- Email: [email protected]
Time trends in warfarin-associated hemorrhage
Time Trends in Warfarin-Associated Hemorrhage Nils Kucher,
MD,
Luis R. Castellanos, MD, Rene Quiroz, MD, MPH, Sophia Koo, John Fanikos, RPh, MBA, and Samuel Z. Goldhaber, MD
BS,
The annual incidence of warfarin-related bleeding at Brigham and Women’s Hospital increased from 0.97/1,000 patient admissions in the first time period (January 1995 to October 1998) to 1.19/1,000 patient admissions in the second time period (November 1998 to August 2002) of this study. The proportion of patients with major and intracranial bleeding increased from 20.2% and 1.9%, respectively, in the first time period, to 33.3% and 7.8%, respectively, in the second. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;94:403– 406)
arfarin has well-documented benefits in the treatment and prevention of venous and arterial W thromboembolic disorders, although it exposes patients to an increased risk of hemorrhage.1–5 The intensity of anticoagulation and the concomitant use of medications known to potentiate the effect of oral anticoagulants are risk factors for major bleeding.5–15 Our objective was to investigate trends over time in hospitalized patients with warfarin-related bleeding. •••
We identified 233 patients with warfarin-related bleeding at Brigham and Women’s Hospital from January 1995 to August 2002 using the electronic database of our hospital by searching for the following 2 International Classification of Diseases-9th Revision (ICD)-9 codes: (1) medications primarily affecting blood constituents causing adverse effects (E 934.2) and (2) accidental poisoning by agents affecting blood constituents (E 858.2). We used the Thrombolysis In Myocardial Infarction bleeding criteria to define minimal, minor, and major hemorrhages.16 Patients were required to be actively treated with warfarin, or to have discontinued warfarin within 5 days before the bleeding event. We reviewed medical charts for additional medications known to potentiate the bleeding risk, that is, (1) the concomitant use of any of the following: aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), intravenous unfractionated heparin, subcutaneous unfractionated heparin ⱖ10,000 U/day, lowmolecular-weight heparin (LMWH), clopidogrel, abciximab, eptifibatide, argatroban, and lepirudin; (2) the discontinuation of any of the following anticoagulant medications and antiplatelet agents within 24 From the Departments of Medicine, Radiology, and Pharmacy, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. This study was sponsored in part by AstraZeneca, Wilmington, Delaware, for which Dr. Goldhaber is a consultant. Dr. Goldhaber’s address is Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. Email: sgoldhaber@ partners.org. Manuscript received January 30, 2004; revised manuscript received and accepted April 2, 2004. ©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 94 August 1, 2004
FIGURE 1. The number of patients per 1,000 per year with warfarin-related bleeding at Brigham and Women’s Hospital.
hours before the bleeding event: intravenous unfractionated heparin, subcutaneous unfractionated heparin ⱖ10,000 U/day, LMWH, clopidogrel, abciximab, or eptifibatide; and (3) the discontinuation of aspirin or other NSAIDs within 3 days before the hemorrhagic event. Medical records were also reviewed for baseline demographics, admitting diagnoses, co-morbidities, bleeding risk factors, anatomic sites of hemorrhage, and laboratory values. We obtained all-cause mortality at 30 days and a composite nonfatal end point of stroke, myocardial infarction, systolic hypotension (ⱖ20% decrease in systolic blood pressure to ⬍90 mm Hg), critical anemia (ⱖ20% decrease in hematocrit to ⱕ20%), or the requirement for surgical or angiographic intervention to control the hemorrhage. The study was approved by the Partners Human Research Committee. Patients with warfarin-associated bleeding were identified during 1 of 2 time periods of equal duration at which they presented to Brigham and Women’s Hospital. The first time period covered January 1, 1995 through October 31, 1998, and the second time period covered November 1, 1998 through August 31, 2002. We calculated the incidence of warfarin-related hemorrhage using the number of warfarin-related bleeding events per time period divided by the total number of admissions to Brigham and Women’s Hospital per time period (time period 1: n ⫽ 107,101; time period 2: n ⫽ 108,050). We used a binomial test of proportions to compare incidence of warfarin-related hemorrhage between time periods 1 and 2. Discrete variables were compared with the Fisher’s exact 2-sided test. Continuous variables were compared with Student’s t test or the Wilcoxon rank-sum test. Survival rates were compared between patients 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2004.04.050
403
