Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER

Jawad H Butt; Toru Kondo; Mingming Yang; Pardeep S Jhund; Kieran F Docherty; Muthiah Vaduganathan; Brian L Claggett; Adrian F Hernandez; Carolyn S P Lam; Silvio E Inzucchi; Felipe A Martinez; Rudolf A de Boer; Mikhail N Kosiborod; Akshay S Desai; Lars Køber; Piotr Ponikowski; Marc S Sabatine; Sanjiv J Shah; Natalia Zaozerska; Ulrica Wilderäng; Olof Bengtsson; Scott D Solomon; John J V McMurray

doi:10.1093/eurheartj/ehad276

Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER

Jawad H Butt, Toru Kondo, Mingming Yang, Pardeep S Jhund, Kieran F Docherty, Muthiah Vaduganathan, Brian L Claggett, Adrian F Hernandez, Carolyn S P Lam, Silvio E Inzucchi, Felipe A Martinez, Rudolf A de Boer, Mikhail N Kosiborod, Akshay S Desai, Lars Køber, Piotr Ponikowski, Marc S Sabatine, Sanjiv J Shah, Natalia Zaozerska, Ulrica WilderängOlof Bengtsson, Scott D Solomon, John J V McMurray^*

^*Corresponding author for this work

Department of Cardiology

28 Citations (Scopus)

Abstract

AIMS: Because an increased risk of amputation with canagliflozin was reported in the CANVAS trials, there has been a concern about the safety of sodium-glucose cotransporter 2 inhibitors in patients with peripheral artery disease (PAD) who are at higher risk of amputation.

METHODS AND RESULTS: A patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the efficacy and safety of dapagliflozin in patients with heart failure (HF) with reduced, mildly reduced/preserved ejection fraction, respectively, was conducted. In both trials, the primary outcome was the composite of worsening HF or cardiovascular death, and amputation was a prespecified safety outcome. Peripheral artery disease history was available for 11 005 of the total 11 007 patients. Peripheral artery disease was reported in 809 of the 11 005 patients (7.4%). Median follow-up was 22 months (interquartile range 17-30). The rate of the primary outcome (per 100 person-years) was higher in PAD patients than that in non-PAD patients: 15.1 [95% confidence interval (CI) 13.1-17.3) vs. 10.6 (10.2-11.1]; adjusted hazard ratio 1.23 (95% CI 1.06-1.43). The benefit of dapagliflozin on the primary outcome was consistent in patients with [hazard ratio 0.71 (95% CI 0.54-0.94)] and without PAD [0.80 (95% CI 0.73-0.88)] (Pinteraction = 0.39). Amputations, while more frequent in PAD patients, were not more common with dapagliflozin, compared with placebo, irrespective of PAD status (PAD, placebo 4.2% vs. dapagliflozin 3.7%; no PAD, placebo 0.4% vs. dapagliflozin 0.4%) (Pinteraction = 1.00). Infection rather than ischaemia was the main trigger for amputation, even in patients with PAD.

CONCLUSION: The risk of worsening HF or cardiovascular death was higher in patients with PAD, as was the risk of amputation. The benefits of dapagliflozin were consistent in patients with and without PAD, and dapagliflozin did not increase the risk of amputation.

Original language	English
Journal	European Heart Journal
Volume	44
Issue number	24
Pages (from-to)	2170-2183
Number of pages	14
ISSN	0195-668X
DOIs	https://doi.org/10.1093/eurheartj/ehad276
Publication status	Published - 25 Jun 2023

Keywords

Diabetes Mellitus, Type 2/complications
Heart Failure/drug therapy
Humans
Peripheral Arterial Disease/drug therapy
Sodium-Glucose Transporter 2 Inhibitors/adverse effects
Stroke Volume
Heart failure with preserved ejection fraction
Amputation
Peripheral artery disease
Clinical trial
Heart failure with reduced ejection fraction

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10.1093/eurheartj/ehad276

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Butt, J. H., Kondo, T., Yang, M., Jhund, P. S., Docherty, K. F., Vaduganathan, M., Claggett, B. L., Hernandez, A. F., Lam, C. S. P., Inzucchi, S. E., Martinez, F. A., de Boer, R. A., Kosiborod, M. N., Desai, A. S., Køber, L., Ponikowski, P., Sabatine, M. S., Shah, S. J., Zaozerska, N., ... McMurray, J. J. V. (2023). Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER. European Heart Journal, 44(24), 2170-2183. https://doi.org/10.1093/eurheartj/ehad276

