Expert Opinion

SECURE, ADVOR and REVIVED: Clinical Trials Presented at ESC 2022

Abstract

In this article, three important clinical trials presented at the 2022 European Society of Cardiology Congress have been selected for a brief discussion. These are the SECURE, ADVOR and REVIVED-BCIS2 trials, all of which are investigator-initiated studies whose findings are of interest given their potential to impact clinical practice, ultimately improving current patient care and clinical outcomes.

Disclosure:GM is on the editorial board of European Cardiology Review; this did not influence peer review.

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Correspondence Details:Guiomar Mendieta, National Centre for Cardiovascular Investigation Carlos III (CNIC), Calle de Melchor Fernández Almagro, 3, Madrid, 28029, Spain. E: guiomar.mendietabadimon@gmail.com

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A total of 36 studies in 10 Hot Line sessions were presented at this year’s European Society of Cardiology Congress. What was notable in this 2022 edition compared to prior meetings was the increased number of investigator-initiated trials, of which I have selected three important ones for a brief discussion given their novel findings and potential impact on clinical practice.

I will begin with the Secondary Prevention of Cardiovascular Disease in the Elderly Trial (SECURE) (n=2,499), which investigated whether a polypill strategy containing aspirin, ramipril and atorvastatin would improve medication adherence by simplifying usual-care treatment into one pill.1 Over a median follow-up of 3 years, a polypill strategy in older post-MI patients (mean age 76 years; 31% women), resulted in a 24% relative risk reduction in the primary composite endpoint of cardiovascular death, nonfatal type 1 MI, nonfatal ischaemic stroke or urgent revascularisation (HR 0.76; 95% CI [0.60–0.96]; p=0.02) compared to usual care. This benefit was consistent across the 16 prespecified subgroups, and there were no differences regarding adverse events. Adherence levels and treatment satisfaction regarding medication were higher in the polypill arm versus usual care both at 6 and 24 months. Our population is increasingly ageing and post- MI survival rates have improved over recent decades.2–4 Nevertheless, the incidence of recurrent cardiovascular events remains high despite the availability of effective secondary prevention treatments, and we know that poor patient adherence is associated with worsened outcomes.5,6,7 The SECURE trial, therefore, addresses a relevant clinical question with important implications for clinical care worldwide. The trial has some inevitable limitations to bear in mind, such as an increased susceptibility to bias inherent to its open-label design and 14% participant withdrawal during follow-up (probably aggravated by the COVID-19 pandemic), as well as the lower than expected event rates leading to a potential loss in statistical power. Nevertheless, its results are certainly exciting and will surely impact clinical practice. The SECURE trial investigators are to be commended for having successfully carried out the first polypill trial in secondary prevention.

Up next is Acetazolamide in Decompensated Heart Failure With Volume Overload (ADVOR) (n=519), a multicenter, randomised, placebo-controlled, pragmatic trial conducted exclusively in Belgium. The trial tested whether a combination of intravenous (IV) loop diuretic therapy (which acts distally in the nephron) with a diuretic agent targeting the proximal tubule such as acetazolamide, would boost loop diuretic efficacy in patients hospitalised for acute decompensated heart failure (ADHF) and volume overload.8 On a background of standardised IV loop-diuretic therapy, acetazolamide 500 mg IV daily was associated with a higher incidence of successful decongestion at 3 days (42.2% versus 30.5%) compared to placebo (risk ratio 1.46; 95% CI [1.17–1.82]; p<0.001) in patients across the spectrum of left ventricular ejection fraction (LVEF), representative of current clinical practice (mean age 78 years; 38% women; median N-terminal pro B-type natriuretic peptide 6,173 pg/ml). This benefit was associated with a shorter length of hospital stay, but not a lower incidence of all-cause death or re-hospitalisation for heart failure (HF) given the lack of power to detect any differences in this key secondary endpoint. Interestingly, an incremental reduction in congestion over consecutive days in acetazolamide-treated patients was observed, an effect driven by higher diuresis and remarkably greater natriuresis in the acetazolamide arm, emphasising the importance of early and aggressive treatment on hospital admission. No differences were observed between the two groups regarding safety. We know persistent congestion at hospital discharge has a poor prognosis and, although only 15% of patients were successfully decongested after 3 days of treatment in the DOSE trial, high-dose IV loop diuretic therapy is the ‘go-to’ treatment strategy in ADHF patients with volume overload.9–12 Despite it being one of the most common reasons for hospital admission, randomised clinical data assessing effective treatment strategies in ADHF are relatively scarce.13 The ADVOR trial therefore, addresses a currently unmet need of profound clinical relevance. Inevitably, the generalisability of results is limited to white patients and the trial’s specific inclusion and exclusion criteria further restrict the applicability of the findings and should be carefully considered. Nonetheless, given the novelty of the study in proposing an effective early and aggressive treatment strategy that incorporates an easy-to-use, off-patent and seemingly safe diuretic agent, this trial is a home-run for Belgium and a decisive step forward in the treatment of ADHF worldwide.

The Study of Efficacy and Safety of Percutaneous Coronary Intervention to Improve Survival in Heart Failure (REVIVED-BCIS2) (n=700) is the first trial to have investigated whether revascularisation with percutaneous coronary intervention (PCI) has a role in the treatment of patients with severe left ventricular dysfunction and coronary artery disease.14 Over a median follow-up of 3.4 years, revascularisation with PCI on top of optimal medical therapy (OMT) compared to OMT alone did not result in a lower incidence of the primary endpoint of all-cause death or hospitalisation for HF (HR 0.99; 95% CI [0.78–1.27]; p=0.96), nor any benefit in terms of improved LVEF or quality-of-life scores. Conceived amidst a lack of data across the globe, with guideline recommendations (if any), based on a level of evidence C, there was hope that PCI could offer similar benefits to those observed in the STICH trial without the first 30-day peri-procedural excess mortality associated with coronary artery bypass graft surgery.15,16 However, this question begs a longer-term follow-up, as was done in the STICH trial.17 That being said, additional analyses of the trial data are warranted to precisely determine to whom the findings of REVIVED apply. In the meantime, the facts that the primary endpoint was mainly driven by all-cause death rather than hospitalisation for HF, and that improvements in LVEF were observed irrespective of randomised treatment, highlight the importance of OMT in this patient population and anticipate continued improvement with the increasing implementation of contemporary HF therapies.

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