periods except for secondary prophylaxis after stroke, which was more Time Period 1 Time Period 2 frequently used in the second time Variable No. (n ⫽ 104) (n ⫽ 129) p Value period. The frequency of concomitantly Men 111 40 71 Women 122 64 58 0.012 administered medication that potenAge ⬍62 yrs 76 36 40 tiates the bleeding risk, including other Age 62–75 yrs 96 45 51 anticoagulants, antiplatelet agents, or Age ⬎75 yrs 61 23 38 0.447 warfarin potentiators, increased from Admission with bleeding 146 67 77 0.296 Atrial fibrillation 94 35 59 0.062 74.0% in the first time period to 86.8% Coronary artery disease 90 42 48 0.621 in the second time period (p ⫽ 0.018) Systemic hypertension 86 30 56 0.022 (Figure 2). This was due mainly to Congestive heart failure 64 32 32 0.311 increased administration of warfarin Infection 50 21 29 0.672 potentiators and LMWHs over time. Previous ischemic stroke 46 12 34 0.005 Surgery ⬍3 wks 34 13 21 0.417 The use of ⱖ2 warfarin potentiators Previous gastrointestinal bleeding 34 18 16 0.292 was less common in the first (24%) Cancer 31 13 18 0.745 than in the second time period (41%) Diabetes mellitus 30 12 18 0.584 (p ⫽ 0.008). Chronic renal insufficiency 29 17 12 0.105 Chronic lung disease 24 7 17 0.107 The median international normalAcute coronary syndrome 21 7 14 0.275 ized ratio (INR) at the onset of bleedSepsis 12 5 7 0.832 ing was 3.75 (interquartile range Indications for warfarin 2.00 to 7.95) in the entire cohort, Prosthetic heart valve 49 25 24 0.312 3.80 (interquartile range 1.10 to Deep venous thrombosis therapy 46 22 24 0.627 Atrial fibrillation 44 18 26 0.581 81.50) in the first time period, and Secondary prophylaxis after stroke 29 7 22 0.018 3.70 (interquartile range (1.10 to Pulmonary embolism therapy 22 11 11 0.595 31.00) in the second time period. Hemorrhage site* Overall, the median INR was 4.4 (inGastrointestinal 93 42 51 0.895 Genitourinary 42 19 23 0.931 terquartile range 3.70 to 5.40) among Superficial hematoma 39 17 22 0.886 patients with intracranial hemorSurgical site 23 11 12 0.746 rhage. The proportion of patients Retroperitoneal 14 5 9 0.489 with increased INR above the inIntracranial 12 2 10 0.045 tended therapeutic range was similar Intra-abdominal 9 4 5 0.991 Vessel puncture site 7 3 4 0.923 between the first (57%) and the secOther 36 14 22 0.451 ond time period (59%) (p ⫽ 0.894). None of the 44 patients taking *Some patients had ⬎1 bleeding site. only warfarin died, although the median INR and interquartile ranges receiving warfarin alone versus warfarin combination were higher (6.5, 2.9 to 14.1) than in patients taking warfarin combined with medications that potentiated therapy using a log-rank test. Warfarin-related bleeding events occurred in 233 the bleeding risk (3.4, 1.7 to 7.4; p ⫽ 0.0005). All 13 patients (104 in time period 1 and 129 in time period deaths occurred in patients on warfarin in combination 2). The annual incidence of warfarin-related bleeding with other medications that potentiated the bleeding among hospitalized patients increased from 0.97/ risk (log-rank p ⫽ 0.0728) (Figure 3). Overall, 144 1,000 patient admissions in the first time period to patients (62%) were treated with warfarin potentiators 1.19/1,000 patient admissions in the second time pe- before the bleeding event. The most commonly used riod (p ⫽ 0.033) (Figure 1). The proportion of patients warfarin potentiators were quinolone antibiotics with major bleeding events increased from 20.2% in (32%), levothyroxine (15%), simvastatin (10%), and the first to 33.3% in the second time period (p ⫽ amiodarone (10%). One-third (n ⫽ 78) of all patients 0.028). Intracranial bleeding occurred in 1.9% in the received warfarin plus ⱖ2 warfarin potentiators. Most of the 13 deaths (83%) occurred within the first and in 7.8% in the second time period (p ⫽ 0.045). The proportion of patients who died within 30 first week after the onset of bleeding (Figure 3). days was 4.8% in the first and 6.2% in the second time Bleeding contributed significantly to or was the main cause of death in 9 patients. Among the patients who period (p ⫽ 0.777). The combined nonfatal end point of stroke, myo- experienced the nonfatal end point, 19% required ancardial infarction, hypotensive shock, critical anemia, giographic or surgical intervention to control the hemor the requirement for surgical or angiographic inter- orrhage, 12% had a decrease in hematocrit to ⱕ20%, vention to control the hemorrhage occurred in 30% of 6% had a decrease in systolic blood pressure to ⱕ90 patients in both time periods. In the second time mm Hg, 2% experienced strokes, and 2% had a myoperiod, bleeding occurred more often in men, in pa- cardial infarction after the hemorrhagic event. Laboratory values at the time of the bleeding event, tients with systemic hypertension, and in patients with a history of ischemic stroke (Table 1). The indications including INR, activated partial thromboplastin time, for anticoagulation were similar between the time hemoglobin, platelets, and creatinine, were similar in TABLE 1 Patient Characteristics
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FIGURE 2. Proportion of patients with bleeding events on anticoagulant combinations in time periods 1 (n ⴝ 104) and 2 (n ⴝ 129). p ⴝ 0.018 for patients on any combination with warfarin; p ⴝ 0.015 for patients on warfarin with warfarin potentiator; p ⴝ 0.017 for patients on warfarin with LMWH; p ⴝ 0.087 for patients on warfarin with unfractionated heparin; p ⴝ 0.252 for patients on warfarin with aspirin >81 mg/day. ASA ⴝ aspirin; UFH ⴝ unfractionated heparin.
