PracticeUpdate: Cardiology

ARRHYTHMIAS/HEART RHYTHM DISORDERS

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Cardiovascular biomarker score improves risk prediction in patients with atrial fibrillation Comment by T. Jared Bunch MD

Cardiovascular biomarker score and clinical outcomes in patients with atrial fibrillation: a subanalysis of the ENGAGE AF-TIMI 48 randomized clinical trial JAMA Cardiology Take-home message • This study investigated the feasibility of adding biomarkers to the current system for determining risk when making treatment decisions for patients with atrial fibrillation (AF). The authors determined the baseline levels for D-dimers, cTnI, and NT-proBNP in patients enrolled in the double-blind, double- dummy ENGAGE AF-TIMI 48 clinical trial for AF patients at moderate to high risk for stroke. All three of the biomarkers were present in 4880 of the 5002 patients enrolled and were linked to increased risk (2.8- to 4.2-fold; P < 0.001 for all three). When combined with the current method for determining risk, the CHA2DS2-VASc score, there was a significant improvement in risk prediction, with a 59.4% net improvement in reclassification. • Usingmultiple biomarkers significantly improved the accuracy of risk assessment for patients with AF compared with the current scoring system. The authors recommend considering the inclusion of biomarkerswhenmaking therapeutic decisions for patients with AF. Abstract IMPORTANCE Treatment decisions in atrial fibrillation (AF) are based on clinical assessment of risk. The CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age 65-74 [1 point] or ≥75 years [2 points], diabetes mellitus, and stroke, transient ischemic attack or thromboembolism [2 points]– vascular disease, and sex category [female]) risk score is pragmatic and widely used but has only moderate discrimination. OBJECTIVE To develop and test a cardiovascular bio- marker score for indication of risk in patients with AF. DESIGN, SETTING, AND PARTICIPANTS The ENGAGE AF-TIMI 48 trial was a randomized, double-blind, double-dummy clinical trial comparing 2 once-daily edoxaban dose regimens with warfarin in 21 105 patients with AF at moderate to high risk of stroke. This prespecified subanalysis was performed in 4880 patients enrolled at randomization in the biomarker substudy. Cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and D-dimer levels were measured at baseline. A multimarker risk score was developed to determine the probability of stroke, systemic embolic events, or death by as- signing tiered points for higher concentrations of the biomarkers. MAIN OUTCOMES AND MEASURES Risk score and clinical outcomes based on cardiac troponin I, N- terminal pro-B-type natriuretic peptide, and D-dimer levels at baseline. RESULTS Of the 5002 patients enrolled in the biomarker substudy of the ENGAGE AF-TIMI 48 trial, 4880 patients (97.6%) had all 3 biomarkers available at randomization (1820 [37.3%] were women; median [interquartile range] age, 71 [64–77] years). After adjustment for the CHA2DS2-VASc score, each biomarker was associated with a 2.8-fold to 4.2-fold gradient of risk comparing the highest vs lowest concentrations across groups of increasing concentrations (P  <0.001 for trend for each). The multimarker risk score identified a more than 15- fold gradient of risk after adjustment for CHA2DS2- VASc score. When added to the CHA2DS2-VASc score, the biomarker score significantly enhanced prognostic accuracy by improving the C statistic from 0.586 (95% CI, 0.565–0.607) to 0.708 (95% CI, 0.688–0.728) (P<0.001) and reclassification with a net reclassification improvement of 59.4% (P<0.001). CONCLUSIONS AND RELEVANCE A prototype multimarker risk score significantly enhanced risk assessment for stroke, systemic embolic events, or death compared with traditional clinical risk stratification. Incorporation of biomarkers into clinical decision making to define therapeutic management in AF warrants consideration. JAMA Cardiol 2016 Oct 05;[Epub ahead of print], Ruff CT, Giugliano RP, Braunwald E, et al.

Stroke is a major worldwide source of morbidity and mortality with incidence rates that continue to climb dramatically in middle-lower income countries and elderly populations. 1,2 Atrial fibrillation (AF) is associated with more disabling and severe strokes compared with strokes from other causes, resulting in significantly higher rates of disability and mortality. 3 AF is felt to be a preventable cause of stroke due to the availability of highly

