Combination Therapy to Prevent Cardiovascular Disease
Authors: Richard Smith, Tara McCready, Salim Yusuf
Journal: JAMA (2013)

CARDIOVASCULAR DISEASE IS THE MAJOR CAUSE OF mortality and morbidity globally and affects half of all individuals over their lifetimes. The burden of cardiovascular disease in developing countries is increasing substantially, and cardiovascular disease is becoming the leading cause of death. The concept of combining antihypertensive drugs, a statin, and aspirin into a single, fixed-dose, combination pill to prevent myocardial infarction and stroke is now a dozen years old, but still no such pill is licensed in most countries. Only a small proportion—perhaps fewer than 10%—of individuals in the world who have, or are at high risk of developing, cardiovascular disease receive appropriate drugs for preventing future myocardial infarction or stroke. Many people at high risk are not identified because of a lack of systematic screening. Of those who are diagnosed, many are not treated because of unavailability or unaffordability of drugs, cumbersome treatment regimens, and lack of wellfunctioning health systems. Even patients who do receive treatment often have poorly controlled risk factor profiles because of an emphasis on treating individual conditions like hypertension or diabetes rather than the overall risk of cardiovascular disease. Moreover, adherence is universally poor, with less than half of those patients who are prescribed antihypertensive, lipid-lowering, or antidiabetic drugs continuing treatment beyond 1 year. These issues lead to a massive treatment gap and an opportunity for reducing cardiovascular disease. Actions like reducing tobacco consumption within the population are essential, but including the key medications necessary to reduce the risk of cardiovascular disease into a single pill could increase use of effective and inexpensive medications, thereby lowering costs and improving treatment adherence. In most lowand middle-income countries it will also be necessary to strengthen health systems with systematic screening and follow-up through greater use of nonphysician health workers and innovative and simple communication technologies. Different fixed-dose combination pills are now available in India, Mexico, and Central and South America. At least 6 randomized trials have shown that the combination of several antihypertensive agents, a statin, and aspirin can substantially reduce blood pressure and lipid levels and, when aspirin is included, inhibit platelet aggregation. The pills are well tolerated and have low rates of adverse effects and discontinuation. The trials have shown high adherence, although most have been of short duration. However, a recent large trial analyzing patients from 12 to 18 months showed that compared with usual care and separate drugs, combination pills produced a greater reduction in blood pressure and lipid levels. However, none of the trials as yet has included clinical outcomes, and there is debate among researchers and regulators over the importance of large outcome studies. Most will want trials with clinical outcomes to consider a combination pill for use in primary prevention. At least 2 large international trials (TIPS-3 and HOPE-3) are currently under way testing a combination pill (or its concept) against placebo, but it will be several years before results are available. While showing that each component of a combination pill contributes to the overall benefit is theoretically optimal, such trials are simply not practical given the necessary size and follow-up time that will be needed. As discussed during panel sessions held at the Global Summit on Combination Polypharmacy for Cardiovascular Disease in Hamilton, Canada, in 2012, regulators might not insist on this type of study if there is convincing evidence that a combination pill leads to a substantial reduction in cardiovascular disease (40% or 50% more than usual care), a level of benefit that cannot be expected from using any single agent. Licensing is an essential step for developing combination therapy, but these treatments present new problems for regulators. Both the US Food and Drug Administration and the European Medicines Agency have approved 2and 3-drug combinations, but neither has approved combinations of 4 or 5 drugs. An emerging opinion among researchers and some regulators is that outcome studies are not needed (nor practical nor ethical) for licensing of fixed-dose combination pills for secondary prevention as long as the expected effects on