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Keywords:

  • Anticoagulants;
  • cerebral hemorrhage;
  • platelet aggregation inhibitors;
  • systematic review

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Conflict of Interest
  10. References

Patients with intracerebral hemorrhage frequently have indications for antithrombotic therapy. This represents a therapeutic dilemma as intracerebral hemorrhage is considered a contraindication to antithrombotic medication. Previous systematic reviews have revealed no long-term randomised studies addressing this issue. Our objective was to review observational studies describing the long-term follow-up of patients receiving antithrombotic therapy following intracerebral hemorrhage. Searches were conducted in MEDLINE and EMBASE from 1984 to 2008 for any observational studies detailing use of antithrombotic treatments in patients with intracerebral hemorrhage. Included studies must have had follow-up extending beyond discharge. The primary endpoint was recurrent intracerebral hemorrhage. Secondary endpoints were ischemic events and serious vascular events. 1,301 articles were reviewed: two epidemiological studies and six case series met the inclusion criteria. These described a total of 46 subjects receiving antiplatelet agents (from one study) and 42 patients receiving oral anticoagulants (from one study and six case-series). For patients receiving subsequent aspirin there were seven recurrent intracerebral hemorrhages and four subsequent thrombo-occulsive events. Amongst patents restarting oral anticoagulation there were four recurrent intracerebral bleeds and nine subsequent thrombo-occulsive events. There is a marked paucity of evidence to guide clinicians when planning the long-term management of patients with intracerebral hemorrhage and cogent indications for antithrombotic therapy. Published guidance addressing this issue is not evidence based. In the continued absence of randomised studies addressing antithrombotic use following intracerebral hemorrhage, there is a clear requirement for further high quality observational data on the clinical impact of antithrombotic therapy in this important patient group.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Conflict of Interest
  10. References

The use of antiplatelet medication is well established as reducing risk of death, myocardial infarction and occlusive stroke [1]. Similarly anticoagulant medications are proven as effective in the primary and secondary prevention of venous thromboembolism, myocardial infarction and thromboembolic stroke [2]. However it has also been shown that use of both antiplatelet and anticoagulant medicines increases rates of intracerebral hemorrhage [1–3]. The consensus view is that having an intracerebral hemorrhage infers increased risk of a recurrent hemorrhagic event amongst surviving patients [4], and for this reason intracerebral hemorrhage is generally considered a contraindication to the use of these antithrombotic medicines.

A common dilemma in clinical practice arises when patients present with intracerebral hemorrhage whilst taking antiplatelet or anticoagulant therapies, or when patients with a history of intracerebral hemorrhage subsequently develop conditions for which such medicines are indicated [5]. This issue of antithrombotic use following intracerebral hemorrhage has previously been addressed in a systematic review of randomised studies [6]. However this review found only studies of short-term treatment with most patients randomised to receive antiplatelet medicines following presumed ischemic stroke, and with therapy stopped following diagnosis of intracerebral hemorrhage. For antiplatelet drugs the relative risk of death was 0.96 (95% CI 0.62 to 1.50) and for recurrent intracranial hemorrhage was 1.02 (95% CI 0.58 to 1.80). These wide confidence intervals ruled out neither modest harm nor moderate benefit. No studies were found that addressed the safety of antithrombotic prescribing following intracerebral hemorrhage in the longer term.

Observational studies can often provide the only means of investigating the safety or otherwise of medicines where patients have both indications and contraindications to therapy, a situation which would make a randomised controlled trial ethically difficult to justify. The objective of this study therefore was to undertake an inclusive systematic review of published observational studies of antithrombotic prescribing following intracerebral hemorrhage where such a prescribing dilemma exists.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Conflict of Interest
  10. References

Criteria for Considering Studies for This Review

This review was limited to observational studies with follow-up extending beyond discharge.

Types of Study

Any observational outcome study that included details of the antithrombotic treatment of patients with intracerebral hemorrhage.

Types of Participant

Study subjects must have suffered a radiologically-confirmed intracerebral hemorrhage. Only studies in adults were considered.

Types of Intervention

Any use of antiplatelet or anticoagulant medicines following an intracerebral hemorrhage was considered regardless of dosage.

Types of Outcome Measure

The primary endpoint was recurrent intracerebral hemorrhage. The secondary endpoints were serious thromboocclusive events (thromboocclusive stroke, myocardial infarction).

