Overcoming clinical inertia in heart failure management: Role of SGLT2 inhibitors
Optimal therapy for heart failure with reduced ejection fraction (HFrEF) remains underused due to clinical inertia. A recent post hoc analysis of the DAPA-HF trial serves as a call for change, as patients with longer duration of HFrEF survivorship were found to have higher rates of worsening heart failure (HF) and cardiovascular (CV) death. Importantly, benefits of the sodium-glucose co-transporter 2 (SGLT2) inhibitor, dapagliflozin, on these outcomes were shown to be consistent across the spectrum of HF duration, with the greatest absolute benefit seen in longest-duration HF.
Optimal HFrEF therapies remain underused
Guideline-directed medical therapy (GDMT) for HFrEF has remained underused. For instance, data from the CHAMP-HF registry (n=3,518) showed that among eligible outpatients with chronic HFrEF, 26.2 percent were not prescribed angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blocker (ARB) or angiotensin receptor-neprilysin inhibitor (ARNI) therapy, 32.9 percent were not prescribed beta-blocker therapy, while 65.9 percent were not prescribed mineralocorticoid receptor antagonists (MRAs). Even when GDMT was used, few patients received target doses of ACEIs/ARBs (17.5 percent), ARNI (14 percent) or beta-blockers (27.5 percent). [J Am Coll Cardiol 2019;73:2365-2383]
“Examining data from roughly a decade ago from the IMPROVE-HF registry, one sees … no meaningful improvement in GDMT use over time,” wrote Dr Muhammad Shahzeb Khan from the University of Mississippi, Jackson, Mississippi, US, and colleagues in a recent article. [Circ Heart Fail 2020, doi: 10.1161/CIRCHEARTFAILURE.120.008030; Circulation 2010;122:585-596]
Contributors to clinical inertia
“Strong evidence supports clinical inertia as a major contributor to current gaps in GDMT use,” wrote Khan and colleagues. [J Am Coll Cardiol 2019;73:2365-2383; JACC Heart Fail 2020;8:739-741] “Clinical inertia may be strongest for patients with longstanding HFrEF, particularly those who have survived for years with existing therapy with relative clinical stability and few hospitalizations.”
“The potential tendency to focus on the possibility of side effects (whether those risks are large or small), combined with patients’ tendency to overestimate survival, may contribute to the underuse of GDMT and clinical inertia,” they noted.
A recent post hoc analysis of the DAPA-HF trial, which assessed the impact of HFrEF duration on outcomes and the effect of dapagliflozin across HF duration, serves as a reminder of the importance of overcoming clinical inertia in HF care. [Circ Heart Fail 2020, doi: 10.1161/CIRCHEARTFAILURE.120.007879]
Dapagliflozin significantly reduces HF events and mortality in HFrEF
In the phase III DAPA-HF trial in patients with HFrEF with or without diabetes (n=4,744), dapagliflozin significantly reduced the risk of the primary composite outcome of worsening HF (hospitalization for HF [HHF] or an urgent visit resulting in intravenous therapy for HF) or CV death by 26 percent vs placebo (hazard ratio [HR], 0.74; 95 percent confidence interval [CI], 0.65 to 0.85; p<0.001), with a number needed to treat (NNT) of 21. This benefit was consistent across subgroups, regardless of age, gender, race, New York Heart Association functional class, left ventricular ejection fraction, N-terminal pro–B-type natriuretic peptide level, HHF history, background HF therapy, diabetes status, HF aetiology, body mass index, or renal function at baseline. [N Engl J Med 2019;381:1995-2008; Circulation 2020;142:e369; Circulation 2020;141:100-111; JACC Heart Fail 2020;8:811-818; JAMA 2020;323:1353-1368]
