A dapagliflozin labeling change comes next
Mitchel L. Zoler/MDedge News
Dr. Mikhail N. Kosiborod
After the first 8 months of treatment in the DAPA-HF trial, 58% of the 2,373 patients who received dapagliflozin had a clinically meaningful improvement in their total KCCQ symptom score of at least 5 points, compared with a 51% rate in the 2,371 patients in the control arm, a statistically significant difference. This meant that the number needed to treat with dapagliflozin was 14 patients to produce one additional patient with at least a 5-point KCCQ improvement compared with controls, a “very small” number needed to treat, Dr. Kosiborod said in an interview.
Addition of the KCCQ to the panel of assessments that patients underwent during DAPA-HF reflected an evolved approach to measuring efficacy outcomes in clinical trials by including patient-reported outcomes. Earlier in 2019, the Food and Drug Administration released draft guidance for heart failure drug development that explicitly called for efficacy endpoints in pivotal studies that measure how patients feel and function, and stating that these endpoints can be the basis for new drug approvals.
“To many patients, how they feel matters as much if not more than how long they live,” Dr. Kosiborod noted. The goals of heart failure treatments are not only to extend survival and reduced hospitalizations, but also to improve symptoms, function, and quality of life, he said.
“There is a lot of interest now in having outcomes in heart failure trials that are more meaningful to patients, like feeling better and being able to do more,” noted Dr. Walsh.
The DAPA-HF results also showed that patients had similar rates of reduction in death, heart failure hospitalization, or urgent clinical visits, regardless of how severely they were affected by their heart failure when they began dapagliflozin treatment. The researchers ran an analysis that divided the entire trial population into tertiles based on their KCCQ score on entering the study. Patients in the most severely-affected tertile had a 30% cut in their rate of death or acute heart failure exacerbation on dapagliflozin compared with placebo, while patients in the tertile with the mildest symptoms at baseline had a 38% reduction in their primary outcome incidence compared with controls who received placebo. Concurrently with Dr. Kosiborod’s report, the results appeared in an article online (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044138).
Outcomes by age
Not surprisingly in DAPA-HF, the older patients were, the sicker, Dr. McMurray observed. Of the study’s 1,149 patients (24% of the study cohort) who were at least 75 years old, 62% had chronic kidney disease, compared with a 14% prevalence among the 636 patients younger than age 55. The 75-and-older group showed a steeper, 32% decline in incidence of the primary endpoint – a composite of cardiovascular (CV) death, HF hospitalization, or urgent HF visit requiring intravenous therapy – than in the other studied age groups: a 24% decline in those 65-74 years old, a 29% cut in those 55-64 years old, and a 13% drop in patients younger than 55 years old.
In addition, patients aged 75 years or greater were just as likely as the overall group to show at least a 5-point improvement in their KCCQ Total Symptom Score on dapagliflozin, as well as about the same reduced rate of deterioration compared with placebo as tracked with the KCCQ.
Patients “got as much benefit in terms of symptoms as well as morbidity and mortality,” Dr. McMurray concluded. Concurrently with the meeting report the results appeared in an article online (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044133).
“These data are of critical importance, as improving patient-reported outcomes in heart failure, especially in highly symptomatic patients, is an important goal in drug development,” G. Michael Felker, MD, wrote in an editorial accompanying the two published analyses (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044578). These new analyses also highlight another attractive feature of dapagliflozin and, apparently, the entire class of SGLT2 inhibitors: They “ ‘play well with others’ when it comes to overlapping intolerances that often limit (either in reality or in perception) optimization of GDMT [guideline-directed medical therapy]. Although SGLT2 inhibitor therapy may lead to volume depletion and require adjustment of diuretics, the SGLT2 inhibitors generally lack some of the other dose-limiting adverse effects (such as renal dysfunction, hyperkalemia, and hypotension) that can make aggressive up-titration of GDMT problematic, particularly in older patients or those with more advanced disease,“ wrote Dr. Felker, professor of medicine at Duke University in Durham, N.C. “We stand at the beginning of a new era of ‘quadruple therapy’ for HFrEF with beta-blockers, an angiotensin receptor neprilysin inhibitor, mineralocorticoid receptor antagonists, and SGLT2 inhibitors,” he concluded.
A version of this article also appears on Medscape.com