Major Bleeding Complications in a Specialized Anticoagulation Service

Major Bleeding Complications in a Specialized Anticoagulation Service John Fanikos, RPh, MBAb, Nicole Grasso-Correnti, BSNa, Ravi Shah, BSa, Nils Kucher, MDa, and Samuel Z. Goldhaber, MDa,* Major bleeding complications were investigated in 2,460 patients with 3,684 patientyears of warfarin exposure from 2000 to 2003. The most common indications for anticoagulation were atrial fibrillation (30%), venous thromboembolic disease (28%), and mechanical heart valve prosthesis (15%). Eleven patients had 12 nonfatal major bleeding complications, with no fatal bleeds during the study. The incidence of major bleeding complications was 0.12%/year; there were 0.32 bleeds/100 patient-years of coverage. Of the 12 bleeding events, 5 (42%) were intracranial hemorrhages. The average hospitalization cost per patient was $15,988, and the average length of hospitalization was 6.0 days. © 2005 Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96:595–598) Although warfarin is effective in preventing and treating arterial and venous thrombosis, it exposes patients to increased risk for hemorrhage. The reported annual incidence of warfarinassociated major bleeding complications has ranged from 1.0% to 5.0%, with a 0.5% to 1.1% rate of fatal hemorrhage.1– 4 The incidence of warfarin-associated major and intracranial hemorrhage at Brigham and Women’s Hospital has increased over time.5 Brigham and Women’s Hospital operates a large anticoagulation service and supervises a patient population with diverse anticoagulation requirements. In this study, we investigated major bleeding complications in 2,460 patients managed by the Brigham and Women’s Hospital Anticoagulation Service from 2000 to 2003. We also determined the hospital costs and duration of hospitalization associated with these bleeding complications. •••

We reviewed medical records to determine baseline demographics, principal indications for anticoagulation, the intensity of anticoagulation, co-morbidities, bleeding risk factors, anatomic sites of hemorrhage, and international normalized ratios (INRs) at the time of the bleeding complications. Major bleeding was defined by the Thrombolysis In Myocardial Infarction criteria.6 Bleeding rates were determined by calculating the proportion of bleeding events per patient-years of warfarin exposure. During the study period, the software program Coumacare (Bristol-Myers Squibb Company, New York, New York) was interfaced with the hospital’s computer network. The 2 systems were

Departments of aMedicine and bPharmacy, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. Manuscript received January 3, 2005; revised manuscript received and accepted March 30, 2005. * Correspondence author. Tel. 617-732-7566; fax: 617-264-5144. E-mail address: [email protected] (S.Z. Goldhaber). 0002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.03.104

used, often requiring duplicate data entries, to monitor and document anticoagulation therapy. A warfarin dosage algorithm was available, but dosage adjustments were at the discretion of the individual practitioner. The Brigham and Women’s Hospital Anticoagulation Service uses a multidisciplinary team (nurses, pharmacists, and physician assistants) and uses a ratio of 1 health care provider to approximately 350 patients. The providers educate patients about their cardiovascular illnesses, train them on their medication requirements, and focus on the pharmacology of warfarin. Patients are encouraged to participate and collaborate in guiding their warfarin dosing. A prospective quality assurance program tracks bleeding complications. Bleeding events are entered into the hospital’s computer system at the time of occurrence. A nurse and/or pharmacist immediately investigates for follow-up details. Hospitalization cost per event was defined as the costs of any supplies or services that were billed to the patient as a result of hospitalization. Hospitalization costs included emergency department care, operating room use, hospital room and board, hospital-based physicians’ fees, nursing labor, dialysis, clinical laboratory studies, imaging studies, ancillary services, medications, diagnostic testing, and interventional procedures. The Brigham and Women’s Anticoagulation Service managed 2,460 patients with 3,684 patient-years of warfarin exposure from January 2000 to December 2003. Mean age was 59.7 years. The primary indication for anticoagulation was atrial fibrillation (30%), followed by venous thromboembolic disease (28%) and mechanical heart valve prosthesis (15%). There were no fatal bleeding events during the study. The incidence of major bleeding complications was 0.12%/year, and there were 0.32 bleeds/100 patient-years of warfarin exposure. Overall, 11 patients had 12 nonfatal major bleeding complications (Table 1). Mean age was 57 years. Of the 11 patients with major bleeding complications, 6 (55%) were men and 5 (45%) were women. Major bleedwww.AJConline.org

