Cushman, William C.

Hypertension is the single most important modifiable risk factor for preventable disability and death worldwide and disproportionately affects socially disadvantaged populations. We face a paradox—blood pressure control is low and recent trends suggest it is even declining, despite the availability of inexpensive and effective therapies. A variety of barriers on the system, patient, and healthcare provider side hinder effective drug-based risk factor management. Clinical inertia represents a major barrier on the clinician side, as well as workload and limited education. Common barriers on the patient side include limited English proficiency, low health literacy, and nonadherence with misaligned incentives, limited resources, lack of structured clinical pathways, and reimbursement issues. New innovations in the field of RNA-targeted therapies and device-based interventions could prevent and potentially even cure diseases previously designated as chronic health conditions, such as hypertension. Such novel therapies could potentially overcome several major barriers to effective treatment, including nonadherence. Drug development of novel, long-acting treatments requires consideration of specific clinical trial design aspects, including safety collection, benefit: risk assessment, the development and assessment of novel, qualitative surrogate end points, such as time-in-therapeutic range, the use of representative trial settings as well as the definition of standard of care in placebo-controlled trials, which should be of reasonably high-quality allowing for credible evaluation of effectiveness. Here, we provide an overview on barriers to effective treatment and a framework for trials assessing novel treatments for cardiovascular disease risk factors, including early and broad implementation programs.

Orthostatic hypotension (OH) is frequently observed with hypertension treatment, but its contribution to adverse outcomes is unknown. The SPRINT (Systolic Blood Pressure Intervention Trial) was a randomized trial of adults, age ≥50 years at high risk for cardiovascular disease with a seated systolic blood pressure (BP) of 130 to 180 mm Hg and a standing systolic BP ≥110 mm Hg. Participants were randomized to a systolic BP treatment goal of either <120 or <140 mm Hg. OH was defined as a drop in systolic BP ≥20 or diastolic BP ≥10 mm Hg 1 minute after standing from a seated position. We used Cox models to examine the association of OH with cardiovascular disease or adverse study events by randomized BP goal. During the follow-up period (median 3years), there were 1170 (5.7%) instances of OH among those assigned a standard BP goal and 1057 (5.0%) among those assigned the intensive BP goal. OH was not associated with higher risk of cardiovascular disease events (primary outcome: hazard ratio 1.06 [95% CI, 0.78–1.44]). Moreover, OH was not associated with syncope, electrolyte abnormalities, injurious falls, or acute renal failure. OH was associated with hypotension-related hospitalizations or emergency department visits (hazard ratio, 1.77 [95% CI, 1.11–2.82]) and bradycardia (hazard ratio, 1.94 [95% CI, 1.19–3.15]), but these associations did not differ by BP treatment goal. OH was not associated with a higher risk of cardiovascular disease events, and BP treatment goal had no effect on OH’s association with hypotension and bradycardia. Symptomless OH during hypertension treatment should not be viewed as a reason to down-titrate therapy even in the setting of a lower BP goal. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01206062.

Background Blood pressure ( BP ) varies over time within individual patients and across different BP measurement techniques. The effect of different BP targets on concordance between BP measurements is unknown. The goals of this analysis are to evaluate concordance between (1) clinic and ambulatory BP , (2) clinic visit‐to‐visit variability and ambulatory BP variability, and (3) first and second ambulatory BP and to evaluate whether different clinic targets affect these relationships. Methods and Results The SPRINT (Systolic Blood Pressure Intervention Trial) ambulatory BP monitoring ancillary study obtained ambulatory BP readings in 897 participants at the 27‐month follow‐up visit and obtained a second reading in 203 participants 293±84 days afterward. There was considerable lack of agreement between clinic and daytime ambulatory systolic BP with wide limits of agreement in Bland‐Altman plots of −21 to 34 mm Hg in the intensive‐treatment group and −26 to 32 mm Hg in the standard‐treatment group. Overall, there was poor agreement between clinic visit‐to‐visit variability and ambulatory BP variability with correlation coefficients for systolic and diastolic BP all <0.16. We observed a high correlation between first and second ambulatory BP ; however, the limits of agreement were wide in both the intensive group (−27 to 21 mm Hg) and the standard group (−23 to 20 mm Hg). Conclusions We found low concordance in BP and BP variability between clinic and ambulatory BP and second ambulatory BP . Results did not differ by treatment arm. These results reinforce the need for multiple BP measurements before clinical decision making.

