Published online before print June 19, 2006, doi: 10.1161/CIRCULATIONAHA.106.616219
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(Circulation. 2006;113:2906-2913.)
© 2006 American Heart Association, Inc.
Epidemiology |
Risk of Death or Reinfarction Associated With the Use of Selective Cyclooxygenase-2 Inhibitors and Nonselective Nonsteroidal Antiinflammatory Drugs After Acute Myocardial Infarction
From the Department of Cardiology, Gentofte University Hospital, Hellerup (G.H.G., S.Z.A.); National Institute of Public Health, Copenhagen (G.H.G., J.N.R., S.R., P.B., S.Z.A., M.M.); Department of Rheumatology, Rigshospitalet, Copenhagen (S.J.); Department of Cardiovascular Medicine, Bispebjerg University Hospital, Copenhagen (P.B., T.K.S., C.T.-P.); Department of Cardiology, Hvidovre University Hospital, Copenhagen (J.F.); and Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen (L.K.), Denmark.
Correspondence to Gunnar H. Gislason, MD, Department of Cardiology, Gentofte University Hospital, DK-2900 Hellerup, Denmark. E-mail gg{at}heart.dk
Received January 24, 2006; revision received March 30, 2006; accepted April 17, 2006.
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Abstract |
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Background— The selective cyclooxygenase-2 (COX-2) inhibitors and other nonselective nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with increased cardiovascular risk, but the risk in patients with established cardiovascular disease is unknown. We analyzed the risk of rehospitalization for acute myocardial infarction (MI) and death related to the use of NSAIDs including selective COX-2 inhibitors in patients with prior MI.
Methods and Results— All patients with first-time MI between 1995 and 2002 as well as all prescription claims for NSAIDs after discharge were identified from nationwide Danish administrative registers. The risk of death and rehospitalization for MI associated with the use of selective COX-2 inhibitors and nonselective NSAIDs was studied with the use of multivariable proportional hazards models and case-crossover analysis. A total of 58 432 patients were discharged alive and included in the study; 9773 experienced rehospitalization for MI, and 16 573 died. A total of 5.2% of patients received rofecoxib, 4.3% celecoxib, 17.5% ibuprofen, 10.6% diclofenac, and 12.7% other NSAIDs. For any use of rofecoxib, celecoxib, ibuprofen, diclofenac, and other NSAIDs, the hazard ratios and 95% confidence intervals for death were 2.80 (2.41 to 3.25; for rofecoxib), 2.57 (2.15 to 3.08; for celecoxib), 1.50 (1.36 to 1.67; for ibuprofen), 2.40 (2.09 to 2.80; for diclofenac), and 1.29 (1.16 to 1.43; for other NSAIDS); there were dose-related increases in risk of death for all of the drugs. There were trends for increased risk of rehospitalization for MI associated with the use of both the selective COX-2 inhibitors and the nonselective NSAIDs.
Conclusions— Selective COX-2 inhibitors in all dosages and nonselective NSAIDs in high dosages increase mortality in patients with previous MI and should therefore be used with particular caution in these patients.
Key Words: cyclooxygenase-2 inhibitors • drugs • mortality • myocardial infarction • nonsteroidal antiinflammatory drugs
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Introduction |
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The selective cyclooxygenase-2 (COX-2) inhibitors have been used widely for the treatment of pain and rheumatic disease since they were introduced in the late 1990s. However, the use of the COX-2 inhibitors and the associated excess cardiovascular risk has caused increasing concern since the publication of the Vioxx Gastrointestinal Outcomes Research (VIGOR) study1 in 2000. Although some studies have reported mixed results with regard to the cardiovascular risk,2–4 several recently published randomized trials and population-based studies have established an increased risk of acute myocardial infarction (MI) and thromboembolic events related to the use of most COX-2 inhibitors.5–14 This caused the pharmaceutical company Merck to withdraw their COX-2 inhibitor rofecoxib (Vioxx) from the market, and health authorities in several countries have issued a warning about the cardiovascular risk associated with the use of COX-2 inhibitors.
