Figure 1
PRISMA Flow Chart of Dapagliflozin in Patients with Heart Failure.
Table 1
Summary of the Included Studies.
| STUDY | POPULATION | INTERVENTION | CONTROL | OUTCOMES | SOURCE OF FUNDING |
|---|---|---|---|---|---|
| Ibrahim 2020 | Patients with T2DM admitted with decompensated HFrEF | Dapagliflozin 10 mg with recommended therapy. | Recommended therapy | Weight loss and dyspnea improvement. | The authors reported receiving no fund for this study |
| McMurray 2019 | Patients with HFrEF | Dapagliflozin (10 mg once daily) with recommended therapy. | Placebo with recommended therapy. | The primary outcome: a composite of worsening HF or CV death. The secondary outcomes: 1) a composite of hospitalization for HF or CV death; 2) the total number of hospitalizations for HF and CV deaths; 3) the change in the total symptom score on the KCCQ; 4) a composite of worsening renal function; and 5) death from any cause. | AstraZeneca |
| McMurray 2021 | Patients with CKD, with and without type 2 diabetes, with or without HF. | Dapagliflozin 10 mg | Placebo | The primary outcome: a composite of the time to the first occurrence of any of the following: 50% decline in eGFR, onset of ESKD, or kidney/CV death. Secondary outcomes were: 1) a kidney composite outcome (primary endpoint minus CV death); 2) a CV composite outcome consisting of HF hospitalization or death from CV causes; 3) death from any cause; 4) time-to-first HF hospitalization; and 5) total number of HF hospitalizations. | AstraZeneca |
| Nassif 2019 | Patients with HFrEF | Dapagliflozin 10 mg daily in addition to guideline directed standard of care therapy | Placebo in addition to guideline directed standard of care therapy | Primary end points were (1) Mean NT-proBNP and (2) a composite of the proportion of patients that achieved a meaningful improvement in health status (≥5-point increase in KCCQ-OS) or (≥20% decrease in NT-proBNP). Key secondary end points included proportion of patients with meaningful change in KCCQ, and NT-proBNP at each time point, mean BNP and proportion of patients with meaningful change in BNP, functional status based on 6-minute walk test, change in weight, systolic BP and HbA1c. Exploratory end points included a composite of hospitalization for HF or urgent HF visits. | AstraZeneca |
| Nassif 2021 | Patients with HFpEF | Dapagliflozin | Placebo. | Primary endpoint is change in KCCQ-CS. Secondary endpoints included the 6MWT, KCCQ-OS, clinically meaningful changes in KCCQ-CS and -OS, and changes in weight, natriuretic peptides, glycated hemoglobin and systolic blood pressure Exploratory clinical endpoints: HF hospitalizations or urgent HF visits. | AstraZeneca |
| Palau 2022 | Stable patients with HFrEF | Dapagliflozin | Placebo | The primary outcome: a change in peakVO2 at 1 and 3 months. The secondary outcomes: 1) changes at 1 and 3 months in 6MWT distance; 2) quality of life (MLHFQ); and 3) echocardiographic parameters (diastolic function, left chamber volumes, and left ventricular EF). | Grant from AstraZeneca, Clinical Research and Clinical Trials Unit including Health Research Institute, Spanish Clinical Research Network, and CIBER Cardiovascular |
| Singh 2020 | Patients with T2DM and HFrEF | Dapagliflozin 10 mg daily plus usual therapy | Placebo plus usual therapy | The primary outcome: change in LVESV. The secondary outcomes: 1) LVEDV; 2) LVMI; 3) LVEF; and 4) a range of clinical and biochemical markers of HF. | Grant from the European Foundation for the Study of Diabetes, Clinical Diabetes Research Program in Macrovascular Complications of Diabetes. Other support by National Health Service Education for Scotland/Chief Scientist Office Post- Doctoral Clinical Lectureship and the British Heart Foundation |
| Solomon 2022 | Patients with HFpEF | Dapagliflozin (10 mg once daily) plus usual therapy | Placebo plus usual therapy | The primary outcome: a composite of worsening HF or CV death. The Secondary outcomes: 1) the total number of worsening HF events and CV deaths; 2) the change in the total symptom score on the KCCQ; 3) CV death; and 4) death from any cause. | AstraZeneca |
| Wiviott 2019 | Patients with T2DM who had or were at risk for ASCVD. | Dapagliflozin | Placebo | The primary safety outcome was a composite of major adverse cardiovascular events, defined as CV death, MI, or ischemic stroke. The primary efficacy outcomes were MACE, and a composite of CV death or hospitalization for HF. The secondary efficacy outcomes were a renal composite (≥40% decrease in eGFR to <60 ml/minute/1.73 m2 of body surface area, new ESKD, or death from renal or CV causes) and death from any cause. | AstraZeneca and Bristol-Myers Squibb |
Table 2
Baseline Characteristics of the Patients in the Included Studies.
