Q: How effective is spironolactone for treating resistant hypertension? EVIDENCE-BASED ANSWER: VERY EFFECTIVE. Spironolactone reduces systolic blood pressure (SPB) by 11 to 17 mm Hg and diastolic blood pressure (DPB) by up to 6 mm Hg in patients with resistant hypertension taking 3 or more medications (strength of recommendation [SOR]: C, meta-analysis of randomized controlled trials [RCTs] of disease-oriented evidence).Corey Lyon, DO; Brigitte Utter, MD, University of Colorado, Family Medicine Residency, Denver; Kristen DeSanto, MSLS, MS, RD, University of Colorado, Health Sciences Library, Denve

DeSanto, Kristen

Lyon, Corey

Utter, Brigitte

English

University of Missouri: MOspace

Evidence-based answers from the  Family Physicians Inquiries NetworkE11MDEDGE.COM/FAMILYMEDICINE VOL 68, NO 5  |  JUNE 2019  |  THE JOURNAL OF FAMILY PRACTICECLINICAL INQUIRIESEVIDENCE-BASED ANSWERACorey Lyon, DO;  Brigitte Utter, MDUniversity of Colorado Family Medicine Residency, Denver Kristen DeSanto, MSLS, MS, RDUniversity of Colorado Health Sciences Library, DenverDEPUTY EDITORRick Guthmann, MD, MPHAdvocate Illinois Masonic Family Medicine Residency, ChicagoQ How effective is  spironolactone for treating  resistant hypertension?  very effective. Spironolactone  reduces systolic blood pressure (SBP) by 11 to 17 mm Hg and diastolic blood pressure (DBP) by up to 6 mm Hg in patients with resistant hypertension taking 3 or more medications (strength of recommendation [SOR]: C, meta-analysis of randomized controlled trials [RCTs] of disease-oriented evidence). ONLINEEXCLUSIVEEvidence summaryA 2017 meta-analysis of 4 RCTs (869 pa-tients) evaluated the effectiveness of pre-scribing spironolactone for patients with resistant hypertension, defined as above-goal blood pressure (BP) despite treatment with at least 3 BP-lowering drugs (at least 1 of which was a diuretic).1 All 4 trials com-pared spironolactone 25 to 50 mg/d with placebo. Follow-up periods ranged from 8 to 16 weeks. The primary outcomes were sys-tolic and diastolic BPs, which were evaluated in the office, at home, or with an ambulatory monitor. Spironolactone markedly lowers systolic and diastolic BPA statistically significant reduction in SBP oc-curred in the spironolactone group compared with the placebo group (weighted mean dif-ference [WMD] = −16.7 mm Hg; 95% confi-dence interval [CI], −27.5 to −5.8 mm Hg). DBP also decreased (WMD = −6.11 mm Hg; 95% CI, −9.34 to −2.88 mm Hg). Because significant heterogeneity was found in the initial pooled results (I2 = 96% for SBP; I2 = 85% for DBP), investigators per-formed an analysis that excluded a single study with a small sample size. The re-anal-ysis continued to show significant reductions in SBP and DBP for spironolactone compared with placebo (SBP: WMD = −10.8 mm Hg; 95% CI, −13.16 to −8.43 mm Hg; DBP: WMD = −4.62 mm Hg; 95% CI, −6.05 to −3.2 mm Hg; I2 = 35%), confirming that the excluded trial was the source of heterogeneity in the initial analysis and that spironolactone continued to significantly lower BP for the treatment group compared with controls.Add-on treatment with spironolactone also reduces BPA 2016 meta-analysis of 5 RCTs with a total of 553 patients examined the effectiveness of add-on treatment with spironolactone (25-50 mg/d) for patients with resistant hypertension, defined as failure to achieve BP < 140/90 mm Hg despite treatment with 3 or more BP-lowering drugs, in-cluding one diuretic.2 Spironolactone was compared with placebo in 4 trials and with ramipril in the remaining study. The follow-up periods were 8 to 16 weeks. Researchers separated BP outcomes into 24-hour ambulatory systolic/diastolic BPs and office systolic/diastolic BPs. The 24-hour ambulatory BPs were sig-nificantly lower in the spironolactone group compared with the control group (24-hour SBP: WMD = −10.5 mm Hg; 95% CI, −12.3 to −8.71 mm Hg; 24-hour DBP: WMD = −4.09 mm Hg; 95% CI, −5.28 to −2.91 mm Hg). CONTINUEDE12 THE JOURNAL OF FAMILY PRACTICE  |   JUNE 2019  |   VOL 68, NO 5CLINICAL INQUIRIESSpironolactone reduces systolic blood pressure by 11 to 17  mm Hg and diastolic blood pressure by  up to 6 mm Hg  in patients  with resistant  hypertension taking 3 or more medications.No significant heterogeneity was noted in these analyses. Office-based BPs also were markedly reduced in spironolactone groups compared with controls (office SBP: WMD = −17 mm Hg; 95% CI, −25 to −8.95 mm Hg); office DBP: WMD = −6.18 mm Hg; 95% CI, −9.3 to −3.05 mm Hg). Because the office-based BP data showed significant heterogeneity (I2 = 94% for SBP and 84.2% for DBP), 2 studies deter-mined to be of lower quality caused by lack of detailed methodology were excluded from