[메디칼업저버 박선혜 기자] AstraZeneca’s SGLT-2 inhibitor, Posiga (ingredient name: dapagliflozin), has established itself as a treatment for complete heart failure regardless of left ventricular ejection fraction (LVEF).
Forxiga was shown to significantly reduce the risk of cardiovascular death or hospitalization for heart failure in the phase 3 DELIVERY clinical trial in patients with reduced ejection fraction heart failure (HFrEF) followed by milder ejection fraction heart failure is less (HFmrEF) or preserved heart. failure (HFpEF). has been proven
In addition, in the results of an integrated analysis of the phase 3 clinical trial DELIVER and DAPA-HF, which has been useful as a treatment of HFrEF, the effect of Forxiga was shown consistently regardless of the ejection fraction.
The results of the research were unveiled on the 27th at the European Society of Cardiology Annual Conference (ESC 2022) to be held online and offline in Barcelona, Spain from the 26th to the 29th.
Concurrent with the announcement, the DELIVER phase 3 clinical trial results were published in NEJM, and the results of the integrated analysis were published in the August 27 online issue of Nature Medicine.
DELIVERY, reduced ejection fraction → improved heart failure patients included
SGLT-2 inhibitors are therapeutic agents that have proven effective in significantly reducing morbidity and mortality in HFrEF patients with an LVEF of less than 40%. Based on this, domestic and international heart failure guidelines strongly recommend SGLT-2 inhibitors as a treatment for HFrEF.
However, unlike HFrEF, treatment options for patients with HFmrEF or HFpEF with LVEF greater than 40% were limited. Boehringer Ingelheim’s Jardiance (empagliflozin) has emerged as a HFpEF treatment through the EMPEROR-Reserved phase 3 clinical trial, but uncertainty remains regarding the effectiveness of SGLT-2 inhibitors in some patient groups.
In particular, the range of ejection fraction was high in the group of patients with less treatment efficacy, and data on patients who started treatment during or immediately after hospitalization were limited. In addition, the reduced ejection fraction improved, and patients over 40% were excluded from the study.
A key feature of the randomized, double-blind, placebo-controlled Phase 3 clinical trial is that it evaluated the clinical utility of Forxiga by recruiting a wider range of patients with heart failure than the previous study.
The study enrolled 6263 HFmrEF or HFpEF patients over 40 years of age with NYHA functional grades II to IV and LVEF >40%. Previously, patients with an LVEF of less than 40% but subsequently improved and greater than 40% were also enrolled, accounting for 18% of the total patient group. Inpatients or recently admitted patients were also included in the study.
The mean age of the entire patient group was 72 years, 44% were female, and the mean LVEF was 54%. 77% of patients were taking an ACEI, ARB, or ARNI, 83% were taking beta-blockers, and 43% were taking an MRA.
The entire patient group was randomized 1:1 to a group taking Posiga 10 mg once daily (forxiga group, 3131 patients) and a placebo group (3132 patients). At follow-up (median) 2.3 years, the discontinuation rate was 14%.
The primary endpoint was evaluated by summing up death from cardiovascular disease or worsening heart failure. Exacerbation of heart failure was defined as an unplanned admission to hospital for heart failure or an emergency visit for heart failure.
Consistent benefits of Forsiga depending on LVEF and treatment environment
As a result of the study, the primary target incidence rates were 16.4% (512 patients) in the posiga group and 19.5% (610 patients) in the placebo group, and the incidence rates per 100 people were 7.8 and 9.6 of cases, respectively.
Accordingly, the risk of developing the primary endpoint was significantly lower in the Forxiga group than in the placebo group by 18% (HR 0.82; 95% CI 0.73 to 0.92; P=0.0008). The minimum number of patients treated (NNT), which shows how many people took the drug before one patient saw the effect of the treatment, was 32.
According to the evaluation factors, the incidence of worsening heart failure was 11.8% (368 patients) in the Forshiga group and 14.5% (455 patients) in the placebo group, and the risk of worsening heart failure was significantly lower in the Forsiga group. by 21% (HR 0.79; 95% CI 0.68 to 0.91) . They also found that the risk of hospitalization for heart failure was 23% lower in the Posiga group (HR 0.77; 95% CI 0.67 to 0.89).
