Efficacy of rivaroxaban to prevent stroke in atrial fibriallation maintained in elderly

Efficacy and Safety of Rivaroxaban Compared with Warfarin among Elderly Patients with Nonvalvular Atrial Fibrillation in the ROCKET AF Trial

Literature - Halperin JL et al., Circulation 2014 - Circulation. 2014 Jun 3

Halperin JL, Hankey GJ, Wojdyla DM et al.; on behalf of the ROCKET AF Steering Committee and Investigators.
Circulation. 2014 Jun 3. [Epub ahead of print]


The net benefit of anticoagulation with warfarin rises with age [1], to reduce the risk of ischemic stroke in patients with atrial fibrillation (AF) [2]. The risk of bleeding when on anticoagulation increases with age, thus anticoagulation needs to be frequently monitored. Sensitivity to warfarin, polypharmacy and comorbidites [3] complicate maintenance of stable anticoagulation in elderly patients. As a consequence, elderly patients are undercoagulated, leaving them at high risk of stroke [4]. Novel anticoagulants (specific factor IIa or Xa inhibitors) have the advantage that they do not need regular monitoring, and have few drug and food interactions. This might facilitate more effective stroke prophylaxis in elderly AF patients.
This is a prespecified secondary analysis of the Rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in AF (ROCKET-AF) [5,6] to compare the efficacy (prevention of stroke and systemic embolism (SE)) and safety (bleeding) between warfarin and rivaroxaban in patients of >75 years and older, vs. those younger than 75 at study entry. 6229 patients (44%) were aged >75 years (median age: 79 years in both men and women). The median age in the younger group was 66 years. Follow-up duration was 24 months.

Main results

  • Compliance to randomised therapy was similar for both treatments in older patients (59.4% for warfarin, 59.3% for rivaroxaban), and younger patients (69.9% and 68.7%).
  • Stroke and SE were more common in older patients than in younger patients (2.57 vs. 2.05 per 100 patient-years (py), P=0.0068).
    Among older patients, the primary event rates were 2.29 (95%CI: 1.92-2.73) per 100 py with rivaroxaban and 2.85 (95%CI: 2.43-3.34) per 10 py with warfarin (HR: 0.80, 95%CI: 0.63-1.02).
    In younger patients, primary event rates were 2.00 (95%CI: 1.69-2.35) and 2.10 (95%CI: 1.79-2.46) per 100 py respectively (HR: 0.95, 95%CI: 0.76-1.19).
  • Primary event rates were higher in older women than in older men, but rivaroxaban lowered event rates to a similar extent in both sexes.
  • Rates of major bleeding were higher in older patients (4.63, 95%CI: 4.21-5.09 per 100 py) than in younger patients (2.74, 95%CI: 2.47-3.04, P<0.0001).
    No differences in rate of major bleeding were seen between treatments, in either age group.
  • Older patients on rivaroxaban had higher rates of the combined endpoint of major or clinically relevant non-major bleeding than those on warfarin (P(interaction)=0.009). The interaction was restricted to extracranial bleeding and mainly driven by a higher rate of gastrointestinal bleeding in elderly patients on rivaroxaban.
  • Rate of haemorrhagic stroke was not affected by age.

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This analysis shows that, although stroke and SE are more common in patients with nonvalvular AF of over 75 years than in younger patients, the effect of rivaroxaban on the prevention of stroke and SE is consistent across both age groups. Rates of major bleeding were higher in older than in younger patients, but not significantly different between treatment groups. In older patients, rivaroxaban was associated with a higher risk of major or clinically relevant non-major bleeding, which was restricted to extracranial bleeding. Intracranial bleeds had previously been shown to be lower with rivaroxaban than warfarin.
Thus, factor Xa inhibition is as effective as adjusted-dose warfarin to anticoagulate elderly patients with nonvalvular AF. Simplified anticoagulation management may improve stroke prevention in high-risk elderly patients.

Editorial comment [7]

“Halperin and colleagues, using data from the ROCKET AF trial demonstrate the utility of using rivaroxaban in older adults. Regardless of the medication chosen, however, older patients must always be treated cautiously due to an increased risk of stroke and bleeding, and additional challenges related to drug interactions. Despite the higher risk of primary events as well as risk due to the medications themselves, newer oral anticoagulants may be suitable alternatives to warfarin in older patients due to specific advantages; no need for regular monitoring, more rapid onset of action, and fewer drugand food interactions.As additional data is gathered in this large and higher risk population, our ability to guide optimal use in terms of risk/benefit as well as choose the optimalmedication/dosage and mitigate drug interaction, will expand and lead to better care of our older
patients.However, while there is no doubt about the benefits of oral anticoagulation in theelderly, focus must be placed on reducing their risk.”

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1. Singer DE, Chang Y, Fang MC et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med. 2009;151:297–305.
2. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857–867.
3. DiMarco JP, Flaker G, Walsdo A, et al.; AFFIRM Investigators. Factors affecting bleeding risk during anticoagulant therapy in patients with atrial fibrillation: observations from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Am Heart J. 2005;149:650–656.
4. Hylek EM, D’Antonio, Evans-Molina C, et al. Translating the results of randomized trials into clinical practice: the challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation. Stroke. 2006;37:1075–1080.
5. ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010;159:340–347.
6. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–891.
7. Freedman JE, Gersh BJ. Atrial Fibrillation and Stroke Prevention in Aging Patients: What's Good Can be Even Better. Circulation. published online June 3, 2014

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