polymeal would be lower than the polypill.
The Polycap study is discussed further in a recent NPC podcast.
Patients: 2053 people aged between 45 and 80 years without established CV disease but with one CV risk factor (type 2 diabetes, BP>140mmHg systolic or 90mmHg diastolic but less than 160/100mmHg, smoker within past 5 years, increased waist to hip ratio [>0.85 for women and >0.90 for men], LDL-cholesterol >3.1mmol/L or HDL-cholesterol <1.04mmol/L).
Intervention and comparison: Polycap daily (containing hydrochlorthiazide 12.5mg, atenolol 50mg, ramipril 5mg [2.5mg for the first 7 days], simvastatin 20mg and aspirin 100mg), or one of eight other regimens: aspirin alone, simvastatin alone, hydrochlorthiazide alone, three combinations of two of the BP-lowering drugs, all three BP-lowering drugs alone, or the three BP-lowering drugs plus aspirin. There were 412 people in the Polycap group and about 200 people in each of the comparator groups. Participants received the treatment for 12 weeks and were followed up for 16 weeks.
Outcomes: The Polycap was non-inferior to its individual constituents in lowering blood pressure and heart rate. It lowered LDL-cholesterol and urinary 11-dehydrothromboxane B2 (an indicator of antiplatelet activity) slightly less effectively than with simvastatin or aspirin alone (respectively). Discontinuation rates and reasons were similar in all nine groups. In the Polycap group, 6.3% participants developed dizziness or hypotension, 5.3% developed cough, 1.2% developed gastritis or dyspepsia, 1.7% developed fatigue, 0.2% developed bradycardia, the serum creatinine of 8.5% increased by >50%, the serum potassium increased to >5.5mmol/L in 4.4% and the ALT (called serum glutamic pyruvic transaminase, SGPT in the paper) doubled in 2.9%.
Sponsorship: Cadila Pharmaceuticals, Ahmedabad, India.
More information on CV risk, its assessment and management be found on the cardiovascular section of NPC
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