Q J Med 2000; 93: 513-521
© 2000 Association of Physicians
Analysis of risk factors involved in oral-anticoagulant-related intracranial haemorrhages
From the Clinical Pharmacology Unit, Aberdeen Royal Infirmary, Aberdeen, UK
Received 16 February 2000 and in revised form 7 June 2000
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Summary |
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We examined risk factors for intracranial bleeding while on oral anticoagulants (OACs) in 68 patients admitted to hospital over a 6-year period, and 204 out-patient controls followed-up in an OAC clinic. Under multivariate analysis, significant risk factors for OAC-related intracranial bleeds were hypertension (OR (95%CI) 2.69 (1.04–6.97), duration of OAC therapy
12 months (OR 3.74 (1.21–11.56)), duration 
96 months (OR 0.25 (0.07–0.88)), and International Normalized Ratio on admission >4.5 (OR 10.92 (2.46–48.43)). A logistic regression model including the above variables along with a history of ‘cerebrovascular disease’ (OR 2.32 (0.98–5.46)) correctly predicted intracranial bleeding (or its absence) during OAC therapy in 85% of all patients. The risk associated with advanced age and concomitant aspirin use was not significantly increased in this analysis. It is important to achieve tight control of INR, particularly in the early months of treatment. Patients with previous cerebrovascular disease are at increased risk of intracranial bleeding on warfarin, and hypertensive patients should have especially close monitoring and optimal control of their blood pressure. |
Introduction |
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A few observational studies have previously investigated possible factors that may contribute to an increased risk of any type of bleeding while on oral anticoagulant (OAC) treatment.1–7 In four, advanced age was found to increase the risk of major OAC-related bleeding 1.8- to 3.2-fold (at different ages
65 years).1,2,4,5 Two studies failed to demonstrate a significantly increased risk of OAC-related bleeding at an advanced age.3,6 Hypertension increased the risk of bleeding by a factor of 1.7–2.8.1,2 Recent initiation of OAC therapy (3 months) carried an increased risk of any type of bleeding in three cohort studies (relative risk, RR 1.9–5.9).2,3,5 Aspirin was not found to increase the risk of major OAC-related haemorrhage in two recent cohort studies.1,3 Six studies found the bleeding risk to be strongly related to the intensity of oral anticoagulation, with a RR 1.4–1.8 for every unit increase starting from International Normalized Ratio (INR) 2.0, and a RR 3.0–7.9 for INR 4.5.1–5,7 The incidence of intracerebral bleeding unrelated to OAC use clearly increases with advancing age (from 5 up to 20/100 000 persons/year).8,9 In a review of six cohort studies, hypertension was found to be a major risk factor for intracerebral haemorrhage (RR 4–5),8 although this relationship was somewhat weaker in a recent large case-control study (odds ratio, OR 2.55).10 In two case-control studies, aspirin in its usual prophylactic dose did not significantly increase the risk of intracerebral bleeding.10,11
Even though they occur relatively infrequently, intracranial (especially intracerebral) haemorrhages are responsible for a large proportion of all OAC-related case fatalities.8 It is generally assumed that the prognosis of OAC-related intracranial haemorrhages is worse than bleeds unrelated to OAC use, mainly because of the greater chance of extension.8,12 Apart from the usual intrinsic risk factors of intracerebral bleeds, such as advanced age and systolic hypertension, other patient-related risk factors may be more closely associated with OAC-related haemorrhages than with unrelated haemorrhages (e.g. ischaemic cerebrovascular disease).8 On the other hand, it is also possible that the risk factors normally related to OAC therapy (e.g. recent initiation, elevated INR) carry a different weight when considered specifically for intracranial haemorrhages rather than for all major haemorrhages in general.12
Since the widespread introduction of CT scanning in the early 1980s, there have been as many as 15 separate publications on OAC-related intracranial haemorrhages,13–27 in addition to one review article.28 The epidemiological value of these studies must, however, be questioned. The study designs are usually rather primitive: eight studies are simple case series (n=6–105, mean 19 patients);16,17,21,22,24–27 five studies compare OAC-related to non-OAC-related haemorrhages (n=33–79, mean 47 OAC-treated patients);13–15,18,23 one study contrasts OAC-treated patients admitted with an intracranial haemorrhage after trauma to those admitted without preceding trauma (68 patients);20 and only one study has a case-control design (121 cases, controls from local OAC outpatient clinic).19
