Mette Charlot, MD; Ole Ahlehoff, MD; Mette Lykke Norgaard, MD; Casper H. Jørgensen, MD; Rikke Sørensen, MD; Steen Z. Abildstrøm, MD, PhD; Peter Riis Hansen, MD, PhD, DMSc; Jan Kyst Madsen, MD, DMSc; Lars Køber, MD, DMSc; Christian Torp-Pedersen, MD, DMSc; Gunnar Gislason, MD, PhD
This article has been corrected. For original version, click "Original Version (PDF)" in column 2.
Controversy remains on whether the dual use of clopidogrel and proton-pump inhibitors (PPIs) affects clinical efficacy of clopidogrel.
To examine the risk for adverse cardiovascular outcomes related to concomitant use of PPIs and clopidogrel compared with that of PPIs alone in adults hospitalized for myocardial infarction.
A nationwide cohort study based on linked administrative registry data.
All hospitals in Denmark.
All patients discharged after first-time myocardial infarction from 2000 to 2006.
The primary outcome was a composite of rehospitalization for myocardial infarction or stroke or cardiovascular death. Patients were examined at several assembly time points, including 7, 14, 21, and 30 days after myocardial infarction. Follow-up was 1 year.
Of 56 406 included patients, 9137 (16.2%) were re-hospitalized for myocardial infarction or stroke or experienced cardiovascular death. Of the 24 702 patients (43.8%) who received clopidogrel, 6753 (27.3%) received concomitant PPIs. The hazard ratio for cardiovascular death or rehospitalization for myocardial infarction or stroke for concomitant use of a PPI and clopidogrel among the cohort assembled at day 30 after discharge was 1.29 (95% CI, 1.17 to 1.42). The corresponding ratio for use of a PPI in patients who did not receive clopidogrel was 1.29 (CI, 1.21 to 1.37). No statistically significant interaction occurred between a PPI and clopidogrel (P = 0.72).
Unmeasured and residual confounding, time-varying measurement errors of exposure, and biases from survival effects were possible.
Proton-pump inhibitors seem to be associated with increased risk for adverse cardiovascular outcomes after discharge, regardless of clopidogrel use for myocardial infarction. Dual PPI and clopidogrel use was not associated with any additional risk for adverse cardiovascular events over that observed for patients prescribed a PPI alone.
The Danish Medical Research Council and the Danish Heart Foundation.
Observational studies show mixed signals about risk for cardiovascular events with the dual use of proton-pump inhibitors (PPIs) and clopidogrel compared with clopidogrel alone.
This observational study, based on administrative data from all hospitals in Denmark, found that patients who received clopidogrel and PPIs at discharge after a first-time myocardial infarction had similar risks for cardiovascular death, myocardial infarction, or stroke as did those of patients who received PPIs alone.
Possible confounding and no information on adherence or over-the-counter drug use limit interpretation.
Concurrent PPI and clopidogrel use after myocardial infarction may not be associated with additional risk over that observed with PPIs alone.
MI = myocardial infarction; PPI = proton-pump inhibitor.
Appendix Table 1.
Appendix Table 2.
Appendix Table 3.
Appendix Table 4.
PPI = proton-pump inhibitor.
Time-dependent, propensity score–matched Cox proportional hazards analysis. PPI = proton-pump inhibitor.
* Used as reference.
Size needed to account for the elevation of risk from 1 to 1.29. OREC = association between drug use category and confounder; RRCD = association between confounder and disease outcome.
Appendix Table 5.
Time-dependent, propensity score–matched Cox proportional hazards analysis. Diabetes was defined as requiring glucose-lowering medication. PCI = percutaneous coronary intervention; PPI = proton-pump inhibitor.
Proportion of patients, by individual hospital, who received clopidogrel (top) or a PPI (bottom) within 1 year of discharge after a myocardial infarction. Outliers are small hospitals with few patients. PPI = proton-pump inhibitor.
Appendix Table 6.
