Dapagliflozin in Patients with

Heart Failure and Reduced

Ejection Fraction
• Principal investigator:- McMurray JJV et al, BHF Cardiovascular
Research Centre, University of Glasgow, Glasgow, United Kingdom
• Sponsored by:- Astrazenaca
• Conducted in:- 410 centers in 20 countries
• Study period:- February 15, 2017 through August 17, 2018
• Publizhed in:- NEJM on November 21, 2019
• Type of study- RCT
• Aim:- To evaluate the efficacy and safety of the SGLT2 inhibitor
dapagliflozin in patients with heart failure and a reduced ejection
fraction, regardless of the presence or absence of diabetes.
• Research question:- Whether SGLT2 inhibitor Dapagliflozin is useful in
the treatment of heart failure in patients with T2 DM and without T2
DM?
Inclusion criteria
• Age of at least 18 years
• Symptomatic heart failure- NYHA class II, III, or IV symptoms
• Left ventricular ejection fraction (LVEF) ≤ 40%
• N-terminal pro–B-type natriuretic peptide ≥ 600 pg/ml (if
hospitalized for heart failure within last 12 months ≥ 400 pg/ml;
if atrial fibrillation/flutter ≥ 900 pg/ml)
Exclution criteria
• Estimated glomerular filtration rate <30 ml/min/1.73 m2
• Symptomatic hypotension or systolic blood pressure <95 mm Hg
• Type 1 diabetes mellitus
• Recent treatment with or unacceptable side effects associated with
an SGLT2 inhibitor
Methods
• Phase 3, placebo-controlled trial, double blinded
• Total number of enrollees: 4,744
• Duration of follow-up: 18.2 months
• Mean patient age: 66 years
• Percentage female: 24%
• Percentage with diabetes: 42%
• Experimental group received T. Dapagliflozin 10mg OD, while control
group received plcebo along with contemporary treatment with beta
blocker(96%), RAAS blockers(94%), MRA(71%).
• Patients were evaluated at 14 days and 60 days after randomization
• Assessment of heart failure and volume status, adverse events, and
an evaluation of renal function and potassium levels
• Additional trial visits were scheduled at 4 months and at 4-month
intervals thereafter
• In the end, 2039 of the patients were still taking dapagliflozin (98.1%)
and 1993 patients (98.2%) were receiving placebo
Outcome
• Primary outcome:- Worsening HF event or cardiovascular death (worsening
HF event = unplanned HF hospitalization or an urgent heart failure visit
requiring intravenous therapy)
• Secondary outcomes
1. A composite of hospitalization for heart failure or cardiovascular death
2. total number of hospitalizations for heart failure (including repeat admissions) and
cardiovascular deaths
3. the change from baseline to 8 months in the total symptom score on the Kansas City
Cardiomyopathy Questionnaire
4. a composite of worsening renal function- defined as a sustained decline in the eGFR
of 50% or greater, ESRD {defined as a sustained [≥28 days] eGFR of <15 ml per
minute per 1.73 m2, sustained dialysis, or renal transplantation}, or renal death
5. death from any cause
KCCQ 12
• The total symptom score on the Kansas City Cardiomyopathy
Questionnaire (KCCQ) range from 0 to 100, with higher scores
indicating fewer symptoms and physical limitations associated with
heart failure
Prespecified safety analyses
• Serious adverse events
• adverse events associated with the discontinuation of a trial
treatment
• adverse events of interest (i.e., volume depletion, renal events, major
hypoglycemic events, bone fractures, diabetic ketoacidosis, and
amputations)
• a diagnosis of Fournier’s gangrene
• laboratory findings of note.
Statistical Analysis
• Sample size calculated was 4500
• Power of 90%
• Hazard ratio of 0.80
• 844 primary outcome events were required
• alpha level of 0.05
• A mixed model was used for repeated measurement to analyze longitudinal
measures (e.g., glycated hemoglobin level and body weight) and estimated the
least-squares mean differences between treatment groups, together with 95%
confidence intervals.