Editorial p 2868
Clinical Perspective p 2913
The more traditional nonselective nonsteroidal antiinflammatory drugs (NSAIDs) have long been used uncritically in the treatment of pain and rheumatic diseases, but knowledge about the cardiovascular safety of the nonselective NSAIDs is sparse. Nevertheless, results from recently published population-based studies have also raised concern about the cardiovascular risk of NSAIDs in general.9,15,16
Patients with acute MI have an increased risk of recurrent MI and death. Little is known about the extent to which the cardiovascular risk of selective COX-2 inhibitors relates to this population and whether other nonselective NSAIDs are also associated with increased risk. Therefore, we used nationwide administrative registers of hospitalization and drug dispensing from pharmacies in Denmark to study the risk of recurrent MI and death related to the use of selective COX-2 inhibitors and nonselective NSAIDs in patients discharged after first-time acute MI between 1995 and 2002.
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Methods |
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The Danish National Patient Registry has since 1978 registered all hospital admissions in Denmark. Each admission is registered by 1 primary diagnosis and 1 or more secondary diagnoses by the International Classification of Diseases(ICD), until 1994 the ICD-8 and from 1994 the ICD-10.
The Danish Registry of Medicinal Product Statistics (national prescription registry) has since 1995 kept records of every prescription dispensed from pharmacies in Denmark. Each medication is classified by the Anatomical Therapeutical Chemical system, and the registry also includes information about the date of dispensing, formulation, strength, and quantity dispensed. Information on patients’ vital status (dead or alive) was obtained from the civil registration system through Statistics Denmark. In Denmark, every resident is provided with a permanent and unique civil registration number that enables linkage between these administrative registries.
Population
From the National Patient Registry we identified all patients, aged 
30 years, hospitalized with acute MI (ICD-10 code I21 to I22) for the first time between 1995 and 2002. The diagnosis of acute MI has been validated in the National Patient Registry, with a specificity of >90%.17 A more detailed description of selection of patients has been published previously.18 All patients who were alive at discharge were included in the present study and analyzed for the risk of death and rehospitalization for MI.
Drug Use
From the national prescription registry, all claimed prescriptions of NSAIDs (Anatomical Therapeutical Chemical code M01A) by the study cohort were identified. The 2 most frequently used COX-2 inhibitors, rofecoxib (M01AH02) and celecoxib (M01AH01), were analyzed separately because they represented >90% of all COX-2 inhibitors used. Similarly, the nonselective NSAIDs ibuprofen (M01AE01) and diclofenac (M01AB05) represented the majority of nonselective NSAIDs used and were therefore analyzed separately. All other NSAIDs were categorized as 1 group in the analyses.
Dosages
The national prescription registry does not include information on prescribed daily dosage of the medication. Therefore, by calculating average dosages from up to 3 consecutive prescriptions, the daily dosage was estimated at each new prescription dispensing. This method allowed for dosages to change at dispensing of a new prescription. The method has been described in detail previously.19 To analyze whether there was a dose-related response in risk of death or rehospitalization for MI, the 2 COX-2 inhibitors (rofecoxib and celecoxib) and the 2 nonselective NSAIDs (ibuprofen and diclofenac) were divided into low or high dosages. The upper limit of low dosage was defined as the lower recommended daily dosage for the individual NSAIDs, ie, 25 for rofecoxib, 200 for celecoxib, 1200 for ibuprofen, and 100 mg for diclofenac. NSAIDs other than the aforementioned ones were not divided into specific dosages.
Comorbidity and Socioeconomic Status
Comorbidity was defined from diagnoses at discharge from index MI as specified in the Ontario acute MI mortality prediction rule.20 The comorbidity index was further enhanced by adding diagnoses from the year before the event, as done by Rasmussen et al.21 Diagnoses used in the comorbidity index are shown in Table 1. Socioeconomic status was defined by the individual average yearly gross income during a 5-year period before the index MI (excluding the year of index MI). Patients were divided into tertiles according to income.
