Role of Dose Potency in the Prediction of Risk of Myocardial Infarction Associated With Nonsteroidal Anti-Inflammatory Drugs in the General Population

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1 Journal of the American College of Cardiology Vol. 52, No. 20, by the American College of Cardiology Foundation ISSN /08/$34.00 Published by Elsevier Inc. doi: /j.jacc NSAIDs and Myocardial Infarction Role of Dose Potency in the Prediction of Risk of Myocardial Infarction Associated With Nonsteroidal Anti-Inflammatory Drugs in the General Population Luis Alberto García Rodríguez, MD,* Stefania Tacconelli, PHD, Paola Patrignani, PHD Madrid, Spain; and Chieti, Italy Objectives Background Methods Results Conclusions We studied the association between the frequency, dose, and duration of different nonsteroidal antiinflammatory drugs (NSAIDs) and the risk of myocardial infarction (MI) in the general population. We verified whether the degree of inhibition of whole blood cyclooxygenase (COX)-2 by average circulating drug levels can be a surrogate biochemical predictor of the risk of MI by NSAIDs. There is evidence that both traditional NSAIDs and selective inhibitors of COX-2 may increase the risk of MI. From the THIN (The Health Improvement Network) database, we identified 8,852 cases of nonfatal MI in patients 50 to 84 years old between 2000 and 2005 and conducted a nested case-control analysis. We correlated the risk of MI with the degree of inhibition of platelet COX-1 and monocyte COX-2 in vitro by average therapeutic concentrations of individual NSAIDs. The risk of MI was increased with current use of NSAIDs (relative risk [RR]: 1.35; 95% confidence interval [CI]: 1.23 to 1.48). The risk increased with treatment duration and daily dose. We found a significant correlation between the degree of inhibition in vitro of whole blood COX-2 (r , p ), but not whole blood COX-1 (r , p 0.947), and the risk of MI associated with individual NSAIDs that lacked complete suppression ( 95%) of platelet COX-1 activity. Individual NSAIDs with a degree of COX-2 inhibition 90% at therapeutic concentrations presented an RR of 1.18 (95% CI: 1.02 to 1.38), whereas those with a greater COX-2 inhibition had an RR of 1.60 (95% CI: 1.41 to 1.81). Our findings suggest that the variable risk of MI among NSAIDs that do not inhibit platelet COX-1 completely and persistently is largely related to their extent of COX-2 inhibition. (J Am Coll Cardiol 2008;52: ) 2008 by the American College of Cardiology Foundation Nonsteroidal anti-inflammatory drugs (NSAIDs), a chemically heterogeneous group of agents that comprises traditional (t)nsaids and NSAIDs selective for cyclooxygenase (COX)-2 (coxibs), are commonly used in the general population for treating pain and inflammatory conditions. They act mostly through the inhibition of COX-2 dependent prostanoids (1). NSAIDs are distinguished on the basis of their COXisozyme selectivity in vitro, described as the ratio of the concentrations required to inhibit the activity of the From the *Centro Español de Investigación Farmacoepidemiológica (CEIFE), Madrid, Spain; and the Department of Medicine and Center of Excellence on Aging, G. d Annunzio University, School of Medicine, CeSI, Chieti, Italy. The database portion (THIN) was funded by an unrestricted research grant from Pfizer to CEIFE. The corresponding author has full authorship rights to the manuscript and was not obligated to include any Pfizer comments in the submitted manuscript. The biochemistry study was supported by a grant from the European Community s Sixth Framework Program (Eicosanox, LSMH-CT ) to Dr. Patrignani. Manuscript received May 2, 2008; revised manuscript received July 22, 2008, accepted August 6, isozymes by 50% (IC50 for COX-1/IC50 for COX-2). This is assessed using the human whole blood assays that evaluate the effects of drugs on platelet COX-1 and monocyte COX-2 (2,3). They are capacity indexes of COX- See page 1637 isozyme activities to generate prostanoids from endogenous sources of arachidonic acid, and their pharmacological inhibition is not influenced by different pathological conditions. Thus, the dose of aspirin for cardioprotection selected by the assessment of thromboxane (TX) B 2 levels in the whole blood assay in healthy and young subjects (4) was appropriate also for elderly patients with cardiovascular (CV) disease (5). The assessment of COX-1/COX-2 ratios in vitro describes an experimental COX-isozyme selectivity that mirrors the chemical features of the different NSAIDs. It showed that COX-2 selectivity of NSAIDs is a continuous