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Table 1 Brigham and Women’s Hospital Anticoagulation Service: 12 case descriptions of major hemorrhage Age (yrs)/Sex

Indication

INR Range

Event INR

Prior INR

Duration of Warfarin (days)

Location of Hemorrhage

Intervention

LOS

Cost

61/M 72/M 85/M 58/F 74/F 29/F 29/F 42/F 39/M 55/F 53/M 54/M

AF AF AF MVR (SJ) MVR (SJ) AVR (BS) AVR (BS) MV repair PE Calf DVT SMV thrombus AMI

2–3 2–3 2–3 2.5–3.5 2.5–3.5 2–2.5 2–2.5 2–3 3–4 2–3 2–3 2–3

10.6 5.2 4.3 4.4 3.1 3.2 ⬎12 1.6 3.1 4.6 2.4 4.0

2.0 2.9 3.0 1.9 3.2 6.0 1.4 2.05 2.8 2.9 2.3 3.7

644 10 200 37 1,324 389 1,170 11 13 12 160 22

GI Pericardial sac Intracranial Retroperitoneal Intracranial Intracranial Intracranial Pericardial sac Pericardial sac Vaginal GI Intracranial

Transfusion Pericardial catheter/window Transfusion Renal artery embolization 0 0 0 Pericardial window Pericardiocentesis Transfusion Transfusion Craniotomy

1 7 4 13 4 2 11 5 — 3 2 14

$3,192 $19,328 $5,718 $30,915 $10,969 $2,707 $19,376 $7,810 — $4,209 $7,203 $64,446

AF ⫽ atrial fibrillation; AMI ⫽ acute myocardial infarction; AVR ⫽ aortic valve replacement; BS ⫽ Bjork-Shiley; DVT ⫽ deep vein thrombosis; GI ⫽ gastrointestinal; LOS ⫽ length of hospital stay; MV ⫽ mitral valve; MVR ⫽ MV replacement; PE ⫽ pulmonary embolism; SJ ⫽ St. Jude; SMV ⫽ superior mesenteric vein.

ing occurred during the first 90 days of treatment in 50% of patients. Of the 12 bleeding events, 5 (42%) were intracranial hemorrhages. Two of the 5 intracranial hemorrhages occurred in the setting of an INR ⬎4.0. At the time of the bleeding complications, 10 INRs (83%) were documented at ⬎3.0, 1 (8%) was ⬍2.0, and 1 (8%) was within the target INR range of 2.0 to 3.0. The mean dose of warfarin at the time of the bleeding complications was 5.15 mg. Although no events were related to warfarin-drug interactions or dosing errors, 5 patients were taking aspirin as prescribed at the time of the bleeding events. One patient had discontinued clopidogrel 2 days before developing an intracranial hemorrhage. One patient, a 29-year-old woman with progeria and a Bjork-Shiley aortic valve, had 2 intracranial hemorrhages. The first intracranial hemorrhage occurred in the setting of an INR ⬎12.0. The second event occurred when her INR was within therapeutic range. No surgical intervention was performed with either event, and the patient was discharged home on each occasion with no residual deficits. Of the 3 remaining patients who had intracranial hemorrhages, 2 had no residual neurologic deficits. The extent of recovery of the third patient is unknown. Cost data were obtained for 10 of the 11 patients. One patient, a 39-year-old man who had a hemorrhagic pericardial effusion, was admitted to an outside institution and therefore was not included in the cost survey. The total cost for these patients (including 1 patient admitted twice for 2 separate episodes of intracranial hemorrhage) was $175,873. The average cost per patient was $15,988, and the average length of hospitalization was 6 days. The costs per hospital admission ranged from $2,707 to $64,446. The patient whose admission resulted in costs of $64,446 had an intracranial hemorrhage and required 2 neurosurgical procedures. When this patient was excluded, the mean cost per hospital admission was $11,142. He was discharged to a