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Rajasree Pai Ramachandra Pai
Univeristy of Connecticut Health Center, Farmington
September 22, 2010
Incomplete and Inconclusive
A comparison between the different PPIs would have been more helpful in making conclusions here as different PPIs have different levels of interactions with clopidogrel. The mechanisms of drug interaction is also of interest in this era of polypharmacy
St. Luke's-Roosevelt Hospital Center, NY, NY ; Beth-Israel/Long Island college hospital, Brooklyn, N
October 7, 2010
Clopidogrel and PPI: Importance of Smoking in Studies with Cardiovascular Outcomes
This letter is in reference to the recent article by the Charlot et al, "Proton-Pump Inhibitors Are Associated With Increased Cardiovascular Risk Independent of Clopidogrel Use: A Nationwide Cohort Study" September 21, 2010 vol. 153 no. 6 378-386 (1). The authors have tried to study a very important and controversial subject which is of great concern in cardiovascular patients. Gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD) and its complications namely, upper gastrointestinal bleeding is a very prevalent condition all over the world. Approximately 7% of US population suffers from symptoms of GERD/PUD. GERD and PUD and bleeding complications lead to significant mortality and impair quality of life (2). Apart from decreasing rebleeding rates and mortality in acute bleeding in peptic ulcer disease, proton pump inhibitors (PPI's) have also shown to decrease the symptoms, decrease mortality increase quality adjusted life years and shown to be cost- effective for GERD (3) More than 60 million prescriptions for GERD were estimated to have been filled at retail pharmacies in 2004 (2). Coronary artery disease is equally prevalent and this study raises serious questions in regards to prescribing PPI's with concomitant clopidogrel or for that matter as the authors hinted, PPI's at all in patients with history of coronary artery disease. First of all, there are many similarities in the demographics of these 2 conditions. The significant ones are they are more prevalent in age >65, and common risk factors like smoking (4,5) and obesity (6).
Coming back to the study, Charlot et al have collected this massive database from registry and performed a propensity score matched analyses. The most important variable in cardiovascular outcomes has been smoking and body mass index. The authors did not mention anywhere the history of smoking and body mass index. The authors do mention in their limitations, but this a major flaw in the study. As we already know they both have high risk of cardiovascular death (CVD) and reflux disease, hence the bias. Moreover, smoking can cause relative risk of CVD as high as 3 times more than non-smokers which can explain such a high association of PPI use and CVD in these patients. Apart from smoking and obesity in terms of confounders, there are other associations such as history of non-steroidal anti-inflammatory medications and GERD.
It is interesting to see the risk of cardiovascular death was mostly contributed with strokes and less with myocardial infarction, hazard ratio: 1.36 vs. 1.13 respectively, in patients without clopidogrel. A recent study assessing association with reflux esophagitis and risk of stroke by Sheu et al (7) showed increased risk of stroke associated with patients with history of reflux esophagitis. Surprisingly, history of smoking was not reported by Sheu et al too, nor were the results adjusted for history of smoking. This implies that if there is a true association, the risk is definitely higher for stroke than for MIs, which should be evaluated further.
Before this cohort study, many other observational, propensity matched studies and randomized controlled trials have yield varied results. A meta-analysis of 13 of the studies showed no significant association between PPI use and overall mortality, however (relative risk 1.09; 95% CI 0.94-1.26; p=0.23), (8) shown in this meta-analyses, the upper limit of point estimate is not more than 26%. Furthermore, the mean (SD) duration of therapy with PPI in patients without clopidogrel in the study by Charlot et al is 147 days (120 days) or 5 months. This is considerably longer than usual duration, as AGA recommends therapy in GERD for approximately 2-3 months and life style modifications. In persistence of symptoms, chronic PPI therapy for 6 months and/or surgical options (3,9). FDA did go over the board in limiting use of concomitant PPI and clopidogrel use without definite evidence.
With the results of this study, we conclude that; smoking is a very important risk factor for CVD outcomes and every study assessing CVD outcomes should include smoking as a covariate. The affects seen in the study by Charlot et al can be explained by smoking and obesity as a confounding variable. Prior meta-analyses have failed to prove PPI as an independent risk factor for CVD outcomes. Finally, physicians should not hesitate to prescribe a PPI to patients with cardiovascular disease who definitely need it, with considerable attention to the duration of therapy until we get a definite answer from a randomized controlled clinical trial.
References: 1. Charlot M, Ahlehoff O, Norgaard ML, Jorgensen CH, Sorensen R, Abildstrom SZ, Hansen PR, Madsen JK, Kober L, Torp-Pedersen C, Gislason G. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med;153:378-86.
