Summary

• In the ATLAS ACS-TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 51) study, a total of 3993 (25.7%) patients were on a proton-pump inhibitor (PPI) following randomization.¹ The concomitant use of PPIs and study drug was comparable across treatment groups. Use of a PPI was not linked to an increased risk of cardiovascular (CV) events, regardless of treatment arm.²
• COMPASS (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) was a phase 3, event-driven, double-blind, randomized study designed to evaluate whether treatment with XARELTO 2.5 mg twice daily plus aspirin (ASA) 100 mg once daily or XARELTO 5 mg twice daily alone is more effective than ASA 100 mg once daily alone for prevention of myocardial infarction (MI), stroke, or CV death in patients with a history of stable atherosclerotic vascular disease (coronary artery disease [CAD] or peripheral artery disease [PAD]).^3,4
  • In a randomized comparison of the COMPASS study, pantoprazole was compared with placebo in patients who were not already receiving a PPI.^5,6 Pantoprazole therapy did not significantly reduce clinically significant upper gastrointestinal (GI) events in patients with stable CAD or PAD receiving XARELTO and/or ASA therapy.⁵ There was no significant difference between the pantoprazole and placebo groups in the primary efficacy composite outcome of MI, stroke, or CV death, and no statistically significant difference between groups in secondary efficacy outcomes and safety events (except for enteric infections).⁶
  • The most common site of major bleeding was GI, occurring in 1.5% of patients who received XARELTO plus ASA, in 1% of patients who received XARELTO alone, and in 0.7% of patients who received ASA alone.⁴
• In a sub-analysis of the Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial, the incidence of bleeding events was lower in patients on a PPI compared to those not on a PPI (P=0.03).⁷
• An observational cohort study of Asian patients with atrial fibrillation (AF) and a prior history of upper gastrointestinal bleeding (GIB) found a significant reduction in the risk of major GIB in the PPI + XARELTO (HR 0.597, 95% CI 0.426–0.836) co-therapy group.⁸
• Additional citations identified during a literature search are included in the REFERENCES section for your review. ^9,10

CLINICAL STUDIES

Acute Coronary Syndrome (ACS)

ATLAS ACS-TIMI 51 was a phase 3, randomized, placebo-controlled, multicenter, event-driven study designed to determine whether XARELTO (2.5 mg twice daily or 5 mg twice daily), when added to standard care, is safe and reduces the risk of the composite of CV death, MI, or stroke in subjects with ACS compared with placebo.¹¹

• The study was divided into 2 treatment stratums: stratum 1 compared XARELTO to ASA therapy alone, while stratum 2 compared XARELTO to ASA plus a thienopyridine.¹¹
• In stratum 2 of the study, 2203 (15.2%) study participants were receiving omeprazole or esomeprazole, along with study drugs.²
• The concomitant use of PPIs and study drug was comparable across treatment groups.¹
• The efficacy of XARELTO, at 2.5 mg twice daily and 5 mg twice daily, was consistent in reducing the risk of CV death, MI, or stroke at day 30 in patients receiving a PPI and in those not receiving a PPI (hazard ratio [HR]: 0.94, 95% confidence interval [CI]: 0.51-1.76 and HR: 0.69, 95% CI: 0.52-0.91, respectively).²
• There was no heterogeneity for patients who were on or not on a PPI in regards to long-term bleeding risk.²
• The concomitant use of a PPI with XARELTO was not associated with an increased risk of CV events in patients on a thienopyridine (HR: 1.06; 95% CI: 0.89-1.25).²

CAD and PAD

COMPASS was a phase 3, event-driven, double-blind, double-dummy, randomized, multicenter study designed to evaluate whether treatment with XARELTO 2.5 mg twice daily plus ASA 100 mg once daily or XARELTO 5 mg twice daily alone is more effective than ASA 100 mg once daily alone for secondary prevention of MI, stroke, or CV death in patients with a history of stable atherosclerotic vascular disease (CAD or PAD). In a randomized comparison of the COMPASS study, pantoprazole was compared with placebo in patients who were not already receiving a PPI (see Moayyedi et al [2019]^5,6 below).^3,4