2 JACC Vol. 52, No. 20, 2008 November 11, 2008: García Rodríguez et al. Traditional NSAIDs, Coxibs, and MI 1629 variable preventing separation of tnsaids from coxibs 6). ( the United Kingdom (15). The The whole blood assays also permit estimation of achievedstudy cohort included patients COX-isozyme selectivity in humans, which is the ratio ofages 50 to 84 years between Jan and October 2005 isozyme inhibition at a given plasma concentration. Impor-uartantly, achieved selectivity of NSAIDs varies as a consequencewith at least 2 years of enrollment with the general practitio- of the dose administered. The introduction of NSAIDs selective for COX-2, whichner and at least 1 health contact were developed to reduce the risk of serious gastrointestinalin the previous 3 years before complications dependent, at least in part, on the inhibitiontheir start date. Patients with of COX-1 while achieving comparable efficacy, has raised cancer were excluded from the new concerns now centered on CV safety 7). ( Originally, these cohort. All members of this co- were followed up from the concerns were reported solely for coxibs. Subsequently, we havehort learned that some tnsaids may share a CV risk similar to start date until the earliest occur- of one of the following end selective COX-2 inhibitors. The body of evidence consists ofrence data from clinical trials 8) ( and from a growing number of points: MI detection, cancer, observational studies, most of which have been performed85th birthday, death, or end of using large automated databases 9). ( study period. The final cohort Inhibition of TXA 2 -dependent platelet function in vivo consisted of 716,395 persons fol- occurs when platelet COX-1 dependent capacity to syn-lowethesize TXA 2 (as assessed by measuring serum TXB 2 levels) years. up for an average of 4.1 is reduced 95% (10). In fact, recent findings suggest that We applied similar methods of case ascertainment and local release of tiny concentrations of TXA 2 from activated validation as performed in 2 recent studies (16,17). We platelets may play an important role in platelet thrombusidentified patients with a recorded diagnosis of MI during formation. They activate the tyrosine-kinase based signaling pathway (11), which may translate into full platelet considered incident cases of MI after review of their the study period (n 12,499), resulting in 10,653 patients activation in the presence of weak platelet agonists orcomputerized patient profile. We then validated a random subthreshold concentrations of stronger agonists. This leads sample of 500 patients with the primary care physicians. to the concept of functional COX-2 selectivity by NSAIDs, The collaboration of the primary care physicians was excellent (response rate of 91%), and we achieved a similar high namely, inhibition of COX-2 in the presence of an insufficient reduction of platelet COX-1 activity to translate intoconfirmation rate (95%) compared with previous studies inhibition of platelet function. (16,17). We retained for the analysis nonfatal incident cases In the present study, we used data from the THIN (The of MI, defined as patients alive within 1 month after the Health Improvement Network) database to evaluate the occurrence of MI; the final number of cases was 8,852. A association between prospectively collected information on group of 20,000 control subjects were randomly selected the frequency, dose, and duration of different types ofrom the list of eligible person-days (index date) and NSAIDs and the risk of nonfatal myocardial infarctionfrequency matched to the cases on sex, age within 1 year, (MI) in the general population. Additionally, we