Author + information
- Received November 9, 2015
- Revision received December 13, 2015
- Accepted December 22, 2015
- Published online April 12, 2016.
- S0735109716003983-5e30e29862c6529178d287d34cc127b7Muthiah Vaduganathan, MD, MPHa,
- S0735109716003983-37afa527b4484b499b30e4278e1d3017Deepak L. Bhatt, MD, MPHa,∗ (, )
- S0735109716003983-1c0a837a60bc9586a9e64cc285040941Byron L. Cryer, MDb,
- S0735109716003983-f9e71affeab1144358cc7c8c5853f385Yuyin Liu, MSc,d,
- S0735109716003983-0bff887744e9422cc47f2c3193dfede0Wen-Hua Hsieh, PhDc,
- S0735109716003983-3c6daae0557f1e59030c8ecee71b8275Gheorghe Doros, PhDc,d,
- S0735109716003983-b86a51107aab8c198771d95addb49ae6Marc Cohen, MDe,
- S0735109716003983-2ff2f4c7d05bd6d9fbf4c9795a1fb3a6Angel Lanas, MD, DScf,
- S0735109716003983-d9d0d72f900403ab521627f13fdd8df5Thomas J. Schnitzer, MD, PhDg,
- S0735109716003983-7e56870d4b964c2c663a00861c9317a1Thomas L. Shook, MDh,
- S0735109716003983-a415aef7ad4fbd2a0077b64da075444fPablo Lapuerta, MDi,
- S0735109716003983-fa000d4c166125990bb23fc6d27ba84fMark A. Goldsmith, MD, PhDj,
- S0735109716003983-cfe6f27ca28978843b6d6c31bbd094efLoren Laine, MDk,l,
- S0735109716003983-7924741f5232b343e95b3ebb90045d08Christopher P. Cannon, MDa,c,
- COGENT Investigators
- aBrigham and Women’s Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts
- bUniversity of Texas Southwestern and Veterans Affairs North Texas Health Care System, Dallas, Texas
- cHarvard Clinical Research Institute, Boston, Massachusetts
- dDepartment of Biostatistics, Boston University, Boston, Massachusetts
- eNewark Beth Israel Medical Center, Newark, New Jersey
- fUniversity of Zaragoza, Instituto de Investigación Sanitaria Aragón, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Zaragoza, Spain
- gDepartments of Physical Medicine and Rehabilitation and Internal Medicine—Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- hParexel International, Waltham, Massachusetts
- iLexicon Pharmaceuticals, Basking Ridge, New Jersey
- jConstellation Pharmaceuticals, Cambridge, Massachusetts
- kYale School of Medicine, New Haven, Connecticut
- lVA Connecticut Healthcare System, West Haven, Connecticut
- ↵∗Reprint requests and correspondence:
Dr. Deepak L. Bhatt, Brigham and Women’s Hospital Heart & Vascular Center, 75 Francis Street, Boston, Massachusetts 02115.
Background The COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) showed that proton-pump inhibitors (PPIs) safely reduced rates of gastrointestinal (GI) events in patients requiring dual antiplatelet therapy (DAPT). However, utilization of appropriate prophylactic PPI therapy remains suboptimal, especially with low-dose aspirin.
Objectives The authors investigated the safety and efficacy of PPI therapy in patients receiving DAPT in low- and high-dose aspirin subsets.
Methods Randomized patients with available aspirin dosing information in COGENT (N = 3,752) were divided into “low-dose” (≤100 mg) and “high-dose” (>100 mg) aspirin groups. The primary GI and cardiovascular endpoints were composite upper GI events and major adverse cardiac events, respectively. All events were adjudicated by independent, blinded gastroenterologists and cardiologists.
