Resumption of antiplatelet therapy in patients with primary intracranial hemorrhage-benefits and risks: A meta-analysis of cohort studies

Accepted Manuscript Resumption of antiplatelet therapy in patients with primary intracranial hemorrhage-benefits and risks: A meta-analysis of cohort studies

Xueying Ding, Xi Liu, Changhong Tan, Maojia Yin, Teng Wang, Ying Liu, Lijuan Mo, Xin Wei, Xinjie Tan, Fen Deng, Lifen Chen PII: DOI: Reference:

S0022-510X(17)34441-6 doi:10.1016/j.jns.2017.11.009 JNS 15655

To appear in:

Journal of the Neurological Sciences

Received date: Revised date: Accepted date:

30 August 2017 18 October 2017 8 November 2017

Please cite this article as: Xueying Ding, Xi Liu, Changhong Tan, Maojia Yin, Teng Wang, Ying Liu, Lijuan Mo, Xin Wei, Xinjie Tan, Fen Deng, Lifen Chen , Resumption of antiplatelet therapy in patients with primary intracranial hemorrhage-benefits and risks: A meta-analysis of cohort studies. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jns(2017), doi:10.1016/ j.jns.2017.11.009

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ACCEPTED MANUSCRIPT Resumption of Antiplatelet Therapy in Patients with Primary Intracranial Hemorrhage-Benefits and Risks: A Meta-analysis of Cohort Studies

Xueying Ding1 , Xi Liu1 , Changhong Tan1 , Maojia Yin1 , Teng Wang1 , Ying Liu1 ,

Department of Neurology, The Second Affiliated Hospital of Chongqing Medical

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Lijuan Mo1 , Xin Wei1 , Xinjie Tan1 , Fen Deng1,* , Lifen Chen1,*

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University, Chongqing, 400010, China

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*Correspondence to: Lifen Chen

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Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China.

Fax: 86-23-63711527

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Tel: 86-23-63693088

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Fen Deng

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E-mail: [email protected]

Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China. Tel: 86-23-63693088 Fax: 86-23-63711527 E-mail: [email protected]

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ACCEPTED MANUSCRIPT Abbreviations AP, antiplatelet; ICH, Intracranial hemorrhage; NOS, Newcastle-Ottawa Quality

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Assessment Scale; RR, relative risk; CI, confidence interval.

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ACCEPTED MANUSCRIPT Abstract Background: Clinical disagreement over antiplatelet (AP) resumption in patients with primary intracranial hemorrhage (ICH) has long existed. This meta-analysis aimed to evaluate the benefits of AP resumption on preventing ischemic or thromboembolic events against its risks of promoting ICH recurrence or hematoma

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expansion.

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Methods: All relevant articles published in Pubmed, EMBASE, the Cochrane Library,

combined relative risk (RR) was calculated.

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and Science Direct from January 1950 to March 2017 were sourced, and the

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Results: A total of 3648 articles were found, and after screening, 6 cohort studies including 1916 patients were included in this meta-analysis. AP resumption was

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associated with a decreased risk of ischemic or thromboembolic eve nts (RR, 0.61; 95% confidence interval (CI), 0.48–0.79; P<0.01). There was no significant difference

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in the risk of ICH recurrence or hematoma expansion between patients with or without AP resumption (RR, 0.84; 95% CI, 0.47–1.51; P=0.56).

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Conclusion: AP resumption in patients with primary ICH reduced the risk of ischemic or thromboembolic events, without significant increase of risk of ICH recurrence or

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hematoma expansion.

Keywords: Antiplatelet therapy; Intracranial hemorrhage; Hematoma expansion; Ischemia; Thromboembolism

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ACCEPTED MANUSCRIPT 1. Introduction Intracranial hemorrhage (ICH) is one of the devastating complications of antithrombotic therapy with high associated morbidity and mortality [1, 2]; the incidence of ICH increased by 47% from 1990 to 2010 worldwide [3]. The use of antiplatelet (AP) therapy could increase the risk of ICH, the number of emergency

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patients with AP-related ICH is increasing, especially in industrialized countries [4].

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Moreover, patients with primary ICH trend to have ICH recurrence and hematoma

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expansion [5-7].

