25th September 2022, Dr Chee L Khoo
We looked at the Australian guidelines on management of heart failure (HF) recently and in particular, how it impacts upon the management of these patients in primary care. The guidelines recommended the four pillars of management but also reinforced the categories of HF. Did you know that the numbers that define the different categories of HF is somewhat arbitrary? Nothing magical really happens at ejection fraction (EF) of 40% or 50%. These numbers were the numbers that were conveniently used in clinical trials and is now used to define the categories of HF. Are they really distinct categories or are they the same disease at different stages of the trajectory? Much of the evidence of benefit we have seen relates to patients with HF with reduced EF (HFrEF). Few pharmacologic treatment options exist for patients with heart failure and a mildly reduced EF (HFmrEF) or HF with preserved EF (HFpEF). Well, until recently.
Although I refer to the EF limits as “arbitrary”, somehow our treatment success seems to follow those defined numbers. We have data demonstrating that beta-blockers, ACE inhibitors or ARBs, angiotensin receptor–neprilsyin inhibitor (ARNI), mineralo-corticoid receptor antagonists (MRAs) individually reduce mortality and morbidity in patients with HFrEF. Yet, trials after trials failed to demonstrate efficacy of those class of agents in HFpEF.
We had the first glimmer of hope when EMPEROR – PRESERVED published 12 months ago. 5988 patients with HF with EF ≥ 40% were randomised to either 10mg of empagliflozin or placebo. After a median duration of 26.2 months, empagliflozin was shown to reduce the combined risk of cardiovascular death or hospitalisation for heart failure by 21% irrespective of whether they had diabetes or not. After EMPEROR – PRESERVED published its results, there was some criticism that the population not quite HFpEF. The median EF was 54% but one third had EF between 40-50%, one third had EF between 50-60% and one third had EF >60% which means really only 2/3 of the patients had HFpEF while 1/3 had EFmrEF (40-50%) under the new guidelines. Nonetheless, this is the first time any drug class have demonstrated efficacy in patients with HFpEF. What about the other SGLT2i?
We now have data from the other SGLT2i, dapagliflozin. DELIVER is a randomised controlled HF trial involving patients with HFpEF. Details of the trial were published in August this year in the NEJM. Further details were announced and discussed at the EASD in Stockholm, Sweden last week and I was privileged to be there in person. I thought it was worthwhile sharing the data with you.
6263 patients were enrolled from 353 centres in 20 countries and randomised to either dapagliflozin 10mg daily or placebo. The following were eligible if they:
- Were ≥ 40 years of age
- Had Stabilised heart failure
- With or without type 2 diabetes mellitus
- Had left ventricular ejection fraction ≥ 40%
- Had evidence of structural heart disease
- Had elevated natriuretic peptide level
Patients who had had a previous left ventricular ejection fraction of 40% or less were eligible provided that they had an ejection fraction of more than 40% at the time of enrolment. Importantly, patients could have been enrolled either as outpatients or during hospitalization for heart failure.
At baseline, 44% patients had T2D. Just like in EMPEROR – PRESERVED, approximately 1/3 of patients had EF between 40-50%, 1/3 of patients had EF between 50-60% and 1/3 had EF >60%. The eGFR both the dapagliflozin and placebo groups were 61±19 ml/min/1.73 m2.
The primary outcome was a composite of worsening heart failure or cardiovascular death. Secondary outcomes were the total number of worsening heart failure events and cardiovascular deaths, the change from baseline in the total symptom score on the Kansas City Cardiomyopathy Questionnaire (KCCQ).
The results
Overall, in the primary outcome, dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death by 18% among patients with heart failure and a mildly reduced or preserved ejection fraction (p<0.001). If you breakdown the components of the primary outcomes, dapagliflozin reduced worsening HF by 21% ((p<0.001) and cardiovascular death by 12% (p<0.001).
When they looked at the number of cardiovascular deaths and first and recurrent worsening heart failure events (secondary outcomes), dapagliflozin reduced those events by 23% compared to placebo (p<0.001).
More details
The effect of dapagliflozin on the primary outcome was consistent across all prespecified subgroups. In other words, dapagliflozin effect was similar irrespective of:
- Age – whether >72 y or <72 y
- T2D or not
- Acute HF in hospital or H within 30 days of hospitalisation or HF that develop later than 30 days
- Classes of NYHA – whether Class II – III or Class IV
- Ejection fraction level – whether 40-50%, 50-60% or >60%
- Presence of AF or not
- eGFR level – whether < 60 or > 60 ml/min/1.73 m2
- Presence of previous HFrEF but now >40% following treatment
This additional trial from another SGLT2 inhibitor provide more convincing evidence that SGLT2i has a role in the management of heart failure irrespective whether it’s HFrEF, HFmrEF, HFpEF or HFimpEF. This cannot be said about the other agents which we are recommending for HFrEF.
At the moment, the PBS Authority only recognise SGLT2i for HFrEF but I have no doubt that in time, it will be approved for HFpEF with such convincing data. Watch this space.
References:
Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, Shah SJ, Desai AS, Jhund PS, Belohlavek J, Chiang CE, Borleffs CJW, Comin-Colet J, Dobreanu D, Drozdz J, Fang JC, Alcocer-Gamba MA, Al Habeeb W, Han Y, Cabrera Honorio JW, Janssens SP, Katova T, Kitakaze M, Merkely B, O’Meara E, Saraiva JFK, Tereshchenko SN, Thierer J, Vaduganathan M, Vardeny O, Verma S, Pham VN, Wilderäng U, Zaozerska N, Bachus E, Lindholm D, Petersson M, Langkilde AM; DELIVER Trial Committees and Investigators; DELIVER Trial Committee and Investigators. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022 Sep 22;387(12):1089-1098. doi: 10.1056/NEJMoa2206286.