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. 2024 Dec 16;14(4):211–217. doi: 10.1089/ther.2023.0055

Comparison of Clopidogrel Versus Ticagrelor for Percutaneous Coronary Intervention (PCI) Patients Managed with Therapeutic Hypothermia: A Systematic Review and Meta-Analysis

Barka Sajid 1, Zarnab Tufail 2, Maria Asim 3, Sania Riaz 4, Sahar Imtiaz 5, Hamna Khan 5, Muhammad Asad Shabbir 2, Syed Muhammad Bilal Shah 5, Fariha Ejaz 6, Muhammad Wajeeh Anis 7, Arais Khan 8, Aliza Ahmed 1, Marium Rana 5, Fiza Sohail 1, Muhammad Umair Anjum 5, Muhammad Omar Larik 7,✉
PMCID: PMC11665264  PMID: 37870599

Abstract

Various antiplatelet drugs, such as clopidogrel and ticagrelor, are available on the market for use after percutaneous coronary intervention (PCI). However, the efficacy of such drugs in patients being managed with therapeutic hypothermia (TH) has always been debated. In light of this controversy, this systematic review and meta-analysis was performed to enhance existing literature. Various databases were searched for potentially relevant studies from inception to April 2023, including PubMed, Cochrane Library, and Scopus. The risk of bias was assessed using the Newcastle–Ottawa scale for cohort studies and the Cochrane risk of bias tool for randomized controlled trials. Outcomes of interest included risk of bleeding, stent thrombosis, and all-cause mortality. Five studies were shortlisted for inclusion into the meta-analysis, featuring a total of 245 patients receiving either clopidogrel or ticagrelor. Overall, no significant differences were noted when the use of clopidogrel and ticagrelor was compared in PCI patients being managed with TH. To the best of our knowledge, this is the most comprehensive meta-analysis comparing the outcomes of clopidogrel and ticagrelor in PCI patients being managed with TH. Despite existing studies claiming an altered efficacy of clopidogrel in such conditions, our meta-analytic findings could not prove this relationship. Due to the limited sample size, further comprehensive and randomized studies are encouraged to arrive at a robust conclusion.

Keywords: clopidogrel, ticagrelor, therapeutic hypothermia, percutaneous coronary intervention, meta-analysis

Introduction

Acute coronary syndrome (ACS) is a term used to describe conditions associated with sudden reduced blood flow to the heart, which include unstable angina and myocardial infarction (MI), and is one of the major causes of global mortality (Bergmark et al., 2022). ACS is a manifestation of coronary heart disease, usually arising as a result of plaque disruption in coronary arteries (atherosclerosis) and the formation of thrombus (Singh et al., 2023).

Common risk factors contributing to the development of ACS include smoking, hypertension, diabetes, hyperlipidemia, physical inactivity, and family history (Cheema et al., 2020). ACS is also one of the leading causes of death in the United States, killing 382,820 people in 2020 alone (Tsao et al., 2023). Stringent protocols have been designed for management of patients with ACS to prevent morbidity, mortality, and recurrence of cardiac events, to reduce the overall disease burden, and ultimately improve patient outcomes and quality of life (Kolansky, 2009).

Such management strategies include percutaneous coronary intervention (PCI), dual antiplatelet therapy, and therapeutic hypothermia (TH) (Patel and Arora, 2010). Moreover, recent guidelines suggest the use of mild TH for patients with MI (Jiang et al., 2021). The rationale for using targeted TH is to improve the favorability of neurological outcomes due to ischemic injury (Jacob et al., 2015).

Various antiplatelet drugs (prasugrel, ticagrelor, and clopidogrel) that are recommended for management of ACS (Cohen and Downey, 2014) are available on the market. Early oral and intravenous management with such drugs, accompanied by reperfusion therapy, is associated with decreased ischemic damage to the myocardium, increased viability of cardiac tissue, and a reduced rate of recurrent thrombosis (Cohen and Downey, 2014).

Several studies have been performed, comparing the efficacy of clopidogrel and ticagrelor in patients with acute coronary events managed with percutaneous coronary intervention (Guan et al., 2018). Clopidogrel, prasugrel, and ticagrelor are known as P2Y12 inhibitors and are used in conjunction with aspirin to treat stent thrombosis (ST)-segment elevation MI and have shown efficacy and safety in large, randomized clinical trials (Guimarães and Tricoci, 2015).