Butt, JH, Kondo, T, Yang, M, Jhund, PS, Docherty, KF, Vaduganathan, M, Claggett, BL, Hernandez, AF, Lam, CSP, Inzucchi, SE, Martinez, FA, de Boer, RA, Kosiborod, MN, Desai, AS, Køber, L, Ponikowski, P, Sabatine, MS, Shah, SJ, Zaozerska, N, Wilderäng, U, Bengtsson, O, Solomon, SD & McMurray, JJV 2023, 'Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER', European Heart Journal, vol. 44, no. 24, pp. 2170-2183. https://doi.org/10.1093/eurheartj/ehad276

@article{fb3776f0431f40e6b99145a877d3d8d5,

title = "Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER",

abstract = "AIMS: Because an increased risk of amputation with canagliflozin was reported in the CANVAS trials, there has been a concern about the safety of sodium-glucose cotransporter 2 inhibitors in patients with peripheral artery disease (PAD) who are at higher risk of amputation.METHODS AND RESULTS: A patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the efficacy and safety of dapagliflozin in patients with heart failure (HF) with reduced, mildly reduced/preserved ejection fraction, respectively, was conducted. In both trials, the primary outcome was the composite of worsening HF or cardiovascular death, and amputation was a prespecified safety outcome. Peripheral artery disease history was available for 11 005 of the total 11 007 patients. Peripheral artery disease was reported in 809 of the 11 005 patients (7.4\%). Median follow-up was 22 months (interquartile range 17-30). The rate of the primary outcome (per 100 person-years) was higher in PAD patients than that in non-PAD patients: 15.1 [95\% confidence interval (CI) 13.1-17.3) vs. 10.6 (10.2-11.1]; adjusted hazard ratio 1.23 (95\% CI 1.06-1.43). The benefit of dapagliflozin on the primary outcome was consistent in patients with [hazard ratio 0.71 (95\% CI 0.54-0.94)] and without PAD [0.80 (95\% CI 0.73-0.88)] (Pinteraction = 0.39). Amputations, while more frequent in PAD patients, were not more common with dapagliflozin, compared with placebo, irrespective of PAD status (PAD, placebo 4.2\% vs. dapagliflozin 3.7\%; no PAD, placebo 0.4\% vs. dapagliflozin 0.4\%) (Pinteraction = 1.00). Infection rather than ischaemia was the main trigger for amputation, even in patients with PAD.CONCLUSION: The risk of worsening HF or cardiovascular death was higher in patients with PAD, as was the risk of amputation. The benefits of dapagliflozin were consistent in patients with and without PAD, and dapagliflozin did not increase the risk of amputation.",

keywords = "Diabetes Mellitus, Type 2/complications, Heart Failure/drug therapy, Humans, Peripheral Arterial Disease/drug therapy, Sodium-Glucose Transporter 2 Inhibitors/adverse effects, Stroke Volume, Heart failure with preserved ejection fraction, Amputation, Peripheral artery disease, Clinical trial, Heart failure with reduced ejection fraction",

author = "Butt, \{Jawad H\} and Toru Kondo and Mingming Yang and Jhund, \{Pardeep S\} and Docherty, \{Kieran F\} and Muthiah Vaduganathan and Claggett, \{Brian L\} and Hernandez, \{Adrian F\} and Lam, \{Carolyn S P\} and Inzucchi, \{Silvio E\} and Martinez, \{Felipe A\} and \{de Boer\}, \{Rudolf A\} and Kosiborod, \{Mikhail N\} and Desai, \{Akshay S\} and Lars K{\o}ber and Piotr Ponikowski and Sabatine, \{Marc S\} and Shah, \{Sanjiv J\} and Natalia Zaozerska and Ulrica Wilder{\"a}ng and Olof Bengtsson and Solomon, \{Scott D\} and McMurray, \{John J V\}",

