PATHWAY-2

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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.
PubMedFull text

Clinical Question

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

Bottom Line

When spironolactone was added to a regimen of ACEI or ARB, CCB and diuretic, a higher reduction in home systolic blood pressure was seen and a higher proportion of patients achieved home systolic blood pressure control (target < 135 mmHg) compared to placebo, doxazosin and bisoprolol. The achieved diastolic home blood pressure did not differ statistically between spironolactone, doxazosin and 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. [1] [2] [3] [4] The PATHWAY-2 trial was not only larger than the previous ones, but it was also the only one to compare spironolactone to active comparators. PATHWAY-2 found that the average reduction in home systolic blood pressure was greater with spironolactone compared with placebo, doxazosin and bisoprolol, and the mean increase in serum potassium was 0.4 mmol/L with spironolactone

Guidelines

The term resistant hypertension was coined by Calhoun et al in 2008 in a scientific statement of the American Heart Association. [5] Two guidelines were published since then.

ESH/ESC guidelines for the management of arterial hypertension [6] (2013, adapted)

  • Check whether the drugs included in the existing regimen have any BP lowering effect, and withdraw those with minimal or no effect (Class I, level of evidence C)
  • Mineralocorticoid receptor antagonists, amiloride, and doxazosin should be considered if no contraindication (Class IIa, level of evidence B)
  • In case of ineffectiveness of drug treatment, invasive procedures (renal denervation or baroreceptor stimulation) may be considered (Class IIb, level of evidence C)

ASH/ISH guidelines for the management of hypertension in the community [7] (2014, adapted)

  • For blood pressure not controlled with 3 drugs, add a mineralocorticoid antagonist such as spironolactone, a beta-blocker, a centrally acting agent, an alpha-blocker, or a direct vasodilator

As of April 2016, no guidelines have been published to reflect the results of this trial.

Design

  • Multicenter, double-blind (investigators and participants), crossover, randomized, controlled trial
  • N ITT = 335 (randomized)
    • N mITT = 314 (at least one follow-up)
    • N PP = 230 (completed all 4 crossover cycles)
  • Setting: 12 secondary care and 2 primary care centers in the United Kingdom
  • Enrollment: May 15, 2009 to July 8, 2014
    • Protocol published and entered on ClinicalTrials.gov in 2015 (NCT02369081)
  • Total duration: maximum 52 weeks
    • Run-in period of one month of single-blind placebo before randomization
    • Crossover: four cycles of 12 weeks each
    • No wash-out period between cycles
  • Analysis: modified intention-to-treat
  • Primary outcome: difference in the average home systolic blood pressure between spironolactone and placebo

Population

Inclusion Criteria

  • Resistant hypertension
    • Mean home SBP > 130 mmHg or clinic SBP 5 mmHg or more above target of 140 mmHg for non-diabetics or 135 mmHg 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
  • Age 18-79 years

Exclusion Criteria

  • Non-adherence to antihypertensives or to placebo run-in phase
  • Clinic BP > 200/120 mmHg
  • 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
  • Contra-indications or intolerance to study drugs (e.g. asthma)
  • Sustained atrial fibrillation
  • MI or stroke in the 6 months prior

Baseline Characteristics

  • Mean age: 61 years
  • Male gender: 69%
  • Mean weight: 94 kg
  • Mean eGFR: 91 mL/min
  • Diabetes: 14%
  • Smoker 7.8%
  • Mean home BP, HR: 148/84 mmHg, 73 bpm
  • Mean clinic BP, HR: 157/90 mmHg, 77 bpm

Interventions

  • Randomization to add-on once daily oral spironolactone 25 mg, doxazosin modified release 4 mg, bisoprolol 5 mg or placebo
    • Drugs masked by re-encapsulation
  • BP monitored at home over the 4 days prior to clinic visits at weeks 6 and 12 of each cycle
  • Visit at 6 week with forced up-titration to twice initial dose of each study drug (spironolactone 50mg, doxazosin modified release 8 mg, bisoprolol 10 mg)
    • If up-titration not tolerated, participant would start the next cycle
  • Visit at 12 weeks and direct cross-over to the next cycle with the next drug in sequence

Outcomes

Comparisons are 1) spironolactone vs. placebo, 2) spironolactone vs. doxazosin MR, and 3) spironolactone vs. bisoprolol.

Primary Outcome

Mean home SBP reduction
1) -12.8 vs. -4.1: mean difference -8.70 mmHg (95% CI -9.72 to -7.69; P <0.0001);
2) -12.8 vs. -8.7: mean difference -4.03 mmHg (95% CI -5.04 to -3.02 mmHg; P <0.0001);
3) -12.8 vs. -8.3: mean difference 4.48 mmHg (95% CI -5.50 to -3.46; P <0.0001).

Secondary Outcomes

Mean clinic SBP reduction
1) -20.7 vs. -10.8: mean difference -9.92 mmHg (95% CI -11.3 to -8.59; P <0.001);
2) -20.7 vs. -16.3: mean difference 4.42 mmHg (95% CI -5.75 to -3.09; P <0.001);
3) -20.7 vs. -16.3: mean difference -4.45 mmHg (95% CI -5.80 to -3.11; P <0.001).
Home SBP control rates (< 135 mmHg)
1) 58.0% vs. 23.9% (OR 0.23; 95% CI 0.16 to 0.33; P < 0.001)
2) 58.0% vs. 41.5% (OR 0.52; 95% CI 0.37 to 0.73; P <0.001);
3) 58.0% vs. 43.3% (OR 0.55; 95% CI 0.39 to 0.77; P< 0.001).