Results Median duration of follow-up was 110 days. Low-dose aspirin users (n = 2,480; 66.1%) were more likely to be older, female, and have higher rates of peripheral artery disease, prior stroke, and hypertension, whereas high-dose aspirin users (n = 1,272; 33.9%) had higher rates of hyperlipidemia, smoking, a history of percutaneous coronary intervention, and were more than twice as likely to be enrolled from sites within the United States (80.4% vs. 39.8%). High-dose aspirin was associated with similar 180-day Kaplan-Meier estimates of adjudicated composite GI events (1.7% vs. 2.1%; adjusted hazard ratio: 0.88; 95% confidence interval: 0.46 to 1.66) and major adverse cardiac events (4.8% vs. 5.5%; adjusted hazard ratio: 0.73; 95% confidence interval: 0.48 to 1.11) compared with low-dose aspirin. Randomization to PPI therapy reduced 180-day Kaplan-Meier estimates of the primary GI endpoint in low-dose (1.2% vs. 3.1%) and high-dose aspirin subsets (0.9% vs. 2.6%; p for interaction = 0.80), and did not adversely affect the primary cardiovascular endpoint in either group.
Conclusions Gastroprotection with PPI therapy should be utilized in appropriately selected patients with coronary artery disease requiring DAPT, even if the patients are on low-dose aspirin. (Clopidogrel and the Optimization of Gastrointestinal Events Trial [COGENT]; NCT00557921)
Given similar antiplatelet inhibition and theoretically lower bleeding risk (1–3), lower-dose aspirin is generally preferred for secondary prevention of cardiovascular events compared with higher-dose aspirin (4), especially when used in combination with more potent P2Y12 antagonists (5). Dual antiplatelet therapy (DAPT) poses significant risks of bleeding, particularly gastrointestinal (GI) bleeding, even with low-dose aspirin (6). GI bleeding in high-risk patients with coronary artery disease (CAD) is independently associated with poor prognosis (7), and on-treatment dyspepsia appears to be clinically important and may influence compliance with antiplatelet therapy (8). As such, safe and effective strategies limiting gastric toxicity are much needed.
The COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial; NCT00557921), despite being terminated prematurely due to loss of funding, demonstrated that omeprazole reduced rates of composite upper GI events (1.1% vs. 2.9%; p < 0.001) (9) and patient-reported dyspepsia (10) at 180 days compared with placebo in patients with CAD requiring DAPT, and achieved this without increasing rates of major adverse cardiac events (MACE) (9). Whether proton-pump inhibitor (PPI) use reduces GI risk consistently across aspirin doses has not definitively been established. Furthermore, utilization of appropriate prophylactic PPI therapy remains suboptimal, especially with low-dose aspirin (11). In this context, our post hoc analysis of the COGENT aimed to determine the overall GI and cardiovascular safety and efficacy of PPI therapy in patients on low-dose and high-dose aspirin.
The study design and primary results of COGENT have been previously described (9). In brief, the COGENT was a global, prospective, phase III randomized, placebo-controlled, double-blind, double-dummy clinical trial of a fixed-combination of clopidogrel 75 mg and omeprazole 20 mg compared with clopidogrel 75 mg alone. Daily enteric-coated aspirin was administered to all study patients in open-label fashion, but specific dosing was left to the treating clinician. Patients older than 21 years of age requiring DAPT for at least 12 months, regardless of indication, were included as long as P2Y12 therapy was initiated ≤21 days before enrollment. Exclusion criteria included anticipated hospital discharge within 48 h, recent use of gastroprotection (including PPIs, H2-receptor antagonists, sucralfate, or misoprostol), known GI erosive esophagitis or variceal disease, prior non-endoscopic gastric surgery, concomitant use of oral anticoagulation therapy (which could not be safely discontinued at study entry), and recent exposure to fibrinolytic therapy. The ethics committees and institutional review boards of each individual site locally approved the study protocol, and all patients provided explicit informed consent for trial participation.
