Individual Proton Pump Inhibitors and Outcomes in Patients With Coronary Artery Disease on Dual Antiplatelet Therapy: A Systematic Review.
ABSTRACT: Observational studies evaluating the possible interaction between proton pump inhibitors (PPIs) and clopidogrel have shown mixed results. We conducted a systematic review comparing the safety of individual PPIs in patients with coronary artery disease taking clopidogrel.Studies performed from January 1995 to December 2013 were screened for inclusion. Data were extracted, and study quality was graded for 34 potential studies. For those studies in which follow-up period, outcomes, and multivariable adjustment were comparable, meta-analysis was performed.The adjusted odds or hazard ratios for the composite of cardiovascular or all-cause death, myocardial infarction, and stroke at 1 year were reported in 6 observational studies with data on individual PPIs. Random-effects meta-analyses of the 6 studies revealed an increased risk for adverse cardiovascular events for those taking pantoprazole (hazard ratio 1.38; 95% CI 1.12-1.70), lansoprazole (hazard ratio 1.29; 95% CI 1.09-1.52), or esomeprazole (hazard ratio 1.27; 95% CI 1.02-1.58) compared with patients on no PPI. This association was not significant for omeprazole (hazard ratio 1.16; 95% CI 0.93-1.44). Sensitivity analyses for the coronary artery disease population (acute coronary syndrome versus mixed) and exclusion of a single study due to heterogeneity of reported results did not have significant influence on the effect estimates for any PPIs.Several frequently used PPIs previously thought to be safe for concomitant use with clopidogrel were associated with greater risk of adverse cardiovascular events. Although the data are observational, they highlight the need for randomized controlled trials to evaluate the safety of concomitant PPI and clopidogrel use in patients with coronary artery disease.
Project description:BACKGROUND:Proton-pump inhibitors (PPIs) and clopidogrel are frequently coprescribed, although the benefits and harms of their concurrent use are unclear. OBJECTIVE:To examine the association between concurrent use of PPIs and clopidogrel and the risks for hospitalizations for gastroduodenal bleeding and serious cardiovascular disease. DESIGN:Retrospective cohort study using automated data to identify patients who received clopidogrel between 1999 through 2005 after hospitalization for coronary heart disease. SETTING:Tennessee Medicaid program. PATIENTS:20,596 patients (including 7593 concurrent users of clopidogrel and PPIs) hospitalized for myocardial infarction, coronary artery revascularization, or unstable angina pectoris. MEASUREMENTS:Baseline and follow-up drug use was assessed from automated records of dispensed prescriptions. Primary outcomes were hospitalizations for gastroduodenal bleeding and serious cardiovascular disease (fatal or nonfatal myocardial infarction or sudden cardiac death, stroke, or other cardiovascular death). RESULTS:Pantoprazole and omeprazole accounted for 62% and 9% of concurrent PPI use, respectively. Adjusted incidence of hospitalization for gastroduodenal bleeding in concurrent PPI users was 50% lower than that in nonusers (hazard ratio, 0.50 [95% CI, 0.39 to 0.65]). For patients at highest risk for bleeding, PPI use was associated with an absolute reduction of 28.5 (CI, 11.7 to 36.9) hospitalizations for gastroduodenal bleeding per 1000 person-years. The hazard ratio associated with concurrent PPI use for risk for serious cardiovascular disease was 0.99 (CI, 0.82 to 1.19) for the entire cohort and 1.01 (CI, 0.76 to 1.34) for the subgroup of patients who had percutaneous coronary interventions with stenting during the qualifying hospitalization. LIMITATIONS:Unmeasured confounding and misclassification of exposure (no information on adherence or over-the-counter use of drugs) and end points (not confirmed by medical record review) were possible. Because many patients entered the cohort from hospitals with relatively few cohort members, the analysis relied on the assumption that after adjustment for observed covariates, PPI users from one such hospital could be compared with nonusers from a different hospital. CONCLUSION:In patients with serious coronary heart disease treated with clopidogrel, concurrent PPI use was associated with reduced incidence of hospitalizations for gastroduodenal bleeding. The corresponding point estimate for serious cardiovascular disease was not increased; however, the 95% CI included a clinically important increased risk. PRIMARY FUNDING SOURCE:Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute.