However, the efficacy and safety of clopidogrel are limited by the slow and variable transformation of the prodrug to the active metabolite, accompanied by an increased risk of bleeding, ST, and MI in patients with a poor response, persistent hyporesponsiveness even at higher doses in patients with diabetes mellitus, and more adverse clinical outcomes with concomitant use of clopidogrel and proton pump inhibitors (Guan et al., 2018).

In light of this, a more efficacious and safer antiplatelet drug was required to replace clopidogrel. Ticagrelor, also known as AZD6140, has recently been shown to be beneficial in ACS patients, making it the first reversibly binding, oral, direct-acting P2Y12 receptor antagonist with a faster onset and more platelet inhibitory effects (Guan et al., 2018; Wallentin et al., 2009). Ticagrelor produced higher mean levels of platelet aggregation inhibition than clopidogrel, and the highest dosages of ticagrelor produced consistently high levels of inhibition, in patients with stable atherosclerotic disease (Storey et al., 2007).

Ultimately, with TH demonstrating a potential role in altering the pharmacokinetic properties and bioavailability of administered drugs, in addition to the lack of available data and clinical studies assessing the effect of TH on P2Y12 inhibitors such as clopidogrel and ticagrelor in patients with PCI, it is important to enhance the existing literature by pooling of existing studies.

Therefore, we performed a systematic review and meta-analysis assessing the efficacy of clopidogrel and ticagrelor in PCI patients being actively managed with TH.

Materials and Methods

Data sources and search strategy

This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines (Page et al., 2021). Literature from electronic databases, including PubMed, Cochrane Library, Scopus, and Google Scholar, was systematically searched from inception to April 2023. The extensive search strategy used for each database is given in Supplementary Table S1. Institutional review board (IRB) approval was not required for this study, as all data were obtained from public datasets.

Reference lists of potentially relevant articles were also searched for any additional articles that conformed to the prespecified eligibility criteria. To ensure robustness within the methodology of this meta-analysis, a rigorous assessment was performed using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR-2) criteria (Shea et al., 2017).

Study selection and eligibility criteria

Studies retrieved through the systematic search were exported to the EndNote Reference Library, version X8.1 (Clarivate Analytics), to screen for any duplicate articles and subsequently eliminate them from the study list. Two investigators (B.S. and Z.T.) independently assessed the remaining studies at title and abstract level, followed by a thorough full-text review, to confirm relevance of the selected studies. A third investigator (M.A.) was called to resolve any disagreements between the results of the independent investigators.

Prespecified eligibility criteria were employed to facilitate the accurate selection of relevant studies, which included (1) studies comparing outcomes after use of clopidogrel or ticagrelor, (2) studies reporting patient data after PCI, (3) studies reporting data on patients undergoing TH, (4) studies reporting at least one of the prespecified outcomes, and (5) published studies that were either prospective or retrospective in nature.

Any review articles (systematic reviews and narrative reviews), case reports, letter to the editors, or studies that did not conform to the prespecified eligibility criteria were excluded from inclusion.

Data extraction and quality of assessment

The following outcomes and patient data were extracted from all included studies: (1) baseline characteristics of patients, (2) mortality rate, (3) bleeding rated 3a or 5 as per the BARC scale, and (4) incidence of ST. Two reviewers (Z.T. and M.A.S.) independently assessed each of the included studies using the Newcastle–Ottawa scale for assessment of cohort studies or the Cochrane risk of bias tool for randomized controlled trials (Higgins et al., 2011; Wells et al., 2023).

Any discrepancies, if present, were resolved by a third independent reviewer (M.O.L.) after mutual discussion.

Statistical analyses

Review Manager (RevMan, version 5.3; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) was used for all statistical analyses pertaining to the meta-analysis, with the use of the random-effects model. Statistical significance was observed with a p-value of ≤0.05. All dichotomous outcomes reported in this analysis were compared using odds ratios.

Evaluation of heterogeneity was performed using the Higgins I2 value, with values under 25% demonstrating none-to-mild heterogeneity, values under 75% demonstrating moderate heterogeneity, and any values exceeding these limits deemed significantly heterogeneous (Higgins et al., 2003).

