Meeting NewsPerspective

DAPA-HF: Dapagliflozin’s HF benefits consistent regardless of age, symptom severity

Mikhail Kosiborod

PHILADELPHIA — Treatment with the SGLT2 inhibitor dapagliflozin reduced risk for CV death and worsening HF across a broad spectrum of age, independent of symptomatic impairment at baseline, according to two new post-hoc analyses of the DAPA-HF trial presented at the American Heart Association Scientific Sessions.

The analyses also showed dapagliflozin (Farxiga, AstraZeneca) improved symptom burden, physical function and quality of life in patients with HF with reduced ejection fraction.

“Dapagliflozin not only reduced CV death and hospitalizations, but also significantly improved symptoms, physical limitations and quality of life in patients with heart failure with reduced ejection fraction,” Mikhail Kosiborod, MD, FACC, FAHA, cardiologist at Saint Luke’s Mid America Heart Institute and professor of medicine at the University of Missouri-Kansas City School of Medicine, told Healio. “These effects were substantial and clinically important.”

A key secondary objective of DAPA-HF was to examine the effects of dapagliflozin 10 mg on the 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score, Kosiborod said during a press conference. The KCCQ measures four clinical domains, including frequency and severity of symptoms, physical limitation, quality of life and social limitation. Scores range from 0 to 100, with higher scores reflecting better health status.

For the post hoc analysis, the researchers analyzed data from 4,443 participants with HFrEF and an available KCCQ score at baseline (median score, 77.1), assessing KCCQ score again at 4 and 8 months. Researchers stratified participants by KCCQ total symptom score and used Cox proportional hazard models to examine the effects of dapagliflozin on KCCQ total symptom score, clinical summary score and overall summary score. Responder analyses were used to compare the proportions of participants assigned dapagliflozin vs. placebo with a clinically meaningful change in KCCQ at 8 months.

Consistent effects

Researchers observed consistent effects of dapagliflozin compared with placebo across KCCQ total symptom score tertiles for reducing the primary endpoint of CV death or worsening HF, with HRs of 0.7 (95% CI, 0.57-0.86) in the lowest tertile, 0.77 (95% CI, 0.61-0.98) in the middle tertile and 0.62 (95% CI, 0.46-0.83) in the highest tertile. At 8 months, participants treated with dapagliflozin experienced a greater improvement in mean KCCQ total symptom score (mean, 2.8 points), clinical summary score (mean, 2.5 points) and overall summary score (mean, 2.3 points; P < .0001 for all) compared with those assigned placebo, Kosiborod said.

Additionally, fewer participants treated with dapagliflozin experienced a deterioration in KCCQ total symptom score compared with those in the placebo group (OR = 0.84; 95% CI, 0.78–0.9) and more participants experienced small (less than 10 points; OR = 1.15; 95% CI, 1.08-1.23), moderate (10 to 19 points; OR = 1.15; 95% CI, 1.08-1.22) and large (20 or more points; OR = 1.14; 95% CI, 1.07-1.22) improvements.

The findings suggest a “very consistent message,” Kosiborod said, adding that the numbers needed to treat range between 12 and 18 patients compared with placebo after just 8 months of treatment.

“In our view, dapagliflozin offers a new approach, not just for reducing death from hospitalizations, but improving symptoms, physical limitations and quality of life in patients with HF with reduced ejection fraction,” Kosiborod said during a presentation.

Effects by age

John J.V. McMurray

In a separate analysis, John J.V. McMurray, MD, professor of cardiology at the Institute of Cardiovascular and Medical Sciences at University of Glasgow in Scotland, and colleagues assessed data from 4,474 DAPA-HF participants (mean age, 66 years) stratified into four age groups: aged less than 55 years (n = 636), aged 55 to 64 years (n = 1,242), aged 65 to 74 years (n = 1,717) and aged at least 75 years (n = 1,149). The primary outcome was the composite of an episode of worsening HF or CV death.

The researchers found that dapagliflozin reduced worsening HF events and death across all age categories, with larger absolute benefits in older patients. Compared with placebo, researchers found that the rate of the primary outcome per 100 person-years across the four age groups was 13.6 (95% CI 10.4-17.9), 15.7 (13.2-18.7), 15.1 (13.1-17.5) and 18 (15.2-21.4), respectively, corresponding with HRs of 0.87 (95% CI, 0.6-1.28), 0.71 (95% CI, 0.55-0.93), 0.76 (95% CI, 0.61-0.95), and 0.68 (95% CI, 0.53-0.88).