FIGURE 3. Survival curves of patients treated with warfarin alone versus warfarin plus additional medications that may increase bleeding risk.
the 2 time periods. Although the administration of vitamin K (51.2% vs 61.2%; p ⫽ 0.116) and packed red blood cells (58.7% vs 55.8%; p ⫽ 0.663) did not change over time, fewer patients received fresh frozen plasma (37.8% vs 62.2%; p ⫽ 0.032) or platelet transfusions (2.9% vs 11.6%; p ⫽ 0.013) in the first than in the second time period, respectively. •••
We found an increased incidence of warfarin-related hemorrhage over time, especially major and intracranial hemorrhages according to the Thrombolysis In Myocardial Infarction classification. Increased use of combined anticoagulant regimens and warfarin po-
tentiators is the most likely explanation. Most patients (81%) with warfarin-related bleeding events received concomitant medication that increased the bleeding risk,17 including other anticoagulants, antiplatelet agents, NSAIDs, or warfarin potentiators. There was increased use of warfarin potentiators over time, a contributing factor in 11 of the 13 deaths. Laboratory tests, such as the INR or activated partial thromboplastin time, were less helpful for predicting bleeding events in patients on combined anticoagulant regimens, because no difference in coagulation assays was observed in the 2 time periods despite an increase in the use of warfarin combinations in the second time period. As expected, the INRs were above the target range in patients who bled.15,18,19 However, the elevation was small, with a median INR of only 3.75. The median INR was 4.4 in our 12 patients with intracranial bleeding. In a recently published study of anticoagulated patients with nonvalvular atrial fibrillation, INRs from 4.0 to 4.5 were associated with a high rate of intracranial hemorrhage: 2.7/100 patient-years compared with 0.5/100 patient-years for INRs of 2.6 to 3.0.2 Expanded indications for warfarin, such as secondary prevention after stroke, may have increased the rate of intracranial hemorrhage in the second period of our study. Although all intracranial bleeding events in our study occurred spontaneously, increased use of catheter interventions might further contribute to an increase in intracerebral hemorrhages. In a study of 42,451 patients with 1,250,000 INRs from 46 Swedish anticoagulation clinics, the death rate doubled with each unit of INR increase ⬎2.5.15 Although mildly elevated INRs above the target range cause bleeding, INRs targeting lower, less effective levels of anticoagulation increase the risk of thrombotic events. For example, in a case-control study of patients with nonrheumatic atrial fibrillation and warfarin anticoagulation from the Massachusetts General Hospital database, the risk of stroke doubled with INRs of 1.7 compared with INRs of 2.0.18 In aggregate, the findings from these studies emphasize the narrow therapeutic parameters for warfarin anticoagulation. The clinical validity of ICD-9 coding for identifying patient populations has been questioned,20 and we cannot exclude selection bias or confounding in our study. Some patients with minor bleeding may not have been coded using the ICD-9 code E 934.2 (medications primarily affecting blood constituents causing adverse effects). We also cannot exclude the possibility that more thorough reporting and coding of warfarin-related bleeding took place during the second time period of our study. The introduction of improved imaging techniques to diagnose bleeding, such as multirow detector computed tomography or magnetic resonance imaging, may have contributed to the observed increase in bleeding events during the second time period of the study. In addition, we lacked a control group of patients on warfarin without bleeding events. BRIEF REPORTS
