The main question for this trial is if in patients with resistant hypertension treated with an ACEI or ARB, a CCB and a diuretic, is the addition of spironolactone superior to placebo, doxazosin or bisoprolol to control blood pressure? Before this trial, the choice of a fourth antihypertensive agent to a typical ACE inhibitor or ARB combined with a calcium channel blocker and a thiazide diuretic was empirical. Three RCTs before this study had shown that spironolactone was superior to placebo when added to existing BP medications, but no prior trial had compared spironolactone directly to other medications. The hypothesis of the investigators was that resistant hypertension was due to sodium retention. To test this hypothesis, they chose was spironolactone, a diuretic and tested it as a fourth agent against doxazosin, bisoprolol, or placebo. Doxazosin what chosen as it addressed peripheral resistance. Bisoprolol was chosen as it decreased renin and cardiac output. Since blood pressure is the product of cardiac output and peripheral arterial resistance, their choice of BP agents in the trial showcased elegant trial design. It is also an example of how basic physiology influences clinical practice in nephrology so regularly.
BLOOD PRESSURE = (CARDIAC OUTPUT x TOTAL PERIPHERAL ARTERIAL RESISTANCE)
This study screened 436 patients with uncontrolled blood pressure despite at least three months of maximally tolerated doses of three drugs including a diuretic (resistant hypertension). These drugs had to be an ACE inhibitor or ARB, a calcium channel blocker, and a diuretic. 88 patients were excluded and 335 were randomized. The randomized patients then rotated through four cycles of once daily dosing of spironolactone, doxazosin, bisoprolol, and placebo. The reason the trial says that the patients were randomized is because different permutations of the order of the sequential antihypertensives (or placebo) were randomly generated. The treatment cycles lasted for six weeks a low dose of each study drug followed by forced titration to a high dose of each study drug. If a patient could not tolerate a particular drug, they were moved to the next drug in the sequence. There was no washout period between the four cycles in the trial. The entire length of the trial was one year.The primary endpoint was average home systolic BP.
The average reduction in home systolic blood pressure by spironolactone was 8.7mmHg. This was around 4mmHg better than doxazosin or bisoprolol. The outcome of this trial is that spironolactone is the best fourth agent for BP lowering in resistant HTN. This was an important trial which greatly helps management of resistant hypertension indicating that spironolactone is the best 4th agent.
The PATHWAY-2 Trial: Williams, B., MacDonald, T. M., Morant, S., Webb, D. J., Sever, P., McInnes, G., ... & Mackenzie, I. (2015). Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. The Lancet, 386(10008), 2059-2068.
The PATHWAY-2 Trial PMID: 26414968
Useful summaries of the PATHWAY-2 Trial: Wiki Journal Club