“These results have broad international relevance and applicability,” noted Professor Williams, who is from University College London, and the British Hypertension Society Research Network.
“The PATHWAY-2 study showed that spironolactone was overwhelmingly the most effective blood pressure-lowering therapy compared to bisoprolol or doxazosin and suggest that the predominant underlying cause of resistant hypertension is sodium retention - even among patients with baseline diuretic therapy. This establishes, for the first time, a clear hierarchy for drug treatment of resistant hypertension which should influence future treatment guidelines and clinical practice globally.”
Resistant hypertension is defined as uncontrolled blood pressure (BP) despite treatment with at least 3 BP-lowering medications. Prior to PATHWAY-2 there was no strong evidence supporting recommendations for the most appropriate additional drug to control blood pressure, and “there has been a growing perception that controlling BP in resistant hypertension is beyond the reach of existing drug therapies,” explained Professor Williams. “But PATHWAY-2 shows that control is possible in the majority of patients, using a drug that has been available for many decades.”
While the pathogenesis of resistant hypertension is poorly understood, one hypothesis is that it could be related to sodium retention – a result of reduced diuretic doses in recent years, he said.
PATHWAY 2 examined whether additional diuretic therapy with spironolactone would be the most effective at reducing BP compared to treatment with two other antihypertensives that have different mechanisms of action: doxazosin which acts to reduce arterial resistance, and bisoprolol which acts to reduce cardiac output.
The study included patients with resistant hypertension who were already treated with maximally tolerated doses of a combination of three drugs: an ACE-inhibitor or angiotensin receptor blocker (ARB); a calcium channel blocker (CCB); and a thiazide type diuretic. “The key question was, which drug should be added to get blood pressure controlled,” said Professor Williams.
Uncontrolled BP was defined as seated clinic systolic BP of 140 mmHg or more for non-diabetic patients, or 135 mmHg or more for patients with diabetes, and a home systolic BP (HSBP) 130mmHg for all patients. In addition to their baseline BP therapy, patients were randomised to sequentially receive 12 weeks of spironolactone (25-50mg), bisoprolol (5-10mg), doxazosin (4-8mg modified release) and placebo in random order.
Blood pressure was measured with an automated BP monitor and recorded both in the clinic as well as at home over 4 consecutive days at baseline as well as at 6 and 12 weeks of each treatment cycle.
The primary end-point was average home systolic blood pressure (HSBP) for each of the treatments, with clinic systolic BP being a secondary endpoint.
In 314 patients, spironolactone had superior HSBP control compared to placebo (a reduction of 8.70 mmHg, P<.001); doxazosin (a reduction of 4.03 mmHg, P<0.001), and bisoprolol (a reduction of 4.48 mmHg, P<0.001); as well as the mean of doxazosin and bisoprolol (a reduction of 4.26 mmHg, P<0.001).
Overall, almost three quarters of patients with uncontrolled blood pressure saw a major improvement in their blood pressure on spironolactone, with almost 60% meeting a stringent measure of blood pressure control (P<0.001). Spironolactone was the best drug at lowering blood pressure in 60%, whereas bisoprolol and doxazosin where the best drug in only 17% and 18% respectively.
Clinic measurements mirrored the HSBP measurements except there was a large placebo effect in the clinic that was not seen at home.
“This is the first study to use home BP rather than clinic BP as a primary outcome in these patients,” noted Professor Williams. “Not only did this reduce the placebo effect but it also eliminated patients with ‘white coat hypertension’ whose BP may have been spuriously elevated due to clinic anxiety.”
The findings “challenge the concept that that resistant hypertension cannot be treated adequately with drug therapies, and suggest that treatments which have a natriuretic action, in that they promote sodium excretion, are likely to be the most effective,” he concluded.
This trial, and PATHWAY-3, being presented in the same Hotline session, are part of the PATHWAY programme of trials in Hypertension undertaken by academic investigators within the British Hypertension Society, led by Professor Morris Brown of the University of Cambridge, Professor Williams, and Professor Tom MacDonald of the University of Dundee.
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