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Statistical Analysis
To ensure the strength of our findings, we used 2 different statistical methods to estimate the risk of taking selective COX-2 inhibitors or nonselective NSAIDs after an MI. At first, Cox proportional hazards models were used when the exposure covariates (drug) were included as time-dependent variables, meaning that patients were only considered at risk when they were taking the drug. The Cox models were adjusted for age, gender, year of first MI, length of treatment, concomitant medical treatment (Table 1), socioeconomic status, and comorbidity. Model assumptions—the linearity of continuous variables, the proportional hazards assumption, and lack of interaction—were tested and found valid unless otherwise indicated. The other method was the case-crossover design with the use of conditional logistic regression.22 The case-crossover design is based on the case-base paradigm, but instead of using matched controls, the case serves as its own control. Only patients experiencing an event of interest are included in the case-crossover analysis. Among these patients, the number having medication available in the case period (which is the period immediately before the event of interest) is compared with the number having medication available in the control period (which is a period further back in time than the case period but of the same length as the case period). The case-crossover design eliminates the effect of many potential confounders by keeping characteristics such as age, sex, socioeconomic status, and comorbidity fixed. We defined the case period as 0 to 30 days before the event (MI or death), and, to enhance the strength of the analyses, we selected 2 control periods as 60 to 90 and 90 to 120 days before the event. The numbers needed to harm (NNH) were calculated for each drug from unadjusted mortality ratios. All statistical calculations were performed with the SAS statistical software package version 8.2 for UNIX servers (SAS Institute Inc, Cary, NC).
Ethics
The Danish Data Protection Agency approved this study, and data at the individual level were made available to us such that specific individuals could not be identified. Retrospective register studies do not require ethical approval in Denmark.
The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.
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Results |
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The total of 71 515 patients were admitted with first-time MI during 1995–2002; 58 432 (81.7%) were alive at discharge and included in the study. After discharge, 21 093 patients (36.1%) claimed at least 1 prescription of 1 of the NSAIDs. A detailed description of baseline characteristics of the study population and distribution between treatment groups is shown in Table 1. Patients taking nonselective NSAIDs were younger and more were male than patients taking selective COX-2 inhibitors, but otherwise there were no major differences between the treatment groups.
The duration of treatment was similar with rofecoxib, celecoxib, and ibuprofen, at 37 to 40 days, but the duration of treatment was only 20 days for diclofenac and 83 days for other NSAIDs (Table 2). There were 9773 rehospitalizations (18.6%) for MI and 16 561 deaths (28.3%) during the observation period. Higher death rates were associated with exposure to all of the NSAIDs compared with nonexposure, but the death rates were highest among those exposed to rofecoxib and celecoxib (Table 2). The NNH values were calculated from unadjusted mortality ratios and are shown as number of patients needed to treat with each drug for 1 year to cause 1 additional death (Table 2).
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Cox Proportional Hazards Analysis
Results from the Cox proportional hazards analysis for hazard ratios for death and rehospitalization for MI are shown in Table 3 and illustrated in Figures 1 and 2
. There was significantly increased risk of death associated with any use of both the nonselective NSAIDs and the selective COX-2 inhibitors. After the most commonly used nonselective NSAIDs, ibuprofen and diclofenac, and selective COX-2 inhibitors, rofecoxib and celecoxib, were divided into low and high dosages, the Cox proportional hazards analysis demonstrated a clear dose-related response in the increase in the risk of death for all drugs. There was a trend for increased risk of readmission for MI related to the use of both the selective COX-2 inhibitors and nonselective NSAIDs; however, the dose-related increase in risk was not as evident as that observed for death.