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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 intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019 –1026. 3. The European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995;333:5–10. 4. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 1993;95:315–328. 5. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994;120:897–902. 6. Saour JN, Sieck JO, Mamo LA, Gallus AS. Trial of different intensities of anitcoagulation in patients with prosthetic heart valves. N Engl J Med 1990;322: 428 –432. 7. Launbjerg J, Egeblad H, Heaf J, Nielsen NH, Fugleholm AM, Ladefoged K. Bleeding complications to oral anticoagulant therapy: multivariate analysis of 1010 treatment years in 551 outpatients. J Intern Med 1991;229:351–355. 8. 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. 9. Hirsh J, Dalen J, Anderson DR, Poller L, Bussey H, Ansell J, Deykin D. Oral anitcoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119(suppl):8S–21S. 10. Hylek EM, Heiman H, Skates SJ, Sheehan MA, Singer DE. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA 1998;279: 657–662. 11. Penning-van Beest FJ, van Meegen E, Rosendaal FR, Stricker BH. Drug interactions as a cause of overanticoagulation on phenprocoumon or acenocou-
marol predominantly concern antibacterial drugs. Clin Pharmacol Ther 2001;69: 451–457. 12. Visser LE, Penning-van Bees FJ, Kasbergen AA, De Smet PA, Vulto AG, Hofman A, Stricker BH. Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants. Thromb Haemost 2002;88:705–710. 13. Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food. Ann Intern Med 1994;121:676 –683. 14. Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 2001;119(suppl):108S–121S. 15. Ode´ n A, Fahle´ n M. Oral anticoagulation and risk of death: a medical record linkage study. BMJ 2002;325:1073–1075. 16. Bovill EG, Tracy RP, Knatterud GL, Stone PH, Nasmith J, Gore JM, Thompson BW, Tofler GH, Kleiman NS, Cannon C, Braunwald E. 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. 17. 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. 18. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996;335:540 –546. 19. Poli D, Antonucci E, Gensini GF, Abbate R, Prisco D. Asymptomatic excessive coumarin anticoagulation is a risk factor for thrombotic and bleeding complications of oral anticoagulant therapy. J Thromb Haemost 2003;1:1840 – 1841. 20. McCarthy EP, Iezzoni LI, Davis RB, Palmer RH, Cahalane M, Hamel MB, Mukamal K, Phillips RS, Davies DT Jr. Does clinical evidence support ICD9-CM diagnosis coding of complications? Med Care 2000;38:868 –876.
Usefulness of a Hand-Carried Cardiac Ultrasound Device for Bedside Examination of Pericardial Effusion in Patients After Cardiac Surgery Huai Luo, MD, Ming Chen, MD, Alfredo Trento, MD, Takashi Miyamoto, MD, Sergio L. Kobal, MD, Yoram Neuman, MD, Noune Aslanian, MD, Tasneem Z. Naqvi, MD, Kirsten Tolstrup, MD, and Robert J. Siegel, MD To identify the incidence of pericardial effusion in patients after cardiac surgery using a hand-carried cardiac ultrasound device, 200 patients were assessed on postoperative day 3. If a pericardial effusion was found, patients were monitored for 3 consecutive days with a hand-carried cardiac ultrasound device. Within 72 hours after surgery, 43 patients (21.5%) had developed an effusion, of whom 2 patients had cardiac tamponade and 41 patients (21%) had a small pericardial effusion. No difference was found in the incidence of effusion based on the type of cardiac surgery. Of patients with a small pericardial effusion on day 3 after surgery, an additional 2 of 41 (5%) developed cardiac tamponade. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;94:406 – 407)
tive noninvasive diagnostic method for the evaluation of pericardial fluid accumulation after cardiac surgery. Until recently, this evaluation has required the use of relatively large diagnostic ultrasound machines that can be difficult to maneuver and are not always readily available in the acute cardiac care unit. With the introduction of a small, comparatively inexpensive, handcarried cardiac ultrasound device (HCCUD), echocardiographic technology can be kept in the acute care unit to be immediately available for bedside use by clinicians. This study uses HCCUD in the postoperative cardiac surgical intensive care unit to identify the incidence of pericardial effusion in patients who have had open-heart surgery, as well as to characterize the impact of HCCUD on diagnosis and treatment in this patient group.
From the Divisions of Cardiology and Cardiac Surgery, Cedars-Sinai Medical Center, Los Angeles, California. Dr. Siegel’s address is: Division of Cardiology, Room # 5335, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048. E-mail: [email protected]. Manuscript received January 26, 2004; revised manuscript received and accepted April 14, 2004.