Study Design/Methods

• A total of 27,395 patients were recruited from 602 centers in 33 countries between February 2013 and May 2016.
• Key inclusion criteria included: PAD; CAD with ≥1 of the following: age ≥65 years or age <65 years and documented atherosclerosis or revascularization involving ≥2 vascular beds or ≥2 additional risk factors: current smoker, diabetes mellitus, renal dysfunction with estimated glomerular filtration rate (eGFR) <60 mL/min, heart failure (HF), or nonlacunar ischemic stroke ≥1 month ago. Key exclusion criteria included: stroke within 1 month or any history of hemorrhagic or lacunar stroke; severe HF with known ejection fraction <30% of New York Heart Association class III or IV symptoms; need for dual antiplatelet therapy (DAPT), other nonASA antiplatelet therapy, or oral anticoagulant therapy; eGFR <15 mL/min; systemic treatment with strong inhibitors of both CYP3A4 and P-glycoprotein or strong inducers of CYP3A4.
• Patients receiving a PPI at baseline were not eligible for the pantoprazole randomization.
• Dosing interventions were as follows (patients stratified according to center and use of PPI therapy at time of randomization):
  • XARELTO 2.5 mg twice daily and ASA 100 mg once daily
  • XARELTO 5 mg twice daily and placebo once daily
  • Placebo twice daily and ASA 100 mg once daily
• Patients who were not already receiving a PPI were randomized in a 1:1 ratio to receive pantoprazole 40 mg once daily or placebo for prevention of upper GI complications, including bleeding, ulceration, obstruction, or perforation.
• Primary efficacy outcome: the composite of MI, stroke, or CV death
• Primary safety outcome (based on modified International Society on Thrombosis and Hemostasis [ISTH] criteria): major bleeding, including fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and bleeding leading to hospitalization (including presentation to an acute care facility without overnight stay)

Results

Baseline Characteristics

• Mean age was 68.2 years, 22.0% of patients were female, 90.6% had a history of CAD, 27.3% had a history of PAD, 3.8% had a history of stroke, and <1% had an eGFR of <30 mL/min.
• Baseline nonsteroidal anti-inflammatory drug use was reported in approximately 5% of patients in each group; baseline PPI use was reported in approximately 36% of patients in each group.⁴

Efficacy/Safety

• For efficacy and safety outcomes, see Table: Primary Efficacy and Safety Outcomes in Overall COMPASS Patients.

Moayyedi et al (2019)^5,6 conducted a 3x2 partial factorial, multicenter, double-blind, randomized, placebo-controlled study of COMPASS participants to evaluate whether pantoprazole is more effective than placebo in preventing upper GI events in participants receiving ASA and/or XARELTO.

• The dosing regimen, methodology, and baseline characteristics for the overall COMPASS study are summarized above.
• A total of 17,598 participants from the COMPASS study were randomized to pantoprazole (40 mg daily, n=8791) or placebo (n=8807).
• The primary reason for exclusion from the PPI portion of the study was that participants were considered to have a clinical need for PPI (based on physician’s judgment) at the time of randomization.
• Moayyedi et al evaluated various efficacy and safety outcomes; results have been published separately.^5,6
  • In the first analysis, the primary efficacy outcome was time to first upper GI clinical event (defined as a composite of overt bleeding [hematemesis and/or melena] with a gastroduodenal lesion that is bleeding at the time of the procedure, overt upper GI bleeding of unknown origin, occult bleeding [drop in hemoglobin of ≥2 g/dL], symptomatic gastroduodenal ulcer with ≥3 days of GI pain, or ≥5 gastroduodenal erosions with ≥3 days of GI pain, or upper GI obstruction or perforation).⁵
  • In the second analysis, rates of CV disease events (eg, MI, stroke, CV death, coronary heart disease, and acute limb ischemia), as defined by the primary and secondary efficacy outcomes for the XARELTO and/or ASA arms of the COMPASS study, were compared between the pantoprazole and placebo arms. Safety outcomes of special interest included pneumonia, C difficile infection, other enteric infections, fracture, gastric atrophy, chronic kidney disease, and dementia. Diabetes mellitus and chronic obstructive lung disease were also evaluated, but not as the primary focus.⁶
• Baseline characteristics were similar between groups. Mean age was 67.6 years, 78% of participants (n=13,792) were male, 23% (n=4,074) were current smokers, 5% (n=872) were taking NSAIDs, 3% (n=515) were taking SSRIs, and 2.6% (n=228) had a past history of peptic ulcer disease.
• Median follow-up was 3.01 years. Twenty-one percent (n=1,884) of pantoprazole-treated participants and 22% (n=1,975) of placebo-treated participants permanently discontinued medication.  
• In the first analysis, pantoprazole therapy did not significantly reduce clinically significant upper GI events in participants with stable CAD or PAD receiving XARELTO and/or ASA therapy (see Table: Primary Efficacy Outcome of Clinically Significant Upper Gastrointestinal Event).⁵

