By Michael Crawford, MD, Editor
Dr. Crawford reports no financial relationships relevant to this field of study.
SYNOPSIS: A randomized, double-blind, placebo-controlled study in resistant hypertension patients on three drugs, including a diuretic, showed that the addition of spironolactone was superior to doxazosin and bisoprolol for lowering blood pressure and it was well tolerated.
SOURCES: Williams B, et al. 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;386:2059-2068.
Sternlicht H, Bakris GL. Spironolactone for resistant hypertension-hard to resist? Lancet 2015;386:2032-2034.
Resistant hypertension is common, and the choice of additional drug therapy in this condition is not clear. Investigators tested three drug classes as additional therapy beyond the recommended angiotensin-converting-enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB), calcium blocker plus diuretic. An alpha-blocker to further reduce peripheral resistance (doxazosin), a beta-blocker to reduce renin (bisoprolol), and additional diuresis with spironolactone were tested in a randomized, double-blind, placebo-controlled, crossover trial. The study included patients on maximally tolerated doses of the recommended three classes of drugs who had a clinical blood pressure (BP) of > 140 mmHg systolic or > 135 for diabetics and average home BP measures > 130 over 4 days (18 measurements). After 1 month of single-blind placebo, patients were rotated through four regimens for 6 weeks at the lower dose and 6 weeks at the higher dose: spironolactone 25-50 mg/day, doxazosin 4-8 mg/day, bisoprolol 5-10 mg/day, and placebo. The primary endpoint was the average of three home systolic BP twice a day for 4 days (24 measurements). Plasma renin was measured at baseline, and serum electrolytes were measured at each visit. Researchers screened 436 patients 18-79 years of age, randomized 335 patients (mean age 61 years), and placed 314 patients in the intention-to-treat analysis. Two hundred thirty patients completed the entire protocol. The average decrease in systolic BP on spironolactone was significantly greater than on placebo (-8.7 mmHg, P < 0.0001) and the response to doxazosin (-4.0 mmHg, P < 0.0001) and bisoprolol (-4.5 mmHg, P < 0.0001). Spironolactone’s superiority persisted across all measured renin levels except the very highest, where it was equally as efficacious the other two drugs. Adverse events were not different with the three drugs, and only six patients on spironolactone had a potassium > 6.0 mmol/L on one occasion only (maximum 6.5). The authors concluded that spironolactone was the most efficacious fourth drug for patients with drug-resistant hypertension.
Resistant hypertension is defined as levels above the patients target on maximally tolerated doses of three drugs, one of which is a diuretic, and afflicts about 10% of treated hypertensives. Current guidelines suggest adding a fourth drug, but do not specify which one. It has been suggested that resistant hypertension is a result of non-compliance, not necessarily with drug therapy but rather lifestyle modifications such as reduced salt intake, alcohol consumption, and weight loss. The most important of these is probably salt intake. In this study, 24-hour urine-sodium excretion on placebo was 8 g. Thus, the concept of additional diuresis has arisen. Some believe that switching to a longer-acting diuretic, such as chlorthalidone or indapamide, works, but this has not been systematically studied. Another concept is that those treated with long-term ACEI/ARB develop aldosterone escape, leading to salt and water retention. Therefore, previous observational studies suggest aldosterone antagonists may be efficacious in resistant hypertension. This study tested this hypothesis and compared spironolactone to two other classes of agents: beta-blocker and alpha-blocker.
In this population of predominantly white subjects, spironolactone was remarkably effective. It was twice as effective as bisoprolol and doxazosin. Also, about 60% achieved target BP (< 135 systolic) on spironolactone vs about 40% on the other two drugs. Although bisoprolol and doxazosin were better than placebo, only spironolactone showed a dose response relationship, suggesting that higher doses, if tolerated, would produce better results. The authors suggested that the use of spironolactone in resistant hypertension may reduce the fuel for non-pharmacologic approaches such as renal denervation. Also, the study raises the question as to whether the earlier use of spironolactone would be beneficial. In the past, combination pills with hydrochlorothiazide and spironolactone were popular to reduce the incidence of hypokalemia. Perhaps these agents should receive another look in light of these data.
This study has several strengths. The authors used average home BP, which is always lower, as their endpoint measure. There was a big placebo effect noted in clinic BP (-10 mmHg) but not with average home BP. The population was relatively large for this type of study and several biochemical measures were taken, which will be reported later.
There are also weaknesses. The trial was of short duration and has no outcome data. The patients were predominantly white and had glomerular filtration rates (GFR) > 45.
There were remarkably few adverse events and they were not different between the three drugs (all < 3%). Hyperkalemia was infrequent and resulted in no serious events. The authors noted that serum sodium decreased 1.2 mmol/L on average, and potassium increased 0.5 mmol/L. Estimated GFR decreased, but no more than you would expect while administering another diuretic. Whether this has long-term consequences is unknown. The authors did not observe gynecomastia, but the length of exposure to spironolactone is probably too short to see this side effect.
The editorial by Sternlicht and Bakris concluded that despite the imperfections in this study, using spironolactone for resistant hypertension is “hard to resist.” Future studies should clarify general applicability and whether a more aggressive thiazide diuretic approach would be just as effective.