Search Strategy for Identification of Studies

Only papers from 01-Jan-1984 onwards were reviewed as before this time CT scanning was not widely available [6]. Searches of English language publications were conducted in both MEDLINE (Ovid) and EMBASE (Ovid). The search used previously developed strategies combining inclusive terms for intracranial hemorrhage [7], anticoagulants & antiplatelet medicines [8], and observational studies [9]. A hand search of the bibliographies of the retrieved articles was conducted to identify further publications of interest.

Methods of the Review

The abstracts identified in the search were screened to exclude irrelevant papers. The text of retrieved papers was screened to assess: (i) whether the research question had been addressed, (ii) methodological quality, (iii) whether bibliography contained any useful references. Single case reports were excluded.

Assessment of Methodological Quality

The selection, comparability and outcomes of the studies were assessed using the scoring system of the Newcastle-Ottawa Scale (NOS) group for case-control and cohort studies [10]. The criteria by which the quality of the studies was assessed were based on the selection (representativeness of exposed cohort, selection of nonexposed cohort, description of exposure), comparability (controlling for potential confounders) and outcome (assessment of outcome, duration of follow-up, level of follow-up). As most of the relevant studies retrieved were case series for which no standards of quality exist, these were assessed based on the ascertainment of exposure, outcome and duration of follow-up.

Data Extraction

Data were extracted onto a prespecified form under the following headings: type of intracerebral hemorrhage, duration of follow-up, number of patients receiving subsequent antithrombotic medicines, type of antithrombotic medication used, indication for antithrombotic medicines, number of patients suffering secondary intracranial hemorrhages and number of patients suffering subsequent thromboocclusive events.

Data Synthesis & Analysis

A summary of the eligible cohort studies is contained in the text and in tables. A summary of relevant case series publications has been tabulated.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Conflict of Interest
  10. References

The databases of both MEDLINE and EMBASE were last searched on 26 December 2008. In total the database and “hand” search of reference lists resulted in 1,301 abstracts being screened with the full text of 366 papers being retrieved (Figure 1). Abstracts were mostly excluded because they did not address the principal research question or because they had an inappropriate population. There were eight qualifying studies (two epidemiological studies and six case series) with sufficient duration of follow-up.

image

Figure 1. Systematic review flowchart showing number of papers considered.

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Epidemiological Studies

Two studies were found that contained adequate numbers of patients together with a meaningful control group (Table 1) [11,12]. The study by Viswanathan et al. addressed only the issue of antiplatelet use postintracerebral hemorrhage with patients receiving subsequent anticoagulants excluded [11]. This study achieved a 7 star rating (out of a possible 8) for the NOS criteria. Two hundred and seven survivors of intracerebral hemorrhage were followed up for a median of 19.5 months of which 46 (22%) subsequently received antiplatelet medication. There were a total of 39 recurrent intracerebral hemorrhages, of which 7 were amongst antiplatelet users. There were 11 subsequent ischemic cardiovascular events 4 of which were in antiplatelet receiving patients. The risk for recurrent lobar intracerebral hemorrhage in antiplatelet users was 1.2 (95% CI 0.4 to 3.3) and for deep intracerebral hemorrhage was 1.2 (95% CI 0.1 to 14.3). The risk of subsequent ischemic events was also not significant (HR 1.2; 95% CI 0.3–4.8).

Table 1.  Epidemiological studies with long-term follow-up of patients with/without antithrombotic therapy following intracerebral hemorrhage
Author, yearn patientsAgeSex (M:F)AT indicationDuration of follow-upSubsequent intracerebral hemorrhagesSubsequent T/O events
  1. * n/s not state—baseline characteristics of exposed and unexposed cohorts were not described

  2. AT, antithrombotic; T/O thromboocclusive; Rx, prescribed; AP, antiplatelet; oAC, oral anticoagulation; IHD, ischemic heart disease; AF, atrial fibrillation; PHV, prosthetic heart valve; IS, ischemic stroke; TIA, transient ischemic attack; VT, venous thromboembolism.

Viswanathan et al., 2006 [11]Patients Rx APs
4672.1114:9323 IHD, 7 AF, 7 PHV, 5 IS/TIA, 4 unknownmedian 19.5 months74
Patients not receiving APs
161n/s*n/s*n/s*n/s*327
Claassen et al., 2008 [12]Patients Rx oAC
2370.813:109 AF, 10 PHV, 3 VT, 1 othermean 49.8 months36
Patients not receiving oAC
2575.814:1114 AF, 2 PHV, 7 VT, 2 othermean 36.1 months013

