TOPCAT

Published

Pitt B, et al. "Spironolactone for heart failure with preserved ejection fraction". The New England Journal of Medicine. 2014. 370(15):1383-1392.
PubMed • Full text • PDF

Clinical Question

Among patients with heart failure with preserved ejection fraction, does spironolactone reduce CV mortality, aborted cardiac arrest, or HF hospitalizations when compared to placebo?

Bottom Line

Among patients with heart failure with preserved ejection fraction, spironolactone does not reduce the composite endpoint of CV mortality, aborted cardiac arrest, or HF hospitalizations when compared to placebo. However, it is associated with small reduction in HF hospitalizations.

Major Points

The efficacy of aldosterone antagonists in reducing mortality for those with HFrEF was demonstrated in RALES (1999; spironolactone) and EMPHASIS-HF (2011; eplerenone). In contrast to the multiple effective regimens for HFrEF (e.g. beta blockers, ACE-inhibitors/ARBs, aldosterone antagonists), few therapies improve outcomes for HFpEF. Aldosterone antagonists had not been studied in a large RCT involving patients with HFpEF.

The 2014 Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) randomized 3,445 patients with mostly controlled blood pressure to spironolactone or placebo. Patients were included if they had LVEF ≥45%, findings of HF, and either a HF hospitalization or elevated BNP. With a follow-up of 3.3 years, there was no difference in the primary composite outcome of CV mortality, aborted cardiac arrest, or HF hospitalization. However, spironolactone was associated with a "nominal" reduction in HF hospitalizations (12.0% vs. 14.2%; NNT 45). On subgroup analysis, spironolactone was associated with a significant reduction in the primary outcome for those in the Americas but not those in Eastern Europe. This revelation led to a 2017 analysis comparing Eastern European (Russian/Georgian) participants vs. those enrolled in North and South America. In this analysis, spironolactone metabolites were undetectable in a much larger proportion of those from Eastern Europe. Further, potassium levels typically did not vary among Eastern European participants, suggestive of non-consumption of the medication. The authors imply that Eastern European participants did not receive the study medication at such a rate that their data are unreliable.

Current ACC/AHA HF guidelines recommend diuretic use for symptom relief in patients with HF volume overload with HFpEF. Whether the diuretic effects of spironolactone prevented acute decompensated HF exacerbations is unclear.

Guidelines

As of May 2014, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, randomized, placebo-controlled, trial
• N=3,445
  • Spironolactone (n=1,722)
  • Placebo (n=1,723)
• Setting: 233 sites in 6 countries
• Enrollment: 2006-2012
• Mean follow-up: 3.3 years
• Analysis: Intention-to-treat
• Primary outcome: CV mortality, aborted cardiac arrest, or HF hospitalization

Population

Inclusion Criteria

• Age ≥50 years
• ≥1 sign and symptom:
  • Symptoms present at screening: PND, orthopnea, or DOE
  • Signs in past year: Rales post-cough, JVP ≥10 cmH2O, edema of lower extremities, or CXR with pleural effusion, pulmonary effusion, pulmonary congestion, cardiomegaly
• LVEF ≥45% in prior 6 months and after any event that would reduce EF
• SBP <140 mmHg or <160 mmHg if on ≥3 antihypertensives
• Serum potassium <5 mmol/L
• One of the following:
  • HF hospitalization in prior 12 months with a component of the inpatient care involving HF management
  • Elevated BNP in prior 60 days
• If child-bearing potential, negative pregnancy test, use of contraception, and not lactating

Exclusion Criteria

• Severe illness limiting life expectancy to <3 year
• GFR <30 mL/min/1.73 m2 or creatinine ≥2.5 mg/dL
• ALT or AST >3x ULN
• COPD on home O2, oral corticosteroids, or COPD hospitalization in prior year, or severity concerning to investigator
• HOCM, infiltrative disease, pericardial constriction, heart transplant, LVAD
• Uncorrected valvular disease of significance or likely need for surgery during trial
• AF with HR >90 BPM
• MI, CABG, PCI, or stroke in prior 90 days
• Orthostatic hypotension
• GI condition limiting absorption
• Intolerance
• Use of lithium
• Participation in another trial of a therapeutic
• Condition limiting adherence
• Potassium ≥ 5 mmol/L in prior 2 weeks or ≥5.5 mmol/L in prior 6 months

Baseline Characteristics

From the spironolactone group. Groups were similar.

• Demographics: Age 69 years (≥75 years 29%), female 52%, white 89%, N. or S. America 52%, Russia or Georgia 48%
• PMH: Current smoker 10%, CAD 57%, AF 35%, DM 33% (on insulin 13%), eGFR <60 mL/min/1.73m² 39%, HTN 91%, MI 26%, HLD 59%, COPD 12%, stroke 7%
• PSH: PCI or CABG 23%
• Medications: Diuretics 81%, ACE-inhibitor/ARB 84%, beta blocker 78%, CCB 36%, ASA 65%, statin 52%, long-acting nitrate 15%, warfarin 23%
• Baseline data: BP 130/80 mmHg, HR 68 BPM, BMI 31 kg/m2
  • Labs: BNP 236 pg/mL, NT-proBNP 887 pg/mL, potassium 4.3 mmol/L, creatinine 1.0 mg/dL (eGFR 65.3 mL/min/1.73 m2), Hgb 13.2 g/dL
• HF data: LVEF 56%
  • NYHA class:
    • I: 3%
    • II: 63%
    • III: 33%
    • IV: <1%
• Eligibility:
  • HF hospitalization in prior year: 71%
  • Elevated BNP in prior 60 days: 29%

Interventions

• Patients were randomized to a group, stratified by enrollment eligibility criteria (HF hospitalization or elevated BNP):
  • Spironolactone - Initiated at 15 mg PO qday then increased to 45 mg po qday in first 4 months. Further dose adjustments were made as needed.
  • Placebo
• Potassium and creatinine monitoring was performed with medication modifications
• Other HF management per the treatment team

Outcomes

Presented as spironolactone vs. placebo.

