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The Association of Intensive Blood Pressure Treatment and Non-Fatal Cardiovascular or Serious Adverse Events in Older Adults with Mortality: Mediation Analysis in SPRINT

Randomized clinical trials of hypertension treatment intensity evaluate the effects on incident major adverse cardiovascular events (MACEs) and serious adverse events (SAEs). Occurrences after a non-fatal index event have not been rigorously evaluated. The aim of this study was to evaluate the association of intensive (<120 mmHg) to standard (<140 mmHg) blood pressure (BP) treatment with mortality mediated through a non-fatal MACE or non-fatal SAE in 9361 participants in the Systolic Blood Pressure Intervention Trial. Logistic regression and causal mediation modelling to obtain direct and mediated effects of intensive BP treatment. Primary outcome was all-cause mortality (ACM). Secondary outcomes were cardiovascular (CVM) and non-CV mortality (non-CVM). The direct effect of intensive treatment was a lowering of ACM [odds ratio (OR) 0.75, 95% confidence interval (CI): 0.60-0.94]. The MACE-mediated effect substantially attenuated (OR 0.96, 95% CI: 0.92-0.99) ACM, while the SAE-mediated effect was associated with increased (OR 1.03, 95% CI: 1.01-1.05) ACM. Similar patterns were noted for intensive BP treatment on CVM and non-CVM. We also noted that SAE incidence was 3.9-fold higher than MACE incidence (13.7 vs. 3.5%), and there were a total of 365 (3.9%) ACM cases, with non-CVM being 2.6-fold higher than CVM [2.81% (263/9361) vs. 1.09% (102/9361)]. The SAE to MACE and non-CVM to CVM preponderance was found across all age groups, with the ≥80-year age group having the highest differences. The current analytic techniques demonstrated that intensive BP treatment was associated with an attenuated mortality benefit when it was MACE-mediated and possibly harmful when it was SAE-mediated. Current cardiovascular trial reporting of treatment effects does not allow expansion of the lens to focus on important occurrences after the index event. The benefit of intensive (<120 mmHg) blood pressure (BP) treatment, reduction in all-cause mortality (ACM), was attenuated when mediated through non-fatal major adverse cardiovascular events. This was driven by cardiovascular mortality (CVM). The harm of intensive BP treatment, increase in ACM, was amplified when mediated through serious adverse events. This was driven by non-CVM. Current reporting of treatment effects in cardiovascular trials does not allow for expansion of the lens to focus on important occurrences after the index event.

Authors: Krishnaswami, Ashok;Rich, Michael W;Kwak, Min Ji;Goyal, Parag;Forman, Daniel E;Damluji, Abdulla A;Solomon, Matthew;Rana, Jamal S;Kado, Deborah M;Odden, Michelle C

Eur J Prev Cardiol. 2023 Aug 01;30(10):996-1004.

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