Clopidogrel + PPI

[Yariko]

Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis
J. M. Siller-Matula1, B. Jilma1, K. Schrör2, G. Christ3, K. Huber4

Objective: To investigate whether proton pump inhibitors (PPIs) negatively affect clinical outcome in patients treated with clopidogrel.
Methods: Systematic review and meta-analysis. Outcomes evaluated were combined major adverse cardiac events (MACE), myocardial infarction, stent thrombosis, death and gastrointestinal bleeding. Studies included were randomised trials or post-hoc analyses of randomised trials and observational studies reporting adjusted effect estimates.
Results: Twenty five studies met the selection criteria and included 159,138 patients. Administration of PPIs together with clopidogrel corresponded to a 29% increased risk of combined major cardiovascular events (risk ratio RR=1.29, 95%CI=1.15-1.45) and a 31% increased risk of myocardial infarction (RR=1.31, 95%CI=1.12-1.53). In contrast, PPI use did not negatively influence the mortality (RR=1.04, 95%CI=0.93-1.16), whereas the risk to develop a gastrointestinal bleeding under PPI treatment decreased by 50% (RR=0.50, 95%CI=0.37-0.69). The presence of a significant heterogeneity might indicate that the evidence is biased, confounded or inconsistent. The sensitivity analysis, however, yielded that the direction of the effect remained unchanged irrespective of the publication type, study quality, study size or risk to develop an event. Two studies indicate that PPIs have a negative effect irrespective of clopidogrel exposure.
Conclusions: Concomitant PPI use might be associated with an increased risk of cardiovascular events but does not influence the risk of death. Prospective randomised trials are required to investigate whether a cause-and-effect relationship truly exists and to explore whether different PPIs worsen clinical outcome in clopidogrel treated patients as the PPI-clopidogrel drug-drug interaction seems not to be a class effect.
[Ссылки доступны только зарегистрированным пользователям ]

[Maltsev]

[Ссылки доступны только зарегистрированным пользователям ]

News Author: Fran Lowry
CME Author: Laurie Barclay, MD


CME Released: 09/27/2010; Valid for credit through 09/27/2011

September 27, 2010 — Proton pump inhibitors (PPIs) are associated with an increased risk for adverse cardiovascular outcomes independent of clopidogrel use in patients who have had a myocardial infarction (MI), according to a new study published in the September 21 issue of the Annals of Internal Medicine.

The study, by Mette Charlot, MD, from Copenhagen University Hospital Gentofte, Hellerup, Denmark, and colleagues, also found that concomitant PPI and clopidogrel use was not associated with any additional risk for adverse cardiovascular events vs that observed for patients prescribed a PPI alone.

"...PPIs are often given in combination with clopidogrel and aspirin to reduce the risk for upper gastrointestinal bleeding," write Dr. Charlot and colleagues. "Clinical studies involving selected populations show conflicting results regarding risk for adverse cardiovascular events associated with the dual use of clopidogrel and PPIs."

The study authors note that the US Food and Drug Administration and the European Medicines Agency have discouraged the combined use of these drugs unless strongly indicated and emphasize the need for further studies.

In this study, the investigators sought to examine the risk for adverse cardiovascular outcomes related to concomitant use of PPIs and clopidogrel vs use of PPIs alone in a large, unselected cohort of patients who were hospitalized with first-time MI.

They used Danish national administrative databases to identify all consecutive patients 30 years and older who were hospitalized with acute MI between 2000 and 2006 and who survived for at least 30 days.

The primary outcome was a composite of rehospitalization for MI or stroke or cardiovascular death. Patients were examined 7, 14, 21, and 30 days after MI and were then observed for 1 year.

Of the 56,406 patients in the analysis, 9137 (16.2%) died from cardiovascular causes or were rehospitalized for MI or stroke. Clopidogrel was associated with lower event rates, and PPIs were associated with higher event rates. The event rates were highest among patients who received a PPI but not clopidogrel (26.3%), the study authors report.

