Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation

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Graham DJ, et al. "Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation". JAMA Internal Medicine. 2016. 176(11):1662-1671.
PubMed


Clinical Question

In elderly patients with nonvalvular atrial fibrillation, is treatment with rivaroxaban more effective at reducing the risk of stroke, bleeding, or mortality when compared with dabigatran?

Bottom Line

Rivaroxaban when compared to dabigatran was shown to be equally effective at reducing the risk of thromboembolic stroke. However, rivaroxaban is associated with increased rates of intracranial bleeding and extracranial bleeding, i.e. gastrointestinal bleeding, compared to dabigatran.

Major Points

Dabigatran and rivaroxaban are non–vitamin K oral anticoagulants approved for stroke prevention in patients with nonvalvular atrial fibrillation (AF). Each of these medications have been compared to and found to be at least as effective as warfarin individually for the prevention of stroke in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY trial) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF trial). From these results, indirect comparisons have been made between dabigatran and rivaroxaban. Although this study is not a head-to-head randomized control trial, each target-specific oral anticoagulants (TSOAC) is compared directly to one another in a retrospective fashion.

Guidelines

2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation

  • In patients with nonvalvular AF, the use of anticoagulation therapy for the prevention of stroke is based on patient specific risk factors, which is measured using the CHA2DS2-VASc score.
  • With prior stroke transient ischemic attack (TIA), or a CHA2DS2-VASc score >/= 2
    • Use warfarin (INR 2.0 to 3.0), dabigatran, rivaroxaban, or apixaban
  • If unable to maintain a therapeutic INR level with warfarin
    • Use a direct thrombin or factor Xa inhibitor (dabigatran, rivaroxaban, or apixaban)
  • If CHA2DS2-VASc = 0
    • It is reasonable to omit antithrombotic therapy

Design

  • Restropective, new-user cohort study
  • N=118,891
    • Dabigatran (n=52,240, 15,524 person-years on-treatment)
    • Rivaroxaban(n=66,651, 20,199 person-years on-treatment)
  • Setting: United States
  • Enrollment: Medicare patients that filled their first prescription for either drug from November 4, 2011 through June 30, 2014
  • Mean follow-up: Dabigatran: 108; Rivaroxaban: 111
  • Primary outcome: Risk of thromboembolic stroke, intracranial hemorrhage (ICH), major extracranial bleeding including gastrointestinal bleeding, and mortality

Population

Inclusion Criteria

  • Inpatient or outpatient diagnosis of AF or atrial flutter
  • Age >65 YO
  • Enrolled in fee-for-service Medicare Part A, Part B, or Part D
  • Filled first prescription between November 4, 2011 through June 30 2014
  • Treatment at standard doses

Exclusion Criteria

  • Enrollment in Medicare Part C
  • Less than 6 months of Medicare enrollment
  • Age <65 YO
  • Prior treatment with warfarin or any TSOAC
  • Patients residing in a skilled nursing facility or nursing home
  • Receivement of hospice care on date of qualifying prescription
  • Hospitalization beyond the index date
  • Kidney transplant/dialysis patients
  • Diagnoses or indications for anticoagulation within the 6 months preceding the study entry
    • Mitral valve disease, heart valve repair/replacement, DVT, PE, or joint replacement

Baseline Characteristics

Dabigatran vs. Rivaroxaban, respectively

  • Age
    • 65-74: 50/51
    • 75-84: 40/40
    • >/=85: 10/9
  • Female sex: 47/47
  • Race/ethnicity
    • White: 91/92
    • Black: 4/3
    • Other: 5/4
  • Diabetes: 34/32
  • Hypercholesterolemia: 39/40
  • Hypertension: 86/86
  • Kidney failure
    • Acute: 3/3
    • Chronic: 10/8
  • Obesity: 14/15
  • PUD: <1/<1
  • Prior hospitalized bleeding event: <1/<1
  • Smoking: 18/20
  • Acute MI
    • Past 1-30 days: 1/1
    • Past 31-182 days: 1/1
  • Coronary revascularization: 14/15
  • Heart failure
    • Hospitalized: 3/3
    • Outpatient: 13/11
  • Other ischemic heart disease: 44/45
  • Stroke
    • Past 1-30 days: 2/2
    • Past 31-182 days: 1/1
  • Other cerebrovascular disease: 11/11
  • Transient ischemic attack: 6/6
  • Cardioablation: 2/2
  • Cardioversion: 9/9
  • Other medical conditions
    • Falls: 5/5
    • Fractures: 1/1
    • Syncope: 8/9
    • Walker use: 2/2
  • CHADS2 score
    • 0-1: 33/34
    • 2: 40/40
    • 3: 19/18
    • >/=4: 8/8

