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Use of oral anticoagulant drugs is associated with carotid intraplaque hemorrhage in atherosclerosis patients: a meta-analysis

  • Xin Cao
  • Jun ZhangEmail author
  • Daoying GengEmail author
Open Access
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Abstract

Patients with carotid atherosclerosis, especially the elderly population, take antithrombotic medicine regularly. However, no previous meta-analysis has focused on one of the possible side effects of such drugs, namely intraplaque hemorrhage (IPH). To determine whether antiplatelet drugs or anticoagulants are associated with an increased risk of carotid IPH. We searched Pubmed, Embase, Ovid MEDLINE, Cochrane Library for relevant studies that were published in English, from January 1st, 1989 to January 1st, 2019. We pooled the odds ratio (OR) with 95% confidence interval (CI) from individual studies and conducted quality assessment, heterogeneity, publication bias analysis and sensitivity analysis. A total of four cross-sectional studies, involving 2714 participants with carotid atherosclerotic plaques was included into this meta-analysis. We found a significant association between the use of anticoagulants and higher risk of carotid IPH (OR 1.95; 95% CI 1.16–3.30, P = 0.92; I2 = 0). No significant association was found between the use of antiplatelet drugs and increased risk of carotid IPH (OR 1.34; 95% CI 0.68–2.61, P = 0.03; I2 = 65%). Our meta-analysis reveals that it is the use of oral anticoagulants rather than antiplatelet drugs that may be associated with an increased risk of carotid IPH in atherosclerosis patients.

Keywords

Intraplaque hemorrhage Carotid atherosclerosis Antithrombotic Antiplatelet Anticoagulants 

Highlights

  • The association between oral antithrombotic drugs with carotid intraplaque hemorrhage.

  • Anticoagulants increase the risk of intraplaque hemorrhage.

  • Antiplatelet drugs do not cause intraplaque hemorrhage.

  • The first meta-analysis about this topic.

  • Our findings have implications for developing clinical guidelines, interpretation of previous and future trials, and for understanding the mechanism of IPH and progression of vulnerable plaques.

Introduction

Cerebral arterial thrombosis initiated by disruption of atherosclerotic plaques is the most crucial trigger for the onset of ischemic stroke. Vulnerable plaques in carotid atherosclerosis that are prone to develop thrombotic complications can lead to disability or even deadly consequences. According to the American Heart Association (AHA), main pathological features of vulnerable plaques include lipid-rich necrotic core, thin or ruptured fibrous cap, intraplaque hemorrhage (IPH), plaque surface calcification, inflammatory cell infiltration and angiogenesis [1, 2, 3]. The role of IPH in the progression and destabilization of vulnerable plaque has been recognized through many mechanistic prospective studies. Such hemorrhages can cause abrupt enlargement of the lipid-rich core with the accumulation of free cholesterol released from erythrocyte membranes [4, 5]. Moreover, IPH can further increase inflammation levels via stimulating the activity of macrophages [6]. The released hemoglobin facilitates with the production of reactive oxygen radicals in lesions [7]. The deformation of hemorrhagic plaques causes changes in external hemodynamics and surrounding pressure to rise [8]. A series of studies have described IPH as a predictor of cerebral vascular ischemic events in patients with carotid atherosclerosis [9, 10].

Arterial thromboembolism, which initially is a platelet-driven process followed by activation of the coagulation cascade, underlies various acute vascular events such as stroke, myocardial infarction, and limb ischemia [11]. Consequently, platelet aggregation inhibitors and anticoagulant drugs are the most commonly used antithrombotic prevention and treatment for thrombotic cerebrovascular disease. Although these prophylactic treatment strategies are highly effective in lowering the risk of cardiovascular events [12, 13, 14], both of antiplatelet and anticoagulant drugs have life-threatening side effects like bleeding [15, 16]. A Plaque at Risk (PARISK) study demonstrated a positive association between the use of antiplatelet agents and presence of carotid IPH on magnetic resonance imaging [17]. According one histopathological study based on a large volume of specimens from carotid endarterectomy, coumarin-type anticoagulant treatment was an independent predictor for the presence of IPH in the carotid atherosclerotic plaques [18]. Therefore, several controversial issues on this topic remain unsolved. For starters, the impact of antithrombotic therapies on the composition changes in already existing atherosclerotic carotid plaque has been rarely studied. Second, whether the antiplatelet drugs or anticoagulants have substantially similar effect on the occurrence of carotid IPH is still unknown. In addition, no relevant meta-analysis and quantitative analysis have been conducted before.