The pre-specified primary GI endpoint of the overall COGENT and the current analysis was composite upper GI clinical events (including overt upper GI bleeding of known or unknown origin, bleeding of presumed GI origin with a clinically significant reduction in hematocrit, symptomatic gastroduodenal ulcer, persistent GI pain with evidence of endoscopy-confirmed gastroduodenal erosions, obstruction, or perforation). The secondary GI endpoint was symptomatic, endoscopy-confirmed erosive esophagitis (gastroesophageal reflux disease [GERD]). Non–GI-related bleeding events were also documented. The pre-specified primary cardiovascular endpoint of the overall COGENT and the current analysis was the composite of cardiovascular death, nonfatal myocardial infarction, coronary revascularization, or ischemic stroke. All GI and cardiovascular events were blindly adjudicated by teams of independent gastroenterologists and cardiologists, respectively. Investigator-reported GI and cardiovascular events as well as patient-reported dyspepsia symptoms, assessed using the Severity of Dyspepsia Assessment (SODA) questionnaire (12,13) at 4- and 24-week follow-up, were also reported.
Patients in the intention-to-treat population were divided into 2 groups: 1) “low-dose” aspirin, defined as daily maintenance doses of 75 mg or 81 mg; and 2) “high-dose” aspirin, defined as daily maintenance doses of 150 mg, 162 mg, 300 mg, or 325 mg. Baseline characteristics, along with GI and cardiovascular outcomes, were compared in both treatment arms in low- and high-dose aspirin subsets. Discrete variables are presented as n (%) and compared using chi-square or Fisher exact tests, whereas continuous variables are presented as mean ± SD and median (interquartile range [IQR]), and compared using Student t tests. All clinical endpoints are presented as Kaplan-Meier estimates at 180 days.
Interaction analyses were performed to determine the interaction between treatment assignment (with PPI or placebo) and aspirin dose using the Breslow-Day test for discrete variables, one-way analysis of variance tests for continuous variables, and Cox proportional hazards models for time-dependent variables. Global region was categorized as United States- and non–United States-based on site of enrollment. Cumulative incidence curves were constructed for the primary GI and cardiovascular endpoints, stratified by treatment assignment (with PPI or placebo), separately for low- and high-dose aspirin dosing subsets. The number needed to treat (NNT) to prevent 1 major composite upper GI event after 6 months of PPI therapy was calculated using the formula: NNT = 1 / absolute risk reduction (where absolute risk reduction was equal to Kaplan-Meier estimates of event rates at 180 days in the placebo group minus that in the omeprazole group). Major GI and cardiovascular events were also compared between low- and high-dose aspirin groups. To account for confounding by indication, Cox proportional hazards models were used to estimate effect sizes of high- versus low-dose aspirin, expressed as hazard ratios (HRs) and 95% confidence intervals (CI). Multivariate models accounted for a pre-determined set of high-risk covariates including age, sex, region (United States vs. non-United States), percutaneous coronary intervention (PCI), acute coronary syndrome presentation, history of GI bleeding or ulcer, and PPI treatment assignment. No adjustments for multiple comparisons were made. A p value of <0.05 was considered statistically significant. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, North Carolina).
The COGENT was prematurely terminated due to the sponsor filing for bankruptcy. From January 2008 to December 2008, the COGENT randomized 3,761 patients from 393 sites across 15 countries. Of the total randomized, intention-to-treat cohort, 3,752 (99.8%) patients had available aspirin dosing information. Patients were divided into low-dose (≤100 mg; n = 2,480; 66.1%) and high-dose (>100 mg; n = 1,272; 33.9%) aspirin groups. Aspirin doses of 75 or 81 mg daily were consistently the most frequently administered, followed by 325 mg, at baseline and all major follow-up time points in the COGENT (Figure 1).
The baseline characteristics of patients assigned to PPI and placebo arms were well-balanced in both aspirin subsets (Table 1). However, clinical profiles varied substantially by aspirin dosing. Low-dose aspirin therapy was more frequently utilized in older patients, women, and participants who were less overweight/obese compared with high-dose aspirin. High-dose aspirin therapy was associated with a higher rate of documented negative Helicobacter pylori infection (65.9% vs. 44.5%) compared with low-dose therapy. Low-dose aspirin users had higher rates of established peripheral artery disease, prior stroke, and hypertension, whereas high-dose aspirin users had higher rates of hyperlipidemia and a history of PCI within 14 days of randomization (91.3% vs. 61.6%). High-dose aspirin users were more than twice as likely to be enrolled from sites within the United States compared with low-dose aspirin users (80.4% vs. 39.8%). There was no difference in history of GI bleeding or ulcer between the groups. Patients on high-dose aspirin during the study were more likely to have been prescribed aspirin and clopidogrel (initiated within 21 days of randomization) before study entry compared with patients on low-dose aspirin. High-dose aspirin users (median 115 days; IQR: 57 to 178 days) had longer follow-up durations compared with low-dose aspirin users (median 67 days; IQR: 52 to 126 days).