The objective of this study was to investigate further the patient- and treatment-related risk factors for OAC-induced intracranial haemorrhages. A case-control study into this problem has so far been conducted only once, more than 8 years ago, and before the widespread introduction of OAC therapy for non-rheumatic atrial fibrillation.19
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Methods |
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Between January 1993 and March 1999, a total of 1512 patients were admitted to Aberdeen Royal Infirmary (ARI) with an intracranial haemorrhage, identified as the principal diagnosis for discharge (International Classification of Diseases, ICD-9 or ICD-10) codes. As controls, we drew a sample of out-patients followed up in the anticoagulation clinic at ARI. This clinic had been established about 6 years ago, and its database contained, at the time of the study, the names of 825 patients. The database only allowed us to identify those who had recently been reviewed, and not to select patients for a certain period during which they must have been followed-up in the clinic. We therefore decided to draw a random sample of patients who had attended the clinic in the last 6 months. There is, however, good reason to believe that the practice in the OAC clinic has not notably changed in the last 6 years, as the senior staff have remained the same over that period. On the basis of patient notes, we recorded the following patient information for cases and controls: gender, age, existence of hypertension (i.e. past history or current antihypertensive treatment), diabetes mellitus, hypercholesterolaemia, cardiovascular disease (i.e. atrial fibrillation, ischaemic heart disease, or congestive heart failure), cerebrovascular disease, venous thromboembolism, alcohol abuse, liver and renal disease, cancer, previous OAC-related haemorrhages. We also recorded the following treatment characteristics: duration of OAC therapy, number of concomitant drugs, aspirin use, INR as measured on admission to hospital or in the out-patient clinic, time interval between the latter two INR measurements, accordance with the Scottish Intercollegiate Guidelines Network (SIGN)-guidelines.29 In order to increase the statistical power of the risk factor analysis, we compared the patient- and treatment-related characteristics of patients admitted with an OAC-related intracranial or intracerebral haemorrhage to those of a three-fold number of outpatients from the anticoagulation clinic. Cases and controls were not individually matched. We studied the frequency distributions for patient age, duration of OAC therapy, number of concomitant drugs, INR value as measured on admission or in the out-patient clinic, and the time interval between the most recent check and the preceding one. As these variables did not appear to be normally distributed, the non-parametric Mann-Whitney U test was used for the comparison of means of two unmatched groups. A 5% significance level was assumed for all hypothesis testing. The above-mentioned continuous variables were furthermore converted into categorical data (age categories <65, 65–79, >79 years; duration of OAC therapy
12, 13–95, 96 months; use of 3 or >3 concomitant drugs (apart from warfarin); INR <2, 2–4.5, >4.5; most recently checked INR value 42 or >42 days ago). Univariate odds ratios (with 95% CIs) were calculated for these categorical variables, as well as for the dichotomous parameters mentioned above (gender, presence of hypertension, diabetes mellitus, etc.). We then proceeded with multiple logistic regression to calculate multivariate odds ratios (and 95% CIs) (Forward method). We furthermore determined how much weight each of these factors carried (Enter method), as well as the sensitivity, specificity, positive and negative predictive values for the constructed models. All analyses were done twice, once for all cases of intracranial haemorrhage and once exclusively for cases of intracerebral haemorrhage (no. of controls each time=3xno. of cases). All statistical analyses used SPSS version 8.0. |
Results |