Portable hand-carried echocardiography was performed in 200 consecutive patients admitted to the postsurgical acute cardiac care unit during a 3-month period from March 1, 2003 to May 31, 2003 at Cedars-Sinai Medical Center in Los Angeles, California. The patients were randomly selected without regard to
ericardial effusion has been documented as 1 of the common postoperative complications of carP diac surgery. Echocardiography is the most effec1–3
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©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 94 August 1, 2004
0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2004.04.051
MD,
Luis R. Castellanos, MD, Rene Quiroz, MD, MPH, Sophia Koo, John Fanikos, RPh, MBA, and Samuel Z. Goldhaber, MD
BS,
The annual incidence of warfarin-related bleeding at Brigham and Women’s Hospital increased from 0.97/1,000 patient admissions in the first time period (January 1995 to October 1998) to 1.19/1,000 patient admissions in the second time period (November 1998 to August 2002) of this study. The proportion of patients with major and intracranial bleeding increased from 20.2% and 1.9%, respectively, in the first time period, to 33.3% and 7.8%, respectively, in the second. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;94:403– 406)
arfarin has well-documented benefits in the treatment and prevention of venous and arterial W thromboembolic disorders, although it exposes patients to an increased risk of hemorrhage.1–5 The intensity of anticoagulation and the concomitant use of medications known to potentiate the effect of oral anticoagulants are risk factors for major bleeding.5–15 Our objective was to investigate trends over time in hospitalized patients with warfarin-related bleeding. •••
We identified 233 patients with warfarin-related bleeding at Brigham and Women’s Hospital from January 1995 to August 2002 using the electronic database of our hospital by searching for the following 2 International Classification of Diseases-9th Revision (ICD)-9 codes: (1) medications primarily affecting blood constituents causing adverse effects (E 934.2) and (2) accidental poisoning by agents affecting blood constituents (E 858.2). We used the Thrombolysis In Myocardial Infarction bleeding criteria to define minimal, minor, and major hemorrhages.16 Patients were required to be actively treated with warfarin, or to have discontinued warfarin within 5 days before the bleeding event. We reviewed medical charts for additional medications known to potentiate the bleeding risk, that is, (1) the concomitant use of any of the following: aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), intravenous unfractionated heparin, subcutaneous unfractionated heparin ⱖ10,000 U/day, lowmolecular-weight heparin (LMWH), clopidogrel, abciximab, eptifibatide, argatroban, and lepirudin; (2) the discontinuation of any of the following anticoagulant medications and antiplatelet agents within 24 From the Departments of Medicine, Radiology, and Pharmacy, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. This study was sponsored in part by AstraZeneca, Wilmington, Delaware, for which Dr. Goldhaber is a consultant. Dr. Goldhaber’s address is Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. Email: sgoldhaber@ partners.org. Manuscript received January 30, 2004; revised manuscript received and accepted April 2, 2004. ©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 94 August 1, 2004
FIGURE 1. The number of patients per 1,000 per year with warfarin-related bleeding at Brigham and Women’s Hospital.
hours before the bleeding event: intravenous unfractionated heparin, subcutaneous unfractionated heparin ⱖ10,000 U/day, LMWH, clopidogrel, abciximab, or eptifibatide; and (3) the discontinuation of aspirin or other NSAIDs within 3 days before the hemorrhagic event. Medical records were also reviewed for baseline demographics, admitting diagnoses, co-morbidities, bleeding risk factors, anatomic sites of hemorrhage, and laboratory values. We obtained all-cause mortality at 30 days and a composite nonfatal end point of stroke, myocardial infarction, systolic hypotension (ⱖ20% decrease in systolic blood pressure to ⬍90 mm Hg), critical anemia (ⱖ20% decrease in hematocrit to ⱕ20%), or the requirement for surgical or angiographic intervention to control the hemorrhage. The study was approved by the Partners Human Research Committee. Patients with warfarin-associated bleeding were identified during 1 of 2 time periods of equal duration at which they presented to Brigham and Women’s Hospital. The first time period covered January 1, 1995 through October 31, 1998, and the second time period covered November 1, 1998 through August 31, 2002. We calculated the incidence of warfarin-related hemorrhage using the number of warfarin-related bleeding events per time period divided by the total number of admissions to Brigham and Women’s Hospital per time period (time period 1: n ⫽ 107,101; time period 2: n ⫽ 108,050). We used a binomial test of proportions to compare incidence of warfarin-related hemorrhage between time periods 1 and 2. Discrete variables were compared with the Fisher’s exact 2-sided test. Continuous variables were compared with Student’s t test or the Wilcoxon rank-sum test. Survival rates were compared between patients 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2004.04.050
403
