Safety of Discontinuation of Anticoagulation in Patients with Intracranial Hemorrhage at High Thromboembolic Risk

ORIGINAL CONTRIBUTION Safety of Discontinuation of Anticoagulation in Patients With Intracranial Hemorrhage at High Thromboembolic Risk

Thanh G. Phan, FRACP; Merian Koh, MB,BS; Eelco F. M. Wijdicks, MD

Background: Limited data are available to guide the patients. The median time not taking warfarin in this co- management of anticoagulation in patients with intra- hort was 10 days. Three patients had an ischemic stroke cranial hemorrhage (ICH) at high thromboembolic risk. within 30 days of warfarin therapy discontinuation. Us- ing Kaplan-Meier survival estimates, the probability of Objective: To review the management of anticoagula- having an ischemic stroke at 30 days following warfarin tion in patients with ICH at high thromboembolic risk. therapy cessation in groups 1, 2, and 3 was 2.9% (95% confidence interval, 0%-8.0%), 2.6% (95% confidence in- Patients and Methods: We reviewed the manage- terval, 0%-7.6%), and 4.8% (95% confidence interval, 0%- ment of anticoagulation in 141 patients who have a high 13.6%), respectively. In the 35 patients who had warfa- risk of ischemic stroke and have ICH while taking war- rin therapy restarted, none had recurrence of ICH during farin. The 30-day risk of ischemic stroke while not tak- the same hospitalization. ing anticoagulation treatment was determined using Kaplan-Meier survival estimates. Conclusions: Discontinuation of warfarin therapy for 1 to 2 weeks has a comparatively low probability of em- Results: The indications for anticoagulation were a pros- bolic events in patients at high embolic risk. This should thetic heart valve (52 patients [group 1]), atrial fibrilla- be taken into consideration when deciding whether to tion and cardioembolic stroke (53 patients [group 2]), continue or discontinue anticoagulation in these pa- and a recurrent transient ischemic attack or an ischemic tients at high embolic risk. Early recurrence of ICH is ex- stroke (36 patients [group 3]). A prior ischemic stroke ceedingly uncommon. occurred in 14 (27%) of group 1 patients and in 23 (43%) of group 2 patients. Death occurred in 43% of the 141 Arch Neurol. 2000;57:1710-1713

NNUALLY, intracranial hem- hemorrhage is not known. Discontinua- orrhage (ICH) causes com- tion of warfarin seems safe, but lack of plications in 1% to 2% of strong scientific underpinnings contin- patients with a prosthetic ues to disconcert physicians confronted heart valve or atrial fibril- with these complex patients. Data have lation who are taking warfarin for throm- only come from small retrospective se- A 1,2 3-7 boembolic prophylaxis. Rapid reversal ries. To assess the risk of discontinuation and resumption of warfarin treat- For editorial comment ment in patients with ICH, we conducted see 1682 a hospital-based study in a large cohort of patients. of anticoagulation in the presence of ICH is needed to prevent enlargement of the RESULTS hematoma, resulting in brain herniation. While not taking warfarin, the immedi- CLINICAL FEATURES ate concern in an unprotected patient is ischemic stroke and systemic emboliza- We studied 141 patients with 146 epi- From the Department tion. In addition, the interval to resump- sodes of ICH while taking warfarin. The of Neurology, Mayo Clinic and tion of anticoagulation and its associated median patient age was 74 years (range, Foundation, Rochester, Minn. potential risk of recurrence of cerebral 23-98 years). Sixty percent of the pa-

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Table 1. Baseline Demographic Characteristics PATIENTS AND METHODS in 141 Patients With a Cerebral Hemorrhage*

