UMPIRE's Ruling: Fixed-Dose Combo Improves Adherence, Lowers Cholesterol and BP

November 05, 2012

LOS ANGELES — A fixed-dose combination tablet that includes aspirin, a statin, and two antihypertensive medications improves adherence to therapy and results in a significant reduction in LDL-cholesterol levels and blood pressure when compared with patients randomized to usual care.

Overall, investigators observed a 33% increase in adherence over a 15-month period, suggesting that fixed-dose combination therapy might go a long way toward reducing cardiovascular events in this population of high-risk patients and those with established cardiovascular disease. Patients who had to discontinue medical therapy with the fixed-dose combination quickly reverted back to usual care and its accompanying low rate of adherence, report investigators.

"Universally, patients like it," lead investigator Dr Simon Thom (Imperial College, London, UK) told heartwire about patient preference for the fixed-dose combination therapy. "We asked patients at the end of the trial whether they would like to continue with this were it available, and surveys done in the United States have done the same thing, and there is a universal enthusiasm for it. We recruited remarkably quickly; it was the quickest recruitment phase that I've been involved in, and when we completed the study, people were disappointed when said we're sorry, we can't continue with this because it's not yet on the market."

The results of the study, known as the Use of a Multidrug Pill in Reducing Cardiovascular Events (UMPIRE), were presented today at the American Heart Association 2012 Scientific Sessions. Although the treatment is now called fixed-dose combination therapy, its more popular name is the polypill, or polypharmacy.

Improving adherence with a single tablet

As reported previously by heartwire , the polypill concept gained notoriety in a 2003 paper by Sir Nicholas Wald and Dr Malcolm Law (University of London, UK) in BMJ that provocatively claimed a combination tablet could significantly reduce the risk of ischemic heart disease and stroke. The British doctors raised the possibility of one day using the drug to treat all patients with cardiovascular disease, as well as those 55 years of age and older, without measuring any risk factors. Recently, a group of experts gathered at the Global Summit on Combination Polypharmacy for Cardiovascular Disease, organized by Dr Salim Yusuf (McMaster University, Hamilton, ON), to discuss the potential applications of polypharmacy to reduce the worldwide burden of cardiovascular disease.

The underlying assumption of polypharmacy for cardiovascular disease is that a single drug with multiple compounds would improve risk-factor control because patients would be more likely to adhere to one medication.

The UMPIRE study was designed to test exactly that adherence hypothesis and included 2004 patients randomized to fixed-dose combination therapy with aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg, and atenolol 50 mg or to usual care. A second combination substituted hydrochlorothiazide 12.5 mg for atenolol. At all times, physicians could add additional medications, stop the fixed-dose combination therapy and begin treatment with usual medications, or switch from one version of the combination therapy to the other combination.

Patients were included in the study based on their cardiovascular risk profile, with 88% of patients in both treatment arms having established cardiovascular disease and 28% with diabetes mellitus. Approximately 60% of patients in the fixed-dose combination arm were already taking aspirin, a statin, and two antihypertensive medications that would be included in their single polypill. In total, 88% of patients were taking a statin before randomization and 91% were taking aspirin.

At the completion of the 15-month study, 86% of patients in the fixed-dose combination study arm were taking the medication compared with 65% in the usual-care arm, a statistically significant difference. The higher rate of adherence translated into an improvement in LDL-cholesterol levels and blood pressure. The benefit was observed in all subgroups, but researchers observed a significant improvement in adherence in patients who weren't taking all four medications at baseline. Similar results were observed in patients randomized in India and in Europe.

UMPIRE: Primary outcomes

Outcome Fixed-dose combination (n=1002) Usual care (n=1002) Treatment effect (95% CI)
Adherence (%) 86 65 1.33 (1.26 to 1.41)
Systolic blood pressure (mm Hg) 129.2 131.7 -2.6 (-4.0 to -1.1)
LDL cholesterol, mmol/L (mg/dL) 2.18 (84.3) 2.29 (88.5) -0.11 (-0.17 to -0.05)


Thom noted that in the MI FREEE trial, eliminating the copay for evidence-based cardiovascular medicines resulted in an adherence rate of less than 50%, a figure that was significantly higher than patients who had to make copayments, but low nonetheless. As a result, additional measures need to be adopted in order to close the adherence gap.

"If we could address the shortfall in adherence, we would do more [for cardiovascular disease prevention] than generating another blockbuster drug for a single risk factor," Thom told heartwire . "If we could persuade physicians and patients through a partnership of understanding to devise a technique for developing continued medication use, continued adherence, we would address a great deal of the target of cardiovascular disease prevention that faces us."

Discussing the results during the late-breaking clinical-trials session, Dr Andrew Tonkin (Monash University, Melbourne, Australia) noted that the UMPIRE results likely underestimate the true benefit of the polypill approach, since there was very high baseline use of medications at study onset, and the "usual-care" group showed high levels of medication adherence. "Both physicians and government should pay attention to these results." he said.

On average, a good idea

Commenting on the results from heartwire , Dr Dariush Mozaffarian (Brigham and Women's Hospital, Boston, MA) said the fixed-dose combination therapy used in UMPIRE differs from the original Wald-and-Law polypill concept in that patients are screened for cardiovascular risk factors and prescribed the medication based on that risk.

"I think the real potential benefit in UMPIRE is compliance, giving everybody a single pill that is easier to take, rather than a handful of pills," he said. "I think, on average, that's actually a good idea. If people have indications for these medicines, why not combine them into a single pill and make it easier for them to take? I think the polypill is a good idea for people who already have the indications."

For proponents of a polypill concept, where the single tablet is prescribed to all patients of a certain age regardless of risk factors, Mozaffarian has some concerns about the potential for harm. In low-risk patients, the increase in side effects could easily tip the risk/benefit ratio toward harm. Equally important, there would be a concern that individuals prescribed a polypill for primary cardiovascular disease prevention might feel invincible and not alter their risky health behaviors. "Before the polypill concept can be truly done, I think it needs to be tested carefully in a randomized trial," he said.

UMPIRE is part of a collaborative effort called Single Pill to Avert Cardiovascular Events (SPACE) being run by the George Institute in Sydney, Australia. Other trials in the SPACE collaboration include the Kanyini Guidelines Adherence with the Polypill (GAP) study, which is completed but unpublished, and the Improving Adherence Using Combination Therapy (IMPACT) trial, which is ongoing in New Zealand.