Further information: Medical Treatment of Unstable Angina, Acute Non–ST-Elevation Myocardial Infarction, and Coronary Artery Spasm (see p937) and Percutaneous Coronary Intervention for Unstable Coronary Artery Disease (see p1005) from Cardiovascular Medicine, 3rd Edn*

In August of 2009, a summary of an article published in JAMA [1] was posted on this website [2].  The article addressed the possibility of adverse effects occurring in patients who used clopidogrel and proton pump inhibitors (PPIs) together, with the primary concern being that the effectiveness of clopidogrel could be reduced, leaving patients at risk of thrombotic events.  During the American Heart Association 2009 Scientific Sessions in Orlando, FL, November 14–18, 2009, the Food and Drug Administration (FDA) issued a new public-health warning [3] that reinforced the concern regarding adverse reactions.  Several clinical investigators who were interviewed in Orlando expressed surprise over the FDA’s newly issued warning, citing several randomized trials whose results had not shown an indication of adversity.  The statement by the FDA recommended that patients taking clopidogrel should consult their healthcare provider before also taking a PPI, such as omeprazole.  An article [4] and editorial [5] recently published in Circulation are abstracted and cited here and add additional information to the controversy.

In view of the controversy surrounding the safety issues for patients using clopidogrel and a PPI together, investigators conducted a retrospective study [4] conducted from three large databases in order to address study design issues in an effort to determine whether a higher rate of adverse outcomes occurred in patients taking clopidogrel and PPIs versus patients taking clopidogrel alone.  Included in the current study were patients enrolled in the following programs: the Provincial Healthcare System funded by the British Columbia government; the Pharmaceutical Assistance Contract for the Elderly in Pennsylvania; and the Pharmaceutical Assistance to the Aged and Disabled in New Jersey.  In all, there were 64,561 patients of 65 years of age and over in the  cohort who underwent percutaneous coronary intervention or hospitalization for acute coronary syndrome between 2001 and 2005, and the results of the study showed a modest increase in risk of hospitalization or death from myocardial infarction (MI), but with wide confidence intervals and no substantial or statistically significant clopidogrel-PPI interaction, leading the authors to believe that the studies using conventional adjustment may not have adequately accounted for confounding in this treatment group.  In this study, the investigators employed a more extensive confounding adjustment and verified that after adjustment, the PPI users were not significantly more likely to be at increased risk for MI or death, and not likely to exceed a 20% risk increase.

In an editorial [5] that accompanied this article, the author studied the entire body of evidence and concluded that while he believed there was no doubt that a pharmacological interaction existed, the issue was not one of clinical relevance.  The majority of patients are not threatened by the interaction.  However, there are unidentifiable patients who would be adversely affected by the combined use of clopidogrel and a PPI because of their genetic profiles, other currently taken drugs, or with other comorbidities, and therefore, until further information can be obtained, caution in prescribing the use of the two drugs together should be exercised.

[1] Ho M, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary symptoms. JAMA 2009;301:937-44

[2] Risk of Adverse Outcomes Associated with Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following ACS. http://cardiovascular-medicine.com/?p=178

[3] Food and Drug Administration. Public-health advisory: Updated safety information about a drug interaction between clopidogrel bisulfate (marketed as Plavix) and omeprazole (marketed at Prilosec and Prilosec OTC). http://www.fda.gov/Drugs/drugsafety/publichealthadvisories/ucm190825.htm November 17, 2009

[4] Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation 2009;120:2322-29

[5] Juurlink DN. Proton pump inhibitors and clopidogrel: putting the interaction in perspective. Circulation 2009;120:2310-12

Further information: Regulation of Cardiac Contraction and Relaxation (see p1189) from Cardiovascular Medicine, 3rd Edn*

From 1996 to 2000, 8290 patients were enrolled in a clinical trial titled, “Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE),” [1] to evaluate the use of ACE inhibitors in patients with stable coronary artery disease (CAD). Recently, the PEACE investigators used a subset of those patients to determine whether or not the risk of future cardiovascular events could be detected in patients who had stable coronary artery disease (CAD), but not heart failure or left ventricular systolic dysfunction, when a recently developed and highly sensitive assay was used to measure cardiac troponin T [2]. The highly sensitive assay can measure troponin levels that are lower than a factor of 10 than those measured with conventional assays. From the original group of patients, this study used stored plasma samples from 3679 patients for whom baseline troponin T measurements were available, and results were analyzed relative to the occurrence of cardiovascular events during a median follow-up period of 5.2 years. Results showed that in 3593 (97.7%) patients with stable CAD, the concentrations of troponin T when measured with the highly sensitive assay were at or above the limit of detection (0.001 µg/l), and equal to or greater than the 99th percentile for apparently healthy patients (0.0133 µg/l) in 407 patients (11.1%).

