Fixed-Dose Combination in Patients with or at High Risk of CVD

Results of a randomized, open-label, blinded-end-point trial show significantly improved medication adherence at 15 months and significant, albeit small, improvements in systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) in patients with or at high risk of cardiovascular disease (CVD) managed by a fixed-dose combination (FDC) strategy compared with usual care [JAMA. 2013;310(9):918-929].

The UMPIRE (Use of a Multidrug Pill in Reducing Cardiovascular Events) trial was undertaken to assess the long-term effects of a FDC strategy on medication adherence and changes to SBP and LDL-C in patients with established CVD or those at risk of CVD compared with patients treated with usual care.

Although prior studies have shown improved short-term effects of a FDC strategy for cardiovascular patients compared with placebo or no treatment, the UMPIRE study is the first trial to evaluate a FDC strategy over a prolonged interval in this same patient population.

The study included 2004 participants enrolled between July 2010 and July 2011 in India and Europe and randomized to usual care (n=1002) or to 1 of 2 FDC formulations (n=1002). The FDC formulations consisted of a once-daily regimen of 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 50 mg atenolol (FDC version 1) or a once-daily regimen of 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 12.5 mg hydrochlorothiazide (FDC version 2).

All participants eligible for the trial were ≥18 years of age with either established CVD (history of coronary heart disease, ischemic cerebrovascular disease, or peripheral vascular disease) or an estimated 5-year CVD risk of ≥15%, who had clear indications with no contraindications for the components of either FDC formulations. Individuals were excluded from the study if changes to their medications were deemed clinically inappropriate or if the individual was unlikely to follow the trial procedures.

At median follow-up of 15 months, 86% of the participants randomized to a FDC strategy maintained medication adherence compared with 65% of those in the usual care group (unadjusted relative risk [RR] of 1.33; 95% confidence interval [CI], 1.26-1.41; P<.001). Participants in the FDC group also had significantly greater reductions in SBP (-2.6 mm Hg; 95% CI, -4.0--1.1 mm Hg; P<.001) and LDL-C (-4.2 mg/dL; 95% CI, -6.6--1.9 mg/dL; P<.001).

The benefits of a FDC strategy were greater when looking at a subgroup of 727 patients with low medication adherence at baseline. Medication adherence in this subgroup at the end of the study was 77% versus 23% in participants with a high medication adherence at baseline (RR of 3.35; 95% CI, 2.74-4.09; P<.001 for interaction). In this subgroup, SBP was reduced by 4.9 mm Hg (95% CI, 7.3-2.6 mm Hg; P=.01) and LDL-C by 6.7 mg/dL (95% CI, 10.5-2.8 mg/dL; P=.11).

No significant differences between the FDC and usual care groups were found in serious adverse events or cardiovascular events (5% vs 3.5%, respectively). Overall, 85 participants in the FDC group had a cardiovascular event as a first event compared with 35 in the usual care group (RR of 1.45; 95% CI, 0.94-2.24; P=.09). In the FDC group, 118 (11.8%) of participants had at least 1 serious event compared with 102 (10.2%) in the usual care group.

According to the study’s authors, the findings of this study suggest that a FDC strategy may play a role in increasing the uptake of medications in patients with CVD not currently receiving treatment. “Scaled-up access to core cardiovascular medicines is in keeping with national CVD prevention goals in India, Europe, and the United States and could contribute importantly to World Health Organization goals for noncommunicable disease control,” the authors concluded.