periods except for secondary prophylaxis after stroke, which was more Time Period 1 Time Period 2 frequently used in the second time Variable No. (n ⫽ 104) (n ⫽ 129) p Value period. The frequency of concomitantly Men 111 40 71 Women 122 64 58 0.012 administered medication that potenAge ⬍62 yrs 76 36 40 tiates the bleeding risk, including other Age 62–75 yrs 96 45 51 anticoagulants, antiplatelet agents, or Age ⬎75 yrs 61 23 38 0.447 warfarin potentiators, increased from Admission with bleeding 146 67 77 0.296 Atrial fibrillation 94 35 59 0.062 74.0% in the first time period to 86.8% Coronary artery disease 90 42 48 0.621 in the second time period (p ⫽ 0.018) Systemic hypertension 86 30 56 0.022 (Figure 2). This was due mainly to Congestive heart failure 64 32 32 0.311 increased administration of warfarin Infection 50 21 29 0.672 potentiators and LMWHs over time. Previous ischemic stroke 46 12 34 0.005 Surgery ⬍3 wks 34 13 21 0.417 The use of ⱖ2 warfarin potentiators Previous gastrointestinal bleeding 34 18 16 0.292 was less common in the first (24%) Cancer 31 13 18 0.745 than in the second time period (41%) Diabetes mellitus 30 12 18 0.584 (p ⫽ 0.008). Chronic renal insufficiency 29 17 12 0.105 Chronic lung disease 24 7 17 0.107 The median international normalAcute coronary syndrome 21 7 14 0.275 ized ratio (INR) at the onset of bleedSepsis 12 5 7 0.832 ing was 3.75 (interquartile range Indications for warfarin 2.00 to 7.95) in the entire cohort, Prosthetic heart valve 49 25 24 0.312 3.80 (interquartile range 1.10 to Deep venous thrombosis therapy 46 22 24 0.627 Atrial fibrillation 44 18 26 0.581 81.50) in the first time period, and Secondary prophylaxis after stroke 29 7 22 0.018 3.70 (interquartile range (1.10 to Pulmonary embolism therapy 22 11 11 0.595 31.00) in the second time period. Hemorrhage site* Overall, the median INR was 4.4 (inGastrointestinal 93 42 51 0.895 Genitourinary 42 19 23 0.931 terquartile range 3.70 to 5.40) among Superficial hematoma 39 17 22 0.886 patients with intracranial hemorSurgical site 23 11 12 0.746 rhage. The proportion of patients Retroperitoneal 14 5 9 0.489 with increased INR above the inIntracranial 12 2 10 0.045 tended therapeutic range was similar Intra-abdominal 9 4 5 0.991 Vessel puncture site 7 3 4 0.923 between the first (57%) and the secOther 36 14 22 0.451 ond time period (59%) (p ⫽ 0.894). None of the 44 patients taking *Some patients had ⬎1 bleeding site. only warfarin died, although the median INR and interquartile ranges receiving warfarin alone versus warfarin combination were higher (6.5, 2.9 to 14.1) than in patients taking warfarin combined with medications that potentiated therapy using a log-rank test. Warfarin-related bleeding events occurred in 233 the bleeding risk (3.4, 1.7 to 7.4; p ⫽ 0.0005). All 13 patients (104 in time period 1 and 129 in time period deaths occurred in patients on warfarin in combination 2). The annual incidence of warfarin-related bleeding with other medications that potentiated the bleeding among hospitalized patients increased from 0.97/ risk (log-rank p ⫽ 0.0728) (Figure 3). Overall, 144 1,000 patient admissions in the first time period to patients (62%) were treated with warfarin potentiators 1.19/1,000 patient admissions in the second time pe- before the bleeding event. The most commonly used riod (p ⫽ 0.033) (Figure 1). The proportion of patients warfarin potentiators were quinolone antibiotics with major bleeding events increased from 20.2% in (32%), levothyroxine (15%), simvastatin (10%), and the first to 33.3% in the second time period (p ⫽ amiodarone (10%). One-third (n ⫽ 78) of all patients 0.028). Intracranial bleeding occurred in 1.9% in the received warfarin plus ⱖ2 warfarin potentiators. Most of the 13 deaths (83%) occurred within the first and in 7.8% in the second time period (p ⫽ 0.045). The proportion of patients who died within 30 first week after the onset of bleeding (Figure 3). days was 4.8% in the first and 6.2% in the second time Bleeding contributed significantly to or was the main cause of death in 9 patients. Among the patients who period (p ⫽ 0.777). The combined nonfatal end point of stroke, myo- experienced the nonfatal end point, 19% required ancardial infarction, hypotensive shock, critical anemia, giographic or surgical intervention to control the hemor the requirement for surgical or angiographic inter- orrhage, 12% had a decrease in hematocrit to ⱕ20%, vention to control the hemorrhage occurred in 30% of 6% had a decrease in systolic blood pressure to ⱕ90 patients in both time periods. In the second time mm Hg, 2% experienced strokes, and 2% had a myoperiod, bleeding occurred more often in men, in pa- cardial infarction after the hemorrhagic event. Laboratory values at the time of the bleeding event, tients with systemic hypertension, and in patients with a history of ischemic stroke (Table 1). The indications including INR, activated partial thromboplastin time, for anticoagulation were similar between the time hemoglobin, platelets, and creatinine, were similar in TABLE 1 Patient Characteristics
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FIGURE 2. Proportion of patients with bleeding events on anticoagulant combinations in time periods 1 (n ⴝ 104) and 2 (n ⴝ 129). p ⴝ 0.018 for patients on any combination with warfarin; p ⴝ 0.015 for patients on warfarin with warfarin potentiator; p ⴝ 0.017 for patients on warfarin with LMWH; p ⴝ 0.087 for patients on warfarin with unfractionated heparin; p ⴝ 0.252 for patients on warfarin with aspirin >81 mg/day. ASA ⴝ aspirin; UFH ⴝ unfractionated heparin.
