• Heart Failure Patients Feel Better Soon After Starting SGLT-2 Inhibitor

    DEFINE-HF trial not a slam dunk for dapagliflozin, however

    PHILADELPHIA -- The effects of SGLT-2 inhibition on heart failure symptoms may be observed within months of starting treatment, according to the DEFINE-HF trial presented here.

    Meaningful improvement in health status or NT-proBNP -- at least a 5-point increase in Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary scores or 20% drop in NT-proBNP -- favored dapagliflozin (Farxiga) over placebo (OR 1.8, 95% CI 1.0-3.1), with a number needed to treat of 10.

    Results were consistent across subgroups, including patients with and without type 2 diabetes, Kosiborod said at a late-breaking trial session at the Heart Failure Society of America meeting.

    The KCCQ sub-domains of total symptom score, physical limitation score, and quality of life score showed dapagliflozin recipients improving over placebo with widening advantage from 6 weeks to 12 weeks. Only the KCCQ social limitation score remained indistinguishable from placebo.

    "All of these differences, I would argue, are clinically meaningful and statistically significant," Kosiborod emphasized.

    Although dapagliflozin treatment did not lower NT-proBNP levels over 12 weeks in DEFINE-HF, the overall literature points to the drug's "sustained health status benefits," the presenter said, given that dapagliflozin reduced cardiovascular death or worsening heart failure and improved KCCQ scores at 8 months in the recently-reported DAPA-HF trial.

    "It depends on your philosophy," Kosiborod responded, noting that the trial started in 2014, well before the notion that SGLT2-inhibition would work in heart failure.

    The investigator argued that the discrepancy in findings between NT-proBNP and the responder analysis can be attributed to an unfavorable noise-signal ratio. "I think it's very clear that these are not just simple diuretics," he told the audience.

    Kosiborod's group conducted the double-blind trial at 26 sites in 16 U.S. states.

    Trial participants were people with heart failure with reduced ejection fraction (HFrEF) already on optimal medical and device therapy. Patients were enrolled with New York Heart Association Class II and III symptoms and NT-proBNP at least 400 pg/mL (or BNP exceeding 100 pg/mL).

     

    After screening, investigators randomized 263 people 1:1 to dapagliflozin or placebo. Assigned treatments were stopped at week 12 and study participants asked for a safety visit to the office at week 13.

    Baseline characteristics of the cohort were "typical of a chronic HFrEF patient" and similar between arms: average age around 61 years; 73% men; more than half with ischemic heart disease, more than 60% with type 2 diabetes; ejection fraction around 26%; and two-thirds with New York Heart Association Class II symptoms.

    Notably, about 40% of the group was African American, a demographic that is usually underrepresented.

    As for background medications, the majority of the study group was on beta-blockers, mineralocorticoid receptor antagonists, loop diuretics, and ACE inhibitors or angiotensin receptor blockers (the dapagliflozin arm was especially likely to be on beta-blockers and anticoagulants).

    Kosiborod's team linked SGLT-2 inhibition to numerical but non-significant improvements in BNP, 6-minute walk test, hemoglobin A1c, weight, and systolic blood pressure.

    An audience member questioned the lack of effect on the 6-minute walk test with the improved KCCQ scores.

    One explanation is that KCCQ gives patients a 2-week recall period whereas the 6-minute walk test reflects just one point in time how the patient feels and how hard the study coordinator feels like pushing him or her, Kosiborod responded. Moreover, KCCQ is more specific for heart failure, he added.

     

    DEFINE-HF was funded by AstraZeneca.

    Kosiborod disclosed receiving research grants from and/or having personal ties to AstraZeneca, Boehringer Ingelheim, Amgen, Novo Nordisk, Sanofi, Applied Therapeutics, Bayer, Merck, Janssen, and Novartis.

    Source:

    HFSA

    Source Reference: Kosiborod M "Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: the DEFINE-HF trial" HFSA 2019.

     


    Read the original article on Medpage Today: Heart Failure Patients Feel Better Soon After Starting SGLT-2 Inhibitor

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