| STUDY | STUDY GROUPS (N) | HF AT BASELINE | AGE | FEMALE (%) | NYHA (%) | IHD (%) | DM (%) | BASELINE LVEF | BASELINE NT PROBNP PG/ML | PRIOR CV THERAPY (%) |
|---|---|---|---|---|---|---|---|---|---|---|
| Ibrahim 2020 | Dapagliflozin + Standard therapy (50) | 50 | 62.02 ± 8.8 | 22 (44) | NR | NR | 50 (100) | 32.54 ± 2.99 | NR | ACE-I: 37 (74) ARBs: 9 (18) ARNI: 4 (8) BBs: 3 (6) Digitalis: 18 (36) MRAs: 41 (82) Thiazide: 5 (10) |
| Standard therapy (50) | 50 | 60.64 ± 9.9 | 24 (48) | NR | NR | 50 (100) | 32.23 ± 2.49 | NR | ACE-I: 33 (66) ARBs: 12 (24) ARNI: 2 (4) BBs: 2 (4) Digitalis: 20 (40) MRAs: 43 (86) Thiazide: 4 (8) | |
| McMurray 2019 | Dapagliflozin (2373) | 2373 | 66.2 ± 11.0 | 564 (23.8) | II: 1606 (67.7) III: 747 (31.5) IV: 20 (0.8) | 1316 (55.5) | 993 (41.8) | 31.2± 6.7 | 1428 (857–2655) | ACE-I: 1332 (56.1) ARBs: 675 (28.4) ARNI: 250 (10.5) BBs: 2278 (96.0) Digitalis: 445 (18.8) MRAs: 1696 (71.5) Diuretic: 2216 (93.4) |
| Placebo (2371) | 2371 | 66.5 ± 10.8 | 545 (23.0) | II: 1597 (67.4) III: 751 (31.7) IV: 23 (1.0) | 1358 (57.3) | 990 (41.8) | 30.9± 6.9 | 1446 (857–2641) | ACE-I: 1329 (56.1) ARBs: 632 (26.7) ARNI: 258 (10.9) BBs: 2280 (96.2) Digitalis: 442 (18.6) MRAs: 1674 (70.6) Diuretic: 2217 (93.5) | |
| McMurray 2021* | Dapagliflozin (2152) | 235 (10.9%) | 61.8± 12.1 | 709 (32.9) | NR | NR | 1455 (67.6) | NR | NR | ACE-I: 673 (31.3) ARBs: 1444 (67.1) Diuretic: 928 (43.1) Statin: 1395 (64.8) |
| Placebo (2152) | 233 (10.8%) | 61.9± 12.1 | 716 (33.3) | NR | NR | 1451 (67.4) | NR | NR | ACE-I: 681 (31.6) ARBs: 1426 (66.3) Diuretic: 954 (44.3) Statin: 1399 (65.0) | |
| Nassif 2019 | Dapagliflozin (131) | 131 | 62.2 ± 11.0 | 36 (27.5) | II: 91 (69.5) III: 40 (30.5) | 70 (53.4%) | 81 (61.8) | 27.2±8.0 | 1136 (668, 2465) | ACEI/ARB: 76 (58.0) ARNI: 47 (35.9) BBs: 130 (99.2) Hydralazine: 19 (14.5) Long-acting nitrates: 17 (13.0) MRA: 76 (58.0) Loop diuretics: 114 (87.0) Digoxin: 25 (19.1) Lipid-lowering agents: 107 (81.7) Anticoagulant agent: 58 (44.3) |
| Placebo (132) | 132 | 60.4 ± 12.0 | 34 (25.8) | II: 82 (62.1) III: 50 (37.9) | 69 (52.3%) | 85 (64.4) | 25.7±8.2 | 1136 (545, 2049) | ACEI/ARB: 80 (60.6) ARNI: 38 (28.8) BBs: 124 (93.9) Hydralazine: 26 (19.7) Long-acting nitrates: 22 (16.7) MRA: 84 (63.6) Loop diuretics: 111 (84.1) Digoxin: 21 (15.9) Lipid-lowering agents: 104 (78.8) Anticoagulant agent: 42 (31.8) | |
| Nassif 2021 | Dapagliflozin (162) | 162 | 69 (64, 77) | 92 (56.8) | II: 96 (59.3) III/IV: 65 (40.1) | 32 (19.8) | 90 (55.6) | 60 (55, 65) | 641 (373, 1210) | ACEI/ARB: 98 (60.5%) ARNI: 2 (1.2%) BBs: 119 (73.5%) Hydralazine: 25 (15.4%) Long-acting nitrates: 34 (21.0%) MRA: 50 (30.9%) Loop diuretics: 151 (93.2%) Lipid-lowering agents: 132 (81.5%) Anticoagulant agent: 71 (43.8%) |
| Placebo (162) | 162 | 71 (63, 78) | 92 (56.8) | II: 90 (55.6) III/IV: 72 (44.4) | 31 (19.1) | 91 (56.2) | 60 (54, 65) | 710 (329, 1449) | ACEI/ARB: 98 (60.5) ARNI: 3 (1.9) BBs: 116 (71.6) Hydralazine: 18 (11.1) Long-acting nitrates: 27 (16.7) MRA: 68 (42.0) Loop diuretics: 135 (83.3) Lipid-lowering agents: 127 (78.4) Anticoagulant agent: 84 (51.9) | |
