Refractory Hypertension and Risks of Adverse Cardiovascular Events and Mortality in Patients With Resistant Hypertension: A Prospective Cohort Study

Abstract

Background The long-term prognosis of refractory hypertension (RfHT), defined as failure to control blood pressure (BP) levels despite an antihypertensive treatment with ≥5 medications including a diuretic and mineraloreceptor antagonist, has never been evaluated. Methods and Results In a prospective cohort study with 1576 patients with resistant hypertension, patients were classified as refractory or nonrefractory based on uncontrolled clinic (or office) and ambulatory BPs during the first 2 years of follow-up. Multivariate Cox analyses examined the associations between the diagnosis of RfHT and the occurrence of total cardiovascular events (CVEs), major adverse CVEs, and cardiovascular and all-cause mortality, after adjustments for other risk factors. In total, 135 patients (8.6%) had RfHT by uncontrolled ambulatory BPs and 167 (10.6%) by uncontrolled clinic BPs. Over a median Follow-Up of 8.9 years, 338 total CVEs occurred (288 major adverse CVEs, including 124 myocardial infarctions, and 96 strokes), and 331 patients died, 196 from cardiovascular causes. The diagnosis of RfHT, using either classification by clinic or ambulatory BPs, was associated with significantly higher risks of major adverse CVEs, cardiovascular mortality, and stroke incidence, with hazard ratios varying from 1.54 to 2.14 in relation to patients with resistant nonrefractory hypertension; however, the classification based on ambulatory BPs was better in identifying higher risk patients than the classification based on clinic BP levels. Conclusions Patients with RfHT, particularly when defined by uncontrolled ambulatory BP levels, had higher risks of major adverse CVEs and mortality in relation to patients with resistant but nonrefractory hypertension, supporting the concept of refractory hypertension as a true extreme phenotype of antihypertensive treatment failure.

Keywords: ambulatory blood pressure monitoring; cardiovascular events; cohort study; mortality; refractory hypertension; risk factors.

Figure 1. Kaplan–Meier estimation of cumulative incidence of total CVEs (A and B) and MACE (C and D) in 1576 patients with resistant hypertension categorized as having RfHT or non‐RfHT, defined by ambulatory mean 24‐hour BPs (≥130/80 mm Hg, A and C) and by clinic BPs (≥140/90 mm Hg, B and D) during Follow‐Up.

HRs were from fully adjusted models. BP indicates blood pressure; CVE, cardiovascular event; HR, hazard ratio; MACE, major averse cardiovascular events; and RfHT, refractory hypertension.

Figure 2. Kaplan–Meier estimation of cumulative incidence of CV deaths (A and B) and strokes (C and D) in 1576 patients with resistant hypertension categorized as having RfHT or non‐RfHT, defined by ambulatory mean 24‐hour BPs (≥130/80 mm Hg, A and C) and by clinic BPs (≥140/90 mm Hg, B and D) during Follow‐Up.

HRs were from fully adjusted models. BP indicates blood pressure; CV, cardiovascular; HR, hazard ratio; and RfHT, refractory hypertension.