Effects of a Fixed-Dose Combination Strategy on Adherence and Risk Factors in Patients With or at High Risk of CVD: The UMPIRE Randomized Clinical Trial
Does the use of a fixed-dose combination of aspirin, statin, and two blood pressure–lowering agents versus usual care improve long-term adherence to indicated therapy and two major cardiovascular disease (CVD) risk factors, systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C), among patients with CVD?
The UMPIRE (Use of a Multidrug Pill in Reducing Cardiovascular Events) trial was a randomized, open-label, blinded-endpoint trial, which included 2,004 participants enrolled from July 2010 to July 2011, in India and Europe. The trial follow-up concluded in July 2012. Men and women ages 18 years or older with high CV risk, defined as either established CVD (history of coronary heart disease, ischemic cerebrovascular disease, or peripheral vascular disease) or an estimated 5-year CVD risk of 15% or greater were eligible. Participants were randomly assigned (1:1) to fixed-dose combinations (in two combinations) (n = 1,002) containing either: 1) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 50 mg atenolol, or 2) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 12.5 mg hydrochlorothiazide, or to usual care (n = 1,002). The primary outcomes of interest were adherence (self-reported) to medication and changes in SBP and LDL-C from baseline. Self-reported adherence to all medications was recorded as the number of days medication was taken in the week prior to the visit (value between 0-7 days).
A total of 2,138 potential participants were screened: 134 were ineligible and 2,004 were randomized (1,000 in India and 1,004 in Europe) between July 2010 and July 2011. Among the 1,002 participants randomized to the fixed-dose combinations group, physicians started therapy with fixed-dose combination version 1 for 589 (58.8%) and fixed-dose combinations version 2 for 413 (41.2%). Baseline characteristics of the fixed-dose combinations and usual care groups were similar. The majority of participants (n = 1,771 [88%]) were included on the basis of established CVD. The median duration of follow-up was 15 months (interquartile range, 12-18 months) for both groups. At baseline, mean BP was 137/78 mm Hg, LDL-C was 91.5 mg/dl, and 1,233 (61.5%) of 2,004 participants reported use of antiplatelet, statin, and two or more BP-lowering medications. The fixed-dose combination group had improved adherence versus usual care (86% vs. 65%; relative risk [RR] of being adherent, 1.33; 95% confidence interval [CI], 1.26-1.41; p < 0.001) with concurrent reductions in SBP (−2.6 mm Hg; 95% CI, −4.0 to −1.1 mm Hg; p < 0.001) and LDL-C (−4.2 mg/dl; 95% CI, −6.6 to −1.9 mg/dl; p < 0.001) at the end of the study. Larger benefits were observed among patients with lower adherence at baseline. There were no significant differences in serious adverse events or CV events (50 [5%] between the groups).
The investigators concluded that among patients with or at high risk of CVD, use of a fixed-dose combination strategy for BP, cholesterol, and platelet control versus usual care resulted in significantly improved medication adherence at 15 months and statistically significant, but small improvements in SBP and LDL-C.
This trial provides data on improved adherence and small but significant improvements in CVD risk factors among a high-risk population related to fixed combinations of medications. Further research is thus warranted, including data on cost for this type of secondary and primary prevention among patients at high risk for CVD events.
Keywords: Coronary Artery Disease, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Coronary Disease, Blood Pressure, Blood Platelets, Europe, Simvastatin, Peripheral Vascular Diseases, Medication Adherence, Lisinopril, Cholesterol, Cerebrovascular Disorders, India, Cardiovascular Diseases, Confidence Intervals, Hydrochlorothiazide
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