Recent evidence has shown that clopidogrel and proton pump inhibitors (PPIs) are metabolized by the same pathway and that patients taking both drugs have greater levels of platelet reactivity and more adverse outcomes than patients taking only clopidogrel. We sought to examine the effect of a PPI at discharge from the hospital after percutaneous coronary intervention with drug-eluting stents on the incidence of major adverse cardiac events (MACE) at 1 year. We compared 502 patients who were not prescribed a PPI at discharge and 318 patients who were prescribed a PPI. All patients were taking clopidogrel. We followed patients for 1 year with regard to MACE, including death, Q-wave myocardial infarction, target vessel revascularization, and stent thrombosis. We performed multivariate Cox regression to adjust for confounding variables, including compliance with clopidogrel, to assess the effect of a PPI at discharge on the 1-year outcomes. The baseline characteristics of patients discharged with a PPI were similar to those of patients discharged without a PPI. Univariate survival analysis of the outcomes showed a greater rate of MACE (13.8% vs 8.0%, p = 0.008) and overall mortality (4.7% vs 1.8%, p = 0.02) in the PPI group. After multivariate analysis, the adjusted MACE hazard ratio for PPI at discharge was 1.8 (95% confidence interval 1.1 to 2.7, p = 0.01). In conclusion, in patients undergoing percutaneous coronary intervention with drug-eluting stents and receiving clopidogrel, the prescription of a PPI at discharge was associated with a greater rate of MACE at 1 year.
Dual antiplatelet therapy with aspirin and clopidogrel is the standard of care for patients with an acute coronary syndrome or for those undergoing percutaneous coronary intervention (PCI). This places patients at considerably greater risk, however, of gastrointestinal bleeding. As a result, a recent expert consensus document has recommended that all patients receiving dual antiplatelet therapy receive a proton pump inhibitor (PPI) to attenuate this bleeding risk. Given that clopidogrel is metabolized by the same cytochrome P450 (CYP) pathway as PPIs, their concomitant administration would be expected to inhibit the metabolism of clopidogrel to its active form. This has been supported by evidence that omeprazole increases platelet reactivity in patients taking clopidogrel, which could potentially lead to an increase in adverse cardiovascular outcomes. We, therefore, sought to examine the relation between PPIs and adverse cardiovascular outcomes in patients undergoing PCI with drug-eluting stents, hypothesizing that PPIs would increase the risk of adverse clinical outcomes at 1 year.
Methods
We prospectively entered clinical, procedural, and follow-up data for patients undergoing PCI with drug-eluting stents at a single center and performed a retrospective analysis of this database. The indications for PCI included stable angina, unstable angina, and acute myocardial infarction. We randomly selected 820 patients and determined whether they were prescribed a PPI at discharge. We then assessed them for clinical events at 1 year. The study period encompassed April 2003 to April 2007.
All patients received aspirin 325 mg and clopidogrel 300 to 600 mg (at the operator’s discretion) before the procedure. Anticoagulation regimens were chosen at the operator’s discretion and included unfractionated heparin targeted to achieve an activated clotting time of <200 to 300 seconds, with or without a glycoprotein IIb/IIIa inhibitor, or bivalirudin 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hour for the duration of the procedure. After the procedure, aspirin 325 mg/day was continued indefinitely and clopidogrel was maintained for a minimum of 6 months.
The present study was approved by the institutional review board at Washington Hospital Center and MedStar Research Institute (Washington, DC). A dedicated data coordinating center performed all data management and analyses. The prespecified clinical and laboratory data during the hospitalization periods were obtained from hospital charts reviewed by independent research personnel who were unaware of the objectives of the present study. Clinical follow-up at 30 days, 6 months, and 1 year was conducted by telephone interview or office visits. The occurrence of major late clinical events was recorded, including death (all-cause), myocardial infarction, and stent thrombosis. Compliance with clopidogrel was also assessed during follow-up interviews/visits. If patients reported they were not taking clopidogrel, they were asked when they had stopped. All clinical events were adjudicated by source documentation of independent physicians who were not involved in the procedures. All patients routinely underwent pre- and post-PCI 12-lead electrocardiography to detect procedure-related ischemic changes and/or the presence of new pathologic Q waves. Blood samples at 6 and 24 hours before and after PCI were taken to assess the creatine kinase-MB isoenzyme. If the creatine kinase-MB was elevated above the reference range (4 mg/dl), the measurements were repeated every 8 hours until it had returned to less than the reference range.
