Blog entry by Meguid El Nahas

Picture of Meguid El Nahas
by Meguid El Nahas - Thursday, 1 October 2015, 7:42 AM
Anyone in the world

 2015 Sep 18. pii: S0140-6736(15)00257-3. doi: 10.1016/S0140-6736(15)00257-3. [Epub ahead of print]

Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.




Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure.


In this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18-79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or ≥135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25-50 mg), bisoprolol (5-10 mg), doxazosin modified release (4-8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and number, NCT02369081.


Between May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (-8·70 mm Hg [95% CI -9·72 to -7·69]; p<0·0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; -4·26 [-5·13 to -3·38]; p<0·0001), and superior when compared with the individual treatments; versus doxazosin (-4·03 [-5·04 to -3·02]; p<0·0001) and versus bisoprolol (-4·48 [-5·50 to -3·46]; p<0·0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6·0 mmol/L on one occasion.


Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition.


The British Heart Foundation and National Institute for Health Research.


So called resistant hypertension is often the result of:

1. Inadequate treatment

2. Poor compliance

The PATHWAY-2 study by the British Hypertension Society highlights the importance of hyperaldosteronism, sodium retention and volume expansion in the pathogenesis of "Resistant Hypertension". It showed a significant improvement in BP control upon the addition of Spironolactone (a mineralcorticoid receptor antagonist).

Spironolactone was superior to a beta-blocker (Bisoprolol) or an alpha blocker (Doxazosin) or placebo as an add on treatment, over 3 months, to patients already on optimised/maximum (A [ACE inhibitor]+C [Calcium antagonist]+D [Diuretics]) treatment.

The question remains whether the observed benefit is due to:

Increased natriuresis


a specific anti-aldosterone effect

More suitable controls would have been:

1. Either stricter dietary sodium restriction (known to optimise the anti-hypertensive effect of ACE inhibitors/ARBs)


2. an increase in the existent diuretic therapy (D), also previously shown to optimise treatment with RAS inhibitors.

Finally, a study of Hypertension control including patients aged:

18 to 79...

and GFR from normal to 45 ml/min...

calls for more analysis of subgroups response to the proposed therapeutic approach and raises questions as to whether all hypertensive are the same regardless or age and regardless of kidney function in terms of pathophysiology and response to therapy.




[ Modified: Thursday, 1 January 1970, 1:00 AM ]