Effects of blood pressure lowering treatment in hypertension: 8. Outcome reductions vs. discontinuations because of adverse drug events-meta-analyses of randomized trials

Background: Previous meta-analyses of randomized controlled trials (RCTs) of blood pressure (BP)-lowering treatment provided overwhelming evidence that treatment markedly reduces risk of cardiovascular outcomes in hypertensive patients. However, adverse events associated with BP-lowering treatment have never been surveyed systematically. Objectives: Identifying among BP-lowering RCTs those reporting a common and meaningful index of treatment-attributed adverse events, and describing the burden of these adverse events accompanying the benefits of mortality and morbidity reduction induced by treatment. Methods: The database consisted of the BP-lowering RCTs (active vs. placebo or less active treatment) we have described (70 RCTs, 255970 participants, 1091964 patient-years). A common index of relevant adverse events was identified as permanent treatment discontinuation attributed to treatment adverse events. Risk ratios and 95% confidence intervals, standardized to a SBP/DBP reduction of 10/5mmHg, of seven fatal and nonfatal outcomes and of treatment discontinuations for adverse events were calculated (random-effects model). The relationships of outcome reductions and discontinuation excess to SBP and DBP reductions were investigated by meta-regressions. Results: Forty-four RCTs provided data on treatment discontinuations for adverse events and six more on serious adverse events because of treatment (179949 patients, 719796 patient-years). In these 50 RCTs, a significant 24% reduction of major cardiovascular event risk was associated with a significant 89% increase in the risk of discontinuations (33 major cardiovascular effects prevented and 84 excess discontinuations/1000 patients for 5 years). Metaregression analysis indicated that both outcome reductions and treatment discontinuation excess were significantly related to the extent of SBP and DBP reduction, but absolute treatment discontinuation excess disproportionally increased with larger BP reductions than increase in outcome risk reduction. Furthermore, a standard SBP reduction was found associated with a constant relative reduction, but a smaller absolute reduction of cardiovascular events, and a greater relative excess of treatment discontinuations when the achieved SBP was below 130mmHg rather than in higher ranges. Conclusion: The burden of adverse events associated with BP-lowering treatment should be considered not to deny patients the overwhelming benefits of BP lowering, but whenever the extent of the BP lowering or the BP target to be achieved are discussed.