By Harold L. Karpman, MD, FACC, FACP

Clinical Professor of Medicine, David Geffen School of Medicine, UCLA, Cardiovascular Medical Group

Dr. Karpman reports no financial relationships relevant to this field of study.

SYNOPSIS: Compared to selected other hypotensive drugs, spironolactone was found to be the most effective drug addition for resistant hypertension when added to previous angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, calcium channel blocker, and thiazide therapy.

SOURCE: 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 randomized, double-blind, crossover trial. Lancet 2015;386:2059-2063.

Drug-resistant hypertension is usually defined as blood pressure elevation that is not controlled, even after three recommended blood pressure lowering drugs (i.e., an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) plus a calcium channel blocker (CCB) and a thiazide-like diuretic) are administered at maximum tolerated doses. Because resistant hypertension often is not controlled by drugs from the three categories, an effective fourth-line drug treatment has been sought by many groups.

Since it has been speculated that sodium retention predominantly causes resistant hypertension, Williams et al1 selected the diuretic spironolactone because of observational and randomized, controlled trial data suggesting good blood pressure lowering efficacy in resistant hypertension.2 They conducted a 12-month, double-blind, placebo-controlled crossover trial in which patients were enrolled from 14 sites in the United Kingdom.3 Patients presented with blood pressure readings of ≥ 140 mmHg (or ≥ 135 mmHg for diabetic patients) despite treatment for at least three months with maximally tolerated doses of the three drug groups (ACE or ARB, CCB, and diuretic). Participants rotated through four cycles of once-daily oral therapy with spironolactone, doxazosin, bisoprolol, and placebo. Researchers used home blood pressures rather than clinic blood pressures to eliminate at baseline participants with so-called white coat hypertension or a potential placebo effect. Spironolactone substantially increased the likelihood of achieving blood pressure control when compared to bisoprolol or doxazosin, with almost 60% of participants achieving blood pressure control within three months after starting spironolactone therapy.

COMMENTARY

The results of the Williams et al study certainly are encouraging and suggest clinicians should consider using spironolactone as the fourth drug in a regimen for the treatment of resistant hypertension. Researchers found the drug to be well-tolerated, and the doses of only 25-50 mg daily used in this study were low compared to the 200-400 mg daily that many physicians have used clinically in their practices. Because only 25 mg was the most common daily dose in previous studies, which have shown that the main biochemical effects associated with spironolactone therapy are a reduction in serum sodium and an increase in serum potassium levels, it was important to monitor electrolytes and renal function after initiation of spironolactone therapy.4 The Williams et al study was the first randomized, controlled trial directly comparing different active drug treatments in resistant hypertension, and it appears to have produced an unequivocally positive result for spironolactone. Therefore, clinicians should consider adding spironolactone to the standard ACE/ARB, CCB, and diuretic therapeutic regimen in patients with resistant hypertension.

REFERENCES

  1. 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 randomized, double-blind, crossover trial. Lancet 2015;386:2059-2063.
  2. Morganti A, European study group for the validation of DiaSorin LIAISON Direct Renin Assay. A comparative study of inter and intra-laboratory reproducibility of renin measurement with a conventional enzymatic method and a new chemiluminescent assay of immuno reactive renin. J Hypertens 2010;28:
    1307-1312.
  3. Williams B, MacDonald TM, Caulfield M, et al. Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2: Protocol for a randomized crossover trial to determine optimal treatment for drug-resistant hypertension. BMJ Open 2015;5:e008951.
  4. Dahal K, Kunwar S, Rijal J, et al. The effects of aldosterone antagonists in patients with resistant hypertension: A meta-analysis of randomized and nonrandomized studies. Am J Hypertens 2015;28:1376-1385.