PATHWAY-2: Does the Road Lead to Spironolactone for Resistant Hypertension?

Resistant hypertension (RH) is frequently encountered in primary care practice and often presents a significant clinical challenge because limited evidence-based guidance exists.¹ RH is a major cause of cardiovascular disease and death, and has been associated with a 50% increased risk of myocardial infarction, stroke, congestive heart failure, and chronic kidney disease when compared to patients without RH.^2,3   The American Heart Association defines RH as uncontrolled BP despite maximal treatment with a three-drug regimen, ideally including a diuretic.³ The exact prevalence of RH is unknown, but large randomized controlled trials suggest it affects one in five patients with elevated BP.^3,4,5 In patients without identifiable secondary causes, treatment is based on patient-specific characteristics.^4,6 The pathophysiological cause of RH remains unknown but may include high renin-angiotensin system stimulation and increased aldosterone production.⁵ Patients most likely to have RH include those who are older (>75 years), obese, African American, female, or have diabetes or chronic kidney disease.^4,7

Previous research findings suggest chlorthalidone, spironolactone, and eplerenone are all effective add-on therapies when BP remains uncontrolled with typical first line agents.^1,6,8,9  However, the unanswered research question remains: How does add-on therapy, with an aldosterone antagonist, directly compare to other agents that could be used for RH.

The Pathway-2 study provides the first direct comparative evaluation of three different four-drug antihypertensive regimens. The British Heart Foundation and National Institutes for Health funded the Pathway-2 study with the goal to identify an “optimal” treatment option for patients with RH.  Based on previous research findings, the investigators hypothesized that the primary cause of RH is related to excessive sodium retention possibly due to inadequate use of diuretics.^4,10 The Pathway-2 study was designed as a 12-month, double-blind, placebo-controlled, multiple crossover trial, enrolling 335 patients between the age of 18 and 79 years old from the United Kingdom. 

Patients with uncontrolled seated systolic BP (SBP > 140 mm Hg; > 135 mm Hg with diabetes) measured in clinic and who had been treated for at least three months with maximally tolerated doses of an ACE-I or ARB, a CCB, and a diuretic (any except spironolactone) were eligible for the study. Exclusion criteria included: patients with an eGFR <45ml/min/1.73m², recent (<6 months) cardiovascular event requiring hospitalization (e.g., myocardial infarction or stroke), type-1 diabetes, patients on any treatment that may affect BP control (e.g., NSAIDs, corticosteroids), or patients having compelling indications for an alpha-antagonist or beta-blocker. There was a four-week run in period to rule out poor adherence to current therapy as a cause for RH and those deemed non-adherent were subsequently excluded from trial participation.  Baseline characteristics of the enrolled study participants are found in Table 1.

Table 1: Baseline characteristics of the patients enrolled in PATHWAY-2 (n=335)

The study used average home systolic BP readings as the primary endpoint and clinic measurements as the secondary endpoint. Every patient used the same brand of automated BP monitors for home over four consecutive days at baseline, 6, and 12 weeks of each treatment cycle.

Patients received spironolactone (25 and 50 mg), bisoprolol (5 and 10 mg), doxazosin modified release (4 and 8 mg), and placebo — each for 12 weeks during 4 treatment cycles. The order of the treatment cycles was randomly assigned. Within each 12-week cycle, patients were started at a lower dose for the first 6 weeks then forced titrated to a higher dose for the next 6 weeks. Of the 335 patients randomized, 21 were lost to follow-up during the initial treatment period; therefore, data from the remaining 314 patients were used for the intent-to-treat analysis. Only 230 patients completed all four treatment cycles (285 received spironolactone, 282 received doxazosin, 285 received bisoprolol and 274 received placebo). Results comparing the mean home systolic BP changes for each drug treatment (baseline verses final visit) as well as spironolactone vs placebo, beta-blocker and alpha-blocker therapies are found in Table 2.

