Giving people an inexpensive pill containing generic drugs that prevent heart attacks — an idea first proposed 20 years ago but rarely tested — worked quite well in a new study, slashing the rate of heart attacks by more than half among those who regularly took the pills.
If other studies now underway find similar results, such multidrug cocktails — sometimes called “polypills” — given to vast numbers of older people could radically change the way cardiologists fight the soaring rates of heart disease and strokes in poor and middle-income countries
Even if the concept is ultimately adopted, there will be battles over the ingredients. The pill in the study, which involved the participation of 6,800 rural villagers aged 50 to 75 in Iran, contained a cholesterol-lowering statin, two blood-pressure drugs and a low-dose aspirin.
But the study, called PolyIran and published Thursday by The Lancet, was designed 14 years ago. More recent research in wealthy countries has questioned the wisdom of giving some drugs — particularly aspirin — to older people with no history of disease.
The stakes are high. As more residents of poor countries survive childhood into middle age and beyond — and as rising incomes contribute to their adoption of cigarette smoking and diets high in sugar and fat — a polypill offers a way to help millions lead longer, healthier lives.
About 18 million people a year die of cardiovascular disease, and 80 percent of them are in poor and middle-income countries threatened by rising rates of obesity, diabetes, tobacco use and sedentary living.
Medical experts, however, are sharply divided over the polypill concept.
Its advocates — including some prominent cardiologists — point to the study as evidence that the World Health Organization should endorse distributing such pills without a prescription to hundreds of millions of people over age 50 around the globe. Some have estimated that widespread use could cut cardiac death rates by 60 to 80 percent.
“The polypill concept is very important and it’s surprising that it’s taking so long for people to accept it,” said Dr. Salim Yusuf, director of the Population Health Research Institute at McMaster University in Canada and an expert on cardiac health in poor countries, who was not involved in the Iran study. “This study takes us one step closer.”
Other leading cardiologists consider the approach unethical and dangerous. Because aspirin, statins and blood-pressure drugs all have side effects, they argue, no one should get them without first being assessed for risk factors like high blood pressure, high cholesterol or family history.
“I’m a skeptic of the one-size-fits-all, four-drugs-for-everyone approach,” said Dr. Steven E. Nissen, head of the department of cardiovascular medicine at the Cleveland Clinic. “It runs counter to what most of us in the U.S. consider good medical practice.”
Simple tests, including cholesterol tests that use only a finger prick, are available, he noted.
Dr. Thomas R. Frieden, a former director of the Centers for Disease Control and Prevention and now the president of Resolve to Save Lives, an organization that seeks to lower worldwide cardiac deaths, said he thought a four-drug pill like the one used in the study was appropriate only for people who had suffered a cardiac event.
Some blood pressure medications are safe enough to give to untested people, he said, but aspirin, which can cause bleeding in the brain, and statins, which can, in rare cases, cause liver and muscle damage, are not.
The Iran study was conducted by doctors from Tehran University, the University of Birmingham in Britain and other institutions.
It was the first study of such a multidrug pill that was large and long-lasting enough to measure “clinical outcomes” — how many people actually had heart attacks, strokes or episodes of heart failure while taking the pills, rather than just how many, for example, lowered their blood pressure or cholesterol.
Similar studies are underway in many countries.
However, since there is so much controversy about the ingredients used in the medication, each study has its own pill recipe.
Dr. Yusuf is leading the TIPS 3 trial on about 5,700 people in Bangladesh, Canada, Colombia, India, Malaysia, the Philippines, Tanzania and Tunisia; it uses a pill containing three blood-pressure drugs and a statin. (The trial’s three other “arms” use low-dose aspirin, vitamin D and a placebo pill.) It is expected to end in March.
And the SECURE trial is recruiting about 3,200 patients in seven European countries who are over 65 and have already had one heart attack. Its pill contains aspirin, a statin and a single blood-pressure drug. It is expected to end in late 2021.
In the Iran trial, those assigned to take pills had a third fewer cardiac events over five years than the control group, whose participants got face-to-face advice and monthly text reminders to lose weight, stop smoking, eat healthy food and exercise.
(Because it was conducted in northern Iran, they were also advised to avoid another local habit — opium smoking.)
All participants were asked to return their used blister packs of pills. Those who appeared to have taken at least 70 percent of them had the highest protective effect — 57 percent fewer cardiac events.
The rates of serious adverse events were similar in both groups. Only a few in each trial arm suffered from bleeding in the brain, the stomach or the intestines, all of which can be caused by aspirin.
Mysteriously, although the cholesterol levels of those who got the pills dropped significantly during the trial, their blood pressure levels did not.
That puzzled several experts who looked at the results, including Dr. Frieden, who said the two anti-hypertension drugs used — a diuretic and an ACE inhibitor — should have significantly cut blood-pressure levels.
“That result doesn’t make sense,” he said.
Dr. Tom Marshall, a cardiac disease prevention specialist at the University of Birmingham and a co-author of the study, acknowledged the anomaly, saying, “I wish I had the answer.”
Baseline blood pressures in the population were not high, averaging 130 over 79, he said.
Dr. Frieden said he was also troubled that the trial did not explain whether blood pressure readings were taken by machine or by people with stethoscopes. Some machines and some poorly trained humans get inaccurate results, he said.
The trial was conducted in the “Golestan Cohort,” a group of more than 50,000 Turkmen-speaking people currently enrolled in cancer studies administered by Iranian researchers in coordination with the W.H.O. and the National Cancer Institute.
Dr. Rekha Mankad, director of the Women’s Heart Clinic at the Mayo Clinic in Minnesota, who was not involved in the Iran study, said it had some flaws, including early problems with how clusters were chosen and the fact that each cluster inevitably included some people already on heart-disease medication.
Nonetheless, she said, the overall study was well-designed and she particularly praised the fact that half the participants were women.
“And,” she added, “the adherence rate was fantastic.”
More than 80 percent of the study participants took most of their pills.
Poor adherence, she said, is one of the biggest problems that polypills are meant to fight.
Not only do poor people have little access to doctors or pharmacies, she noted, but “patients constantly say, ‘Listen, doc, I take too many pills,’ and drop something.”
“This is one pill with all the major things patients need,” she added. “Now we need to see how difficult it will be to apply it to the real world.”