Oct 8, 2006 ... by the potential for drug-drug interactions. Today, there are 225 drug-drug
interactions listed in Facts and Comparisons for warfarin, of which 79 ...
EDITORIAL SUBJECTS IN THIS ISSUE
■■ False-Positive Versus True-Positive Drug-Drug Interactions With Warfarin Warfarin is a marvelous, life-saving drug in the prevention of atherothrombotic events such as myocardial infarction, stroke, venous thromboembolism, and deep vein thrombosis. However, warfarin has somewhat unpredictable anticoagulant effects that require continuous monitoring of prothrombin time and the international normalization ratio (INR), and the search continues for a drug with efficacy comparable to warfarin but with lower risk of over- and underanticoagulation.1 The need for continuous monitoring of warfarin is magnified by the potential for drug-drug interactions. Today, there are 225 drug-drug interactions listed in Facts and Comparisons for warfarin, of which 79 are categorized as a Level 1 interaction, the highest severity level.2 A Level 1 interaction is described as: “Potentially severe or life-threatening interaction; occurrence has been suspected, established or probable in well-controlled studies. Contraindicated drug combinations may also have this number.” Another 48 drugs are listed as Level 2 interaction, “Interaction may cause deterioration in a patient’s clinical status; occurrence suspected, established or probable in well controlled studies.” Curiously, in this issue of JMCP, Zhang et al. in their examination of medical and pharmacy administrative claims found that only metronidazole and the cephalosporins in concomitant use with warfarin were associated with bleeding events as recorded on medical claims.3 On its face, this finding might suggest that patient safety could be improved by electronic prescribing via a decision support tool to detect these drug-drug interactions prior to dispensing. Metronidazole is listed as a Level 1 drug-drug interaction in the Facts and Comparisons interaction database, and the cephalosporins that are listed in the drug-drug interaction database (cefazolin, cefotetan, cefoxitin, and ceftriaxone) are Level 2 interactions. However all 4 cephalosporins are injectable, not oral dose forms, and the research performed by Zhang et al. did not include injectable cephalosporins. In other words, in the research performed by Zhang et al. of administrative claim records for the drugs associated with bleeding events when used with warfarin, only 1 drug, metronidazole, is listed in a commonly used drug-drug interaction database. Therefore, electronic surveillance of concomitant drug use would not have detected the apparent interaction with oral cephalosporins unless the drug-drug interaction filter was set at the class level and not the drug-specific level. In addition to the possible false-positive interaction of warfarin with oral cephalosporins, the research performed by Zhang et al. is equally important for what it did not find. Specific Level 1 interactions with nonsteroidal anti-inflammatory drugs (NSAIDs), barbiturates, cimetidine, ciprofloxacin, amiodarone, and Level 2 interactions with carbamazepine, chloramphenicol, griseofulvin, and rifampin were not associated with bleeding events as recorded in medical claims. In other
words, these Level 1 and Level 2 interactions would generate potentially false-positive warnings in an electronic decisionsupport system for prescribing. There is another point worth noting in the research performed by Zhang et al. Of the drugs selected by the researchers for study, imipramine, co-trimoxazole, and carbenicillin are not listed in any of the 4 severity levels among the drug-drug interactions with warfarin in the current version of Facts and Comparisons Drug Interaction Facts. Although not mentioned by the authors in the results or discussion of their findings, these 3 drugs were presumably used to confirm the truenegative interaction with warfarin. So, the tally in the research reported by Zhang et al. is 1 true-positive interaction out of 225 potential drug-drug interactions and 3 apparent true-negative interactions. Based on these research findings, a decision-support tool in an electronic prescribing system would generate false-positive messages for interactions with dozens of drugs such as the NSAIDs, and false-negative interactions of warfarin with the oral cephalosporins would occur. On the other hand, research such as this, with administrative claims data, cannot inform us about the key coincidental events. It is entirely possible that the drug interaction occurred without clinical consequence because the dose of warfarin was changed, perhaps by a clinical pharmacist working in collaboration with a physician. The present study by Zhang et al. does remind us of the many areas of research yet to pursue. Administrative claims data in the United States will not permit us, in most cases, to adequately study the relationship of nonprescription drug use, such as aspirin, acetaminophen, or over-the-counter NSAIDs such as ibuprofen, on outcomes such as bleeding events. Administrative claims data in the United States will also not support assessment of the hypothesis that alcohol consumption, for example, may contribute to an increased risk of bleeding for the Level 2 drug-drug interaction of warfarin with statin drugs such as lovastatin. For this hypothesis, a randomized, controlled trial is necessary