Recent advances in understanding and managing resistant/refractory hypertension

Data from clinical studies of spironolactone versus adrenergic blockers

The landmark PATHWAY-2 study found significant benefits with the use of spironolactone in patients with resistant hypertension on a standard three-drug therapy with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, amlodipine, and indapamide⁴. The study was a double-blind four-way crossover study that assessed the use of spironolactone (25 or 50 mg) versus bisoprolol (5 to 10 mg), doxazosin (5 to 10 mg), or placebo. To exclude non-adherence, the study was monitored with pill count and measurement of serum angiotensin-converting enzyme activity. Spironolactone was superior to both active treatments and placebo, and mean reductions in BP were 8.70, 4.48, and 4.03 mm Hg with spironolactone, bisoprolol, and doxazosin, respectively. Importantly, about 60% of the spironolactone users achieved BP control versus 43.3% of the bisoprolol and 41.5% of the doxazosin users⁴.

Apart from the beneficial effect of spironolactone in patients with resistant hypertension, the PATHWAY-2 study offered three important findings. First, despite the superiority of spironolactone over bisoprolol and doxazosin, the use of the latter two drugs was associated with significant reductions in BP compared with placebo. Thus, the European guidelines recommend the use of bisoprolol and doxazosin for the treatment of resistant hypertension when spironolactone is contraindicated or not tolerated¹. Second, uptitration of spironolactone dose from 25 to 50 mg resulted in a greater reduction in BP at week 12 of the study. The BP-lowering effect of spironolactone uptitration was higher compared with the corresponding increases in the dose of either bisoprolol or doxazosin (−3.86 mm Hg with spironolactone versus −0.88 mm Hg for doxazosin, −1.49 mm Hg for bisoprolol, and −0.68 mm Hg for placebo). Last, while spironolactone reduced BP levels irrespective of renin levels, an enhanced benefit in patients with suppressed renin levels was observed, and there was up to a 20 mm Hg reduction in home BP in patients with the lowest renin levels⁴.

Important clinical information for the management of resistant hypertension arose from three recent substudies of the PATHWAY-2 trial. In the first substudy, the plasma aldosterone, renin, and aldosterone-to-renin ratio were assessed as predictors of home systolic BP response in 126 patients. Plasma aldosterone-to-renin ratio and plasma renin levels were found to be predictors of BP response to spironolactone. In the second one, the impact of each drug on the thoracic fluid content (an index of fluid retention) and vascular resistance was examined (226 patients). Thoracic fluid content was significantly reduced (by 6.8%) from baseline with spironolactone but not with the other active treatments. Given the overall outcomes of the PATHWAY-2 study, this finding supports the theory that patients with resistant hypertension are characterized by volume overload, secondary to aldosterone excess, explaining the greater benefits observed with spironolactone¹. In the third substudy, the effect of amiloride on systolic BP was examined in a 6- to 12-week open-label run-out phase, in which patients on spironolactone were crossed over from spironolactone to amiloride (146 patients). Amiloride use resulted in a remarkable reduction in BP levels of 20.4 mm Hg, comparable to the 18.3 mm Hg observed with spironolactone, suggesting that amiloride might be an effective alternative agent for these patients. Based on these findings, the European guidelines propose the use of amiloride as an alternative option if spironolactone is contraindicated or not well tolerated¹⁵.

Data from clinical studies of spironolactone versus central acting drugs

Although concrete evidence supports the superiority of mineralocorticoid receptor antagonists over alpha- and beta-blockers for patients with resistant hypertension, there is a lack of evidence regarding the use of central acting drugs in such patients. In this setting, the recent Resistant Hypertension Optimal Treatment (ReHOT) study compared the impact of spironolactone and clonidine in 187 patients with resistant hypertension¹⁶. BP control assessed with office and 24-hour ambulatory BP monitoring was similar across the two groups of patients. However, the 24-hour systolic and diastolic BP reduction and the daytime diastolic BP reductions observed with spironolactone were significantly greater than those observed with clonidine. Given the easier dosage scheme of spironolactone and the greater benefits in various ambulatory BP parameters, spironolactone seems to be a preferable option over clonidine¹⁷.

