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Celecoxib for colorectal adenomas increased CV events
  1. David Juurlink, MD, PhD, FRCPC
  1. University of Toronto, Toronto, Ontario, Canada

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 Q In patients with a history of colorectal neoplasia who are at risk of recurrent adenomatous polyps, how safe is celecoxib with respect to cardiovascular (CV) events?

    Clinical impact ratings GP/FP/Primary care ★★★★★★☆ IM/Ambulatory care ★★★★★★☆ Oncology ★★★★★☆☆ Gastroenterology ★★★★★☆☆ Cardiology ★★★★★☆☆

    METHODS

    Embedded ImageDesign:

    randomised placebo controlled trial (Adenoma Prevention with Celecoxib [APC] Study).

    Embedded ImageAllocation:

    unclear allocation concealment.*

    Embedded ImageBlinding:

    blinded (clinicians, patients, judicial assessors of outcomes, and monitoring committee).*

    Embedded ImageFollow up period:

    2.8–3.1 years.

    Embedded ImageSetting:

    91 sites in the US, Canada, Australia, and the UK.

    Embedded ImagePatients:

    2035 patients 32–88 years of age (mean age 60y, 68% men) who had had endoscopic polypectomy to remove colorectal adenomas.

    Embedded ImageIntervention:

    twice daily celecoxib, 200 mg (n = 685); celecoxib, 400 mg (n = 671); or placebo (n = 679). Patients were stratified by centre and use or non-use of aspirin for CV prophylaxis.

    Embedded ImageOutcomes:

    composite endpoint of death from CV causes, myocardial infarction (MI), stroke, or heart failure. Secondary composite endpoints included the addition of angina and need for a CV procedure.

    Embedded ImagePatient follow up:

    all patients completed at least 2.8–3.1 years of follow up (intention to treat analysis).

    MAIN RESULTS

    The trial was stopped early with a 77% completion rate. 800 mg/day of celecoxib led to a greater risk of the CV composite endpoint than did placebo (table). The risk decreased slightly when angina (hazard ratio [HR] 2.3, 95% CI 1.1 to 4.7) and need for a CV procedure (HR 1.9, CI 1.0 to 3.3) were added to the composite endpoint. Compared with placebo, 800 mg/day of celecoxib increased CV death or non-fatal MI (HR 3.8, CI 1.3 to 11.5) and CV death, non-fatal MI, or stroke (HR 3.4, CI 1.4 to 8.5), regardless of whether patients took low doses of aspirin. Risks of CV events were increased with 400 mg/day of celecoxib, but only reached borderline statistical significance for CV death or non-fatal MI (HR 3.0, CI 1.0 to 9.3) and CV death, non-fatal MI, or stroke (HR 2.5, CI 1.0 to 6.4).

    Cardiovascular (CV) safety of 400 and 800 mg/day of celecoxib for colorectal adenomas at 2.8–3.1 years*

    CONCLUSION

    In patients with a history of colorectal neoplasia who were at risk of recurrent adenomatous polyps, celecoxib led to a dose related increase in cardiovascular events.

    Abstract and commentary also appear in ACP Journal Club.

    Commentary

    It seemed like a good idea at the time: drugs that selectively inhibited cyclooxygenase 2 (COX 2) would inhibit the synthesis of prostaglandins responsible for pain and inflammation, without interfering with the important “housekeeping” functions of COX 1, such as maintenance of gastric mucosal integrity.1 It soon became apparent, however, that the COX 2 inhibitors (led by celecoxib and rofecoxib) were not wonder drugs at all. Efficacy was similar to their non-selective counterparts, but they were considerably more expensive and conferred only a slight gastrointestinal safety advantage. Nevertheless, these drugs became pharmaceutical juggernauts used by tens of millions of patients worldwide.

    The possibility that COX 2 inhibitors might increase risk of CV events was first raised in a large trial of rofecoxib.2 The 5 fold higher incidence of MI with rofecoxib, 50 mg/day was initially attributed to a cardioprotective effect of naproxen, the active comparator. Despite its rather thin biological plausibility, this assertion could not be refuted given the absence of a placebo group. Subsequent observational studies and other randomised trials of COX 2 inhibitors reached inconsistent conclusions, particularly on the hazards of celecoxib. However, the trials of Bresalier et al and Solomon et al provide new evidence that COX 2 inhibitors, as a class, increase risk of CV events in a dose dependent fashion.

    Why? The most widely held hypothesis is that unlike traditional NSAIDs, COX 2 inhibitors selectively inhibit endothelial prostacyclin synthesis without blocking the synthesis of thromboxane A2 in platelets, resulting in platelet aggregation and vasoconstriction. If this is the case, it is reasonable to ask why low dose aspirin did not seem protective in the APPROVE trial. In fact, it probably was. By virtue of being treated with aspirin, these patients (who were initially excluded from the trial) were almost certainly at increased risk of CV events a priori, and the concomitant use of aspirin probably attenuated the observed association between rofecoxib and CV events.

    Other more meaningful questions arise naturally from these 2 studies. Why did it take so long to clearly establish this association? Part of the answer rests in the high background incidence and “expectedness” of CV events, especially in older patients treated with COX 2 inhibitors, and the complex “web of causation” that makes it virtually impossible to definitively attribute even a single CV event to these drugs. Another explanation stems from the challenges of observational epidemiology. Foremost among these is the fact that patients treated with COX 2 inhibitors were often older and “sicker” than patients given traditional NSAIDs, making it difficult to ferret out the modifying influences of bias and confounding on CV outcomes.

    A more difficult and sensitive question relates to the toll exacted by COX 2 inhibitors at the population level. The true magnitude is unknowable, but given the popularity of these drugs and the absolute risk estimates of Bresalier et al and Solomon et al (notably, estimates derived from relatively “well” patients), it is likely that COX 2 inhibitors have caused many excess deaths from MI, heart failure, and stroke.

    While science and the courts look into the rearview mirror, clinicians and patients wonder how best to use these drugs in the future. Rofecoxib has been removed from the market, but celecoxib and other COX 2 inhibitors remain available. Although a considerable body of evidence suggests that celecoxib may be safer than rofecoxib, it is clearly not risk free. In light of celecoxib’s mediocre track record as an anti-inflammatory, it seems reasonable to ask whether it or COX 2 inhibitors should be used at all. Clinicians may have differing opinions on this. Recognising that no drug is completely free of risk, it seems sensible to restrict the use of COX 2 inhibitors to a small minority of patients without overt vascular disease who require an anti-inflammatory but are at high risk of gastrointestinal haemorrhage or are intolerant of other NSAIDs. These patients should be apprised of the possible risks and if they consent to treatment, both the dose and duration of therapy should be minimised.

    References

    View Abstract

    Footnotes

    • * See glossary.

    • For correspondence: Dr S D Solomon, Brigham and Women’s Hospital, Boston, MA, USA. ssolomonrics.bwh.harvard.edu

    • Sources of funding: National Cancer Institute and Pfizer.

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