analysis, yielding continued statistically sig-nificant reductions in SBP (WMD = −11.7 mm Hg; 95% CI, −14.4 to −8.95 mm Hg) and DBP (WMD = −4.07 mm Hg; 95% CI, −5.6 to −2.54 mm Hg) compared with controls. Het-erogeneity also decreased when the 2 studies were excluded (I2 = 21% for SBP and I2 = 59% for DBP).How spironolactone compares with alternative drugsA 2017 meta-analysis of 5 RCTs with 662 patients evaluated the effectiveness of spi-ronolactone (25-50 mg/d) on resistant hy-pertension in patients taking 3 medications compared with a control group—placebo in 3 trials, placebo or bisoprolol (5-10 mg) in 1 trial, and an alternative treatment (can-desartan 8 mg, atenolol 100 mg, or alpha methyldopa 750 mg) in 1 trial.3 Follow-up periods ranged from 4 to 16 weeks. Research-ers evaluated changes in office and 24-hour ambulatory or home BP and completed separate analyses of pooled data for spirono-lactone compared with placebo groups, and spironolactone compared with alternative treatment groups. Investigators found a statistically signifi-cant reduction in office SBP and DBP among patients taking spironolactone compared with control groups (SBP: WMD = −15.7 mm Hg; 95% CI, −20.5 to −11 mm Hg; DBP: WMD = −6.21 mm Hg; 95% CI, −8.33 to −4.1 mm Hg). A significant decrease also occurred in 24-hour ambulatory home SBP and DBP (SBP: MD = −8.7 mm Hg; 95% CI, −8.79 to −8.62 mm Hg; DBP: WMD = −4.12 mm Hg; 95% CI, −4.48 to −3.75 mm Hg). Patients treated with spironolactone showed a marked decrease in home SBP compared with alternative drug groups (WMD = −4.5 mm Hg; 95% CI, −4.63 to −4.37 mm Hg), but alternative drugs reduced home DBP significantly more than spironolactone (WMD = 0.6 mm Hg; 95% CI, 0.55-0.65 mm Hg). Marked heterogeneity was found in these analyses, and the authors also noted that reductions in SBP are more clinically rel-evant than decreases in DBP.RecommendationsThe 2017 American Heart Association/American College of Cardiology evidence-based guideline recommends considering adding a mineralocorticoid receptor agonist to treatment regimens for resistant hyperten-sion when: office BP remains ≥ 130/80 mm Hg; the patient is prescribed at least 3 antihyper-tensive agents at optimal doses including a diuretic; pseudoresistance (nonadherence, inaccurate measurements) is excluded; re-versible lifestyle factors have been addressed; substances that interfere with BP treatment (such as nonsteroidal anti-inflammatory drugs and oral contraceptive pills) are excluded; and screening for secondary causes of hypertension is complete.4  The United Kingdom’s National Insti-tute for Health and Care Excellence (NICE) evidence-based guideline recommends con-sidering spironolactone 25 mg/d to treat resistant hypertension if the patient’s potas-sium level is 4.5 mmol/L or lower and BP is higher than 140/90 mm Hg despite treatment with an optimal or best-tolerated dose of an angiotensin-converting enzyme inhibi-tor or angiotensin II receptor blocker plus a calcium-channel blocker and diuretic.5    Editor’s takeawayThe evidence from multiple RCTs convincing-ly shows the effectiveness of spironolactone. Despite the SOR of C because of a disease-oriented outcome, we do treat to blood pres-sure goals, and therefore, spironolactone is a good option.                                   JFPReferences 1.   Zhao D, Liu H, Dong P, et al. A meta-analysis of add-on use of spi-ronolactone in patients with resistant hypertension. Int J Cardiol. 2017;233:113-117. E13MDEDGE.COM/FAMILYMEDICINE VOL 68, NO 5  |  JUNE 2019  |  THE JOURNAL OF FAMILY PRACTICE 2.   Wang C, Xiong B, Huang J. Efficacy and safety of spironolac-tone in patients with resistant hypertension: a meta-analysis of randomised controlled trials. Heart Lung Circ. 2016;25:1021-1030.  3.   Liu L, Xu B, Ju Y. Addition of spironolactone in patients with re-sistant hypertension: a meta-analysis of randomized controlled trials. Clin Exp Hypertens. 2017;39:257-263.  4.   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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2017. https://doi.org/10.1161 /HYP.0000000000000065. Accessed June 6, 2019.  5.   National Institute for Health and Care Excellence. Hyperten-sion in adults: diagnosis and management. Clinical guideline [CG127]. August 2011. https://www.nice.org.uk/guidance /cg127/chapter/1-guidance#initiating-and-monitoring- antihypertensive-drug-treatment-including-blood-pressure- targets-2. Accessed June 6, 2019. 

How effective is spironolactone for treating resistant hypertension?

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How effective is spironolactone for treating resistant hypertension?

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