Given the assumption that this mechanism explains the observed cardiovascular complications of COX-2 inhibitors, how would such a hazard be expected to become clinically manifest?
First, the actual degree of selectivity attained at the vascular interface in vivo would be an important variable. Although assays in whole blood in vitro suggest a clear segregation between the degree of selectivity attained by the drugs under consideration, there are substantial interindividual differences in drug response (59
) and consequent overlap in the degree of selectivity attained in vivo. Selectivity for COX-2 can be viewed as a continuous variable within the class of NSAIDs. Indeed, some tNSAIDs — diclofenac, nimesulide, meloxicam, and nabumetone — express average selectivity for COX-2 similar to that of celecoxib in human whole blood in vitro (28
). Sufficient concentration of any selective COX-2 inhibitor becomes nonselective as it begins to inhibit COX-1, at least in vitro (28
). Second, the more prolonged the drug exposure (determined by dose, duration of action, and duration of treatment), the more likely an adverse consequence. Third, concordant administration of low-dose aspirin, which favors inhibition of COX-1 (61
), would be expected to mitigate but not abolish the hazard. The degree and duration of simultaneous inhibition of the 2 COX enzymes would also be expected to influence the existence of a cardiovascular hazard from tNSAIDs (see below). Finally, IP–/–
mice are more responsive to thrombogenic stimuli; they do not develop spontaneous thrombosis (7
). Thus, a clinical or genetic predisposition to thrombosis would favor emergence of a drug-related cardiovascular event.
Aside from the question posed by clinical pharmacology, the first evidence consistent with the hypothetical cardiovascular hazard emerged in the Vioxx Gastrointestinal Outcome Research (VIGOR) study (62
), in which a 2-fold divergence in the incidence of serious GI adverse events between rofecoxib and the tNSAID naproxen coincided with a 5-fold divergence in the incidence of myocardial infarction (20 versus 4 events). This study was conducted with a high dose (50 mg/day) of rofecoxib in patients in whom low-dose aspirin was precluded. Most of the patients suffered from RA, a disease associated with an odds ratio of a myocardial infarction roughly 50% higher than in patients with osteoarthritis or no arthritis (63
). These results generated considerable controversy; some researchers claimed that rofecoxib was neutral and that the result reflected a cardioprotective effect of naproxen, based on its extended duration of action (64
), permitting this mixed inhibitor of COX-1 and COX-2 to behave like aspirin.
The corresponding outcomes study of celecoxib (Celecoxib Long-term Arthritis Safety Study [CLASS]) was published in a highly unorthodox manner (65
). Partial presentation of the data seemed to suggest that high-dose (800 mg/day) celecoxib had caused fewer GI adverse effects than its tNSAID comparators; however, this turned out not to be the case when the full data set was revealed (66
). This study, conducted with, on average, a shorter-lived, less selective COX-2 inhibitor than rofecoxib, also demonstrated no difference in the incidence of cardiovascular events. Around 20% of the patients took aspirin, and much was made of the apparent divergent incidence of GI adverse effects on ibuprofen versus celecoxib in a post hoc analysis of nonaspirin users. Perhaps aspirin had masked the GI advantage of celecoxib. However, if so, it may also have masked the cardiovascular hazard. A similar underpowered and retrospective analysis suggests that cardiovascular events occurred more often with celecoxib than with ibuprofen in nonaspirin users. Interestingly, the incidence of both GI and cardiovascular events on diclofenac and celecoxib appeared to be similar (67
In summary, the number of events reported in the VIGOR study was small. However, if the estimate of the difference between the 2 treatment groups was reliable, this was larger than might be expected from an “aspirin-like” effect of naproxen; clearly it was compatible with the coincidence of a cardiovascular hazard from rofecoxib and some protection from naproxen.
The traditional approach to drug safety is to rely upon pharmacoepidemiology. However, this is an insensitive detector system when the need is to identify a small absolute increase — maybe 1–2% in retrospect — in the absolute incidence of a problem that occurs commonly in the age group under study. In addition to these limitations, epidemiological (observational) studies are subject to many sources of bias, and in this particular case, the common use of prescription databases was also potentially confounded by unrecorded over-the-counter use of tNSAIDs and aspirin.
Further attention to the prospect of a cardiovascular hazard from the COX-2 inhibitors (coxibs) was prompted initially by a comparison of trial data for both drugs, including the VIGOR and CLASS studies, with a control group, based on data drawn from the placebo groups of 4 primary prevention trials of low-dose aspirin (68
). However, this indirect analysis was subject to considerable methodological criticism. The estimated cardiovascular event rates in 2 of the placebo groups lay below while 2 were above those calculated for rofecoxib and celecoxib. Roughly 70% of the data for the pooled estimate in the control group was drawn from the first 2 studies. However, the controversy around this paper prompted a spate of observational studies. Several (69
) but not all of these detected a cardiovascular hazard associated with 50 mg/d rofecoxib, but most failed to do so with lower doses such as that (25 mg/d) used in the randomized controlled-outcome trial (RCT), the Adenomatous Polyp Prevention on Vioxx (APPROVe) study, that subsequently led to the withdrawal of the drug (72
). Most observational studies and overview analyses of the small, short studies that provided the basis for drug approval also failed to detect a hazard from celecoxib (73
) and valdecoxib (74
). Pharmacoepidemiology alone did not clearly discriminate between a hazard peculiar to rofecoxib and a mechanism-based effect.