effective anticoagulation therapies. S troke risk stratification for anticoagulation use in AF patients is traditionally based on validated clinical risk scores. The most commonly used risk scores are CHADS 2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes, and stroke or transient ischemic attack [2 points]) andCHA 2 DS 2 -VASc (cardiac failure or dysfunction, hypertension, age 65–74 [1 point] or ≥ 75 years [2 points], diabetes mellitus, and stroke, transient ischaemic attack, or thromboembolism [2 points]–vascular disease, and sex [female gender]). These scores are derived from relatively broad static clinical components. As AF is often a risk marker of a dynamic systemic vascular disease state, of which stroke is a consequence, 4 it is not surprising that the broad risk stratification scores based on static baseline clinical variables perform poorly for stroke prediction. 5 In fact, the vast majority of these risk assessment tools have a C-statistic from 0.5 to 0.6, including both CHADS 2 and CHA 2 DS 2 -VASc – a statistical finding suggestive of a predictive accuracy only slightly better than chance. 5 This study brings up a necessary question. Why do we continue to use risk scores such as CHADS 2 or CHA 2 DS 2 -VASc that have very limited utility and a prognostic accuracy that is modestly better than flipping a coin? The key to improving stroke prediction and all other untoward outcomes associated with AF is finding tools that better diagnose and define the underlying systemic vascular dis- ease state. Since AF is a chronic progressive disease state in most patients, these tools need to be dynamic to redefine risk with disease evolution. Biomarkers that accurately measure contemporary vascular inflammation, vascu- lar stiffness and/or reactivity, adverse cardiac response and remodelling to exposure to el- evated filling pressures, and local and systemic hypercoagulability may provide the dynamic resource necessary to truly define stroke risk across broad AF populations. The ENGAGEAF-TIMI 48 trial was a ran- domised, prospective trial of 21,105 patients comparing edoxaban with warfarin in AF pa- tients at moderate to high risk of stroke. This study included a biomarker substudy of 4880 patients in which troponin I, NT-proBNP, and D-dimer levels were measured at study enroll- ment. 6 These biomarkers were analysed indi- vidually and then collectively in a biomarker risk score as to their association with incident stroke, thromboembolism, and death. The biomarker scores were then compared with CHA 2 DS 2 -VASc scores to determine which had better prognostic accuracy. First, for both D-dimer and NT-proBNP separated in quartiles and for troponin I separated in tertiles, there was a graded as- sociation with increasing serum levels and risk of stroke, thromboembolism, and death (P < 0.001 for all). More importantly, after

adjustment for CHA 2 -VASc scores, the multivariate hazard ratios remained significant for each biomarker ranging, from 1.22 to 1.39 in the lower serum levels to 2.83 to 4.16 in the higher serum levels. Next in this study, the prognostic accuracy of the CHA 2 DS 2 -VASc system was reassessed, and the C-statistic was 0.586; again suggestive of predictive utility only slightly better than chance. If a single biomarker is added to the CHA 2 DS 2 -VASc scoring system, this C-sta- tistic increased to 0.647 to 0.674. The three- component biomarker scored performed better than CHA 2 DS 2 -VASc and CHA 2 DS 2 -VASc with any one of the individual biomarkers, with a C-statistic of 0.700. Adding CHA 2 DS 2 -VASc to the three-component biomarker score only very marginally improved the diagnostic ac- curacy (C-statistic, 0.708). This study brings up a necessary question. Why do we continue to use risk scores such as CHADS 2 or CHA 2 DS 2 -VASc that have very limited utility and a prognostic accuracy that is modestly better than flipping a coin? First, these scores are easy to remember and have become part of standard-of-care nomencla- ture, consensus guidelines, and medical edu- cation. In other words, they are entrenched in our clinical practice. Second, these scores are derived from simple clinical demographics that can be collected by any physician or clinic and are not reliant on sometimes expensive testing such as testing for biomarkers or ad- vanced cardiac imaging. Finally, since neither scoring system works well, society consensus guidelines have evolved to recommended anti- coagulation in nearly all AF patients (CHADS 2 and CHA 2 DS 2 -VASc score ≥ 1). Since most AF patients are treated, the prognostic accuracy of the risk scores becomes less significant. 7 Long-term anticoagulation exposure is not without significant risks. Macro- and micro- bleeds can have devastating effects on organ function, leading to higher rates of mortality, disease-related morbidities, and disability. Risks of both bleeding and stroke evolve over time and both increase with aging. As AF pa- tients age, anticoagulation underuse is more often a problem than overuse; a problematic DS 2

trend that has persisted even after the in- troduction of direct oral anticoagulants. 8 If risk scores have a greater prognostic utility for both stroke and bleeding risks, physi- cian decisions to use anticoagulation will likely increase and improve, and guide- line recommendations can become more focused and helpful. However, in order to reach these improvements, we have to be willing to move beyond CHADS 2 and CHA 2 DS 2 -VASc risk scores and question our current models and understanding of AF and stroke. In the meantime, based on the results of this study clinicians should consider the additive value of biomarkers. For example, in further risk-stratifying a female patient at low-moderate risk (CHA 2 DS 2 -VASc score of 1 or 2) an elevated NT-proBNP and troponin I will raise the risk to moder- ate. In contrast, if these levels are low then the patient is low-risk. Another considera- tion is using these serum biomarkers in a patient at moderate risk of both bleeding and stroke to try to further investigate the risk-benefit ratio of anticoagulation. References 1. Feigin VL, Lawes CM, Bennett DA, et al. Lancet Neurol 2009;8(4):355-369. PIIS1474-4422(09)70025-0/abstract 2. Yiin GS, Howard DP, Paul NL, et al. Circulation 2014;130(15):1236-1244. 3. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke 1996;27(10):1760-1764. 4. Bunch TJ, May HT. Eur Heart J In press. 5. Lip GY, Nieuwlaat R, Pisters R, et al. Chest 2010;137(2):263-272. 6. Ruff CT, Giugliano RP, Braunwald E, et al. JAMA Cardiol In press. 7. Kirchhof P, Benussi S, Kotecha D, et al. Eur Heart J 2016; In press. 8. Alamneh EA, Chalmers L, Bereznicki LR. Am J Cardiovasc Drugs 2016;16(3):183-200.

Dr Bunch is Medical Director of Electrophysiology for Intermountain Healthcare, Intermountain Heart Institute, Intermountain Medical Center in Utah.

VOL. 1 • No. 3 • 2016