verified theand calendar year. functional COX-2 selectivity by average circulating concentrations of the doses of tnsaids and coxibs, mostly takenexclusive time windows: current, when the supply of the We categorized exposure to NSAIDs into mutually from the population of the THIN database, and found that most recent prescription lasted until index date or ended in most tnsaids were as COX-2 selective as coxibs withthe 7 days before the index date; recent, when it ended respect to platelet function. Then, we aimed to address the between 8 and 90 days before the index date; past, when it hypothesis that the degree of inhibition of whole bloodended between 91 and 365 days before the index date; and COX-2 in vitro by plasma concentrations corresponding tononuse, when there was no recorded use in the year before the average NSAID therapeutic dose in patients (an index of drug potency/exposure) (12 14) predicts the relative risk (RR) of MI for each individual NSAID functionally selective for COX-2 observed in the general population. Methods A detailed description of the methods used in the THIN analysis can be found in the Online Appendix. THIN nested case-control study. We conducted a population-based, retrospective cohort study with nested case-control analysis using data from the THIN database in Abbreviations and Acronyms CAD coronary artery disease CI confidence interval COX cyclooxygenase coxibs selective inhibitors of COX-2 CV cardiovascular MI myocardial infarction NSAID nonsteroidal antiinflammatory drug RR relative risk tnsaid traditional nonsteroidal antiinflammatory drug TX thromboxane the index date. The category of current use was further subdivided: single, when there was use of only 1 individual NSAID within the month before the index date; multiple, when the patient received prescriptions for 2 or more individual NSAIDs within the week before the index date; and switcher, when there was use of only 1 NSAID in the week before the index date but there was use of at least 1 other NSAID in the window 8 to 30 days before the index date. Among current single users, we evaluated the effect of NSAIDs according to duration, dose, and plasma half-life/ formulation. We analyzed the risk among new users, defined as patients who were free of any NSAID use in the

3 1630 García Rodríguez et al. JACC Vol. 52, No. 20, 2008 Traditional NSAIDs, Coxibs, and MI November 11, 2008: year preceding the first NSAID prescription after start date (18). We also performed a sensitivity analysis using a 0 to 30 days time window to define current use. In vitro whole blood assays. We selected the specific cutoff values in milligrams between low-medium daily dose and high daily dose of NSAIDs used in the THIN population. The inhibitory effects toward platelet COX-1 and monocyte COX-2 by therapeutic concentrations of different NSAIDs (12 14) were determined in vitro using the human whole blood assays (3,4). The doses (Cmax) were as follows: naproxen 750 mg (253 M), ibuprofen 1,200 mg (39 M), meloxicam 7.5 mg (3 M), celecoxib 200 mg (1.8 M), rofecoxib 25 mg (1 M), indomethacin 75 mg (3 M), etoricoxib 90 mg (3.6 M), diclofenac 100 mg (0.8 M), piroxicam 20 mg (16.6 M), and etodolac SR 400 mg (26 M). Peripheral venous blood samples were withdrawn from 10 healthy subjects (ages 22 to 35 years), who gave their written informed consent. The in vitro study was approved by the local ethics committee, and it did not need Institutional Review Board review. Statistical analysis. We estimated the odds ratio and 95% confidence intervals (CIs) for MI associated with NSAID use compared with nonuse using unconditional logistic regression with Statview (SAS Institute, Cary, North Carolina). The mechanism of control sampling used in our study (known as incidence density sampling) means that the likelihood of being selected as a control is proportional to the person-time at risk (19). Under this design, the odds ratio is an unbiased estimator of the incidence rate ratio, also commonly referred as RR. Conditional logistic regression models stratified for matching factors (age, sex, and calendar