Should patients with cardiovascular risk factors receive intensive treatment of hypertension to < 120/80 mm Hg target?: A protagonist view from SPRINT

Based on the main results of the Systolic Blood Pressure Intervention Trial (SPRINT), we strongly believe that older hypertensive patients at high cardiovascular (CV) risk should receive intensive treatment to a target systolic blood pressure (SBP) of < 120 mm Hg [1–2]. SPRINT tested the hypothesis that intensive treatment of SBP to a target of < 120 mm Hg would reduce clinical events more than standard treatment to a target of < 140 mm Hg. SPRINT enrolled persons age 50 years or greater with SBP 130–180 mm Hg (treated or untreated), and at high CV risk. In particular, SPRINT over enrolled high-risk subgroups, including those age ≥ 75 years (SPRINT-Senior), blacks, and those with chronic kidney disease (CKD) or cardiovascular disease (CVD). The mean 10-year Framingham CVD risk score for all participants was 20%.

SBP fell rapidly in the intensive-treatment group (target SBP < 120mm Hg), reaching a level ~ 15 mm Hg lower than in the standard group at 1 year (121.4 vs. 136.7 mm Hg) with administration of an average of 1 more antihypertensive medication. The SPRINT intervention was stopped early (median 3.26 years of follow-up) due to a 25% reduction in the primary composite endpoint (myocardial infarction (MI), non-MI acute coronary syndrome (non-MI ACS), stroke, acute decompensated heart failure (HF) and CV death) and a 27% reduction in all-cause mortality in the intensive-treatment group. The effects of the intensive intervention on the primary outcome and all-cause mortality were consistent across all pre-specified subgroups (presence or absence of previous CVD or CKD, male or female sex, black or nonblack race, age ≥ 75 years or <75 years and baseline SBP tertile). The benefits of intensive treatment were numerically greater (34% reduction in the primary outcome and 33% reduction in all-cause mortality) in the SPRINT-Senior subgroup [2]. There were no significant differences in CV or mortality benefits of intensive BP treatment by baseline frailty or functional status. The number needed to treat (NNT) for 3.26 years to prevent 1 primary outcome was 61 in the study as a whole and 28 in the SPRINT-Senior subgroup; to prevent 1 death, 90 in the study as a whole and 41 in the SPRINT-Senior subgroup. The pattern of adverse events in those ≥ 75 years old was similar to that in the cohort as a whole.

The large benefits of intensive treatment came at some cost. While serious adverse events (SAEs) overall were not different between randomized groups, SAEs due to hypotension, syncope, electrolyte abnormalities, and acute kidney injury or acute renal failure were more frequent in the intensive vs standard-treatment groups, 4.7% vs 2.5% of patients, respectively. However, in the CKD subgroup, progression resulting in ≥ 50% reduction in eGFR, long-term dialysis, or renal transplantation was rare and similar in both treatment groups. Although hypotension and syncope were more common in the intensive-treatment group, measured orthostatic hypotension was more common in the standard-treatment group and there was no significant difference in injurious falls.

The impressive reductions in CV outcomes and all-cause mortality in SPRINT have significant public health implications. A recent analysis of NHANES 2007–2012 data estimated the prevalence, number, and characteristics of US adults meeting SPRINT eligibility criteria and used these to determine the broader population to whom SPRINT could be generalized [3]. The report concluded that 16.8 million US adults (7.6% of the total population) and 8.2 million with treated hypertension (16.7% of the treated hypertensive population) would meet eligibility requirements for SPRINT. Thus, at a minimum, this number would likely benefit from adoption of the intensive SPRINT treatment goal.

SPRINT excluded patients with diabetes or prior stroke because ongoing NIH-sponsored trials, Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Secondary Prevention of Small Subcortical Strokes (SPS3) trials, were examining similar BP targets in these populations. ACCORD found a statistically non-significant 12% reduction in risk of the primary outcome in the intensive-treatment group, a 95% confidence interval that included the possibility of a 27% lower risk, consistent with the CV benefit seen in SPRINT. ACCORD also found a significant 41% reduction in stroke in the intensive-treatment group. The non-significant 11% reduction in stroke with intensive BP treatment in SPRINT may be related to exclusion of persons with prevalent stroke or transient ischemic attack, due merely to chance or low stroke rates: 95% confidence interval was wide and included the possibility of a 37% reduction in stroke. ACCORD had a smaller sample size than SPRINT (4,733 vs 9,361), enrolled a younger cohort (62 vs. 68 years), excluded persons with CKD, and did not include HF or non-MI ACS in the primary composite endpoint. ACCORD had a factorial design that compared intensive vs. standard glycemic and lipid treatment targets and BP targets. There was 26% reduction in the primary outcome with intensive compared with standard BP treatment in the standard glycemic treatment group [4]. Thus, outcome differences between ACCORD and SPRINT could be related to study design, treatment interactions or chance.

An important caveat when adopting the SPRINT intensive BP treatment strategy is to consider the BP measurement technique in SPRINT. SPRINT used a validated automated device for office BP measurements and a standard protocol: participants were seated with their back and arm supported, feet on the floor, appropriate cuff size, and underwent 5 minutes of unobserved rest prior to measurement. The final clinic BP was based on an average of 3 consecutive BPs taken 1 minute apart. In busy outpatient clinic settings, BP measurements are frequently taken manually by a provider using a sphygmomanometer with incorrect patient position, little or no rest period, and improper cuff size and placement, generally leading to overestimation of BP. Such overestimation may result in overtreatment with antihypertensive medications, potentially increasing the risk of SAEs if treating to the intensive SPRINT BP target.

Based largely on results of SPRINT, the 2016 Canadian Hypertensive Education Program (CHEP) Guidelines recommend intensive BP treatment to target SBP ≤ 120 mm Hg in high-risk patients (Grade B)[5]. The CHEP Report commented that “the risks of intensive BP control would undoubtedly be greater in conventional clinical practice” than in SPRINT and concluded that a shared decision-making process involving both patient and healthcare provider is necessary for the safe implementation of intensive BP control.

SPRINT provides important data on the efficacy and safety of intensive SBP control in older, high-risk patients. Questions have been raised about the generalizability of SPRINT results to high-risk populations excluded from the trial, i.e., those with HF, secondary hypertension, severe CKD, and institutionalized elderly, or to lower CV risk populations (<50 years or >50 years with Framingham 10-year risk score <15%). Given the absence of clinical trial data about the benefits and harms of targeting SBP < 120 mm Hg in these groups, extrapolation of the SPRINT findings to larger populations of hypertensive and pre-hypertensive persons is left to the clinical judgement of healthcare providers and of future guideline development committees.