Overall, 43.8% of the study cohort received clopidogrel, and 27.3% also received concomitant PPIs. The hazard ratio (HR) for the primary endpoint for concomitant use of a PPI and clopidogrel at day 30 after discharge from the hospital was 1.29 (95% confidence interval [CI], 1.17 - 1.42; P < .001). The HR for use of a PPI without clopidogrel was 1.29 (95% CI, 1.21 - 1.37; P < .001). There was no statistically significant interaction between a PPI and clopidogrel (P = .72).

However, there was a statistically significant interaction between percutaneous coronary intervention (PCI) and PPIs in the group that received clopidogrel. In this group, there was a statistically significant higher risk for cardiovascular death or rehospitalization for MI or stroke in patients who had PCI (HR, 1.40; 95% CI, 1.19 - 1.64) vs patients who did not have PCI (HR, 1.21; 95% CI, 1.07 - 1.38).

"Our study furthers the research in this area by investigating the risk for cardiovascular events in a nationwide, unselected population that represents the average patient who has had a myocardial infarction," the study authors write. "We suspect that the increased cardiovascular risk in all patients who received a PPI can be explained by differences in baseline comorbid conditions that were unmeasured or measured imperfectly," they add.

The study authors caution that these data from a mostly white study population may not be generalizable to other racial and ethnic groups. Also, information on the indications for PPI therapy was lacking.

"In conclusion, PPIs seem to be associated with an increased risk for adverse cardiovascular outcomes regardless of clopidogrel use, but concomitant PPI and clopidogrel use was not associated with any additional increase in risk over that observed for patients who received a PPI alone," the study authors write, adding: "These results seem to refute concerns about increased risk for ischemic events during concomitant PPI and clopidogrel therapy."

Editorial: Reflection on Regulatory Decisions

In an accompanying editorial, João Paulo de Aquino Lima, MD, from the Federal University of Ceará School of Medicine, Fortaleza, Brazil, and James M. Brophy, MD, PhD, from McGill University, Montreal, Canada, write that regulatory and cardiovascular specialists may be less convinced of the intrinsic value of PPIs. They also point out that the role of clopidogrel "is no longer sacrosanct" as the expiration of its patent approaches and as more potent antiplatelet agents such as prasugrel and ticagrelor come on the market.

"The unflattering episodes of cardiovascular drug safety with rofecoxib and rosiglitazone may also account for a regulatory willingness to accept less stringent evidence and to be perceived as proactive," they write.

The study indicates that the existing regulatory decisions are based on a lack of quality clinical studies and rely instead on in vitro platelet inhibition studies, which can be unreliable in cardiovascular medicine. "Unbiased science should be the final arbiter in determining the risk for any putative drug interaction, but the modulating role that the social, cultural, economic, and political context in which medicine and clinical research is practiced should be appreciated," the editorialists conclude.

The Danish Medical Research Council and the Danish Heart Foundation supported this study. A complete description of disclosure information for the study authors is available here . Dr. Lima and Dr. Brophy have disclosed no relevant financial relationships.

Ann Intern Med. 2010;153:378-386, 413-415. Abstract

Clinical Context

Clopidogrel, a platelet inhibitor that lowers the risk for new ischemic cardiovascular events when given with aspirin, is often prescribed to patients after an MI. To lower the risk for upper gastrointestinal tract bleeding, PPIs are often prescribed along with clopidogrel and aspirin.

Whether the concomitant use of clopidogrel and PPIs affects the clinical efficacy of clopidogrel is unclear. Because of concerns regarding the risk for MI and other adverse cardiovascular reactions, the US Food and Drug Administration and the European Medicines Agency recently warned against the combined use of PPIs and clopidogrel except for patients in whom the indication for simultaneous use of these drugs is very strong.