In addition, ischemic heart disease and cerebrovascular disease are tremendous

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public health problems that together account for more than 20% of all deaths globally [8], and myocardial infarction and ischemic stroke are the most severe types of these

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diseases. Unfortunately, they are of considerable risk of recurrence, the hospitalization rate of recurrent myocardial infarction in one year after onset is approximately 9-12%,

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and the annual risk of ischemic stroke recurrence is approximately 3-4% [9, 10]. To prevent ischemic or thromboembolic events in patients with the indication of AP

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therapy, the application of antiplatelet therapies is rapidly increasing, especially considering the aging of population [11-13]. Therefore, a clinical dispute arises that

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whether patients with both primary ICH and the indication of AP therapy should resume AP therapy [14]. Because of the risk of ICH recurrence, primary ICH is usually considered as contraindication of AP therapy [14]. However, without AP therapy, many patients may suffer from ischemic and thromboembolic events. Unfortunately, only few randomized controlled trial and no guidelines or expert consensus clarified the benefits and risks of AP resumption in patients with primary ICH [15-17]. Furthermore, an unnecessary delay or termination of AP therapy in the patients with

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ACCEPTED MANUSCRIPT the indication of AP therapy could increase the ischemic or thromboembolic risk. Therefore, whether to resume AP therapy or not requires physicians to make a balance between risk of hemorrhage and thromboembolism. This meta-analysis aimed to explore the effects of AP resumption on promoting ICH recurrence and hematoma expansion and preventing ischemic or thromboembolic

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clinical decision of AP resumption in primary ICH patients.

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events in patients with both primary ICH and the indication of AP therapy, and help

2. Methods

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2.1. Search Strategy

We systematically searched all relevant literature published in Pubmed, EMBASE,

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the Cochrane Library, and Science Direct databases from January 1950 to March 2017. The search terms used were (“intracranial hemorrhages” OR “cerebral hemorrhages”

“clopidogrel” OR

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OR “brain hemorrhages”) AND (“antithrombotic” OR “antiplatelet” OR “aspirin” OR “ticlopidine”

OR

“cilostazol”

OR

“dipyridamole” OR

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“anticoagulant”) AND (“recurrent intracranial hemorrhage” OR

“hematoma

expansion” OR “venous thrombosis” OR “arterial thrombosis” OR “myocardial

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infarction” OR “ischemic stroke” OR “transient ischemic attack”). Articles published in both English and Chinese were included. Additionally, the bibliographies of the retrieved articles were also reviewed.

2.2. Study Selection Studies were initially screened by titles and abstracts, and the chosen articles after initial screening underwent secondary full- text screening. The specific inclusion criteria were as follows: (1) randomized controlled trials or cohort studies; (2) studies

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ACCEPTED MANUSCRIPT compared primary ICH patients with or without AP resumption; and (3) studies with outcomes

including

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recurrence,

hematoma

expansion,

ischemic

or

thromboembolic events such as myocardial infarction, arterial thrombos is, venous thrombosis, ischemic stroke, and transient ischemic attack. The specific exclusion criteria were as follows: (1) review, case report, letter, and

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other antithrombotic agents in patients during follow-up.

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commentary; and (2) studies with medicine terminated or changed from AP agents to

2.3. Data Extraction and Study Quality Assessment

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The following information was extracted from the included studies: name of the first author, publication year, country, number of patients, age and sex of patients,

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location of ICH, type of AP agents, timing of AP resumption, duration of follow-up, and outcomes of ICH recurrence, hematoma expansion, myocardial infarction, arterial

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or venous thrombosis, and ischemic stroke or transient ischemic attack. Two researchers independently evaluated each study using the Newcastle-Ottawa

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Quality Assessment Scale (NOS) [18]. The NOS scale is recommended by The Cochrane Collaboration, and consists of three parts: selection of study groups,

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comparability of groups and ascertainment of outcome. Any disagreements between the two reviewers (D. X., and L. X.) were discussed and resolved by consensus with a third researcher (C. L).

2.4. Statistical Analysis The combined relative risk (RR) with 95% confidence interval (CI) was calculated using Review Manager 5.3 software (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.) to estimate the benefits and risks of AP

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ACCEPTED MANUSCRIPT resumption. P<0.05 was considered statistically significant. Heterogeneity among the included studies was assessed by the χ2 test and I2 statistic. Heterogeneity was considered significant if the P-value of the χ2 test was < 0.1 or I2 ≥ 50% [19-21]. If there was no significant heterogeneity according to Mantel-Haenszel analysis, the fixed-effects model was used to pool data across the included studies, otherwise, the

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random-effects model was used [22, 23], and sensitivity analysis was performed to

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address the influence of each single study on the overall results by dislodging one

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study at a time and calculating the combined RR for the remaining studies.

