By: Nancy Rizkalla, PharmD Candidate c/o 2015
NSAIDs are effective agents used in the management of several types of pain. They mitigate the negative effects of inflammation by inhibiting two key enzymes called cyclooxygenase (COX)—COX-1 and COX-2—and their subsequent products. However, the inhibition of these enzymes’ other beneficial functions is associated with negative side effects. In particular, COX-1 inhibition is associated with reduction in gastro-protective barriers, causing gastric irritation. To circumvent this unwanted effect and aim to only reduce the pro-inflammatory factors, selective COX-2 inhibitors that would reduce the formation of inflammatory mediators without compromising the beneficial effects of COX-1 byproducts were developed.
Unfortunately, it was soon discovered that this selective inhibition was not without risks. As it turned out, selective COX-2 inhibitors—while sparing patients of negative gastrointestinal (GI) effects—increased the risk for CV events, possibly due to the inhibition of vasodilatory products produced by COX-2 mechanisms without the balancing effect of reduced platelet aggregation that is afforded by COX-1 inhibition. This left clinicians with the following dilemma: how should high CV risk patients who opt for therapy with selective COX-2 inhibitors be treated? Is low-dose aspirin (used as prophylaxis for CV events) effective in counteracting the increased risk brought on by selective COX-2 inhibitors?
To date, no randomized controlled clinical trials have addressed this question. No studies have been conducted that directly compared selective COX-2 inhibitor use alone with the combination of a selective COX-2 inhibitor and low-dose aspirin to see if there was a subsequent reduction in CV events. Instead, randomized controlled clinical studies have been conducted to address the theoretical pharmacodynamic interaction that may exist with concomitant aspirin and selective COX-2 inhibitor use.
The basis for this interaction is that the selective COX-2 inhibitor may exhibit some affinity for COX-1 and compete with aspirin for binding sites, thereby reducing the effectiveness of aspirin-induced irreversible COX-1 inhibition.
A study conducted by Greenberg et al analyzed whether the concomitant use of rofecoxib and low-dose aspirin reduced the antiplatelet activity of aspirin.1 It was found that this combination did not, in fact, reduce the antiplatelet activity of aspirin, and it was noted that this combination was well tolerated—alleviating the fear that it may produce unwanted GI effects due to the addition of aspirin. On the other hand, in a study conducted by Jermany et al, the concomitant use of lumiracoxib and low-dose aspirin was assessed; and while the antiplatelet activity of aspirin was not found to be compromised, three adverse events (not classified as “serious”) occurred in the group receiving both lumiracoxib and aspirin.2
Two noteworthy studies were conducted that begin to shed light on the aforementioned question: the Celecoxib Long-term Arthritis Safety Study (CLASS) conducted by Silverstein et al, and the comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) conducted by Farkouh et al.3,4 In the CLASS trial, the use of celecoxib, ibuprofen, or diclofenac for six months was compared to assess rates of CV events—aspirin use up to 325mg/day was permitted. In regards to the question at hand, there was no noted increase in the incidence of cardiovascular events associated with celecoxib or NSAIDs, irrespective of aspirin use. Amongst patients not taking aspirin concomitantly, however, there was a greater reduction in upper GI toxicity.3 In the TARGET trial, treatment with lumiracoxib, naproxen, or ibuprofen was compared in respect to cardiovascular morbidity, and groups of patients on concomitant aspirin therapy were further stratified. At the 1-year follow up, the results did not show a statistically significant difference between patients in the aspirin population vs. the non-aspirin population. Still, among patients taking aspirin, those receiving lumiracoxib showed a trend toward fewer cardiovascular events as compared to patients receiving ibuprofen. This result may be due to the well-known pharmacodynamic interaction between ibuprofen and aspirin—which results in reduced aspirin efficacy— if their administration is not properly staggered.4
The Adenoma Prevention with Celecoxib (APC) trial demonstrated that high-dose, long-term celecoxib use was associated with an increase in the risk of thrombotic cardiovascular events.5 In the beginning of the trial, 30% of patients reported aspirin use. Thirty-three months after the trial was started, it was stopped by the National Cancer Institute because of an increase in the risk of cardiovascular events observed in both celecoxib arms. A number of post hoc analyses of the APC data examined whether patient factors could identify those at particularly high or low risk for thrombotic CV events. Of relevance, the aspirin user subgroup did not have a lower risk of CV events than those not using aspirin.5 This data was not statistically significant, and it still must be emphasized that we have inadequate evidence to determine whether concomitant administration of aspirin with selective COX-2 inhibitor therapy will provide any cardio-protection.