CV death and all-cause mortality were also significantly reduced with dapagliflozin, by 18 percent (HR, 0.82; 95 percent CI, 0.69 to 0.98) and 17 percent (HR, 0.83; 95 percent CI, 0.71 to 0.97), respectively, making it the only SGLT2 inhibitor that has demonstrated a significant mortality benefit in a HF trial. (Figure)
The phase III EMPEROR-Reduced trial showed a similar reduction in risk of the primary composite outcome of CV death or HHF with empagliflozin vs placebo (HR, 0.75; 95 CI, 0.65 to 0.86; p<0.001) in patients with HFrEF with or without diabetes (n=3,730). The HRs for CV death and all-cause mortality were 0.92 (95 percent, 0.75 to 1.12) and 0.92 (95 percent CI, 0.77 to 1.10), respectively. [N Engl J Med 2020, doi: 10.1056/NEJMoa2022190]
Longer HF duration, higher risk of adverse outcomes
In a recent post hoc analysis of the DAPA-HF trial, patients with longer-duration HF were found to be older (mean age, 68.1 years in those with HF for >5 years vs 64.4 years in those with HF for ≥2–≤12 months), with more comorbidities (hypertension, 76.5 percent vs 70.4 percent; MI, 48.4 percent vs 36.7 percent; stroke, 11.6 percent vs 7.8 percent; obesity, 36.1 percent vs 32.8 percent; atrial fibrillation, 43.9 percent vs 31.2 percent; chronic kidney disease, 45.8 percent vs 32.1 percent) and more severe symptoms. [Circ Heart Fail 2020, doi: 10.1161/CIRCHEARTFAILURE.120.007879]
Rates of the primary outcome (per 100 person-years) also increased with HF duration, from 10.2 for HF ≥2–≤12 months and 10.6 for HF >1–2 years, to 15.5 for HF >2–5 years and 15.9 for HF >5 years.
Dapagliflozin: Benefit consistent across HF duration
“The relative benefit of dapagliflozin in terms of the primary outcome was consistent across the spectrum of HF duration, with no statistical evidence of heterogeneity,” noted Khan and colleagues. [Circ Heart Fail 2020, doi: 10.1161/CIRCHEARTFAILURE.120.008030]
The HR for the primary outcome was 0.64 (95 percent CI, 0.53 to 0.78) for HF >5 years, and 0.86 (95 percent CI, 0.63 to 1.18) for HF ≥2–≤12 months. (Table) [Circ Heart Fail 2020, doi: 10.1161/CIRCHEARTFAILURE.120.007879]
“The absolute benefit was the greatest in longest-duration HF, with a number needed-to-treat of 18 vs 28 for HF >5 years vs ≥2–≤12 months,” the researchers highlighted. “Consistent benefit in all outcomes was demonstrated with dapagliflozin across the spectrum of HF duration.”
While adverse events (AEs) and discontinuation of randomized therapy were more common with increasing duration of HF, these were not increased with dapagliflozin vs placebo across the spectrum of HF duration.
Overcoming clinical inertia: Time for SGLT2 inhibitors in HF
Patients with long duration of HFrEF survivorship may be most vulnerable to the negative consequences of clinical inertia, Khan and colleagues noted. [Circ Heart Fail 2020, doi: 10.1161/CIRCHEARTFAILURE.120.008030]
“Conversations with patients and clinicians on medication decisions should include the risk of not trying a disease-modifying medication for HFrEF, or the risk of not trying to escalate towards the maximally tolerated or target dose,” they suggested. “Risks of not initiating SGLT2 inhibitor therapy in HFrEF include excess risk of death, HHF, progression of renal disease, and worsening of quality of life.”
“For the purposes of implementation, the unique features of SGLT2 inhibitors may compare well to an ideal HFrEF therapy,” they added. “These features include simplicity of the regimen (ie, one pill, once per day, one dose, no titration), substantial effects on clinical and patient-reported outcomes that appear early, a strong safety and tolerability profile with minimal or no effect on systolic blood pressure and no excess risk of renal AEs, as well as affordability and accessibility.” [N Engl J Med 2019;381:1995-2008; N Engl J Med 2020;383:1413-1424; Circulation 2020, doi: 10.1161/CIRCULATIONAHA.120.051783]