The study by Claassen et al. addressed the continuation of anticoagulation in patients following warfarin associated intracerebral hemorrhage [12]. This study achieved a 3 star rating according to the NOS criteria. Forty eight patients with ICH survived to discharge and were followed up for a median of 36 months. Twenty three of these were restarted on oral anticoagulation. Of those who restarted warfarin there were three subsequent intracerebral hemorrhages (2 traumatic, 1 nontraumatic), 2 subsequent ischemic strokes and 4 subsequent myocardial infarctions. Of those who were not restarted on warfarin there were no subsequent intracranial hemorrhages, 5 ischemic strokes, 6 myocardial infarctions and 2 nonstroke thromboembolisms. The low number of events during follow-up meant that a meaningful multivariate analysis adjusting for potential confounders could not be done and relative risk estimates for the separate endpoints of thromboembolic events and secondary intracerebral hemorrhage were not calculated. The unadjusted risk for the combined endpoint of thromboembolic events and recurrent intracerebral hemorrhage was 1.4 (95% CI 0.4–4.9). Although there was a high level of completeness, all four of the original 52 patients lost to follow-up came from the “nonrestarted” group, a fact that could have an important effect on the conclusions if all suffered the same outcome.

Case Series

Case series were small in scale, consisted of patients observed in clinical practice and addressed the issue of anticoagulant medicines following hospitalisation for intracerebral hemorrhage. Whilst there were no meaningful comparators and potential confounders were not controlled for, cases were well defined (radiologically-confirmed), had their drug exposure adequately described and had high level of follow-up. Some of these studies consisted of series of consecutive cases which could be considered representative of the patient population, although this distinction was not always clear. Six of these case series addressed the principal issue of the use of antithrombotic medicines postintracerebral bleed [13–20], and these are summarised in Table 2. In total these studies describe the follow-up of 20 patients with intracerebral hemorrhage who received anticoagulation of durations of 6 months or more. Amongst these patients there were 2 subsequent intracerebral hemorrhages and 3 subsequent major thromboocclusive events.

Table 2.  Case series with long-term follow-up
Author, yearTotal patients’ in studyICH patients’ Rx ATAgeSex (M:F)AT indicationDuration of follow-upAT typeSubsequent hemorrhagic strokesT/O eventsDeaths not related to AT therapy
  1. Rx, prescribed; NS, not stated; ICH, intracerebral hemorrhage; AT, antithrombotic; PHV, prosthetic heart valve; PE, pulmonary embolism; MI, myocardial infarction; PVD, peripheral vascular disease; oAC, oral anticoagulation.

Butler & Tait, 1998 [13–15]35544–70NSPHV23 monthsoAC031
Nakagawa, 1995 [16]41111:0PHV36 monthoAC00 
Nagano, 1991 [17]2217, 602:0PHV6 months minoAC10 
Lau, 1991 [18]4240–651:3PHVUp to 3 yearsoAC00 
Babikian et al., 1988 [19]6335–772:1PHV6 monthsoAC001
Punthakee et al., 2002 [20]20746–823:85 PHV, 2 PE, 1MI, 1PVD, 1 arrythmias, 1 unstable angina2.8 years meanoAC0???1

Excluded Studies

Thirteen other studies addressed the use of both oral and parenteral anticoagulants following different types of intracranial hemorrhage, however the follow-up times were short (i.e., followed-up to discharge or up to 28 days) or had no statement of the duration of follow-up [21–35]. Other studies predated the study period [36], had index events, exposures or outcomes that were not clearly defined [37–40], considered only subarachnoid hemorrhage [41] or were not in English [42].

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Conflict of Interest
  10. References

We have conducted a systematic review of published English language observational studies that addressed the issue of patients with intracerebral hemorrhage and subsequent antithrombotic medication. Previous reviews of randomised control trials in this area revealed only a few studies that only addressed the short-term use of antithrombotic drugs in patients in the acute setting only and therefore provide little evidence to guide clinicians when faced with the dilemma of antithrombotic use in the longer-term management of patients with intracerebral hemorrhage [6]. This lack of evidence from randomised controlled trials probably reflects the ethical challenges of prescribing subjects a medication to which they have an apparent contraindication, and the practical issue of recruiting patients with a disabling condition [43]. Our review has therefore concentrated on observational studies and has revealed there is also a marked paucity of observational data on which to assess the risks and benefits attributable to antithrombotic medicines following intracerebral hemorrhage. The available literature describing the long-term follow-up of such patients consists of 8 publications including a total of only 46 patients receiving aspirin and 42 patients receiving oral anticoagulation.

