Despite the numerous improvements and breakthroughs developed in the field of interventional cardiology and pharmacotherapy in the past decades, patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention remain at high risk of cardiovascular events recurrence. Most randomized control trials have so far tested interventions targeting one specific pathway: thrombosis, inflammation, cholesterol level, cardiac remodeling, or fibrosis. Even when successful, the benefits of these interventions have frequently been limited by related side effects (for instance bleeding in the case of antithrombotic therapy) and/or some kind of glass ceiling effect due to the complex interplay of various pathophysiological mechanisms involved in cardiovascular disease. Back in 2019, the TIMI (Thrombolysis In Myocardial Infarction) study group provided a novel score with different biomarkers evaluating different pathobiological axes. This score includes the high-sensitivity C-reactive protein, with a threshold at 2 mg/L, the growth-differentiation factor-15, with a threshold at 1,800 pg/mL, high-sensitivity troponin T, with a threshold at 14 ng/L, and n-terminal pro-B type natriuretic peptide, with a threshold at 450 pg/mL, reflecting systemic inflammation, myocardial fibrosis, myocardial injury, or ventricular strain, respectively. As all these biomarkers have been individually associated with outcomes among patients with coronary disease, this multimarker approach allows for a more global evaluation and stratification of the residual risk.  In a landmark analysis, performed in patients post–acute coronary syndrome of IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), a stepwise increase of the risk of cardiovascular death, myocardial infarction (MI), or stroke, as well as cardiovascular death or heart failure, was observed with intermediate score (ie, 1 or 2 elevated biomarkers) and high score (ie, 3 or 4 elevated biomarkers), compared with low score (ie, no elevated biomarkers).  In this issue of the Journal of the American College of Cardiology, Fagundes et al evaluated the prognosis impact of the same multimarker risk score to specifically predict coronary artery–related events in the population of the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial. Although both trials included slightly different populations and were performed in different decades, the repartition of patients into the 3 risk categories remains remarkably similar, with approximately one-half of the population presenting an intermediate score, a third presenting a low score, and approximately 20% presenting a high score. Consistent with the previous analysis, the authors reported a stepwise increase of the risk of major cardiac events (ie, coronary death, MI, or revascularization) and complex revascularization (ie, complex percutaneous coronary intervention or with coronary artery bypass grafting) with increasing score values (Figure 1). Of note, for both composite endpoints, the graded association was stronger when using the global risk score rather than each individual biomarker.

The TIMI Multi-Biomarkers Score

This figure describes the component of the TIMI multi-biomarkers risk score, the reported prevalence of each category, and the graded association between higher scores and the risk of CV death, MI or stroke, and CV death or heart failure at 7 years based on the IMPROVE-IT cohort and coronary revascularization and the complexity of the revascularization at 3 years from the FOURIER trial. adjHR = adjusted HR; ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; GDF-15 = growth-differentiation factor-15; hsCRP = high-sensitivity C-reactive protein; hsTnT = high-sensitivity troponin T; MI = myocardial infarction; NT-proBNP = n-terminal pro-B type natriuretic peptide; TIMI = Thrombolysis In Myocardial Infarction.

Not only does this study validate the multi-biomarker score in a new cohort of patients and with new coronary-focused outcomes, but it also opens novel and interesting avenues, on a global approach of cardiovascular risk. The idea of targeting different pathophysiological mechanisms in a synergistic fashion is currently explored in some randomized controlled trials, such as the CLEAR SYNERGY (Colchicine and Spironolactone in Patients With MI/SYNERGY Stent Registry; NCT03048825) trial, which randomizes in a 2 × 2 factorial design 7,000 patients with MI to colchicine and/or spironolactone versus placebo. This type of trial always struggles with enrichment or selection criteria to address the appropriate population, sufficiently exposed to the events that need to be prevented by the interventions. Whether this or another multi-biomarker score could replace a tedious list of enrichment criteria is unknown and would deserve attention in future trials. Proof-of-concept trials could also use this risk score as a surrogate endpoint to test a new drug aiming at reducing cardiovascular risk. Beyond clinical research, we could imagine in the future to base our therapeutic decisions on such a score, just like we decide anticoagulation in patients with atrial fibrillation according to the CHA₂DS₂-VASc score. Will we see one day individualization of treatments and new and/or expensive cardiovascular therapies prescribed to patients with the appropriate risk, using this type of multi-biomarker approach? In other words, will we see the right cardiovascular care at the right cost using an inexpensive biomarker approach? Will our decisions of expensive and sometimes lifelong treatments be driven by a bio-score, such as PCSK9 inhibitors, SGLT2 inhibitors, CSL112 (a novel intravenous formulation of apolipoprotein A-I currently in phase 3), interleukin-1 or -6 receptor inhibitors, etc. This time for a change has not come yet but the preservation of our health care systems may have to go through this new age of medicine.

This being said, this multi-biomarker risk score is clearly not without limitations, at least in its current state. First, the risk score assumes an equal prognostic value to each of its components while both studies (IMPROVE-IT and FOURIER) found that elevated high-sensitivity troponin T and n-terminal pro-B type natriuretic peptide were associated with much higher hazard ratios than high-sensitivity C-reactive protein and growth-differentiation factor-15, which might depreciate a biomarker risk score that assigns equal weights to the biomarkers. Second, the categorical nature of the variables, albeit user friendly, prevents any subtle analysis. Third, the score proposed here does not include well known biological risk factors linked to other pathogenetic pathways such as low-density-lipoprotein cholesterol, glomerular filtration rate, microalbuminuria, or hemoglobin level.  Further questions also remain on the impact of the intervention (here lipid-lowering therapy) across risk categories: the greatest relative and absolute benefit from evolocumab occurs in the low-risk category as defined by the biomarker score, suggesting that hypercholesterolemia was a primary risk factor in this group, while the impact of the anti-PCSK9 may have been diluted by competing pathophysiological mechanisms in the intermediate- and high-risk categories. Conversely, the impact of ezetimibe in the IMPROVE-IT cohort was the strongest in the high-risk category; however, no apparent risk reduction was observed in the low-risk category.

Time will tell if a multi-biomarker score can drive our decisions to prevent cardiovascular events like we currently do with the CHA₂DS₂-VASc score for atrial fibrillation or the SYNTAX score for revascularization of coronary disease.

This article is reproduced from JACC journals.

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