ROCKET AF Analysis Isolates Predictors of Intracranial Hemorrhage in A-fib Population

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Patients with atrial fibrillation (A-fib) randomized to receive the direct factor Xa inhibitor rivaroxaban instead of warfarin and those with a history of congestive heart failure (CHF) are less likely to develop intracranial hemorrhage while on anticoagulation, according to an analysis of the ROCKET AF trial published online April 17, 2014, ahead of print in Stroke. A host of other factors including race, older age, and high diastolic blood pressure were found to be associated with increased risk.

In the original ROCKET AF trial, published in 2011 in the New England Journal of Medicine, 14,264 A-fib patients were randomized to receive fixed-dose rivaroxaban (20 mg daily or 15 mg daily in those with creatinine clearance 30-49 mL/min) or dose-adjusted warfarin (target international normalized ratio 2.0-3.0).

For the new study, researchers led by Graeme J. Hankey, MD, of The University of Western Australia (Perth, Australia), looked at rates, outcomes, and predictors of intracranial hemorrhage in the ROCKET AF population.

CHF, Rivaroxaban Reduce Risk

Over a median of 1.94 years of follow-up, 172 patients (1.2%) experienced intracranial hemorrhage, resulting in an annual rate of 0.67%. At 30 days, 43% of patients with intracranial hemorrhage died (100% attributed to the complication). At 90 days, 51% had died (96.6% attributed to the complication).

On multivariable Cox proportional hazards modeling, independent predictors of intracranial hemorrhage were race, age, reduced serum albumin, reduced platelet count, previous stroke or transient ischemic attack (TIA), and increased diastolic pressure. Conversely, randomization to rivaroxaban and history of congestive heart failure (CHF) were both predictors of reduced risk of intracranial hemorrhage (table 1).

Table 1. Factors Associated with Intracranial Hemorrhage in ROCKET AF

 

HR (95% CI)

P Value

Race (vs white or other)
Asian
Black

 
2.02 (1.39-2.94)
3.25 (1.43-7.41)

 
< 0.001

Randomization to Rivaroxaban

0.60 (0.44-0.82)

0.001

Age (per 10-year increase)

1.35 (1.13-1.63)

0.001

Albumin (per 0.5 g/dL decrease)

1.39 (1.12-1.73)

0.003

Platelets <210x109/L
(per 10x109/L below 210x109/L)

1.08 (1.02-1.13)

0.004

History of CHF

0.65 (0.47-0.89)

0.007

Previous Stroke or TIA

1.42 (1.02-1.96)

0.036

Diastolic Blood Pressure (per 10 mm Hg increase)

1.17 (1.01-1.36)

0.042


History of CHF and randomization to rivaroxaban were not predictors of ischemic stroke.

Overall, the model demonstrated a good ability to discriminate individuals with and without intracranial hemorrhage (C-index, 0.69; 95% CI 0.64-0.73). Additionally, sensitivity analyses showed that the primary model in the intention-to-treat population was internally consistent in the safety, on-treatment population.

When geographical region was entered into the model, residence in Eastern Europe vs Western Europe, North America, Latin America, or Asia Pacific (HR 0.37; 95% CI 0.25-0.55) and reduced creatinine clearance (HR 1.11; 95% CI 1.04-1.19 per 10 mL/min decrease) emerged as additional independent predictors of intracranial hemorrhage, whereas race, age, and history of CHF did not. A model in which use of antithrombotic agents (aspirin, vitamin K antagonists, and thienopyridines) was considered found that baseline use of a thienopyridine significantly increased the hazard of intracranial hemorrhage (HR 2.57; 95% CI 1.30-5.07; P = 0.006), while previous vitamin K antagonist use was associated with lower risk (HR 0.68; 0.50-0.94; P = 0.018).

Confirms Safety Advantage for Rivaroxaban

“Our findings of a higher risk of anticoagulant-associated [intracranial hemorrhage] in Asians, blacks, the elderly, and patients with a history of stroke and elevated blood pressure are consistent with other observational studies and schema for predicting an increased risk of major (intracranial and extracranial) hemorrhage among anticoagulated individuals in other populations, supporting the external validity of our results,” Dr. Hankey and colleagues write.

However, they note that low platelet count, particularly a low-normal platelet count, has not previously been shown to independently correlate with risk of intracranial hemorrhage.

The higher risk for intracranial hemorrhage with declining serum albumin, they add, “may reflect that both warfarin and rivaroxaban are highly protein bound,” while lower risk in patients with a history of CHF “may reflect a hypercoagulable state in heart failure.”

As for the association with Eastern Europe, the researchers say this is “extraordinary, not previously reported, and unlikely to be plausible,” adding that there was no significant association between residence in Eastern Europe and risk of ischemic stroke.

Dr. Hankey and colleagues acknowledge that they were unable to adjust for baseline variables that may influence risk of intracranial hemorrhage, nor did they record specific details of how intracranial hemorrhage was treated when it did occur.

“These data suggest that [intracranial hemorrhage] during anticoagulation may be reduced by lowering blood pressure and using rivaroxaban instead of warfarin,” the study authors conclude. “The external validity of these findings requires testing in other [A-fib] populations.”

 


Source:
Hankey GJ, Stevens SR, Piccini JP, et al. Intracranial hemorrhage among patients with atrial fibrillation anticoagulated with warfarin or rivaroxaban: the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation. Stroke. 2014;Epub ahead of print.

 

 

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Disclosures
  • ROCKET AF was supported by research grants from Bayer HealthCare AG and Johnson &amp; Johnson.
  • Dr. Hankey reports receiving honoraria for serving on executive committees for Bayer and Johnson &amp; Johnson.

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