Prosthetic Atrial Fibrillation Recurrent TIA We retrospectively reviewed the medical records of Heart Valve and Cardioembolic or Stroke 141 patients undergoing anticoagulation who had ICH Group Stroke Group Group between January 1, 1976, and December 31, 1999. Characteristic (n = 52) (n = 53) (n = 36) This study was approved by the Institutional Re- Age, y view Board. Twenty-six patients with a metallic valve Mean 67.9 76.5 70.5 and ICH have been described previously.7 Patients Median 73 78 72 with ICH who were taking anticoagulation treat- Range 23-88 54-98 47-90 ment for deep venous thrombosis or pulmonary em- Prior TIA or stroke 14 (27) 23 (43) 36 (100) bolus were considered to be at low risk of embolic Atrial fibrillation 18 (35.6) 49 (92.5) 0 stroke and were excluded from the analysis. The hos- and cardioembolic pital course and 30-day follow-up were reviewed un- stroke til the first defining event, any embolic complica- Abnormal 30 (65.2) 20 (55.5) 3 (21.4) echocardiographic tion, ICH, or death. Abnormal transthoracic or results transesophageal echocardiographic results were de- Echocardiography 6 (11.5) 17 (32.1) 23 (62.2) fined as a left atrial size greater than 40 mm, an ejec- not done tion fraction of less than 40%, hypokinesis, a septal Hypertension 18 (34.6) 32 (60.4) 23 (62.2) 8,9 defect, and thrombus. If patent foramen ovale was Smoking 25 (48.1) 22 (41.5) 23 (62.2) the only abnormality on echocardiography, then it Diabetes 9 (17.3) 7 (13.2) 4 (10.8) was coded as a normal echocardiographic study be- IHD or CCF 20 (38.5) 29 (54.7) 13 (35.1) cause of controversy over its significance as an in- Duration taking dependent risk factor for ischemic stroke.9,10 In ad- warfarin, y dition, none of the patients in our series were taking Mean 6.9 3.9 3.5 warfarin because of patent foramen ovale. Either in- Median 5.5 3.0 1.0 travenous heparin or oral warfarin treatment was then Range 0.42-14.70 0.006-5.70 0.008-12.10 restarted, depending on the treating physicians. Prothrombin time Intracranial hemorrhage was divided into intra- on admission, s cerebral hemorrhage (including cerebellar hemor- Mean 31.3 22.5 25.0 Median 22.7 19.6 21.2 rhage, brainstem hemorrhage, lobar hemorrhage, and Range 11.5-240.0 9.7-60.5 13.9-74.8 basal ganglia hemorrhage), subarachnoid hemorrhage (SAH), subdural hematoma (SDH), and pri- *Data are given as the number (percentage) of patients unless otherwise mary intraventricular hemorrhage (IVH). Patients indicated. TIA indicates transient ischemic attack; IHD, ischemic heart disease; with a hemorrhagic infarct were excluded from the and CCF, congestive cardiac failure. analysis. Patients were divided into 3 groups according to the indications for long-term anticoagulation. Group 1 consisted of 52 patients with prosthetic heart mean prothrombin times were 26.4 and 21.3 seconds valves. Group 2 consisted of 53 patients with atrial (range, 9.7-240.0 seconds) on admission for the 3 groups. fibrillation and cardioembolic stroke.11 Group 3 con- In group 1, 14 patients had mitral metallic valves, 31 had sisted of 36 patients with recurrent transient ische- aortic metallic valves, and 7 had combined mitral and aor- mic attacks or ischemic stroke despite therapy with tic metallic valves. In this group, 14 patients had Björk- aspirin, ticlopidine hydrochloride, or clopidogrel. Shiley (single-tilting disk) valves, 17 had Starr-Edwards Statistical analysis using the log-rank test was (caged-ball) valves, and 11 had St Jude (bileaflet–tilting used to compare the likelihood of mortality among disk) valves. Seventeen patients had various types of the various types of ICH. The 30-day risk of ische- valves, including 3 Medtronic-Hall (single–tilting disk) mic stroke while not taking anticoagulation treatment was determined using Kaplan-Meier survival es- valves, 3 Braunwald-Cutter (caged-ball) valves, and 2 Car- timates (censored for when heparin or warfarin bomedic (bileaflet-tilting disk) valves; 9 had biopros- therapy was restarted). thetic valves.

