New Perspectives on Clopidogrel Resistance Systematic Review and Meta-analysis

Background: Clopidogrel resistance can be defined as the failure of clopidogrel to inhibit its target of action. The prevalence of clopidogrel resistance in various studies ranges between 5%–44%. Clopidogrel resistance is a serious scary condition whereby clopidogrel drug is less or not effective for some patients than expected. Hence the present Systematic review was conducted to explore the new perspectives of Clopidogrel and to evaluate the effect of genetic cytochrome CYP2C19 (CYP2C19*2, CYP2C19*3) of the key drug metabolizing enzymes on the response to the antiplatelet effect of clopidogrel. To provide insights into the commentary summarizes the clinical evidence on the pharmacokinetic determinants of clopidogrel efficacy. Material and Method: Systematic review is a type of literature reviews that collects and critically analyzes multiple research studies using methods that are selected before one or more research questions are formulated and then finding and analyzing studies that relate to and answer those questions in a structured methodology. Results: Accumulated information from suggested the presence of high incidence of clopidogrel resistance. Associated with acute coronary syndrome (ACS), Acute myocardial infarction (AMI) and stroke. There was no significant difference in the incidence of resistance according to the type of studies. Conclusion: Accumulated information from previous studies and the present systematic review suggested the presence of high incidence of clopidogrel resistance. This resistance was associated with serious complications such as acute coronary syndrome (ACS), Acute myocardial infarction (AMI) and stroke. Systematic Review Alrahbeni; JPRI, 33(64A): 194-202, 2021; Article no.JPRI.80491 195


INTRODUCTION
Coagulation is the process by which the blood changes from a liquid form to a form which seems like a gel, in other words, the blood clots. Usually, this occurs as a result of body hemostasis in which a ruptured blood vessel needs to be closed up. The body hence activates the process of coagulation in collaboration of fibrin deposit and the action of the platelet, the blood clots to stop the bleeding [1].
Platelets are also known as thrombocytes; they work in collaboration with other mechanisms to stop bleeding during blood vessel injury. Antiplatelets are agents that are introduced in the body which reduce the capability of platelets to stick together. These agents are normally employed to help patients under high risk of myocardial infarction. Myocardial infarction may be caused by blood clotting in major heart arteries blocking nutrients and oxygen to heart muscles [2]. Some patients are under high risk of a heart attack and have tendencies of having a blood clot in the blood vessels blocking important nutrients to vital organ muscles. In such situations anti-platelet medications are prescribed to reduce the platelet aggregation leading to reducing their capability to form a clot, which in turn reduces the risk of the patient experiencing any unwanted clotting in their blood vessels which may cause a stroke or heart attack [3].
One of the groups of Anti platelet action is the platelet aggregation inhibitor is Clopidogrel. This medicine is prescribed for the prevention of a high-risk occurrence of myocardial infarction and atrial fibrillation. The proteases-activated receptor is the third group which also acts to inhibit important protease in the clotting process [4]. Clopidogrel is an anti-platelet medicine which is normally employed by medical professionals to reduce to risk of myocardial infarction and stroke. This medicine is however in most cases administered together with aspirin in the case of heart attacks and following placement of a coronary stent. It is administered orally and has side effects like nausea, heartburn, and headaches [5]. Clopidogrel, an oral irreversible P2Y12 receptor antagonist, is widely used in clinical practice in comparison to other P2Y12 antagonists such as ticagrelor or prasugrel. P2Y12 inhibitors are crucial for patients with the acute coronary syndrome (ACS) and post percutaneous coronary intervention (PCI) to prevent future thrombotic events [6].
Clopidogrel is a pro-drug, which is activated in two steps, first by CYP2C19, CYP1A2 and CYP2B6, then by CYP2C19, CYP2C9, CYP2B6 and CYP3A. The active metabolite then specifically and irreversibly inhibits the P2Y12 subtype of Adenosine diphosphate (ADP) receptor, which is important in activation of platelets and eventual cross-linking by the protein fibrin [7].
Since there is a dearth of information on clopidogrel and its resistance form and subsequent cardiovascular events, the present systematic review was conducted with to evaluate the effect of genetic polymorphisms CYP2C19 (CYP2C19*2, CYP2C19*3) of the key drug metabolizing enzymes on the response to the anti-platelet effect of clopidogrel and to provide insights into the commentary summarizes the clinical evidence on the pharmacokinetic determinants of clopidogrel efficacy. Along with this from the present systematic review it would be easy to clarify the results of some studies that were carried out about the markers of the genetic effect of CYP2C19 on clopidogrel response.

MATERIAL AND METHODS
The Five Steps to Conduct a Systematic Review.
Based on Khan et al, 2003 [8], a systematic review consists of five steps and they are; Step 1: Framing questions for a review The problem to be addressed by the review will be specified in the form of clear structured questions before beginning the review work.
Step 2: Identifying relevant work Studies from multiple resources will be searched with selection criteria that flow directly from the review questions. Reasons for inclusion and exclusion will be recorded.
Step 3: Assessing the quality of studies Selected studies will be subjected to a more refined quality assessment by using general critical appraisal guidelines and design-based quality checklists.
Step 4: Summarizing the evidence The study characteristics, quality and effects as well as the statistical methods will be tabulated to explore the differences between studies and combine their effects (meta-analysis).
Step 5: Interpreting the findings The risk of publication bias will be explored. Exploration for heterogeneity will determine whether the overall summary can be trusted. Any recommendations will be graded by reference to the strengths and weaknesses of the evidence.

