Editor’s Note: This is Part II (CON) of a two-part Journal Scan review. Go to Part I (PRO).

The following are key points from an antagonist viewpoint regarding whether patients with cardiovascular (CV) risk factors should receive intensive treatment of hypertension to <120/80 mm Hg target:

1. Epidemiological studies show a graded increase in CV disease risk at systolic blood pressure (BP) above 115 mm Hg and diastolic BP above 75 mm Hg. However, it is unclear if drug therapy targeting BP to these levels reduces CV events and is safe. Observational studies suggest that aggressive BP lowering to levels below 120/80 mm Hg produce a J-curve phenomenon with increased risk especially for coronary events. More reliable data are provided by randomized trials.
2. Three recent trials have specifically compared intensive systolic BP lowering to targets of <120-130 mm Hg versus traditional guideline-recommended targets of generally <140 mm Hg, and the “older” HOT (Hypertension Optimal Treatment) trial randomized patients to diastolic BP targets of ≤90, ≤85, or ≤80 mm Hg. All trials differed regarding patients’ risk, treatment and duration, outcomes, and most importantly BP measurement techniques.
3. The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial randomized 4,733 patients with diabetes (mean age 63 years and BP 139/76 mm Hg) to intensive therapy to a systolic BP target <120 mm Hg or to a “standard” target <140 mm Hg. Intensive therapy lowered BP by 14.2/6.1 mm Hg, but did not reduce the primary outcome of CV death, myocardial infarction (MI), stroke, heart failure (HF), or overall coronary events. The SPS3 (Subcortical Strokes) trial randomized 3,020 patients (mean age 63 years, BP 143/79 mm Hg) with a recent small subcortical stroke to a systolic BP target <130 mm Hg or between 130-149 mm Hg. The difference in systolic BP was 11 mm Hg, but there was no significant reduction in the primary outcome, recurrent stroke, or in the secondary outcome, the composite of MI and vascular death.
4. The only trial that showed benefit for intensive systolic BP lowering to <120 mm Hg is SPRINT (Systolic Blood Pressure Intervention Trial), conducted in 9,361 patients with “high normal BP” in high-risk patients with either chronic kidney disease, clinical or subclinical CV disease or Framingham risk ≥15% (mean age 68 years, BP 140/78 mm Hg), and diabetes or previous stroke excluded. SPRINT was terminated early with BP lowered by 14.8/7.6 mm Hg. There was a 25% relative risk reduction (RRR) in the primary composite outcome of MI, acute coronary syndrome, stroke, HF, or CV death and HF, CV and all-cause death, but not in MI and stroke. In contrast, the HOT trial found no significant reduction in CV events in a cohort with higher systolic and diastolic BP (170/89 mm Hg) and without previous CV events, and found overall no significant reduction in CV events for more aggressive diastolic BP targets, except in the subset of patients with diabetes.
5. SPRINT is the exception among trials evaluating aggressive BP-lowering targets that may be related to several unique features. Importantly, early termination may result in overestimated benefit. After adjusting for this potential bias, the true RRR in major CV events is about 15%, which is closer to estimates in a meta-analysis of trials comparing more versus less intensive BP lowering. It is strange that there was no significant reduction in MI or stroke, considering the latter being most closely related to BP. The reduction in HF may have been related to increased use of diuretics and not the lower BP. Standardized BP measurements based on an average of three measurements were used, which are not standard practice. SPRINT targets in clinical practice without implementing the SPRINT BP measurement protocol, and careful follow-up may result in lower BP levels and more side effects. Two widely different BP targets were used. An intermediate target (e.g., 130 mm Hg) could have achieved the same benefit with fewer side effects. The target and frequency of evaluation may be difficult to implement in routine clinical practice. Finally, the 25% RRR far exceeds that of other trials evaluating aggressive BP targets.
6. SPRINT was compared to the recent HOPE-3 (Heart Outcomes Evaluation-3) trial. HOPE-3 was conducted in an intermediate-risk population without CV disease (yearly major CV event rates of 0.94% vs. 2.19% in SPRINT), 80% of participants were treatment-naïve at baseline, BP measurements were obtained by a health care provider, and a simple BP-lowering regimen with a fixed-dose combination of an angiotensin-receptor blocker and a thiazide diuretic (at low doses) was compared to placebo without titration to prespecified targets. Overall, there was no significant reduction in major CV events. However, in a prespecified subgroup analysis, a significant 27% reduction in major CV events was shown in participants in the upper third of baseline systolic BP (>143.5 mm Hg, mean of 154.1 mm Hg) despite a more modest 6/3 mm Hg BP lowering, with no benefit in those with lower entry BP. These benefits were safely enhanced by simultaneous administration of a statin (40% RRR). These findings support antihypertensive therapy in mild uncomplicated hypertension with initiation of therapy at systolic BP >140 mm Hg. Results of the subgroup analysis suggest that aggressive targets in this intermediate-risk population are not justified. In contrast to SPRINT, follow-up visits were infrequent and streamlined, so that the HOPE-3 approach is widely applicable.

Keywords: Antihypertensive Agents, Blood Pressure, Diabetes Mellitus, Diuretics, Heart Failure, Hypertension, Metabolic Syndrome, Myocardial Infarction, Primary Prevention, Renal Insufficiency, Chronic, Risk Factors, Stroke, Systole

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