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Evidence summaries

Spironolactone for Hypertension

Addition of low-dose spironolactone to existing triple-drug therapy appears to lower blood pressure compared to placebo in patients with resistant hypertension. Level of evidence: "B"

A Cochrane review [Abstract] 1 included 5 cross-over studies (137 patients, duration ranging from 4 to 6 weeks) and 1 parallel group study (25 patients received spironolactone and 25 patients received placebo for 8 weeks). None of the included studies reported results for all cause mortality, cardiovascular mortality, non-cardiovascular mortality, serious adverse events, fatal and non-fatal myocardial infarction, and fatal and non-fatal stroke. The cross-over studies found a reduction in systolic blood pressure (SBP) of 20.09 mmHg (95% CI 16.58 to 23.06) and a 6.75 mmHg (95% CI 4.8 to 8.69) reduction in diastolic blood pressure (DBP). There may be a dose response effect with spironolactone up to 50 mg/day, but the confidence intervals around the mean end-of-study blood pressure for doses ranging 25-500 mg/day all overlapped. It appears that doses >50mg/day do not produce further reductions in either SBP or DBP. One cross-over study found that spironolactone 25 mg/day did not statistically significantly change SBP or DBP compared to placebo, SBP -9.9 (95% CI -21.15 to 1.35); DBP -2.34 (95% CI -7.92 to 3.06). The risks of potential side effects, hyperkalemia, gynaecomastia, upper gastrointestinal bleeds, with the use of spironolactone must be weighed against the benefits of decreased blood pressure with no proven decrease in adverse cardiovascular outcomes.

A double-blind, placebo-controlled, crossover trial 2 enrolled adults with high blood pressure despite treatment for at least 3 months with maximally tolerated doses of 3 drugs. Patients rotated through 12 weeks of once daily treatment with each of spironolactone (25-50 mg), bisoprolol (5-10 mg), doxazosin modified release (4-8 mg), and placebo, in addition to their baseline blood pressure drugs. 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home SBP by spironolactone was superior to placebo (-8.70 mmHg, 95% CI -9.72 to -7.69), superior to the mean of the other 2 active treatments (doxazosin and bisoprolol), and superior when compared with the individual treatments. Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. In 6 of the 285 patients who received spironolactone, serum potassium exceeded 6.0 mmol/L on one occasion.

A meta-analysis 3 included 5 RCTs to assess the effect of additional spironolactone on blood pressure in patients with resistant hypertension. Spironolactone reduced office SBP by 15.73 mmHg (95% CI -20.45 to -11.0) and office DBP by 6.21 mmHg (95% CI -8.33 to -4.1) compared to placebo group. In comparison with alternative drugs including beta-blocker, candesartan, or alpha methyldopa, spironolactone reduced home SBP by 4.5 mmHg (95% CI -4.63 to -4.37).

A meta-analysis of add-on use of spironolactone in patients with resistant hypertension 4 included 4 studies with a total of 869 subjects with a mean follow-up of 12±3weeks. The reduction of SBP and DBP in patients treated with spironolactone was greater than placebo (WMD for SBP -16.67mmHg, 95% CI -27.54 to -5.80; WMD for DBP -6.11mmHg (95% CI -9.34 to -2.88).

A meta-analysis of RCTs 5 included 5 studies with a total of 553 subjects. Compared with control therapies, additional spironolactone treatment in resistant hypertension decreased 24-h ambulatory SBP (ASBP, WMD -10.50, 95% CI -12.30 to -8.71), 24-h ambulatory DBP (ADBP, WMD -4.09, 95% CI -5.28 to -2.91), daytime ASBP (WMD -10.20, 95% CI -12.41 to -7.99), daytime ADBP (WMD -4.14, 95% CI -5.50 to -2.78), night-time ASBP (WMD -10.02, 95% CI -12.63 to -7.41), night-time ADBP (WMD -3.21, 95% CI -4.84 to -1.58), office SBP (WMD -16.99, 95% CI -25.04 to -8.95) and office DBP (WMD -6.18, 95% CI -9.30 to -3.05).

Comment: The quality of evidence is downgraded by indirectness (lack of long-term data and lack of data on adverse cardiovascular outcomes).

    References

    • Batterink J, Stabler SN, Tejani AM, Fowkes CT. Spironolactone for hypertension. Cochrane Database Syst Rev 2010;(8):CD008169. [PubMed]
    • 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. [PubMed]
    • Liu L, Xu B, Ju Y. Addition of spironolactone in patients with resistant hypertension: A meta-analysis of randomized controlled trials. Clin Exp Hypertens 2017;39(3):257-263. [PubMed]
    • Zhao D, Liu H, Dong P et al. A meta-analysis of add-on use of spironolactone in patients with resistant hypertension. Int J Cardiol 2017;233():113-117. [PubMed]
    • Wang C, Xiong B, Huang J. Efficacy and Safety of Spironolactone in Patients with Resistant Hypertension: A Meta-analysis of Randomised Controlled Trials. Heart Lung Circ 2016;25(10):1021-30. [PubMed]

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