In the compilation of data after adjustments were made for other prognostic risk factors, a strong increase was shown in the incidence of cardiovascular death (adjusted hazard ratio [AHR] per unit increase in the natural logarithm of the troponin T level, 2.09; 95% confidence interval [CI], 1.60–2.74; P<0.001) and of heart failure (AHR, 2.20; 95% CI, 1.66–2.90; P<0.001) in this group. However, in regard to myocardial infarction (MI), there were 233 fatal or nonfatal acute MIs with a weak but significant increase in the cumulative incidence of MIs with increasing troponin T levels, but after adjustment, the association was no longer considered significant (HR, 1.16; 95% CI, 0.97–1.40; P=0.11). Also shown was a weak association between risk of MI and increasing quartiles of troponin T, but after adjustment, the association was not significant. Authors concluded that in patients with stable CAD whose troponin T levels were well below the detection limit of previous assays, but with increased troponin T values compared to normal controls, there was a strong association with the incidence of cardiovascular death and heart failure, but troponin T levels were not independently associated with incidence of MI.

Readers may also wish to read summaries posted in October on the this website of articles published in the August 27, 2009 issue of The New England Journal of Medicine regarding the use of sensitive troponin assays for the detection of acute MI [3,4,5,6].

[1] The PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2009;351:2058-68

[2] Omland T, de Lemos JA, Sabatine MS, et al. A sensitive cardiac troponin T assay in stable coronary artery disease (PEACE trial investigators) N Engl J Med 2009;361:2538-47

[3] New generation sensitive troponin assays. http://cardiovascular-medicine.com/?p=189 (Accessed 3.2.10)

[4] Schouten O, Boersma E, Hoeks SE, et al. Fluvastatin and perioperative events in patients undergoing vascular surgery. N Engl J Med 2009;361:980-9

[5] Keller T, Zeller T, Peetz D, et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med 2009;361:868-77

[6] Morrow D. Clinical application of sensitive troponin assays. N Engl J Med 2009;361:913-15

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* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Further information: Classification of Genetic Disorders (see p2551) from Cardiovascular Medicine, 3rd Edn*

In order to conduct a somewhat novel experiment, the investigators in a multicenter case-control study titled the Precocious Coronary Artery Disease (PROCARDIS) study [1] used a newly available chip designed to assay single-nucleotide polymorphisms (SNPs) to examine genetic associations in coronary artery disease (CAD) and to assess the associations of LPA gene variants with Lp(a) lipoprotein levels. From four European countries, 3145 patients with CAD and 3352 control subjects were recruited, and a novel gene chip that contained 48,742 SNPs in 2100 candidate genes was used to test the CAD patients and the control subjects. The chip identified three chromosomal regions that were correlated with the risk of coronary disease: 6q26-27, 9p21, and 1p13. The 6q26-27 region contained the LPA gene, and the investigators used comprehensive SNP typing to characterize the spectrum of variation at the LPA locus for both the Lp(a) lipoprotein level and the risk of coronary disease. At least 36% of the total variation in the Lp(a) lipoprotein level was explained by two common variants at rs10455872 and rs3798220 that were independently associated with an increased risk of coronary disease: common variant rs10455872 at the LPA locus had odds ratio (OR) for coronary disease of 1.70 (95% CI, 1.49–1.95) and common variant rs3798220 had an OR of 1.92 (95% CI, 1.48–2.49). The two LPA variants had a linear-dose response with both the Lp(a) lipoprotein level and the risk of coronary disease. The investigators concluded that LP(a) lipoprotein has a causal role in coronary disease.

In an editorial accompanying the paper [2], the author acknowledged the conclusions reached by the investigators regarding the role of Lp(a) lipoprotein as a causal factor in coronary disease. However, he raised the issue of whether or not this knowledge has clinical relevance. He questioned the mechanism by which an increased level of Lp(a) lipoprotein led to an increased risk of coronary disease. He suggested that a therapeutic intervention that selectively lowered the Lp(a) lipoprotein level without other effects needed to be tested in a randomized clinical trial to gain a valid understanding of its role. He also expressed concerned that the study only included white subjects, specifically, white Europeans, and additional work would be needed to determine whether or not the variation in Lp(a) lipoprotein levels had a causal effect in other patient populations.

[1] Clarke R, Peden JF, Hopewell JC, et al. Genetic Variations Associated with Lp (a) Lipoprotein Level and Coronary Disease. N Engl J Med 2009;361:2518-28

[2] Kathiresan. Lp(a)Lipoprotein Redux – From Curious Molecule to Causal Risk Factor. N Engl J Med 2009;361:2573-2574

Note: You may need subscriptions to access content from links on this page. You are responsible for obtaining these subscriptions.

* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.