Is spironolactone a good choice for black people to treat high blood pressure?

Spironolactone has been shown to be effective in treating patients, including black people, with resistant hypertension.^1–4 Resistant hypertension is defined as high blood pressure (BP) that is uncontrolled despite the use of three complementary antihypertensives or BP that requires the use of four or more medications to achieve control. It affects about 13% to 17% of the adult population in the US, depending on which cutoff is used (130/80 or 140/90) to define control.⁵

Much of the existing evidence in the literature is based on non-black populations. Recent clinical practice guidelines emphasize the need for tailored therapy for black people, because the available evidence suggests that black people have a better response to some antihypertensive treatments than others.^6,7 While available evidence supports the use of spironolactone in black people, clinical studies that have included African-Americans or others of African descent were not always designed specifically to measure the efficacy and safety of spironolactone in these patients.^1–4 More research studies, particularly large randomized double-blind placebo-controlled clinical trials, are needed to evaluate the efficacy of spironolactone among black people.

As a group, black people have a higher rate of hypertension, earlier onset of high BP, and are more likely to be resistant to drug therapy for hypertension than white patients.^5,7 BP in black people may be more sensitive to the effects of aldosterone.⁸ The reason for this difference among black patients is not well understood, but the existence of these differences suggests it is important to include more individuals of various races, particularly black people, in antihypertensive drug studies.^9–11

In a small randomized, placebo-controlled, double-blind study, 98 African American patients with resistant hypertension on multiple antihypertensives were given spironolactone, amiloride, a combination of both, or a placebo. The addition of spironolactone resulted in a modest drop in both systolic and diastolic BP (mean systolic drop 4.6 mm Hg, standard error [SE] ±1.6 mm Hg, p=0.006; and mean diastolic drop of 1.8 mm Hg, SE ±1.0 mm Hg, p=0.07). The number of black patients taking spironolactone was small (20), limiting the interpretation of results.

In a study of 76 patients with resistant hypertension, including 41 African-Americans, participants were given low-dose spironolactone (12 – 25 mg initially, titrated to 50 mg if BP uncontrolled) in addition to a multidrug regimen that included a diuretic, an angiotensin converting enzyme inhibitor (ACEI) and/or an angiotensin II receptor blocker.² Spironolactone lowered BP on average by 25/12 mm Hg after six months. Reductions in BP were similar among black and white patients.

Another study compared responses of 29 black hypertensive patients (26 women and 3 men) taking either spironolactone (100 mg – 400 mg/day) or hydrochlorothiazide (100 mg/day).¹ Mean diastolic BP fell 18 mm Hg with hydrochlorothiazide and 15 mm Hg with 400 mg spironolactone (standard deviation not given). The authors were evaluating if patient’s level of renin activity affected their response to either diuretic and found that, regardless of renin levels, black women appear to be quite responsive to spironolactone and hydrochlorothiazide.

The Randomized Aldactone Evaluation Study (RALES) was a double-blind randomized, placebo-controlled trial designed to evaluate the efficacy of spironolactone in preventing cardiac-related hospitalizations and death in patients with heart failure (HF). Patients with NYHA functional class III or IV HF who were taking ACEIs and diuretics were included in the study. Patients were randomized to take 25 mg spironolactone or placebo daily. After eight weeks the spironolactone was increased to 50 mg, if there were signs of HF progression without hyperkalemia. In an analysis of the study data after its conclusion, spironolactone proved more effective for the 1,543 non-black people than for the 120 black people.¹² It lowered the combined end point of death or hospitalization for HF in non-black people (hazard ratio [HR] 0.63, 95% confidence interval [CI] [0.55 – 0.73]) but not in black people (HR 1.07, CI [0.67 – 1.71],p=0.032). Overall, black people taking spironolactone experienced less hyperkalemia and more hypokalemia than non-black people taking spironolactone. Although the study design and the size of the black population limit the conclusions that can be drawn, the findings suggest that the side effect profile and effectiveness of spironolactone may be different for black people and non-black people. Similar variations in potassium response comparing black to non-black patients have been reported elsewhere.^13,14

^References

1. Holland OB, Gomez-Sanchez C, Fairchild C, Kaplan NM. Role of renin classification for diuretic treatment of black hypertensive patients. Arch Intern Med 1979; 139.
2. Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens 2003; 16 (11 I): 925-930.
3. Saha C, Eckert GJ, Ambrosius WT, et al. Improvement in blood pressure with inhibition of the epithelial sodium channel in blacks with hypertension. Hypertension 2005; 46 (3): 481-487.
4. Williams B, MacDonald TM, Morant S, 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 (10008): 2059-2068.
5. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018; 71 (19): e127-e248.
6. Brewster LM, van Montfrans GA, Kleijnen J. Systematic review: antihypertensive drug therapy in black patients. Ann Intern Med 2004; 141 (8): 614-627.
7. Flack JM, Sica DA, Bakris G, et al. Management of high blood pressure in blacks: an update of the International Society on Hypertension in Blacks consensus statement. Hypertension 2010; 56 (5): 780-800.
8. Mohandas A, Suboc TB, Wang J, et al. Mineralocorticoid exposure and receptor activity modulate microvascular endothelial function in African Americans with and without hypertension. Vasc Med 2015; 20 (5): 401-408.
9. Andrew ME, Jones DW, Wofford MR, et al. Ethnicity and unprovoked hypokalemia in the ARIC study. Am J Hypertens 2002; 15 (7 I): 594-599.
10. Brewster LM, Seedat YK. Why do hypertensive patients of African ancestry respond better to calcium blockers and diuretics than to ACE inhibitors and beta-adrenergic blockers? A systematic review. BMC Med 2013; 11 : 141.
11. Rizos C V, Elisaf MS. Antihypertensive drug therapy in patients with African ancestry. Expert Opin Pharmacother 2014; 15 (8): 1061-1064.
12. Vardeny O, Cavallari LH, Claggett B, et al. Race influences the safety and efficacy of spironolactone in severe heart failure. Circ Heart Fail 2013; 6 (5): 970-976.
13. Cavallari LH, Groo VL, Momary KM, Fontana D, Viana MA, Vaitkus P. Racial differences in potassium response to spironolactone in heart failure. Congest Heart Fail 2006; 12 (4): 200-205.
14. Cavallari LH, Fashingbauer LA, Beitelshees AL, et al. Racial differences in patients’ potassium concentrations during spironolactone therapy for heart failure. Pharmacotherapy 2004; 24 (6): 750-756.