The mortality rate from cardiovascular disease was 7.4% (231 patients) in the Forxiga group and 8.3% (261 patients) in the placebo group ~1.05). The risk of all-cause mortality was 6% lower in the Posiga group (HR 0.94; 95% CI 0.83 to 1.07).
In addition, the Forsiga group also significantly improved patient symptom burden as assessed by the University of Kansas Cardiomyopathy Questionnaire (KCCQ) compared to the placebo group.
These results were consistently demonstrated in sub-analyses by LVEF or patient treatment environment. Compared with the placebo group, the risk of developing the primary target point in the Posiga group was lower by LVEF of 13% in the 49% or less group, 21% in the 50-59% group, and 22% in the 60% or higher group.
In the group of patients who were hospitalized at the time of enrollment or who were hospitalized within 30 days, the risk of developing the primary target point in the Posiga group was not statistically significant compared to the placebo, but showed a 22% lower trend. . The risk of the primary target in the Posiga group, which did not fall under this category, was significantly lower at 18%.
Additionally, in the group of patients with an improved LVEF of 40% or less, the primary endpoint risk was significantly lower in the Forxiga group than in the placebo group by 26%. In the other patient groups, the primary endpoint risk in the Posiga group was significantly lower by 16%.
The incidence of adverse events was similar in both groups. The incidence of serious adverse events, including death, was 43.5% in the Forxiga group and 45.5% in the placebo group, and the rate of treatment discontinuation due to adverse events was the same at 5.8%.
As a result, Forxiga significantly reduced the risk of cardiovascular death or worsening heart failure and improved the burden of heart failure in patients with HFmrEF or HFpEF.
In particular, it is significant that the treatment benefit of Forxiga has not decreased even in the patient group with the highest LVEF, and a significant effect appeared regardless of the patient’s treatment environment.
Professor Scott D. Solomon, Brigham and Women’s Hospital, USA, who presented the results of the study, said, “In addition to the lower incidence of the primary endpoint in the Posiga group, the risk was also significantly lower by 18%. consistent across pre-defined subgroups.” “This is strong evidence to support the use of SGLT-2 inhibitors as primary treatment for heart failure regardless of LVEF or treatment environment, ” he said.
“If there are no contraindications, Posey should prescribe the ejection fraction before measuring it”
Next, the results of a meta-analysis of Fossi by integrating DAPA-HF and DELIVER, the representative phase 3 clinical trials, were released.
An integrated analysis was carried out to check whether the benefits of Possiga were shown consistently across the whole LVEF range, as the EMPEROR-Preserved study published last year suggested that the effect of Jardiance could be weakened if the LVEF was high.
A total of 11,007 patients were analyzed, including 4,744 HFrEF patients enrolled in DAPA-HF and 6263 HFmrEF or HFpEF patients enrolled in DELIVER. The average age was 69 years and 35% were women.
After 22 months of follow-up (median), the benefit of Posiga treatment was confirmed in all heart failure patients regardless of LVEF.
The risk of death from cardiovascular disease was 14% (HR 0.86; 95% CI 0.76 to 0.97) in the Posiga group compared with placebo and 10% for death from all causes (HR 0.90; 95% CI 0.82 to 0.99) △ Total heart failure 29% in hospital (RR 0.71; 95% CI 0.65 to 0.78) △ Death from cardiovascular disease, myocardial infarction or stroke (MACE) 10% (HR 0.90; 95% CI 0.8 to 1.00) △ Hospital first heart failure 26% (HR 0.74; 95% CI 0.66 to 0.82) △ Death from cardiovascular disease or hospitalization for first heart failure was 22% (HR 0.78; 95% CI 0.72 to 0.86) is lower.
In addition, in the analysis according to the LVEF, the Forxiga group showed a better trend than the placebo group in the overall range, and the treatment benefit of the Forxiga group was consistent even if the LVEF was high.
Professor Pardeep Jhund from the University of Glasgow, UK, who carried out the analysis, said, “This study is clinically important given that patients with heart failure have to wait for the results of a heart scan to measure ejection fraction and determine which treatment that is needed.” “Forxiga is effective in all heart failure patients,” he said. “If there are no contraindications, prescribing Forxiga before measuring ejection fraction can improve patient access to life-saving drugs,” he said.
