Cyclo-oxygenase-2 Inhibitors and Peripheral Thrombosis – A Case Report Demonstrating a Possible Adverse Effect
Article Outline
Abstract
Cyclo-oxygenase-2 inhibitors are thought to be associated with an increased risk of cardiovascular events as a result of alteration in hemostasis. We report the case of a 39-year-old patient with minimal risk factors for cardiovascular disease who was prescribed a cyclo-oxygenase-2 inhibitor. He presented with symptoms of distal vessel thrombosis which was confirmed with angiography; this provides further evidence of the possible association of cyclo-oxygenase-2 inhibitors and thrombus formation.
Keywords: Cyclo-oxygenase 2 inhibitors, Thromboembolism, Peripheral vascular diseases, Adverse effects
Introduction
Recent clinical trials have demonstrated a possible increase in cardiovascular events associated with cyclo-oxygenase-2 (COX-2) inhibitors. This is attributed to a disruption in normal physiological hemostasis which contributes to thrombus formation, an essential component in the pathophysiology of cardiovascular disease. In the following case report, we present a case of peripheral thrombosis in a young patient with minimal risk factors who was also prescribed a COX-2 inhibitor.
Case Report
In August 2004, a 39-year-old man with longstanding ulcerative colitis and associated arthritis, presented with an 8-week history of pain in his right foot, which was worse when walking and in cold environments. He had no major risk factors for peripheral vascular disease other than total cholesterol of 5.6
mmol/l. His medications included prednisolone, mesalazine, calcichew and celecoxib which he had been taking for two years prior to this presentation.
On examination, the right forefoot appeared pale with evidence of venous guttering. Ankle brachial pressure index readings were 1.1 bilaterally. A clinical diagnosis of distal vessel occlusion was made.
An intra-arterial digital subtraction angiogram demonstrated diseased vessels below the mid-calf of the right leg, including occlusion of the anterior tibial and peroneal arteries and a much attenuated posterior tibial artery (Fig. 1).
Figure 1
Intra-arterial digital subtraction angiogram of the right calf and ankle showing occlusion of the distal arteries below the mid-calf.
It was commented upon that this was in keeping with vascular disease secondary to a hypercoaguable state. A cardiology review, which included an ECG and echocardiogram, concluded that there was no cardiac abnormality or potential source of emboli. Thrombophilia screening, cryoglobulins and immunoglobulin electrophoresis were all negative; homocysteine levels were normal. A vasculitic screen was positive for atypical p-ANCA and weakly positive for ANA; other markers were negative.
The patient was treated with a 5-day course of prostacyclin infusions which resulted in resolution of his symptoms.
Discussion
Non-steroidal anti-inflammatory drugs (NSAIDs) have been used effectively as both analgesic and anti-inflammatory agents; however, they also demonstrate a significant gastrointestinal side effect profile. The development of more selective cyclo-oxygenase (COX) inhibitors has provided a similar class of drug with a reduced gastrointestinal effect.1 However, over recent years, a variety of clinical trials have highlighted a possible association with COX-2 inhibitors and an increased risk of cardiovascular and cerebrovascular events. While the Vioxx Gastrointestinal Outcomes Research Study (VIGOR) compared the incidence of gastrointestinal side effects of rofecoxib and naproxen in patients with rheumatoid arthritis, results showed that the relative risk of developing a thrombotic cardiovascular event with rofecoxib was 2.38 (95% confidence interval 1.39–4.00; p=0.002) compared to naproxen.2 A more recent study, the Adenoma Prevention with Celecoxib (APC), was discontinued due to the cardiovascular effects observed.3 In this study 1% of patients in the placebo group died from cardiovascular causes compared to 2.3% receiving 200mg celecoxib twice daily and 3.4% receiving 400mg twice daily showing a dose related increase in deaths from cardiovascular causes.
One proposed mechanism of the cardiovascular effect of COX-2 inhibitors is the disruption of hemostasis which occurs during vascular stimulation such as rupture of an atheromatous plaque.4 In the vascular endothelium COX-2 is responsible for prostacyclin (PGI2) production, a prostaglandin which inhibits platelet aggregation and proliferation of vascular muscle cells while promoting vasodilatation. Thromboxane A2 (TXA2), which is a major product of platelet COX-1, promotes platelet aggregation, vasoconstriction and vascular proliferation; in other words the opposite effects of prostacyclin. During vascular stimulation there is an increase in both PGI2 and TXA2 maintaining hemostasis. However, when there is inhibition of endothelial prostacyclin by a COX-2 inhibitor, the effects of TXA2 predominate resulting in a prothrombotic state.5
There have been reports of thrombosis in ulcerative colitis; however, these have mainly been venous. Arterial thrombi affecting aortoiliac, femoropopliteal, and digital arteries have been reported but more commonly in Crohn's disease. These predominantly occur postoperatively or during acute exacerbations.6
In the absence of risk factors and given the young age of the patient in this case, the presentation of peripheral vascular symptoms could be attributed to COX-2 inhibitors. The proposed mechanism of this association, namely an induced prothrombotic state, was further implicated by the angiographic findings.
In the majority of studies concerning COX-2 inhibitors and cardiovascular disease, outcomes have included myocardial infarction and stroke; however since there is a similar underlying mechanism of thrombus formation, we postulate that there may be an association between COX-2 inhibitors and peripheral thrombotic episodes. While there have been no such cases reported in the literature, this case report highlights such a possibility.
Conflict of Interest
The authors have no conflict of interest.
References
- . The coxibs, selective inhibitors of cyclo-oxygenase-2. N Engl J Med. 2001;345:433–442
- Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000;343:1520–1528
- Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352:1071–1080
- . Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286:954–959
- . The cardiovascular toxicity of selective and nonselective cyclo-oxygenase inhibitors: comparisons, contrasts and aspirin confounding. J Clin Pharmacol. 2005;45:742–750
- . Extensive arterial and venous thrombosis in a patient with ulcerative colitis – a case report. MedGenMed. 2005;7(2):10
PII: S1533-3167(08)00028-9
doi:10.1016/j.ejvsextra.2008.11.002
© 2008 European Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
Refers to article:
- Cyclo-oxygenase-2 Inhibitors and Peripheral Thrombosis—A Case Report Demonstrating a Possible Adverse Effect , 27 January 2009
