ORIGINAL CONTRIBUTION

Association of Warfarin Therapy Duration After Bioprosthetic Aortic Valve Replacement With Risk of Mortality, Thromboembolic Complications, and Bleeding Charlotte Me´rie, MD Lars Køber, MD, DMSc Peter Skov Olsen, MD, DMSc Charlotte Andersson, MD, PhD Gunnar Gislason, MD, PhD Jan Skov Jensen, MD, PhD, DMSc Christian Torp-Pedersen, MD, DMSc

B

IOLOGICAL PROSTHESES ARE PREferred to mechanical valves for aortic valve replacement (AVR) surgery in elderly patients older than 65 years because of shorter life expectancy and lack of a need to use anticoagulation treatment in the long term. Especially in these patients, the tradeoff between thromboembolic complications due to the valve implant and bleeding events as adverse effects from anticoagulation therapy must be balanced. Nevertheless, appropriate duration of anticoagulation treatment postoperatively is yet to be established because the risk of complications when the treatment is discontinued is unknown. Current guidelines1-3 of anticoagulation treatment after bioprosthetic AVR surgery recommends 3 months of warfarin treatment. However, this recommendation is primarily based on results from 1 retrospective study4 with limited number of events hampered by the observational design as well as low power like all other studies within this scope.

For editorial comment see p 2147. 2118

JAMA, November 28, 2012—Vol 308, No. 20

Context The need for anticoagulation after surgical aortic valve replacement (AVR) with biological prostheses is not well examined. Objective To perform a nationwide study of the association of warfarin treatment with the risk of thromboembolic complications, bleeding incidents, and cardiovascular deaths after bioprosthetic AVR surgery. Design, Setting, and Participants Through a search in the Danish National Patient Registry, 4075 patients were identified who had bioprosthetic AVR surgery performed between January 1, 1997, and December 31, 2009. Concomitant comorbidity and medication were retrieved. Poisson regression models were used to determine risk. Main Outcome Measures Incidence rate ratios (IRRs) of strokes, thromboembolic events, cardiovascular deaths, and bleeding incidents by discontinuing warfarin as opposed to continued treatment 30 to 89 days, 90 to 179 days, 180 to 364 days, 365 to 729 days, and at least 730 days after surgery. Results The median duration of follow-up was 6.57 person-years. Estimated rates of events per 100 person-years in patients not treated with warfarin compared with those treated with warfarin with comparative absolute risk were 7.00 (95% CI, 4.07-12.06) vs 2.69 (95% CI, 1.49-4.87; adjusted IRR, 2.46; 95% CI, 1.09-5.55) for strokes; 13.07 (95% CI, 8.76-19.50) vs 3.97 (95% CI, 2.43-6.48; adjusted IRR, 2.93; 95% CI, 1.54-5.55) for thromboembolic events; 11.86 (95% CI, 7.81-18.01) vs 5.37 (95% CI, 3.54-8.16; adjusted IRR, 2.32; 95% CI, 1.28-4.22) for bleeding incidents; and 31.74 (95% CI, 24.69-40.79) vs 3.83 (95% CI, 2.35-6.25; adjusted IRR, 7.61; 95% CI, 4.37-13.26) for cardiovascular deaths within 30 to 89 days after surgery; and 6.50 (95% CI, 4.67-9.06) vs 2.08 (95% CI, 0.99-4.36; adjusted IRR, 3.51; 95% CI, 1.54-8.03) for cardiovascular deaths within 90 to 179 days after surgery. Conclusion Discontinuation of warfarin treatment within 6 months after bioprosthetic AVR surgery was associated with increased cardiovascular death. www.jama.com

JAMA. 2012;308(20):2118-2125

In this nationwide study, we investigated whether discontinuation of warfarin treatment within prespecified periods after bioprosthetic AVR surgery was associated with increased risk of thromboembolic complications, cardiovascular death, and bleeding incidents during a period of 13 years.

Author Affiliations: Department of Cardiology, Copenhagen University Hospital Gentofte, Copenhagen, Denmark (Drs Me´ rie, Andersson, Gislason, Skov Jensen, and Torp-Pedersen); and Department of Cardiology (Dr Køber) and Department of Cardiothoracic Surgery (Dr Skov Olsen), Copenhagen University Hospital Rigshospitalet, Denmark. Corresponding Author: Charlotte Me´ rie, MD, Department of Cardiology, Copenhagen University Hospital Gentofte, Niels Andersens Vej 65, 2900 Hellerup, Denmark ([email protected]).

©2012 American Medical Association. All rights reserved.