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Case-Crossover Analyses
Odds ratios for death and readmission for MI from the conditional logistic regression analyses with the use of the case-crossover design are shown in Table 4. These analyses confirmed the results of the Cox proportional hazards analyses, with increased risk of death associated with any use of both the nonselective NSAIDs and the selective COX-2 inhibitors and higher risk with higher dosages. The trend for increased risk of readmission for MI was even more evident in the case-crossover analyses.
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Supplementary Analyses
We tested for interactions for each of the COX-2 inhibitors and NSAIDs with available covariates, and the analyses were repeated in subgroups of sex and median age with similar results. There were no important interactions with available covariates.
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Discussion |
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This study demonstrated dose-related excess mortality associated with the use of NSAIDs in patients with prior MI. There was a trend for increased risk of rehospitalization for MI, although the dose-related response in risk was not as clear as for death.
The VIGOR study was the first to report increased cardiovascular risk associated with the selective COX-2 inhibitors.1 Since then, several studies,5,6,8,12,23 although not all,2,24–26 have confirmed the findings. Several recently published observational studies have also indicated an increased cardiovascular risk associated with the nonselective NSAIDs.7–9,13
The present study is the first to address the risk of all NSAIDs in a selected population of post-MI patients. These patients are elderly, are frequently treated with NSAIDs, and have a high risk of additional cardiovascular events. Many of the randomized trials have excluded these patients. The results of the present study indicate acute or subacute effects of both the selective COX-2 inhibitors and nonselective NSAIDs on the cardiovascular system because events were closely tied to the timing of taking the drugs, and most patients were receiving treatment for a short time. In the Adenomatous Polyp Prevention on Vioxx (APPROVe) study, increased risk of thrombotic events associated with use of rofecoxib only became apparent after 18 months of treatment, but there was an earlier separation between groups in the incidence of heart failure after 5 months of treatment.5 The Adenoma Prevention with Celecoxib (APC) study was stopped because of excess cardiovascular events and deaths after 3 years, but the survival curves began to diverge after 12 months.6 A study by Nussmeier et al12 on patients after coronary artery bypass graft surgery found increased cardiovascular risk after only 10 days of treatment with selective COX-2 inhibitors. A meta-analysis by Juni et al23 found no association between duration of treatment with rofecoxib and cardiovascular risk, and other observational studies have shown that recent use of NSAIDs increases risk, whereas risk of remote use is less apparent.7,9 Current data therefore suggest harmful effects after short-term as well as after long-term treatment. This may be influenced further by the baseline cardiovascular risk of the individual patient.
Prior observational studies have failed to show increased cardiovascular risk of the selective COX-2 inhibitor celecoxib.7,8,10 In the present study the risks associated with celecoxib and rofecoxib could be compared directly and were similar. This increases the likelihood that the harmful effects can be attributed to the drug class rather than the peculiarities of one of the drugs. Because the population in the present study comprised post-MI patients, this might indicate more abrupt effects on a vulnerable cardiovascular system, and the harmful effects of celecoxib may therefore become more apparent than in previous studies.
The dose relationship found in this study is overall in agreement with previous studies.5,6,8 The upper limit of low dosage was in this study defined as the lower limit of recommended daily dosage for the individual NSAIDs studied, but there may be differences in pharmacological properties of the individual NSAIDs not accounted for in the current definition. Nevertheless, the increased risk associated with any use of the selective COX-2 inhibitors and high dosages of the 2 nonselective NSAIDs, demonstrated in the present study, needs to be acknowledged.
Most patients receive treatment with low-dose acetylsalicylic acid (aspirin) after MI to prevent recurrent cardiovascular events.27 The effect of aspirin on the associated excess cardiovascular risk of COX-2 inhibitors has been the subject of debate, and some studies have excluded patients receiving aspirin. The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) involved treatment with lumiracoxib, stratified to the concomitant use of aspirin. There was an insignificant trend toward lower incidence of cardiovascular events in the lumiracoxib group receiving concomitant aspirin compared with those who did not receive aspirin.28 Therefore, the relatively low risk of recurrent MI observed in the present study compared with the risk of death may be due to the protective role of aspirin. Another contributing factor may be that many patients died out of hospital, perhaps because of recurrent infarctions.