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3. Results 3.1. study selection

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After the exclusion of duplicates, 3648 articles remained, 3631 articles were excluded by screening the titles and abstracts, mainly because they were reviews, case

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reports, letters, or not relevant to our analysis. Of the remaining 17 articles, 9 were excluded because they were only about anticoagulants [24-32], one was excluded

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because the majority of participants who had resumed antithrombotic agents had their medicine terminated or changed during the follow-up [33], and one was excluded

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because there was no clear record of which kind of antithrombotic agents, oral anticoagulant, or AP therapy was resumed [34]. Finally, only 6 articles met the inclusion criteria [35-40]. The study selection is presented in flow chart form in Fig. 1.

3.2. Study Characteristics The 6 included studies were all cohort studies, and the characteristics of these 6 studies are presented in Table 1. 2 studies were conducted in China, the rest were

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ACCEPTED MANUSCRIPT conducted in the UK, Japan, Canada, and Denmark. The 6 studies were published between 2010 and 2016 and contained 3118 patients, among these patients, 825 were assigned to the AP resumption group, 1091 were assigned to the non-AP resumption group, while 1202 patients resumed antithrombotic agents other than AP agents were not concerned in this meta-analysis. The number of patients in each study ranged from

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51 to 1752, both sexes were enrolled in the 6 studies, and mean or median age of

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patients, location of ICH, type of AP agents, timing of AP resumption, duration of

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follow-up, and NOS scores of the 6 studies are all showed in Table 1.

Expansion in Primary ICH Patients

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3.3. AP Resumption did not Significantly Increase ICH Recurrence and Hematoma

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The 6 studies offered data containing 1916 patients (825 in AP resumption group, 1091 in non-AP resumption group) [35-40]. Pooled result using the random-effects

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model showed that there was no significant difference between AP resumption group and non-AP resumption group for ICH recurrence or hematoma expansion (RR, 0.84;

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95% CI, 0.47–1.51; P=0.56) (Fig. 2), with evident heterogeneity (P<0.01; I2 =71%).

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3.4. AP Resumption Significantly Decreased Ischemic or Thromboembolic Events in Primary ICH Patients 5 studies were eligible with 1647 patients (753 in AP resumption group, 894 in non-AP resumption group) [35, 37-40]. Pooled result using fixed-effects model showed that AP resumption was associated with a reduced risk of ischemic or thromboembolic events, compared to non-AP resumption group (RR, 0.61; 95% CI, 0.48–0.79; P<0.01) (Fig. 3). No significant heterogeneity was found among these 5 studies (P=0.29; I2 =20%).

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3.5. Sensitivity Analysis Because significant heterogeneity was showed when assessing the relationship between AP resumption and the risk of ICH recurrence or hematoma expansion, a sensitivity analysis was performed. The combined RRs of sensitivity analysis were

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summarized in Table 2, and range from 0.64 (95% CI, 0.39–1.04) to 1.09 (95% CI,

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0.64–1.83).

3.6. Publication Bias

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Two funnel plots were constructed, one for the 6 studies which discussed the ICH recurrence or hematoma expansions, the other for the 5 studies which discussed

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ischemic and thromboembolic events. And both of the two funnel plots revealed a

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slight asymmetry, indicating there is mild publication bias (Fig. 4).

4. Discussion

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This meta-analysis included 6 cohort studies, the pooled result showed that AP resumption significantly reduced the risk of ischemic or thromboembolic events in

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patients with primary ICH. In clinic, AP is an important and cost-effective therapy in the secondary prevention of ischemic stroke, myocardial infarction and other ischemic or thromboembolic events [11, 41]. Interestingly, our pooled result indicated that AP resumption do not increase the risk of ICH recurrence or hematoma expansion. Currently, few research discussed the effect of AP therapy on ICH recurrence and hematoma expansion. A previous study suggested AP therapy after lobar ICH may increase the risk of ICH recurrence [42], however, another research of neuroimaging suggested AP therapy may not increase

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ACCEPTED MANUSCRIPT the risk of hematoma expansion [43]. Our meta-analysis indicated that it is rational to resume AP therapy in primary ICH patients because AP resumption reduced the risk of ischemic or thromboembolic events without increasing the risk of ICH recurrence or hematoma expansion. However, the included studies in our meta-analysis contains only 1916 patients, among whom 228 patients had ICH recurrence or hematoma

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expansion, the limited number of patients may lead to an underestimation of the risk

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of ICH recurrence or hematoma expansion. In addition, the included studies used

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various types of AP agents, and their risks of hemorrhagic events are different [41]. So the difference in risk of ICH recurrence or hematoma expansion due to AP agents may

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be concealed.

