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Outpatient worsening HF in HFrEF patients reduced by SGLT2 inhibition

ahajournals.org
Literature - Docherty KF, Jhund PS, Anand I, et al. - Circulation. 2020 Sep 4. doi: 10.1161/CIRCULATIONAHA.120.047480.

Introduction and methods

One of the most commonly used clinical outcome in trials with heart failure with reduced ejection fraction (HFrEF) patients is CV death or hospitalization due to worsening of HF. Worsening of symptoms and signs leading to hospitalization is a marker of increased risk of readmission and death [1,2]. For this reason, HF hospitalization has been considered an important end-point in clinical trials, including episodes of worsening HF that requires intravenous (IV) treatment [3-5]. However, many more patients are treated for worsening symptoms in an outpatient manner by intensified oral therapy [6-8]. Thus, focusing only on HF hospitalization might underestimate the frequency of clinical worsening in HFrEF patients and mask the possible prognostic importance of other HF events.

This Dapagliflozin And Prevention of Adverse Outcome in Heart Failure (DAPA-HF) substudy evaluated the frequency of episodes of outpatient worsening HF, the treatment for these episodes, the prognostic importance of these events and the effect of 10 mg dapagliflozin once daily on episodes of worsening HF.

The DAPA-HF trial was a prospective, randomized, double-blind, placebo-controlled trial in patients with HFrEF, that assessed the efficacy and safety of the SGLT2 inhibitor dapagliflozin (10 mg once daily) added to the patient’s standard treatment. HF patients (n=4744 and ≥18 years) with a New York Heart Association (NYHA) functional class II-IV and LVEF ≤40% and optimally treated with pharmacological and device therapy, as well as a NT-proBNP level of ≥600 pg/mL (≥400 pg/mL when hospitalized for HF within the previous 12 months, or ≥900 pg/mL when experiencing atrial fibrillation/atrial flutter). The primary outcome was a composite of CV death or an episode of worsening HF defined as unexpected hospitalization due to HF or an urgent visit resulting in IV-therapy for HF. The secondary outcomes included the composite of CV death or HF hospitalization. For this analysis, the prespecified exploratory endpoint was a wider composite reflecting worsening HF including: 1) worsening HF leading to initiation of new oral treatment or intensification of oral therapy, 2) hospitalization for HF, 3) urgent HF hospital visit, 4) time to first occurrence of CV death. At study visits information on outpatient intensification of HF therapy was collected and completed on a specific case report form page. Median follow-up was 18.2 months.

Main results

  • Of all patients in the DAPA-HF trial, 604 (12.7%) patients had outpatient HF worsening resulting in intensification of oral therapy, 33 (0.7%) had an urgent visit to the hospital and received IV therapy, 549 (11.6%) were hospitalized due to HF worsening, and 500 (10.5%) died of CV causes.
  • Examining the first manifestation of HF worsening among all patients revealed that 1) 407 (8.6%) patients had an outpatient episode resulting in intensification of HF therapy, 2) 489 (10.3%) patients needed hospitalization due to HF, 3) 20 (0.4%) patients needed an urgent HF visit resulting in IV-therapy, and 4) 295 (6.2%) patients died of CV causes.
  • Dapagliflozin had a significant effect on the prespecified expanded 4-component composite outcome compared with placebo, with an HR of 0.73 (95% CI:0.65-0.82, P<0.0001).
  • Each single component of the expanded 4-component composite was significantly reduced by dapagliflozin compared with placebo: 1) for CV death HR was 0.82 (95% CI:0.69-0.98, P=0.029), 2) for hospitalization due to HF HR was 0.70 (95% CI:0.59-0.83, P<0.0001), 3) for urgent HF visit HR was 0.43 (95% CI:0.20-0.90, P=0.021), 4) for outpatient intensification of HF therapy HR was 0.74 (95% CI:0.63-0.87, P=0.0003).
  • Of all HFrEF patients who experienced a first outpatient worsening HF (n=407), 76.9% of patients had an intensification of diuretic therapy and 45.7% had an adjustment in their existing HF medication or started a new additional HF therapy. Patients on dapagliflozin who experienced a first outpatient HF worsening event were less frequently treated with an intensified diuretic for >4 weeks compared to placebo (9.0% vs. 11.9%,respectively; HR 0.72, 95% CI:0.61-0.87, P=0.0004). Also the addition of a new HF therapy in the patients receiving dapagliflozin was significantly less compared to the placebo group (5.5% vs. 7.6%, respectively; HR 0.70, 95% CI:0.56-0.88, P=0.002).
  • The number of patients needed to treat (NNT) with dapagliflozin to prevent one patient from experiencing an event was 16 for the expanded 4-component composite compared to 21 for the primary composite.
  • The adjusted risk of death in patients with a first non-fatal worsening HF event relative to patients experiencing no HF worsening was 6 fold higher (HR 6.21, 95% CI:5.07-7.62) following an HF hospitalization, 3 fold higher following an urgent visit to an hospital due to HF (HR 3.0, 95% CI:1.39-6.48), and approximately 3 fold higher following an outpatient episode of HF worsening (HR 2.67, 95% CI:20.3-3.52).

Conclusion

Episode of worsening HF in HFrEF patients in an outpatient setting and treated with intensive oral therapy was by far more common than patients hospitalized and treated with IV-therapy. Outpatient worsening HF was a prognostic marker of mortality and manifestations were reduced by 10 mg dapagliflozin treatment, daily, compared to placebo.

Outcome definition guidelines only include outpatient HF worsening events treated with IV-therapy However, the authors argue that because outpatient HF worsening events treated with oral therapy were more common than those treated with IV-therapy, and these events have the same prognostic outcome, outpatient worsening HF events should be considered for inclusion in the primary outcome of a future clinical trial.

References

1. Solomon SD, Dobson J, Pocock S, et al. Candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) investigators. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation. 2007;116:1482-7.

2. Ahmed A, Allman RM, Fonarow GC, et al. Incident heart failure hospitalization and subsequent mortality in chronic heart failure: a propensity-matched study. J Card Fail. 2008;14:211-8.

3. Wasfy JH, Zigler CM, Choirat C, Wang Y, Dominici F, Yeh RW. Readmission Rates After Passage of the Hospital Readmissions Reduction Program: A Pre-Post Analysis. Ann Intern Med. 2017; 166: 324-331.

4. Vidic A, Chibnall JT, Hauptman PJ. Heart failure is a major contributor to hospital readmission penalties. J Card Fail. 2015; 21: 134-7.

5. Hicks KA, Mahaffey KW, Mehran R, et al. Standardized Data Collection for Cardiovascular Trials Initiative (SCTI). 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials. J Am Coll Cardiol. 2018; 71: 1021-1034.

6. Skali H, Dwyer EM, Goldstein R, et al. Prognosis and response to therapy of first inpatient and outpatient heart failure event in a heart failure clinical trial: MADIT-CRT. Eur J Heart Fail. 2014;16:560-5.

7. Okumura N, Jhund PS, Gong J, et al. Importance of Clinical Worsening of Heart Failure Treated in the Outpatient Setting: Evidence From the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF). Circulation. 2016;133:2254-62.

8. Greene SJ, Mentz RJ, Felker GM. Outpatient Worsening Heart Failure as a Target for Therapy: A Review. JAMA Cardiol. 2018;3:252-

Find this article online at Circulation

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