PATHWAY-2

Published

Williams B, et al. "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. 2015. 386(10008):2059-2068.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In patients with resistant hypertension treated with an ACEI/ARB, CCB, and a diuretic, is the addition of spironolactone superior to placebo, doxazosin, or bisoprolol to control blood pressure?

Bottom Line

Among patients with resistant hypertension managed with ACEI/ARB, CCB, and a diuretic, adding spironolactone improved BP control compared to adding either placebo, doxazosin, or bisoprolol.

Major Points

Four smaller randomized, placebo-controlled trials had previously found conflicting results about the benefit of adding spironolactone for reducing blood pressure for resistant hypertension. PATHWAY-2 was a large multicenter, double-blind study randomly assigning patients with resistant hypertension to sequential therapy with spironolactone, doxazosin, bisoprolol, or placebo after a 1-month single-blind placebo run-in. Each therapy was given for 12 weeks, initiated at a low dose and then doubled after week 6. An intention-to-treat analysis found that the average reduction in home systolic blood pressure was greater (P<0.0001) with spironolactone compared with placebo (-8.70 mm Hg), doxazosin (-4.03 mm Hg), and bisoprolol (-4.48 mm Hg). The authors also observed a differential benefit for spironolactone for SBP reduction by renin level. Specifically, the reduction in SBP was greatest in the subgroup with low renin who were also randomized to spironolactone. The authors hypothesized that low renin may represent high volume status, i.e. sodium retention. Spironolactone was the only study medication that was a diuretic and its benefit might be related to its volume reduction. Discontinuation due to renal impairment or hyperkalemia was uncommon. The authors concluded that among patients with hypertension resistant to combination therapy with ACEI/ARB, CCB, and a diuretic, spironolactone was more effective at blood pressure lowering compared to doxazosin and bisoprolol.

Guidelines

2017 ACC AHA AAPA ABC ACPM AGS APhA ASH ASPC NMA PCNA Hypertension (2017, adapted)

• In particular, the recent PATHWAY-2 RCT demonstrated the superiority of spironolactone over alpha and beta blockers.
• Spironolactone and eplerenone are preferred agents in primary aldosteronism and resistant hypertension. Spironolactone is associated with greater risk of gynecomastia and impotence as compared with eplerenone. This is common add-on therapy in resistant hypertension. Avoid use with potassium supplements, other potassium-sparing diuretics, or significant renal dysfunction. Eplerenone often requires twice-daily dosing for adequate BP lowering.

Design

• Multicenter, double-blind, randomized, controlled trial with crossover
• N=335 outpatients with resistant hypertension
  • Spironolactone (n=285)
  • Doxazosin (n=282)
  • Bisoprolol (n=285)
  • Placebo (n=274)
• Setting: 14 centers in the UK
• Enrollment: 2009-2014
• Analysis: Intention-to-treat
• Primary outcome: Difference in average home systolic BP between spironolactone and placebo

Population

Inclusion Criteria

• Age 18-79 years
• Resistant hypertension
  • Mean home SBP >130 mm Hg or clinic SBP ≥5 mm Hg above target (140 mm Hg for non-diabetics, or 135 mm Hg for diabetics)
  • Treatment for at least 3 months with lisinopril 20 mg, amlodipine 10 mg, and bendroflumethiazide 2.5 mg, or their equivalents or intolerant to one category or tolerating a lower dose

Exclusion Criteria

• Non-adherence to antihypertensives or to placebo run-in phase
• Clinic BP >200/120 mm Hg
• Secondary or accelerated hypertension
• Use of oral corticosteroids or NSAIDs
• Type 1 diabetes mellitus
• eGFR <45 mL/min
• Serum potassium outside normal range on two successive measurements during screening
• Contraindications or intolerance to study drugs (eg, asthma)
• Sustained atrial fibrillation
• MI or stroke in the 6 months prior

Baseline Characteristics

• Mean age: 61 years
• Female sex: 31%
• Mean weight: 93.5 kg
• Mean eGFR: 91 mL/min
• Diabetes: 14%
• Smoker 7.8%
• Mean home BP: 148/84 mm Hg
• Mean clinic BP: 157/90 mm Hg

Interventions

• All patients underwent a one-month single-blind placebo run-in phase, during which patients could be excluded if they did not tolerate placebo.
• Thereafter, patients received sequential therapy with one of four study drugs: spironolactone, doxazosin, bisoprolol, or placebo.
• The order of the sequence was randomly assigned.
• Each drug was given for 12 weeks, initiated at a low dose and then increased to the high dose after 6 weeks:
  • Spironolactone 25-50 mg/d
  • Doxazosin 4-8 mg/d
  • Bisoprolol 5-10 mg/d
  • Placebo
• If dose increase was not tolerated, participant would move on to the next cycle
• Drugs were masked by re-encapsulation

Outcomes

Primary Outcome

Mean home SBP reduction

Agent	Blood pressure (mm Hg)	Change from baseline (mm Hg)
Spironolactone	134.9	-12.8
Doxazosin	139.0	-8.7
Bisoprolol	139.4	-8.3
Placebo	143.6	-4.1

Comparison between arms

The reduction in SBP was greater for spironolactone than any other drug when compared individually (P<0.0001). As shown in Figure 3, the reduction in SBP was greatest among those with lowest renin levels.

Adverse Events

Serious adverse events

Spironolactone 2%

Doxazosin 2%

Bisoprolol 3%

Placebo 2%

Any adverse event

Spironolactone 19%

Doxazosin 23%

Bisoprolol 23%

Placebo 15%

Withdrawal for adverse event

Spironolactone 1%


Doxazosin 3%

Bisoprolol 1%

Placebo 1%

Criticisms

• Potential for selective reporting of outcomes. Registration of the trial design on ClinicalTrials.gov took place a few months before study end. No explanation as to why only the systolic BP was chosen in the analyses.
• Potential for attrition bias: Loss to follow-up seems differential and greater with the doxazosin cycle.
• Mean dose of effective or tolerated drug not reported
• Short duration of follow-up: Unknown if BP lowering effects would be sustained in time. Long-term adverse effects likely not captured
• Direct switch from one drug to another: Potential safety concerns when stopping doxazosin and bisoprolol abruptly.

Funding

• Funded by non-industry grants (British Heart Foundation and National Institute for Health Research)
• Authors have multiple ties with the pharmaceutical industry