Legacy effect of delayed blood pressure lowering drug treatment in middle-aged adults with mildly elevated blood pressure: systematic review and meta-analysis

To investigate if there is evidence for a 'legacy effect' for blood pressure (BP) lowering treatment, that is, worse health outcomes from not initiating drug treatment at a systolic BP threshold of 140 mmHg in middle-age adults. We systematically reviewed studies comparing the effects of delayed BP treatment (placebo/untreated during the trial or no previous treatment at trial entry) vs. early treatment (actively treated during the trial or previous BP treatment at trial entry) on mortality in the short term (5-year in-trial period) and long term (≥10 years in total period). The data were pooled using Peto ORs. A subgroup analysis by 10-year Framingham risk score was performed. Three studies (ALLHAT, Oslo and PREVEND-IT) involving 4746 participants were included. The results were heavily influenced by the ALLHAT trial. We found no significant difference in all-cause mortality between 'delayed BP' and 'early treatment' in the short-term OR 0.95 (95% CI 0.68-1.32) or long-term OR 0.90 (95% CI 0.78-1.04), with similar results for mortality from cardiovascular disease (CVD). The effects of delayed BP lowering treatment on long-term all-cause and CVD mortality did not vary with baseline risk of CVD. The review showed no clinically adverse 'legacy effect' on mortality or major CVD event from not treating middle-aged adults at a systolic BP threshold of 140 mmHg or over. The results were consistent for all CVD risk subgroups. Although these studies are non-randomised post-hoc analyses, they may allay concerns that early treatment of elevated systolic BP is necessary to prevent CVD events in primary prevention populations.