Study Highlights

• The goal of this nationwide cohort study was to assess the risk for adverse cardiovascular outcomes associated with concomitant use of PPIs and clopidogrel vs PPIs alone in adults hospitalized for MI.
• Using linked administrative registry data from all hospitals in Denmark, the investigators identified all patients discharged from 2000 to 2006 after first-time MI.
• The main study endpoint was a composite of rehospitalization for MI or stroke or cardiovascular death.
• Follow-up evaluations were performed at 7, 14, 21, and 30 days after MI and at various other time points through 1 year.
• Rehospitalization for MI or stroke or cardiovascular death occurred in 9137 (16.2%) of 56,406 included patients.
• Concomitant PPIs were prescribed to 6753 (27.3%) of 24,702 patients (43.8%) who received clopidogrel.
• There was a reduction in the risk for gastrointestinal tract bleeding related to PPI therapy for patients who received clopidogrel, but this reduction was not statistically significant.
• Among the participants evaluated at day 30 after discharge, the HR for cardiovascular death or rehospitalization for MI or stroke associated with concomitant use of a PPI and clopidogrel was 1.29 (95% CI, 1.17 - 1.42; P < .001).
• For use of a PPI in patients who did not receive clopidogrel, the corresponding HR was 1.29 (95% CI, 1.21 - 1.37; P < .001).
• There was no statistically significant interaction between use of a PPI and use of clopidogrel (P = .72).
• There was no evidence of differences in risk among the subtypes of PPIs, with or without clopidogrel.
• There was also no evidence of differences in risk related to heart failure, diabetes, age, hospitals, or PPI dosages.
• However, there was a statistically significant interaction between PCI and PPIs in the group that received clopidogrel.
• In this group, there was a statistically significant higher risk for cardiovascular death or rehospitalization for MI or stroke in patients who had PCI (HR, 1.40; 95% CI, 1.19 - 1.64) vs patients who did not have PCI (HR, 1.21; 95% CI, 1.07 - 1.38).
• On the basis of these findings, the investigators concluded that regardless of clopidogrel use for MI, PPIs seem to be linked to an increased risk for adverse cardiovascular outcomes after discharge but that dual use of PPIs and clopidogrel was not associated with any additional risk for adverse cardiovascular events vs that observed for patients prescribed a PPI alone.
• Limitations of this study include possible unmeasured and residual confounding, time-varying measurement errors of exposure, lack of data on adherence or over-the-counter drug use, and biases from survival effects.

Clinical Implications

Regardless of clopidogrel use, PPI use was linked to an increased risk for adverse cardiovascular outcomes after hospital discharge for a first MI, based on a nationwide Danish cohort study.
In a nationwide Danish cohort study, dual use of PPIs and clopidogrel was not associated with any additional risk for adverse cardiovascular events vs that observed for patients prescribed a PPI alone.

[Abugov]

COGENT Published: No Adverse Interaction Between Omeprazole, Clopidogrel
By Jason Kahn

Despite contrary data from numerous observational and platelet reactivity studies, results from a large, randomized trial show no adverse clinical…

[Rodionov]

И вот еще лыко в строку: последний NEJM: [Ссылки доступны только зарегистрированным пользователям ]

Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI.

[Abugov]

Khomitskaya одобрил(а): Сергей Александрович, уже неоднократно COGENT в этой теме выкладывали

Виноват, исправлюсь.

[Yariko]

В продолжение темы о снижении GI bleeding [Ссылки доступны только зарегистрированным пользователям ]

Outcomes With Concurrent Use of Clopidogrel and Proton-
Pump Inhibitors A Cohort Study
Wayne A. Ray, PhD; Katherine T. Murray, MD; Marie R. Griffin, MD, MPH; Cecilia P. Chung, MD, MPH; Walter E. Smalley, MD, MPH; Kathi Hall, BS; James R. Daugherty, MS; Lisa A. Kaltenbach, MS; and C. Michael Stein, MB, ChB
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.
Ann Intern Med. 2010;152:337-345.