Project description:Background Prior reports indicate that the effect of P2Y12 inhibitors may be different in East Asian patients ("East Asian paradox"); therefore, understanding the outcomes associated with potent P2Y12 inhibitors in different populations is clinically important. Methods and Results In this observational cohort study using administrative healthcare data sets, we compared safety and effectiveness of contemporary P2Y12 inhibitors in patients with acute coronary syndrome. The primary safety outcomes were major and any bleeding, and the primary effectiveness outcomes were major cardiovascular events (a composite of cardiovascular death, myocardial infarction, or stroke) and all-cause mortality. Among 70 715 patients with acute coronary syndrome, 56 216 (79.5%) used clopidogrel, 11 402 (16.1%) used ticagrelor, and 3097 (4.4%) used prasugrel. The median follow-up period was 18.0 months (interquartile range: 9.6-26.4 months). In a propensity-matched cohort, compared with clopidogrel, ticagrelor was associated with a higher risk of any bleeding (hazard ratio: 1.23; 95% CI, 1.14-1.33) but a lower risk of mortality (hazard ratio: 0.76; 95% CI, 0.63-0.91). Prasugrel, compared with clopidogrel, was associated with higher risks of any bleeding (hazard ratio: 1.23; 95% CI, 1.06-1.43) and major bleeding (hazard ratio: 1.50; 95% CI, 1.01-2.21) but a similar risk of effectiveness outcomes. No significant difference was noted between ticagrelor and prasugrel with respect to key safety or effectiveness outcomes. Several sensitivity analyses showed similar results. Conclusions In East Asian patients with acute coronary syndrome, compared with clopidogrel, ticagrelor was associated with an increased risk of bleeding but a decreased risk of mortality. Prasugrel was associated with an increase of any bleeding without difference in effectiveness outcomes. The risks of bleeding and ischemic events were similar between ticagrelor and prasugrel.
Project description:Proton pump inhibitors (PPIs) reduce gastrointestinal bleeding events but may alter clopidogrel metabolism. We sought to understand the comparative effectiveness and safety of prasugrel versus clopidogrel in the context of proton pump inhibitor (PPI) use.Using data on 11 955 acute myocardial infarction (MI) patients treated with percutaneous coronary intervention at 233 hospitals and enrolled in the TRANSLATE-ACS study, we compared whether discharge PPI use altered the association of 1-year adjusted risks of major adverse cardiovascular events (MACE; death, MI, stroke, or unplanned revascularization) and Global Use of Strategies To Open Occluded Arteries (GUSTO) moderate/severe bleeding between prasugrel- and clopidogrel-treated patients. Overall, 17% of prasugrel-treated and 19% of clopidogrel-treated patients received a PPI at hospital discharge. At 1 year, patients discharged on a PPI versus no PPI had higher risks of MACE (adjusted hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.21-1.58) and GUSTO moderate/severe bleeding (adjusted HR 1.55, 95% CI 1.15-2.09). Risk of MACE was similar between prasugrel and clopidogrel regardless of PPI use (adjusted HR 0.88, 95% CI 0.62-1.26 with PPI, adjusted HR 1.07, 95% CI 0.90-1.28 without PPI, interaction P=0.31). Comparative bleeding risk associated with prasugrel versus clopidogrel use differed based on PPI use but did not reach statistical significance (adjusted HR 0.73, 95% CI 0.36-1.48 with PPI, adjusted HR 1.34, 95% CI 0.79-2.27 without PPI, interaction P=0.17).PPIs did not significantly affect the MACE and bleeding risk associated with prasugrel use, relative to clopidogrel.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01088503.
