Evidence-based answers from the Family Physicians Inquiries Network CLINICAL INQUIRIES ONLINE EXCLUSIVE Corey Lyon, DO; Brigitte Utter, MD Q How effective is University of Colorado Family Medicine Residency, Denver spironolactone for treating Kristen DeSanto, MSLS, MS, RD University of Colorado resistant hypertension? Health Sciences Library, Denver EVIDENCE-BASED ANSWER DEPUTY EDITOR Rick Guthmann, MD, very effective. Spironolactone taking 3 or more medications (strength of MPH reduces systolic blood pressure recommendation [SOR]: C, meta-analysis Advocate Illinois Masonic A Family Medicine Residency, (SBP) by 11 to 17 mm Hg and diastolic of randomized controlled trials [RCTs] of Chicago blood pressure (DBP) by up to 6 mm Hg disease-oriented evidence). in patients with resistant hypertension Evidence summary with placebo (SBP: WMD = −10.8 mm Hg; A 2017 meta-analysis of 4 RCTs (869 pa- 95% CI, −13.16 to −8.43 mm Hg; DBP: WMD tients) evaluated the effectiveness of pre- = −4.62 mm Hg; 95% CI, −6.05 to −3.2 mm Hg; scribing spironolactone for patients with I2 = 35%), confirming that the excluded trial resistant hypertension, defined as above- was the source of heterogeneity in the initial goal blood pressure (BP) despite treatment analysis and that spironolactone continued with at least 3 BP-lowering drugs (at least 1 to significantly lower BP for the treatment of which was a diuretic).1 All 4 trials com- group compared with controls. pared spironolactone 25 to 50 mg/d with placebo. Follow-up periods ranged from 8 to Add-on treatment with spironolactone 16 weeks. The primary outcomes were sys- also reduces BP tolic and diastolic BPs, which were evaluated A 2016 meta-analysis of 5 RCTs with a total in the office, at home, or with an ambulatory of 553 patients examined the effectiveness monitor. of add-on treatment with spironolactone (25-50 mg/d) for patients with resistant Spironolactone markedly lowers hypertension, defined as failure to achieve systolic and diastolic BP BP < 140/90 mm Hg despite treatment A statistically significant reduction in SBP oc- with 3 or more BP-lowering drugs, in- curred in the spironolactone group compared cluding one diuretic.2 Spironolactone was with the placebo group (weighted mean dif- compared with placebo in 4 trials and ference [WMD] = −16.7 mm Hg; 95% confi- with ramipril in the remaining study. The dence interval [CI], −27.5 to −5.8 mm Hg). follow-up periods were 8 to 16 weeks. DBP also decreased (WMD = −6.11 mm Hg; Researchers separated BP outcomes into 95% CI, −9.34 to −2.88 mm Hg). 24-hour ambulatory systolic/diastolic BPs Because significant heterogeneity was and office systolic/diastolic BPs. found in the initial pooled results (I2 = 96% The 24-hour ambulatory BPs were sig- for SBP; I2 = 85% for DBP), investigators per- nificantly lower in the spironolactone group formed an analysis that excluded a single compared with the control group (24-hour study with a small sample size. The re-anal- SBP: WMD = −10.5 mm Hg; 95% CI, −12.3 to ysis continued to show significant reductions −8.71 mm Hg; 24-hour DBP: WMD = −4.09 in SBP and DBP for spironolactone compared mm Hg; 95% CI, −5.28 to −2.91 mm Hg). CONTINUED MDEDGE.COM/FAMILYMEDICINE VOL 68, NO 5 | JUNE 2019 | THE JOURNAL OF FAMILY PRACTICE E11 CLINICAL INQUIRIES No significant heterogeneity was noted in compared with alternative drug groups these analyses. (WMD = −4.5 mm Hg; 95% CI, −4.63 to −4.37 Office-based BPs also were markedly mm Hg), but alternative drugs reduced home reduced in spironolactone groups compared DBP significantly more than spironolactone with controls (office SBP: WMD = −17 mm Hg; (WMD = 0.6 mm Hg; 95% CI, 0.55-0.65 95% CI, −25 to −8.95 mm Hg); office DBP: mm Hg). Marked heterogeneity was found WMD = −6.18 mm Hg; 95% CI, −9.3 to −3.05 in these analyses, and the authors also noted mm Hg). Because the office-based BP data that reductions in SBP are more clinically rel- showed significant heterogeneity (I2 = 94% evant than decreases in DBP. 