Subgroup Analysis

Mean home SBP reduction at final visit of each cycle (i.e. maximum drug dose) in the per-protocol population
1) -14.9 vs. -3.4: mean difference -11.4 mmHg (95% CI -12.9 to -9.95; P <0.001);
2) -14.9 vs. -8.6: mean difference -6.28 mmHg (95% CI -7.75 to -4. 81; P <0.001);
3) -14.9 vs. -8.4: mean difference -6.48 mmHg (95% CI -7.96 to -5.01; P <0.0001).

Additional Analysis

Mean home diastolic BP reduction from baseline diastolic BP
Spironolactone -5.7 mmHg (95% CI -6.3 to -5.1)
Placebo: -1.4 mmHg (95% CI -2.0 to -0.9)
Doxazosin -5.1 mmHg (95% CI -5.7 to -4.5)
Bisoprolol: -6.3 (95% CI -6.9 to -5.7)

Adverse Events

Change in serum sodium from baseline (mmol/L)

  • -1.91 vs. 0.11 vs -0.07 vs. -0.17

Change in serum potassium from baseline (mmol/L)

  • 0.43 vs. 0.03 vs. 0.08 vs. 0.15

Change in serum creatinine from baseline (micromol/L)

  • 8.43 vs. 2.12 vs. 7.28 vs. 5.57

Change in eGFR from baseline (mL/min)

  • -10.02 vs. 0.15 vs. -7.32 vs. -6.05

Dizziness

  • 6.1% vs. 4.5% vs. 6.0% vs. 12.2%

Postural dizziness

  • 0.3% vs. 0.3% vs. 4.6% vs. 1.7%

Fatigue

  • 7.4% vs. 3.1% vs. 3.3% vs. 6.1%

Muscle spasms

  • 1.0% vs. 0.0% vs. 6.6% vs. 1.7%

Bradycardia

  • 6.4% vs. 0.7% vs. 1.7% vs. 1.0%

Hyperkalemia (>6.0 mmol/L)

  • 2% with spironolactone

Withdrawals due to adverse events

  • 1% vs. 1% vs. 3% vs. 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 i.e. greater with the doxazosin cycle
  • Home SBP target of < 135 mmHg for both diabetics and non-diabetics
  • 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

Further Reading

  1. Václavík J et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension 2011. 57:1069-75.
  2. Václavík J et al. Effect of spironolactone in resistant arterial hypertension: a randomized, double-blind, placebo-controlled trial (ASPIRANT-EXT). Medicine (Baltimore) 2014. 93:e162.
  3. Oxlund CS et al. Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial. J. Hypertens. 2013. 31:2094-102.
  4. Abolghasmi R & Taziki O Efficacy of low dose spironolactone in chronic kidney disease with resistant hypertension. Saudi J Kidney Dis Transpl 2011. 22:75-8.
  5. Calhoun DA et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008. 51:1403-19.
  6. Mancia G et al. 2013 ESH/ESC Practice Guidelines for the Management of Arterial Hypertension. Blood Press. 2014. 23:3-16.
  7. Weber MA et al. Clinical practice guidelines for the management of hypertension in the community a statement by the American Society of Hypertension and the International Society of Hypertension. J. Hypertens. 2014. 32:3-15.

[1] [2] [3] [4] [5] [6] [7] [8] [9]

[10]
  1. 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. Lancet 2015. 386:2059-68.
  2. Calhoun DA et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008. 51:1403-19.
  3. Mancia G et al. 2013 ESH/ESC Practice Guidelines for the Management of Arterial Hypertension. Blood Press. 2014. 23:3-16.
  4. Weber MA et al. Clinical practice guidelines for the management of hypertension in the community a statement by the American Society of Hypertension and the International Society of Hypertension. J. Hypertens. 2014. 32:3-15.
  5. Dahal K et al. The Effects of Aldosterone Antagonists in Patients With Resistant Hypertension: A Meta-Analysis of Randomized and Nonrandomized Studies. Am. J. Hypertens. 2015. 28:1376-85.
  6. Václavík J et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension 2011. 57:1069-75.
  7. Václavík J et al. Effect of spironolactone in resistant arterial hypertension: a randomized, double-blind, placebo-controlled trial (ASPIRANT-EXT). Medicine (Baltimore) 2014. 93:e162.
  8. Djoumessi RN et al. Effect of low-dose spironolactone on resistant hypertension in type 2 diabetes mellitus: a randomized controlled trial in a sub-Saharan African population. BMC Res Notes 2016. 9:187.
  9. Oxlund CS et al. Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial. J. Hypertens. 2013. 31:2094-102.
  10. Abolghasmi R & Taziki O Efficacy of low dose spironolactone in chronic kidney disease with resistant hypertension. Saudi J Kidney Dis Transpl 2011. 22:75-8.