Systolic Blood Pressure and Mortality: Role of Reverse Causation

To the Editor: Using data acquired from the Health and Retirement Study (HRS), the study by Wu and colleagues joins a host of other observational studies reporting an inverse relationship between high systolic blood pressure (SBP) and mortality. The inclusion of measures of grip strength and gait speed in this study provides further evidence that functional status may modify this relationship, but the fundamental limitations inherent in all observational studies that have addressed this relationship compel us to comment. Furthermore, the conclusions derived from two large randomized clinical trials (RCT) of hypertensive treatment in older adults, both including frail adults, conflict with this observational study’s findings and conclusions. The Hypertension in the Very Elderly Trial (HYVET) and Systolic Blood Pressure Intervention Trial (SPRINT) reached similar conclusions regarding the mortality benefits identified in older adults with hypertension—aged 80 and older for HYVET and 75 and older for SPRINT— actively treated to a target SBP of less than 150 mmHg in HYVET (relative to placebo treatment) and less than 120 mmHg in SPRINT (relative to a standard treatment target of <140 mmHg). The significant 21% decrease in overall mortality in HYVET and 33% decrease in SPRINT participants led to recommendations to end both studies earlier than planned. Both trials included sizable proportions of frail participants; 23.1% of HYVET participants and 16.3% of SPRINT participants had a frailty index score of 0.25 or greater, and 29.4% of SPRINT participants had slow gait speed (<0.8 m/s). The treatment benefits for both trials’ primary outcomes and overall mortality were evident even in frail participants. What then accounts for the stark contrast between the mortality benefit identified in older, frail adults with hypertension in RCTs and the inverse relationship found in observational studies? Among several differences in study design, the most important concern is the inherent limitation of reverse causation in observational studies. A recent observational cohort study that tracked SBP trajectories for the 5 years before death in 144,403 individuals aged 80 older provides a compelling example of this limitation. Consistent with Wu and colleagues and other observational studies, mortality was greatest in those with SBP less than 110 mmHg, although there was a decline in the SBP trajectory noted in the last 3 months of life in individuals undergoing treatment for hypertension and those not undergoing treatment. This terminal decline in SBP provided the best explanation for the observed association between low SBP and mortality in this and probably other observational studies. Although Wu and colleagues attempted to minimize reverse causation by excluding HRS participants who died in the first 2 years of follow-up, this approach fails to fully reduce residual confounding. Moreover, the HRS population is heterogeneous and includes persons with and without hypertension. Individuals with low SBP as a consequence of actively and appropriately managed antihypertensive therapy titrated to a specific SBP target are not equivalent to those who happen to have a low SBP measured in an observational study. The mortality benefit in the first group—even for those with impaired gait speed and frailty—has been convincingly demonstrated. By contrast, the onset of low SBP observed in a frail, older adult with or without hypertension should prompt concern because it may be a harbinger of preterminal decline. We applaud Wu and colleagues’ call to “further advance precision medicine,” but we contend that a person-centric, benefit-based approach to determining a SBP treatment goal that is founded on rigorous evidence derived from the available RCTs should inform this decision. We fully recognize that, because of the exclusion criteria required for RCTs, the benefits observed in HYVET and SPRINT cannot be generalized to all older adults with hypertension. That said, there are an estimated 5.8 million individuals in the United States aged 75 and older with hypertension who meet SPRINT entry criteria (64% of the 9.1 million with hypertension). Furthermore, projections from National Health and Nutrition Examination Survey data suggest that the mortality benefit observed with intensive therapy in SPRINT would translate to preventing 67,300 (95% confidence interval = 58,600–77,200) deaths per year in the SPRINTeligible population age 75 and older. We conclude that treatments to achieve a lower SBP target are indicated because this confers significant benefits—inclusive of mortality—even in those with frailty or impaired gait speed. The findings from Wu and colleagues should not deter clinicians from considering this treatment approach for eligible individuals.