HOSPITALIZATION AND FOLLOW-UP

tients were men. The demographic characteristics are The median time not taking warfarin was 10 days (range, shown in Table 1. The type of hemorrhage was intra- 0-30 days). There were 3 patients with ischemic events cerebral hemorrhage in 87 patients (61.7%), SDH in 43 within 30 days: 1 in the posterior cerebral artery region, (30.5%), SAH in 8 (5.7%), and IVH in 3 (2.1%). The me- 1 lacunar stroke, and 1 vertebrobasilar transient ische- dian duration of anticoagulation for the cohort taken from mic attack (Table 2). Using Kaplan-Meier survival es- the start of warfarin therapy to admission with ICH was timates, the probability of having ischemic events at 7 5 years (range, 2 months to 14.7 years). A prior tran- days following warfarin treatment cessation in groups 1, sient ischemic attack or ischemic stroke occurred in group 2, and 3 was 2.9% (95% confidence interval [CI], 0%- 1 in 27% and in group 2 in 43% of the patients. The me- 8.0%), 2.6% (95% CI, 0%-7.6%), and 4.8% (95% CI, 0%- dian admission Glasgow Coma Scale score was 14. An- 13.6%), respectively. This remained unchanged at 14 and ticoagulation was reversed with fresh frozen plasma and 30 days after ictus. By 7 day, 18 (35%) of the patients in vitamin K on admission in all patients. The median and group 1 died, 16 (30%) in group 2 died, and 18 (50%)

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Table 2. Characteristics of the Patients With Ischemic Events After Discontinuation of Warfarin Therapy for Intracerebral Hematoma*

Type of Indication for Carotid US or Echocardiographic Time to Stroke Patient Age, y Hemorrhage Anticoagulation Angiographic Results Results Recurrence, d Stroke Syndrome 83 ICH AF ND ND 5 Occipital infarct 43 SAH Aortic metallic Normal Normal 5 Lacunar infarct valve (BJ) 73 SDH TIA High-grade stenosis Normal 4 Vertebrobasilar TIA of the BA

*All 3 patients were men. US indicates ultrasonographic; ICH, intracerebral hemorrhage; AF, atrial fibrillation; ND, not done; SAH, subarachnoid hemorrhage; BJ, Björk-Shiley; SDH, subdural hematoma; TIA, transient ischemic attack; and BA, basilar artery.