The prostanoids are generated from arachidonic acid by COX-1– and COX-2–mediated metabolism and have a wide range of biological actions. A detailed discussion of the potential mechanisms has been published previously.29,30 In brief, COX-1 is involved in the generation of thromboxane A2, which is a vasoconstrictor and platelet agonist and promotes smooth muscle proliferation. COX-2 mediates synthesis of prostaglandin I2, which is a potent vasodilator, inhibits platelet function, and promotes renal sodium excretion. Platelets express only COX-1, but endothelial cells express both COX-1 and COX-2.
An unbalanced inhibition of only COX-2 therefore early caused some concern about cardiovascular side effects, but the theory of balanced versus unbalanced COX inhibition is now debatable because the nonselective NSAIDs are also associated with increased cardiovascular risk. However, other mechanisms may explain the harmful effects of NSAIDs on the cardiovascular system. Ibuprofen has been found to compete with low-dose aspirin in binding to the COX-1 pathway in the platelets, but, in contrast to low-dose aspirin, the block is not irreversible and therefore leaves the patient only partially protected against thrombosis.31 Furthermore, clinical and observational studies have demonstrated increased risk of heart failure, fluid retention, destabilization of blood pressure control, and development of hypertension associated with the use of selective COX-2 inhibitors and nonselective NSAIDs.32–35 In addition, animal models indicate that imbalance in thromboxane A2/prostaglandin I2 homeostasis could promote cardiac fibrosis and cardiac hypertrophy as well as modulate response to endothelial injury.30,36
Previous studies have focused mainly on combined end points, whereas we are able to demonstrate an association with all-cause mortality. We find low NNH values (Table 2) for COX-2 inhibitors and high-dosage nonselective NSAIDs, whereas in the APC trial NNH for a combined end point is &70. This illustrates that the harmful effects of these drugs appear much more severe in patients with a previous MI.
Strengths and Limitations of the Study
The Danish National Patient Registry as well as the national prescription registry have been shown to be accurate.17,37 In Denmark, ibuprofen is the only NSAID that is available over-the-counter without prescription and only in a low dosage and limited quantity at each dispensing. Therefore, it is unlikely that over-the-counter use of NSAIDs has a major impact on this study. We assumed that most of our patients used aspirin on a daily basis, as shown in epidemiological surveys of post-MI patients.27 If aspirin use was lower in the group taking NSAIDs, a higher event rate would be expected in that group, but because aspirin is primarily dispensed over the counter, the effects of aspirin cannot be assessed properly. The Cox models used provide control of available confounders, but the control for confounding by indication—that the patients put on treatment are sicker than those not treated—may not be adequate. For this reason, we performed supplementary analyses using the case-crossover design. By using the case as its own control, the effects of chronic confounders are almost eliminated. Confounding is still possible, however. If the risk of death was increased by the pain-eliciting conditions only, the observed association between COX-2 and NSAID intake and increased risk of death would be due to confounding. Whereas such confounding cannot be excluded in an observational study, the dose-response effect, the different effect of different drugs used for similar indications, and the clear relation between degree of COX-2 inhibition and risk all indicate the importance of the drugs rather than the indications.
Conclusions and Clinical Implications of the Study
The present study demonstrates that treatment with 2 COX-2 inhibitors and high dosages of 2 nonselective NSAIDs are associated with a highly increased risk of death in patients with prior MI. The results add important information to the treatment of high-risk patients, notably those with prior MI, and must be viewed together with the rest of the evidence. Given the additional evidence from randomized trials and other observational studies of selective COX-2 inhibitors and nonselective NSAIDs, these drugs should be used with particular caution in patients with a prior MI. Post-MI patients with pain conditions relieved by these drugs should discuss carefully with their doctor the balance between benefits and risk of treatment.
