PATHWAY2: Spironolactone Effective in Lowering Blood Pressure in Resistant Hypertension

August 31, 2015

LONDON, UK — The addition of spironolactone to patients with resistant hypertension currently treated with renin-angiotensin-aldosterone system (RAAS) blockers, calcium-channel blockers (CCBs), and a thiazidelike diuretic resulted in a significant reduction in systolic blood pressure, according to the results of a new study[1].

The addition of spironolactone to the ACE-inhibitor/angiotensin-receptor blocker (ARB), CCB, and thiazidelike diuretic—referred by investigators as A+C+D therapy—resulted in larger reductions in systolic blood pressure than adding the beta-blocker bisoprolol, the alpha-adrenergic blocker doxazosin, or placebo.

Dr Bryan Williams

The results of the study, known as Optimal Treatment of Drug-Resistant Hypertension—PATHWAY2, were presented today at the the European Society of Cardiology (ESC) 2015 Congress by Dr Bryan Williams (University College London, UK).

"When we look at the achieved blood pressure on these different treatment options, the average home systolic blood pressure on spironolactone was 134.9 mm Hg, which is just below the target level of 135 mm Hg," said Williams. "In other words, we were controlling a large percentage of these patients previously defined as [having] uncontrollable hypertension."

Resistant Hypertension Patients and Long-term Risk

In the general hypertensive population, approximately one in 10 individuals has drug-resistant hypertension. "That would equate to about 100 million people globally," said Williams. "These people are at an especially high risk of cardiovascular events due to their long-term exposure to high blood pressure and the fact that many of them have other conditions such as diabetes and chronic kidney disease."

During an ESC press conference, Williams said the US guidelines, European guidelines, as well as others, have converged in recent years, where the general treatment recommendation in hypertension is to use an ACE inhibitor/ARB, CCB, and diuretic. At present, though, the optimal next step in patients with uncontrolled hypertension is unknown. Data from nonrandomized trials have suggested spironolactone might be beneficial in these patients, given that resistant hypertension is characterized by inappropriately low plasma renin levels, said Williams.

In PATHWAY2, 335 patients with drug-resistant hypertension—defined as uncontrolled blood pressure despite treatment with maximally tolerated doses of the three antihypertensive medications—were randomized into the crossover study. At randomization, patients taking A+C+D therapy were treated for four 12-week treatment cycles with spironolactone 25 to 50 mg, doxazosin 4 to 8 mg, bisoprolol 5 to 10 mg, and placebo. There was no washout between treatment cycles, and blood pressure was measured at home at 6 and 12 weeks (and averaged for total pressure during the treatment cycle).

At baseline, the mean at-home blood pressure was 147.6/84.2 mm Hg and the mean clinic blood pressure was 157.0/90.0 mm Hg. Overall, treatment with spironolactone resulted in the largest reduction in systolic blood pressure, decreasing 12.8 mm Hg over 12 weeks of treatment, with an even larger in-clinic reduction observed (approximately a 20-mm-Hg reduction from baseline).

Compared with placebo, adding spironolactone to A+C+D therapy reduced at-home systolic blood pressure an additional 8.7 mm Hg, while compared with the mean reduction achieved with doxazosin and bisoprolol, systolic blood pressure with spironolactone was reduced an additional 4.26 mm Hg.

PATHWAY2: Achieved Home Systolic Blood Pressure (mm Hg)

Treatment Home systolic blood pressure (mm Hg) Change from baseline (mm Hg)
Spironolactone 134.9 -12.8
Doxazosin 139.0 -8.7
Bisoprolol 139.4 -8.3
Placebo 143.6 -4.1

PATHWAY2: Primary Outcome (Difference in Home Systolic Blood Pressure vs Comparators)

Comparators (n=314) Home systolic blood pressure difference (mm Hg) P
Spironolactone vs placebo -8.70 <0.001
Spironolactone vs mean bisoprolol/doxazosin -4.26 <0.001
Spironolactone vs doxazosin -4.03 <0.001
Spironolactone vs bisoprolol -4.48 <0.001

"At the end of the study, despite these patients being deemed uncontrollable for their hypertension, we managed to control almost 60% on spironolactone therapy," said Williams. In contrast, just 42% of the doxazosin-treated patients and 44% of the bisoprolol-treated patients met the 135-mm-Hg treatment target, he added.

Safety Signal and Future of Device Therapy

Overall, there was no safety signal observed with spironolactone compared with other active therapies. Williams said physicians will need to monitor serum potassium levels and renal function if patients are treated with the drug long term. He also noted gynecomastia occurs in approximately 6% of men when treated over longer durations.

The beneficial effect, however, of lowered blood pressure in a difficult-to-treat patient population is unquestionable, according to the researchers. "The result in favor of spironolactone is unequivocal," said Williams, adding that patients should not be diagnosed with resistant hypertension unless their systolic blood pressure remains elevated despite treatment with A+C+D therapy and spironolactone.

To heartwire from Medscape, Williams noted that of the 325 patients randomized and treated in PATHWAY2, just 15 patients would have been eligible for randomization on the basis of their blood pressure at the study's completion into the various renal-denervation studies.

"In other words, we managed to control the vast majority of these patient to a level below the randomization criteria for renal denervation trials," said Williams. "Of course, there will still be a few patients who will be resistant, but we suspect in many of those we will often find an underlying cause with more intensive evaluation. I think the idea there are 20% or 30% of patients out there with resistant hypertension is wrong."

The study was funded by the British Heart Foundation and National Institute for Health Research.


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