year) produced similar results (data not shown). We used a p value 0.05 as the threshold of statistical significance. We adjusted for matching variables, use of other medications (aspirin, antihypertensive drugs, statins, other lipidlowering drugs, oral steroids, and warfarin), comorbidity (diabetes mellitus, hypertension, hyperlipidemia, rheumatoid arthritis, osteoarthritis, anemia, coronary artery disease [CAD], and cerebrovascular disease), smoking, body mass index, and health care utilization indicators. Variables that changed the estimates of NSAID use by 10% or more were included in the multivariable model. Specific stratified analyses were performed by sex, age, and history of CAD. Linear regression analysis was performed using InStat (GraphPad, San Diego, California) to estimate correlations between relative risk obtained from the THIN study and indexes of COX inhibition of individual NSAIDs. Concentration-response curves were fitted and IC 50 (drug concentration required for obtaining 50% of inhibition) values were analyzed with PRISM (GraphPad). Results Relative Treatment Risk Duration, of MI According and Daily to Dose Use, of NSAIDs* Table 1 Relative Risk of MI According to Use, Treatment Duration, and Daily Dose of NSAIDs* NSAID Exposure Controls (n 20,000) MI Cases (n 8,852) RR (95% CI) Recency Nonuse 15,513 6,434 Reference Current use 1, ( ) Single 1, ( ) Multiple ( ) Switcher ( ) Recent use 1, ( ) Past use 1, ( ) Duration 30 days ( ) days ( ) 1 3 years ( ) 3 years ( ) Daily dose Low-medium dose ( ) High dose ( ) *Relative risk (RR) adjusted for age, sex, calendar year, body mass index, general practitioner visits, referrals, smoking, Townsend score, ischemic heart disease, diabetes mellitus, rheumatoid arthritis, chronic obstructive pulmonary disease, and anticoagulants, antihypertensives, oral steroids, and aspirin use. Specific cutoff values for dose (in mg) were as follows: aceclofenac 200, acemetacin 120, azapropazone 600, celecoxib 200, diclofenac 100, diflunisal 1,500, etodolac 400, etoricoxib 90, fenbufen 900, fenoprofen 1,200, flurbiprofen 150, ibuprofen 1,200, indomethacin 75, ketoprofen 150, ketorolac 30, mefenamic acid 1,000, meloxicam 7.5, nabumetone 1,000, naproxen 750, piroxicam 10, rofecoxib 25, sulindac 200, tenoxicam 10, tiaprofenic 600, and valdecoxib 20. Doses less than or equal to the cutoff value were grouped under low-medium doses, and doses greater than the cutoff value were grouped under high doses. CI confidence interval; MI myocardial infarction; NSAID nonsteroidal anti-inflammatory drug. The overall incidence rate of nonfatal MI in our population, ages 50 to 85 years, was 4.1/1,000 person-years. The incidence was much greater among patients with antecedents of CAD (13.9) than among those without a history of CAD (3.0). Table 1 shows the risk associated with use of NSAIDs. The estimate of RR of MI with current single NSAID use was 1.35 (95% CI: 1.23 to 1.48). NSAID users who stopped treatment between 3 months and 1 year in advance had a risk similar to that of nonusers (RR: 1.02, 95% CI: 0.94 to 1.12). The RR of MI was 1.13 (95% CI: 0.92 to 1.39) among current users in their first month of treatment and 1.53 (95% CI: 1.28 to 1.82) when taking NSAIDs for 3 years. There was also a greater risk among users of high dose compared with users of low-medium dose (RR: 1.28, 95% CI: 1.07 to 1.53). Table 2 shows RRs of MI according to plasma half-life and formulation. Users of slow-release formulations had an RR of 1.22 (95% CI: 0.96 to 1.54) compared with users of the regular formulation. When daily dose was taken into account, the slightly greater risk among users of the slowrelease formulation was only observed in the low-medium dose category. Figure 1A shows the estimates of RR for individual NSAIDs. Most of them presented an RR compatible with a small increased risk or no increased risk, although the amount of information was insufficient to provide precise estimates. Only diclofenac and rofecoxib use were clearly associated with a greater risk of MI (RR: 1.67, 95% CI: 1.44 to 1.94; and RR: 1.46, 95% CI: 1.10 to 1.92, respectively).