FIGURE 3. Survival curves of patients treated with warfarin alone versus warfarin plus additional medications that may increase bleeding risk.
the 2 time periods. Although the administration of vitamin K (51.2% vs 61.2%; p ⫽ 0.116) and packed red blood cells (58.7% vs 55.8%; p ⫽ 0.663) did not change over time, fewer patients received fresh frozen plasma (37.8% vs 62.2%; p ⫽ 0.032) or platelet transfusions (2.9% vs 11.6%; p ⫽ 0.013) in the first than in the second time period, respectively. •••
We found an increased incidence of warfarin-related hemorrhage over time, especially major and intracranial hemorrhages according to the Thrombolysis In Myocardial Infarction classification. Increased use of combined anticoagulant regimens and warfarin po-
tentiators is the most likely explanation. Most patients (81%) with warfarin-related bleeding events received concomitant medication that increased the bleeding risk,17 including other anticoagulants, antiplatelet agents, NSAIDs, or warfarin potentiators. There was increased use of warfarin potentiators over time, a contributing factor in 11 of the 13 deaths. Laboratory tests, such as the INR or activated partial thromboplastin time, were less helpful for predicting bleeding events in patients on combined anticoagulant regimens, because no difference in coagulation assays was observed in the 2 time periods despite an increase in the use of warfarin combinations in the second time period. As expected, the INRs were above the target range in patients who bled.15,18,19 However, the elevation was small, with a median INR of only 3.75. The median INR was 4.4 in our 12 patients with intracranial bleeding. In a recently published study of anticoagulated patients with nonvalvular atrial fibrillation, INRs from 4.0 to 4.5 were associated with a high rate of intracranial hemorrhage: 2.7/100 patient-years compared with 0.5/100 patient-years for INRs of 2.6 to 3.0.2 Expanded indications for warfarin, such as secondary prevention after stroke, may have increased the rate of intracranial hemorrhage in the second period of our study. Although all intracranial bleeding events in our study occurred spontaneously, increased use of catheter interventions might further contribute to an increase in intracerebral hemorrhages. In a study of 42,451 patients with 1,250,000 INRs from 46 Swedish anticoagulation clinics, the death rate doubled with each unit of INR increase ⬎2.5.15 Although mildly elevated INRs above the target range cause bleeding, INRs targeting lower, less effective levels of anticoagulation increase the risk of thrombotic events. For example, in a case-control study of patients with nonrheumatic atrial fibrillation and warfarin anticoagulation from the Massachusetts General Hospital database, the risk of stroke doubled with INRs of 1.7 compared with INRs of 2.0.18 In aggregate, the findings from these studies emphasize the narrow therapeutic parameters for warfarin anticoagulation. The clinical validity of ICD-9 coding for identifying patient populations has been questioned,20 and we cannot exclude selection bias or confounding in our study. Some patients with minor bleeding may not have been coded using the ICD-9 code E 934.2 (medications primarily affecting blood constituents causing adverse effects). We also cannot exclude the possibility that more thorough reporting and coding of warfarin-related bleeding took place during the second time period of our study. The introduction of improved imaging techniques to diagnose bleeding, such as multirow detector computed tomography or magnetic resonance imaging, may have contributed to the observed increase in bleeding events during the second time period of the study. In addition, we lacked a control group of patients on warfarin without bleeding events. BRIEF REPORTS
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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 intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019 –1026. 3. The European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995;333:5–10. 4. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 1993;95:315–328. 5. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994;120:897–902. 6. Saour JN, Sieck JO, Mamo LA, Gallus AS. Trial of different intensities of anitcoagulation in patients with prosthetic heart valves. N Engl J Med 1990;322: 428 –432. 7. Launbjerg J, Egeblad H, Heaf J, Nielsen NH, Fugleholm AM, Ladefoged K. Bleeding complications to oral anticoagulant therapy: multivariate analysis of 1010 treatment years in 551 outpatients. J Intern Med 1991;229:351–355. 8. 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. 9. Hirsh J, Dalen J, Anderson DR, Poller L, Bussey H, Ansell J, Deykin D. Oral anitcoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119(suppl):8S–21S. 10. Hylek EM, Heiman H, Skates SJ, Sheehan MA, Singer DE. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA 1998;279: 657–662. 11. Penning-van Beest FJ, van Meegen E, Rosendaal FR, Stricker BH. Drug interactions as a cause of overanticoagulation on phenprocoumon or acenocou-
