Among patients with resistant hypertension (RHTN), there are those whose blood pressure (BP) remains uncontrolled in spite of maximal medical therapy. This retrospective analysis aims to characterize these patients with refractory hypertension. Refractory hypertension was defined as BP that remained uncontrolled after ≥ 3 visits to a hypertension clinic within a minimum 6-month follow-up period. Of the 304 patients referred for RHTN, 29 (9.5%) remained refractory to treatment. Patients with refractory hypertension and those with controlled RHTN had similar aldosterone levels and plasma renin activity (PRA). Patients with refractory hypertension had higher baseline BP (175±23/97±15 vs. 158±25/89±15 mmHg, p=0.001/0.005) and heart rate, and higher rates of prior stroke and congestive heart failure. During follow-up, the BP of patients with refractory hypertension remained uncontrolled (168.4±14.8/93.8±17.7 mmHg) in spite of use of an average of 6 antihypertensive medications, while those of patients with controlled RHTN decreased to 129.3±11.2/77.6±10.8 mmHg. Spironolactone reduced the BP by 12.9±17.8/6.6±13.7 mmHg in patients with refractory hypertension, and by 24.1±16.7/9.2±12.0 mmHg in patients with controlled RHTN. In patients with RHTN, approximately 10% remain refractory to treatment. Similar aldosterone and PRA levels and a diminished response to spironolactone suggest that aldosterone excess does not explain the treatment failure.

In this review, we discuss the possible pathophysiological mechanisms and the role of arterial stiffness as a biomarker, a blood pressure–independent predictor of cardiovascular morbidity and mortality. The effects of different antihypertensive drug classes on noninvasively assessed markers of arterial stiffness are also discussed. Current evidence will be reviewed regarding the effect of drugs on arterial stiffness, including the peripheral and central effects of angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, dihydropyridine calcium channel blockers, beta blockers (including vasodilating beta blockers), diuretics, and mineralocorticoid antagonists.

Obstructive sleep apnoea (OSA) and hypertension commonly coexist. Observational studies indicate that untreated OSA is strongly associated with an increased risk of prevalent hypertension, whereas prospective studies of normotensive cohorts suggest that OSA may increase the risk of incident hypertension. Randomized evaluations of continuous positive airway pressure (CPAP) indicate an overall modest effect on blood pressure (BP). Determining why OSA is so strongly linked to having hypertension in cross-sectional studies, but yet CPAP therapy has limited BP benefit needs further exploration. The CPAP studies do, however, indicate a wide variation in the BP effects of CPAP, with some patients manifesting a large antihypertensive benefit such that a meaningful BP effect can be anticipated in some individuals. OSA is particularly common in patients with resistant hypertension (RHTN). The reason for this high prevalence of OSA is not fully explained, but data suggest that it may be related to the high occurrence of hyperaldosteronism in patients with RHTN. In patients with RHTN, it has been shown that aldosterone levels correlate with severity of OSA and that blockade of aldosterone reduces the severity of OSA. Overall, these findings are consistent with aldosterone excess contributing to worsening of underlying OSA. We hypothesize that aldosterone excess worsens OSA by promoting accumulation of fluid within the neck, which then contributes to increased upper airway resistance.

Refractory hypertension is an extreme phenotype of treatment failure defined as uncontrolled blood pressure (BP) in spite of ≥5 classes of antihypertensive agents, including chlorthalidone and a mineralocorticoid receptor antagonist. A prospective evaluation of possible mechanisms of refractory hypertension has not been done. The goal of this study was to test for evidence of heightened sympathetic tone as indicated by 24-hr urinary (U-) normetanephrine levels, clinic and ambulatory heart rate (HR), HR variability (HRV), arterial stiffness as indexed by pulse wave velocity (PWV), and systemic vascular resistance (SVR) compared to patients with controlled resistant hypertension. Forty-four consecutive patients, 15 with refractory and 29 with controlled resistant hypertension, were evaluated prospectively. Refractory hypertensive patients were younger (48±13.3 vs. 56.5±14.1 years, p=0.038) and more likely female (80.0 vs 51.9 %, p=0.047) compared to patients with controlled resistant hypertension. They also had higher U-normetanephrine levels (464.4±250.2 vs. 309.8±147.6 μg/24h, p=0.03), higher clinic HR (77.8±7.7 vs. 68.8±7.6 bpm, p=0.001) and 24-hr ambulatory HR (77.8±7.7 vs 68.8±7.6, p=0.0018), higher PWV (11.8±2.2 vs. 9.4±1.5 m/s, p=0.009), reduced HRV (4.48 vs. 6.11, p=0.03), and higher SVR (3795±1753 vs. 2382±349 dyne·sec·cm5·m2, p=0.008). These findings are consistent with heightened sympathetic tone being a major contributor to antihypertensive treatment failure and highlight the need for effective sympatholytic therapies in patients with refractory hypertension.

BackgroundWe aimed to estimate the prevalence of refractory hypertension (RfH) and to determine the clinical differences between these patients and resistant hypertensives (RH). Secondly, we assessed the prevalence of white‐coat RfH and clinical differences between true‐ and white‐coat RfH patients.Methods and ResultsThe present analysis was conducted on the Spanish Ambulatory Blood Pressure Monitoring Registry database containing 70 997 treated hypertensive patients. RH and RfH were defined by the presence of elevated office blood pressure (≥140 and/or 90 mm Hg) in patients treated with at least 3 (RH) and 5 (RfH) antihypertensive drugs. White‐coat RfH was defined by RfH with normal (<130/80 mm Hg) 24‐hour blood pressure. A total of 11.972 (16.9%) patients fulfilled the standard criteria of RH, and 955 (1.4%) were considered as having RfH. Compared with RH patients, those with RfH were younger, more frequently male, and after adjusting for age and sex, had increased prevalence of target organ damage, and previous cardiovascular disease. The prevalence of white coat RfH was lower than white‐coat RH (26.7% versus 37.1%, P<0.001). White‐coat RfH, in comparison with those with true RfH, showed a lower prevalence of both left ventricular hypertrophy (22% versus 29.7%; P=0.018) and microalbuminuria (28.3% versus 42.9%; P=0.047).ConclusionsThe prevalence of RfH was low and these patients had a greater cardiovascular risk profile compared with RH. One out of 4 patients with RfH have normal 24‐hour blood pressure and less target organ damage, thus indicating the important role of ambulatory blood pressure monitoring in guiding antihypertensive therapy in difficult‐to‐treat patients.