Intensive systolic blood pressure (SBP) control improved outcomes in SPRINT (Systolic Blood Pressure Intervention Trial). Our objective was to expand on reported findings by analysis of baseline characteristics, primary outcomes, adverse events, follow-up blood pressure, and medication use differences by baseline SBP (tertile 1 [T1], <132; tertile 2 [T2], 132–145; and tertile 3 [T3], >145 mm Hg). Participants with higher baseline SBP tertile were more often women and older, had higher cardiovascular risk, and lower utilization of antihypertensive medications, statins, and aspirin. Achieved SBP in both treatment arms was slightly higher in T2 and T3 compared with T1 and fewer in the T3 groups achieved SBP targets compared with T1 and T2 groups. The primary composite outcome with intensive versus standard SBP treatment was reduced by 30% in T1, 23% in T2, and 17% in T3 with no evidence of an interaction ( P =0.77). Event rates were lower in the intensive arm, and there was no evidence that this benefit differed by SBP tertile. There was no difference in the hazard for serious adverse events in any of the 3 tertiles. Medication utilization differed across the SBP tertiles at baseline with a lesser percentage of diuretics and angiotensin-converting enzyme inhibitors/angiotensin receptor blocker drugs in the higher tertiles—a finding that reversed during the trial. The beneficial effects of intensive SBP lowering were not modified by the level of baseline SBP. Within the parameters of this population, these findings add support for clinicians to treat blood pressure to goal irrespective of baseline SBP.

Background: In individuals with a low diastolic blood pressure (DBP), the potential benefits or risks of intensive systolic blood pressure (SBP) lowering are unclear. Methods: SPRINT (Systolic Blood Pressure Intervention Trial) was a randomized controlled trial that compared the effects of intensive (target <120 mm Hg) and standard (target <140 mm Hg) SBP control in 9361 older adults with high blood pressure at increased risk of cardiovascular disease. The primary outcome was a composite of cardiovascular disease events. All-cause death and incident chronic kidney disease were secondary outcomes. This post hoc analysis examined whether the effects of the SBP intervention differed by baseline DBP. Results: Mean baseline SBP and DBP were 139.7±15.6 and 78.1±11.9 mm Hg, respectively. Regardless of the randomized treatment, baseline DBP had a U-shaped association with the hazard of the primary cardiovascular disease outcome. However, the effects of the intensive SBP intervention on the primary outcome were not influenced by baseline DBP level ( P for interaction=0.83). The primary outcome hazard ratio for intensive versus standard treatment was 0.78 (95% confidence interval, 0.57–1.07) in the lowest DBP quintile (mean baseline DBP, 61±5 mm Hg) and 0.74 (95% confidence interval, 0.61–0.90) in the upper 4 DBP quintiles (mean baseline DBP, 82±9 mm Hg), with an interaction P value of 0.78. Results were similar for all-cause death and kidney events. Conclusions: Low baseline DBP was associated with increased risk of cardiovascular disease events, but there was no evidence that the benefit of the intensive SBP lowering differed by baseline DBP. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01206062.

The appropriate target for BP in patients with CKD and hypertension remains uncertain. We report prespecified subgroup analyses of outcomes in participants with baseline CKD in the Systolic Blood Pressure Intervention Trial. We randomly assigned participants to a systolic BP target of <120 mm Hg (intensive group; n =1330) or <140 mm Hg (standard group; n =1316). After a median follow-up of 3.3 years, the primary composite cardiovascular outcome occurred in 112 intensive group and 131 standard group CKD participants (hazard ratio [HR], 0.81; 95% confidence interval [95% CI], 0.63 to 1.05). The intensive group also had a lower rate of all-cause death (HR, 0.72; 95% CI, 0.53 to 0.99). Treatment effects did not differ between participants with and without CKD ( P values for interactions ≥0.30). The prespecified main kidney outcome, defined as the composite of ≥50% decrease in eGFR from baseline or ESRD, occurred in 15 intensive group and 16 standard group participants (HR, 0.90; 95% CI, 0.44 to 1.83). After the initial 6 months, the intensive group had a slightly higher rate of change in eGFR (−0.47 versus −0.32 ml/min per 1.73 m 2 per year; P <0.03). The overall rate of serious adverse events did not differ between treatment groups, although some specific adverse events occurred more often in the intensive group. Thus, among patients with CKD and hypertension without diabetes, targeting an SBP<120 mm Hg compared with <140 mm Hg reduced rates of major cardiovascular events and all-cause death without evidence of effect modifications by CKD or deleterious effect on the main kidney outcome.