In addition, when assessing the relationship between AP resumption and the risk

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of ICH recurrence or hematoma expansion, sensitivity analysis revealed that the heterogeneity could be mainly attributed to 2 studies [36, 39]. In one of the 2 studies

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account for heterogeneity, only aspirin was used [36], while in the other 5 studies patients used aspirin, clopidogrel, ticlopidine, other AP agents, or unspecified. And the

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risk of adverse effects (including hemorrhagic events) caused by aspirin is higher than that caused by other AP agents such as clopidogrel, ticlopidine [44]. So the

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heterogeneity due to this study [36] may probably be attributed to the use of aspirin. This finding suggest that clinicians could consider avoiding the use of aspirin when resume AP therapy in primary ICH patients. The other study account for heterogeneity was conducted on patients with atrial fibrillation [39], while the other 5 studies did not select patients according to their electrocardiography. Interestingly, in this study [39], patients with atrial fibrillation resumed AP therapy had decreased risk of ICH recurrence compared to non-AP resumption patients. In contrary, a research including 7554 patients suggested AP therapy increased the risk of major hemorrhage in patients

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ACCEPTED MANUSCRIPT with atrial fibrillation [45]. The opposite results may be caused by different types of AP agents, different characteristics of patients and other factors. So the safety of AP resumption in ICH patients with atrial fibrillation is controversial, and further randomized controlled trail is needed. Furthermore, as the baseline risk of hemorrhagic events between AP resumption group and non-AP resumption group,

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which could be reflected by CHA2 DS2 -VASc and HAS-BLED scores, was unknown

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in this study [39], it is possible that the patients with AP resumption may have lower

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risk of ICH recurrence at baseline due to potential selection bias. And it is also possible that the differences in timing of AP resumption, location of ICH, the duration

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of follow-up and other factors may contribute to the heterogeneity. In the 6 included studies on ICH recurrence or hematoma expansion, no

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significant difference was found between AP resumption group and non-AP resumption group. However, several factors may lead to selection bias. For example,

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patients with lobar hemorrhages have higher risk of hemorrhagic recurrence [46], and may be more likely to be judged unsuitable for AP therapy. So further well-designed

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randomized controlled trials are necessary to evaluate the relationship between AP resumption and ICH recurrence or hematoma expansion.

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Besides, several limitations also exist in this meta-analysis. First, only articles in English and Chinese were included, the language limitation may leads to bias. Second, all the included studies were observational studies, and patients may have difficulties in maintaining adequate adherence to the AP therapy. Third, heterogeneity inevitably exists between different studies. But current data is inadequate for subgroup analysis on the type of AP agents, doses of drug, timing of AP resumption, hematoma volume, the location of ICH and other factors, so it is of difficulty to identity the source of heterogeneity. Fourth, although widely used in clinic, dual AP treatment, such as

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ACCEPTED MANUSCRIPT aspirin and clopidogrel, which is reported to increase the risk of hemorrhagic events [47], was rarely reported in the included studies. Fifth, the difference of race, lifestyle, comorbidity, and other factors among patients cannot be avoid, but all the included studies were cohort studies, due to non-randomized grouping, the effect of these confounders is higher than randomized controlled trials. And as we mentioned above,

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recall bias, selection bias, and publication bias may also affect the conclusions. Finally,

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only 6 cohort studies were included in this meta-analysis. The lack of sufficient data

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and the limited number of patients may decrease the reliability of our results. Notably, a randomized controlled trial named The REstart or STop Antithrombotics

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Randomised Trial (RESTART) is currently being performing in United Kingdom [48], and the results may provide further and stronger evidence on this issue.

