PATHWAY-2: Spironolactone benefits patients with resistant hypertension

LONDON — In patients with resistant hypertension despite guideline-directed medical therapy, the addition of spironolactone produced a greater reduction in BP than the addition of an alpha-blocker or beta-blocker, and enabled a majority of patients to bring their hypertension under control, according to the results of the PATHWAY-2 study.

Perspective from José Ramón González-Juanatey, MD, PhD, FESC, FACC

“The result in favor of spironolactone is unequivocal,” Bryan Williams, MD, FRCP, FESC, FAHA, chair of medicine at University College London, said during a European Society of Cardiology Congress press conference. “Spironolactone is the most effective treatment for resistant hypertension. These results should directly influence guideline treatment of 100 million people globally.”

Bryan Williams

Researchers enrolled 335 patients (mean age, 61 years; 68% men) with resistant hypertension despite use of a diuretic, calcium channel blocker and ACE inhibitor or angiotensin blocker, in accordance with a number of worldwide guidelines. PATHWAY-2 is the first randomized controlled trial comparing spironolactone with other BP-lowering drugs in this population, Williams said.

After a 4-week run-in period, patients underwent four 12-week treatment cycles. Each cycle consisted of either spironolactone 25 mg/day to 50 mg/day, the beta-blocker bisoprolol 5 mg/day to 10 mg/day, the alpha-blocker doxazosin MR 4 mg/day to 8 mg/day, or placebo.

The primary endpoint was the difference in mean home systolic BP between spironolactone and placebo. If that was significant, the researchers were to analyze the difference in mean home systolic BP between spironolactone and the average of bisoprolol and doxazosin, and if that was significant, they were to analyze the difference in mean home systolic BP between spironolactone and bisoprolol and doxazosin individually.

Among the 314 patients available for analysis, spironolactone reduced home systolic BP by –8.7 mm Hg (95% CI, –9.72 to –7.69) vs. placebo (P < .001). Further, the therapy reduced home systolic BP by –4.26 mm Hg (95% CI, –5.13 to –3.38) vs. the mean of bisoprolol and doxazosin, by –4.48 mm Hg (95% CI, –5.5 to –3.46) vs. bisoprolol and by –4.03 mm Hg (95% CI, –5.04 to –3.02) vs. doxazosin (P < .001 for all).

Patients reduced their BP by a mean of –12.8 mm Hg on the spironolactone cycle, vs. –8.7 mm Hg on the doxazosin cycle, –8.3 mm Hg on the bisoprolol cycle and –4.1 mm Hg on the placebo cycle, Williams said.

Results for clinic systolic BP were similar, and there were no significant differences in adverse events between the cycles, he said.

Using least-squares estimates, Williams and colleagues determined that the percentage of patients with BP under control, defined as home systolic BP < 135 mm Hg, during the spironolactone cycle was 58%, vs. 41.5% during the doxazosin cycle (OR = 0.52; 95% CI, 0.37-0.73), 43.3% during the bisoprolol cycle (OR = 0.55; 95% CI, 0.39-0.78) and 23.9% during the placebo cycle (OR = 0.23; 95% CI, 0.16-0.33).

“Patients should not be defined, in our view, as resistant [hypertensive] going forward unless their [BP] remains uncontrolled on spironolactone,” Williams said. “This has very significant implications for the design of trials looking at resistant hypertension with other technologies such as device-based therapy.”

At the end of the study, of all the patients in the trial, only 15 would qualify for enrollment in a renal denervation trial, he said. – by Erik Swain

Reference:

Williams B, et al. Hot Line IV: Hypertension. Presented at: European Society of Cardiology Congress; Aug. 29-Sept. 2; London.

Disclosure: Williams reports no relevant financial disclosures.

Perspective

José Ramón González-Juanatey, MD, PhD, FESC, FACC

These results are really important. For the first time, it was clearly demonstrated that a very old treatment with a good pathophysiological background exerts tremendous effect in resistant hypertension. This is among the best news at the ESC Congress. We learned that spironolactone in this trial and a combination of amiloride and hydrochlorothiazide in the PATHWAY-3 trial are very efficient at treating resistant hypertension and stage1-2 hypertensive patients at very low cost. This is also important for public health systems, not only in poor countries but also in rich countries. It presents a very low-cost alternative to device therapy, which can be very expensive, in patients with resistant hypertension.

José Ramón González-Juanatey, MD, PhD, FESC, FACC

President, Spanish Society of Cardiology

Disclosures: González-Juanatey reports no relevant financial disclosures.