Heart failure

What do the results of PARADISE-MI mean for earlier use of ARNI therapy in HF?

Wednesday, 17 Nov 2021

The PARADISE-MI (Prospective ARNI Versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events after Myocardial Infarction) study1 showed no significant reduction in heart failure (HF) events for sacubitril/valsartan compared to the angiotensin converting enzyme (ACE) inhibitor ramipril. However, the results do provide reassurance that there is no disadvantage to starting angiotensin receptor-neprilysin inhibitor (ARNI) therapy early after an event, says heart failure specialist Associate Professor John Amerena from University Hospital, Geelong.

PARADISE-MI1 compared ARNI and ACE inhibitor therapy in post-MI patients

The PARADISE-MI trial was conducted to assess whether giving sacubitril/valsartan to patients within 7 days of an acute myocardial infarction (AMI) would lead to reductions in cardiovascular (CV) death, hospitalisation for HF, and development of outpatient heart failure, compared to giving an ACE inhibitor (ramipril).1 None of the patients had known HF before the qualifying MI at the time of enrolment, but did have reduced left ventricular ejection fraction (LVEF  ≤40%) and/or pulmonary congestion, plus at least one additional risk factor for heart failure subsequent to it.

Patients (n = 5,661) were randomised to either sacubitril/valsartan (target dose 97/103 mg twice daily; n=2,830) or ramipril (target dose 5 mg bd; n=2,831) within 7 days of presentation with AMI. Inclusion criteria were LVEF ≤40% and/or pulmonary congestion, plus another HF risk factor (age ≥70 years, atrial fibrillation, estimated glomerular filtration rate <60 mL/min/1.73m2, diabetes mellitus, prior MI, LVEF <30%, Killip class ≥III, ST-segment elevation MI without perfusion). Exclusion criteria included prior HF, clinical instability and an estimated glomerular filtration rate of <30 mL/min/1.73m2.

Patients were followed for a median of 22 months. The primary outcome of CV death or incident HF (outpatient symptomatic HF or HF leading to hospitalisation) was 11.9% for sacubitril/valsartan and 13.2% for ramipril (hazard ratio [HR] 0.90; 95% confidence interval [CI] 0.78–1.04; P=0.17).

Over a median of 22 months, there was no difference between sacubutril/valsartan and ramipril in the secondary outcomes of death from CV causes (5.9% versus 6.7% respectively; HR 0.87; 95% CI 0.71–1.08) or all-cause mortality (7.5% versus 8.5% respectively; HR 0.88; 95% CI 0.73–1.05), and death from CV causes or hospitalisation for HF (10.9% versus 11.8% respectively; HR 0.91; 95% CI 0.78–1.07). Treatment was discontinued due to adverse events in 12.6% of patients randomised to sacubutril/valsartan and 13.4% of patients randomised to ramipril.

Discussing the results, A/Prof Amerena notes, “The trial didn’t reach the primary endpoints, but it showed that there is no disadvantage in starting sacubitril/valsartan early [for heart failure]. It didn’t do better than ramipril but certainly there was no adverse effect in starting it early after an AMI.”

We know that in the more chronic situation, an ARNI is beneficial in heart failure management compared with an ACEI (enalapril), so there’s no reason to think that in the shorter term it should not be as beneficial, although the PARADISE-MI study was not able to demonstrate this definitively. As well, the PIONEER-HF2 study, showed very favourable outcomes using sacubitril/valsartan in the acutely decompensated HF population looking at surrogate outcomes. We are confident that sacubitril/valsartan is not harmful [in the  acute setting}, and although it wasn’t better compared to ramipril in this study, three months down the track it could be, as the benefits may accrue with time,” A/Prof Amerena explains.

The move towards earlier use of ARNI for HF patients

Globally, the heart failure guidelines3 are moving toward an earlier use of ARNI therapy in patients with heart failure,” says A/Prof Amerena. “The criteria for reimbursement5 for sacubitril/valsartan in Australia is that a patient needs to be on an ACE/ARB before it can be started, as in the PARADIGM-HF trial.4 ARNI therapy is obviously better,4 so why delay it? The only difference with PARADISE-MI was that it was in a post-MI population, whereas the big studies in HF have been done in stable ambulatory patients,” he notes.

One such study in outpatients is PARADIGM-HF4 in patients with HF with reduced ejection fraction (HFrEF). This trial compared sacubitril/valsartan and enalapril, both added to other HF medication in patients with HF with reduced ejection fraction (HFrEF; n = 8 442).

The trial was stopped early after a median follow-up of 27 months because of the overwhelming benefit seen with sacubitril/valsartan. It found that sacubitril/valsartan was superior to enalapril in reducing the risks of death and of hospitalisations for heart failure. At the time of study closure, the primary outcome (composite of death from CV causes or hospitalisation for HF) had occurred in 914 patients (21.8%) randomised to sacubitril/valsartan and 1 117 (26.5%) patients randomised to enalapril (hazard ratio for sacubitril/valsartan 0.80; 95% CI 0.73–0.87; P <0.001).4

Earlier ARNI therapy may preserve LV function

If patients are in hospital with HF after an infarct, they’re likely to go on and develop chronic HF and there’s an argument to say that if you give a more effective agent earlier, it will stop remodelling and may preserve LV systolic function. Certainly surrogate data from PIONEER-HF2 suggested that’s the case,” says A/Prof Amerena.

In the PIONEER-HF2 study, patients with HFrEF hospitalised with acute decompensated HF were randomised to sacubitril/valsartan or enalapril, following haemodynamic stabilisation. Initiation of sacubitril/valsartan led to a greater reduction in the primary endpoint of  N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration compared to enalapril therapy. Safety outcomes – worsening of renal function, hyperkalaemia, symptomatic hypotension, and angioedema – did not differ significantly between the two groups.

Current restrictions to earlier ARNI therapy in Australia

In Australia, sacubitril/valsartan is reimbursed for patients with symptomatic chronic HFrEF on concomitant optimal standard HF treatment, including an ACE inhibitor or an angiotensin II antagonist, and a beta-blocker (unless there is a contraindication or intolerance to these agents).5

The PBS listing therefore precludes first-line use of ARNI therapy in patients naïve to either ACE inhibitor or ARB.  “There’s no good reason not to start ARNI therapy in hospital, except that in Australia, the patient is supposed to be stable and already on an ACE or ARB [to be eligible for reimbursed therapy]. The period of time for stability isn’t specified, and, we know that if a patient is discharged on a specific therapy they are much more likely to be on it in 6-12 months time” explains Prof Amerena.

Learnings from PARADISE-MI

So how do the PARADISE-MI results add to the knowledge base on ARNI therapy for HF management? A/Prof Amerena considers the findings should be interpreted in the context of existing data that supports earlier, more effective HF treatment: “There’s no disadvantage in starting ARNIs early in the heart failure management plan. Globally, the guidelines are starting to recommend use of ARNIs first-line as an alternative to ACEI/ARBs in management of HFrEF, as early intervention may delay and prevent progression of the disease in the future,” he says.


This article was sponsored by Novartis. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the Entresto product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.


  1. Angiotensin receptor-neprilysin inhibition in acute myocardial infarction. N Engl J Med 2021;385:1845–1855.
  2. Velazquez E et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med 2019;380:539–548.
  3. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart Journal 2021;42(36):3599–3726.
  4. McMurray JH et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371:993–1004.
  5. Entresto PBS listing. pbs.com.au













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