Editorial

VIOXX and cardiovascular events: a class effect?

Keywords: NSAID; COX2 inhibitor; Cyclooxygenase

1. Introduction

The removal of rofecoxib (Vioxx) from the market decidedon September 30, 2004, by Merck-MSD caused a dramaticflare-up in the COX2-inhibitor controversy. The company’sdecision was based on data from the APPROVE trial compar-ing rofecoxib to a placebo in the prevention of colorectal pol-yps. A significant increase in cardiovascular events was notedin the rofecoxib arm. Should this result bring all COX2 inhibi-tors into disrepute and encourage physicians to prefer con-ventional nonsteroidal antiinflammatory drugs (NSAIDs)? Inother terms, is the cardiovascular risk increase seen with rofe-coxib a class effect related to selective cyclooxygenase-2(COX2) inhibition or is it due to specific properties of therofecoxib molecule?

2. The APPROVE trial

The APPROVE trial was a 3-year randomized placebo-controlled trial designed to evaluate rofecoxib 25 mg/day inthe prevention of colorectal polyps. There were 2586 patientswith a mean age of 59 years. Cardiovascular risk factors andaspirin use were comparable in the two groups. Cardiovascu-lar event rates were similar in the two groups during the first18 months. Subsequently, however, rates remained unchangedin the placebo group but increased in the rofecoxib group, inwhich the main cardiovascular events were myocardial inf-arction and cerebrovascular accidents. Over the 36-monthtreatment period, 118 major cardiovascular events wererecorded, 78 in the rofecoxib group and 41 in the placebogroup (P < 0.008). The relative risk of cardiovascular eventsin the rofecoxib group was 1.98 (95% confidence interval,1.20–3.15). This is the first rofecoxib versus placebo trialshowing a significant difference in cardiovascular events.

3. A class effect?

This possibility has been a focus of concern since the pub-lication in 1999 of the VIGOR trial results [1]. In the VIGORtrial, 8076 patients with rheumatoid arthritis were allocated

at random to either rofecoxib 50 mg/d or naproxen 1000 mg/d.None of the patients were taking aspirin for cardiovascularrisk reduction. Although fewer gastrointestinal side effectsoccurred with rofecoxib, there was a significant increase inmyocardial infarctions (0.4% versus 0.1% with naproxen),and this increase was particularly marked in the subgroupwith cardiovascular risk factors. This finding sparked contro-versy about the cardiovascular safety profile of rofecoxib[2,3]. According to one hypothesis, the difference was ascrib-able to the known antiplatelet effects of naproxen. Anotherhypothesis, however, was that selective COX2 inhibition byrofecoxib increased the risk of cardiovascular events by caus-ing an imbalance in vascular compartment prostaglandin pro-duction, with an excess of platelet thromboxane and there-fore increased platelet aggregation.

If this second hypothesis is true, then cardiovascular eventrates should be increased with all COX2 inhibitors. Some evi-dence that this may be the case has been obtained, for instancewith valdecoxib and parecoxib (Bextra* and Dynastat*,respectively, Pfizer). In two studies, of which one has beenpublished [4], cardiovascular event rates were increased whenthese drugs were used to relieve pain after coronary bypassgrafting. Conversely, no evidence of adverse cardiovasculareffects has been reported for celecoxib (Celebrex*, Pfizer);however, neither can such effects be ruled out, as no long-term studies similar toAPPROVE have been published. Long-term studies over several years are underway to investigatecelecoxib therapy for preventingAlzheimer’s disease or coloncancer. The largest study of NSAID therapy published to datecompared lumiracoxib (Prexige*, Novartis) 800 mg/d to ibu-profen 2400 mg/d or naproxen 1000 mg/d given for 1 year to18,325 patients with osteoarthritis [5]. No significant increasein cardiovascular events was noted with the COX2 inhibitor.However, a trend to an increase in cardiovascular events wasfound in the lumiracoxib group comparatively to the naproxengroup (0.38% versus 0.21%; P = 0.14); there was no differ-ence versus the ibuprofen group (0.38% versus 0.21%, P= 0.14). Finally, etoricoxib (Arcoxia*, Merck-MSD) is beingevaluated in a vast 3-year study of 20,000 patients withosteoarthritis or rheumatoid arthritis designed to evaluate car-diovascular events and other variables (MEDAL: Multina-tional Etoricoxib vs. Diclofenac Arthritis Long-term).

