#NephJC returns to Hypertension: PATHWAY-2

Tuesday Oct 27th 9 pm EDT

& Wednesday Oct 28th 8 pm BST and 12 noon Pacific

Lancet. 2015 Sep 18. pii: S0140-6736(15)00257-3. doi: 10.1016/S0140-6736(15)00257-3.

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

Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G, Ford I, Cruickshank JK, Caulfield MJ, Salsbury J, Mackenzie I, Padmanabhan S, Brown MJ; British Hypertension Society's PATHWAY Studies Group.

PMID: 26414968

The Pre-Chat Summary

Next week on NephJC we revisit hypertension, featuring the PATHWAY-2 trial, published open access at The Lancet [full text link].

The aim of the study was to examine the effect of a fourth line anti-hypertensive in resistant hypertension, defined as clinic systolic BP ≥140 (≥135 if diabetic) & home systolic BP (18 readings over 4 days) ≥130 despite 3 drugs including a RAAS inhibitor, calcium channel blocker and diuretic. We are used to resistant hypertension at NephJC towers, with collective disappointment expressed by us when SYMPLICITY HTN-3 dropped. With the realization that renal denervation is not the panacea we longed for, there is renewed interest, once again, in pharmacological agents. Spironolactone has been accruing evidence demonstrating benefit in resistant hypertension, including some small RCTs. The additional finding of low plasma renin despite the use of agents which should elevate renin supports the role of excess sodium retention.


Pathway-2 was a 12-month double-blind, placebo-controlled, crossover trial, enrolling patients aged 18–79 years from the UK. The primary aim was to determine whether spironolactone, doxazosin or bisoprolol, is the most effective add-on treatment for resistant hypertension. A secondary aim was to determine whether plasma renin levels predict the most effective treatment for an individual patient. 


  • 1 month single-blind placebo run-in
  • Subjects then rotated through 4 cycles of (1) spironolactone 25–50 mg, (2) doxazosin 4–8 mg, (3) bisoprolol 5–10 mg & (4) placebo.
  • There was no washout period between cycles.

They employed pre-specified hierarchical primary endpoints:

  1. Difference in the home systolic BP between spironolactone and placebo, followed if significant by
  2. Difference in home systolic BP between spironolactone and the average of the other two active drugs, followed if significant by
  3. Difference in home systolic BP between spironolactone and each of the other two active drugs.


Patient baseline characteristics:

Note the low rate of diabetes and normal renal function. Moreover, the BP’s weren’t too bad, although they were on 3 drugs already.

Mean reduction in home systolic BP throughout the treatment cycle with spironolactone was superior to each of:

  • placebo (–8·70 mm Hg [95% CI −9·72 to −7·69]; p<0·0001)
  • other two active treatments (−4·26 [–5·13 to 3·38]; p<0·0001
  • each of the other individual treatments; doxazosin (–4·03 [–5·04 to 3·02]; p<0·0001) and bisoprolol (–4·48 [–5·50 to −3·46]; p<0·0001)

What about adverse events? Did not appear to be an issue, see below.

From the appendix, it was evident that eGFR dropped approximately 10mls/min (93 to 83 mls/min) and serum potassium increase 0.4 mmol/L with spironolactone. However, only six of 285 patients (2%) on spironolactone developed a serum potassium on a single occasion > 6·0 mmol/L.

Did baseline renin predict response?

From the authors: ‘There was a clear inverse relation between the home systolic blood pressure fall with spironolactone and plasma renin, not seen with bisoprolol or doxazosin. Moreover, the blood pressure response to spironolactone was superior to bisoprolol and doxazosin across most of the plasma renin distribution’.


This is a well conducted RCT which is unequivocal in its support for spironolactone in resistant hypertension. The crossover design maximises efficiency in the study although the lack of a washout period is a puzzle to me. The definition of resistant hypertension was not based on ambulatory 24 hour BPs which might concern some. Also, from the nephrologists point of view, those with an eGFR of <45mls/min were excluded so on the whole these are not patients we see in our practice.

Questions I would love to see answered moving forward include:

  1. When should we use Spironolactone, do we have to wait until a patient is already on 3 drugs?!
  2. What to do with our CKD patients with resistant hypertension, how safe and effective is spironolactone?
  3. Does this beneficial BP effect translate into improved mortality?

Please join usfor the #NephJC live chats:

Tuesday Oct 27th 9 pm EDT

Wednesday Oct 28th 8 pm BST and 12 noon Pacific

Summary by Paul Phelan