Patients With Resistant Hypertension: What’s the Best Pharmacologic Strategy?

Eric A. Dietrich, PharmD, BCPS, and Kyle Davis, PharmD, BCPS

In last issue’s column,1 we discussed the case of JG, a patient with newly diagnosed hypertension (HTN). Upon diagnosis, consistent with national guidelines (ie, the Eighth Joint National Committee),2 JG was started on a thiazide diuretic, namely chlorthalidone.

Over the next several months, despite continual efforts to reduce his weight, control his salt intake, and increase his activity level, JG’s blood pressure (BP) remained elevated. Accordingly, he was started on amlodipine, which was titrated to 10 mg daily, and lisinopril, which was titrated to 40 mg daily. Despite both the pharmacologic and nonpharmacologic efforts, JG’s BP remained elevated at 155/91 mm Hg. What is the next best step for JG to control his BP?


Because JG was on at least 3 antihypertensive medications and his BP remained uncontrolled, he would be classified as having resistant HTN. Resistant HTN is associated with an increased risk for cardiovascular events and other negative consequences.3 Initial interventions in such patients include optimization of nonpharmacologic measures such as diet, increased exercise, weight loss, tobacco cessation, and limiting the intake of alcohol and salt; diuretic optimization (eg, switching from hydrochlorothiazide to chlorthalidone) also is a recommended strategy.2

Additionally, assurance of adherence to the prescribed medication regimen is invaluable; clearly, with an increasing number of medications, the chances for nonadherence also increase.3 Because these patients already are on 3 medications (and, hopefully, the 3 recommended first-line options of a diuretic, an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, and a calcium-channel blocker), the remaining therapeutic options generally offer less-robust evidence of benefit and a potentially increased risk of adverse effects compared with first- or second-line alternatives. Agents such as ɑ2-agonists (eg, clonidine), ɑ1-receptor blockers (eg, doxazosin, prazosin), β-blockers (eg, atenolol, carvedilol), direct-acting vasodilators (hydralazine), and nitrates are potential options to further gain BP control. Additionally, the aldosterone antagonist spironolactone has been recommended as an option but is not generally considered to be an “antihypertensive” agent. With this many options available, selecting the most appropriate agent in the face of continued uncontrolled BP is essential. But which agent is the best one to add?

The Evidence

Numerous treatment options are available for patients with resistant HTN, but little evidence has been available to guide clinicians in this difficult clinical scenario. Two large landmark studies, ASPIRANT and PATHWAY-2, have evaluated the use of spironolactone in patients with resistant HTN.

The ASPIRANT trial4 evaluated the effect of spironolactone, 25 mg once daily, or placebo in patients with resistant HTN. The study defined resistant HTN as patients with systolic BP greater than 140 mm Hg or diastolic BP greater than 90 mm Hg while receiving 3 antihypertensive agents, with at least 1 of them being a diuretic. Patients with diabetes or chronic kidney disease also were enrolled if their systolic BP was greater than 130 mm Hg or diastolic BP was greater than 80 mm Hg. Following 8 weeks of therapy, spironolactone significantly reduced mean systolic daytime BP (−9.3 mm Hg vs −3.9 mm Hg, P = .024). Furthermore, spironolactone significantly reduced mean nighttime, 24-hour, and office-visit systolic BP at 8 weeks. Although spironolactone reduced diastolic BP, this outcome was not statistically significant compared with placebo. Additionally, no patients were withdrawn from the study due to hyperkalemia or renal insufficiency.

Recently, the PATHWAY-2 trial5 evaluated the relative efficacy of spironolactone, doxazosin, bisoprolol, or placebo in patients with resistant HTN to clarify the optimal treatment regimen. At baseline, patients had a clinic systolic BP greater than 140 mm Hg (> 135 mm Hg for patients with diabetes) on 3 maximally tolerated medications. A total of 285 patients were randomized to receive 12 weeks of spironolactone (25-50 mg), bisoprolol (5-10 mg), doxazosin modified-release (4-8 mg), or placebo, added to the baseline medication regimen; the dose of the study medication was doubled at week 6 to the maximum dose if the patient’s BP remained uncontrolled. Also important, patients were rotated through each treatment option, and 230 patients completed all cycles. At the end of the study, spironolactone resulted in the greatest reduction in systolic BP (−8.7 mm Hg vs placebo) and was superior to either doxazosin or bisoprolol. The benefit of spironolactone also was maintained across the spectrum of baseline plasma renin concentrations, although its benefits were greater among patients with a higher plasma renin concentration. Importantly, spironolactone was well tolerated, and only 6 of 285 patients experienced a serum potassium level above 6 mEq/L.

Adverse Effects

The most concerning adverse effect of spironolactone is hyperkalemia. However, this is a dose-dependent effect, and it occurred infrequently at the studied doses in resistant HTN (in only 6 of 285 patients in PATHWAY-2; the highest serum potassium in ASPIRANT was 5.5 mEq/L after 8 weeks of spironolactone). Gynecomastia also may occur in some patients, causing them to discontinue the medication. The aldosterone antagonist eplerenone lacks this adverse effect, but its efficacy in the setting of resistant HTN has not been adequately studied and may not provide the same effect on BP. Furthermore, the increased cost of eplerenone compared with spironolactone further limits the benefit of eplerenone in this setting.

Clinical Application

Based on recent trial results, JG should be started on spironolactone, 25 mg daily, in addition to his current regimen in order to have the best chances for attaining a controlled BP. In addition to the favorable results from the ASPIRANT and PATHWAY-2 trials highlighting the superiority of spironolactone, the practical benefits of the addition of spironolactone include once-daily dosing, affordability, and small tablet size; it also may help limit any hypokalemia resulting from a thiazide or thiazide-like diuretic. JG should be monitored for hyperkalemia with a basic metabolic panel measured in 1 week. He also should be educated on the potential for developing gynecomastia and to alert his health care provider should this symptom occur. 

Eric A. Dietrich, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy and completed a 2-year fellowship in family medicine where he was in charge of an anticoagulation clinic. He works for the College of Pharmacy and the College of Medicine at the University of Florida in Gainesville.

Kyle Davis, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy in Gainesville and completed a 2-year residency in internal medicine at Indiana University in Indianapolis. He is an internal medicine specialist at Ochsner Medical Center in Jefferson, Louisiana.


  1. Dietrich EA, Davis K. Hydrochlorothiazide for hypertension: is it the diuretic of choice? Consultant. 2016;56(6):544-545.
  2. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520.
  3. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008;117(25):e510-e526.
  4. Václavík J, Sedlák R, Plachý M, et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension. 2011;57(6):1069-1075.
  5. Williams B, MacDonald TM, Morant S, et al; British Hypertension Society’s PATHWAY Studies Group. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015;386(10008):2059-2068.