Primary Care Corner with Geoffrey Modest MD: Spironolactone in drug-resistant hypertension

By Dr. Geoffrey Modest

Another study, PATHWAY-2, reinforced the utility of spironolactone in patients with drug-resistant hypertension (see doi.org/10.1016/S0140-6736(15)00257-3).

Details:

• 285 patients (69% men, mean weight 93.5 kg, 7.8% smokers, mean home BP 148/84, clinic BP 157/90, K 4.1, Na 140, 14% diabetic) with seated clinic systolic pressure >140 mmHg (or >135 mmHg if diabetic) and home systolic pressure > 130 mmHg (18 readings over 4 days) despite treatment for at least 3 months with maximally tolerated doses of 3 drugs. Those with eGFR <45 ml/min were excluded. To make sure that the resistant hypertension was not from medication nonadherence, they measured home systolic pressure 6 hours after directly observed therapy, checked returned tablet counts and measured serum ACE activity.
• Patients were rotated through add-on treatment with daily spironolactone (25-50mg), bisoprolol (5-10mg), doxazocin modified release (4-8mg) and placebo, starting at the lower dose and increasing to the higher one after 6 weeks
• Primary endpoint was the difference in averaged home systolic BP between the different meds
• Results:
  • 230 patients completed all of the above treatment cycles
  • Average reduction in systolic BP by spironolactone was 8.70 mmHg over placebo (7.69 to 9.72, p<0.001), and 10.2 mmHg on the highest dose of 50mg
  • ​Average reduction in systolic BP by spironolactone was 4.26 mmHg over the mean of the other 2 active drugs (3.38-5.13, p<0.001)
  • ​Average reduction in systolic BP by spironolactone was 4.03 mmHg over doxazocin (3.02-5.04, p<0.001)​, and 4.9 mmHg on the highest dose of 8mg
  • ​Average reduction in systolic BP by spironolactone was 4.48 mmHg over bisoprolol (3.46-5.50, p<0.001)​, and 4.2 mmHg on the highest dose of 10mg
  • Spironolactone was the most effective drug through most of the range of baseline plasma renin levels, though was especially good in those with the lowest plasma renin levels and with decreasing efficacy as the renin levels increased in a linear fashion.
  • 6 of the 285 patients on spironolactone had serum potassium >6.0 mmol/L on one occasion. No increase in gynecomastia with spironolactone (though short duration of study).
  • See graph below of medication efficacy

As with the current study, many of us have adapted the traditional definition of drug resistant hypertension of 3 drugs at maximal dosage including a diuretic appropriate for their renal function to mean specifically an ACE-I/ARB, calcium channel blocker and diuretic (i.e., not usually including a b-blocker). The current study is the first head-to-head study of spironolactone to other 4th drugs in controlling refractory hypertension. A few observations:

• This study relied on home-based blood pressure measurements.  There are a slew of articles touting the utility of ambulatory or home-based blood pressure over office-based findings, some summarized in my old blogs and many were reviewed in a meta-analysis (see BMJ 2011;342:d3621), showing that clinical outcomes much more closely track the non-office based measurements. One particularly relevant study looked at 556 patients with baseline resistant hypertension followed 4.8 years and found that only the ambulatory and not the office-based blood pressures predicted cardiovascular events, and even found that 40% of those felt to have resistant hypertension on medications actually were not hypertensive on ambulatory 24h blood pressure monitoring (see Arch Intern Med. 2008;168(21):2340-2346). The 2011 NICE (Natl Institute for Health and Clinical Excellence in the UK) guidelines for hypertension emphasize the importance of ambulatory or home-based blood pressure measurements, noting that the data are more extensive for ambulatory 24 hr monitoring.
• Overall the results for seated clinic pressures mirrored those of the home-based pressures, though interestingly the placebo effect was large in the clinic pressures and was not seen in the home ones. (Office: spironolactone decreased SBP 20.7, doxazocin and bisoprolol 16.3 and placebo 10.8; home: spironolactone 14.3, doxazocin 9.5, bisoprolol 9.0 and placebo 4.4)
• The NICE guidelines alsopoint out 6 studies showing spironolactone efficacy as a 4th drug for those with refractory hypertension. My own experience mirrors this. I have been using spironolactone as my 4th drug for at least the past 5 years and have been very impressed with the results. And, as in the studies, this even applies to patients who have high normal potassium levels (i.e., not just to those with low potassium, who one might think were more likely to have primary hyperaldosteronism and perhaps be more responsive to spironolactone — though it was notable that spironolactone was particularly effective in those with low renin levels). I have mostly used 25mg, occasionally increasing to 50mg, though there are some studies in patients without resistant hypertension showing a dose-response curve with higher doses.