• Time-to-event data were evaluated with the use of Kaplan–Meier estimates
and Cox proportional-hazards models, stratified according to diabetes status,
with a history of hospitalization for heart failure and treatment-group
assignment
• Cox models were used to calculate hazard ratios, 95% confidence intervals, and
two-sided P values and used a semiparametric proportional-rates model to
calculate total (including recurrent) events
• Total symptom score was analysed on the Kansas City Cardiomyopathy
Questionnaire as a composite, rank-based outcome, incorporating patient
vital status at 8 months along with a change in score from baseline to 8 months
in surviving patients, using the rank analysis of covariance method
• safety analyses were performed in patients who had undergone
randomization and received at least one dose of dapagliflozin or
placebo
• All the analyses were performed with the use of Stata software,
version 15 (StataCorp) and R, version 3.5.1
Results
Primary outcome
• Worsening heart failure (hospitalization or an urgent visit resulting in
intravenous therapy for heart failure) or death from cardiovascular
causes- 386 patients (16.3%) in the dapa group Vs 502 patients
(21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence
interval [CI], 0.65 to 0.85; P<0.001)
• NNT=1/ARR
• ARR= Control event rate- experimental event rate
=21.2–16.3 = 4.9
• NNT= 1 /0.049 = 20.4
Secondary outcome
• Cardiovascular death: 9.6% with dapagliflozin vs. 11.5% with
placebo
• Hospitalization for heart failure: 9.7% with dapagliflozin vs. 13.4%
with placebo
• Worsening of renal function: 1.2% with dapagliflozin vs. 1.6%
with placebo (p = 0.17)
Safety
• Serious adverse events related to volume depletion occurred in 29
patients (1.2%) in the dapagliflozin group and in 40 patients (1.7%)
in the placebo group (P = 0.23)
• Serious renal adverse events occurred in 38 patients (1.6%) in the
dapagliflozin group and in 65 patients (2.7%) in the placebo group (P =
0.009)
• The primary outcome occurred in
16.3% of the dapagliflozin group
compared with 21.2% of the placebo
group (hazard ratio, 0.74; 95%confidence
interval [CI], 0.65 to 0.85;P<0.001).
• NNT- 21
• The primary outcome was the same in
prespecified subgroups, including
according to diabetes status.
• The primary outcome was a
composite of death from
cardiovascular causes, hospitalization
for heart failure, or an urgent visit
resulting in intravenous therapy for
heart failure
Patients in NYHA functional
class III or IV appeared to have
less benefit than those in class II
The cumulative
incidences of the primary
outcome, hospitalization
for heart failure
• Of the patients receiving dapagliflozin,
231 (9.7%) were hospitalized for heart
failure, as compared with 318 patients
(13.4%) receiving placebo (hazard ratio,
0.70; 95% CI, 0.59 to 0.83)
Death from cardiovascular causes occurred in
227 patients (9.6%) who received
dapagliflozin and in 273 (11.5%) who
received placebo (hazard ratio, 0.82; 95% CI,
0.69 to 0.98)
A total of 276 patients (11.6%) in the
dapagliflozin group and 329 patients (13.9%)
in the placebo group died from any cause
(hazard ratio, 0.83; 95% CI, 0.71 to 0.97)
Limitations
• Less than 5% of the patients were black
• Relatively few were very elderly with multiple coexisting illnesses
• The baseline use of sacubitril–valsartan (which is more effective
than renin–angiotensin system blockade alone at reducing the
incidence of hospitalization and death from cardiovascular causes)
was low
Conclusion
• Among patients with HFrEF, the risk of worsening heart failure or
death from cardiovascular causes was lower with dapagliflozin than
placebo,regardless of the presence or absenceof diabetes.
• The DAPA-HF trial showed that dapagliflozin was superior to placebo
at preventing cardiovascular deaths and heart failure events.