A SECURE polypill as a strategy at the heart of secondary prevention

Comment on the article ‘Polypill strategy in secondary cardiovascular prevention’, presented at the European Society of Cardiology Congress and simultaneously published in The New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2208275. The Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE),1 a Phase 3, open-label, randomized, controlled trial that was supported by public and private partnerships, randomized 2499 patients aged ≥75 (or aged ≥65 years with ≥1 cardiovascular risk factor) who had a myocardial infarction (MI) in the prior 6 months to a polypill-based strategy consisting of aspirin (100 mg), atorvastatin (20 or 40 mg), and ramipril (2.5, 5, or 10 mg), or to usual care, defined as pharmacotherapy based on current European Society of Cardiology guidelines.2 The primary outcome was a composite of cardiovascular death, non-fatal Type 1 MI, non-fatal ischaemic stroke, or urgent revascularization. The key secondary endpoint was a composite of cardiovascular death, non-fatal Type 1 MI, or non-fatal ischaemic stroke. The average age of participants was 76 years, 31% were women, 78% had hypertension, 57% had diabetes, and 51% had a history of smoking. The median time between the index MI and randomization was 8 days. Most patients in the polypill group (92%) received 40 mg of atorvastatin, whereas 40% of the patients in the usual-care group were treated with high-intensity statin therapy. Most patients in both groups (>90%) received an additional antiplatelet agent. During a median follow-up of 36 months, the primary composite outcome occurred in 118 (9.5%) patients in the polypill group and 156 (12.7%) in the usual-care group [hazard ratio (HR) 0.76; 95% confidence interval (CI), 0.60–0.96; P < 0.001 for non-inferiority; P = 0.02 for superiority]. Among the components of the primary outcome, cardiovascular death occurred in 48 (3.9%) patients in the polypill group and 71 (5.8%) in the usual-care group (HR 0.67; 95% CI, 0.47–0.97). Treatment effects for the primary outcome were similar in pre-specified subgroups (country, age, sex, diabetes, chronic kidney disease, and prior revascularization). The key secondary endpoint occurred in 101 (8.2%) patients in the polypill group and 144 (11.7%) in the usual-care group (HR 0.70; 95% CI, 0.54–0.90; P = 0.005). All-cause mortality was similar in both groups (HR 0.97; 95% CI, 0.75–1.25), with the reduction in cardiovascular deaths offset by a higher number of non-cardiovascular deaths (equally accounted for by cancer and undetermined deaths) in the polypill group. High levels of self-reported medication adherence at 24 months were seen in a higher percentage of patients in the polypill group (74 vs. 63%; risk ratio, 1.17; 95% CI, 1.10–1.25). However, at 24 months, no substantial differences were measured in the mean systolic and diastolic blood pressure (135/75 vs. 136/75 mmHg) and mean LDL-cholesterol levels (68 vs. 67 mg/dL) between the groups. The incidence of total adverse events (33% in the polypill group and 32% in the usual-care group) and non-fatal serious adverse events (19% in the polypill group and 18% in the usual-care group) was similar. A polypill strategy to control the growing challenge of cardiovascular disease has been extensively debated since its first proposal two decades ago. The use of a polypill has been claimed as an effective solution for those who have poor access to care and budget limitations, while simplifying healthcare delivery, improving cost-effectiveness, and promoting evidence-based therapy.3–5 In countries with limited resources, the polypill may provide better protection than inadequate care, in primary prevention.6 The post-MI population, currently involving older individuals, requires different pharmacological agents taken long term to prevent recurrence, with questions about adherence and sustainability. Patient adherence to secondary prevention medications is higher immediately after the acute event but wears off after the first 6 months. The lack of adherence has been associated with poorer outcomes.7 SECURE was the first randomized trial to evaluate the impact of a polypill on recurrent cardiovascular events in post-MI patients.1 Notably, the benefit that was observed in the SECURE trial occurred despite high rates of use of evidence-based therapies in the usual-care group. Importantly, the study found that patients in the polypill group had a higher level of treatment adherence than those in the control group, thus confirming the findings of the earlier FOCUS study,8 and in part explaining the benefits of the polypill. However, the one-quarter reduction in the primary outcome appears disproportionate with respect to the 10% absolute increase in adherence. Unfortunately, data on adherence at 3 years, when the Kaplan–Meier curves for the primary outcome continue to diverge, were not available. Moreover, the eight-item self-reported Morisky Medication Adherence Scale was used in the SECURE trial to measure adherence. Together with the open-label design of the trial, self-reporting might have introduced important biases in the evaluation of adherence itself. Given that neither blood pressure nor LDL-cholesterol levels differed significantly between the two groups, the alleged higher adherence may have contributed to improvements in the levels of unmeasured risk factors, such as residual inflammatory risk. In both groups, >65% of patients had LDL-cholesterol levels >55 mg/dL during follow-up, which raises the possibility that non-LDL-cholesterol benefits of statins played a role. Furthermore, a greater adherence to the aspirin component of the polypill, especially in the elderly population in whom long-term treatment with aspirin is often questioned, may have added to its overall benefit.9 Whether combined effects of statins, ACE inhibitors and aspirin might produce benefits not yet characterized but sufficient to improve the primary outcome remains to be in investigated.10,11 A distinctive feature of the SECURE trial design was the availability of six different formulations of the polypill, including two doses of atorvastatin and three doses of ramipril.1 This flexibility addresses one of the potential concerns regarding the use of fixed-dose combination pills as secondary prevention.9 Although the SECURE findings complement prior trials by extending the benefits of a polypill strategy to older, post-MI patients, the trial has some limitations. The trial design did not allow for treatment blinding; however, the event adjudicators were unaware of group assignment, and the outcome evaluations were unbiased. No adjustment was made for multiple comparisons of secondary outcomes, so any difference between groups in the incidence of cardiovascular death should be viewed as hypothesis generating. In conclusion, the use of a fixed-dose polypill for cardiovascular prevention is safe and promotes a moderately higher adherence to guideline-recommended medications. Although the mechanisms remain unexplained, a growing body of evidence now supports the efficacy of the polypill in reducing the incidence of cardiovascular events in different clinical settings. Whether it can be made affordable and accessible is yet to be seen. There are several practical obstacles to the implementation of such a strategy, including the relative lack of commercial interest in developing a polypill, which will likely require public and private partnerships to be accomplished.