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Shamliyan et al. Vessel Plus 2020;4:35 I http://dx.doi.org/10.20517/2574-1209.2020.34 Page 3 of 13

systematic reviews, published and unpublished randomized controlled clinical trials (RCTs), and real-
world evidence from the high quality nationally representative controlled observational studies [30,31] . All
of the authors looked at the retrieved publications as well as the evidence-based guidelines that provided
definitions of HFpEF and recommend treatments for HFpEF. We documented the eligibility of studies in a
reference database.

We planned a quantitative direct meta-analysis of similar interventions and outcomes using random effects
[46]
models in compliance with recommended meta-analytic methods . We intended to calculate pooled
relative risk, absolute risk difference, number needed to treat and number of attributable events per 1000
treated with 95% confidence intervals (CI). We proposed to examine inconsistency in treatment effects
[30]
with recommended I2 statistics (if I2 was > 50%) . We planned pooled analyses regardless of statistically
[46]
significant heterogeneity . Instead, we proposed exploring heterogeneity with a priori defined patient
[46]
characteristics, e.g., definitions of HFpEF, outcomes, and study quality .
Since post hoc analyses of statistical power is not recommended [47-50] , we downgraded the quality of
evidence for imprecision based on an estimated priori optimal information size in an adequately powered
[51]
RCT (e.g., ≥ 250 patients with the event) .
We concluded statistical significance at a 95% confidence level using Statistics/Data Analysis, STATA
software (StataCorp LP, College Station, Texas).

We judged the risk of bias in primary studies with the Cochrane risk of bias tool [52-54] . We judged the
quality of evidence according to the recommendations by the grading of recommendations assessment,
development and evaluation (GRADE) methodology . We downgraded the quality of evidence from RCTs
[55]
according to the domains of the risk of bias in the body of evidence, directness of comparisons, precision
and consistency in treatment effects, and the probability of the reporting bias .We assigned low quality of
[55]
evidence to all nonrandomized studies, upgrading the quality for the evidence of a strong or dose-response
[56]
association . We concluded insufficient evidence when valid information about treatment effects was not
identified.

RESULTS
We excluded the majority of clinical studies of SGLT2- inhibitors because they did not report patient
outcomes in adults with HFpEF (search strings are available in the appendix and the list of excluded
publications and registered studies is available by the request from the authors). We identified post hoc
subgroup individual patient data meta-analysis of the CANVAS (Canagliflozin Cardiovascular Assessment
[57]
Study) Program that examined canagliflozin when compared with placebo in patients with HFpEF [Table 1] .
We identified post-hoc subgroup analysis of the pivotal DECLARE-TIMI 58 (Dapagliflozin Effect on
Cardiovascular Events-Thrombolysis in Myocardial Infarction 58) RCT that examined dapagliflozin
[58]
when compared with placebo in patients with HFpEF [Table 1] . We also identified unpublished results
from pivotal EMPERIAL trials that examined empagliflozin when compared with placebo in patients
with HFpEF [59-61] . We identified post-hoc subgroup analysis of the pivotal VERTIS CV RCT (Evaluation
of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial) that examined ertugliflozin when
compared with placebo in patients with HFpEF [Table 1] .
[62]
We did not identify observational studies that reported patient outcomes after SGLT2- inhibitors in
patients with HFpEF and concluded probable publication bias because several completed registered studies
remain unpublished. We downgraded the quality of evidence for high risk of bias in post-hoc subgroup
analyses, imprecision in treatment effects due to small number of events, and probable publication bias. We
concluded that the evidence is insufficient for definitive clinical recommendation to use SGLT2- inhibitors