Meta-analytic data of mineralocorticoid antagonists versus other drug classes

Important information emerged from meta-analytic data for the use of mineralocorticoid receptor antagonists in patients with resistant hypertension. In 869 patients from four trials, spironolactone as add-on therapy was associated with a reduction in BP of 16.67/6.11 mm Hg¹⁶. A meta-analysis of 662 patients and five trials found that the addition of spironolactone in patients with resistant hypertension resulted in a reduction in office BP levels of 15.73/6.21 mm Hg compared with placebo, but compared with other drugs (beta-blocker, candesartan, or alpha methyldopa), spironolactone reduced home systolic BP by 4.5 mm Hg¹⁸. In a meta-analysis of five studies and 553 patients with resistant hypertension, spironolactone reduced 24-hour, daytime, nighttime, and office BP by 10.50/4.09, 10.20/4.14, 10.02/3.21, and 16.99/6.18 mm Hg, respectively¹⁹. Last, a meta-analysis of five studies and 755 patients with resistant hypertension found a greater reduction in systolic BP levels of 7.4 mm Hg (in the randomized studies) and 11.9 mm Hg (in the non-randomized studies) with mineralocorticoid receptor antagonists compared with other fourth-line options (bisoprolol, doxazosin, furosemide, or other renin–angiotensin system blockers)²⁰.

Collectively, accumulating evidence suggests that mineralocorticoid receptor antagonists are the optimal choice as the fourth-line option in patients with resistant hypertension, and data favor their use over central acting drugs, alpha- and beta-blockers. Most data come from studies with spironolactone. However, eplerenone may be considered as an alternative when adverse effects (such as gynecomastia or vaginal bleeding) are observed with spironolactone therapy²¹, although strong data with eplerenone use are currently missing. Given the substantial fluid retention observed in these patients and the findings of the PATHWAY-2 study, amiloride is an alternative option, while treatment with doxazosin, bisoprolol, or clonidine may also be considered when either mineralocorticoid receptor antagonists or amiloride is contraindicated or adverse events occur.

Renal sympathetic denervation

The early RSD studies SYMPLICITY HTN-1²⁶ and -2²⁷ showed impressive reductions in BP and created high expectations for the future of the procedure in the hypertension treatment field. However, the first randomized sham-controlled study (SYMPLICITY HTN-3) failed to show any significant benefits of RSD over sham control in the reduction of both office and ambulatory BP in patients with drug-resistant hypertension²⁸, and the technique fell into hibernation. Although several pitfalls were identified, the incomplete denervation and lack of circumferential, four-quadrant sympathetic fiber interruption were the main factors pointed out as causes of the negative findings of the study²⁹. Three recent randomized sham-controlled studies used improved technologies and techniques to achieve optimal renal denervation and offered encouraging results.

The first one was the SPYRAL HTN-OFF MED trial, a randomized sham-controlled study of patients with untreated hypertension. Patients were randomly assigned to RSD of all accessible renal arterial vessels with the Symplicity Spyral multi-electrode catheter or the Symplicity G3 S (n = 38) or a sham procedure (n = 42). After 3 months, RSD resulted in significantly greater reductions in office and ambulatory BP levels compared with those of the sham control group (BP reduction differences of −7.7/−4.9 mm Hg and −5.0/−4.4 mm Hg in office and ambulatory BP, respectively). Importantly, no patient reported any safety concerns³⁰. Similar results were observed in the SPYRAL HTN-ON MED trial, a randomized sham control study (of patients with uncontrolled hypertension on one to three anti-hypertensive drugs) that used the same techniques described for SPYRAL-OFF MED. RSD resulted in a greater reduction in office and ambulatory BP compared with the sham technique group (BP reduction differences of −6.8/−3.5 mm Hg and −7.4/−4.1 mm Hg in office and ambulatory BP, respectively). No reports of renal artery stenosis or worsening of renal function were reported³¹. The RADIANCE-HTN SOLO study was the third study that examined whether RSD performed with endovascular ultrasound reduces ambulatory BP in patients with hypertension in the absence of anti-hypertensive medication. After 2 months, significantly greater decreases in BP of −6.5/−4.1, −4.1/−1.8, and −7.1/−3.6 mm Hg in office, ambulatory, and home BP were reported with RSD compared with the sham control group³².

A recent study assessed the efficacy of different ablation methods in reducing BP³³. Particularly, patients with resistant hypertension were assigned to either treatment with radiofrequency RSD of the main renal arteries, side branches, and accessories or an endovascular ultrasound-based RSD of the main renal artery. After 3 months, BP levels were significantly more reduced in the ultrasound ablation group compared with the radiofrequency ablation group of the main renal artery (−13.2 ± 13.7 versus −6.5 ± 10.3 mm Hg, respectively). Importantly, no significant difference was found between the radiofrequency ablation groups (−8.3 ± 11.7 mm Hg in the additional side branch ablation) or between the ultrasound and the side branch ablation groups, suggesting potential superiority of ultrasound over radiofrequency ablation of the main artery in reducing BP levels³³. However, larger studies are needed to confirm or dispute the superiority of one technique over the other. Up to then, no approach could be considered the preferred or first-choice option.