[Pakhomov]

мои 5 копеек в обшую дискусиию: Исследование COGENT: Ведущий исследователь говорит, что он будет использовать ИПП у пациентов находящихся на двойной антитромбоцитарной терапии.
[Ссылки доступны только зарегистрированным пользователям ]
Он добавил: " Но главной целью исследования являлось предоставление данных для доказательства того что профилактический прием ИПП снижает риск гастроинтестинальных кровотечений у пациентов получающих двойную антитромбоцитарную терапию. Я думаю что это было упущено, т.к. основное внимание конечно было сфокусировано на взаимодействии clopidogrel-ИПП. Это первое рандомизированное клиническое исследование которое показало что профилактический прием ИПП действительно уменьшает гастроинтестинальные кровотечения. И что было показано впервые так это то что ИПП уменьшают рецидивы гастроинтестинальных кровотечений у пациентов которые уже имели случаи гастроинтестинальных кровотечений, но эти данные были получены у пациентов которые имели неособенно высокий риск гастроинтестинальных кровотечений. Вот основное сообщение исследования COGENT." .....
" Я думаю, что это исследование дает убедительные доказательства, что следует использовать профилактический прием ИПП в настоящее время у пациентов, у которых используется двойная антитромбоцитарная терапия. Но я не говорю врачам, что они должны это применять в своей собственной практике, я же теперь буду использовать ИПП у своих пациентов находящихся на двойной антитромбоцитарной терапии с целью сокращения ГИ кровотечений основываясь на этих результатах."

[Gilarov]

Опубликованы результаты COGENT
[Ссылки доступны только зарегистрированным пользователям ]

[Gilarov]

Опубликован апдейт консенсуса по празолам и тиенопиридинам:
[Ссылки доступны только зарегистрированным пользователям ]

[Yariko]

Консенсус очень порадовал, абсолютно совпал с моим представлением об этом вопросе

[Gilarov]

Новая смелая теория взаимодействия PPI и клопидогрела
March 11, 2011 (Dallas, Texas) — Authors of yet another analysis trying to get to the bottom of the real or perceived risk of combining clopidogrel with a proton-pump inhibitor (PPI) have a new and provocative theory as to just where the signal of increased events may be coming from [1].

Writing in the March 15, 2011 issue of the American Journal of Cardiology, Dr Subhash Banerjee (Veterans Affairs North Texas Health Care System, Dallas) and colleagues saw no differences in one- and six-year major adverse cardiac event (MACE) rates among their series of propensity-matched, post-PCI patients taking both clopidogrel and a PPI vs those taking clopidogrel alone. But what they did see was that many of the patients who went on to have a MACE while taking both clopidogrel and a PPI had filled prescriptions for nitroglycerin and a first-time or alternate PPI within 30 days of their adverse event.

They propose that physicians faced with a patient complaining of nonspecific chest pain or epigastric discomfort sometimes hedge their bets by prescribing both an antianginal drug and a PPI. And in some of these cases, those symptoms are a harbinger of the coming MACE. As such, PPIs aren't a causal factor but rather a marker for what they term "misindication bias."

"We just had this gut feeling, after observing how patients are put on and off PPIs, that physicians were prescribing a PPI concomitantly with antianginal drugs, because there is huge misdiagnosis of angina, which is often due to confusion with gastroesophageal reflux disease or other epigastric-discomfort–like symptoms that are treated very commonly with antacids and PPIs," Banerjee told heartwire . "What we found is that 30 days prior to a MACE event, rescue use of nitroglycerin was significantly higher in patients who were on a PPI vs those who are not, suggesting that these patients were having [cardiac] symptoms 30 days before their MACE events and that those symptoms were not always being recognized."