Project description:BACKGROUND:There is considerable debate about whether concomitant use of proton pump inhibitors (PPIs) should be recommended for patients who are prescribed clopidogrel after acute coronary syndrome. Most pharmacokinetic and pharmacodynamic studies in vivo were conducted using small sample sizes and were single centered, resulting in conflicting data. HYPOTHESIS:PPIs may attenuate the antiplatelet effect of clopidogrel in vivo and lead to an increased risk of cardiovascular events. METHODS:PubMed, the Cochrane Library, Embase, Web of Science, and China Biology Medicine Disc were searched. Randomized controlled trials that compared pharmacodynamic impacts of a PPI on the efficacy of clopidogrel in vivo were included. Two independent reviewers evaluated study quality and extracted data for meta-analysis. RESULTS:We identified 8 eligible studies. Compared to clopidogrel treatment alone, patients who received both a PPI and clopidogrel had less of a decrease in the platelet reactivity index (weighted mean difference [WMD]: 8.18; 95% confidence interval [CI]: 6.81-9.56; P<0.00001), less adenosine 5'-diphosphate-induced platelet aggregation inhibition (WMD: 7.28; 95% CI: 2.44-12.11; P=0.003), higher P2Y12 reaction units (WMD: 40.58; 95% CI: 19.31-61.86; P=0.0002), and higher risks of clopidogrel resistance (odds ratio [OR]: 2.49; 95% CI: 1.49-4.14; P=0.0005). There were no significant differences, however, for the incidences of major adverse cardiovascular events between the 2 groups (OR: 1.07; 95% CI: 0.44-2.59; P=0.88), and treatment with a PPI and clopidogrel significantly reduced the risk of adverse gastrointestinal events (OR: 0.16; 95% CI: 0.04-0.62; P=0.008). CONCLUSIONS:Concomitant use of a PPI with clopidogrel attenuated the antiplatelet effect of clopidogrel, but may be clinically unimportant because there were no clinical differences in the risk for major adverse cardiovascular events.
Project description:Proton-pump inhibitors (PPIs) seem to increase the incidence of cardiovascular events in patients with coronary artery disease (CAD), mainly in those using clopidogrel. We analysed the impact of PPIs on the prognosis of patients with stable CAD.We followed 706 patients with CAD. Primary outcome was the combination of secondary outcomes. Secondary outcomes were 1) acute ischaemic events (any acute coronary syndrome, stroke, or transient ischaemic attack) and 2) heart failure (HF) or death.Patients on PPIs were older [62.0 (53.0-73.0) vs. 58.0 (50.0-70.0) years; p = 0.003] and had a more frequent history of stroke (4.9% vs. 1.1%; p = 0.004) than those from the non-PPI group, and presented no differences in any other clinical variable, including cardiovascular risk factors, ejection fraction, and therapy with aspirin and clopidogrel. Follow-up was 2.2±0.99 years. Seventy-eight patients met the primary outcome, 53 developed acute ischaemic events, and 33 HF or death. PPI use was an independent predictor of the primary outcome [hazard ratio (HR) = 2.281 (1.244-4.183); p = 0.008], along with hypertension, body-mass index, glomerular filtration rate, atrial fibrillation, and nitrate use. PPI use was also an independent predictor of HF/death [HR = 5.713 (1.628-20.043); p = 0.007], but not of acute ischaemic events. A propensity score showed similar results.In patients with CAD, PPI use is independently associated with an increased incidence of HF and death but not with a high rate of acute ischaemic events. Further studies are needed to confirm these findings.
Project description:Background: Clopidogrel and proton pump inhibitors (PPIs) are metabolized by cytochrome P450 enzymes. Contradictory results have been reported on possible complications of simultaneous PPI and clopidogrel use. Our aim was to investigate the clinical relevance of this debate with a systematic review and meta-analysis. Methods: The PubMed, Embase, and Cochrane Central Register of Controlled Trials electronic databases were searched for human studies [randomized controlled trials (RCTs) and observational studies] using the PICO format (P: patients on clopidogrel; I: patients treated with PPI; C: patients without PPI treatment; O: cardiovascular risk). We screened eligible studies from 2009 to 2016. After study exclusions, we extracted data from 27 articles for three outcomes: major adverse cardiac event (MACE), myocardial infarction (MI) and cardiovascular (CV) death. The meta-analysis was registered on PROSPERO (CRD42017054316). Results: Data were extracted on 156,823 patients from the 27 trials included (MACE: 23, CV death: 10, MI: 14). The risks of MACE (RR = 1.22, 95% CI = 1.06-1.396, p = 0.004) and MI (RR = 1.43, 95% CI = 1.24-1.66, p < 0.001) were significantly higher in the PPI plus clopidogrel group. However, subgroup analysis demonstrated that this significance disappeared in RCTs (RR = 0.99, 95% CI = 0.76-1.28, p = 0.93) in the MACE outcome group. There was no effect of combined PPI and clopidogrel therapy on CV death outcome (RR = 1.21, 95% CI = 0.97-1.50, p = 0.09). Conclusion: Concomitant use of PPIs and clopidogrel has been proved not to be associated with elevated cardiovascular risks according to RCTs. Based on our results, no restrictions should be applied whenever PPIs and clopidogrel are administered simultaneously.