A similar finding was observed for an oral COX-2 inhibitor valdecoxib and its intravenous formulation, parecoxib, in two trials in patients undergoing coronary artery bypass graft (CABG): CABG I and CABG II.5 In the CABG I trial, treatment with valdecoxib vs. placebo was assessed, and in the CABG II trial, treatment with intravenous parecoxib followed by valdecoxib, intravenous placebo followed by valdecoxib, or intravenous placebo followed by oral placebo was assessed. It was found that valdecoxib with concomitant aspirin treatment in the CABG I and CABG II trials was associated with an increased cardiovascular risk compared with placebo. Both of these findings suggest that the increased CV risk associated with selective COX-2 inhibitor use may not simply be due to an imbalance between COX-1 and COX-2 inhibition.5
Based on this limited evidence failing to demonstrate any benefits provided by concomitant treatment with aspirin, clinical experts and practice guidelines have favored the side of caution and not recommended this combination in patient care. In addition to the lack of cardio-protection afforded by the aspirin, as previous studies have demonstrated, aspirin may negate any GI-protective effects of selective COX-2 inhibitors—causing more harm than good.2,4 A 2007 statement from the American Heart Association® commented regarding the use of a selective COX-2 inhibitor and aspirin: “Of note, the combination of aspirin (necessary for protection against cardiovascular events) and a coxib may ameliorate the gastric mucosal protective effect of COX-2 inhibition. The combination of the two may also prolong the time for recovery from gastric mucosal injury.” 6 Moreover, the 2012 American College of Rheumatology® Recommendations for the Use of Non-Pharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and Knee state the following: “In the clinical scenario where the patient with OA is taking low-dose aspirin (≤325 mg per day) for cardioprotection and the practitioner chooses to use an oral NSAID, the TEP (Technical Expert Panel) strongly recommends using a nonselective NSAID other than ibuprofen in combination with a proton-pump inhibitor. This recommendation is based, in part, on the FDA warning that the concomitant use of ibuprofen and low-dose aspirin may render aspirin less effective when used for cardioprotection and stroke prevention because of a recognized pharmacodynamic interaction. Studies have not demonstrated this same type of pharmacodynamic interaction with diclofenac or celecoxib; nonetheless, the TEP strongly recommends that a COX-2 selective inhibitor should not be used in the above situation. ” 7 Consistent with this approach, product labeling for Celebrex® (celecoxib) states that it can be used with low-dose aspirin but that there is no evidence to support that this combination will reduce the risk of serious thrombotic CV events, and that the combination of celecoxib and aspirin will increase the rate of GI complications compared to celecoxib use alone.8
In summary, if a patient already requires treatment with low-dose aspirin, concomitant treatment with a selective COX-2 inhibitor is not contraindicated. Clinicians should keep in mind, however, that the patient may not be reducing their risk for CV events, the risk for GI complications will be increased, and that the patient should be treated accordingly. Furthermore, in patients who do not ordinarily require treatment with low dose aspirin, but is considering treatment with a selective COX-2 inhibitor, the addition of low-dose aspirin is not required, as there is no concrete evidence of benefits resulting from this approach.
- Greenberg HE, Gottesdiener K, Huntington M, et al. A new cyclooxygenase-2 inhibitor, rofecoxib (VIOXX), did not alter the antiplatelet effects of low-dose aspirin in healthy volunteers. J Clin Pharmacol. 2000; 40(12 Pt 2): 1509-15.
- Jermany J, Branson J, Schmouder R, Guillaume M, Rordorf C. Lumiracoxib does not affect the ex vivo antiplatelet aggregation activity of low-dose aspirin in healthy subjects. J Clin Pharmacol. 2005; 45(10): 1172-8.
- Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS Study: A Randomized Controlled Trial. A Celecoxib Long-term Arthritis Safety Study. JAMA—J Am Med Assoc. 2000; 284(10): 1247-1255.
- Farkouh ME, Kirshner H, Harrington RA, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet. 2004; 364(9435): 675-84.
- Solomon DH. Selective cyclooxygenase 2 inhibitors and cardiovascular events. Arthritis Rheum. 2005; 52(7): 1968-78.
- Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007; 115(12): 1634-42.
- Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012Recommendations for the Use of Non-Pharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and Knee. Arthrit Care Res. April 2012; 64(4): 465-474.
- Celebrex® (Celecoxib) [package insert]. New York, NY: Pfizer; Revised January, 2013