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Loop Diuretic Use and Outcomes in Chronic Stable Heart Failure With Preserved Ejection Fraction–Reply

      To The Editor:
      Effective treatments to mitigate the rising prevalence of heart failure (HF) with preserved ejection fraction (HFpEF), hospitalizations, and mortality remain limited. Loop diuretics are the mainstay of treating congestive HFpEF, although their use is associated with worse HF-related outcomes.
      • Peacock W.F.
      • Costanzo M.R.
      • De Marco T.
      • et al.
      Impact of intravenous loop diuretics on outcomes of patients hospitalized with acute decompensated heart failure: insights from the ADHERE registry.
      To date, the effect of diuretic combination therapies on HF-related outcomes has not been fully clarified in HFpEF. Outcomes in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial were significantly reduced by mineralocorticoid receptor antagonists (MRAs) among participants with HFpEF enrolled in the Americas.
      • Pfeffer M.A.
      • Claggett B.
      • Assmann S.F.
      • et al.
      Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial.
      We therefore explored the associations between use of baseline loop diuretics and their interactions with MRAs on primary composite outcome—including cardiovascular death, aborted cardiac arrest, and hospitalizations for HF—and secondary outcomes, including all-cause mortality and all-cause hospitalizations among participants enrolled in the TOPCAT trial in the Americas.
      Participants without baseline diuretic use (N=189) were propensity matched in a 3:1 fashion with those with baseline diuretic use (N=567) on specific baseline characteristics, as shown in the Figure, after excluding those with missing covariates (N=3). Risk of adverse clinical outcomes were compared among the propensity-matched cohorts using unadjusted cumulative incidence curves. In the overall study cohort (N=1767), we performed multivariate Cox proportional-hazard models to evaluate the effect of baseline diuretic use on outcomes. Our primary model was adjusted for age, sex, New York Heart Association (NYHA) class, use of antihypertensive medications, diabetes, atrial fibrillation, hypertension, previous hospitalization for HF, blood urea nitrogen, creatinine, systolic blood pressure, body mass index, and treatment arm. In addition, a separate analysis adjusted for N-terminal pro brain natriuretic peptide (NT-proBNP [only 20% available]). Treatment allocation (MRA vs placebo) effects on outcomes were assessed using multiplicative interaction terms.
      Among 1767 participants, mean age was 71.5±9.7 years, 50.1% were men, 78.3% were white, 64.8% had NYHA class I/II, mean NT-proBNP was 1644.2±1923.4 pg/mL, and 89.1% used diuretics at baseline. Participants with baseline diuretic use (N=1575) were more likely to have hypertension, diabetes, atrial fibrillation, NYHA III/IV functional class, previous hospitalizations for HF, and higher use of beta blockers and angiotensin converting-enzyme inhibitors or angiotensin receptor blockers.
      In the propensity-matched analysis (N=756), standard mean difference was <10% for participant characteristics among the matched groups with vs without baseline diuretic use (data not shown). The cumulative incidence of primary composite end point, all-cause mortality, and all-cause hospitalizations were similar across propensity-matched groups (Figure).
      Figure thumbnail gr1
      FigureCumulative incidence of primary composite end point, all-cause mortality, and hospitalization by diuretics use at baseline. Cumulative incidence of outcomes using 3:1 propensity-matched score based on age, sex, New York Heart Association class, use of antihypertensive medications, diabetes, atrial fibrillation, hypertension, hospitalization for heart failure, blood urea nitrogen, creatinine, systolic blood pressure, body mass index, and treatment arm (N=756, including 189 participants without baseline diuretic use).
      In the overall cohort with available covariates (N=1726), we observed 507 primary composite events, 367 all-cause deaths, and 1044 all-cause hospitalizations. Baseline diuretic use was not associated with risk of primary composite end point or all-cause mortality in the primary model (Table). However, baseline diuretic use was associated with modestly higher risk of all-cause hospitalizations (hazard ratio [HR]; 95% confidence interval [CI], 1.25 [1.00, 1.56]; P=.047). There was no significant treatment interaction between use of MRAs and baseline diuretic use for outcomes. In the sensitivity analysis limited to participants with available baseline NT-proBNP, additional adjustment for NT-proBNP showed consistent pattern of association between baseline diuretic use and risk of primary composite end point as observed in the primary analysis (HR; 95% CI, 1.76 [0.77, 4.02]; P=.18).