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 Recommendations analysis, yielding continued statistically sig- The 2017 American Heart Association/ nificant reductions in SBP (WMD = −11.7 American College of Cardiology evidence- mm Hg; 95% CI, −14.4 to −8.95 mm Hg) and based guideline recommends considering DBP (WMD = −4.07 mm Hg; 95% CI, −5.6 to adding a mineralocorticoid receptor agonist −2.54 mm Hg) compared with controls. Het- to treatment regimens for resistant hyperten- erogeneity also decreased when the 2 studies sion when: office BP remains ≥ 130/80 mm Hg; were excluded (I2 = 21% for SBP and I2 = 59% the patient is prescribed at least 3 antihyper- Spironolactone for DBP). tensive agents at optimal doses including a reduces systolic diuretic; pseudoresistance (nonadherence, blood pressure How spironolactone compares inaccurate measurements) is excluded; re- by 11 to 17 with alternative drugs versible lifestyle factors have been addressed; mm Hg and A 2017 meta-analysis of 5 RCTs with 662 substances that interfere with BP treatment diastolic blood patients evaluated the effectiveness of spi- (such as nonsteroidal anti-inflammatory pressure by ronolactone (25-50 mg/d) on resistant hy- drugs and oral contraceptive pills) are up to 6 mm Hg pertension in patients taking 3 medications excluded; and screening for secondary 4 in patients compared with a control group—placebo causes of hypertension is complete. in 3 trials, placebo or bisoprolol (5-10 mg) The United Kingdom’s National Insti- with resistant in 1 trial, and an alternative treatment (can- tute for Health and Care Excellence (NICE) hypertension desartan 8 mg, atenolol 100 mg, or alpha evidence-based guideline recommends con- taking 3 or more methyldopa 750 mg) in 1 trial.3 Follow-up sidering spironolactone 25 mg/d to treat medications. periods ranged from 4 to 16 weeks. Research- resistant hypertension if the patient’s potas- ers evaluated changes in office and 24-hour sium level is 4.5 mmol/L or lower and BP is ambulatory or home BP and completed higher than 140/90 mm Hg despite treatment separate analyses of pooled data for spirono- with an optimal or best-tolerated dose of lactone compared with placebo groups, and an angiotensin-converting enzyme inhibi- spironolactone compared with alternative tor or angiotensin II receptor blocker plus a treatment groups. calcium-channel blocker and diuretic.5 Investigators found a statistically signifi- cant reduction in office SBP and DBP among Editor’s takeaway patients taking spironolactone compared The evidence from multiple RCTs convincing- with control groups (SBP: WMD = −15.7 ly shows the effectiveness of spironolactone. mm Hg; 95% CI, −20.5 to −11 mm Hg; DBP: Despite the SOR of C because of a disease- WMD = −6.21 mm Hg; 95% CI, −8.33 to oriented outcome, we do treat to blood pres- −4.1 mm Hg). A significant decrease also sure goals, and therefore, spironolactone is a occurred in 24-hour ambulatory home SBP good option. JFP 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). References Patients treated with spironolactone 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. showed a marked decrease in home SBP 2017;233:113-117. E12 THE JOURNAL OF FAMILY PRACTICE | JUNE 2019 | VOL 68, NO 5 2. Wang C, Xiong B, Huang J. Efficacy and safety of spironolac- blood pressure in adults: a report of the American College of tone in patients with resistant hypertension: a meta-analysis of Cardiology/American Heart Association Task Force on Clinical randomised controlled trials. Heart Lung Circ. 2016;25:1021-1030. Practice Guidelines. Hypertension. 2017. https://doi.org/10.1161 /HYP.0000000000000065. Accessed June 6, 2019. 3. Liu L, Xu B, Ju Y. Addition of spironolactone in patients with re- sistant hypertension: a meta-analysis of randomized controlled 5. National Institute for Health and Care Excellence. Hyperten- trials. Clin Exp Hypertens. 2017;39:257-263. sion in adults: diagnosis and management. Clinical guideline [CG127]. August 2011. https://www.nice.org.uk/guidance 4. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ /cg127/chapter/1-guidance#initiating-and-monitoring- ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for antihypertensive-drug-treatment-including-blood-pressure- the prevention, detection, evaluation, and management of high targets-2. Accessed June 6, 2019. MDEDGE.COM/FAMILYMEDICINE VOL 68, NO 5 | JUNE 2019 | THE JOURNAL OF FAMILY PRACTICE E13.