Patients with extensive carotid atherosclerosis, especially the elderly population, frequently use oral platelet aggregation inhibitors or anticoagulant agents. These drugs may initiate or aggravate IPH. The purpose of our study was to collect and summarize all available data on this issue through a meta-analysis of observational studies, and to determine if the increased risk of carotid IPH is associated with the most commonly used oral antithrombotic drugs, namely antiplatelet drugs or anticoagulants. With the contributor or contributors identified, effective clinical solutions of anti-thrombosis and preventing plaque rupture can then be provided to patients with carotid atherosclerosis.

Methods

This meta-analysis is approved by PROSPERO (International prospective register of systematic reviews). The ID is CRD42019121245. (Available from: http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42019121245).

We followed a pre-specified and peer-reviewed protocol; the PRISMA statement, a 27-item checklist deemed essential for reporting systematic reviews and meta-analysis [19].

Search strategy

We searched multiple electronic databases including Pubmed, Embase, Ovid MEDLINE and Cochrane library for manuscripts that mentioned the relationship between the use of antithrombotic drugs and the higher risk of IPH with language restriction in English, from January 1, 1989 to January 1st, 2019. The search strategy for Ovid database as an example is presented here:
  • #1: ‘carotid plaque’ OR ‘carotid artery plaque’ OR ‘carotid arterial plaque’ OR ‘carotid atherosclerotic plaque’ OR ‘carotid atherosclerosis’ OR ‘carotid artery sclerosis’ OR ‘carotid artery atherosclerosis’

  • #2: ‘intraplaque hemorrhage’ OR ‘IPH’ OR ‘intraplaque haemorrhage’

  • #3: ‘antithrombosis’ OR ‘antithrombotic’ OR ‘antithrombus’ OR ‘anti-clotting’ OR ‘anticoagulants’ OR ‘anticoagulation’ OR ‘antiplatelet’

  • #4: ‘histopathological’ OR ‘pathological’ OR ‘histological’ OR ‘MRI’ OR ‘MR imaging’ OR ‘magnetic resonance imaging’

  • #5: #1 AND #2 AND #3 AND #4

The comprehensive literature search was performed independently by two reviewers to ensure that they satisfied inclusion criteria, any disagreements were resolved by consensus with consultation of experts. We also reviewed and hand searched the reference lists of final included articles to find information pertaining to the topic Search results were limited to human studies, published in English.

Study selection

Studies included met the following criteria: (1) evaluate the association between antithrombotic drugs use and the risk of carotid IPH; (2) provide the odds ratio (OR) with corresponding confidence interval (CI) or sufficient data to calculate crude OR. Two reviewers independently screened titles and abstracts identified by the preliminary searches to select potentially eligible studies. Studies failing to satisfy both criteria were excluded, and in case of ambiguity as to whether each criterion was fulfilled, abstract under consideration was noted for full-text review. In addition, we excluded articles that were not published in English. In case the results by the same author based on the same population appeared in more than one publication, only the most recent or the most complete one was included in the analysis. Data from review articles, case reports, abstracts, and letters were not included. Consultation with a third reviewer (D. Y. Geng) could be utilized If consensus could not be reached.

