Hot Line - Important trial updates: ISCHEMIA-CKD, MASTER DAPT, FOURIER-OLE, FIDELITY and PARADISE-MI
29 Aug 2022
One of today’s Hot Line sessions provided valuable updates on five pivotal CV outcomes trials.
Published in 2020, results from the ISCHEMIA-CKD trial demonstrated that an initial invasive strategy did not reduce the risk of death or non-fatal myocardial infarction (MI) compared with an initial conservative strategy in patients with stable coronary disease, advanced chronic kidney disease (CKD) and moderate or severe ischaemia, at a median follow-up of 2.2 years.1 Today, Professor Sripal Bangalore (New York University School of Medicine - New York, USA) presented extended follow-up data (n=777) that provided the same conclusion. Summarising the data, he says, “In this 5-year follow up of patients from the ISCHEMIA-CKD trial, an initial invasive management strategy did not improve survival when added to guideline directed medical therapy in patients with advanced CKD and chronic coronary disease. Similarly, there were no significant differences in CV death or non-CV death with an invasive versus conservative strategy. Further analyses showed no significant heterogeneity of treatment effect for any subgroup. Of note, the death rate was very high with close to 40% mortality at 5 years indicating a very high risk group of patients who are in urgent need of therapies to reduce this risk.”
In the MASTER DAPT trial, 1 month of dual antiplatelet therapy (DAPT) was non-inferior to therapy continuation (for at least 2 months and up to 1 year) for adverse clinical events, but reduced major or clinically relevant non-major bleeding after percutaneous coronary intervention (PCI) in patients at high bleeding risk.2 Following the 12-month trial, patients in both groups received routine care at their physician’s discretion. Participants (n=4,391) were followed for a further 3 months and results of the prespecified 15-month final analysis were reported today by Professor Marco Valgimigli (Cardiocentro Ticino Foundation - Lugano, Switzerland).
Net adverse clinical events (all-cause death, MI, stroke and major or clinically relevant non-major bleeding) occurred in 8.7% and 9.5% of patients in the abbreviated and standard DAPT groups, respectively (hazard ratio [HR] 0.92; 95% CI 0.76 to 1.12; p=0.399). Major or clinically relevant non-major bleeding remained lower in the abbreviated arm (7.4% versus 10.7%; HR 0.68; 95% CI 0.56 to 0.83; p=0.0001). The researchers also found that physicians tended to continue antiplatelet therapy, both dual and single, for longer than recommended in ESC guidelines. For example, more than 15% of patients not on oral anticoagulation were still on DAPT at 15 months in the standard arm, which was approximately three times higher than in the abbreviated group. Prof. Valgimigli comments, “This unexpected finding may explain the consistency of treatment effects between the randomised and routine care phases of our study. The findings reinforce the need to identify patients at high bleeding risk undergoing PCI so that upfront decisions can be made on antiplatelet treatment and duration to mitigate bleeding risk and optimise outcomes.”
In the FOURIER trial (n=27,564), evolocumab versus placebo reduced the risk of CV events in patients with established CVD on statin therapy, over a median follow up of 2.2 years.3 Today, results were presented from the FOURIER open-label extension (OLE) study in which 6,635 patients who completed FOURIER all received evolocumab (either 140 mg every 2 weeks or 420 mg monthly).
As described by Doctor Michelle O'Donoghue (Brigham And Women's Hospital - Boston, USA), after median follow-up in the extension study of 5.0 years, the incidence of serious adverse events, muscle-related events, new-onset diabetes, haemorrhagic stroke and neurocognitive events with long-term evolocumab did not exceed those with placebo during the parent study and did not increase over time. Furthermore, patients originally randomised to evolocumab versus placebo had a 15% lower risk of CV death, MI, stroke, hospitalisation for unstable angina or coronary revascularisation (HR 0.85; 95% CI 0.75 to 0.96; p=0.008) and a 23% lower risk of CV death (HR 0.77; 95% CI 0.60 to 0.99; p=0.04).
