Editor's note: Commentary based on Sink KM, Evans GW, Shorr RI, et al. Syncope, hypotension, and falls in the treatment of hypertension: results from the randomized clinical systolic blood pressure intervention trial. J Am Geriatr Soc 2018;66:679-86.

Background: Older adults are less likely to have adequate blood pressure (BP) control despite considerable evidence that treatment of hypertension decreases cardiovascular mortality and morbidity.¹ Heightened concerns about increased risk for falls, fall-related injuries and syncope related to anti-hypertensive therapy are among the factors contributing to the apparent under-treatment of hypertension in older patients.^2-4 Further characterization of these risks can improve hypertension treatment decisions in older adults.

Study Question: What were the predictors of syncope, hypotension and falls in the Systolic Blood Pressure Intervention Trial (SPRINT), with particular focus on age?

Funding: SPRINT is funded by the National Institutes of Health, including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke, under Contracts HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, HHSN268200900049C, and Interagency Agreement A-HL-13–002–001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals International, Inc.

Methods: SPRINT enrolled 9,361 patients with hypertension at 102 sites from 2010 to 2013. Participants were randomly assigned to intensive (systolic BP goal <120 mmHg) or standard (systolic BP <140 mmHg) BP control. The study was stopped early, after a median follow-up of 3.26 years, because benefit was seen in the primary outcome (composite of myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, or death from cardiovascular causes) in the intensive treatment arm.⁵ Pre-specified serious adverse events (SAE) included syncope, hypotension, and falls (among others). Potential predictors of SAEs were treatment assignment, demographic characteristics, comorbidities, baseline measurements, and baseline use of cardiovascular medications.

Study Design: Prospective, randomized clinical trial.

Source Population: Adults aged 50 and older with a systolic blood pressure (SBP) of 130 to 180 mmHg at high risk of cardiovascular disease events, but without diabetes, history of stroke, symptomatic heart failure or ejection fraction <35%, dementia, or standing SBP <110 mmHg.

Outcomes for this Analysis: SAEs of syncope, hypotension and falls, as defined by the study protocol.

Statistical Analysis: Proportional hazards analysis was used to estimate the effects of baseline characteristics on time to first SAE, both overall and for the three individual SAEs. A series of multivariate models were fit for each type of outcome. Model 1 included randomized treatment group, age category (<75, 75-84, and >85 years), sex, race and education; model 2 included these factors plus health conditions (cardiovascular disease, chronic kidney disease, body mass index category, alcohol use, frailty); and model 3 included all previous covariates plus baseline measurements (SBP; heart rate; measured orthostatic hypotension; dizziness; number of antihypertensive medications; baseline use of antihypertensive medications). The models were fit separately for each outcome and with and without the two-way interaction between age category and randomized treatment.

Results: 172 (1.8%) participants had syncope, 155 (1.6%) hypotension and 203 (2.2%) falls. Randomization to intensive SBP control was associated with greater risk of hypotension (hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.21–2.32, P = 0.002), and possibly syncope (HR 1.32, 95% CI 0.98–1.79, P = 0.07), but not falls (HR 0.98, 95% CI 0.75–1.29, P = 0.90). Risk of all three outcomes was higher for participants with chronic kidney disease or frailty. Older age was associated with greater risk of syncope, hypotension and falls, but there was no age-by-treatment interaction for any of the three outcomes.

Limitations: SPRINT excluded patients with diabetes, prior stroke, active heart failure within 6 months, end-stage renal disease, or residence in a nursing home. Thus, the relevance of findings to a large proportion of older adults in routine clinical practice is uncertain. Ascertainment bias could lead to over-reporting of adverse outcome in the intensive treatment group.

Conclusions: Patients randomized to intensive SBP control had greater risk of SAEs related to hypotension and possibly syncope, but not falls. However, the greater risk of these events associated with intensive treatment did not vary according to age.

Perspective: This critical analysis of safety adverse events from the SPRINT trial confirms that among older adults with hypertension, the risk of hypotension, syncope and falls during follow-up increases with age. Compared to the standard SBP target of <140 mmHg, older adults treated to an intensive target of <120 mm Hg are at significantly increased risk for hypotension and possibly syncope, but not falls or injurious falls. Further, these risks were not augmented by very advanced age (i.e., >85 years). Since the benefits of anti-hypertensive therapy in reducing mortality and morbidity in patients 75 years of age or older enrolled in the SPRINT trial were unequivocal,⁶ the present analysis supports more aggressive treatment in selected older patients. There are, however, some important caveats. First, the generalizability of the SPRINT findings to a large proportion of adults over age 75 (approximately two-thirds) is uncertain.⁷ Second, older patients with chronic kidney disease and frailty are at greater risk of hypotension, implying that extra caution is warranted when considering intensive therapy in these populations. Third, since the risks and benefits of anti-hypertensive treatment vary substantially from patient to patient, and the importance of these risks and benefits is contingent on patients' goals and preferences, shared decision-making is appropriate when designing therapy for the growing number of older adults with high blood pressure.

References

1. Yoon SS, Gu Q, Nwankwo T, Wright JD, Hong Y, Burt V. Trends in blood pressure among adults with hypertension: United States, 2003 to 2012. Hypertension 2015;65:54-61.
2. Shumway-Cook A, Ciol MA, Hoffman J, Dudgeon BJ, Yorkston K, Chan L. Falls in the Medicare population: incidence, associated factors, and impact on health care. Phys Ther 2009;89:324-32.
3. Tinetti ME, Han L, Lee DS, et al. Antihypertensive medications and serious fall injuries in a nationally representative sample of older adults. JAMA Intern Med 2014;174:588-95.
4. Chen L, Chen MH, Larson MG, Evans J, Benjamin EJ, Levy D. Risk factors for syncope in a community-based sample (the Framingham Heart Study). Am J Cardiol 2000;85:1189-93.
5. SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16.
6. Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial. JAMA 2016;315:2673-82.
7. Bress AP, Tanner RM, Hess R, Colantonio LD, Shimbo D, Muntner P. Generalizability of SPRINT results to the U.S. adult population. J Am Coll Cardiol 2016;67:463-72.

Keywords: Chlorthalidone, Antihypertensive Agents, Hypotension, Orthostatic, Accidental Falls, Prospective Studies, Blood Pressure, National Institute of Neurological Disorders and Stroke (U.S.), Dizziness, Confidence Intervals, Acute Coronary Syndrome, Body Mass Index, Research Personnel, Heart Rate, Random Allocation, Stroke Volume, Benzimidazoles, Oxadiazoles, Syncope, Hypertension, Kidney Failure, Chronic, Diabetes Mellitus, Nursing Homes, Comorbidity, Heart Failure, Stroke, Renal Insufficiency, Chronic, Myocardial Infarction, Dementia, Decision Making, Risk Assessment, Pharmaceutical Preparations, Demography, Geriatrics

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