4 JACC Vol. 52, No. 20, 2008 November 11, 2008: García Rodríguez et al. Traditional NSAIDs, Coxibs, and MI 1631 Relative and Release RiskFormulation of MI According of NSAIDs to Plasma and Stratified Half-Life by Daily Dose* Table 2 Relative Risk of MI According to Plasma Half-Life and Release Formulation of NSAIDs and Stratified by Daily Dose* Cases (n 8,852) Controls (n 20,000) RR 95% CI Overall Nonuse 6,434 15,513 Reference Short/no slow release Long/no slow release Slow release Low-medium dose Nonuse 6,434 15,513 Reference Short/no slow release Long/no slow release Slow release High dose Nonuse 6,434 15,513 Reference Short/no slow release Long/no slow release Slow release *RR adjusted for age, sex, calendar year, body mass index, general practitioner visits, referrals, smoking, Townsend score, ischemic heart disease, diabetes mellitus, rheumatoid arthritis, chronic obstructive pulmonary disease, and anticoagulants, antihypertensives, oral steroids, and aspirin use. Short half-life group: aceclofenac, acemetacin, celecoxib, diclofenac, etodolac, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, tiaprofenic acid, and valdecoxib. Long half-life group: apazone, meloxicam, nabumetone, naproxen, piroxicam, sulindac, tenoxicam, rofecoxib and etoricoxib. Slow-release group: ibuprofen, indomethacin, etodolac, diclofenac, and ketoprofen. Abbreviations as in Table 1. In Figure 1B, we reported the degree of inhibition on whole blood COX-1 and -2 activities in vitro produced by therapeutic concentrations of individual NSAIDs. Except for naproxen and ibuprofen, all other NSAIDs inhibited COX-2 more profoundly than COX-1 at therapeutic concentrations. Importantly, platelet COX-1 was suppressed at the functional range, namely, 95% (10) by therapeutic doses of naproxen but no other NSAIDs. In Figure 1C, we reported a statistically significant correlation (r , p ) between the degree of inhibition of whole blood COX-2 in vitro produced by average circulating therapeutic concentrations and the RR of MI associated with individual NSAIDs: naproxen, which has an effect on platelet COX-1 activity compatible with inhibition of platelet function, was not included. When we grouped individual NSAIDs with a degree of COX-2 inhibition 90% at therapeutic dose (ibuprofen, meloxicam, celecoxib, and etoricoxib), users of these NSAIDs presented an RR of 1.18 (95% CI: 1.02 to 1.38), whereas users of rofecoxib, indomethacin, diclofenac, and piroxicam (COX-2 inhibition 90%) had an RR of 1.60 (95% CI: 1.41 to 1.81, p for interaction 0.01). The effect of dose for individual NSAIDs is shown in Table 3; among users of ibuprofen, the RR for doses up to 1,200 mg daily was 1.00 (95% CI: 0.80 to 1.25), and it was 1.56 (95% CI: 0.90 to 2.71) for doses above 1,200 mg (mainly 1,800 mg). Accordingly, average drug concentrations after dosing with low and high doses of ibuprofen (39 and 111 M, respectively) (8) inhibited whole blood COX-2 activity by 75% and 90%, respectively. Figure 2 shows in more detail the effect of dose among users of diclofenac. A clear dose-response was observed (p for trend ): users of diclofenac 50 mg daily carried an RR of 1.12 (95% CI: 0.57 to 2.19), and the corresponding estimate among users of 150 mg was 1.80 (95% CI: 1.49 to 2.18). Also, the risk was slightly greater when diclofenac was administered as slow release compared with the plain form, even after adjusting for the dose. We looked at whether the effect of aspirin on MI was affected by concomitant use of NSAIDs (Table 4). None of the terms for interaction was statistically significant, although only concomitant use with ibuprofen and naproxen suggested a minor antagonism: the corresponding estimates of relative excess risk due to interaction were 0.16 and When we restricted the analysis to new users of NSAIDs, the overall estimates of risk were similar according to duration and daily dose. Also, there were only minor variations in risk among individual NSAIDs; the corresponding RR among new users of rofecoxib was 1.57 (95% CI: 1.17 to 2.11). No differences were observed in the estimates of RR with a more liberal definition of current use (supply of NSAID lasting until index date or ending in the month before index date) according to recency, duration, or daily dose of NSAIDs (data not shown). We also performed stratified analyses by sex, age, and history of CAD. The overall effect of NSAID use did not seem to be modified by sex, although the RR was slightly higher among females but not statistically significant (data not shown). The relative risk decreased with advancing age. Users of NSAIDs who were 50 to 59 years old presented an RR of 1.61 (95% CI: 1.27 to 2.04); the corresponding estimates among patients ages 60 to 74 and 75 to 84 years old were 1.34 (95% CI: 1.18 to 1.53) and 1.22 (95% CI: 1.03 to 1.45), respectively. The RRs of MI associated with NSAID use in patients with and without antecedents of CAD were 1.18 (95% CI: 0.98 to 1.42)