in group 3 died. By day 14, 20 (38%) of the patients in patients over a median of 19 days (range, 8-42 days) group 1 died, 20 (38%) in group 2 died, and 18 (50%) in while they were not taking warfarin for ICH. Butler and group 3 died. By day 30, 22 (42%) of the patients in group Tait4 observed cerebral ischemic events in 3 of 13 pa- 1 died, 22 (42%) in group 2 died, and 18 (50%) in group tients. Kawamata et al6 did not find any ischemic 3 died. Anticoagulation treatment with either intrave- strokes when warfarin treatment was discontinued for 3 nous heparin or warfarin was restarted by day 7 in 7 (13%) days in 27 patients with ICH. An analogy to the risk of of the patients in group 1, 4 (8%) in group 2, and 1 (3%) warfarin discontinuation in the setting of ICH in high- in group 3. By day 14, the frequency of anticoagulation risk patients for ischemic stroke is the risk in patients was 26 patients (50%) in group 1, 7 (13%) in group 2, and who have mechanical heart valves undergoing elective 1 (3%) in group 3. By day 30, the frequency of anticoagu- surgery. Tinker and Tarhan12 retrospectively reviewed lation was 28 patients (54%) in group 1, 12 (23%) in group the risk of discontinuing warfarin therapy in 159 pa- 2, and 5 (14%) in group 3. An abnormal echocardio- tients with mechanical heart valves undergoing elective graphic result was found in 30 (65%) of those in group 1, surgery, and none of the patients had in-hospital 20 (56%), in group 2, and 3 (21%) in group 3. thromboembolic complications. Further indirect evi- Of the 35 patients in whom anticoagulation therapy dence to support discontinuation of warfarin therapy was restarted with intravenous heparin or oral warfarin, in these patients with ICH comes from the recent Inter- none had recurrence of ICH during hospitalization. national Stroke Trial. Early recurrence of ischemic There were 45 patients who underwent neurosur- stroke in patients with atrial fibrillation was low even gical procedures, ranging from external ventricular drain while taking aspirin.13 to craniectomy. This consisted of 14 patients in the ICH Our data help put into context the potential haz- group, 28 in the SDH group, and 3 in the SAH and IVH ards of management of anticoagulation in patients with group. In the SDH group, 6 patients did not undergo sur- ICH. Warfarin was given for the prevention of stroke in gery and died. All except 1 patient had a large SDH with patients selected for this study on the premise of a high mass effect and a low Glasgow Coma Scale score (Ͻ5) risk of embolization. We found that the estimated risk at presentation. Warfarin treatment was restarted (5-72 of having an ischemic stroke after discontinuation of days after ictus) without evacuation of the hematoma in warfarin therapy within 30 days was relatively low. The 4 patients with small layers of SDH; none of these pa- cumulative risk for ischemic stroke at 30 days in patients developed further clinical deterioration. tients with a metallic valve was 3% (95% CI, 0%-8%); in Death occurred in 43% of the patients and within patients with atrial fibrillation, 3% (95% CI, 0%-7%); 26 days (median, 2.8 days) of hospitalization. Causes of and in those with a recurrent transient ischemic attack death were cerebral hemorrhage (n=46), respiratory fail- or minor stroke, 5% (95% CI, 0%-13%). This is an un- ure (n=4), ischemic heart disease (n=3), septicemia controlled observational study, but we believe bias from (n=2), and uncertain (n=6). The mortality according to selection of patients at low risk is highly unlikely. Prior the type of ICH was as follows: intracerebral hemor- ischemic stroke before ICH occurred in 27% of the rhage, 48%; SDH, 20%; SAH, 38%; and IVH, 100%. The group 1 patients and in 43% of the group 2 patients. In difference in mortality between the intracerebral hem- addition, the median time not taking warfarin was 10 orrhage group and the SDH group reached statistical sig- days, not only allowing for ICH to stabilize or to treat nificance (P=.005). definitively with surgical intervention but to also observe the risks of a treatment-free interval. In the group COMMENT 1 patients, 14 had a mitral valve and 20 had caged-ball (Starr-Edwards and Braunwald-Cutter) valves, condi- The management of anticoagulation in these patients tions associated with a high embolic risk.14 We ac- with ICH has yet to be established, and guidelines can- knowledge that the long period involved in this study not be obtained from the existing literature.3-6 Most of may introduce bias because of changing clinical prac- the patients described in prior studies had mechanical tice, but despite the 23-year period we were able to find heart valves, and the same observation cannot be ex- only 141 patients who had ICH while taking warfarin trapolated to patients taking warfarin for atrial fibrilla- and were at high risk of thromboembolic events. This is tion or recurrent stroke, despite antiplatelet therapy. reflected in the scant data in the literature on how to Babikian et al3 did not observe any ischemic events in 6 manage such patients.