Data extraction and quality assessment

Two investigators extracted the following information from each eligible study independently: the name of first author, year of publication, sample type, sample size, population basic characteristics (mean age, sex ratio, BMI), types of drugs, duration of drugs use, numbers of occurrence of carotid IPH, numbers of patients combined history of other disease (hypertension, diabetes mellitus, hyperlipidemia, transient ischemic attacks (TIA) or stroke, ischemic heart disease), the diagnostic approach of IPH, the ORs with corresponding 95% CI and adjustment for covariates. Differences in data extraction were resolved by consensus, referring back to the original article. The missing or unstated information in the original text would be obtained as much as possible via communicating with the corresponding author. The methodological quality of the included cross-sectional studies was assessed based on the an 11-item checklist recommended by Agency for Healthcare Research and Quality (AHRQ) [20]. An item would score ‘1’ if the answer was ‘YES’, while ‘0’ the answer was ‘NO’ or ‘UNCLEAR’. Article quality was assessed as follows: low quality = 0–3; moderate quality = 4–7; high quality = 8–11. Scores were averaged from the independent assessments of two authors.

Data synthesis and analysis

All statistical analyses were performed through R software version 3.5.0 (R Foundation for Statistical Computing, Vienna, Austria). OR with 95% CI was used to measure the association between the use of antiplatelet drugs and risk of carotid IPH and the association between the use of anticoagulants and risk of carotid IPH.

The heterogeneity of the estimators of OR was tested by Cochran’s Q test at the P < 0.10 level of significance. We also calculated the quantity I2 that describes the percentage variation across studies that is attributed to heterogeneity. An I2 value less than 25% was considered low-level heterogeneity, 25% to 50% as moderate-level, and greater than 50% as high-level. When significant heterogeneity was found (I2 > 50%), the random-effects model was used for meta-analysis. Otherwise, the fixed-effects model was adopted. And if the clinical heterogeneity was too large, a single research analysis should be used instead. Potential publication bias was evaluated by the Egger’s regression asymmetry test and funnel plot analysis. Sensitivity analysis was performed on the results of association between antiplatelet drugs use with IPH, because Derkson [18] did not provide the adjusted OR of multivariate analysis in their study, we had to calculate the crude OR instead. The sensitivity analysis would be performed to check whether this paper had significantly influenced the outcome. For the analysis of IPH occurrence associated with anticoagulants use, we eliminated two of the four studies. Considering the patient recruited who used anticoagulants also took antiplatelet drugs as dual therapy during treatment in Sun’s study [21]. In the study of Liem [17], they did not have the data of the patient using anticoagulants. Consequently, we only summarized the data of the other two studies [18, 22] for analyzing the association between anticoagulants use and carotid IPH. Limited to the small number of studies included in this part, we did not attempt to do publication bias analysis or sensitivity analysis.

Results

Study selection

As shown in the flow chart of Fig. 1, our initial literature search identified 308 relevant articles. A number of 145 articles were excluded for duplication, 136 articles were excluded by title and abstract review, including 132 irrelevant topics or animal studies and four reviews, letters, editorials or case reports. Twenty-seven articles were reviewed in full-text for more detailed evaluation. However, 22 articles did not meet the criteria, neither evaluating the association between antithrombotic drugs use and the risk of carotid IPH, nor providing the odds ratio (OR) with corresponding confidence interval (CI). Moreover, there was 1 research based on the ultrasound to diagnose IPH, we ruled it out because we thought the diagnosis method was not accurate enough. As a result, four cross-sectional studies met the predetermined criteria and were included in the meta-analysis. All these four articles provided data on antiplatelet drugs exposure and risk of IPH, and only 2 of them provided data on anticoagulants exposure and risk of IPH.
Fig. 1

Literature research and selection process of studies included in the analysis

Study characteristics

Table 1 lists all the included studies and their characteristics. All the studies included were published between 2015 and 2018. Four studies, involving a total of 2714 participants with carotid atherosclerotic plaques provided data on the occurrence of IPH after using antiplatelet drugs alone or anticoagulants alone. The number of participants using antiplatelet drugs was 37, 738, 520, 64; and the number of participants using anticoagulants was 116 and 118. In these four studies, the mean age of participants varied from 67 to 72.9 years. Their mean BMI varied from 26.5 to 28.0 kg/m2. The types of antiplatelet drugs include aspirin, clopidogrel and dipyridamole, and the types of anticoagulants include coumarin derivate and vitamin K antagonists (VKA). Mean duration of medication and follow-up period varied among the included studies. The four studies included patients who had history of using statin, hypertension, diabetes mellitus, hyperlipidemia, TIA or stroke, and ischemic heart disease. Some of them were regular smokers. Partial information about the exact number of patients with different symptoms and past histories were unknown. In 3 of the studies, the diagnosis of IPH were performed by magnetic resonance imaging (MRI) examinations while the other study used histopathological approaches. Both the 3.0T high-resolution MRI and the 1.5T MRI can detect the IPH accurately based on the high signal in T1-weighted imaging [23]. We tried to contact authors of some papers for the missing or unstated data but did not obtain any extra valid information.
Table 1