Banerjee and his coauthors point out that most studies looking for an interaction between clopidogrel and PPIs have looked only at discharge medications, rather than trying to understand drug prescription and adherence patterns in the months and years postdischarge. COGENT, the only randomized clinical trial comparing the two strategies, was stopped prematurely but found no increased risk of concomitant drug use. For their study, they looked at rates of all-cause death, nonfatal MI, repeat revascularization, and MACE combined over a six-year period among 23 200 post-PCI patients, all of whom were discharged with a clopidogrel prescription. They then used pharmacy databases to gauge whether patients continued to fill their clopidogrel prescriptions over time and whether they were also getting prescriptions for PPIs and other drugs.
[Ссылки доступны только зарегистрированным пользователям ]

[Yariko]

Subject

Arch Med Res. 2012 May 4.
Adverse Cardiovascular Effects of Concomitant Use of Proton Pump Inhibitors and Clopidogrel in Patients with Coronary Artery Disease: A Systematic Review and Meta-Analysis.
Huang B, Huang Y, Li Y, Yao H, Jing X, Huang H, Li J.
SourceDepartment of Cardiology, West China Hospital, Sichuan University, Chengdu, China.

Abstract
BACKGROUND AND AIMS: Conclusions from clinical studies and previous meta-analyses were inconsistent regarding the cardiovascular effects of concomitant use of proton pump inhibitors (PPIs) and clopidogrel. As new studies are constantly emerging, we performed this meta-analysis to further assess the cardiovascular effects of concomitant use of PPIs and clopidogrel with a focus on individual PPIs.

METHODS: A systematic electronic literature search was conducted in EMBASE, MEDLINE, PubMed and Chinese Biomedical Literature Database(CBM) to identify the studies reporting on the association of concomitant use of PPIs and clopidogrel with adverse cardiovascular outcomes. A hand search of reference lists was performed to identify further studies. Only studies published in English or Chinese were included in this review.

RESULTS: Twenty seven full-text articles and five abstracts with 159,998 patients were included in meta-analysis. Concomitant use of PPIs and clopidogrel is associated with an increased risk of major cardiovascular events (MACE) (HR 1.40, 95% CI 1.19-1.64; OR 1.27, 95% CI 1.13-1.42) and acute coronary syndrome (HR 1.42, 95% CI 1.14-1.77; OR 1.42, 95% CI 1.08-1.87) but not with all-cause mortality (HR 1.30, 95% CI 0.91-1.86; OR 0.92, 95% CI 0.82-1.04), cardiovascular death (HR 1.21, 95% CI 0.60-2.43) and stent thrombosis (HR 1.52, 95% CI 0.87-2.65). In the analyses of individual PPIs, none of the PPIs is associated with an increased MACE risk except for pantoprazole (HR 1.52, 95% CI 1.18-1.94).

CONCLUSIONS: Concomitant use of PPIs and clopidogrel in patients with coronary artery disease is associated with an increased risk of MACE or acute coronary syndrome, but there is insufficient evidence to conclude that there is an interaction between individual PPIs and clopidogrel.

Copyright © 2012 IMSS. Published by Elsevier Inc. All rights reserved.

PMID: 22564422 [PubMed - as supplied by publisher]

[Yariko]

Bhurke SM, Martin BC, Li C, et al. Effect of the clopidogrel-proton pump inhibitor drug interaction on adverse cardiovascular events in patients with acute coronary syndrome. Pharmacotherapy 2012; 32(9): 809-18

Objective: To determine the effect of the drug interaction between PPIs and clopidogrel on the risk of an adverse CV event.
•Methods:
– Design: Population-based, retrospective cohort study of a US claims database.
– Patients: 10,101 patients with a diagnosis of ACS between 2001 and 2008, and who had their first clopidogrel prescription within 90 days of diagnosis.
– Analyses: Patients were stratified according to concurrent use of a PPI (esomeprazole, lansoprazole, omeprazole, pantoprazole or rabeprazole) or clopidogrel alone.
– Main endpoint: Rate of adverse CV events during mean follow-up of 268 days.
•Key Results:
– Concurrent use of clopidogrel plus a PPI was associated with a significant increase in risk of an adverse CV event versus clopidogrel alone (adjusted HR = 1.277).
• Clinical implication: PPIs reduce the antiplatelet efficacy of clopidogrel and clinicians may need to prescribe the concurrent use of these two drugs cautiously.