The principal results of the Prevention And Treatment of Hypertension With Algorithm based therapY (PATHWAY) - Optimal treatment of drug resistant hypertension - PATHWAY 2

Presented at the ESC Congress 2015 by: Bryan Williams (London, UK)

Background
Resistant hypertension has been defined as uncontrolled blood pressure (BP) despite treatment with maximal tolerated doses of 3 BP-lowering medications (an ACE-inhibitor or ARB + calcium channel blocker (CCB) + thiazide-like Diuretic, i.e. A + C + D). It is a sodium retaining state that is characterised by an inappropriately low plasma renin level. Until recently, 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.
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 (A + C + D).
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.

Main results

• 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.
• Spironolactone was well tolerated with no significant excess adverse effects with the caveat that serum potassium levels and renal function should be monitored on treatment and treatment duration was too short to assess incident gynecomastia (~6% in longer-term studies)

Conclusions
PATHWAY-2 is the first RCT to directly compare spironolactone with other active BP-lowering treatments in patients with well characterised resistant hypertension. Spironolactone unequivocally showed to be the most effective treatment for resistant hypertension.
These results should influence treatment guidelines globally and the definition of resistant hypertension - patients should not be defined as resistant hypertension unless their BP remains uncontrolled on spironolactone. In this study, in many patients an underlying cause of hypertension was identified, and in the end only 15 patients turned out to be truly therapy resistant. By applying a structured approach, blood pressure could be controlled in the majority of patients. Although background therapy could vary regionally, international guidelines have converged in the recent past. That means that these results are likely to be generalizable to clinical practice across the globe.
According to prof. Williams, 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”.

- Our reports are based on information made available at the ESC congress -