5 1632 García Rodríguez et al. JACC Vol. 52, No. 20, 2008 Traditional NSAIDs, Coxibs, and MI November 11, 2008: Figure 1 Degree of Inhibition of COX-2 by Average Circulating Concentrations of Individual NSAIDs Functionally Selective for COX-2 Is Relevant to RR of Nonfatal MI (A) Relative risk (RR) and 95% confidence interval (CI) of MI according to use of individual nonsteroidal anti-inflammatory drugs (NSAIDs). (B) Effects of therapeutic concentrations of NSAIDs on whole blood COX-1 (blue bars), mostly from platelets, and COX-2 (green bars), mostly from monocytes, in vitro. The dotted line represents the functional range of inhibition of platelet COX-1, namely, 95% (9). (C) Relationship between degree of inhibition of whole blood COX-2 and RR of MI by individual NSAIDs. Naproxen, which affects platelet COX-1 activity at functional range, is not shown. The linear regression analysis yielded a significant correlation between the 2 variables. It was performed using InStat (GraphPad, San Diego, California). Cele celecoxib; Diclo diclofenac; Etod etodolac; Etori etoricoxib; Ibu ibuprofen; Indo indomethacin; Melo meloxicam; Piro piroxicam; Rofe rofecoxib. and 1.41 (95% CI: 1.27 to 1.47), respectively. Of note, all stratum-specific CIs within each covariate were overlapping. Discussion In this nested case-control study with 8,852 incident nonfatal MI cases, we found that patients taking NSAIDs had a 35% increased risk of MI. The excess risk of MI was observed after 1 month of treatment and appeared to slightly increase with longer treatment duration. In addition to variable pharmacodynamic features, members of the NSAID class share different pharmacokinetics, such as half-life, which was another independent predictor of the CV hazard. Also, increasing daily dose, which determines the extent of COX-1 and -2 inhibition in vivo, was a clear predictor of the corresponding risk of MI. We were able to study the effect of dose and formulation in more detail with diclofenac: a gradual increase in risk accompanied each increasing dose of diclofenac as used in the general population. Over and above the effect of dose, data for slow-release formulations of diclofenac suggested a greater risk

6 JACC Vol. 52, No. 20, 2008 November 11, 2008: García Rodríguez et al. Traditional NSAIDs, Coxibs, and MI 1633 Relative Risk of MI According to Daily Dose of Individual NSAIDs* Table 3 Relative Risk of MI According to Daily Dose of Individual NSAIDs* Individual NSAIDs Cases (n 8,852) Controls (n 20,000) RR 95% CI Nonuse 6,434 15,513 1 Celecoxib Low-medium dose High dose Diclofenac Low-medium dose High dose Ibuprofen Low-medium dose High dose Indomethacin Low-medium dose High dose Meloxicam Low-medium dose High dose Naproxen Low-medium dose High dose Rofecoxib Low-medium dose High dose *RR adjusted for age, sex, calendar year, body mass index, general practitioner visits, referrals, smoking, Townsend score, ischemic heart disease, diabetes mellitus, rheumatoid arthritis, chronic obstructive pulmonary disease, and anticoagulants, antihypertensives, oral steroids, and aspirin use. Specific cutoff values for dose (in mg) were as follows: celecoxib 200, diclofenac 100, ibuprofen 1,200, indomethacin 75, meloxicam 7.5, naproxen 750, and rofecoxib 25. Doses less than or equal to the cutoff value were grouped under low-medium doses, and doses greater than the cutoff value were grouped under high doses. Abbreviations as in Table 1. of MI, probably as a direct consequence of prolonged drug exposure. This level of risk was greater than it was for any of the ones shared by coxibs and reinforces the approach of analyzing the CV risk of each member of the large NSAID family individually (20). The incidence of MI was much greater among patients with antecedents of CAD than it was among patients without a history of CAD. This finding is in agreement with the results of the recent celecoxib meta- Figure 2 Effect of Daily Dose and Formulation of Diclofenac on RR of Nonfatal MI Effect of the daily dose and formulation (slow release compared with plain) of diclofenac on relative risk (RR) of nonfatal myocardial infarction (MI) is shown. The RR and 95% confidence interval of MI according to daily dose of diclofenac are compared with nonuse and stratified by presentation form.