Overall, median duration of follow-up was 110 days (IQR: 55 to 167) for the entire analytic cohort. PPI use reduced rates of the primary GI endpoint in the low-dose (1.2% vs. 3.1%; p = 0.003) and high-dose aspirin subsets (0.9% vs. 2.6%; p = 0.05) (Table 2). The corresponding NNT estimated to prevent 1 major composite upper GI event with 6 months of PPI therapy was 52 in the low-dose aspirin subset and 58 in the high-dose aspirin subset. Aspirin dosing did not appear to modify the benefit of PPI therapy in reducing rates of the primary GI endpoint (interaction p = 0.80). Kaplan-Meier analyses further demonstrated the consistency of PPI benefit in reducing cumulative incidence of GI events in low- and high-dose aspirin subsets (Central Illustration). PPI use consistently reduced each of the components of the primary GI endpoint numerically in both aspirin dosing groups (interaction p range 0.67 to 0.99). Similarly, rates of the secondary GI endpoint were reduced by PPIs in the low-dose (0.7% vs. 1.3%; p = 0.10) and high-dose (0.2% vs. 1.6%; p = 0.02; interaction p = 0.33) aspirin groups. Investigator-defined GI events were also consistently reduced by PPIs in both low-dose (2.6% vs. 5.2%; p = 0.01) and high-dose (3.5% vs. 5.3%; p = 0.13; interaction p = 0.55) aspirin groups. At 4 weeks, PPI therapy significantly reduced mean SODA scores for dyspepsia pain intensity in both aspirin subsets (interaction p = 0.13). Trends favoring PPI benefit on pain-related SODA scores persisted at 24 weeks, but these differences were not statistically significant (Table 2).
PPI therapy did not significantly increase the primary cardiovascular endpoint in low-dose (5.6% vs. 5.5%; p = 0.95) or high-dose (4.2% vs. 5.5%; p = 0.92; interaction p = 0.91) aspirin groups. Kaplan-Meier incidence curves for the primary cardiovascular endpoint by PPI treatment randomization are presented in Figure 2. Similarly, PPIs did not influence investigator-defined cardiovascular events in both aspirin dose subsets (interaction p = 1.00). Rates of non-GI bleeding and all-cause mortality were low and were not influenced by PPI therapy in either aspirin dosing subset (Table 2).
Event rates by aspirin dosing
High-dose aspirin was associated with similar risks of adjudicated composite upper GI events (1.7% vs. 2.1%), GERD (0.9% vs. 1.0%), and MACE (4.8% vs. 5.5%) compared with low-dose aspirin at 180 days (Table 3). After accounting for baseline risk profiles, high-dose aspirin did not influence risk of adjudicated composite upper GI events (adjusted HR: 0.88; 95% CI: 0.46 to 1.66), GERD (adjusted HR: 0.71; 95% CI: 0.28 to 1.77), or MACE (adjusted HR: 0.73; 95% CI: 0.48 to 1.11) compared with low-dose aspirin (Table 3).
Independent predictors of adjudicated primary gastrointestinal events
Age remained the only significant independent predictor of adjudicated composite upper GI events in the final multivariate model (adjusted HR: 1.03 per year; 95% CI: 1.00 to 1.06), whereas randomization to omeprazole (vs. placebo) was independently associated with lower risk of the composite primary GI endpoint (adjusted HR: 0.33; 95% CI: 0.18 to 0.62).