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In summary, this meta-analysis showed that AP resumption reduced the risk of ischemic or thromboembolic events in primary ICH patients without increasing ICH

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recurrence or hematoma expansion. AP resumption may benefits primary ICH patients. More well-designed randomized controlled trials are needed to explore AP resumption

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in primary ICH patients.

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Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgements This study was funded by National Natural Science Foundation of China [grant number 81771391]; Chongqing Municipal Public Health Bureau, Chongqing People’s Municipal Government [grant number 2015ZDXM011]. This study was also supported by the Program for Innovative Research Team of Chongqing Kuanren

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ACCEPTED MANUSCRIPT Hospital.

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Information Management Efficiently (PRIME): study protocol for a stepped-wedge

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Randomised Trial (RESTART). Trials. 18 (2017) 22.

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cluster randomised controlled trial within the REstart or STop Antithrombotics

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ACCEPTED MANUSCRIPT Figure legends Fig. 1. Flow chart of study selection. Fig. 2. Forest plot of the association between antiplatelet (AP) resumption and intracranial hemorrhage (ICH) recurrence or hematoma expansion after ICH. Fig. 3. Forest plot of the association between antiplatelet (AP) resumption and

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ischemic or thromboembolic events after primary intracranial hemorrhage (ICH).

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Fig. 4. Funnel plot of included studies analyzing publication bias. (A) Funnel plot of

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the 6 studies involving the outcomes of intracranial hemorrhage (ICH) recurrence or hematoma expansion; (B) Funnel plot of the 5 studies involving the outcomes of

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ischemic or thromboembolic events.

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ACCEPTED MANUSCRIPT

Table 1. Characteristics and quality assessment of the studies included in the meta-analysis. First Author Year

Country

Male sex (%) 71

Age (years)

Location of ICH

Type of AP

Japan

Number of patients 150

Amano T 2016

77 (mean)

Subdural

Aspirin/ Clopidogrel/ Ticlopidine/ Cilostazol

Chen T 2015

China

269

57.9

67.1 (mean)

N/A

Aspirin

Flynn RW 2010

UK

417

49.9

69.9 (mean)

Lobar Striatum Thalamus Cerebellum Brain stem

Guha D 2016

Canada

479

71.2

Nielsen P B 2015

Denmark

1752

62

Teo KC 2014

China

C A 51

47.1

Duration of follow-up

T P

NOS score

N/A

7

N/A

N/A

6

Aspirin/ Clopidogrel/ Dipyridamole

14.8 months (median)

N/A

8

Subdural

Aspirin/ Clopidogrel

N/A

3.1 months (mean )

7

78 (median)

Intracerebral Subdural Subarachnoid

Aspirin/ Thienopyridines

24 days (median)

5 years

8

74.3 (mean)

Lobar Deep cerebral Cerebellum Brainstem Intraventricular

Aspirin/ Clopidogrel

N/A

2.5 years for AP resumption group 2.6 years for non-AP group

7

72.3 (mean)

D E

T P

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Timing of AP resumption Within one week

C S

U N

A M

I R

ICH, intracranial hemorrhage; AP, antiplatelet; NOS, the Newcastle-Ottawa Quality Assessment Scale; N/A, not available

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ACCEPTED MANUSCRIPT Table 2. Sensitivity analyses of the 6 studies involving the outcomes of intracranial hemorrhage (ICH) recurrence or hematoma expansion for antiplatelet (AP) resumption. RR(95% CI)

Heterogeneity: P; I 2

Amano T, 2016

0.81 (0.44–1.51)

<0.01; 76

Chen T, 2015

0.64 (0.39–1.04)

0.11; 47

Flynn RW, 2010

0.92 (0.48–1.74)

<0.01; 76

Guha D, 2016

0.84 (0.33–2.14)

Nielsen PB, 2015

1.09 (0.64–1.83)

Teo KC, 2014

0.83 (0.44–1.54)

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PT

The articles that were omitted

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RR, relative risk.

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<0.01; 75 0.19; 35 <0.01; 77

SC

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PT

ACCEPTED MANUSCRIPT

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Figure 1

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Figure 2

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Figure 3

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Figure 4

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ACCEPTED MANUSCRIPT Highlights Antiplatelet resumption reduced ischemic or thromboembolic risk in ICH.



Antiplatelet resumption did not increase the risk of ICH recurrence.



Antiplatelet resumption in ICH patients may be rational.

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

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