Effects of a Fixed-Dose Combination Strategy on Adherence and Risk Factors in Patients With or at High Risk of CVD

Abstract

for the UMPIRE Collaborative Group IMPORTANCE Most patients with cardiovascular disease (CVD) do not take recommended medications long-term. The use of fixed-dose combinations (FDCs) improves adherence in several clinical areas. Previous trials of cardiovascular FDCs have assessed short-term effects compared with placebo or no treatment. OBJECTIVE To assess whether FDC delivery of aspirin, statin, and 2 blood pressure-lowering agents vs usual care improves long-term adherence to indicated therapy and 2 major CVD risk factors, systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C). DESIGN, SETTING, AND PARTICIPANTS The UMPIRE trial, a randomized, open-label, blinded-end-point trial among 2004 participants with established CVD or at risk of CVD enrolled July 2010-July 2011 in India and Europe. The trial follow-up concluded in July 2012.INTERVENTIONS Participants were randomly assigned (1:1) to an FDC-based strategy (n=1002) 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=1002). MAIN OUTCOMES AND MEASURESAdherence to medication (defined as self-reported use of antiplatelet, statin, and Ն2 BP-lowering medications) and changes in SBP and LDL-C from baseline.RESULTS At baseline, mean BP was 137/78 mm Hg, LDL-C was 91.5 mg/dL, and 1233 (61.5%) of 2004 participants reported use of antiplatelet, statin, and 2 or more BP-lowering medications. Median follow-up was 15 months (interquartile range, 12-18 months). The FDC group had improved adherence vs usual care (86% vs 65%; relative risk [RR] of being adherent, 1.33; 95% CI, 1.26-1.41; P < .001) with concurrent reductions in SBP (−2.6 mm Hg; 95% CI, −4.0 to −1.1 mm Hg; P < .001) and LDL-C (−4.2 mg/dL; 95% CI, −6.6 to −1.9 mg/dL; P < .001) at the end of the study. Although there was consistency of effects across predefined subgroups, evidence existed of larger benefits in patients with lower adherence at baseline. In this subgroup of 727 participants (36%), adherence at the end of study was 77% vs 23% (RR, 3.35; 95% CI, 2.74-4.09; P < .001 for interaction), SBP was reduced by 4.9 mm Hg (95% CI 7.3-2.6 mm Hg; P = .01 for interaction), and LDL-C was reduced by 6.7 mg/dL (95% CI, 10.5-2.8 mg/dL; P = .11 for interaction). There were no significant differences in serious adverse events or cardiovascular events (50 [5%] in the FDC group and 35 [3.5%] in the usual care group; RR, 1.45; 95% CI, 0.94-2.24; P=.09) between the groups.CONCLUSIONS AND RELEVANCE Among patients with or at high risk of CVD, use of an FDC strategy for blood pressure, cholesterol, and platelet control vs usual care resulted in significantly improved medication adherence at 15 months and statistically significant but small improvements in SBP and LDL-C.

Effectiveness of fixed dose combination medication (‘polypills’) compared with usual care in patients with cardiovascular disease or at high risk: A prospective, individual patient data meta-analysis of 3140 patients in six countries

“…Three trials were collaboratively planned, conducted and analysed, based on the same protocol, with minor regional adaptations: UMPIRE, 6 with participants from the United Kingdom, Ireland, the Netherlands, and India; Kanyini-GAP conducted in Australia 4 and IMPACT conducted in New Zealand. 5 A prospective IPD meta-analysis was also registered with the Australian New Zealand Clinical Trial Registry: ACTRN12612000980831 with a protocol and pre-specified data analysis plan published.…”

“…In the largest trial (UMPIRE), self-reported intensive physical activity levels were not reduced, and moderate activity levels were increased. 6 Among the 724 participants taking a more potent statin at baseline (almost all of whom were taking atorvastatin ≥ 20mg or rosuvastatin ≥10mg), allocation to a polypill did not lead to a deterioration in LDL control at 12 months (LDL difference 0.05; -0.05 to 0.14 mmol/l).…”

“…2,3 Recent trials have indicated that such treatment can improve adherence among patients with CVD or similarly high risk. [4][5][6][7] However, there is uncertainty about the consistency of these findings across different patient groups, across different health care systems in which usual care may vary considerably and with different levels of out-ofpocket medication payments. Furthermore, there are theoretical risks associated with such treatment, including the possibility of poorer outcomes in patients switched to polypills containing off-patent medications (especially if switched from more potent statins) and neglect of lifestyle factors whilst taking a polypill.…”

Adverse Drug Effects and Their Clinical Management: A Personal View

“…More controversial is the use of two drugs to treat the same condition, both of them in lower than recommended doses for effective treatment, in order to avoid adverse drug effects. It should be emphasized that such an approach should be considered very carefully, and an alternative using a single drug may be preferable; however, the use of the so-called poly-pill or multi-pill is an interesting innovation [10].…”

Fixed-Dose Combination Therapy (Polypill) for the Prevention of Cardiovascular Disease

“…Polypills are associated with greater adherence in patients with low baseline adherence compared with patients who already have high adherence. 4 Rather than replace usual care for CVD prevention, polypills will likely be a useful adjunct. …”