Project description:BACKGROUND:Low birthweight has been associated with a higher risk of hypertension, type 2 diabetes mellitus (T2D), and cardiovascular disease. The Barker hypothesis posits that intrauterine growth restriction resulting in lower birthweight is causal for these diseases, but causality is difficult to infer from observational studies. METHODS:We performed regression analyses to assess associations of birthweight with cardiovascular disease and T2D in 237?631 individuals from the UK Biobank. Further, we assessed the causal relationship of such associations using Mendelian randomization. RESULTS:In the observational analyses, birthweight showed inverse associations with systolic and diastolic blood pressure (?, -0.83 and -0.26; per raw unit in outcomes and SD change in birthweight; 95% confidence interval [CI], -0.90 to -0.75 and -0.31 to -0.22, respectively), T2D (odds ratio, 0.83; 95% CI, 0.79-0.87), lipid-lowering treatment (odds ratio, 0.84; 95% CI, 0.81-0.86), and coronary artery disease (hazard ratio, 0.85; 95% CI, 0.78-0.94), whereas the associations with adult body mass index and body fat (?, 0.04 and 0.02; per SD change in outcomes and birthweight; 95% CI, 0.03-0.04 and 0.01-0.02, respectively) were positive. The Mendelian randomization analyses indicated inverse causal associations of birthweight with low-density lipoprotein cholesterol, 2-hour glucose, coronary artery disease, and T2D and positive causal association with body mass index but no associations with blood pressure. CONCLUSIONS:Our study indicates that lower birthweight, used as a proxy for intrauterine growth retardation, is causally related with increased susceptibility to coronary artery disease and T2D. This causal relationship is not mediated by adult obesity or hypertension.
Project description:Prior Studies have suggested better outcomes in smokers compared with nonsmokers receiving clopidogrel ("smoker's paradox"). The impact of a more intensive clopidogrel regimen on ischemic and bleeding risks in smokers with acute coronary syndromes requiring percutaneous coronary interventions remains unclear.We analyzed 17 263 acute coronary syndrome patients undergoing percutaneous coronary intervention from the CURRENT-OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events-Seventh Organization to Assess Strategies in Ischemic Symptoms) trial, which compared double-dose (600 mg day 1;150 mg days 2-7; then 75 mg daily) versus standard-dose (300 mg day 1; then 75 mg daily) clopidogrel in acute coronary syndrome patients. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Interactions between treatment allocation and smoking status (current smokers versus nonsmokers) were evaluated. Overall, 6394 patients (37.0%) were current smokers. For the comparison of double- versus standard-dose clopidogrel, there were significant interactions in smokers and nonsmokers for the primary outcome (P=0.031) and major bleeding (P=0.002). Double- versus standard-dose clopidogrel reduced the primary outcome among smokers by 34% (hazard ratio [HR] 0.66, 95% confidence interval [CI], 0.50-0.87, P=0.003), whereas in nonsmokers, there was no apparent benefit (HR 0.96, 95% CI, 0.80-1.14, P=0.61). For major bleeding, there was no difference between the groups in smokers (HR 0.77, 95% CI, 0.48-1.24, P=0.28), whereas in nonsmokers, the double-dose clopidogrel regimen increased bleeding (HR 1.89, 95% CI, 1.37-2.60, P<0.0001). Double-dose clopidogrel reduced the incidence of definite stent thrombosis in smokers (HR 0.41, 95% CI, 0.24-0.71) and nonsmokers (HR 0.63, 95% CI, 0.42-0.93; P for interaction=0.19).In smokers, a double-dose clopidogrel regimen reduced major cardiovascular events and stent thrombosis after percutaneous coronary intervention, with no increase in major bleeding. This suggests that clopidogrel dosing in patients with acute coronary syndromes should be personalized, taking into consideration both ischemic and bleeding risk.URL: https://www.clinicaltrials.gov. Unique identifier: NCT00335452.