Results

Literature search, characteristics of studies, and assessment of quality

Our initial database search identified 205 potentially relevant studies. After a thorough screening process using prespecified eligibility criteria, six full-text articles were assessed, of which five studies were chosen for inclusion into this systematic review and meta-analysis (Bednar et al., 2016; Gouffran et al., 2016; Jiménez-Brítez et al., 2017; Moudgil et al., 2014; Steblovnik et al., 2016).

The summary of the screening process is illustrated in the PRISMA flowchart, as shown in Figure 1. A total of 245 patients were pooled in this study, with 147 patients receiving ticagrelor and 98 patients receiving clopidogrel.

FIG. 1.

FIG. 1.

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PRISMA flowchart. PRISMA, Preferred Reporting Items for Systematic Review and Meta-Analysis.

Assessment of risk and quality was performed using the Newcastle–Ottawa scale for cohort studies and the Cochrane risk of bias tool for randomized controlled trials (Higgins et al., 2011; Wells et al., 2023). In summary, all included studies demonstrated a moderate risk of bias, with detailed author judgments available in Supplementary Tables S2 and S3.

The baseline clinical characteristics of the included study population is available in Table 1.

Table 1.

Baseline Characteristics of Included Studies

Included studies Study design TH specifications Total patients, n Patients receiving clopidogrel, n Patients receiving ticagrelor, n Mean age, years (SD)
 Hypertension, n (%)
 Diabetes mellitus, n (%)
 Hyperlipidemia, n (%)
 History of previous MI, n (%)
Clopidogrel Ticagrelor Clopidogrel Ticagrelor Clopidogrel Ticagrelor Clopidogrel Ticagrelor Clopidogrel Ticagrelor
Jimenez et al. (2017) Retrospective Temperature of 33 °C for 24 hours 93 61 32 57 (12.0) 57 (9.8) 26 (42.6) 11 (34.3) 10 (16.3) 6 (18.7) 30 (49.1) 12 (37.5) 11 (18.0) 6 (18.7)
Steblovnik et al. (2016) Randomized Temperature of 32-34 °C for 24 hours 37 17 20 — — — — — — — — — —
Gouffran et al. (2016) Retrospective Temperature of 32-34 °C for 24 hours 78 48 30 61 (12.7)   46 (45.5)   19 (18.8)   41 (40.6)   13 (12.0)  
Bednar et al. (2016) Prospective Temperature of 33-34 °C for 12 hours 22 13 9 65 (6.7) 68 (11.9) 5 (38.4) 3 (33.3) 2 (15.3) 0 (0.0) — — 2 (15.3) 5 (33.3)
Moudgil et al. (2014) Prospective Temperature of 33 °C for 24 hours 15 8 7 59 (5.2) 53 (3.8) 2 (29.0) 0 (0.0) 2 (25.0) 0 (0) 3 (37.5) 2 (29.0) 2 (25.0) 1 (14.0)
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MI, myocardial infarction; n, number of patients; SD, standard deviation; TH, therapeutic hypothermia.

Comparison of risk of bleeding

The risk of bleeding (BARC 3/3a and 5a) was reported by three studies. After pooling of relevant studies, it was observed that there were no significant differences in the risk of bleeding when clopidogrel and ticagrelor were compared after PCI, managed with TH (odds ratio [OR]: 1.45; confidence interval [95% CI]: 0.52–4.03; p = 0.48; Fig. 2).

FIG. 2.

FIG. 2.

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Forest plot of risk of bleeding. CI, confidence interval; M-H, Mantel-Haenszel.

Comparison of risk of ST

The risk of ST was reported by five studies. After pooling of relevant studies, it was observed that there were no significant differences in the risk of ST when clopidogrel and ticagrelor were compared after PCI, managed with TH (OR: 1.00; 95% CI: 0.08–12.10; p = 1.00; Fig. 3).

FIG. 3.

FIG. 3.

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Forest plot of stent thrombosis.

Comparison of mortality

The incidence of mortality was reported by three studies. After pooling of relevant studies, it was observed that there were no significant differences in the incidence of mortality when clopidogrel and ticagrelor were compared after PCI, managed with TH (OR: 1.52; 95% CI: 0.66–3.48; p = 0.33; Fig. 4).

