New research published in the European Heart Journal has shown that, among patients who have had a heart attack, it is “extremely difficult” to accurately predict those who will go on to suffer a sudden cardiac death—even in those with a left ventricular ejection fraction (LVEF) of 35% or lower, which is commonly used as a justification for prophylactic defibrillator implantation.
The authors of the study are an international consortium—partners of the EU-funded PROFID project and further data providers, including Niels Peek (University of Manchester, Manchester, UK/The Healthcare Improvement Studies Institute, Cambridge, UK), and Gerhard Hindricks, Nikolaos Dagres (both Deutsches Herzzentrum der Charité, Berlin, Germany) and colleagues.
The PROFID project, which also includes the large PROFID EHRA clinical trial, is funded by the EU’s Horizon 2020 research and innovation programme. The findings of the study have provided the scientific foundation for the PROFID EHRA clinical trial, which is expected to change sudden cardiac death prevention in clinical practice, as noted in a recent press release from the European Society of Cardiology (ESC).
While implantable cardioverter-defibrillators (ICDs) are able to detect and terminate life-threatening ventricular arrhythmias, these defibrillator therapies are limited by “profound difficulty” in identifying patients at elevated sudden cardiac death risk as candidates for implantation. Risk stratification of sudden cardiac death after heart attack—and prevention by defibrillator—currently relies on LVEF. However, improved risk stratification across the whole LVEF range (patients with LVEF ≤35% and patients with LVEF >35%) is required for decision-making on defibrillator implantation.
Against this backdrop, the authors of the present analysis pooled 20 datasets from Europe, the USA and Israel with 140,204 post-myocardial infarction patients containing information on demographics, medical history, clinical characteristics, biomarkers, electrocardiography, echocardiography, and cardiac magnetic resonance imaging (MRI). Separate analyses were performed in patients within the following groups: those carrying a primary prevention cardioverter-defibrillator with LVEF ≤35% (ICD patients); those without cardioverter-defibrillator with LVEF ≤35% (non-ICD patients ≤35%); and those without cardioverter-defibrillator with LVEF >35% (non-ICD patients >35%). The primary outcome was sudden cardiac death or, in defibrillator carriers, appropriate defibrillator therapy.
The analysis found that there were 1,326 primary outcomes in 7,543 ICD patients, 1,193 in 25,058 non-ICD patients ≤35%, and 1,567 in 107,603 non-ICD patients >35%, across mean follow-ups of 30, 46.5 and 57.6 months, respectively. In all of these three subgroups, LVEF poorly predicted sudden cardiac death. In addition, considering additional parameters—including demographics, medical history, clinical parameters, biomarkers, medication, electrocardiography, and echocardiography (and, in a subset of datasets and patients, cardiac MRI)—did not improve the predictive performance for the risk of sudden cardiac death across the three subgroups.
“The current analysis did not yield a tool that predicted the individual sudden cardiac death risk with satisfactory accuracy across a wide range of geographically dispersed datasets,” said Peek. “Whether this result is related to the nature of sudden cardiac death or to inherent limitations of respective datasets cannot be answered. But, the finding is consistent with mounting evidence that it is not possible to develop universally valid prediction models. In this case, a key inherent limitation lies on correct adjudication of cause of death. Misclassifications of cause of death are indeed frequent, reducing the performance of models for sudden cardiac death prediction. Furthermore, sudden cardiac death is the result of a complex, highly dynamic interplay of multiple factors that is difficult to capture, especially with single-time assessments.
“We cannot exclude the possibility that future research may discover novel biomarkers—for instance, genetic or imaging biomarkers, particularly using advanced AI [artificial intelligence] techniques—with which it is possible to better predict the risk of sudden cardiac death, although the low incidence rate and the adjudication of the cause of death will always remain major challenges.”
In the analysis, ICD therapy rates in patients with an ICD and an LVEF ≤35% were significantly higher than the rates of sudden cardiac death in patients with an LVEF ≤35% but without an ICD. Although this finding may relate to some extent to differences between these two groups, it also suggests that only a portion of ICD therapies were lifesaving.
“A further limitation of the analysis is the large heterogeneity of the analysed datasets,” said Hindricks. “This was dictated by the need to combine different datasets in order to achieve the sample size that is required to study the rare outcome of sudden cardiac death. These differences in design, data, outcome ascertainment and follow-up of the analysed cohorts limit the strength of the conclusions. This indicates the need for contemporary data on sudden cardiac death prevention by ICD implantation after myocardial infarction.”
“Recently introduced drugs for heart failure treatment, such as sodium-glucose co-transporter 2 [SGLT2] inhibitors or angiotensin receptor-neprilysin inhibitors, were not available or not yet standard at the time of most cohorts,” Dagres added. “Therefore, it is unclear whether the results of the presented analysis are well-applicable in patients treated with contemporary optimal therapy including these recently introduced agents and the latest revascularisation strategies.”
The authors also emphasise that, in patients with LVEF >35%, the lack of acceptably accurate risk stratification tools combined with the very low sudden cardiac death risk raise questions over the feasibility of attempts at identifying high-risk candidates for targeted protection by defibrillator.
They conclude: “In patients with previous myocardial infarction, LVEF had poor predictive performance for the risk of sudden cardiac death among patients with severely impaired LVEF, and among those with moderately reduced or preserved LVEF. The consideration of a large variety and wide spectrum of further candidate predictors did not improve the predictive performance. Thus, more accurate risk stratification and in particular identification of low-risk individuals with severely reduced LVEF as candidates for omission of defibrillator protection or of high-risk individuals with preserved LVEF as candidates for targeted defibrillator protection was not feasible, neither using LVEF nor using various other candidate predictors.”
The authors believe that these findings, demonstrating inability of LVEF and a range of other common variables to predict sudden cardiac death, “question the feasibility of approaches for personalised decision-making on defibrillator implantation”.
“Considering the declining risk for sudden death, the effect of recently introduced heart failure drugs, the fact that non-sudden deaths account for the large majority of deaths in this population, and the still considerable complication rate of the devices, a re-evaluation of the benefit of routine prophylactic defibrillator implantation in patients with LVEF ≤35% appears necessary,” they add.
Following on from this, as part of the PROFID project, the large-scale PROFID EHRA clinical trial is currently underway to re-evaluate the role of ICD implantation in post-myocardial infarction patients in the context of contemporary medical treatment. Important new information to optimally guide therapy—which will address this serious health issue—is expected, the recent release notes.