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Between January 1993 and March 1999, 1512 patients were admitted to ARI with a diagnosis of intracranial haemorrhage. Sixty-eight were treated with OACs at the time of sustaining their intracranial haemorrhage; 42 (62%) haemorrhages were intracerebral. Patient- and treatment-related characteristics for the 68 patients admitted to ARI with an OAC-related intracranial haemorrhage, and for 204 controls followed-up in the anticoagulation clinic were recorded. For these characteristics, data were missing with regard to the duration of OAC therapy in one patient and no controls, the INR value as checked on admission or in the clinic in three patients and no controls, and the time interval between the most recent and preceding check in 17 patients and four controls. The mean age of all 68 patients admitted with an OAC-related intracranial haemorrhage (70±10 years) did not differ significantly from the mean age of 204 control patients (68±12 years) (p=0.30). The mean duration of OAC therapy was significantly shorter for case patients (34±48 months vs. 86±77 months; p<0.001). Note, however, the very wide distribution of values within both groups (Figure 1
). On the other hand, both cases and controls appeared to have exactly the same mean number (±SD) of concomitant drugs (3.0±1.9; p=0.87). The mean INR values checked on admission to hospital or in the out-patient clinic differed significantly from one another: 3.8±2.1 for cases, vs. 2.7±1.0 for controls (p<0.001) (Figure 2). The INR values had generally been checked a shorter time before hospital admission with an intracranial haemorrhage than before routine clinic review (22±21 days vs. 29±19 days, p=0.001). The mean values of the above variables have also been calculated and compared for the 42 cases of OAC-related intracerebral haemorrhage and for 126 randomly selected control patients: age 71±10 years vs. 66±12 years (p=0.059), duration of OAC therapy 29±43 months vs. 94±81 months (p<0.001), number of concomitant drugs 3.0±1.9 vs. 2.8±2.0 (p=0.69), checked INR value 3.6±2.1 vs. 2.5±0.8 (p=0.003), time period since last check 26±25 days vs. 31±20 days (p=0.027).
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The above continuous variables were further broken down into categorical variables. Together with the previously mentioned dichotomous parameters, these variables were included in univariate risk analysis. The calculated odds ratios for the individual risk factors, along with their 95% CIs, are presented in Table 1
. Apart from the odds ratios indicating the risk of all types of OAC-related intracranial haemorrhage taken together, the odds ratios specifically reflecting the risk of sustaining an intracerebral bleed in the course of OAC therapy are also presented. We have calculated the odds ratios (+95%CIs) for the same variables using multiple logistic regression. The results of multivariate risk factor analysis for OAC-related intracranial and intracerebral haemorrhages are presented in Table 2
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Logistic regression models were constructed to predict the occurrence of OAC-related intracranial and intracerebral haemorrhages, respectively, on the basis of the above-mentioned variables. Details of both models are listed in Table 3
. The first model has a sensitivity of only 34%, a specificity of 98%, a positive predictive value of 77%, and a negative predictive value of 86%. The sensitivity of the second model is only 32%. Its specificity is, however, 99%, its positive predictive value 91%, and its negative predictive value 85%.
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Discussion |
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Much of the epidemiology of OAC-associated intracranial bleeding suffers from weaknesses. A case-control design such as we have used is relatively robust, and allows by far the most in-depth analysis of the risk factors involved in OAC-related intracranial haemorrhages. The four single most important risk factors of OAC-related intracerebral bleeds identified in this study may represent an interplay between risk factors specific for intracerebral haemorrhages (hypertension) on the one hand, and OAC-related haemorrhages (therapy length
12 months, INR >4.5) on the other. The mechanism whereby existing cerebrovascular disease predisposes to intracerebral bleeding is less clear, though vascular pathology such as amyloid angiopathy and fibrinoid necrosis of perforating arteries may prevail in some patients.23 Although the case-control design can certainly add power and efficiency to the study of infrequent events, uncommon, yet important risk factors may also fail to be identified by this approach.19 Case-control studies do not normally provide direct estimates of absolute risk. For the controls in our study, we only used patients followed-up in the anticoagulation clinic at ARI. We had initially hoped that the patient population in this clinic would provide us with a large enough subgroup of cases to enable us to conduct a separate nested case-control study for the confirmation of our findings.19 However, as only 12/68 patients admitted with OAC-related intracranial haemorrhages had previously been followed up in the out-patient clinic, this was not feasible.
