By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
An analysis of the DETERMINE studies of dapagliflozin vs. placebo in patients with heart failure showed some improvement in self-reported symptoms in those with reduced ejection fraction on dapagliflozin but not in the six-minute walk test. No improvements in symptoms or physical activity levels were found in those with preserved ejection fraction on dapagliflozin.
McMurray JJV, Docherty KF, de Boer RA, et al. Effect of dapagliflozin versus placebo on symptoms and 6-minute walk distance in patients with heart failure: The DETERMINE randomized clinical trials. Circulation 2023; Dec 7. doi: 10.1161/CIRCULATIONAHA.123.065061. [Online ahead of print].
Recent large clinical trials of ambulatory patients with heart failure (HF) with reduced (r) or preserved (p) left ventricular ejection fraction (LVEF) have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced heart failure hospitalizations and cardiovascular mortality. Also, symptom reduction has been shown in HF patients on SGLT2 inhibitors using the Kansas City Cardiomyopathy Questionnaire (KCCQ). However, improvements in objective measures of physical function have been inconsistent.
The Dapagliflozin Effect on Exercise Capacity Using a 6-minute Walk Test in Patients with Heart Failure (DETERMINE) trials were designed to further evaluate the effects of dapagliflozin on symptoms and functional capacity in patients with HFr and HFp. These studies were international, multicenter, parallel group, double-blind, randomized, Phase III trials. DETERMINE-r enrolled 313 patients with New York Heart Association (NYHA) class II-IV HF, an EF ≤ 40%, elevated N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels > 400 pg/mL (> 300 pg/mL if hospitalized for HF in the last 12 months or > 800 pg/mL with atrial fibrillation [AF]), and a six-minute walk test (6-WT) between 100 m and 425 m.
DETERMINE-p enrolled 504 symptomatic patients with EF > 40%, evidence of structural heart disease (LV hypertrophy or left atrial enlargement), and an NT-proBNP ≥ 250 pg/mL (or ≥ 500 pg/mL if AF was present). The patients in both limbs of DETERMINE were randomized to dapagliflozin 10 mg/day or placebo for 16 weeks in addition to guideline-directed medical therapy (GDMT). Patients with systolic blood pressure < 90 mmHg, estimated glomerular filtration rate < 25 mL/min/1.73 m², type 1 diabetes, or any contraindication to exercise testing were excluded.
The primary endpoint was a combination of 6-WT distance, and the KCCQ total symptom score (TSS) and physical limitations scale (PLS). In addition, a secondary endpoint tested in 100 patients was vigorous physical activity using a wearable activity monitor (WAM). The safety endpoints were serious adverse events and those requiring discontinuation of the study drugs. In the HFr patients, the median EF was 30% vs. 52% in the HFp patients; median age was 69 years vs. 73 years, respectively; men 74% vs. 63%; and AF 37% vs. 52%. Other clinical characteristics were similar between the two limbs of the study. The mean difference between the dapagliflozin and placebo groups in the HFr limb in the TSS was 4.2 in favor of dapagliflozin (95% confidence interval [CI], 1.0-8.2; P = 0.02). The other two primary outcomes were not statistically significantly different (PLS mean difference, 4.2; 95% CI, 0.03-8.3; P = 0.06 and 6-WT, 3.2 m; 95% CI, -6.5 m to 13 m; P = 0.7).
There was no significant difference in the WAM estimation of physical activity between the HFr dapagliflozin vs. placebo group, but less than half the 100 patients wore the WAM for enough time to analyze the data. In the HFp limb, none of the primary outcomes were statistically different nor was the secondary outcome, which was available in less than three-quarters of the 100 WAM patients. Severe adverse events were uncommon and not different between the dapagliflozin and placebo groups in HFr patients (12% dapagliflozin vs. 15% placebo) and the HFp patients (10% vs. 8%). The authors concluded that dapagliflozin improved self-reported symptoms and was borderline at improving physical limitations but did not improve 6-WT in HFr patients. No outcome was improved in the HFp group by dapagliflozin, and major adverse events were similar in the dapagliflozin and placebo groups.
COMMENTARY
Four large trials have shown that, in ambulatory patients with HF and reduced or preserved EF, SGLT2 inhibitors reduce hospitalizations for HF and the risk of cardiovascular death across the range of EF.1-4 Avoiding hospitalizations and death are worthy goals, but patients also like to feel better and be able to do more physical activity. Symptom reduction has been shown in these prior trials, but improved ability to be physically active has not been consistently demonstrated. Thus, the DETERMINE study is of interest. It has shown that PLS, which assesses routine activities such as walking, dressing, showering, and doing housework, was borderline significantly improved in HFr but not in HFp. Formal 6-WT was not improved in either group.
Similar findings were seen in studies of other approved agents for HF treatment, such as sacubitril/valsartan, which also has been shown to improve survival and reduce hospitalizations. In fact, only intravenous iron and cardiac resynchronization have been shown to increase 6-WT distance in HF patients. Since most of the approved drugs for HF have significant positive effects on patient outcomes, the authors questioned the value of the 6-WT for assessing functional capacity in HF patients.
There are limitations to DETERMINE to consider. The baseline activity level of their patients was quite high in comparison to other HF trials, so demonstrating differences in performance would be harder. Also, COVID-19 curtailed their application of the WAM such that these data were underpowered to see differences compared to placebo. In addition, there was high use of beta-blockers in the HFp group, which may have reduced exercise heart rate and capacity. These considerations emphasize that SGLT2 inhibitors should be added to current GDMT. They are not an alternative therapy.
REFERENCES
- McMurray JJV, Solomon SD, Inzucchi SE, et al; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.
- Packer M, Anker SD, Butler J, et al; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413-1424.
- Anker SD, Butler J, Filippatos G, et al; EMPEROR-Preserved Trial Committees and Investigators. Baseline characteristics of patients with heart failure with preserved ejection fraction in the EMPEROR-Preserved trial. Eur J Heart Fail 2020;22:2383-2392.
- Solomon SD, McMurray JJV, Claggett B, et al; DELIVER Trial Committees and Investigators. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med 2022;387:1089-1098.