7 1634 García Rodríguez et al. JACC Vol. 52, No. 20, 2008 Traditional NSAIDs, Coxibs, and MI November 11, 2008: Relative AccordingRisk to Concomitant of MyocardialUse Infarction of Aspirin and NSAIDs* Table 4 Relative Risk of Myocardial Infarction According to Concomitant Use of Aspirin and NSAIDs* Aspirin Alone RR (95% CI) NSAID Alone RR (95% CI) Aspirin NSAID RR (95% CI) p Value Interaction All NSAIDs 1.04 ( ) 1.39 ( ) 1.33 ( ) 0.36 Celecoxib 1.04 ( ) 1.44 ( ) 1.13 ( ) 0.86 Diclofenac 1.03 ( ) 1.79 ( ) 1.41 ( ) 0.61 Ibuprofen 1.04 ( ) 1.02 ( ) 1.22 ( ) 0.14 Meloxicam 1.03 ( ) 1.61 ( ) 0.78 ( ) 0.17 Naproxen 1.04 ( ) 1.00 ( ) 1.26 ( ) 0.33 Rofecoxib 1.04 ( ) 1.47 ( ) 1.51 ( ) 0.49 *RR adjusted for age, sex, calendar year, body mass index, general practitioner visits, referrals, smoking, Townsend score, ischemic heart disease, diabetes mellitus, rheumatoid arthritis, chronic obstructive pulmonary disease, and use of anticoagulants, antihypertensives, and oral steroids. Reference group for estimates of RR is the same for all comparisons: nonusers of aspirin and NSAIDs. NSAID refers to the specific NSAID exposure indicated in the left column. Abbreviations as in Table 1. analysis by Solomon et al. (21) and concurrently by Arehart et al. (22). We found little evidence for a major effect modification of the antiplatelet effect of aspirin among users of NSAIDs (23). Data were suggestive of a potential reduction of the beneficial effect of aspirin only when taken together with ibuprofen and naproxen, although there was substantial statistical imprecision when examining the presence of this interaction with individual NSAIDs. Yet, this is consistent with the results of clinical pharmacology showing that ibuprofen and naproxen can interfere with the irreversible inhibition of platelet COX-1 by aspirin (24 26). We showed that pharmacodynamic and pharmacokinetic features of individual NSAIDs are all important determinants of CV hazard by COX inhibitors in the general population. Among the NSAIDs studied, only naproxen and ibuprofen were more potent toward whole blood COX-1 than COX-2 in vitro (6,27) (Fig. 2, Online Figs. 1A and 1B). Thus, average therapeutic plasma concentrations of these 2 NSAIDs may be associated with a balanced inhibition of COX-1 and -2 (Fig. 1B). In contrast to low-dose ibuprofen, naproxen and high-dose ibuprofen may suppress platelet COX-1 at the functional range, namely, 95% (10). Complete and perpetual suppression of platelet COX-1 activity is mandatory to fulfill cardioprotection because of a nonlinear relationship between inhibition of platelet TXA 2 generation and inhibition of TXA 2 -mediated platelet aggregation: thus, an excess of 95% inhibition of COX-1 activity is required to influence platelet function. In fact, even tiny concentrations of TXA 2 can activate platelets (11). Naproxen and ibuprofen are characterized by different pharmacokinetics; in other words, naproxen has a long half-life ( 12 h), whereas ibuprofen has a short-half life ( 2 h)(12). Thus, complete and persistent suppression of platelet COX-1 activity may occur in some users of naproxen (27,28), but will be absent among users of lowdose ibuprofen (the most prevalent use in the general population) and rare among users of high-dose ibuprofen. This impact on platelet COX-1 by naproxen might mitigate, even if not obliterate, the hazard conferred by the profound inhibition of COX-2 dependent prostacyclin (29,30). In fact, naproxen was associated with no increased CV risk. All other studied tnsaid and coxib results were more potent toward COX-2 in vitro, from 3- to 255-fold (rofecoxib) (Online Fig. 2). However, none presented a pattern of COX-1 inhibition compatible with prevention of CV events (10). These results showed that most tnsaids are as COX-2 selective as coxibs with respect to platelet function, at therapeutic concentrations. For functional COX-2 selective inhibitors, the degree of inhibition of whole blood COX-2 by plasma concentrations corresponding to the average NSAID therapeutic dose in patients (12 14), which is an index of drug potency/exposure, predicted the RR of MI. When we replaced our estimates of risk for individual NSAIDs with those reported in a recent meta-analysis