Primary Outcome

CV mortality, aborted cardiac arrest, or HF hospitalization

18.6% vs. 20.4% (HR 0.89; 95% CI 0.77-1.04; P=0.14)

Secondary Outcomes

CV mortality

9.3% vs. 10.2% (HR 0.90; 95% CI 0.73-1.12; P=0.35)

Aborted cardiac arrest

0.2% vs. 0.3% (HR 0.60; 95% CI 0.14-2.50; P=0.48)

HF hospitalization

12.0% vs. 14.2% (HR 0.83; 95% CI 0.69-0.99; P=0.04; NNT 45)

All-cause mortality

14.6% vs. 15.9% (HR 0.91; 95% CI 0.77-1.08; P=0.29)

Any hospitalization

44.5% vs. 46.0% (HR 0.94; 95% CI 0.85-1.04; P=0.25)

MI

3.8% vs. 3.7% (HR 1.00; 95% CI 0.71-1.42; P=0.98)

Stroke

3.3% vs. 3.5% (HR 0.94; 95% CI 0.65-1.35; P=0.73)

Additional Analyses

SBP at follow-up

Lower in spironolactone group (P<0.001)

SBP decrease at 8 months: -2.7 vs. -0.2 mmHg (P<0.001)

DBP decrease at 8 months: -2.0 vs. -0.6 mmHg (P<0.001)

Daily dose of intervention medication at month 8 excluding deaths

0 mg: 16.0% vs. 13.2% (includes thos who prematurely withdrew from the study and those who permanently stopped the medication)

15 mg: 16.4% vs. 8.5%

30 mg: 52.6% vs. 58.7%

45 mg: 14.9% vs. 19.6%

Subgroup Analysis

For the primary outcome except where specified.

Randomization stratum

Not hospitalized for HF in year prior to enrollment: 15.9% vs. 23.6% (HR 0.65; 95% CI 0.49-0.87: P=0.003)

CV mortality: 8.2% vs. 12.0% (HR 0.69; 95% CI 0.46-1.03; P=0.069)

Aborted cardiac arrest: 0.4% vs. 0% (no statistical analysis given)

HF hospitalization: 11.2% vs. 16.9% (HR 0.64; 95% CI 0.46-0.90; P=0.011)

Hospitalized for HF in year prior to enrollment: 19.6% vs. 19.1% (HR 1.01; 95% CI 0.84-1.21; P=0.923)

CV mortality: 9.7% vs. 9.5% (HR 1.01; 95% CI 0.78-1.31; P=0.924)

Aborted cardiac arrest: 0.1% vs. 0.4% (HR 0.20; 95% CI 0.02-1.69; P=0.138)

HF hospitalization: 12.3% vs. 13.1% (HR 0.92; 95% CI 0.73-1.14; P=0.440)

P-value for interaction 0.01

Geographic area

Americas: 27.3% vs. 31.8% (HR 0.82; 95% CI 0.69-0.98; P=0.026)

E. Europe: 9.3% vs. 8.4% (HR 1.10; 95% CI 0.79-1.51; P=0.576)

P-value for interaction 0.12

There were no interactions for the following pre-defined subgroups: LVEF based upon local reading, age, gender, ethnicity, HTN, DM, NYHA class, SBP, statin use, pulse pressure, eGFR, BMI, prior MI, HR, race, use of cardiac medications, or use of antihypertensives.

Adverse Events

P-Y means person-years.

Severe

41.6 vs. 41.8/100 P-Y

Early permanent discontinuation of medication

34.3% vs. 31.4% (P=0.074)

Persistent hyperkalemia: 2.6% vs. 1.0% (P<0.001)

Potassium ≥5.5% mmol/L on lowest study medication: 5.9% vs. 1.2% (P<0.001)

Abnormal renal function: 3.9% vs. 2.3% (P=0.006)

Breast tenderness or enlargement: 2.5% vs. 0.3% (P<0.001)

Doubling of serum creatinine

10.2% vs. 7.0% (P<0.001)

Discontinuation for gynecomastia or breast tenderness

Higher in spironolactone (P not given)

Criticisms

• High rate of drug discontinuation for adverse events
• International geographic variability of practices regarding hospitalizations for HF likely skewed outcomes
• Unclear if all patients actually had HFpEF
• Given the use of the ACC/AHA's broad definition of HFpEF, there may have been inclusion of participants who otherwise would not have benefited from the intervention -- use of the ESC definition may have prevented this
• No subgroup analysis for those with myocardial fibrosis
• No measurement of aldosterone levels in participants

Funding

• NHLBI at the NIH
• Authors with numerous financial disclosures