Characteristics of studies included and participants in the meta-analysis

First author, year

Sample type

N

Mean Age (yrs)

Sex, Male

BMI (kg/m2)

IPH

Use of antiplatelet drugs/anticoagulants

Type of antiplatelet drugs/anticoagulants

Duration of using antiplatelet/anticoagulants (years)

Use of statin/history of hypertension/DM/hyperlipidemia/smoker/TIA or stroke/ischemic heart disease

Plaques detection

Liem [17],

2015

Patients with recent amaurosis fugax, TIA or nondisabling stroke, and an ipsilateral carotid stenosis < 70%

100

67.9

69

26.5

45

37/1

Aspirin/Coumarin derivate

6/6

49/66/26/51/24/17/17/25

3.0T high-resolution MRI

Derksen [18],

2011

Patients with cerebrovascular accident or TIA, and some asymptomatic subjects, with the carotid stenosis > 70%

794

67.0

547

NA

644

738/116

Aspirin or dipyridamole or clopidogrel/Coumarin derivate

NA

595/586/184/514/243/666/NA

Histopathological examination

Mujaj [22],

2018

Patients with intima-media thickness ≧ 2.5 mm in one or both carotid arteries

1740

72.9

940

27.3

1205

520/118

Aspirin/VKA

6/0.92

504/NA/250/NA/548/63/198

1.5T MRI

Sun [21],

2016

Asymptomatic subjects with 16% to 79% carotid stenosis

80

70.0

53

28.0

NA

64/1a

Aspirin/Dual therapy

NA

65/61/9/71/50/NA/22

3.0T high-resolution MRI

TIA transient ischemic attacks, IPH intraplaque hemorrhage, DM diabetes mellitus, MRI magnetic resonance imaging, VKA vitamin K antagonists, NA not available

aA patient who used anticoagulants also took antiplatelet drugs as dual therapy during treatment

Quality of study methodologies

The methodological quality of included cross-sectional studies was assessed using an 11-item checklist recommended by AHRQ. The assessment for each study is provided in Table 2, and their quality scores were 6, 6, 8 and 7 respectively. In summary, 1 study was rated as high quality and the rest 3 were rated as moderate quality.
Table 2

The quality assessment for each study based on checklist recommended by Agency for Healthcare Research and Quality (AHRQ)

Studies

Define the source

List inclusion/exclusion criteria

Indicate time period used for identifying patients

Whether subjects were consecutive

Whether subjective components were masked

Assessments for quality assurance

Explain exclusions from analysis

Assess or control confound

Explain how missing data were handled

Summarize response rates and completeness of data

Clarify follow-up data

Total (0–11)

Liem et al. [17], 2015

Y

Y

N

Y

Y

Y

N

Y

N

N

N

6

Derksen et al. [18], 2011

Y

Y

N

Y

Y

Y

N

Y

N

N

N

6

Mujaj et al. [22], 2018

Y

Y

N

Y

Y

Y

Y

Y

Y

N

N

8

Sun et al. [21], 2016

Y

Y

N

Y

Y

Y

Y

Y

N

N

N

7

Y YES, N NO

An item scores ‘1’ if the answer is ‘YES’, while ‘0’ the answer is ‘NO’ or ‘UNCLEAR’

Article quality is assessed as follows: low quality = 0–3; moderate quality = 4–7; high quality = 8–11