Consistent benefits were observed for the components of the primary outcome, all-cause mortality and symptoms, he said.

McMurray noted that, although adverse events and study drug discontinuation increased with age, neither was significantly more common with dapagliflozin in any age group. There were no between-group differences in tolerability or safety events, even among the oldest participants.

Felipe A. Martinez, MD, professor of medicine, Cordoba National University in Argentina, said during a presentation that the absolute benefits observed among older participants were large because they were at higher risk than younger participants.

“Dapagliflozin offers a new approach to the treatment of HF with reduced ejection fraction irrespective of age,” Martinez said.

‘Early, sustained’ benefits

In a discussant presentation, Carolyn S.P. Lam, MBBS, PhD, FRCP, FAMS, FESC, FACC, senior consultant cardiologist and director of the clinical and translational research office at the National Heart Centre Singapore, said the new DAPA-HF quality of life analyses demonstrate dapagliflozin improves HF-related health status, with benefits that are early, sustained and clinically meaningful on an individual patient level. The findings also serve as a “confirmation and extension” of the DEFINE-HF study, Lam said.

As Healio previously reported, DEFINE-HF demonstrated that dapagliflozin was associated with clinically meaningful improvements in HF-related health status or N-terminal pro-B type natriuretic peptide at 12 weeks in participants with HF with reduced ejection fraction with or without diabetes.

“These data are really critical,” Lam said during a press conference. “There is emerging regulatory importance of patient-reported outcomes in HF. But, there are important remaining questions. First, these are post-hoc analyses of a single trial, although a hugely successful trial. Are these effects drug-specific or a class effect?”

Lam said the patient-reported outcomes data can potentially aid in treatment selection and sequencing, though researchers must determine which tools and domains to use.

“Dapagliflozin now fulfils all three goals in HF management: Patients die less, they are hospitalized less, and feel better, and this is regardless of age or diabetes status,” Lam said. “If these data are confirmed in other SGLT inhibition and HF trials, this really suggests that SGLT2 inhibition may be the next foundational pillar of HFrEF treatment.” – by Regina Schaffer

References:

Kosiborod M, et al.

Martinez FA, et al. Late Breaking Science V: Challenges in heart failure management. Both presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.

Kosiborod M, et al. Circulation. 2019; doi:10.1161/CIRCULATIONAHA.119.044138.

Martinez FA, et al. Circulation. 2019; doi:10.1161/CIRCULATIONAHA.119.044133R1.

Disclosure: AstraZeneca funded DAPA-HF. Kosiborod reports he has received grants, honoraria and other research support from Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, Eli Lilly, GlaxoSmithKline, Glytec, Janssen, Merck, Novartis, Novo Nordisk and Sanofi. Lam reports she has received advisory board fees, consultant fees or research support from Abbott Diagnostics, Applied Therapeutics, AstraZeneca, Bayer, Biofourmis, Boehringer Ingelheim, Boston Scientific, Corpus, Corvia, Darma, JanaCare, Janssen, Medtronic, Menarini, MyoKardia, Novartis, Novo Nordisk, Radcliffe Group, Roche Diagnostics, Stealth BioTherapeutics and Vifor. Please see the study for all other authors’ relevant financial disclosures.

Mikhail Kosiborod

PHILADELPHIA — Treatment with the SGLT2 inhibitor dapagliflozin reduced risk for CV death and worsening HF across a broad spectrum of age, independent of symptomatic impairment at baseline, according to two new post-hoc analyses of the DAPA-HF trial presented at the American Heart Association Scientific Sessions.

The analyses also showed dapagliflozin (Farxiga, AstraZeneca) improved symptom burden, physical function and quality of life in patients with HF with reduced ejection fraction.

“Dapagliflozin not only reduced CV death and hospitalizations, but also significantly improved symptoms, physical limitations and quality of life in patients with heart failure with reduced ejection fraction,” Mikhail Kosiborod, MD, FACC, FAHA, cardiologist at Saint Luke’s Mid America Heart Institute and professor of medicine at the University of Missouri-Kansas City School of Medicine, told Healio. “These effects were substantial and clinically important.”