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When interpreting these data, however, the specific char-acteristics of each COX2 inhibitor should be taken intoaccount. For instance, selectivity for COX2 may be lowestfor celecoxib, according to pharmacological studies based onthe reference test [6]. If cardiovascular events constitute aclass effect of COX2 inhibitors, one would expect their rateto decrease with COX2 selectivity. Systemic half-life mayalso affect the cardiovascular safety profile. A COX2-inhibitor with a short half-life administered according to aschedule that lets plasma levels decline over the 24-hour cyclemay allow a return to homeostasis in the target tissues, mostnotably the vascular system. This mechanism might explainthe absence of excess cardiovascular events with celebrex(half-life, 11 h) and the results with lumiracoxib (half-life,6 h), although lumiracoxib is more selective for COX2 thanis rofecoxib (half-life, 17 h).

4. A rofecoxib-specific effect independent fromCOX2 inhibition?

Several clinical and experimental studies comparing cele-coxib to rofecoxib suggest that rofecoxib may increase therisk of arterial hypertension [7]. However, some of these stud-ies have been severely criticized as methodologically unsound(regarding drug dosages, blood pressure measurement tim-ing, etc.). The authors of these studies ascribed the blood pres-sure effects to differences across molecules rather than toselective COX2 inhibition.

Epidemiological data are inconclusive. Although the car-diovascular events recorded with rofecoxib seemed dose-dependent in several observational studies [8,9] and occurredonly after prolonged use [9], some studies found no increasein cardiovascular risk. With celecoxib, no evidence of an effecton cardiovascular risk has been reported.

5. A NSAID effect?

The COX2 inhibitors are NSAIDs and share several sideeffects with conventional NSAIDs. For instance, all NSAIDsincrease systolic blood pressure by about 3–5 mm Hg on aver-age. Although small, this effect is theoretically sufficient toincrease cardiac events, such as heart failure, in high-riskpatients [10]. Another source of concern is that aspirin, evenin moderate dosages (325 mg/d) may increase the rate of cere-brovascular events and myocardial infarctions [11]. In theAPPROVE trial, cardiovascular events in the rofecoxib groupincreased only after 18 months, and a significant blood pres-sure elevation was noted (+2.4–4 mm Hg) as compared to theplacebo group. However, based on a preliminary analysis, theinvestigators concluded that this blood pressure elevation wasnot sufficient to explain the difference in cardiovascular eventrates between the rofecoxib and placebo groups.

6. Practical implications

For all COX2 inhibitors, studies of cardiovascular eventsare ongoing or will be started soon. Until the results are avail-

able, caution is probably the most responsible approach toour patients, who often receive contradictory information fromtheir family or the media. In my opinion, patients with car-diovascular risk factors warranting secondary prophylactictherapy should not receive COX2 inhibitor therapy at the timebeing. These patients are usually on long-term aspirin therapy,a fact that further complicates the selection of a substituteantiinflammatory drug. Low-dose aspirin therapy is associ-ated with partial or complete loss of selectivity for COX2 inthe gastric mucosa. On the other hand, a number of conven-tional NSAIDs (but not COX2 inhibitors) may compete withthe antiplatelet effect of aspirin. Therefore, the appropriate-ness of combining low-dose aspirin with an NSAID requirescareful consideration [12].

Treatment duration should be taken into account: the like-lihood of a cardiovascular event occurring is higher in patientstreated for longer than 12 months, particularly those with car-diovascular risk factors.

This controversy draws attention to a well-known sideeffect of NSAID therapy, namely, hypertension. Closer moni-toring of blood pressure values may be warranted, as well asa policy of working jointly with cardiologists to evaluate thecardiovascular risk profile of each patient.