Use of antiplatelet drugs and risk for IPH

Four studies, including 2714 patients with carotid atherosclerosis provided data on the risk of occurrence IPH after exposing to antiplatelet drugs. Figure 2a illustrated the forest plot of ORs estimates with 95% CIs from individual studies and overall meta-analysis of all four studies. Using the random effects model, the overall pooled ORs demonstrated no significant association between antiplatelet drugs use and the risk of IPH (OR 1.34; 95% CI 0.68–2.61), with high-level heterogeneity among studies (P = 0.03; I2 = 65%, τ2 = 0.2830). The tests for funnel plot asymmetry identified no publication bias. Three of the studies provided adjusted ORs, however, while the study by Derkson [18] did not provide the adjusted OR of multivariate analysis. We tried to contact the corresponding author of this paper to obtain the original data. Due to various reasons, the crude OR had to be calculated instead. The crude OR was 0.50, and the 95% CI was 0.21–1.18. Through the sensitivity analysis (Fig. 2b), omitting this study, the pooled OR of the other 3 studies still suggested no significant association between antiplatelet drugs exposure and the risk of IPH (OR 1.75; 95% CI 0.92–3.33). Thus, the crude OR did not change the outcome statistically.
Fig. 2

a The forest plot of the pooled ORs and 95% CIs for the association between the antiplatelet drugs use and the occurrence of carotid IPH. b The sensitivity analysis of the four included studies

Use of anticoagulants and risk for IPH

Considering the patient used anticoagulants also took antiplatelet drugs as dual therapy in Sun’s study [21], and the absence of data analysis in Liem’s study [17] about the patient using anticoagulants, we ruled out these two studies before performing the meta-analysis. Two studies, including 2534 patients with carotid atherosclerosis provided data on the risk of developing IPH after exposing to anticoagulants. Figure 3 illustrated the forest plot of ORs estimates with 95% CIs from individual studies and overall meta-analysis of the two studies. Using the fixed effect model, the pooled ORs demonstrated a significant association between anticoagulants and the occurrence of IPH (OR 1.95; 95% CI 1.16–3.30), with low-level heterogeneity among studies (P = 0.92; I2 = 0, τ2 = 0). We did not attempt to do an analysis of publication bias or subgroup analyses as there were only 2 studies included in the analysis.
Fig. 3

The forest plot of the pooled ORs and 95% CIs for the association between the anticoagulants use and the occurrence of carotid IPH

Discussion

This study is the first meta-analysis to address association between oral antithrombotic drugs with carotid IPH in participants with carotid atherosclerosis plaque to our knowledge. The most commonly used types of oral antithrombotic drugs in clinical practice are antiplatelet drugs and anticoagulants. We found that it is the use of oral anticoagulants rather than antiplatelet drugs that is associated with a significantly higher risk of developing carotid IPH when compared with the patients who received no anti-thromboembolic treatments. It is meaningful to synthesize the available literature on this subject, as the drug safety in terms of side effects like IPH is a matter of great concern. The findings of this meta-analysis, along with considerations of the relative efficacy of anticoagulants and antiplatelet drugs, should be considered by clinicians when balancing the overall risks and benefits of oral antithrombotic treatments. For example, for a patient with severe atherosclerosis and carotid artery stenosis, especially with a history of stroke, antiplatelet drugs such as aspirin are more recommended than anticoagulants. On the contrary, if a young patient with stable plaque need clinical treatment guidance, the anticoagulants can be taken into account.

The results obtained from our analysis on the association between antiplatelet drugs and the occurrence of carotid IPH should be considered with caution, as the analysis was based on the data collected from only four cross-sectional studies, and one of them had no adjusted ORs. In addition, the 95% CIs of some ORs were wide. The crude OR value obtained by calculation is the only one less than 1. We found the crude OR excluded by sensitivity analysis indeed had a slight effect on the outcome, however, it hardly changed the conclusion statistically. In addition, the high-level heterogeneity among studies (P = 0.03; I2 = 65%) may also be caused by this article. Support for the mechanism was found in a histopathology study, even though the densities of intraplaque microvascular in patients with antiplatelet therapy were higher than those in nontreated patients, it showed no association between IPH burden and antiplatelet drugs [24]. This may be because atherosclerotic plaques contain fewer platelets than normal blood in vessels, making platelet aggregation inhibitors less effective. Since we found no evidence that using antiplatelet drugs was attributable to an increased risk of IPH, doctors should continue to advice patients with the need for thrombolysis to use antiplatelet drugs regularly.