to determine that the risks of an international normalized ratio (INR) of 2.0 or higher are not different among men categorized as nondrinkers, light, moderate, or heavier drinkers.4 On the other hand, administrative claims data may help assess the incidence and prevalence of bleeding episodes associated with use of single and combined antithrombotic drug therapy. Warfarin, for example, is used increasingly with antiplatelet drugs such as dipyridamole or clopidogrel, particularly in patients with multiple indications such as coincident atrial fibrillation and ischemic heart disease. Hallas et al. reported this month in BMJ the results of research with comprehensive administrative data from Denmark in which the risk of upper gastrointestinal (GI) bleeding was 1.1 (95% confidence interval [CI], 0.6-2.1) for clopidogrel, 1.8 (95% CI, 1.5- 2.1) for lowdose aspirin, 1.9 (95% CI, 1.3-2.8) for dipyridamole, and 1.8
686 Journal of Managed Care Pharmacy
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JMCP
October 2006
Vol. 12, No. 8
Editorial Subjects in This Issue
(1.3-2.4) for vitamin K antagonists (such as warfarin).5 Combined use of these drugs significantly increased the risk of GI bleeding, to 2.3 (1.7-3.3) for dipyridamole with aspirin, 5.3 (2.9-9.5) for vitamin K antagonists with aspirin, and 7.4 (3.5-15) for clopidogrel with aspirin. During the study period, from 2000 through 2004, exposure to combined antithrombotic regimens increased by 425% in the population of 470,000 residents of Funen County, Denmark. Some prominent medical journals have banned, for some time, the use of conclusions in articles that “more research is needed” on this subject.6 However, the findings in the article by Zhang et al. beg for more research. Frederic R. Curtiss, PhD, RPh, CEBS Editor-in-Chief
[email protected] REFERENCES 1. Curtiss FR. In search of safe and effective oral anticoagulation. J Manag Care Pharm. 2005;11(8):704-08. Available at: http://www.amcp.org/data/jmcp/ Editorial%20704-708.pdf Accessed October 8, 2006. 2. Drug Interaction Facts on Disc. Facts and Comparisons. Single Drug Query Results for Warfarin. Drug Facts and Comparisons (Clinisphere version, ISBN 1-57439-036-8). St. Louis, MO: Wolters, Kluwer Health, Inc.; September 2006. Accessed October 14, 2006. 3. Zhang K, Young C, Berger J. Administrative claims analysis of the relationship between warfarin use and risk of hemorrhage including drug-drug and drug-disease Interactions. J Manag Care Pharm. 2006;12(8):640-48. 4. Mukamal KJ, Smith CC, Karlamangla AS, Moore AA. Moderate alcohol consumption and safety of lovastatin and warfarin among men: the post-coronary bypass graft trial. Am J Med. 2006;119(5):434-40. 5. Hallas J, Dall M, Andries A, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ. 2006;333(7571):726; Epub, September 19, 2006. 6. Godlee F. Obviously. BMJ. 2006; 333, doi:10.1136. Available at http://bmj. bmjjournals.com/cgi/content/full/333/7572/0-f. Accessed October 15, 2006.
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■■ Rhythm Versus Safety in Amiodarone Therapy Amiodarone (Cordarone, Pacerone) is a powerful antiarrhythmic that is effective in converting atrial fibrillation (AF) to sinus rhythm and superior to sotalol in maintaining sinus rhythm. In 665 patients who were receiving anticoagulants and had persistent AF, Singh et al. found a median time to recurrence of AF of 487 days in the amiodarone group versus 74 days in the sotalol group and 6 days in the placebo group, with improved quality of life and improved exercise performance in the amiodarone group.1 In this study known as the Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T), spontaneous conversion occurred in 72.1% of amiodarone patients, 24.2% for sotalol, and 0.8% for placebo. However, the use of amiodarone in AF is not approved by the U.S. Food and Drug Administration (FDA). The unlabeled (off-label) uses of amiodarone include conversion of atrial fibrillation and maintenance of sinus rhythm, and treatment of supraventricular tachycardia.2 Amiodarone has also been shown to be a useful antiarrhythmic in patients after cardiac surgery in the clinical trial known as PAPABEAR (Prophylactic Amiodarone for the Prevention of Arrhythmias that Begin Early After Revascularization, Valve Replacement, or Repair) in which atrial tachyarrhythmia occurred less frequently in amiodarone patients (16.2%) compared with placebo (29.5%).3 The overall hazard ratio (HR) for tachyarrhythmia was 0.52 (95% confidence interval [CI], 0.34-0.69), and the HR was significantly less than 1.0 for all subgroups of patients, including patients younger than 65 years, patients aged 65 years or older, patients who had coronary artery bypass graft (CABG) only, patients who had valve replacement/repair surgery with or without CABG surgery, patients who received preoperative beta-blocker therapy, and patients who did not receive preoperative beta-blocker therapy. Assessment of the medical treatment of AF from 1991 to 2000 showed that amiodarone replaced quinidine as the dominant sinus rhythm drug by 2000. For 1,355 visits for patients with AF obtained from the National Ambulatory Medical Care Survey (NAMCS), a nationally representative assessment of office-based physician practice, overall use of drugs to control cardiac rhythm decreased from 72% of visits in 1991-1992 to 56% in 1999-2000 (P = 0.01 for trend) due to declining digoxin use (64% to 37%, P