Major bleeding was defined according to the Thrombolysis In Myocardial Infarction study group definition and consisted of intracranial hemorrhage or clinically overt bleeding with a decrease in hemoglobin of ≥5 g/dl or hematocrit of ≥15%. Q-wave myocardial infarction was defined as the appearance of new pathologic Q waves in the coronary distribution of the treated artery with an increase of creatine kinase-MB to ≥2 times the reference values. Major adverse cardiac events (MACE) included death from all causes, Q-wave myocardial infarction, target vessel revascularization, and stent thrombosis. Target vessel revascularization was defined as revascularization occurring in any area along the previously treated vessel. Gastrointestinal bleeding was defined as clinical (“coffee grounds” emesis, melena, or hematochezia) or endoscopic evidence of an actively bleeding upper or lower site. Presumptive evidence included a decrease in hematocrit by 15 points without evidence of a vascular complication. Procedure-related renal insufficiency was defined as an in-hospital creatinine/preprocedure creatinine ratio >1.5.
Continuous variables are presented as the mean ± SD; categorical variables are presented as percentages. Differences in continuous variables between groups were compared using Student’s t test. Proportions were compared using the chi-square test or Fisher’s exact test, as appropriate. p Values <0.05 were considered statistically significant. To test the independent effect of PPI prescription at discharge on the time to an event, a Cox proportional hazard model for MACE was constructed. Covariates for the model were then selected for overall clinical relevance, with the proportional hazards assumption for each covariate tested. This included clopidogrel “compliance”; if a patient was not taking clopidogrel, the number of days since the patient had last taken clopidogrel was included as a time-dependent covariate. The covariates in the model are expressed as hazard ratios with 95% confidence intervals (CIs). Statistical analyses were performed using Statistical Analysis Systems, version 9.1 (SAS Institute, Cary, North Carolina).
Results
The present study included 820 patients who had undergone PCI with drug-eluting stents, of whom 318 (38.8%) were discharged with a PPI. Overall, 519 patients (63.3%) were men, 564 (68.8%) were white, 135 (16.5%) were African American, and 5 (0.6%) were Hispanic. The co-morbidities included a history of myocardial infarction in 200 (25.4%), a history of systemic hypertension in 620 (76.3%), and a history of diabetes mellitus in 281 (34.4%). A total of 74 patients (9.0%) underwent PCI for an acute myocardial infarction, and the average age at presentation was 63.8 ± 11.6 years. The baseline characteristics of the patients discharged with a PPI were roughly similar to those discharged without a PPI ( Table 1 ). The patients discharged with a PPI were more likely to have a diagnosis of hyperlipidemia (87.7% vs 82.4%, p = 0.04) and had lower baseline hematocrit values (38.7% vs 40.9%, p = 0.01). Patients discharged with a PPI were similar to patients discharged without a PPI in regard to the artery of intervention, stent type, stented length, and anticoagulation regimen ( Table 2 ). Of the 318 patients discharged with a PPI ( Table 3 ), 185 (58.2%) were discharged with esomeprazole, 41 (12.9%) were discharged with lansoprazole and omeprazole, 35 (11.0%) were discharged with pantoprazole, and 16 (5.0%) were discharged with rabeprazole. No significant differences were found by specific PPI prescribed in death, Q-wave myocardial infarction, target vessel revascularization, cumulative stent thrombosis, or overall MACE at 1 year.
| Variable | PPI at Discharge | p Value | |
|---|---|---|---|
| No (n = 502) | Yes (n = 318) | ||
| Men | 322 (64.1%) | 197 (61.9%) | 0.53 |
| White | 341 (67.9%) | 223 (70.1%) | 0.51 |
| African American | 87 (17.3%) | 48 (15.1%) | 0.40 |
| Asian | 64 (12.7%) | 37 (11.6%) | 0.64 |
| Hispanic | 4 (0.8%) | 1 (0.3%) | 0.65 |
| Age (years) | 63.7 ± 11.6 | 63.8 ± 11.6 | 0.94 |
| Acute coronary syndrome | 43 (8.6%) | 31 (9.7%) | 0.57 |
| Previous myocardial infarction | 114 (23.7%) | 86 (28.1%) | 0.17 |
| Previous coronary artery bypass surgery | 71 (14.2%) | 45 (14.2%) | 0.99 |