In the context of a large, randomized clinical trial of PPI therapy in patients with CAD on DAPT, aspirin dosing ≤100 mg was utilized in two-thirds of patients and was associated with similar risks of GI events as higher-dose aspirin. Prophylactic PPI therapy consistently reduced rates of adjudicated GI events at 180 days and patient-reported symptoms, even with low-dose aspirin therapy. In the COGENT, the NNT estimated to prevent 1 major composite upper GI event with 6 months of PPI therapy was 52 and 58 in the low-dose and high-dose aspirin subsets, respectively.
COGENT represented an ideal setting to examine optimal gastroprotection approaches by aspirin dosing given that the trial: 1) represented the only large, randomized placebo-controlled experience examining PPI use in this setting; 2) included robust global participation, potentially capturing regional variation in aspirin dosing (5,14); and 3) specifically adjudicated GI and cardiovascular events. The consistency of PPI benefit across aspirin doses may be related to its potent effects on gastric acid suppression.
Variation in aspirin dosing practices
Aspirin is widely prescribed for secondary prevention of cardiovascular events in patients with CAD. Substantial regional and practice-based variations exist regarding aspirin dosing regimens (14). Despite recent shifts towards utilizing lower-dose aspirin therapy, higher-dose aspirin is still used in more than 60% of “real-world” patients discharged after acute myocardial infarction in the United States (15), and it continues to be supported by guideline committees for select high-risk settings. Even in well-selected patients in this contemporary trial, one-third of CAD patients used high maintenance aspirin doses. Data regarding the GI risks associated with varying aspirin doses are limited (16), and meta-analyses have been contradictory (17,18). High maintenance aspirin doses (≥300 mg) were associated with excess cardiovascular events when used in combination with ticagrelor in the PLATO (Platelet Inhibition and Patient Outcomes; NCT00391872) trial, explaining the apparent regional variation in ticagrelor’s clinical efficacy (5). Another trial, CURRENT-OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events−Seventh Organization to Assess Strategies in Ischemic Syndromes; NCT00335452) (19), demonstrated no difference between low- versus high-dose aspirin on primary ischemic and bleeding endpoints at 30 days in patients who presented with acute coronary syndromes referred for an invasive strategy, though there was a lower rate of GI bleeding with low-dose aspirin. Our study demonstrated that risk-adjusted GI and cardiovascular events were similar in subsets of CAD patients prescribed varying aspirin doses. We eagerly await comparative effectiveness data from the ADAPTABLE trial (Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-Term Effectiveness), which will compare low- versus high-dose aspirin strategies in patients with CAD (20).
PPI efficacy with low-dose aspirin
Using low-dose aspirin appears to provide effective antiplatelet protection, but still confers a substantial risk of GI bleeding. These randomized data support the role of prophylactic use of PPIs to attenuate this excess risk without heterogeneity by aspirin dosing in patients requiring DAPT. Consistently, prior small trials have demonstrated efficacy of PPIs with low-dose aspirin in secondary prevention of GI bleeding in other high-risk cohorts, such as patients with a prior history of GI ulcers (21,22). Despite this, PPI use appears to be underutilized for prevention of GI events (11), perhaps related to underestimated clinician estimates of GI risks related to low-dose aspirin. Prophylactic PPI therapy is a data-driven, expert-recommended (6,23), and cost-effective approach to gastroprotection (24) in appropriately selected patients (25–27), even those on low-dose aspirin. Enteric-coated aspirin was protocol-specified in COGENT, but these preparations may be associated with variable drug absorption (28) and antiplatelet effects (29), without significantly attenuating attendant GI bleeding risks (30), compared with standard dispersible aspirin. Definitive cardiovascular outcome data are lacking regarding the use of enteric-coated versus immediate-release preparations of aspirin in patients with CAD. Enteric-coating may decrease dyspepsia and, as such, may have led to some underestimation of omeprazole’s potential benefits in reducing dyspepsia in this trial. New formulations of aspirin may limit GI toxicity (31,32), but further data are required. Ongoing investigation is needed to evaluate the differential GI bleeding risks and effective gastroprotection strategies with newer combinations and longer durations of DAPT (33).