Project description:BACKGROUND: In Canada, access to clopidogrel is restricted by most provincial drug insurance plans in order to contain costs. Until April 2007, the Régie de l'assurance maladie du Québec (RAMQ) Prescription Drug Insurance Plan reviewed special access forms before approving reimbursement for clopidogrel prescriptions. We investigated the impact of this restrictive process on patient's filling of prescriptions and on all-cause mortality following coronary stenting. METHODS: We analyzed prescriptions filled and all-cause mortality in the year following a percutaneous coronary intervention among patients who underwent stent implantation between January 2000 and September 2004. We obtained administrative data from the RAMQ databases. We included patients who filled at least 1 prescription for a nonrestricted cardiovascular drug after hospital discharge. We used Cox proportional models to compare mortality rates as a function of delayed or absent outpatient clopidogrel therapy. RESULTS: Of 13,663 patients, 1571 (11.5%) did not fill any clopidogrel prescription despite filling at least 1 nonrestricted cardiovascular drug prescription after a percutaneous coronary intervention, and 1174 (8.6%) patients filled their clopidogrel prescription with a delay of at least 1 day (median delay 5 days) after filling the nonrestricted cardiovascular drug prescription. After controlling for pertinent covariables, not filling a clopidogrel prescription (hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.35-2.15) and filling with a delay (HR 1.34, 95% CI 1.01-1.80) were associated with a significant increase in all-cause mortality. INTERPRETATION: Restricted access to clopidogrel was associated with about 20% of patients either not receiving clopidogrel or receiving therapy after a delay. Delay or absence of clopidogrel therapy increased the risk of all-cause mortality after percutaneous coronary intervention with stenting.
Project description:Background:It has been reported that harmonics of radial pulse is related to coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). It is still unclear whether or not the first harmonics of the radial pulse spectrum is an early independent predictor of silent coronary artery disease (SCAD) and adverse cardiac events (ACE). Objectives:To measure the risk of SCAD in patients with T2DM and also to survey whether or not an increment of the first harmonic (C1) of the radial pulse increases ACE. Methods:1968 asymptomatic individuals with T2DM underwent radial pulse wave measurement. First harmonic of the radial pressure wave, C1, was calculated. Next, the new occurrence of ACE and the new symptoms and signs of coronary artery disease were recorded. The follow-up period lasted for 14.7 ± 3.5 months. Results:Out of 1968 asymptomatic individuals with T2DM, ACE was detected in 239 (12%) of them during the follow-up period. The logrank test demonstrated that the cumulative incidence of ACE in patients with C1 above 0.96 was greater than that in those patients with C1 below 0.89 (P < 0.01). By comparing the data of patients with C1 smaller than the first quartile and the patients with C1 greater than the third quartile, the hazard ratios were listed as follows: ACE (hazard ratio, 2.29; 95% CI, 1.55-3.37), heart failure (hazard ratio, 2.22; 95% CI, 1.21-4.09), myocardial infarction (hazard ratio, 2.44; 95% CI, 1.51-3.93), left ventricular dysfunction (Hazard ratio, 2.01; 95% CI, 0.86-4.70), and new symptoms and signs for coronary artery disease (hazard ratio, 2.03; 95% CI, 1.45-2.84). As C1 increased, the risk for composite ACE (P < 0.001 for trend) and for coronary disease (P < 0.001 for trend) also increased. The hazard ratio and trend for cardiovascular-cause mortality were not significant. Conclusions:This study showed that C1 of the radial pulse wave is correlated with cardiovascular events. Survival analysis showed that C1 value is an independent predictor of ACE and SCAD in asymptomatic patients with T2DM. Thus, screening for the first harmonic of the radial pulse may improve the risk stratification of cardiac events and SCAD in asymptomatic patients although they had no history of coronary artery disease or angina-related symptom.