| Previous percutaneous coronary intervention | 112 (22.7%) | 78 (25.7%) | 0.34 |
| Diabetes mellitus | 166 (33.1%) | 115 (36.3%) | 0.36 |
| Systemic hypertension | 371 (74.8%) | 249 (78.5%) | 0.22 |
| Hyperlipidemia | 406 (82.4%) | 278 (87.7%) | 0.04 |
| Chronic renal insufficiency | 33 (6.6%) | 31 (9.7%) | 0.11 |
| Peripheral vascular disease | 74 (14.9%) | 48 (15.1%) | 0.91 |
| Congestive heart failure | 95 (21.1%) | 60 (20.8%) | 0.94 |
| Current smoker | 95 (18.9%) | 44 (13.8%) | 0.06 |
| Baseline hematocrit | 40.9 ± 17.9 | 38.7 ± 5.2 | 0.01 |
| Taking clopidogrel at admission | 51 (15.8%) | 37 (18.0%) | 0.51 |
| Variable | PPI at Discharge | p Value | |
|---|---|---|---|
| No (n = 502) | Yes (n = 318) | ||
| Target coronary vessel | |||
| Right | 285 (33.0%) | 171 (29.6%) | 0.18 |
| Left main | 13 (1.5%) | 10 (1.7%) | 0.74 |
| Left anterior descending | 332 (38.4%) | 228 (39.5%) | 0.68 |
| Left circumflex | 197 (22.8%) | 139 (24.1%) | 0.57 |
| Saphenous vein graft | 28 (3.2%) | 28 (4.9%) | 0.12 |
| Stent used | |||
| Cypher | 477 (95.0%) | 309 (97.2%) | 0.13 |
| Taxus | 5 (1.0%) | 2 (0.6%) | 0.71 |
| Stented length (mm) | 21.4 ± 6.0 | 21.3 ± 6.2 | 0.85 |
| Procedural success | 493 (98.2%) | 312 (98.1%) | 0.92 |
| Anticoagulant | |||
| Heparin | 133 (26.5%) | 80 (25.2%) | 0.67 |
| Bivalirudin | 288 (57.4%) | 189 (59.4%) | 0.56 |
| Glycoprotein IIb/IIIa inhibitor | 89 (18.1%) | 44 (14.1%) | 0.14 |
| Outcome | Esomeprazole (n = 185) | Lansoprazole (n = 41) | Omeprazole (n = 41) | Pantoprazole (n = 35) | Rabeprazole (n = 16) | p Value |
|---|---|---|---|---|---|---|
| Major adverse cardiac events | 28 (15.1%) | 4 (9.8%) | 8 (19.5%) | 2 (5.7%) | 2 (12.5%) | 0.44 |
| Death | 14 (7.6%) | 1 (2.4%) | 0 | 0 | 0 | 0.13 |
| Q-wave myocardial infarction | 0 | 0 | 0 | 0 | 0 | — |
| Target vessel revascularization | 14 (7.8%) | 3 (7.3%) | 8 (19.5%) | 2 (5.7%) | 2 (12.5%) | 0.19 |
| Cumulative stent thrombosis | 3 (1.6%) | 0 | 0 | 0 | 0 | 1.0 |
All patients were discharged with clopidogrel. With regard to in-hospital outcomes ( Table 4 ), the patients discharged with a PPI were more likely to have procedure-related renal insufficiency (4.0% vs 1.7%) and a longer length of stay (3.0 vs 2.2 days). No difference was found in the rates of gastrointestinal bleeding in-hospital (1.0% of patients overall). At 30 days, a trend for greater mortality in the PPI group emerged (1.3% vs 0.2%, p = 0.08); however, overall, very few MACE occurred (5 in the PPI group vs 3 in the no PPI group). At 1 year, univariate survival analysis of outcomes showed a greater rate of MACE in the PPI group (13.8% vs 8.0%; hazard ratio 1.8, 95% CI 1.2 to 2.7; Figures 1 and 2 ); the difference was highly significant (p = 0.009). Overall mortality was also greater in the PPI group (4.7% vs 1.8%, p = 0.02). Furthermore, a trend toward a greater incidence was seen of target vessel revascularization in the PPI group (9.2% vs 6.0%, p = 0.08). The rates of cumulative stent thrombosis were similar (0.9% vs 0.6%, p = 0.68), although only 6 stent thromboses in total occurred. After adjustment with multivariate Cox regression analysis ( Figure 3 ), the difference in MACE at 1 year between the patients discharged with a PPI and patients discharged without a PPI remained significant. The PPI at discharge was the only independent variable with a significant p value in the final model. The overall adjusted hazard ratio for PPI at discharge was 1.8 (95% CI 1.1 to 2.7, p = 0.01).
| Outcome | PPI at Discharge | p Value | |
|---|---|---|---|
| No (n = 502) | Yes (n = 318) | ||
| In-hospital | |||
| Discharged with Plavix | 502 (100%) | 318 (100%) | 1.0 |
| Q-wave myocardial infarction | 1 (0.2%) | 1 (0.3%) | 1.0 |
| Creatine kinase-MB >3× normal | 42 (8.4%) | 25 (7.9%) | 0.80 |
| Emergent coronary artery bypass surgery | 0 | 1 (0.3%) | 0.39 |
| Renal insufficiency | 8 (1.7%) | 12 (4.0%) | 0.05 |
| Gastrointestinal bleeding | 3 (0.6%) | 5 (1.6%) | 0.27 |
| Length of stay (SD) | 2.2 ± 2.1 | 3.0 ± 3.9 | <0.001 |
| 30-Day | |||
| Major adverse cardiac events | 3 (0.6%) | 5 (1.6%) | 0.27 |
| Death | 1 (0.2%) | 4 (1.3%) | 0.08 |
| Q-wave myocardial infarction | 1 (0.2%) | 0 | 1.0 |
| Target vessel revascularization | 1 (0.2%) | 1 (0.3%) | 1.0 |
| Cumulative stent thrombosis | 2 (0.4%) | 1 (0.3%) | 1.0 |
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