FIG. 4.

FIG. 4.

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Forest plot of mortality.

Discussion

This systematic review and meta-analysis features a total of 5 clinical studies, resulting in pooling of 245 patients, with 147 patients receiving clopidogrel and 98 patients receiving ticagrelor. The outcomes explored in this meta-analysis include in-hospital ST, all-cause mortality, and the risk of major bleeding. Overall, the results of this meta-analysis indicated no significant differences between clopidogrel and ticagrelor in patients after PCI, managed with TH. To the best of our knowledge, this is the most comprehensive meta-analysis conducted till date, with the largest number of outcomes explored.

Administration of platelet inhibitors, such as P2Y12 inhibitors or glycoprotein IIb/IIIa inhibitors, is a prerequisite for patients undergoing the PCI procedure to relieve the obstructed flow of blood, which might elicit hemorrhagic events (Blanchart et al., 2021). An increased incidence of major bleeding (64.7% with BARC 3 or 5) was reported by Jiménez-Brítez et al. (2017), but no major differences were found in any bleeding (28.6% with clopidogrel vs. 25% with ticagrelor) and major bleeding (11.4% with clopidogrel vs. 12.5% with ticagrelor) cases.

It could be linked to the reduction in temperature due to hypothermia, ultimately resulting in physiological alterations and subsequently affecting the coagulability of thrombin formation and inhibition of platelets, as well as flawed synthesis of clotting enzymes (Jiménez-Brítez et al., 2017; Wallner et al., 2020). Thus, it can be assumed that these differences arise from various changes as a result of targeted temperature management, as opposed to administration of the antiplatelet inhibitors themselves.

Another study conducted by Gouffran et al. (2016) reported an increased incidence of ST with newer P2Y12 agents, namely ticagrelor, in comparison with clopidogrel (17.3% vs. 4.2%) in the same cohort subject to a greater risk of bleeding (36.4% vs. 7.8%). As per the current treatment guidelines, antithrombotic therapy is not currently advised for patients with out-of-hospital cardiac arrest (OHCA) brought on by ACS (Nikolaou et al., 2015).

In contrast, a study conducted by Steblovnik et al. (2016) demonstrated a decrease in ST in patients treated with ticagrelor, without variations in hemorrhagic events, compared with clopidogrel. These results support the pharmacodynamic and pharmacokinetic studies that examined ticagrelor with clopidogrel in patients with OHCA and found similar therapeutic benefits (Bednar et al., 2016; Gouffran et al., 2016; Jiménez-Brítez et al., 2017; Moudgil et al., 2014; Steblovnik et al., 2016).

Both ticagrelor and clopidogrel cohorts illustrated similar rates of in-hospital ST (5% vs. 6%), BARC 3a and 5 hemorrhage (15% vs. 13%), and survival with excellent neurological recovery (both 50%) (Steblovnik et al., 2016). With respect to mortality, our meta-analysis reveals no significant differences between patients treated with clopidogrel and ticagrelor, in similarity with the study by Elbadawi et al. (2018).

ST can be considered as a complex issue that certainly does not arise from clopidogrel's ineffectiveness during mild TH (Jiménez-Brítez et al., 2017). Our findings revealed no distinct differences with respect to clinical outcomes in hypothermia patients on clopidogrel, in comparison with those taking the newer medication. The absence of variation in ST is inconsistent with the experimental results revealing clopidogrel to be less effective than newer medications in TH (Steblovnik et al., 2016).

However, this remains consistent with research demonstrating that platelet tests and clinical outcomes in individuals receiving dual antiplatelet therapy have a weak connection (Steblovnik et al., 2016). A recent experimental study stated that ineffectiveness of enzymatic functions of the liver is imperative for conversion of clopidogrel to its active form, hence TH might potentially have modified its influence on the outcome. Nevertheless, both P2Y12 receptor inhibitors accompanied by aspirin are standard therapy for patients undergoing PCI (Ferreiro et al., 2014).

