Halving cardiovascular risk with combined blood pressure and cholesterol lowering – Why are we not there yet?

Background: We aimed to assess whether the modest major adverse cardiovascular events (MACE) reductions in previous trials testing combined blood pressure (BP) and low density lipoprotein cholesterol (LDL-C) reduction were due to modest risk factor reduction and/or a negative interaction, whereby the joint effects of therapy are less than expected. Methods: We performed a systematic review of randomized controlled trials comparing patients who received combination BP and cholesterol lowering treatment versus placebo. We calculated the expected relative risk reduction (RRR) in MACE based on the observed reductions in systolic BP and LDL-C in each trial and previous meta-analysis of the individual modalities. Results: All five included trials achieved small SBP reductions (range 1 to 6 mmHg) and small-to-moderate LDL-C reductions (range 0.5 to 1.1 mmol/L), which were all less than expected. Each of the three largest trials achieved significant reductions in MACE and the observed vs expected RRRs were closely aligned: - ASCOT observed RRR 32% (95% CI 18–43%) vs expected RRR 24% (95% CI 20–28%); HOPE-3 observed RRR 28%, (95% CI 10–42%) vs expected RRR 28% (95% CI 23%–31%); TIPS-3 observed RRR 20% (95% CI 0%–36%) vs expected RRR 21% (95% CI 18–24%). Conclusions: MACE reductions seen in past trials of combined BP and LDL-C reflect the degree of risk factor reduction. Sustained and substantial reductions in BP and LDL-C (eg. ≥15 mmHg and ≥ 1.5 mmol/L) are required to halve cardiovascular risk, which in turn requires long-term adherence to intensive LDL-C lowering and combination BP therapy.