DAPA-HF: Dapagliflozin also good for heart failure patients without diabetes, of any age, or any health status

In heart failure patients with reduced ejection fraction (HFrEF), dapagliflozin in addition to standard therapy reduced the risk of worsening cardiovascular (CV) events and CV death while simultaneously improving symptoms. This benefit was seen in patients both with and without type 2 diabetes mellitus (T2DM), across all age groups, and without association to the health status of the patient at enrolment.

The main results of DAPA-HF trial were presented by Prof. John J. McMurray (Cardiovascular Research Centre, Scotland) [1]. The goal of this phase 3, randomised, double-blinded trial was to evaluate 10 mg/day dapagliflozin (a sodium-glucose cotransporter 2 [SGLT2] inhibitor) + standard therapy versus placebo + standard therapy in HFrEF patients. Specifically, investigators wanted to determine whether adverse outcomes could be prevented in non-diabetic patients in addition to patients with T2DM. The results were recently published in the New England Journal of Medicine [2]. Two additional prespecified sub-analyses, looking at age and health status, were also presented at the AHA Scientific Sessions [3,4].

The primary outcome was the composite of CV death, hospitalisation for heart failure, or urgent heart failure visit. Key secondary outcomes were separate evaluation of CV death, hospitalisation for heart failure, and worsening of renal function.

In total, 4,744 HFrEF patients with and without T2DM were enrolled with a median follow-up of 18.2 months. Primary outcome events occurred in 16.3% of the dapagliflozin group compared with 21.2% of the placebo group (P<0.001), which translated to a reduction of 26% for the combined endpoint of CV death and worsening of heart failure, alongside standard of care (see Table).

Table: Relative benefit of dapagliflozin as compared with placebo in patients with and without type 2 diabetes mellitus



HR, hazard ratio; T2DM, type 2 diabetes mellitus.

The DAPA-HF cohort included 2,139 patients with T2DM (45%) and 2,605 without T2DM. Those with T2DM had a 21% reduction in CV death with dapagliflozin versus placebo, while the reduction was 15% in patients without diabetes. The relative benefit was reversed in worsening of heart failure: among patients with T2DM, there was a 23% reduction in events versus placebo, while there was a 38% reduction in heart failure events among those without diabetes.

Prof. Felipe A. Martinez (National University of Córdoba, Spain) presented a sub-analysis aimed to examine the effects of age on response to dapagliflozin versus placebo in the DAPA-HF cohort, which spanned the ages of 22-94 years [3]. The benefits of dapagliflozin were evident across all age groups when compared with placebo: 636 patients were <55 years old (13.4%; HR 0.87; 95% CI 0.60-1.28); 1,242 were ages 55-64 (26.2%; HR 0.71;95% CI 0.55-0.93); 1,717 were ages 65-74 (36.2 %; HR 0.76; 95% CI 0.61-0.95); and 1,149 were >75 years (24.2%; HR 0.68; 95% CI 0.53-0.88). The interaction between age and response was not significant (P_interaction=0.76). Results showed that the rate of the primary outcome –a composite of an episode of worsening heart failure or CV death– in each age group in the placebo group was 13.6%, 15.7%, 15.1%, and 18.0%, respectively, versus the dapagliflozin group: 11.8%, 11.4%, 11.4%, and 12.6, respectively [5]. Prof. Martinez said that "dapagliflozin was well tolerated, with no significant difference between dapagliflozin and placebo in any age group,” and that the effects were consistent "both in terms of efficacy and safety." The investigators concluded that dapagliflozin has substantial clinical benefits in older as well as younger patients.

In a separate analysis of the DAPA-HF cohort, presented by Prof. Mikhail N. Kosiborod (Saint Luke's Mid America Heart Institute, USA), dapagliflozin was compared with placebo based on health status as determined by the Kansas City Cardiomyopathy Questionnaire (KCCQ) [4,6]. Data was available for 4,443 patients. Results showed that dapagliflozin versus placebo was associated with a 2.3-point increase in KCCQ overall summary score from baseline to 8 months (P<0.0001). However, dapagliflozin benefits were consistent across all tertiles of KCCQ total symptom scores: lowest tertile (HR 0.70; 95% CI 0.57-0.86), middle tertile (HR 0.77; 95% CI 0.61-0.98), and highest tertile (HR 0.62; 95% CI 0.46-0.83), with no significant association with any of the 3 tertiles individually (P_{heterogeneity}=0.52).

In conclusion, dapagliflozin was beneficial for symptomatic HFrEF patients and was associated with a reduction in CV deaths and heart failure events and improvement in symptoms. Age, diabetes, and baseline health status did not influence the benefit of dapagliflozin. There were no safety signals of concern. These trials will likely change the practice of treating patients with HFrEF with dapagliflozin.

 

1. 
   
   1. McMurray JJ, et al. The dapagliflozin and prevention of adverse-outcomes in heart failure trial (DAPA-HF): results in non-diabetic patients. LBS.05, AHA Scientific Sessions 2019, 14-18 November, Philadelphia, USA.
   2. McMurray JJ, et al. DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 Nov 21;381(21):1995-2008.
   3. Martinez FA, et al. DAPA-HF- Effect of treatment based on age in the dapagliflozin and prevention of adverse-outcomes in heart failure. LBS.05, AHA Scientific Sessions 2019, 14-18 November, Philadelphia, USA.
   4. Kosiborod MN, et al. DAPA-HF- Effect of treatment measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the dapagliflozin and prevention of adverse-outcomes in heart failure. LBS.05, AHA Scientific Sessions 2019, 14-18 November, Philadelphia, USA.
   5. Martinez FA, et al. Efficacy and Safety of Dapagliflozin in Heart Failure With Reduced Ejection Fraction According to Age. Circulation. 2020;141:100–111.
   6. Kosiborod MN, et al. Effects of Dapagliflozin on Symptoms, Function, and Quality of Life in Patients With Heart Failure and Reduced Ejection Fraction: Results From the DAPA-HF Trial. Circulation. 2020 Jan 14;141(2):90-99.

 



Posted on 26 February 202017 May 2024