There are several limitations to this post hoc analysis. The overall trial was not powered to detect differences in safety and efficacy of PPI therapy by aspirin dosing. Comparisons of clinical outcomes between different aspirin dosing regimens were nonrandomized and thus may be subject to residual confounding by indication. The point estimates for GI and cardiovascular risks by aspirin dosing should be interpreted with caution, given the wide CIs. No statistical adjustments were made for multiple comparisons. We used baseline aspirin dose at the time of enrollment in our models; however, aspirin dosing did not appear to change substantially during follow-up. The specific preparation of the clopidogrel–PPI combination used in the COGENT is not commercially available, though that is unlikely to affect the study findings. Although the original trial was prematurely terminated due to loss of funding, it met its initial target sample size, with robust follow-up available in the high-risk period post-randomization. More potent P2Y12 inhibitors, such as prasugrel and ticagrelor, were not widely used in this trial.
These data from COGENT suggest that gastroprotection with PPI therapy should be utilized in appropriately selected patients with CAD requiring DAPT, even if on low-dose aspirin.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Gastrointestinal toxicity is common in patients treated with DAPT even when low doses of aspirin are utilized, and prophylactic administration of a PPI is effective regardless of aspirin dosing.
TRANSLATIONAL OUTLOOK: Further investigation is needed to evaluate the risks of gastrointestinal bleeding and effectiveness of protective strategies using newer combinations and longer durations of DAPT.
For a full list of investigators, please see the online version of this article.
The COGENT was funded by Cogentus Pharmaceuticals; however, this post hoc analysis was conducted independently with biostatistical support from an independent team from Harvard Clinical Research Institute (HCRI). The study investigators had full access to the trial database and retained complete control on the decision to pursue publication. The sponsor did not have right to review or approve the final manuscript. Dr. Bhatt serves on the advisory boards of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; serves on the boards of directors of Boston VA Research Institute and Society of Cardiovascular Patient Care; chairs the American Heart Association Quality Oversight Committee; is vice-chair of the ACTION Registry Steering Committee; serves on data monitoring committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and Population Health Research Institute; has received honoraria from American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org), Belvoir Publications (editor in chief, Harvard Heart Letter), HMP Communications (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), Population Health Research Institute (clinical trial steering committee of COMPASS), Slack Publications (chief medical editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), and WebMD (CME steering committees); is deputy editor of Clinical Cardiology; has received research funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi, and The Medicines Company; is a site co-investigator for Biotronik, Boston Scientific, and St. Jude Medical; is a trustee of the American College of Cardiology; and performs unfunded research for Cogentus (chair of COGENT), FlowCo, PLx Pharma, and Takeda. Dr. Cryer has served as a consultant to Cogent Pharmaceuticals. Dr. Lanas has received an investigator-initiated grant from Bayer Pharma AG; and has served on advisory boards for Bayer Pharma AG. Dr. Shook is an employee of PAREXEL International. Dr. Lapuerta is an employee of Lexicon Pharmaceuticals. Dr. Goldsmith is an employee of Constellation Pharmaceuticals. Dr. Laine served on data safety monitoring boards for Bayer and Bristol-Myers Squibb. Dr. Cannon has served on the advisory boards of Bristol-Myers Squibb, Lipimedix, and Pfizer; and has received research funding from Accumetrics, Arisaph, AstraZeneca, Boehringer Ingelheim, CSL Behring, Essentialis, GlaxoSmithKline, Janssen, Merck Regeneron, Sanofi, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- coronary artery disease
- confidence interval
- dual antiplatelet therapy
- gastroesophageal reflux disease
- hazard ratios
- interquartile range
- number needed to treat
- percutaneous coronary intervention
- proton-pump inhibitor
- Severity of Dyspepsia Assessment
- Received November 9, 2015.
- Revision received December 13, 2015.
- Accepted December 22, 2015.
- American College of Cardiology Foundation
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