note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.",

year = "2023",

month = jun,

day = "25",

doi = "10.1093/eurheartj/ehad276",

language = "English",

volume = "44",

pages = "2170--2183",

journal = "European Heart Journal",

issn = "0195-668X",

publisher = "Oxford University Press",

number = "24",

}

TY - JOUR

T1 - Heart failure, peripheral artery disease, and dapagliflozin

T2 - a patient-level meta-analysis of DAPA-HF and DELIVER

AU - Butt, Jawad H

AU - Kondo, Toru

AU - Yang, Mingming

AU - Jhund, Pardeep S

AU - Docherty, Kieran F

AU - Vaduganathan, Muthiah

AU - Claggett, Brian L

AU - Hernandez, Adrian F

AU - Lam, Carolyn S P

AU - Inzucchi, Silvio E

AU - Martinez, Felipe A

AU - de Boer, Rudolf A

AU - Kosiborod, Mikhail N

AU - Desai, Akshay S

AU - Køber, Lars

AU - Ponikowski, Piotr

AU - Sabatine, Marc S

AU - Shah, Sanjiv J

AU - Zaozerska, Natalia

AU - Wilderäng, Ulrica

AU - Bengtsson, Olof

AU - Solomon, Scott D

AU - McMurray, John J V

PY - 2023/6/25

Y1 - 2023/6/25

N2 - AIMS: Because an increased risk of amputation with canagliflozin was reported in the CANVAS trials, there has been a concern about the safety of sodium-glucose cotransporter 2 inhibitors in patients with peripheral artery disease (PAD) who are at higher risk of amputation.METHODS AND RESULTS: A patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the efficacy and safety of dapagliflozin in patients with heart failure (HF) with reduced, mildly reduced/preserved ejection fraction, respectively, was conducted. In both trials, the primary outcome was the composite of worsening HF or cardiovascular death, and amputation was a prespecified safety outcome. Peripheral artery disease history was available for 11 005 of the total 11 007 patients. Peripheral artery disease was reported in 809 of the 11 005 patients (7.4%). Median follow-up was 22 months (interquartile range 17-30). The rate of the primary outcome (per 100 person-years) was higher in PAD patients than that in non-PAD patients: 15.1 [95% confidence interval (CI) 13.1-17.3) vs. 10.6 (10.2-11.1]; adjusted hazard ratio 1.23 (95% CI 1.06-1.43). The benefit of dapagliflozin on the primary outcome was consistent in patients with [hazard ratio 0.71 (95% CI 0.54-0.94)] and without PAD [0.80 (95% CI 0.73-0.88)] (Pinteraction = 0.39). Amputations, while more frequent in PAD patients, were not more common with dapagliflozin, compared with placebo, irrespective of PAD status (PAD, placebo 4.2% vs. dapagliflozin 3.7%; no PAD, placebo 0.4% vs. dapagliflozin 0.4%) (Pinteraction = 1.00). Infection rather than ischaemia was the main trigger for amputation, even in patients with PAD.CONCLUSION: The risk of worsening HF or cardiovascular death was higher in patients with PAD, as was the risk of amputation. The benefits of dapagliflozin were consistent in patients with and without PAD, and dapagliflozin did not increase the risk of amputation.

AB - AIMS: Because an increased risk of amputation with canagliflozin was reported in the CANVAS trials, there has been a concern about the safety of sodium-glucose cotransporter 2 inhibitors in patients with peripheral artery disease (PAD) who are at higher risk of amputation.METHODS AND RESULTS: A patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the efficacy and safety of dapagliflozin in patients with heart failure (HF) with reduced, mildly reduced/preserved ejection fraction, respectively, was conducted. In both trials, the primary outcome was the composite of worsening HF or cardiovascular death, and amputation was a prespecified safety outcome. Peripheral artery disease history was available for 11 005 of the total 11 007 patients. Peripheral artery disease was reported in 809 of the 11 005 patients (7.4%). Median follow-up was 22 months (interquartile range 17-30). The rate of the primary outcome (per 100 person-years) was higher in PAD patients than that in non-PAD patients: 15.1 [95% confidence interval (CI) 13.1-17.3) vs. 10.6 (10.2-11.1]; adjusted hazard ratio 1.23 (95% CI 1.06-1.43). The benefit of dapagliflozin on the primary outcome was consistent in patients with [hazard ratio 0.71 (95% CI 0.54-0.94)] and without PAD [0.80 (95% CI 0.73-0.88)] (Pinteraction = 0.39). Amputations, while more frequent in PAD patients, were not more common with dapagliflozin, compared with placebo, irrespective of PAD status (PAD, placebo 4.2% vs. dapagliflozin 3.7%; no PAD, placebo 0.4% vs. dapagliflozin 0.4%) (Pinteraction = 1.00). Infection rather than ischaemia was the main trigger for amputation, even in patients with PAD.CONCLUSION: The risk of worsening HF or cardiovascular death was higher in patients with PAD, as was the risk of amputation. The benefits of dapagliflozin were consistent in patients with and without PAD, and dapagliflozin did not increase the risk of amputation.

KW - Diabetes Mellitus, Type 2/complications

KW - Heart Failure/drug therapy

KW - Humans

KW - Peripheral Arterial Disease/drug therapy

KW - Sodium-Glucose Transporter 2 Inhibitors/adverse effects

KW - Stroke Volume

KW - Heart failure with preserved ejection fraction

KW - Amputation

KW - Peripheral artery disease

KW - Clinical trial

KW - Heart failure with reduced ejection fraction

UR - https://www.scopus.com/pages/publications/85164044220

U2 - 10.1093/eurheartj/ehad276

DO - 10.1093/eurheartj/ehad276

M3 - Journal article

C2 - 37220172

SN - 0195-668X

VL - 44

SP - 2170

EP - 2183

JO - European Heart Journal

JF - European Heart Journal

IS - 24

ER -

Heart failure, peripheral artery disease, and dapagliflozin: a patient-level meta-analysis of DAPA-HF and DELIVER

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