| Palau 2022 | Dapagliflozin (45) | 45 | 69.8 (62.4–74.0) | 10 (22.2) | II/IV: 41 (91.1) | 27 (60.0) | 16 (35.6) | 33.7± 5.3 | 1085 (889–2100) | ACEI or ARB or sacubitril/valsartan: 44 (97.8) Sacubitril/valsartan: 40 (88.9) BBs: 41 (91.1) MRA: 35 (77.8) Loop diuretics: 39 (86.7) |
| Placebo (45) | 45 | 67.3 (60.8–75.1) | 11 (24.4) | II/IV: 39 (86.7) | 22 (48.9) | 13 (28.9) | 34 ± 5.3 | 1620 (889–2328) | ACEI or ARB or sacubitril/valsartan: 43 (95.6) Sacubitril/valsartan: 40 (88.9) BBs: 41 (91.1) MRA: 32 (71.1) Loop diuretics: 38 (84.4) | |
| Singh 2020 | Dapagliflozin (28) | 28 | 66.9 ± 7.0 | 10 (35.7) | I: 12 (42.9) II: 13 (46.4) III: 3 (10.7) | 15 (53.6) | 28 (100) | 44.5 ± 12.4 | NR | ACEI/ARB: 25 (89.3) BBs: 24 (85.7) MRA: 13 (46.4) |
| Placebo (28) | 28 | 67.4 ± 6.8 | 9 (32.1) | I: 13 (46.4) II: 11 (39.3) III: 4 (14.3) | 15 (53.6) | 28 (100) | 46.5 ± 11.7 | NR | ACEI/ARB: 25 (89.3) BBs: 22 (78.6) MRA: 10 (35.7) | |
| Solomon 2022 | Dapagliflozin (3131) | 3131 | 71.8 ± 9.6 | 1364 (43.6) | II: 2314 (73.9) III: 807 (25.8) IV: 10 (0.3) | NR | 1401 (44.7) | 54.0 ± 8.6 | AF: 1408 (956, 2256) No AF: 729 (472, 1299) | ACE-I: 1144 (36.5) ARBs: 1133 (36.2) ARNI: 165 (5.3) BBs: 2592 (82.8) MRAs: 1340 (42.8) Loop Diuretic: 2403 (76.7) |
| Placebo (3132) | 3132 | 71.5 ± 9.5 | 1383 (44.2) | II: 2399 (76.6) III: 724 (23.1) IV: 8 (0.3) | NR | 1405 (44.9) | 54.3 ± 8.9 | AF: 1387 (965.5, 2180.5) No AF: 704 (467, 1265) | ACE-I: 1151 (36.7) ARBs: 1139 (36.4) ARNI: 136 (4.3) BBs: 2585 (82.5) MRAs: 1327 (42.4) Loop Diuretic: 2408 (76.9) | |
| Wiviott 2019 | Dapagliflozin (8582) | 852 (9.9%) | 63.9 ± 6.8 | 3171 (36.9) | NR | 2824 (32.9) | 8582 (100) | NR | NR | ACEI/ARB: 6977 (81.3) BBs: 4498 (52.4) Diuretic: 3488 (40.6) Anti-platelet agents: 5245 (61.1) Statin or ezetimibe: 6432 (74.9) |
| Placebo (8578) | 872 (10.2%) | 64.0 ± 6.8 | 3251 (37.9) | NR | 2834 (33.0) | 8578 (100) | NR | NR | ACEI/ARB: 6973 (81.3) BBs: 4532 (52.8) Diuretic: 3479 (40.6) Anti-platelet agents: 5242 (61.1) Statin or ezetimibe: 6436 (75.0) |
[i] * Baseline characteristics of McMurray 2021 study were reported from the original clinical trial data [33].
Figure 2
Risk of Bias Graph.
Figure 3
Forest Plot of A) All-Cause Mortality. B) Heart Failure Hospitalizations. C) Cardiovascular Deaths. D) Cardiovascular Deaths or Heart Failure Hospitalizations.
Figure 4
Forest Plot of A) Urgent Heart Failure Visits. B) Heart Failure Hospitalization or Urgent Heart Failure Visit. C) Worsening Heart Failure Event (hospitalization or urgent visit) or Cardiovascular Death.
Figure 5
HFrEF Subgroup Forest Plots of A) All-Cause Mortality. B) Cardiovascular Deaths. C) Heart Failure Hospitalizations. D) Heart Failure hospitalization or Urgent Heart Failure Visit.
Figure 6
HFpEF Subgroup Forest Plots of A) All-Cause Mortality. B) Heart Failure Hospitalization or Urgent Heart Failure Visit.