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Recurrence of ICH with subsequent deterioration Reprints: Eelco F. M. Wijdicks, MD, Department of Neu- after starting anticoagulation with intravenous heparin rology, Mayo Clinic, W8B, 200 SW First St, Rochester, MN or oral warfarin was low. In fact, no ICH recurred dur- 55905 (e-mail: [email protected]). ing the same hospitalization. Kawamata et al6 did not observe any early recurrent cerebral hemorrhage in their neurosurgical series when anticoagulation was REFERENCES started within 3 days. The alternative to discontinuing warfarin therapy in the presence of ICH is to maintain 1. Morley J, Marinchak R, Rials SJ, Kowey P. Atrial fibrillation, anticoagulation, and 15 anticoagulation with heparin. Only 1 group has re- stroke. Am J Cardiol. 1996;77:38A-44A. ported data on the safety of maintaining anticoagula- 2. Green CJ, Hadorn DC, Bassett K, Kazanjian A. Anticoagulation in chronic non- tion with heparin in the presence of ICH in 4 patients valvular atrial fibrillation: a critical appraisal and meta-analysis. Can J Cardiol. 15 1997;13:811-815. with a mechanical heart valve. Leker and Abramsky 3. Babikian VL, Kase CS, Pessin MS, Caplan LR, Gorelick PB. Resumption of anti- did not find enlargement of the hematoma when they coagulation after intracranial bleeding in patients with prosthetic heart valves. continued anticoagulation therapy with heparin. It is Stroke. 1988;19:407-408. possible that subtle enlargement occurred, not causing 4. Butler AC, Tait RC. Restarting anticoagulation in prosthetic heart valve patients any clinically detectable deterioration in patients with after intracranial haemorrhage: a 2-year follow-up. Br J Haematol. 1998;103: 1064-1066. SDH or intracerebral hematoma. However, to answer 5. Gomez CR, Sandhu J, Mehta P. Resumption of anticoagulation during hyperten- this question, a serial computed tomographic scan sive cerebral hemorrhage with prosthetic heart valve [letter]. Stroke. 1988;19:407. study is needed. In view of the limited data on the safety 6. Kawamata T, Takeshita M, Kubo O, Izawa M, Kagawa M, Takakura K. Manage- of continuation of warfarin in this clinical dilemma, our ment of intracranial hemorrhage associated with anticoagulant therapy. Surg Neu- rol. 1995;44:438-442. data on the relative safety of discontinuation of warfarin 7. Wijdicks EF, Schievink WI, Brown RD, Mullany CJ. The dilemma of discontinu- therapy warrant consideration. In addition, there are no ation of anticoagulation therapy for patients with intracranial hemorrhage and safety data on the continuation of anticoagulation in the mechanical heart valves. Neurosurgery. 1998;42:769-773. presence of SDH, IVH, and SAH. 8. Atrial Fibrillation Investigators. Echocardiographic predictors of stroke in pa- Our study showed that brief (1- to 2-week) discon- tients with atrial fibrillation: a prospective study of 1066 patients from 3 clinical trials. Arch Intern Med. 1998;158:1316-1320. tinuation of anticoagulation therapy in patients with a 9. Autore C, Cartoni D, Piccininno M. Multiplane transesophageal echocardiogra- high embolic risk is relatively safe. These results com- phy and stroke. Am J Cardiol. 1998;81:79G-81G. pare with the long-term risk of embolic events of 4% per 10. Petty GW, Khandheria BK, Chu CP, Sicks JD, Whisnant JP. Patent foramen ovale year in patients with a metallic valve without anticoagu- in patients with cerebral infarction: a transesophageal echocardiographic study. lation but are lower than the 10% to 12% per year found Arch Neurol. 1997;54:819-822. 1,2 11. Feinberg WM. Anticoagulation for prevention of stroke. Neurology. 1998;51 in patients with nonvalvular atrial fibrillation. Our (suppl 3):S20-S22. study provides observations that should be of value to 12. Tinker JH, Tarhan S. Discontinuing anticoagulant therapy in surgical patients with neurologists and cardiologists who manage this clinical cardiac valve prostheses: observations in 180 operations. JAMA. 1978;239:738-739. dilemma. 13. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 Accepted for publication May 15, 2000. patients with acute ischaemic stroke. Lancet. 1997;349:1569-1581. 14. Vongpatanasin W, Hillis LD, Lange RA. Prosthetic heart valves. N Engl J Med. This study was supported by fund IRB 1264-98 from 1996;335:407-416. the Neurologic Research Committee, Mayo Clinic, Roches- 15. Leker RR, Abramsky O. Early anticoagulation in patients with prosthetic heart ter, Minn. valves and intracerebral hematoma. Neurology. 1998;50:1489-1491.

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