Spironolactone primer

Resistant hypertension is an important clinical problem. It is commonly defined as inadequate blood pressure control despite use of three antihypertensive agents of different classes at optimal dosages; one of the three should be an appropriately dosed diuretic. About 10-15% of hypertensive patients have resistant hypertension.

The magical powers of aldosterone antagonists first started to be publicized in the late 90's and in 2003 Calhoun showed a dramatic effect among patients with resistant hypertension:

A total number of 76 subjects were included in the analysis, 34 of whom had biochemical primary aldosteronism. Low-dose spironolactone was associated with an additional mean decrease in BP of 21 ± 21 over 10 ± 14 mm Hg at 6 weeks and 25 ± 20 over 12 ± 12 mm Hg at 6-month follow-up. The BP reduction was similar in subjects with and without primary aldosteronism and was additive to the use of ACE inhibitors, ARBs, and diuretics.

This was backed up by additional observational data as part of the ASCOT trial experience. The investigators found dramatic efficacy from modest doses of spironolactone among the 1,411 patients that received spironolactone as a fourth line agent:

During spironolactone therapy, mean blood pressure fell from 156.9/85.3 mm Hg (SD: ±18.0/11.5 mm Hg) by 21.9/9.5 mm Hg (95% CI: 20.8 to 23.0/9.0 to 10.1 mm Hg; P<0.001); the BP reduction was largely unaffected by age, sex, smoking, and diabetic status.

The first randomized, placebo controlled trial in resistant hypertension was published in 2011. The ASPIRANT trial (PDF) showed a more modest, but still clinically significant reduction blood pressure.

An important caution when looking at spironolactone data is that it appears that black patients  are more sensitive to increases in aldosterone, so one could predict more modest blood pressure improvements with spironolactone in a European population. See Tu et al. (Full text).

Another critical aspect of resistant hypertension is addressing non-adherence. 

A mass spectrometry urine toxicology screening of antihypertensive drugs reported that 53% of patients with resistant hypertension were non-adherent to treatment. Of these, 70% were incompletely adherent and 30% were completely non-adherent. Reduced adherence was not attributed to a particular antihypertensive class. Another urine analysis study found that 23% of patients referred for renal denervation were completely non- adherent to their prescribed antihypertensive treatment.
— From Rossignol et al. The double challenge of resistant hypertension and chronic kidney disease.

This is why PATHWAY-2's attempt to measure minimize non-adherence is so important.

This week's chat on PATHWAY-2 represents the first randomized controlled trial against an active control group. The fact that aldosterone rises above other fourth line agents to provide meaningful advantages in the treatment of resistant hypertension is important.

We are coming to a new age in hypertension management. On November 9, at 2:00 PM at the AHA meeting in Orlando the SPRINT Trial results will be released. This will almost certainly result in a wave of more aggressive blood pressure control. Almost simultaneously we now have access to the first of the next generation potassium binders, patiromer. This brings the hope of avoiding the most frightening of the side effects from aldosterone antagonists, hyperkalemia. These three seemingly unrelated events are going to be major influences on the treatment of hypertension going forward.