SUMMARY  

• There are no head-to-head clinical trials that directly compare the safety and efficacy of XARELTO and clopidogrel for the reduction of major cardiovascular events in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD).
• In this indirect treatment comparison (ITC) performed by Coleman et al, XARELTO plus low-dose aspirin (COMPASS trial) reduced the risk of major adverse cardiovascular events (MACEs) of cardiovascular (CV)  death, stroke, and myocardial infarction (MI) compared with clopidogrel plus lowdose aspirin (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.680.98; CHARISMA trial), without significantly increasing the risk of moderate-to-severe bleeding (HR, 1.15; 95% CI, 0.81-1.62).¹
• A meta-analysis that compared the efficacy and safety of antithrombotic treatment regimens showed that a combination of low-dose aspirin plus XARELTO 2.5 mg twice daily significantly reduced the risk of a MACE (CV death, stroke, or MI) compared with clopidogrel 75 mg monotherapy (HR, 0.53; 95% CI, 0.340.82). However, the risk of major bleeding was higher with low-dose aspirin plus XARELTO 2.5 mg twice daily vs clopidogrel 75 mg monotherapy (HR, 2.1; 95% CI, 1.403.20).²
• Additional citations have been added in the REFERENCES section for review.^3-5

CLINICAL DATA

Coleman et al (2022)¹ performed a systematic literature review and ITC to identify, summarize, and quantify randomized clinical trial (RCT) evidence evaluating combination anticoagulant or P2Y12 inhibitor with low-dose aspirin vs low-dose aspirin alone for the prevention of atherothrombotic events in patients with stable CAD and/or PAD.

Study Design/Methods

• The review included a search of CENTRAL, MEDLINE, and EMBASE to identify RCTs of adult patients with chronic CAD and/or PAD that compared combination anticoagulant or P2Y12 inhibitor with low-dose aspirin (75-162 mg/day) vs low-dose aspirin alone.
• Primary efficacy outcome was MACEs including CV death, stroke, or MI and the primary safety outcome was bleeding. Since the authors anticipated that bleeding outcome definitions may vary across trials and bleeding definitions may differ in the types and severity of bleeds included, bleeding was analyzed using each trial’s primary definition, by individual subtypes (fatal bleeding, intracranial hemorrhage (ICH), and severity).

Results

Authors identified 1388 non-duplicate records, which upon further screening resulted in the reporting of two RCTs: the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial and the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial.

Patient Characteristics

The CHARISMA and COMPASS trial characteristics are shown below in Table: Study Characteristics. The CHARISMA trial enrolled individuals either with or at risk for a CV event, with three quarters having established CV disease. The COMPASS trial enrolled individuals with established stable CAD and/or PAD.

Efficacy

• Results of the ITC suggested that XARELTO plus aspirin is associated with a lower risk of MACEs (CV death, stroke, or MI) compared with clopidogrel plus aspirin (HR, 0.82; 95% CI, 0.68-0.98).
• For the individual components of the MACE composite, XARELTO plus aspirin was associated with lower risk of CV death and stroke and a similar risk of MI vs clopidogrel plus aspirin.
  • CV death: HR, 0.75; 95% CI, 0.57-0.98
  • Stroke: RR, 0.67; 95% CI, 0.49-0.93
  • MI: RR, 0.93; 95% CI, 0.70-1.23

Safety

• Results of the ITC suggested that there was no evidence of a difference in moderatetosevere bleeding between XARELTO plus aspirin and clopidogrel plus aspirin (HR, 1.15; 95% CI, 0.81-1.62). Additionally, there was no evidence of a difference in fatal bleeding or intracranial hemorrhage between the 2 treatment strategies.
  • The COMPASS trial utilized a modified International Society of Thrombosis and Hemostasis (ISTH) major bleeding definition (fatal or symptomatic critical organ bleeding, bleeding into a surgical site requiring reoperation, or bleeding requiring hospitalization).
  • CHARISMA’s primary bleeding outcome was measured using the Global Utilization of Strategies to Open Occluded Arteries (GUSTO) definition (intracranial hemorrhage [ICH] or bleeding resulting in substantial hemodynamic compromise requiring treatment).
  • To address the differences in definitions, the authors utilized supplemental data from both RCTs to compare a combined moderate-to-severe GUSTO bleeding outcome from CHARISMA to either an a priori modified ISTH bleeding or an adjudicated, investigator severity-ranked moderate-to-severe bleeding definition for COMPASS. When the alternative definition of moderate-to-severe bleeding was analyzed, a similar result was seen (RR, 1.19; 95% CI, 0.93-1.52).

