Background

• Heart failure – most common cause of hospitalisations >65 years

- reduced eF (<40%)
- preserved eF(>40%)

• ACEi/ARBs, beta blockers, MRA, ARNI, ivabradine, device therapy –

mortality benefit/decreased hospitalisations in HFrEF

• No drug – increase survival/reduced HHF in HFpEF

Empalgliflozin
• SGLT-2 inhibitor
Study Design
• Phase 3
• Randomised
• Double blind
• Parallel group
• Placebo-controlled

Funding: Boehringer Ingelheim and Eli Lilly

Objective
• To demonstrate superiority of empagliflozin 10 mg OD vs placebo in
patients with symptomatic , chronic HF with preserved EF under
stable treatment of HF symptoms.
• Population: NYHA II-IV CHF with EF > 40%

• Intervention : Empagliflozin 10 mg OD

• Control: Placebo

• Outcome: composite of cardiovascular death + hospitalisation for

heart failure

• Time: 26.2 months

Was the study population clearly defined?
• Yes
Inclusion criteria
• Age > 18
• CHF - NYHA II-IV
• EF> 40%
(within 6 months prior to visit/no previous EF<40%)
• Elevated NT-proBNP(>300 pg/ml without AF; >900 pg/ml in AF)
• Hospitalisation within 12 months prior to visit
• Stable dose of oral diuretics atleast 1 week
• BMI < 45
Exclusion criteria
• MI/CABG/stroke/TIA within 90 days • SBP > 180
• Heart transplant list • Symptomatic hypotension
• ICD within 3 months • COPD on oxygen/steroids
• CRT • AST/ALT/ALP > 3ULN
• Infiltrative/reversible cardiomyopathy • eGFR < 20
• Severe VHD • Hb< 9
• Acute DCHF – iv diuretics/inotropes • h/o ketoacidosis
within 1 week • Major surgery within 90 days
• AF with FVR
• Past use of SGLT-2 inhibitor 1 week
• Pregnancy
• Allergic reaction to SGLT-2
Were the outcome measures clearly defined?
• Yes
Primary outcome
• Composite (cardiovascular death + hospitalisation for heart failure)
Secondary outcomes
• Total number of hospitalisations for heart failure
• Rate of decline in eGFR
Were adequate number of people included in
the study?
• Assumed yearly event rate – 10% (CHARM-Preserved)
• Power – 90%
two sided α = 0.05
• Drop out rate <1%
• Hazard ratio – 0.8
• Recruitment period – 18 months
• Follow up – 20 months

• 4126 patients -> 841 events

How serious was the risk of bias?

Did the intervention and control groups start with the

same prognosis?
Were the patients randomised?
• Yes
• 1:1
• Stratified – region, DM, eGFR, EF
• Unequal block sizes
• Interactive Response technology
Was the allocation concealed?
• Yes
• IRT
Were patients in the study groups similar with
respect to known prognostic factors?
• Yes
Was prognostic balance maintained as the
study progressed?
To what extent was the study blinded?
• Patients, investigations, everyone involved in trial conduct or analysis
Were the groups prognostically balanced
at the study’s completion?
Was the follow up complete?
• 84/2997 incomplete follow up in Empagliflozin : 2.8%
• 88/2991 incomplete follow up in placebo : 2.9%

• 696/2997 (23.2%) in empagliflozin arm discontinued drug

• 699/2991 (23.3%) in placebo arm discontinue drug
Was the trial stopped early?
• No
Were the patients analysed in the groups to
which they were randomised?
• Yes

• Modified intention to treat analysis

No imputation of missing data
Data at end of treatment , last follow up
 Validity of the study
•
Study population: Well defined

•
Outcomes: Well defined

•
Randomization: Done

•
Allocation concealment: Done

•
Blinding: Done

•
Sample size calculation: Adequate

•
Intention to treat analysis: Modified

•
Baseline characteristics: Similar
Results
How large was the treatment effect and how
precise was the estimate of treatment effect?
• Hazard ratio: 0.79
• Confidence interval 0.69-0.90
How can I apply the results to patient care?
Were all clinically relevant outcomes
considered?
• Yes
Were the study patients similar to the patients
in my practice?
• Yes
Are the likely treatment benefits worth the
potential harm and costs?
• ARR – 3.3
• NNT – 30
• Cost – Rs. 51.3 / tablet
Rs. 40,321 to prevent one event (30 patients for 26.2 months)