Collectively, these studies resurfaced the clinical and research interest for RSD in the management of resistant hypertension. Although more patients demonstrated BP reduction with RSD than with the sham procedure, in several study participants who underwent RSD, an increase in BP was noticed, suggesting that some patients are not eligible for RSD. The quest of patient eligibility requires the identification of reliable and accurate predictors of BP response, a very demanding step with unknown outcome. Studies with larger study populations and longer follow-up periods are needed to establish the safety and efficacy of the technique, and several such studies are either planned or being conducted. The results of these studies will either re-enforce the concept of RSD or put the final nail in the coffin of this interventional approach.

Iliac vein and artery anastomosis

The ROX CONTROL HTN study randomly assigned 83 patients with resistant hypertension to either pharmacological treatment plus placement of an arteriovenous coupler or pharmacological therapy alone. After 6 months, significant reductions in office and ambulatory systolic BP of 26.9 and 13.5 mm Hg were noted with the anastomosis device group, respectively. In contrast, such benefits were not observed in the control group (3.7 and 0.5 mm Hg, respectively). Similarly, a significant reduction in diastolic BP was reported with the device. However, implantation of the arteriovenous coupler was associated with ipsilateral venous stenosis in 29% of the patients, who received venoplasty or stenting³⁴. After 12 months, office BP and ambulatory BP were reduced by 25/20.8 and 12.6/15.3 mm Hg, respectively, suggesting that the technique might offer long-lasting benefits in BP levels. Nevertheless, the percentage of patients who presented venous stenosis increased to 33%, who were treated successfully with venous stenting³⁵. In conclusion, although iliac anastomosis showed promise in terms of efficacy, the safety concerns were significant and this approach was recently abandoned.

Carotid baroreceptor activation therapy

Carotid baroreceptor activation therapy is a device-based approach aiming to activate the baroreceptors that signal the brain to activate a sympatholytic response. Such approaches might be useful in conditions characterized by sympathetic overactivity, such as hypertension, heart failure, and arrhythmias^36,37. The potential benefits might be due to the reduction of heart rate (and thus cardiac workload and energy demands) and the manifestation of arterial dilation, which results in reduction of the peripheral resistance and enhancement of renal blood flow and natriuresis.

The Rheos Pivotal Trial assessed the impact of the Rheos system, a device that uses electrical impulses from a pulse generator to chronically activate the baroreflex at the carotid sinus, on BP levels in 265 patients with resistant hypertension. In the first group of patients, treatment was applied for the first 6 months, whereas in the second group, a delayed treatment initiation was implemented at the 6-month visit; 42% of patients in the first group versus 24% in the second group achieved systolic BP of less than 140 mm Hg at 6 months, and more than 50% in both groups had a systolic BP of less than 140 mm Hg at 12 months. However, the procedural safety endpoints of the study were not met since procedural complications occurred in 25% of the patients (transient or permanent nerve injury or general surgical complications)³⁸.

However, the same company developed a second-generation device of smaller size, the Barostim Neo, which uses a smaller electrode on the surface of only one of the sinuses, thus reducing the invasiveness of the procedure and extending the battery life and replacement period³⁹. The Barostim Neo System in the Treatment of Heart Failure/Barostim Hope for Heart Failure and the recent Baroreflex Activation Therapy in Patients with Heart Failure and a Reduced Ejection Fraction trials^40,41 demonstrated significant benefits in the functional status, quality of life, and exercise capacity in patients with heart failure and reduced injection fraction. Importantly, these studies met the safety endpoints; thus, the device was granted approval by the US Food and Drug Administration³⁹. The device has also been approved in Europe for the management of resistant hypertension; the Barostim Neo trial demonstrated a persistent reduction in BP after 6 months (of a systolic BP of approximately 26 mm Hg) and an adequate safety profile^39,42.

Overall, baroreflex activation therapy is approved for the treatment of resistant hypertension in Europe and for the treatment of heart failure with reduced ejection fraction in the US. However, it is more invasive than RSD, the safety of the procedure is not unequivocally proven, and thus it has not gained either wide application or general acceptance by hypertensive experts for the management of resistant hypertension.

The MobiusHD carotid bulb expansion device is an under-examination device that is used to reduce BP through stretching of the carotid artery at the bulb, which in turn activates the carotid baroreceptors. The Controlling and Lowering Blood Pressure with the MOBIUSHD (CALM-FIM_EUR) study recently reported pronounced reduction in BP levels of 24/12 mm Hg in office and 21/12 mm Hg in ambulatory BP with the use of the MobiusHD device in patients with resistant hypertension⁴³. Importantly, the device demonstrated an acceptable safety profile⁴³. Two other trials—the CALM-FIM_US⁴⁴ and the Controlling and Lowering Blood Pressure with the MobiusHD (CALM-2)⁴⁵ studies—are examining the use of the MobiusHD device in patients with resistant hypertension. The results of these studies are eagerly awaited to further clarify the efficacy and safety of this approach and strengthen its role in the management of resistant hypertension.