Data Collection
In this research we used an open Meta analytic program.( Open Meta Analyst).
The program helps the researcher (systematic review) to collect all data related to the study. (Authors, year of publication, gender of the patients, number of patients) During the study, all studies were added until they were analyzed accurately. There were 17 studies that were found and 14 were found to be suitable for the study.
The information recorded during the research period was as follows: this is in general not specific to presence of polymorphisms in the genes CYP2C19.

2.
Type of study.

3.
Year of Publication.

4.
Number of patients in the study. 5.
The number of patient's incidence resistance. 6.
Number of females.

Summary of Studies Reviewed
In a Retrospective cohort created by sen et al (2014) in Turkey, 51 patients taken clopidogrel were included in this study (21 males, 30 females), 3 patients (5.8%) showed resistance to clopidogrel [9].
In a Case control study created by Zhong-ling zhuo et al (2018) in China, 101 patients taken clopidogrel were included in this study (28 males, 73 females), 30 patients (30%) showed resistance to clopidogrel [11].
In a Prospective cohort study created by V arya et al (2015) in India, 72 patients taken clopidogrel were included in this study (60 males, 12 females), 37 patients (51%) showed resistance to clopidogrel [12].

Complications Reported to be Associated with Clopidogrel Resentence
In addition to developing clopidogrel resistance these studies also reported a number of specific complications which when grouped showed that the incidence of Acute coronary syndrome was the highest at 5 Patients (Idrissi et al,2018, case control study) [10], 37patients (V. Arya  This points towards a correlation trend between the development of resistance and Acute coronary syndrome (260 patients).

Fig. 1. Forest plot of the different studies showing a binary probability of resistance
The mean probability of resistance using a binary random effect model was 0.226 (22.6%) with CI between 0.152 -0.301. However, there is a large heterogeneity (p<0.001) ( Table 4). This can be attributed to the significant variation in the studies as shown the forest plot (Fig. 1) The boxes show the effect estimates from the single studies, while the diamond shows the pooled result.
The horizontal lines through the boxes illustrate the length of the confidence interval. The longer the lines, the wider the confidential interval, the less reliable the study results.
The vertical line is the line of no effect (i.e. the position at which there is no clear difference between the intervention group and the control group). To combine it all, our systematic review of the studies chosen shows the following,

1.
There is a high probability to develop clopidogrel resistance in the presence of this specific gene polymorphism.

2.
From the studies included, 9 showed a small confidence interval in comparison to 5 that had a wide confidence interval. This indicates that the 9 studies have a more reliable result than the other 5. The 9 reliable studies were all showing a high correlation between the treatment, the polymorphism and the development of resistance.

3.
Only one study, Miaonan Li et al, 2017 [19] showed no difference or specifically no association between the development of resistance and the gene polymorphism.

4.
Overall, from the diamond, there is a significant (p<0.001) association between the development of clopidogrel resistance and this specific gene polymorphism. The meta-regression showed a strong correlation between the cohort and the case control studies (p<0.001) and no significant difference in incidence of resistance according to the type of study.

Strength and Weakness of this Study
This research was conducted as a systematic review of clopidogrel resistance. This research was discussed after reviewing many of the topics that raise the question of health. The study was prepared after the study of similar topics related to the resistance of clopidogrel.
The research was prepared to be the first systematic review of clopidogrel resistance. It has not been done before.

CONCLUSION
There was large heterogeneity due to significant variations in the studies involved in our metaanalysis which includes patient differences, data collection and analysis. There was a strong correlation between the cohort & the case control studies but there was no significant difference in the incidence of resistance according to the type of study.
In conclusion, the presence of this polymorphism leads to high incidences of clopidogrel resistance and the development of a number of complications such as acute coronary syndrome (ACS), Acute myocardial infarction (AMI) and stroke. The studies included in this review that signifies the development of resistance were both cohort and case control, with strong correlation between both, strengthening the outcome.
To conclude, the author hereby quote from the works used in this paper that the prevalence of clopidogrel resistance in most parts of the world happens to be in accordance with the already reported cases in the western populations. Patients deemed to be carriers of the allele CYP2C19*2/*2 presented with cases of elevated risks of not responding to clopidogrel treatment as compared to the wild-type allele (CYP2C19*1/*1).

RECOMMENDATION
The author would suggest the use of prasugrel or ticagrelor as the alternative anti-platelet agents. Those individuals who had presented with reduced platelet inhibition, high risks associated with cardiovascular events as well as a high degree in terms of residual platelet aggregation. Due to lack of data and information concerning clopidogrel in the US and in Morocco as shown in the reports, it becomes very difficult to ascertain the loss of function (CYP2C19*2, CYP2C19*3) or even gain of function.
These findings lead to the breakthrough that genetic testing should be used to stratify who might need novel anti-platelet therapy. Additional research should also be carried out to characterize other genetic variations thus creating a platform for predicting clopidogrel resistance in a more diverse setting.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.