Increasing age has traditionally been regarded as an important risk factor for OAC-related intracranial haemorrhages. For intracerebral haemorrhages, the absolute increase in incidence of OAC-related events probably reflects the heightened ‘intrinsic’ risk of sustaining a spontaneous intracerebral haemorrhage at a more advanced age.14,18,23 One report has indeed indicated that there was no significant difference in age distribution between patients who sustained an intracerebral bleed while on OAC therapy and others who sustained an unrelated bleed.15 When only patients treated with OACs are considered, i.e. within the frame of a cohort study or a case-control study such as our own, the relative risk and odds ratio of intracranial haemorrhages in older age categories (>65 years) have been reported as statistically significant at 1.4 and 5.8, respectively.1,19 The same estimates for intracerebral haemorrhages only appear to reach borderline significance (1.3 and 3.7, respectively).19,30 No odds ratio for any type of haemorrhage was statistically significant for any of the age categories considered in our study. There is a suggestion of a trend to an increasing odds ratio with age in both univariate and multivariate analyses. We should not dismiss this association entirely, because of the limited statistical power of the study. The age effect, if any, does seem relatively weak, however.
In several series of patients admitted with an OAC-induced intracerebral bleed, hypertension was identified as a risk factor in 30% to 80% of cases.14,15,18,20–24,26,31 It is remarkable that the only case-control study reported so far failed to attach an increased risk of OAC-related intracranial haemorrhage to the presence of hypertension.19 Two reports, subanalyses of much larger studies including all major OAC-related haemorrhages, have found a (borderline) significant increase in risk with hypertension for intracranial haemorrhages (RR 3.4, p=0.05),1 and for intracerebral bleeds in particular (RR 3.6–4.4, p0.04).30 In our study, we have been able to demonstrate that hypertension is a strong independent risk factor, more so for intracranial haemorrhages in general than for intracerebral bleeds.
Ischaemic heart disease was present in 32% of patients admitted with OAC-related intracerebral bleeds in one study, as compared to 14% of patients with unrelated haemorrhages (p<0.01).18 In the only previous case-control study, a history of past myocardial infarction did not alter the risk of sustaining an intracerebral haemorrhage while on OAC therapy.19 In our study, ischaemic heart disease was a statistically significant risk factor for OAC-related intracerebral haemorrhages in multivariate analysis (i.e. clearly independent of aspirin use), but not in univariate analysis. The explanation for this finding is uncertain.
Several studies have found the prevalence of associated cerebrovascular disease to range between 10% and 65% of patients admitted with OAC-related intracerebral haemorrhages.18,20,21,26,31 The only previous case-control study reported that ischaemic cerebrovascular disease was an important risk factor, significantly increasing the chance of sustaining an intracerebral or intracranial haemorrhage in the course of OAC therapy (statistically significant odds ratios in both univariate and multivariate analyses, 2.3–3.1).19 One cross-sectional study found the incidence of OAC-related intracerebral haemorrhages to increase 10-fold if there was a history of preceding cerebrovascular disease (1.1% /year vs. 0.11% /year, i.e. RR 10).15 The subanalysis of a large prospective study estimated the relative risk of sustaining an OAC-induced intracerebral bleed with a history of cerebrovascular disease at 6.3.30 The risk has been estimated in another study at 6.6 for all types of OAC-related intracranial haemorrhage.1 In our study, the odds ratios of OAC-related intracranial and intracerebral haemorrhages for cerebrovascular disease were statistically significant in univariate analysis, though less significant in multivariate analysis. Cerebrovascular disease was, however, included again in the logistic regression models to predict the occurrence of both types of bleed.
Most reports dealing with OAC-related intracranial haemorrhages have discussed the impact of duration of therapy on the risk of bleeding. One opinion is that the risk of an intracranial haemorrhage is increased in the first months after starting OAC therapy,15,18,21,31 while an alternative view states that the risk of sustaining an intracranial bleed increases with increasing length of therapy.14,17,20,22–24,26,30 Very few studies have actually compared the length of OAC therapy in patients who sustain an intracranial haemorrhage with control patients who do not. The findings from our study are entirely in keeping with the first mentioned view. A new observation is that long duration of OAC therapy (96 months) may also confer a relative protection against the risk of sustaining an intracranial haemorrhage. This may possibly indicate a ‘healthy patient’ effect: patients who are perceived to be at the greatest risk of sustaining an intracranial haemorrhage may be taken off OAC therapy prematurely. It is important to note that most cohort studies cannot properly assess the impact of therapy length on the occurrence of major (intracranial) haemorrhages,2–4,6 unless an inception cohort is followed up (i.e. all patients entered into the study at the start of treatment).1,5 Case-control studies, such as our own and the one previously reported,19 are not liable to this potential source of bias.