marol predominantly concern antibacterial drugs. Clin Pharmacol Ther 2001;69: 451–457. 12. Visser LE, Penning-van Bees FJ, Kasbergen AA, De Smet PA, Vulto AG, Hofman A, Stricker BH. Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants. Thromb Haemost 2002;88:705–710. 13. Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food. Ann Intern Med 1994;121:676 –683. 14. Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 2001;119(suppl):108S–121S. 15. Ode´ n A, Fahle´ n M. Oral anticoagulation and risk of death: a medical record linkage study. BMJ 2002;325:1073–1075. 16. Bovill EG, Tracy RP, Knatterud GL, Stone PH, Nasmith J, Gore JM, Thompson BW, Tofler GH, Kleiman NS, Cannon C, Braunwald E. 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. 17. 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. 18. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996;335:540 –546. 19. Poli D, Antonucci E, Gensini GF, Abbate R, Prisco D. Asymptomatic excessive coumarin anticoagulation is a risk factor for thrombotic and bleeding complications of oral anticoagulant therapy. J Thromb Haemost 2003;1:1840 – 1841. 20. McCarthy EP, Iezzoni LI, Davis RB, Palmer RH, Cahalane M, Hamel MB, Mukamal K, Phillips RS, Davies DT Jr. Does clinical evidence support ICD9-CM diagnosis coding of complications? Med Care 2000;38:868 –876.
Usefulness of a Hand-Carried Cardiac Ultrasound Device for Bedside Examination of Pericardial Effusion in Patients After Cardiac Surgery Huai Luo, MD, Ming Chen, MD, Alfredo Trento, MD, Takashi Miyamoto, MD, Sergio L. Kobal, MD, Yoram Neuman, MD, Noune Aslanian, MD, Tasneem Z. Naqvi, MD, Kirsten Tolstrup, MD, and Robert J. Siegel, MD To identify the incidence of pericardial effusion in patients after cardiac surgery using a hand-carried cardiac ultrasound device, 200 patients were assessed on postoperative day 3. If a pericardial effusion was found, patients were monitored for 3 consecutive days with a hand-carried cardiac ultrasound device. Within 72 hours after surgery, 43 patients (21.5%) had developed an effusion, of whom 2 patients had cardiac tamponade and 41 patients (21%) had a small pericardial effusion. No difference was found in the incidence of effusion based on the type of cardiac surgery. Of patients with a small pericardial effusion on day 3 after surgery, an additional 2 of 41 (5%) developed cardiac tamponade. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;94:406 – 407)
tive noninvasive diagnostic method for the evaluation of pericardial fluid accumulation after cardiac surgery. Until recently, this evaluation has required the use of relatively large diagnostic ultrasound machines that can be difficult to maneuver and are not always readily available in the acute cardiac care unit. With the introduction of a small, comparatively inexpensive, handcarried cardiac ultrasound device (HCCUD), echocardiographic technology can be kept in the acute care unit to be immediately available for bedside use by clinicians. This study uses HCCUD in the postoperative cardiac surgical intensive care unit to identify the incidence of pericardial effusion in patients who have had open-heart surgery, as well as to characterize the impact of HCCUD on diagnosis and treatment in this patient group.
From the Divisions of Cardiology and Cardiac Surgery, Cedars-Sinai Medical Center, Los Angeles, California. Dr. Siegel’s address is: Division of Cardiology, Room # 5335, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048. E-mail: [email protected]. Manuscript received January 26, 2004; revised manuscript received and accepted April 14, 2004.
Portable hand-carried echocardiography was performed in 200 consecutive patients admitted to the postsurgical acute cardiac care unit during a 3-month period from March 1, 2003 to May 31, 2003 at Cedars-Sinai Medical Center in Los Angeles, California. The patients were randomly selected without regard to
ericardial effusion has been documented as 1 of the common postoperative complications of carP diac surgery. Echocardiography is the most effec1–3
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©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 94 August 1, 2004
0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2004.04.051