Strengths and limitations

A strong methodological approach was implemented to perform an extensive literature search, with rigorous evaluation using the AMSTAR-2 guidelines (Shea et al., 2017). The systematic review was performed on over four databases, including PubMed/MEDLINE, Cochrane Library, Scopus, and Google Scholar, to maximize inclusion of all potentially relevant articles. Moreover, two independent and experienced investigators participated in the comprehensive search, with separate search strategies designed for each database. Any disagreements were resolved by a third investigator through mutual discussion and scrutiny.

However, this meta-analysis has some limitations that must be highlighted. There are limited studies (and hence sample sizes) available that compare the clinical outcomes of clopidogrel and ticagrelor in the setting of PCI patients being managed with TH, which may have been inadequate in potentially addressing the differences in efficacy of both drugs. Moreover, the potential inclusion and pooling of both observational studies and randomized controlled trials may introduce significant bias, especially with the limited number of randomized controlled trials available for this topic.

As per the risk of bias assessment, the studies were deemed to be mostly of moderate quality, indicating the need for high-quality studies in the future. Furthermore, the study conducted by Gouffran et al. (2016) referred newer drugs to high-risk patients exclusively, introducing further bias. Additionally, coronary angiography to determine ST was not performed on all patients, potentially leading to underestimation of ST as a clinical outcome (Gouffran et al., 2016).

Ticagrelor, being a novel agent, was introduced and administered later during the study, resulting in a shorter follow-up duration in comparison with clopidogrel, possibly introducing extensive bias in the ticagrelor cohort and hence in this meta-analysis (Jiménez-Brítez et al., 2017; Steblovnik et al., 2016). The single-centered, small-scale data pool with fewer patients and lack of diversity resulted in the lack of opportunity to perform subgroup analyses.

Finally, all included studies are relatively older, with outdated data, leading to bias as the use of newer agents (i.e., ticagrelor) may have increased in recent years.

Recommendations

In light of limited available studies comparing the efficacy of clopidogrel and ticagrelor in the particular setting of PCI patients under TH, there is a need for further randomized clinical trials with larger sample sizes to introduce diversity, reduce the risk of bias, and allow an in-depth analysis of the efficacy of drugs through a subgroup analysis, consequently making the results more reliable.

There is a need to discuss and report greater outcomes related to the use of drugs (especially with respect to other organ systems, e.g., the hepatobiliary system and neurological system), in addition to the outcomes already discussed, to verify the already drawn results regarding the efficacy of the antiplatelet therapy.

The results of the mentioned outcomes could have been improved with more systematic usage of confirmatory tests for particular outcomes, such as coronary angiography in patients to diagnose ST, or by confirming the cause of unexplained deaths, which could have reduced the ambiguity with regard to the outcome of mortality.

Conclusions

In conclusion, the results of this meta-analysis revealed no significant differences in the clinical outcomes of ST, incidence of bleeding, and all-cause mortality due to the use of clopidogrel in comparison with the newer medication, ticagrelor, in PCI patients undergoing targeted temperature management through TH. These results are conflicting with experimental research, which suggest clopidogrel's potential inefficiency in TH.

Further comprehensive studies are needed to arrive at a valid conclusion through large, multicenter, randomized controlled trials investigating a larger patient population, with greater number of outcomes being explored.

Authors' Contributions

B.S. was involved in data curation, software, formal analysis, writing—original draft, and writing—review and editing. Z.T. and S.I. were involved in data curation, software, formal analysis, methodology, and writing—original draft. M.A. was involved in data curation, software, formal analysis, and writing—original draft. S.R., H.K., S.M.B.S., F.E., M.W.A., A.A., and M.R. were involved in writing—original draft, and writing—review and editing. M.A.S., A.K., and F.S. were involved in methodology, writing—original draft, and writing—review and editing. M.U.A. was involved in writing—review and editing, and supervision. M.O.L. was involved in conceptualization, writing—review and editing, and supervision.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Supplementary Material

Supplementary Table S1
Supplementary Table S2
Supplementary Table S3

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Table S1
ther.2023.0055_suppl_tables1.pdf (76KB, pdf)
Supplementary Table S2
ther.2023.0055_suppl_tables2.pdf (150.7KB, pdf)
Supplementary Table S3
ther.2023.0055_suppl_tables3.pdf (167.3KB, pdf)

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