2. Everhart JE, Ruhl CE. Burden of digestive diseases in the United States part I: overall and upper gastrointestinal diseases. Gastroenterology 2009;136:376-86.
3. Arguedas MR, Heudebert GR, Klapow JC, Centor RM, Eloubeidi MA, Wilcox CM, Spechler SJ. Re-examination of the cost-effectiveness of surgical versus medical therapy in patients with gastroesophageal reflux disease: the value of long-term data collection. Am J Gastroenterol 2004;99:1023-8.
4. Pandolfino JE, Kahrilas PJ. Smoking and gastro-oesophageal reflux disease. Eur J Gastroenterol Hepatol 2000;12:837-42.
5. Kahrilas PJ, Gupta RR. Mechanisms of acid reflux associated with cigarette smoking. Gut 1990;31:4-10.
6. Hampel H, Abraham NS, El-Serag HB. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications. Ann Intern Med 2005;143:199-211.
7. Sheu JJ, Kang JH, Lou HY, Lin HC. Reflux esophagitis and the risk of stroke in young adults: a 1-year population-based follow-up study. Stroke;41:2033-7.
8. Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Ther;31:810-23.
9. Kahrilas PJ, Shaheen NJ, Vaezi MF, Hiltz SW, Black E, Modlin IM, Johnson SP, Allen J, Brill JV. American Gastroenterological Association Medical Position Statement on the management of gastroesophageal reflux disease. Gastroenterology 2008;135:1383-1391, 1391 e1-5.
Division of Gastroenterology, Yokohama Minami-kyosai Hospital
October 16, 2010
TO THE EDITOR:
I read the article by Charlot and colleagues (1) with great interest. If proton-pump inhibitors (PPIs) are associated with an increased risk of cardiovascular events, the possibility exists that PPIs may have an impact on atherosclerosis. In this connection, I have reported in Japanese that PPIs provoke an elevation in brachial-ankle pulse wave velocity (baPWV), which is proportional to atherosclerosis progression, in patients with reflux esophagitis (2). In this preliminary study, 12 patients treated with PPIs exhibited an increase in their baPWV from 1648 cm/sec to 1670 cm/sec (P<0.05, Wilcoxon signed-ranks test) after 2 months of treatment and 1769cm/sec (P<0.05) 12 months of treatment. Histamine 2- receptor antagonist (H2RA) was administered to another six patients, and their baPWV likewise increased from 1658 cm/sec at baseline to 1745 cm/sec (P<0.05) after 2 months of treatment. Thus the inhibition of gastric acid secretion seems to influence the baPWV and atherosclerosis, although the mechanism remains obscure. Recently, Blackburn and colleagues showed an increased use of PPIs and H2RAs prior to the occurrence of ischemic events (3), passively supporting the hypothesis that gastric acid suppression may be a risk factor for atherosclerosis.
-Fumio Suzaki, MD, Division of Gastroenterology, Yokohama Minami- kyosai Hospital, Yokohama 2360037, Japan
1. Charlot M, Ahlehoff O, Norgaard ML, J?gensen CH, S?rensen R, Abildstr?m SZ,et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med. 2010 Sep 21; 153(6):378-86. [PMID: 20855802] PubMed
2. Suzaki F , Sugiyama M. Progress of Atherosclerosis in Patients with Reflux Esophagitis by Proton Pump Inhibitor. Prog Med. 2007; 27(3):606-609 (Japanese)
3. Blackburn DF, Lamb DA, Mcleod MM, Eurich DT. Increased use of acid -suppressing drugs before the occurrence of ischemic events: a potential source of confounding in recent observational studies. Pharmacotherapy. 2010 Oct;30(10):985-93. [PMID: 20874035 ] PubMed
Charlot M, Ahlehoff O, Norgaard ML, Jørgensen CH, Sørensen R, Abildstrøm SZ, et al. Proton-Pump Inhibitors Are Associated With Increased Cardiovascular Risk Independent of Clopidogrel Use: A Nationwide Cohort Study. Ann Intern Med. ;153:378–386. doi: 10.7326/0003-4819-153-6-201009210-00005
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Published: Ann Intern Med. 2010;153(6):378-386.
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