7. Conclusion

The removal of rofecoxib (Vioxx*) from the market andthe debate that has raged around COX2 inhibitors for the lastfew years should encourage rheumatologists to reappraise therisk/benefit ratio of each NSAID prescription. The variableseverity of disorders treated with NSAIDs complicates thistask. Therefore, prescriptions should be written on a case-by-case basis, taking into account the expected symptomaticeffect of the medication, the disorder being treated, its impacton quality of life, and the availability of other treatmentoptions. At the same time, consideration should be given toeach of the known side effects (e.g., gastrointestinal toxicityand cardiovascular events) and to their expected frequencygiven patient-related risk factors and treatment duration. How-ever, predicting the risk of side effects is difficult, as mosttherapeutic trials include only a very small proportion of thepopulation seen in everyday practice (as shown by the longlists of exclusion criteria). At present, side effect predictionis done empirically, and no evaluation tools suited to every-day practice are available.

The steady accumulation of knowledge about side effectsof NSAIDs, together with the shift from gastrointestinal tocardiovascular events as the main cause for concern, servesas a reminder that all effective medications are associated witha range of adverse effects. Applying the precautionary prin-ciple would lead us to prescribe only placebos except inpatients with diseases that are consistently fatal in the short-term [13]. A more realistic approach consists in having thepatient and physician agree on the level of risk they are pre-pared to accept in order to enjoy the expected beneficial effectsof the medication.

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References

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[2] Berenbaum F. Selective cyclooxygenase-2 inhibitors: hope and facts.Joint Bone Spine 2000;67:499–501.

[3] Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular eventsassociated with selective COX-2 inhibitors. JAMA 2001;286:954–9.

[4] Ott E, Nussmeier NA, Duke PC, Feneck RO, Alston RP, Snabes MC,et al. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxiband valdecoxib in patients undergoing coronary artery bypass surgery.J Thorac Cardiovasc Surg 2003;125:1481–92.

[5] Farkouh ME, Kirshner H, Harrington RA, Ruland S, Verheugt FW,Schnitzer TJ, et al. Comparison of lumiracoxib with naproxen andibuprofen in the therapeutic arthritis research and gastrointestinalevent trial (TARGET), cardiovascular outcomes: randomised con-trolled trial. Lancet 2004;364:675–84.

[6] Tacconelli S, Capone ML, Sciulli MG, Ricciotti E, Patrignani P. Thebiochemical selectivity of novel COX-2 inhibitors in whole bloodassays of COX-isozyme activity. Curr Med Res Opin 2002;18:503–11.

[7] Whelton A. COX-2-specific inhibitors and the kidney: effect onhypertension and oedema. J Hypertens 2002;20(Suppl 6):S31–5.

[8] Graham DJ, Campen DH, Cheetham C, Hui R, Spence M, Ray Wa,et al. Risk of acute cardiac events among patients treated withcyclooxygenase-2 selective and non-selective anti-inflammatorydrugs. In: 20th International Conference on Pharmacoepidemiologyand Therapeutic Risk Management. Aout; 2004 [abstract].

[9] Mamdani M, Rochon P, Juurlink DN, Anderson GM, Kopp A,Naglie G, et al. Effect of selective cyclooxygenase 2 inhibitors andnaproxen on short-term risk of acute myocardial infarction in theelderly. Arch Intern Med 2003;163:481–6.

[10] Bleumink GS, Feenstra J, Sturkenboom MC, Stricker BH. Nonsteroi-dal anti-inflammatory drugs and heart failure. Drugs 2003;63:525–34.

[11] Baron JA, Cole BF, Sandler RS, Haile RW,Ahnen D, Bresalier R, et al.A randomized trial of aspirin to prevent colorectal adenomas. N EnglJ Med 2003;348:891–9.

[12] Berenbaum F. NSAIDs and aspirin: friends or foes? Joint Bone Spine2003;70:89–90.

[13] Boissier MC. Pondering the precautionary principle. Joint Bone Spine2003;70:318–20.

Francis Berenbaum *Saint-Antoine teaching hospital, Pierre and Marie Curie

University Paris VI, FranceE-mail address:

francis.berenbaum@sat.aphp.fr (F. Berenbaum).

Received 2 November 2004; accepted 9 November 2004

Available online 13 December 2004

* Corresponding author. Rheumatology Department,Saint-Antoine Hospital, 184, rue du faubourg Saint-Antoine,

75012 Paris, France. Tél. : +33-1-49-28-25-20;Fax : +33-1-49-28-25-13.

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