Dr. O’Donoghue concludes, “FOURIER-OLE included patients with the longest study exposure to a PCSK9 inhibitor so far. Long-term LDL cholesterol lowering with evolocumab was safe and well tolerated for more than 8 years and led to further reductions in CV events compared with delayed treatment initiation. These data provide further support to guidelines recommending lipid-lowering therapy with PCSK9 inhibitors and targeting very low levels of LDL cholesterol.”
Previously, it has been shown that finerenone reduced the risk of clinically important CV and kidney outcomes versus placebo across the spectrum of CKD in patients with type 2 diabetes using the FIDELITY dataset, a prespecified pooled analysis of patients in the FIDELIO-DKD and FIGARO-DKD trials.4 Today, Professor Gerasimos Filippatos (National and Kapodistrian University of Athens - Athens, Greece) presented an exploratory analysis of FIDELITY data (n=13,026) that specifically investigated all-cause mortality.
The incidence of all-cause mortality was 8.5% with finerenone compared with 9.4% with placebo (HR 0.89; 95% CI 0.79 to 1.00; p=0.051), where the between-group difference narrowly missed statistical significance. Mortality was most commonly attributed to CV causes (4.9% with finerenone versus 5.6% with placebo), with finerenone significantly reducing the risk of sudden cardiac death (HR 0.75; 95% CI 0.57 to 0.996; p=0.046). Prof. Filippatos remarks, “The effect of finerenone on all-cause mortality, CV mortality and sudden cardiac death was consistent irrespective of estimated glomerular filtration rate (eGFR) or urine albumin-to-creatinine ratio at baseline, but seemingly more pronounced in patients with a higher baseline eGFR. This indicates that earlier initiation of finerenone might be warranted to maximise its protective effects in these patients.”
Sacubitril-valsartan was not associated with a significantly lower incidence of the primary outcomes of CV death or incident heart failure (HF) than ramipril in patients with acute MI in the primary analysis of the PARADISE-MI trial.5 Today, Doctor Otavio Berwanger (Academic Research Organization [ARO], Hospital Israelita Albert Einsteinn - Sao Paulo, Brazil) presented results of a post-hoc win-ratio analysis of this trial. He explains, “The win ratio accounts for both the clinical relevance and timing of individual components of an endpoint – more serious events are given a higher priority and are analysed first – making it a useful method for analysing composite outcomes in CV trials. Applying this method to the PARADISE-MI trial extends our understanding of the effects of sacubitril/valsartan in patients with acute MI.”
The hierarchical analysis of the primary composite outcome demonstrated a larger number of wins (15.7%) than losses (13.4%) in the sacubitril/valsartan group, for a win ratio of 1.17 (95% CI 1.03 to 1.33; p=0.015). The two main contributors to the number of wins were CV death (36.9% of wins) and HF hospitalisation (29.8% of wins).
Dr. Berwanger concludes, “The results suggest that if any two patients are compared, one on sacubitril/valsartan and one on ramipril, and they are not a tie, then there is a 1.17 odds that the sacubitril/valsartan patient is the winner. These exploratory analyses do not alter the primary neutral results for the drug in acute MI, but they do provide supportive evidence to guide decisions to replace ACE inhibitors with sacubitril/valsartan once symptomatic HF has developed. The study illustrates how the win ratio approach may be a useful adjunct to the conventional time-to-first event analysis for trials with composite outcomes, especially where ranking the clinical importance of the different types of events is considered relevant.”
1. Bangalore S, et al. N Engl J Med. 2020;382:1608–1618.
2. Valgimigli M, et al. N Engl J Med. 2021;385:1643–1655.
3. Sabatine MS, et al. N Engl J Med. 2017;376:1713–1722.
4. Agarwal R, et al. Eur Heart J. 2022;43:474–484.
5. Pfeffer MA, et al. N Engl J Med. 2021;385:1845–1855.