The results of our study suggested that the previous use of anticoagulants was associated with carotid IPH in patients. Owing to the lack of reported data in 2 studies, we only included ORs of the other 2 cross-sectional studies. Although the findings highlight possible side effects of such drugs, they should be interpreted carefully as the number of studies was small and we cannot rule out small but significant biases. A recent meta-analysis reported that the association between using anticoagulants and the risk of major bleeding also reached statistical significance, and the risk of major bleeding episodes with anticoagulants using VKA (OR 1.76, 95% CI 1.33–2.33) was higher compared to patients treated with aspirin alone (OR 1.16, 95% CI 0.79–1.71) [25]. The underlying mechanism might be that the fragile microvascular are leaky and thus prone to rupture, which have been identified as the source of IPH [26]. In addition, some research data indicate that the incidences of microvascular leakage and capillary bleeding were higher in patients treated with anticoagulants [24, 27]. The similar phenomenon has also been confirmed in animal trials [28]. Our results imply that individualized antithrombotic therapy may be essential and anticoagulants should not be prescribed when risks outweigh benefits, for example, in atherosclerosis patients with signs of vulnerable plaques.

Our analysis does have some limitations. First, there were no randomized controlled trials (RCTs) presenting the most accurate estimate of IPH through a direct comparison of antiplatelet drugs and anticoagulants. We excluded some RCTs because they failed to fulfill the prespecified criteria and all the included articles were written in English. We cannot make causal inference because the four included studies are all cross-sectional studies. Second, the number of included studies and participants being available for the meta-analysis were much fewer than we had expected. The power of this meta-analysis was influenced by small number of included studies and the degree of heterogeneity in them. However, we are confident that all eligible studies have been identified. Third, the diagnostic methods for IPH differed between studies. However, the difference in detecting IPH between MRI and histopathological examinations has been proved very small in previous studies [29, 30, 31]. Fourth, the risk of IPH may vary across different types, dosage or duration of drugs, as a possible consequence of different half-lives and pharmacological mechanism. It is unfortunate though true that our options were extremely limited by the small sample size and the categories of drugs used in their studies. Fifth, some potential confounding factors could not be reconciled in some studies, such as statin use, hypertension, diabetes mellitus, hyperlipidemia, tobacco smoking, etc. They may partially obscure the truth. As the number of prospective serial studies and the refinement of researches in this field is increasing, the above limitations can be solved through sub-group analysis in the future.

Conclusion

Our results suggest that the increased risk of carotid IPH in atherosclerosis patients may be associated with the use of oral anticoagulants agents, rather than antiplatelet drugs. However, for lack of standardization of the type, dosage and duration of anticoagulants use in the included studies, our conclusions can only be regarded as therapeutic recommendations at this stage. Even so, our findings may have implications for developing clinical guidelines, interpretation of previous and future trials, and for understanding the mechanism of IPH and progression of vulnerable plaques. To improve the findings of this meta-analysis, well-designed, large-scale, prospective studies are required in this field in the future.

Notes

Acknowledgements

All authors have full access to all data in the study. Daoying Geng and Jun Zhang take responsibility for the integrity of the data and the accuracy of data analysis. All Authors read and approved the final version of the manuscript.

Funding

The research was funded by the National Key Research and Development Program of China (Grant No. 2016YFA0203700), the Shanghai Municipal Commission of Health (No. 2017BR003), and Shanghai Municipal Commission of Science and Technology (No. 16QA1400900, No. 16410722800, No. 17411953700).

Compliance with ethical standards

Conflict of interest

All authors declare no conflicts of interest.

Supplementary material

11239_2019_1865_MOESM1_ESM.txt (1 kb)
Supplementary material 1 (TXT 1 kb)

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© The Author(s) 2019

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  1. 1.Department of Radiology, Huashan HospitalFudan UniversityShanghaiChina
  2. 2.Institute of Functional and Molecular Medical ImagingFudan UniversityShanghaiChina

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