rehabilitation center for the treatment of a residual neurologic deficit. •••

We observed a low rate of major bleeding complications: 0.32 events/100 patient-years. There were no fatalities from warfarin-related hemorrhage. Most of the bleeding events occurred at supratherapeutic INRs (⬎3; 83%). Although excessive anticoagulation assessed by laboratory coagulation monitoring can predict adverse clinical events,7 an elevated INR may occur only briefly before a bleeding event.8 Most previous studies of anticoagulation clinic management reported major bleeding complication rates from 1.1 to 2.1/100 patient-years of coverage (Table 2). A recent metaanalysis of 33 studies showed that major and fatal bleeding occurred at rates of 7.2 and 1.3 events/100 patient-years, respectively.9 In the Italian Study on Complications of Oral Anticoagulant Therapy, the rate of bleeding complications was 1.1/ 100 patient-years of follow-up, including 5 fatalities from intracranial bleeds.10 In that study, most bleeding episodes occurred with INRs in the sub- or therapeutic range. Four Dutch anticoagulation clinics following 1,608 patients with mechanical heart valve prostheses for 6,475 patient-years of coverage demonstrated a major bleeding rate of 2.1/100 patient-years. Most of the bleeding events were gastrointestinal (36.7%) in origin or involved the skin or muscles (25.8%).11 Of 5 anticoagulation clinics enrolling 928 patients followed for 1,950 patient-years, Fihn et al12 reported 1.7 major bleeding events/100 patient-years of coverage, with 0.2 fatal events/100 patient-years. The University of Florence anticoagulation clinic followed 903 patients for 1,679 patient-years and reported 1.1 major bleeding events/100 patient-years of coverage.13 Chiquette et al14 had a combined major and fatal bleeding

Table 2 Anticoagulation indications, bleeding sites, and event rates Variable

Italian Federation of Anticoagulation Clinics10

Leiden, The Hague, Enschede, and Oost-Gelderland Anticoagulation Clinics11

(n ⫽ 2,460)

(n ⫽ 2,745)

3,684

2,011

30% 28% 15% 15% 3% 0% 0% 9%

17% 33% 17% 0% 3% 0% 5% 25%

41.7% 16.7% 41.6% 0.32

17.4% 30.4% 52.2% 1.1

0.25

0

University of Florence13

University of Texas14

Bergamo Hospital Italy15

5 U.S. Managed Care Organizations16

(n ⫽ 1,608)

Seattle, Buffalo, and Palo Alto VAMC; Universities of Virginia and California, Davis12 (n ⫽ 928)

(n ⫽ 903)

(n ⫽ 176)

(n ⫽ 271)

(n ⫽ 173)

6,475

1,950

1,679

123

669

0% 0% 100% 0% 0% 0% 0% 0%

14% 30% 26% 0% 21% 0% 0% 10%

28% 27% 29% 0% 0% 0% 0% 16%

0% 36.7% 63.3% 2.1

6.5% 74.1% 19.4% 1.6

15.8% 47.3% 36.9% 1.1

0.3

0.2

0.06

14% 21% 14% 0% 6% 10% 15% 20% Not reported

1.6

0

96

0% 0% 100% 0% 0% 0% 0% 0%

100% 0% 0% 0% 0% 0% 0% 0%

0% 0% 100% 1.0

Not reported

0

1.7*

0

Miscellaneous/Bleeding Complications in an Anticoagulation Service

Patient-yrs of anticoagulation Indications Atrial fibrillation VTE Heart valve Orthopedic surgery Neurologic CHF CMP All other Bleeding site Intracranial Gastrointestinal All other Rate of major-bleeding (events per 100 patient-yrs) Fatal bleeding (events per 100 patient-yrs)

Brigham and Women’s Hospital

* Reported as events per patient studied. CHF ⫽ congestive heart failure; CMP ⫽ cardiomyopathy; VAMC ⫽ Veterans Affairs Medical Center; VTE ⫽ venous thromboembolic disease.

