ABC Risk Score Better Predicts Bleeding in Atrial Fibrillation

Pam Harrison

June 03, 2016

UPPSALA, SWEDEN — A biomarker-based model used to assess bleeding risk in atrial fibrillation (AF) patients on anticoagulation outperforms standard bleeding risk scores based on clinical risk factors alone, new research shows[1].

"The benefit of oral anticoagulation in atrial fibrillation is based on a balance between reduction in ischemic stroke and increase in major bleeding events, and right now, the risk of bleeding in patients on oral anticoagulation is mostly assessed by the HAS-BLED score, which is based on clinical risk factors," Dr Ziad Hijazi (Uppsala University, Sweden) told heartwire from Medscape in an email.

"However, several biomarkers have now been shown to provide incremental information about the risk of bleeding in patients with atrial fibrillation, so to improve risk assessment, it's important to include these biomarkers among the candidate variables," he added.

"And our ABC (age, biomarkers, clinical history) bleeding score showed better discrimination and utility than the HAS-BLED and ORBIT scores concerning major bleeding and intracranial hemorrhages, so it should be useful in decision support regarding oral anticoagulation treatment in patients with atrial fibrillation."

The study was published in the June 4, 2016 issue of the Lancet.

Strongest Biomarkers

Hijazi and colleagues selected what they felt were the strongest biomarkers available to assess bleeding risk in AF for their new model. These included growth-differentiating factor-15 (GDF-15), a marker of oxidative stress; cardiac troponin measured with high-sensitivity assays (cTnT-hs), a marker of myocardial injury; cystatin C or estimated glomerular filtration rate (eGFR) for renal function, and hemoglobin or hematocrit, both markers of anemia.

They also included clinical risk factors along with N-terminal pro-B-type natriuretic peptide (NT-proBNP), a stroke risk biomarker.

First, the novel risk score was validated in a large cohort of patients involved in the Apixaban for Reduction in Stroke and other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial that randomized patients to apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) or warfarin. Biomarker data were available for 14,537 ARISTOLE participants. Major bleeding occurred in 662.

Using the new ABC bleeding risk score, Hijazi and colleagues found that the strongest predictors of major bleeding among ARISTOLE participants were GDF-15, hemoglobin, cTnT-hs, age, and history of a prior bleed.

These five variables were subsequently included in their revised ABC bleeding risk-prediction model and its ability to predict major bleeding was compared with that of the HAS-BLED score and newer ORBIT score.

The ABC bleeding risk score showed a c-index of 0.68, Hijazi reported. A c-index of 1.0 implies perfect discrimination between events and nonevents while a c-index of 0.5 is poor and corresponds to flipping a coin.

The HAS-BLED achieved a c-index of 0.61 and the ORBIT a c-index of 0.65. The difference between the ABC bleeding risk score was significant for both the HAS-BLED (P<0.001) and ORBIT (P=0.0008) scores.

"The ABC bleeding score performed equally well in patients treated with warfarin or apixaban, without any significant interaction with the effects of the randomized treatment," investigators observed.

External Validation

Hijazi and colleagues then went on to externally validate their findings based on biomarker data in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY), in which AF patients were randomized to dabigatran (Pradaxa, Boehringer Ingelheim) or warfarin. Biomarker samples were available for 8468 patients, and 463 major bleeding events were observed.

Again, the novel ABC bleeding risk score achieved a higher c-index than the two comparator scores at 0.71 vs 0.62 for the HAS-BLED and 0.68 for the ORBIT ( P<0.0001 and P=0.0016, respectively).

"The ABC bleeding score also outperformed the HAS-BLED and ORBIT scores concerning the predictive value of intracranial hemorrhages," Hijazi noted (c-index 0.66 vs 0.58 and 0.60, respectively).

"Importantly, the results from the external validation confirmed that the ABC bleeding risk score provided a better risk prediction than the other risk scores in the comparison," he added.

The novel biomarker-based bleeding risk score also discriminated bleeding risk well in different AF subgroups and was able to accurately identify bleeding risk even among patients with low HAS-BLED and ORBIT scores.

Asked whether the ABC bleeding risk score is ready for "prime-time," senior author Dr Lars Wallentin (Uppsala University) noted that troponin is already widely available in large parts of the world and Roche expects to launch GDF-15 as a novel biomarker in June 2016.

"Most clinicians are used to nomograms, electronic calculators, or digital apps in everyday practice—for example, to calculate creatinine clearance, GRACE scores, and so forth," Wallentin added. "So availability will probably not be a problem, especially considering the advantage of the ABC bleeding score, which improves risk prediction [of major bleeding in AF patients]."

Several Merits

Commenting to heartwire on the study, Dr Paulus Kirchhof (University of Birmingham, UK) said clinical scoring systems have been used to identify patients at high risk of bleeding, but they often overlap with scoring systems for ischemic strokes. Almost all patients at high risk of bleeding on anticoagulation are also at high risk of stroke without anticoagulation. In most patients, this does not matter as the risk of stroke without anticoagulation is much higher than the risk of bleeding with anticoagulation.

"However, in a few patients at extreme bleeding risk and at relatively low risk for stroke, there may be a need to seek treatment options that reduce the risk of bleeding on anticoagulation such as an approved, reduced dose of a novel oral anticoagulant or even left atrial appendage occlusion or removal," he noted in an email. "In such conditions, it seems very reasonable to measure blood biomarkers such as GDF-15 or creatinine clearance, high-sensitive troponin, or brain natriuretic peptide," but only when difficult decisions regarding oral anticoagulation are made by a multidisciplinary team involving neurologists and cardiologists.

The study was funded by Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, and Roche Diagnostics. Hijazi reports institutional research grants from Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer and lecture fees from Boehringer Ingelheim. Wallentin has received institutional research grants, consultancy and lecture fees, travel support, and honoraria from GlaxoSmithKline; institutional research grants, consultancy and lecture fees, and travel support from AstraZeneca, Bristol-Myers Squibb/Pfizer, and Boehringer Ingelheim; institutional research grants from Merck and Roche; consultancy fees from Abbott; and holds two patents involving GDF-15. Disclosures for the coauthors are listed in the article. Kirchhof reports receiving personal fees from Bayer, Daiichi Sankyo, Medtronic, Boehringer Ingelheim, Bristol-Myers Squibb, German Cardiac Society Akademie, CTI, Medscape, Servier, Pfizer, and Biosense-Webster outside of the submitted work. He also has a patent on AF therapy and a patent on markers for AF pending to University of Birmingham.

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