Group Project on Study Design: PolypillxAspirin Project Notes
GROUPS 3 and 4
Does a polypill, which contains low doses of blood pressure (BP) and lipid
lowering drugs reduce the risk of morbidity and mortality from cardiovascular
disease (CVD); and does aspirin reduce the risk of a composite outcome of
CVD or cancer. Both of these objectives are to be addressed in a randomized
double-blind placebo controlled 2x2 factorial trial.
High blood pressure and cholesterol are leading risks to health in the U.S. and other
economically developed countries. These risks cause a large and growing burden in
developing countries also. The increased risk of a cardiovascular disease (CVD)
event is not restricted to those with “hypertension” or “hypercholesterolemia”, but is
continuous down to at least a blood pressure of 115/75mmHg and total cholesterol
level of 135 mg/dL (4.0 mmol/l). There is now clear evidence from large randomized
trials in people with established cardiovascular disease of benefits of blood pressure
and cholesterol lowering and antiplatelet therapy, largely irrespective of baseline risk
factor levels (1,2). However, there remains uncertainty about whether these benefits
extend to primary prevention among people without hypertension or dyslipidemia. As
a result, very few individuals receive combination therapy for primary prevention,
even though many with multiple, moderate elevations of risk factors are at
considerably elevated cardiovascular risk.
The net benefits of combined treatment with aspirin, blood pressure lowering and a
statin on CVD could be substantial, since each intervention works in addition to the
others. Based on extrapolation from previous trials, more than a halving of
cardiovascular risk might be expected (increasing to two-thirds or more of a
reduction after the first year or two, once the full effects of the component
medications accrue). Aspirin has also been associated with decreased risk of cancer
death (3).
Adverse effects can be minimized with low-dose combinations of blood pressure
lowering agents and of aspirin. Based on extrapolation from previous trials, adverse
effects would be outweighed several-fold by the net benefits among individuals at
moderate-to-high cardiovascular risk. However, direct randomized evidence is
lacking, of both joint benefits on CVD and long-term adverse effects. Short-term
effects of a polypill on blood pressure, lipids and side effects have been reported
(4,5).
Important considerations/questions in the design of this trial are: 1) how much
nutritional-hygienic advice should participants in the study be given? 2) definition of
“above average risk for CVD” (definition of target population); 3) definition of CVD
(e.g., myocardial infarction, stroke, other CVD) and cancer outcome; 4)
management of study participants whose BP and lipids increase to levels indicating
treatment during follow-up; and 5) potential for interaction and impact on sample
size.
You can assume that the polypill contains low doses of a diuretic (chlorthalidone), an
ACE inhibitior (lisinopril), and a statin (simavastatin). Placebos are available for both
the polypill and aspirin
Some literature to get you started is listed below:
1. Wald, N. and M. Law, A strategy to reduce cardiovascular disease by more
than 80%. British Medical Journal, 2003. 326: p. 1419-1424.
2. Reddy KS. The preventive polypill – much promise, insufficient evidence. N
Engl J Med 2007; 356:212.
3. Rothwell PM et al. Short-term effects of daily aspirin on cancer incidence,
mortality, and non-vascular death: analysis of the time course of risks and
benefits in 51 randomised controlled trials. Lancet 2012; 379:1602-1612.
4. The Indian Polycap Study. Effects of a polypill (Polycap) on risk factors in
middle-aged individuals without cardiovascular disease. Lancet 2009;
373:1341-1351.
5. Pill Collaborative Group. An international randomized placebo-controlled trial
of a four-component combination pill (“Polypill”) in people with raised
cardiovascular risk. PLoS One 2011.