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WARFARIN THERAPY AFTER BIOPROSTHETIC AORTIC VALVE REPLACEMENT

METHODS Participants and Study Design

All patients having bioprosthetic AVR with or without coronary artery bypass graft (CABG) surgery performed between January 1, 1997, and December 31, 2009, in Denmark were identified through a search in the Danish National Patient Registry. Patients with prior cardiac surgery or other concomitant surgical procedures were excluded. The Danish Data Protection Agency approved the use of personal data (reference 2007-58-0015, internal reference GEH-2010-001). Retrospective studies do not require ethical approval in Denmark. Hospital diagnoses, procedures, medication, age, sex, and causes of death were retrieved from the National Danish Registries. Due to a law-imposed demand of reporting these data, a high degree of completion is ensured. The Danish National Patient Registry contains information on all hospital admissions and diagnoses in Denmark since 1978. The diagnoses are classified according to the International Classification of Diseases, 8th Revision (ICD-8) and International Statistical Classification of Diseases, 10th Revision (ICD-10) (ie, patients with stroke were identified by stroke diagnoses recorded in the National Hospital Registry as codes I61, I62, I63, and I64). Previously, these diagnoses have proven valid with positive predictive values of 74% to 97%.5,6 Similarly, to retrieve information on comorbidity, we identified prespecified discharge diagnoses (for ICD-8 and ICD-10 codes, see eTable 1, available at http://www.jama .com) in the Danish National Patient Registry dating back 18 years preoperatively. Patients with diabetes were identified through their use of glucoselowering medication. Main Outcome Measures

Primary events studied included stroke, thromboembolic complications (ie, ischemic strokes, myocardial infarctions, and peripheral arterial emboli), bleeding incidents (ie, gastrointestinal, intracranial, urinary tract, and air-

way bleedings7), and cardiovascular death (eTable 2). The term cardiovascular death included all deaths, with a cardiovascular cause registered on the death certificates forming the basis of the Danish National Death Registry. Medication

Use of medication was obtained from the Danish Registry of Medicinal Product Statistics where all prescriptions dispensed from Danish pharmacies since 1995 are recorded. Registration is complete due to linkage to reimbursement from the state, and medication from other sources is limited.8 The information for each medication coded according to the Anatomical Therapeutic Chemical (ATC) System included number and strength of tablets. Calculations regarding the daily warfarin dosage were restricted by a minimal dose of warfarin of 0.625 mg and a maximal dose of 17.5 mg. A patient starting warfarin therapy was assumed to start on a default dose of 5 mg. Whenever a new prescription was claimed, the average dose of up to 3 previous prescription periods was calculated. Those prior prescription periods, which could represent a continuous treatment with at least the minimal dose, were included in that calculation. To avoid conditioning on the future, later prescriptions were not included in calculations. Patients were assumed to continue with the dose below this dose that is a multiple of 0.625 mg (one quarter of a tablet). The minimal and maximal dose set limits to this calculation. Discontinuance of treatment was assumed when there were no tablets left according to the calculations. The value of these calculations are dependent on the calculations not being highly sensitive to assumptions. Sensitivity analyses were performed by using a minimal dose of 5 mg and a default dose of 7.5 mg, and by using an automatic lengthening of any treatment period of either 14 or 30 days. Information obtained on other medication at the time of surgery required that each patient claimed at least 1 prescription on prespecified medication within 3 months before surgery.

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Statistical Analyses

The studied cohort originates from a fixed population defined by all individuals in Denmark alive and aged older than 18 years on or after January 1, 1997, and patients can only be lost to follow-up by emigrating. In the current study period, 3 patients (0.07%) emigrated and were censored at time of emigration. We determined the occurrence of events 30 to 89 days, 90 to 179 days, 180 to 364 days, 365 to 729 days, and at least 730 days after surgery. At these time points, analysis time was split and event rates for patients with and without warfarin treatment were calculated as the number of events divided by the sum of person-time. Patients were censored at event, emigration, or end of follow-up. Poisson regression models were used for survival type analysis to calculate incidence rate ratios as an indicator of relative risk (RR). With an exposure ratio of warfarin treatment vs nontreatment of 3.6, a risk of cardiovascular death of 7.5% among patients without warfarin and a type 1 error risk of .05, we obtained a power of 66% to detect a difference in RR of 1.3, 86% power for an RR of 1.4, and 96% for an RR of 1.5. Subgroup analyses were preplanned and intended to challenge the results by removing patients with a variety of profiles. All P values reported were 2-sided and considered statistically significant if P⬍.05. Statistical analyses were performed by using SAS version 9.2 (SAS Institute) and Stata version 11.1 (StataCorp LP). RESULTS A total of 4075 patients were identified who had bioprosthetic AVR surgery performed after excluding patients in warfarin treatment before surgery (n=684) and patients with a diagnosis of atrial fibrillation within 30 days after surgery (n=1215). A total of 301 patients were both in warfarin treatment before surgery and had atrial fibrillation within 30 days after surgery. In addition, 8 patients discontinued warfarin treatment within the first 30 days after surgery. This period was omitted from the analyses ensuring all patients had an equal JAMA, November 28, 2012—Vol 308, No. 20

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WARFARIN THERAPY AFTER BIOPROSTHETIC AORTIC VALVE REPLACEMENT

Figure 1. Flow Diagram of Patients With Bioprosthetic AVR 5673 Patients who had bioprosthetic AVR with or without CABG surgery from Danish National Patient Registry

1598 Excluded a 1215 Had atrial fibrillation