Limitations

• Potential bias due to cross-RCT differences in patient populations and duration of followup, sensitivity to modeling assumptions, and differences in outcome definitions.
• CHARISMA and COMPASS varied in the proportion of patients who had only vascular risk factors compared to established vascular disease, as well as the proportion of patients with a prior history of stroke.

Zheng et al (2023)² conducted a meta-analysis to compare the efficacy and safety of antithrombotic treatment regimens in patients with stable atherosclerotic cardiovascular disease (S-ASCVD).

Study Design/Methods

• A systematic search of medical databases was conducted, including Pub-Med, Embase, the Cochrane Library, Scopus, and Google Scholar, to identify RCTs (published from inception to August 2022) that described antithrombotic treatment regimens for SASCVD in patients with chronic coronary syndrome and/or PAD and in those with acute coronary syndrome or postpercutaneous coronary intervention who waited at least 1 year before being included in the study.
• The primary efficacy endpoint was a MACE (CV death, stroke, or MI), the safety endpoint was major bleeding, and the net clinical benefit outcome was the composite of MACE and fatal bleeding.

Results

The study consisted of 12 RCTs that included 122,190 patients with 8 antithrombotic treatment regimens.

Patient Characteristics

The mean age ranged from 61.9 to 68.3 years and the median follow-up duration ranged from 15 to 33 months; the proportion of males ranged from 68.4 to 81.7%.

Efficacy

• Overall, 8 RCTs with 89,184 patients were eligible for the primary endpoint analysis.
• A combination of low-dose aspirin plus XARELTO 2.5 mg twice daily significantly reduced the risk of a MACE compared with clopidogrel 75 mg monotherapy (HR, 0.53; 95% CI, 0.340.82). A HR of 1.55 (95% CI, 0.80-2.99) was noted for a MACE with low-dose aspirin plus XARELTO 2.5 mg twice daily vs low-dose aspirin plus clopidogrel 75 mg.  
  • The effect of low-dose aspirin plus XARELTO 2.5 mg twice daily on MACE remained stable with a longer follow-up duration. A stable HR (between 0.4 and 0.6) was observed for low-dose aspirin plus XARELTO 2.5 mg twice daily vs clopidogrel 75 mg monotherapy from 19 to 33 months of followup.

Safety

• Overall, 12 RCTs with 122,190 patients were eligible for the safety endpoint analysis.
• The risk of major bleeding was higher with low-dose aspirin plus XARELTO 2.5 mg twice daily vs clopidogrel 75 mg monotherapy (HR, 2.1; 95% CI, 1.40-3.20). A HR of 1.41 (95% CI, 0.97-2.10) was noted for major bleeding with low-dose aspirin plus XARELTO 2.5 mg twice daily vs low-dose aspirin plus clopidogrel 75 mg.

Net Clinical benefit

• The risk of the composite net clinical benefit outcome of MACE and fatal bleeding was lower with low-dose aspirin plus XARELTO 2.5 mg twice daily vs clopidogrel monotherapy (HR, 0.57; 95% CI, 0.37-0.89).

Limitations

• A limited number of treatment regimens due to a limited number of trials.
• Potential bias due to several trials not providing sufficient information regarding random sequence generation and allocation concealment.
• Potential bias due to some trials not providing all the endpoints.
• Potential variability in the results due to differences in baseline data among the included trials.
• No sub-group analysis was conducted owing to a limited number of trials. Hence, the underlying differences in the drug response in different patients could not be considered as patients with S-ASCVD included those with chronic coronary syndrome and PAD.
• Several pairs of treatment regimens lacked direct comparisons, thereby reducing the robustness of the results.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 18 September 2024.