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complication rate of 1.6 events/100 patient-years in 176 patients; the mean INR at the time of event was 5.6. Cortelazzo et al15 reported a major bleeding rate of 1.0/100 patient-years, with 3 of 7 patients (43%) having INRs ⬎4.5 at hospitalization. In comparison with other centers reporting hemorrhagic complications, our patient population was composed of a smaller percentage of patients with heart valve prostheses and larger percentages of patients requiring anticoagulation after orthopedic surgery and for the treatment of venous thromboembolic disease. These differences may partially explain the differences in the number of reported bleeding events. Like other reporting centers, bleeding events were most likely to occur in the first 90 days of therapy, suggesting the need for close follow-up during the initial period of anticoagulation. In our patients, the principal bleeding site (41.7%) was intracranial. In contrast, other clinics have reported larger proportions (30.4% to 74.1%) of gastrointestinal bleeding. Because intracranial hemorrhage may be spontaneous, especially in the elderly (with or without mild trauma), it is possible that not all of these events were warfarin-related. Comparing major bleeding episodes across anticoagulation clinics is difficult (Table 2). Patient populations, organizational setting, anticoagulant indications, and the definition of a major hemorrhage vary from center to center.16 Although warfarin management varies among centers, those using a multicomponent approach of education, training, self-monitoring, and guided warfarin dosing have reduced the frequency of major bleeding.17 The Brigham and Women’s Hospital Anticoagulation Service invests heavily in the education of patients and family members on the requirements of therapy. This approach, coupled with an emphasis on facilitating and coordinating care among health care providers, may in part explain our low rate of major bleeding.18 1. Hylek EM, Chang YC, Skates SJ, Hughes RA, Singer DE. Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation. Arch Intern Med 2000;160:1612–1617. 2. Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV, Singer DE. Effect of the intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349: 1019 –1026. 3. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 1993;95:315–328. 4. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994;120:897–902.

5. Kucher N, Castellanos LR, Quiroz R, Koo S, Fanikos J, Goldhaber SZ. Time trends in warfarin-associated hemorrhage. Am J Cardiol 2004; 94:403– 406. 6. Bovill EG, Tracy RP, Knatterud GL, Stone PH, Nasmith J, Gore JM, Thompson BW, Tofler GH, Kleiman NS, Cannon C, et al. Hemorrhagic events during therapy with recombinant tissue plasminogen activator, heparin, and aspirin for unstable angina (Thrombolysis In Myocardial Ischemia, Phase IIIB Trial). Am J Cardiol 1997;79:391– 396. 7. Koo S, Kucher N, Nguyen PL, Fanikos J, Marks PW, Goldhaber SZ. The effect of excessive anticoagulation on mortality and morbidity in hospitalized patients with anticoagulant-related major hemorrhage. Arch Intern Med 2004;164:1557–1560. 8. Kucher N, Connolly S, Beckman JA, Cheng LH, Tsilimingras KV, Fanikos J, Goldhaber SZ. International normalized ratio increase before warfarin-associated hemorrhage: brief and subtle. Arch Intern Med 2004;164:2176 –2179. 9. Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism. Ann Intern Med 2003;139:893–900. 10. Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D’Angelo A, Pengo V, Erba N, Moia M, Ciavarella N, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT): Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 1996;348:423– 428. 11. Cannegieter SC, Rosendaal FR, Wintzen AR, Van Der Meer FJ, Vandenbroucke JP, Briët E. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995;333:11–17. 12. Fihn SD, McDonell M, Martin D, Henikoff J, Vermes D, Kent D, White RH. Risk factors for complications of chronic anticoagulation. A multicenter study; Warfarin Optimized Outpatient Follow-Up Study Group. Ann Intern Med 1993;118:511–520. 13. Poli D, Antonucci E, Lombardi A, Cecchi E, Corsini I, Gensini GF, Abbate R, Prisco D. Low incidence of hemorrhagic complications of oral anticoagulant therapy in patients with atrial fibrillation in the daily practice of an anticoagulation clinic. Ital Heart J 2003;4:44 – 47. 14. Chiquette E, Amato MG, Bussey HI. Comparison of an anticoagulation clinic with usual medical care: anticoagulation control, patient outcomes, and health care costs. Arch Intern Med 1998;158:1641– 1647. 15. Cortelazzo S, Finazzi G, Viero P, Galli M, Remuzzi A, Parenzan L, Barbui T. Thrombotic and hemorrhagic complications in patients with mechanical heart valve prosthesis attending an anticoagulation clinic. Thromb Haemost 1993;69:316 –320. 16. Matchar DB, Samsa GP, Cohen SJ, Oddone EZ, Jurgelski AE. Improving the quality of anticoagulation of patients with atrial fibrillation in managed care organizations: results of the managing anticoagulation services trial. Am J Med 2002;113:42–51. 17. Beyth RJ, Quinn L, Landefeld SC. A multicomponent intervention to prevent major bleeding complications in older patients receiving warfarin: a randomized controlled trial. Ann Intern Med 2000;133:687– 695. 18. Grasso-Correnti N, Goldszer RC, Goldhaber SZ. The critical pathways of an anticoagulation service. Crit Path Cardiol 2003;1:41– 45.