There is some uncertainty as to the impact that aspirin has on the risk of sustaining an OAC-related intracranial haemorrhage. One review claimed that aspirin would double the risk of intracerebral bleeding, regardless of dose.28 This conclusion was reached on the pooled data from four randomized controlled trials of combined OAC and aspirin use in patients with prosthetic heart valves, and may therefore be subject to selection bias. On the other hand, in the only two case series in which the use of aspirin had been reported (24 and 28 patients, respectively), none of the patients admitted with OAC-related intracerebral haemorrhages appeared to have taken the combination of drugs.21,31 The role of aspirin in the occurrence of OAC-induced intracranial haemorrhages has never before been investigated in a case-control study. We have found that aspirin use as a risk factor just fails to attain statistical significance in univariate analysis, and in multivariate analysis may appear to be confounded by the (statistically significant) factor of ischaemic heart disease.
As far as the intensity of OAC therapy is concerned, the interpretation of study results reported so far is confounded by the different units used to express intensity (e.g. BCR in 1, PT in 6, PTR in 1, TT in 2, and INR in 5 studies), and by the different cut-off values applied to define ‘overanticoagulation’ (e.g. INR >3.5 up to >4.8). The proportion of patients found to be overanticoagulated has generally ranged from 6% to 38% of patients admitted with an OAC-related intracranial haemorrhage,13–18,20,22–24,26 while the intensity has also been reported to be ‘subtherapeutic’ in up to 28% of patients.17,21–24 Four studies have directly compared the intensity of anticoagulation for patients admitted with an intracranial haemorrhage to that of control populations. Two studies found the proportion of overanticoagulated patients to be significantly higher among patients with intracranial haemorrhages than in control patients (33% vs. 5%, p<0.001; and 10% vs. 3%, p=0.04).13,18 Two other studies failed to demonstrate such a significant difference in the prevalence of overanticoagulation and the mean INR value, respectively.14,23 The only previous case-control study showed that a PTR >2.0 (approx. equivalent to INR >4.0) was the only risk factor that remained statistically significant for all types of haemorrhages, in both univariate and multivariate analyses.19 The results of our study confirm the danger associated with an INR >4.5, but also indicate that subtherapeutic INR values cannot be considered protective against intracranial haemorrhages. However, INR values determined upon admission do not necessarily reflect the INR at the time of sustaining a haemorrhage. Caution is thus warranted when making inferences on the risks associated with intensity of OAC therapy from INR values measured on admission.16,26
Several recommendations can be made for the prevention of OAC-related intracranial bleeds.17–22,24–26,28,32–34 In previous studies, many patients had been found anticoagulated inappropriately (33–66%),17,26 and it therefore is of the utmost importance to consider both the accuracy of diagnosis and the strength of indication before starting OAC therapy.17,18,20,24–26,32 The need for regular monitoring of OAC therapy is of course self-evident.25,32 The lowest effective target INR for each individual indication should be recommended.18,19,21,28,32,34 Apart from setting relatively low target INR values, it may also be useful to develop local guidelines for the management of excessively high levels of intensity.32 Hypertension becomes increasingly prevalent in older age groups and should be carefully controlled prior to and during OAC therapy. On the basis of the above findings, high-risk patients should be identified and considered for alternative therapies to oral anticoagulation.20,32 For example, aspirin may be an alternative to warfarin in selected high-risk patients with atrial fibrillation.
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Address correspondence to Dr J. Berwaerts, Smithkline Beecham ACCI–CRU, Anddenbrooke's Hospital, Hills Road, Cambridge CB2 2GG. e-mail: Joris_M_Berwaerts{at}sbphrd.com
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 M. C. Fang, Y. Chang, E. M. Hylek, J. Rosand, S. M. Greenberg, A. S. Go, and D. E. Singer Advanced Age, Anticoagulation Intensity, and Risk for Intracranial Hemorrhage among Patients Taking Warfarin for Atrial Fibrillation Ann Intern Med, November 16, 2004; 141(10): 745 - 752. [Abstract] [Full Text] [PDF]
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