of observational studies (31), the correlation was still acceptable (r , p ), although with less power as data were reported for only 4 NSAIDs. Analyses of previous clinical studies with rofecoxib 25 mg/day, celecoxib 200 mg twice a day, etoricoxib 90 mg/day, naproxen 220 mg twice a day, and low-dose aspirin 100 mg/day allowed us to detect a statistically significant relationship between the degree of inhibition of whole blood COX-2 ex vivo and inhibition of prostacyclin in vivo (as assessed by the urinary levels of 2,3-dinor-6-keto- PGF 1 )(27,28) (P. Patrignani and S. Tacconelli, unpublished data obtained with celecoxib, rofecoxib, and etoricoxib, June 2006) (Online Fig. 3). This relationship supports the notion that the CV hazard associated with the administration of coxibs and some tnsaids occurs through a common mechanism involving the inhibition of COX-2 dependent prostacyclin (29,30). Failure to detect any correlation (r , p 0.947) between the degree of inhibition of whole blood COX-1 in vitro and the risk of MI by the same NSAIDs (Online Fig. 4) lends little support to one hypothesis suggesting that stronger inhibition of endothelial COX-1 than platelet COX-1 could be the mechanism for the increased risk of thrombotic events by tnsaids and coxibs (32). In the same manner, after leaving out naproxen, which presents some functional suppression of

8 JACC Vol. 52, No. 20, 2008 November 11, 2008: García Rodríguez et al. Traditional NSAIDs, Coxibs, and MI 1635 platelet COX-1, the correlation observed between the achieved COX-2 selectivity (ratio of degree of inhibition of COX-2 and -1 at average plasma concentrations) and the risk of MI was very poor (r , p 0.665) (Online Fig. 5). Another aspect to be considered is the consequence of the inhibition of renal prostanoids by NSAIDs. In susceptible patients, inhibition of prostanoid generation by tnsaids and coxibs causes sodium retention with resulting edema and hypertension (29). Similar to thrombogenesis, COX-1 inhibition may mitigate the consequence of COX-2 inhibition in the kidney. This is compatible with a COX-2 dependent source of vasodilatory prostacyclin and COX-1 dependent origin of vasoconstrictors, like TXA 2, in the kidney (29,33). A few considerations need to be evaluated with respect to the validity of our findings. A potential limitation of studies using computerized prescription data is underascertaining over-the-counter drug use. In our study, misclassification of NSAID exposure is expected to be small, as only ibuprofen could be purchased over the counter in the United Kingdom during the study period. This misclassification would tend to be nondifferential, which, given the small magnitude of the observed association, would have little or no effect on our results. Also, we did not have information on over-thecounter use of aspirin (mainly, short-term analgesic use). Yet the degree of underestimation of aspirin use would be limited in the current study, as prescriptions are free for patients 60 years of age in the United Kingdom. That means the majority of patients requiring cardioprotective aspirin would be likely to receive it on prescription rather than have to pay for the drug over the counter, as reflected by the high prevalence of current low-dose aspirin use in our control series (18%). Myocardial infarction cases were ascertained through review of computerized files with free text comments available in a subset. We tested the validity of our case ascertainment in a random sample of close to 500 questionnaires sent to the general practitioners, resulting in a high confirmation rate of 95%. Actually, the overall incidence of MI in our source population ages 50 to 85 years was slightly over 4 of 1,000 person-years, in line with rates reported in previous studies (17). Conclusions We propose that the extent of inhibition of COX-2 dependent prostacyclin may represent an independent key determinant of the increased risk of MI among NSAIDs with nonfunctional suppression of platelet COX-1, a property shared by most tnsaids and coxibs, and that the assessment of whole blood COX-2 may represent a surrogate end point to predict the CV risk of these drugs. 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