A key secondary objective of DAPA-HF was to examine the effects of dapagliflozin 10 mg on the 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score, Kosiborod said during a press conference. The KCCQ measures four clinical domains, including frequency and severity of symptoms, physical limitation, quality of life and social limitation. Scores range from 0 to 100, with higher scores reflecting better health status.

For the post hoc analysis, the researchers analyzed data from 4,443 participants with HFrEF and an available KCCQ score at baseline (median score, 77.1), assessing KCCQ score again at 4 and 8 months. Researchers stratified participants by KCCQ total symptom score and used Cox proportional hazard models to examine the effects of dapagliflozin on KCCQ total symptom score, clinical summary score and overall summary score. Responder analyses were used to compare the proportions of participants assigned dapagliflozin vs. placebo with a clinically meaningful change in KCCQ at 8 months.

Consistent effects

Researchers observed consistent effects of dapagliflozin compared with placebo across KCCQ total symptom score tertiles for reducing the primary endpoint of CV death or worsening HF, with HRs of 0.7 (95% CI, 0.57-0.86) in the lowest tertile, 0.77 (95% CI, 0.61-0.98) in the middle tertile and 0.62 (95% CI, 0.46-0.83) in the highest tertile. At 8 months, participants treated with dapagliflozin experienced a greater improvement in mean KCCQ total symptom score (mean, 2.8 points), clinical summary score (mean, 2.5 points) and overall summary score (mean, 2.3 points; P < .0001 for all) compared with those assigned placebo, Kosiborod said.

Additionally, fewer participants treated with dapagliflozin experienced a deterioration in KCCQ total symptom score compared with those in the placebo group (OR = 0.84; 95% CI, 0.78–0.9) and more participants experienced small (less than 10 points; OR = 1.15; 95% CI, 1.08-1.23), moderate (10 to 19 points; OR = 1.15; 95% CI, 1.08-1.22) and large (20 or more points; OR = 1.14; 95% CI, 1.07-1.22) improvements.

PAGE BREAK

The findings suggest a “very consistent message,” Kosiborod said, adding that the numbers needed to treat range between 12 and 18 patients compared with placebo after just 8 months of treatment.

“In our view, dapagliflozin offers a new approach, not just for reducing death from hospitalizations, but improving symptoms, physical limitations and quality of life in patients with HF with reduced ejection fraction,” Kosiborod said during a presentation.

Effects by age

John J.V. McMurray

In a separate analysis, John J.V. McMurray, MD, professor of cardiology at the Institute of Cardiovascular and Medical Sciences at University of Glasgow in Scotland, and colleagues assessed data from 4,474 DAPA-HF participants (mean age, 66 years) stratified into four age groups: aged less than 55 years (n = 636), aged 55 to 64 years (n = 1,242), aged 65 to 74 years (n = 1,717) and aged at least 75 years (n = 1,149). The primary outcome was the composite of an episode of worsening HF or CV death.

The researchers found that dapagliflozin reduced worsening HF events and death across all age categories, with larger absolute benefits in older patients. Compared with placebo, researchers found that the rate of the primary outcome per 100 person-years across the four age groups was 13.6 (95% CI 10.4-17.9), 15.7 (13.2-18.7), 15.1 (13.1-17.5) and 18 (15.2-21.4), respectively, corresponding with HRs of 0.87 (95% CI, 0.6-1.28), 0.71 (95% CI, 0.55-0.93), 0.76 (95% CI, 0.61-0.95), and 0.68 (95% CI, 0.53-0.88).

Consistent benefits were observed for the components of the primary outcome, all-cause mortality and symptoms, he said.

McMurray noted that, although adverse events and study drug discontinuation increased with age, neither was significantly more common with dapagliflozin in any age group. There were no between-group differences in tolerability or safety events, even among the oldest participants.

Felipe A. Martinez, MD, professor of medicine, Cordoba National University in Argentina, said during a presentation that the absolute benefits observed among older participants were large because they were at higher risk than younger participants.

“Dapagliflozin offers a new approach to the treatment of HF with reduced ejection fraction irrespective of age,” Martinez said.