      TableSurvival Models with Baseline Loop Diuretic Use as a Primary Predictor of Outcomes in the TOPCAT Trial
      OutcomesEvents (n/N)Baseline diuretic useTreatment group
      Adjusted hazard ratio (95% CI)P valueP value for diuretic treatment interaction
      Primary composite end point
       Without baseline diuretic use507/1726Ref.28.63
       With baseline diuretic use1.20 (0.86, 1.68)
      All-cause mortality
       Without baseline diuretic use367/1726Ref.24.10
       With baseline diuretic use1.26 (0.86, 1.83)
      All-cause hospitalization
       Without baseline diuretic use1044/1726Ref.047.55
       With baseline diuretic use1.25 (1.00, 1.56)
      Primary adjusted model includes covariates of age, sex, New York Heart Association class, use of antihypertensive medication, history of diabetes, history of atrial fibrillation, history of hypertension, history of hospitalization for heart failure, blood urea nitrogen, creatinine, systolic blood pressure, body mass index, and treatment arm.
      Interaction between diuretics and treatment allocation for outcomes as follows: primary composite end point hazard ratio (HR); 95% confidence interval (CI), 1.17 (0.61, 2.26); P=.63; all-cause mortality HR; 95% CI, 1.89 (0.88, 4.06); P=.10; all-cause hospitalizations HR; 95% CI, 1.14 (0.74, 1.76; P=.55.
      TOPCAT, treatment of preserved cardiac function heart failure with an aldosterone antagonist.
      Among patients with HFpEF, use of loop diuretics at baseline was associated with modestly higher risk of all-cause hospitalizations but not primary composite end point or all-cause mortality. Approximately 81% of participants enrolled in TOPCAT were on loop diuretics at baseline. Previous observations among hospitalized patients with HF demonstrated that loop diuretics were associated with worse outcomes,
      • Peacock W.F.
      • Costanzo M.R.
      • De Marco T.
      • et al.
      Impact of intravenous loop diuretics on outcomes of patients hospitalized with acute decompensated heart failure: insights from the ADHERE registry.
      possibly providing an indication of worse baseline health status such as those with right-ventricular dysfunction, chronic kidney disease, or liver disease. Among those with HFpEF, long-term use of loop diuretics may be associated with hemodynamic-related mechanisms, leading to exercise intolerance in HFpEF, and contribute to hospitalizations.
      • Montero D.
      • Flammer A.J.
      Exercise intolerance in heart failure with preserved ejection fraction: time to scrutinize diuretic therapy?.
      In our analysis, we observed higher risk of all-cause hospitalizations among those with baseline diuretic use. There was no significant interaction between use of baseline diuretics and MRAs on outcomes, consistent with a recent analysis in TOPCAT demonstrating that MRAs had favorable effects on hospitalizations for HFpEF beyond diuretic effects.
      • Kalogeropoulos A.P.
      • Thankachen J.
      • Butler J.
      • Fang J.C.
      Diuretic and renal effects of spironolactone and heart failure hospitalizations: a TOPCAT Americas analysis.
      Future studies are needed in chronic HFpEF to better understand how to optimize diuretic therapy while also reducing risk of future hospitalizations.

      ACKNOWLEDGMENTS

      The authors would like to thank the participants of the TOPCAT trial.

      References

        • Peacock W.F.
        • Costanzo M.R.
        • De Marco T.
        • et al.
        Impact of intravenous loop diuretics on outcomes of patients hospitalized with acute decompensated heart failure: insights from the ADHERE registry.
        Cardiology. 2009; 113: 12-19
        • Pfeffer M.A.
        • Claggett B.
        • Assmann S.F.
        • et al.
        Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial.
        Circulation. 2015; 131: 34-42
        • Montero D.
        • Flammer A.J.
        Exercise intolerance in heart failure with preserved ejection fraction: time to scrutinize diuretic therapy?.
        Eur J Heart Fail. 2017; 19: 971-973
        • Kalogeropoulos A.P.
        • Thankachen J.
        • Butler J.
        • Fang J.C.
        Diuretic and renal effects of spironolactone and heart failure hospitalizations: a TOPCAT Americas analysis.
        Eur J Heart Fail. 2020; 22: 1600-1610