Antiplatelet Use

In the case of antiplatelet medicines the current available evidence we found comes from a single observational study by Viswanathan et al. [11] The risk estimates associated with postintracerebral hemorrhage antiplatelet use in this small but high quality study had large confidence interval limits. The author's concluded that antiplatelet use was not associated with a large increased risk of recurrent intracerebral hemorrhage. Some commentators have taken a more cautious interpretation of the results, suggesting that antiplatelet medicines should only be used following intracerebral hemorrhage in high risk patients and that further data is required [44,45]. Others however take the view that this study shows there is no increased risk with antiplatelet medicines following intracerebral hemorrhage and even seem anxious at the low numbers of patients receiving them [46].

Oral Anticoagulants

In the case of anticoagulant drug use following intracerebral hemorrhage the published evidence comes from 1 epidemiological study and 6 case series and consists of 42 patients followed-up for 6 months or more. Amongst these there were 4 recurrent intracerebral bleeds and 9 subsequent thrombocculsive events. Again this represents insufficient evidence to judge the safety of anticoagulant use following intracerebral hemorrhage.

In spite this paucity of evidence there is a variety of opinion and guidance available to prescribers faced with this therapeutic dilemma. As in the case of antiplatelet agents these views frequently display a dichotomy of opinion [4,43,47]. Treatment guidelines typically make little mention of whether antithrombotic medicines when indicated can or should be continued following an intracerebral hemorrhage [48]. Where guidance does exist it is based on “expert” opinion, as is common with such guidelines [49]. Balancing the competing risks of recurrent intracerebral hemorrhage and subsequent ischemia, as has been suggested [50], is impossible as our review has shown the risk of recurrent intracerebral bleeding whilst on oral anticoagulation is not known.

The occurrence of this therapeutic dilemma, already becoming more frequent, can be expected to increase further still [51]. Established risk factors for intracerebral hemorrhage are increasing age, hypertension and hypocholesterolemia, with male sex, high alcohol intake and ethnicity also implicated [52,53]. Many of these factors, in particular age and, hypertension, are shared with ischemic disease for which antithrombotic drugs are commonly indicated [54]. This implies that a substantial proportion of patients presenting with intracerebral hemorrhage will also be at risk of ischemic events from which protection would normally be indicated. In addition the use of anticoagulant therapy for prophylaxis in patients with mechanical prosthetic heart valves and atrial fibrillation has markedly increased in recent years.

This systematic review used an inclusive and comprehensive search strategy and we are confident that we have collected all published English language observational studies addressing the question of antithrombotic use following intracerebral hemorrhage. The review has also encompassed case series and case reports which, in the absence of more robust evidence, have been acknowledged as being useful in hypothesis generation [55]. There are however well known problems with such case reports. They are anecdotal in nature, and cases may be “cherry picked” and therefore unrepresentative of the population of interest. Additionally their typically low numbers and lack of comparison group means that they cannot be used to test for valid statistical associations [55]. It is acknowledged that they represent the lowest level of clinical evidence [56]. Even if sufficient observational studies had been found there would be concerns with issues of confounding and bias, particularly confounding by indication. In such nonrandomised studies, patients perceived as either being at low risk of recurrent intracerebral hemorrhage or at high risk of ischemic events may be more likely to be prescribed antithrombotic medicines. This could lead to an underestimate of the risk of recurrent intracerebral hemorrhage and overestimate of the risk of subsequent ischemic events in those receiving treatment. Attempting to control for such biases will be a major challenge for future studies.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Conflict of Interest
  10. References

Patients with intracerebral hemorrhage frequently have indications for antithrombotic therapy; however such medicines are commonly perceived as contraindicated in this context. In addition to the lack of randomised controlled trial data addressing this issue, our review has revealed there is also a marked paucity of observational data on which to judge the safety of anticoagulant and antiplatelet medicines following intracerebral hemorrhage. As it is unlikely that randomised controlled trials will be performed in this area in the near future, the need for more high quality observational data in this area is crucial [50,57]. Clearly, however, if these studies indicate no harm, the question of whether patients with intracerebral hemorrhage should receive the well established benefits of antithrombotic medications will ultimately require testing in a formal randomised study.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Conflict of Interest
  10. References

Robert Flynn is funded on an unrestricted grant by Chief Scientist Office, Scottish Executive Health Department (Fellowship grant CZF/1/41). All authors contributed to the securing of the funding and the concept of this review. In addition, each author's contributions were as follows: RF Collection & review of reference materials, drafting of the manuscript, interpretation of findings, revision of article. TM Interpretation of findings and critical revision of manuscript. GM Critical revision of manuscript. AD Assisted with review of reference material, drafting article, interpretation of findings, critical revision of article.

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  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgments
  9. Conflict of Interest
  10. References
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