The situation was clarified by the emergence of information from 4 published (and 1 still unpublished; ref. 75
) placebo-controlled trials. The pattern of the clinical information was consistent with the proposed mechanism. For reasons discussed above, a prothrombotic clinical substrate would favor the rapid emergence of adverse cardiovascular events in a relatively small study. An example of such a setting is coronary artery bypass grafting (CABG), which is characterized by intense hemostatic activation (76
). Two placebo-controlled studies of valdecoxib (77
), anteceded by its intravenous prodrug parecoxib, were performed in patients undergoing CABG. Despite their small study sizes (462 and 1636 patients, respectively) and short duration (10 and 14 days of treatment, respectively), pooled analysis of the 2 quite similar studies suggests that parecoxib/valdecoxib elevate the combined incidence of myocardial infarction and stroke by 3-fold in this population (79
). Although the patients were prescribed aspirin, the timing of its administration relative to the incidence of the vascular events is unclear. CABG is also a setting of apparent “aspirin resistance” (80
). These studies are compatible with the rapid emergence of a cardiovascular hazard based on suppression of COX-2–derived PGI2
in a population with preexisting, intense hemostatic activation. Similarly, one would anticipate that a less pronounced prothrombotic substrate, such as the patients with RA in the 9-month VIGOR trial, might reveal a hazard more gradually. The rapidity with which a cardiovascular risk might become manifest would reflect in part the intensity of a genetic or environmental predisposition to thrombosis (Figure ).
Figure 4 Illustration of the expected interaction of baseline cardiovascular and thrombotic risk with components of drug exposure including dose, duration of action, and duration of treatment with a selective inhibitor of COX-2. The approximate relationship of (more ...)
) and Adenoma Prevention with Celecoxib (APC), 2 studies in patients with colonic adenomata, presumed initially to be at low risk of cardiovascular events, revealed the gradual emergence of a cardiovascular risk attributable respectively to rofecoxib (72
) and celecoxib (81
) after dosing for more than 1 year (Figure ). Supportive of this being a true drug-related effect, the hazard in patients taking celecoxib 200 mg/bid and 400 mg/bid appeared to be dose related (81
Several comparative studies of COX-2 inhibitors and tNSAIDs failed to detect a discriminant incidence of cardiovascular events. However, in each case, these studies were substantially underpowered to exclude this possibility. These include the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) (82
), which comprised two 1-year long, comparator studies of lumiracoxib, 1 with ibuprofen, 1 with naproxen. While cardiovascular events tended to be higher in the lumiracoxib group, the study included patients mostly at low risk, and the power of the comparisons was undermined (83
). Furthermore, TARGET was not designed to establish noninferiority of cardiovascular risk among the treatment groups; thus, it had no predefined upper confidence interval for relative risk (84
) and used an intention-to-treat analysis. While it has been suggested that the pharmacokinetics of lumiracoxib favor a transient exposure in the vascular compartment with prolonged availability in the joint space (85
), 400 mg/d of lumiracoxib exceeds considerably the dose necessary to inhibit COX-2 at the time of peak drug action. Given at this dose, it has a prolonged systemic pharmacodynamic half-life, depressing PGIM excretion to a similar extent and for a similar duration as rofecoxib (ref. 86
and P. Patrignani, personal communication). Unpublished studies also substantially underpowered to exclude a cardiovascular hazard include the prematurely and unconventionally terminated Alzheimer’s Disease Anti-inflammatory Prevention (ADAPT) study of celecoxib, naproxen, and placebo in Alzheimer disease and the multinational, placebo-controlled evaluation of celecoxib (400 mg/d) in chemoprevention of colonic adenomata (http://www.clinicaltrials.gov/ct/show/NCT00087256).
In summary, while the number of cardiovascular events in all
of the relevant individual RCTs addressing this issue is small, the currently available clinical evidence is remarkably compatible with a unitary mechanism for which there is comprehensive biological plausibility, attained in vivo. The clinically concordant evidence includes the following: (a) the easiest detection of a signal in epidemiological studies for a long-lived compound with a high degree of selectivity for COX-2, rofecoxib, given at a high dose (50 mg/d); (b) the rapid emergence of a signal in 2 relatively small RCTs of valdecoxib in a setting of intense hemostatic activation and likely aspirin resistance; (c) the intermediate time to detection of a hazard in RA patients in the VIGOR study in whom hemostatic activation and risk of thrombosis is considerably less than in those individuals that have undergone CABG but exceeds that in patients without arthritis; (d) the similarity of the overview analyses of etoricoxib versus naproxen to what was observed in VIGOR (67
) and evidence in trials to date (87
) consistent with a cardiovascular hazard from this drug; (e) the delayed emergence of a hazard in 2 RCTs of prolonged treatment with rofecoxib and celecoxib, which is compatible with risk transformation in patients initially at low risk of cardiovascular disease; and (f) the evidence of hazard involving 3 structurally distinct selective COX-2 inhibitors — belying the notion that this is an off-target effect of rofecoxib. Finally, the issue of a mitigating effect of low-dose aspirin has not been addressed in the RCTs. This seems biologically plausible, as COX-1 knockdown in mice, which genetically mimics the impact of low-dose aspirin (88
), attenuates the prothrombotic and hypertensive effect of COX-2 inhibition (Y. Cheng, personal communication). However, aspirin use was only prespecified in one of the RCTs in humans: TARGET. As mentioned, this was underpowered to address the cardiovascular question. However, the available evidence is compatible with risk attenuation; the relative risk of myocardial infarction was reduced from 2.37 in nonusers to 1.36 in those patients taking aspirin when lumiracoxib was compared with naproxen (83
). However, this might also reflect a differential capacity of naproxen versus lumiracoxib to interact with and undermine the antiplatelet effect of low-dose aspirin (see below).