Table 2: Home systolic blood pressure at final visit of treatment cycle  

Spironolactone provided the greatest BP lowering effect when added as fourth-line treatment to conventional first line therapies.  Mean decreases in home systolic BP readings averaged 4.2 mm Hg on placebo, 8.4 mm Hg on bisprolol, 9.1 mmHg on doxazosin, and 14.4 mm Hg on spironolactone when compared to baseline readings.  Changes in average home diastolic BP were similar for each treatment group compared to baseline.  Clinic readings showed similar systolic BP lowering results when compared to home systolic BP lowering effects, but in general the final overall average clinic systolic BP was about 6 mmHg higher than home systolic BP for each drug, which is consistent with previous research findings.⁵ Of the patients who received spironolactone, 58% had their home systolic BP controlled (SBP < 135 mm Hg) during the 12-weeks compared to 42% with doxazosin, 44% with bisoprolol and 24% with placebo. The increase in dose from weeks 6 to 12 provided statistically significant decreases in systolic BP in only the spironolactone treatment cycle  (dose increased from 25mg to 50mg) with a mean decrease of 3.9 mmHg compared to doxazosin (0.88 mmHg) and bisoprolol (1.49 mmHg).

Adverse effects were evaluated.  No major differences were observed between treatment cycles. The only serious adverse effects noted in the study occurred during the spironolactone cycle — six patients developed asymptomatic elevations in serum potassium >6.0 mmol/L, but none requiring study withdrawal. All treatments increased serum creatinine and decreased eGFR but none caused serious harm or study discontinuation.  The investigators acknowledged they were unable to assess long-term safety and strongly recommended routine monitoring of electrolytes and renal function for the safe use of spironolactone.

Overall, this well designed head to head study provides strong clinical evidence to support spironolactone as effective fourth-line add-on treatment of RH in patients without a compelling indication for alternate therapy (e.g., beta-blocker for angina or alpha-antagonist for benign prostatic hypertrophy).  Notably, this was the first major RH trial to use home BP readings as the primary endpoint, thus reducing the likelihood that participants had white coat hypertension.  It is possible that a limited number of patients in this trial had underlying primary hyperaldosteronism as a secondary cause of RH – and this would have favored spironolactone treatment. Overall consistent BP lowering response with spironolactone in the Pathway-2 and previous RH trials^6-9 strongly supports the use of aldosterone antagonists in combination with conventional diuretic treatments.      

Unfortunately, the generalizability of the Pathway-2 trial findings is somewhat limited for three reasons.  First, the mean home BP in the study population at baseline was relatively low (148/86 mm Hg).  Second, the mean eGFR was 91.1 ml/min/173 mm² which may not be representative of patients with RH.  Finally, the study population consisted of relatively healthy men (and of unknown race).  Given the SPRINT trial results suggest that lowering systolic BP to <120 mm Hg in high risk patients may be beneficial,¹¹ spironolactone might be a good add-on therapy to achieve this lower systolic BP goal.

What cannot be concluded from these findings, are comparative advantages to achieve cardiovascular outcomes, morbidity/mortality benefits, and renal effects of these treatment agents. Further research is needed comparing spironolactone to more potent diuretics (e.g., chlorthalidone or loop diuretics), alpha-2 agonists (e.g. clonidine, guanfacine), direct vasodilators (e.g. minoxidil), mixed alpha/beta blocker (e.g., labetalol) and other potential fourth line agents (e.g. reserpine). Despite the limitations of this study and the need for additional data, spironolactone should be the preferred option in patients with RH after first-line therapies have been maximize – provided the patient has minimal renal impairment and a serum potassium less than 4.5 mEq/L.

Are the PATHWAY-2 results compelling enough to consider spironolactone the preferred add-on drug in patients with RH?  What about eplerenone?  Or labetalol?  Or clonidine?  Or minoxidil plus a beta-blocker?  What’s your go-to fourth-line choice?  

See the related case study of HL – a 57 year old Causacian male who presents for a comprehensive medication management visit.