• In the second analysis, there was no significant difference between pantoprazole and placebo in the COMPASS primary efficacy composite outcome of MI, stroke, or CV death. There was no statistically significant difference between pantoprazole and placebo in the COMPASS secondary CV efficacy outcomes, and no difference when MI (HR: 0.94; 95% CI: 0.79-1.12), stroke (HR: 1.16; 95% CI: 0.94-1.44), and acute limb ischemia (HR: 1.13; 95% CI: 0.73-1.75) were considered separately. Hospitalization rates and all-cause mortality were also similar between arms. See Table: CV Events and Hospitalizations.⁶
• There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections, which were higher in the pantoprazole group. In regards to all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole group vs placebo group; however, since there were only 13 such events, this difference was not statistically significant. See Table: Other Prespecified Safety Outcomes.⁶

Wada et al (2022) conducted a sub-analysis to assess the effect of PPIs on the incidence of bleeding events in patients from the AFIRE trial.^7,12

• AFIRE was a multicenter, randomized, open-label, non-inferiority trial designed to evaluate whether XARELTO alone is noninferior to XARELTO plus an antiplatelet agent in adult patients with AF and stable CAD. A total of 2215 patients were randomized to receive the following:
  • XARELTO 10 mg or 15 mg monotherapy based on the patient’s creatine clearance (n=1107).
  • XARELTO + antiplatelet agent (either aspirin or a P2Y₁₂ inhibitor) based on the physician’s discretion (n=1108).
• Out of the 2215 patients, 1357 patients (61.3%) were receiving a PPI at baseline.
• Bleeding events were lower in patients on a PPI compared to those not on a PPI (hazard risk 0.79; 95% CI, 0.64-0.97, P (for interaction) =0.03).
• The effect of PPI therapy on the cumulative incidence of bleeding events was significantly different between the XARELTO + antiplatelet therapy groups (P=0.01); however, these differences were not observed among patients in the XARELTO monotherapy group (P=0.50).

Observational studies

Lee et al (2021) conducted an observational cohort study, using data from the Korean Health Insurance Review and Assessment databases, to evaluate the protective effect PPI co-therapy with an oral anticoagulant (OAC) on the risk of GIB in Asian patients with AF and a prior history of GIB.⁸

• OAC-naïve patients were defined as just starting an OAC during the study period (January 2010 to April 2018). The study categorized patients into 10 groups according to OAC (warfarin, XARELTO, dabigatran, apixaban, or edoxaban) and if patients received PPI co-therapy or not.
• Overall, out of the 42,048 study patients, 40% (n=16,988) were prescribed PPIs.
• There was 40.4% of XARELTO patients on concomitant PPI therapy.
  • The number of patients on XARELTO, without PPI co-therapy or with PPI co-therapy was 5684 (22.7%) and 3855 (22.7%), respectively.  
• Compared to patients not on PPIs, patients on PPIs were older (71.8±9.6), more likely to be female 7686 (45.2), had a higher CHA₂DS₂-VASc score (38±1.5), higher HAS-BLED score (4.4±1.2), and higher Charlson comorbidity index (4.9±2.6).
• The follow-up period was on average 0.6 years.
• Among patients on regular and reduced doses of XARELTO, there was no significant difference observed in the use of PPI co-therapy.
• The XARELTO group without PPI use had the highest incidence of major GIB (2.62 per 100 person-years).
• There was a significant reduction in the risk of major GIB in the PPI + XARELTO (HR 0.597, 95% CI 0.426–0.836).
• Patients in the XARELTO group observed the largest reduction in the risk of upper GIB with PPI co-therapy (HR 0.549; 95%CI, 0.383-0.788).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 28 May 2024.