Because studies in this field have revealed major safety concerns where none were thought present, the cardiovascular safety of not only the selective COX-2 inhibitors but of all NSAIDs needs to be addressed further.
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Acknowledgments |
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Sources of Funding
This study was supported by an unrestricted research grant from the Danish Pharmaceutical Association (grant 31-03) and the Danish Heart Foundation (grant 05-04-B46-A522-22207).
Disclosures
The corresponding author had full access to all the data in the study and had the final responsibility for the decision to submit for publication. Dr Jacobsen has served as an expert witness for the Danish Council for Patient Complaints. The remaining authors report no conflicts.
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C. Jacobshagen, M. Gruber, N. Teucher, A. G. Schmidt, B. W. Unsold, K. Toischer, P. Nguyen Van, L. S. Maier, H. Kogler, and G. Hasenfuss Celecoxib modulates hypertrophic signalling and prevents load-induced cardiac dysfunction Eur J Heart Fail, April 1, 2008; 10(4): 334 - 342. [Abstract] [Full Text] [PDF]
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E. M. Antman, M. Hand, P. W. Armstrong, E. R. Bates, L. A. Green, L. K. Halasyamani, J. S. Hochman, H. M. Krumholz, G. A. Lamas, C. J. Mullany, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Developed in Collaboration With the Canadian Cardiovascular Society Endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee Circulation, January 15, 2008; 117(2): 296 - 329. [Full Text] [PDF]
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J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine J. Am. Coll. Cardiol., August 14, 2007; 50(7): e1 - e157. [Full Text] [PDF]
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J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine J. Am. Coll. Cardiol., August 14, 2007; 50(7): 652 - 726. [Full Text] [PDF]
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Authors/Task Force Members, J.-P. Bassand, C. W. Hamm, D. Ardissino, E. Boersma, A. Budaj, F. Fernandez-Aviles, K. A.A. Fox, D. Hasdai, E. M. Ohman, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology Eur. Heart J., July 1, 2007; 28(13): 1598 - 1660. [Full Text] [PDF]
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 A. Bardia, J. O. Ebbert, R. A. Vierkant, P. J. Limburg, K. Anderson, A. H. Wang, J. E. Olson, C. M. Vachon, and J. R. Cerhan Association of Aspirin and Nonaspirin Nonsteroidal Anti-inflammatory Drugs With Cancer Incidence and Mortality J Natl Cancer Inst, June 6, 2007; 99(11): 881 - 889. [Abstract] [Full Text] [PDF]
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A. O. Maree and D. J. Fitzgerald Variable Platelet Response to Aspirin and Clopidogrel in Atherothrombotic Disease Circulation, April 24, 2007; 115(16): 2196 - 2207. [Full Text] [PDF]
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E. M. Antman, J. S. Bennett, A. Daugherty, C. Furberg, H. Roberts, and K. A. Taubert Use of Nonsteroidal Antiinflammatory Drugs: An Update for Clinicians: A Scientific Statement From the American Heart Association Circulation, March 27, 2007; 115(12): 1634 - 1642. [Full Text] [PDF]
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B. I. Jugdutt Cyclooxygenase Inhibition and Adverse Remodeling During Healing After Myocardial Infarction Circulation, January 23, 2007; 115(3): 288 - 291. [Full Text] [PDF]
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P. McGettigan and D. Henry Cardiovascular Risk and Inhibition of Cyclooxygenase: A Systematic Review of the Observational Studies of Selective and Nonselective Inhibitors of Cyclooxygenase 2 JAMA, October 4, 2006; 296(13): 1633 - 1644. [Abstract] [Full Text] [PDF]
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J. Karsh Les anti-inflammatoires peuvent-ils etre sans risque? Can. Med. Assoc. J., August 29, 2006; 175(5): 451 - 451. [Full Text] [PDF]
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J. S. Hochman and N. R. Shah What Price Pain Relief? Circulation, June 27, 2006; 113(25): 2868 - 2870. [Full Text] [PDF]
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