Outcomes

Comparisons are dabigatran vs. rivaroxaban Incidence rate per 1,000 person-years (absolute number of events)

Primary Outcomes

Thromboembolic stroke
9.7 (150) vs. 7.7 (156) (HR 0.81; 95% CI 0.65-1.01; P=0.07)
ICH
3.7 (58) vs. 5.8 (118) (HR 1.65; 95% CI, 1.20-2.26; P= 0.002 NNH: 47 over 10 years)
Major extracranial bleeding
26.6 (413) vs. 39.4 (796) (HR 1.48; 95% CI, 1.32-1.67; P< 0.001 NNH: 7 over 10 years)
Major gastrointestinal bleeding
23.3 (362) vs. 32.5 (656) (HR 1.40; 95% CI, 1.23-1.59; P< 0.001 NNH: 10 over 10 years)
Mortality
22.2 (346) vs. 24.7 (500) (HR 1.15; 95% CI, 1.00-1.32; P= 0.051)

Secondary Outcomes

All hospitalized extracranial bleeds
39.2 (608) vs. 54.0 (1091) (HR 1.39; 95% CI 1.25-1.53; P< 0.001)
Acute Myocardial infarction
12.9 (200) vs. 11.0 (223) (HR 0.88; 95% CI 0.72-1.06; P=0.18)

Subgroup Analysis

  • Prespecified subgroup analyses were performed for all outcomes
    • Age
    • Sex
    • Hospitalization within the prior 30 days
    • Concomitant use of antiplatelet agents
    • Chronic kidney disease
    • CHADS2
    • HAS-BLED
  • In a secondary analysis, Cox models were generated to examine risk during predefined intervals of time during therapy because bleeding risks may be greatest during the first 3 months after anticoagulant initiation.We performed a number of sensitivity analyses.To assess whether the main analyses were affected by misclassification of exposed time, we restricted

analysis to patients with at least 2 prescription fills of a study drug, and increased the gap allowance between anticoagulant prescriptions from 3 to 14 days.

  • Post-hoc sensitivity analyses
    • The CHA2DS2-VASc was substituted for the CHADS2 score
    • Initiation of dialysis or kidney transplantation, or admission to a nursing home, skilled nursing facility, or hospice were no longer censored

Criticisms

  • The study had a mean duration of on-treatment follow-up of less than 4 months
    • Limits determination of long-term risks
  • Observational study
    • Introduces bias
  • Only looked at patients greater than 65 years-old who were warfarin naive first time users
    • Results are not generalizable to those patients of younger ages or those that have previously tried another anticoagulation therapy

Funding

  • This study was performed as part of the SafeRx project, a joint initiative of the Centers for Medicare & Medicaid Services (CMS) and the US Food and Drug Administration (FDA), and was funded through an interagency agreement.

Further Reading

  • David J. Graham, MD, MPH; Marsha E. Reichman, PhD; Michael Wernecke, BA; Ya-Hui Hsueh, PhD; Rima Izem, PhD; Mary Ross Southworth, PharmD; Yuqin Wei, MS; Jiemin Liao, MA; Margie R. Goulding, PhD; Katrina Mott, MHS; Yoganand Chillarige,MPA; Thomas E. MaCurdy, PhD; Chris Worrall, BS;Jeffrey A. Kelman, MD, MMSc
  • Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151.
  • Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011; 365(10):883-891.
  • January CT, Wann L, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64(21):2246-2280. doi:10.1016/j.jacc.2014.03.021.