‘Early, sustained’ benefits

In a discussant presentation, Carolyn S.P. Lam, MBBS, PhD, FRCP, FAMS, FESC, FACC, senior consultant cardiologist and director of the clinical and translational research office at the National Heart Centre Singapore, said the new DAPA-HF quality of life analyses demonstrate dapagliflozin improves HF-related health status, with benefits that are early, sustained and clinically meaningful on an individual patient level. The findings also serve as a “confirmation and extension” of the DEFINE-HF study, Lam said.

PAGE BREAK

As Healio previously reported, DEFINE-HF demonstrated that dapagliflozin was associated with clinically meaningful improvements in HF-related health status or N-terminal pro-B type natriuretic peptide at 12 weeks in participants with HF with reduced ejection fraction with or without diabetes.

“These data are really critical,” Lam said during a press conference. “There is emerging regulatory importance of patient-reported outcomes in HF. But, there are important remaining questions. First, these are post-hoc analyses of a single trial, although a hugely successful trial. Are these effects drug-specific or a class effect?”

Lam said the patient-reported outcomes data can potentially aid in treatment selection and sequencing, though researchers must determine which tools and domains to use.

“Dapagliflozin now fulfils all three goals in HF management: Patients die less, they are hospitalized less, and feel better, and this is regardless of age or diabetes status,” Lam said. “If these data are confirmed in other SGLT inhibition and HF trials, this really suggests that SGLT2 inhibition may be the next foundational pillar of HFrEF treatment.” – by Regina Schaffer

References:

Kosiborod M, et al.

Martinez FA, et al. Late Breaking Science V: Challenges in heart failure management. Both presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2019; Philadelphia.

Kosiborod M, et al. Circulation. 2019; doi:10.1161/CIRCULATIONAHA.119.044138.

Martinez FA, et al. Circulation. 2019; doi:10.1161/CIRCULATIONAHA.119.044133R1.

Disclosure: AstraZeneca funded DAPA-HF. Kosiborod reports he has received grants, honoraria and other research support from Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, Eli Lilly, GlaxoSmithKline, Glytec, Janssen, Merck, Novartis, Novo Nordisk and Sanofi. Lam reports she has received advisory board fees, consultant fees or research support from Abbott Diagnostics, Applied Therapeutics, AstraZeneca, Bayer, Biofourmis, Boehringer Ingelheim, Boston Scientific, Corpus, Corvia, Darma, JanaCare, Janssen, Medtronic, Menarini, MyoKardia, Novartis, Novo Nordisk, Radcliffe Group, Roche Diagnostics, Stealth BioTherapeutics and Vifor. Please see the study for all other authors’ relevant financial disclosures.

    Perspective
    Richard E. Pratley

    Richard E. Pratley

    The prespecified subanalysis of the DAPA-HF study by age group adds significant insight into the treatment of HF. HF is strongly associated with age in both patients with diabetes and those without. Prior studies of SGLT2 inhibitors have indicated that the CV benefit of these drugs is preserved in older individuals with type 2 diabetes. This analysis indicates that the benefit of dapagliflozin to reduce the primary endpoint of death or worsening HF was preserved in older individuals. Over 1,000 patients above the age of 75 years were included in this analysis, therefore, the data are quite robust. Notably, although adverse events were common among older individuals in this trial, as expected, they were not more common with dapagliflozin-treated patients relative to those receiving usual care. Thus, these new analyses indicate that dapagliflozin can be safely used in older patients with HF to reduce their risk for death or worsening HF.

    • Richard E. Pratley, MD
    • Samuel E. Crockett Chair in Diabetes Research
      Director of Research and Education Florida Hospital Diabetes Institute
      Senior Investigator and Diabetes Program Head
      Translational Research Institute for Metabolism and Diabetes
      Orlando, Florida

    Disclosures: Pratley reports he receives institutional research grants from Novo Nordisk; speaker and consultancy fees (to his institution) from AstraZeneca and Takeda; consultant fees (to his institution) from Boehringer Ingelheim, Eisai, Eli Lilly, GlaxoSmithKline, Hanmi Pharmaceutical Co., Janssen, Ligand Pharmaceuticals, Merck, Novo Nordisk and Pfizer; and research grants from Eli Lilly, Gilead Sciences, Lexicon Pharmaceutical, Ligand Pharmaceuticals, Merck, Novo Nordisk, Sanofi Aventis U.S. and Takeda.

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