|Year : 2014 | Volume
| Issue : 5 | Page : 417-422
A cohort study to evaluate cardiovascular risk of selective and nonselective cyclooxygenase inhibitors (COX-Is) in arthritic patients attending orthopedic department of a tertiary care hospital
Uma A Bhosale1, Nilofar Quraishi1, Radha Yegnanarayan1, Dileep Devasthale2
1 Department of Pharmacology, Smt. Kashibai Navale Medical College and General Hospital, Narhe, Pune, Maharashtra, India
2 Department of Orthopedics, Smt. Kashibai Navale Medical College and General Hospital, Narhe, Pune, Maharashtra, India
|Date of Web Publication||9-Sep-2014|
Uma A Bhosale
Department of Pharmacology, Smt. Kashibai Navale Medical College, Narhe, Pune - 411 041, Maharashtra
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Cyclooxygenase-2 inhibitors (COX-2-Is) have recently been concerned in the occurrence of adverse cardiovascular (CV) events. Rofecoxib and valdecoxib has been withdrawn from the market, but celecoxib, etoricoxib and parecoxib continues to be used. Other nonsteroidal anti-inflammatory drugs (NSAIDs) may also increase the risk of CV events. However, clinical trial databases for COX-2-Is had created lots of controversies regarding cardiovascular safety of selective and nonselective cyclooxygenase inhibitors (COX-Is). This study was, conducted to assess and compare the CV risk of COX-Is in arthritic patients over a period of time. Materials and Methods: In this prospective cohort study adult arthritics of either sex those were freshly diagnosed or taking COX-Is for < 3 months; were included. Patients were grouped into nonselective and selective COX-2-I groups with reference to treatment they received. The CV risk factors like blood pressure (BP), blood sugar level (BSL), lipid profile, body mass index (BMI) were assessed and compared; demography of CV risk factors was also studied. Data obtained was analysed using Student's 't'-test of OpenEpi statistical software. Results: Study clearly revealed that all NSAIDs exhibit variable CV risk; however, selective COX-2-Is found to exhibit more CV risk. BMI, BP and lipid profile; the potential CV risk factors, showed significant impairment in selective COX-2-Is group; P < 0.01, P < 0.001 and P < 0.05, respectively, compared to baseline and P < 0.05 vs. nonselective COX-Is for BMI. Conclusions: This study portrays the potential CV risk of selective COX-2-Is; confirms and re-evaluate the results of earlier studies in this regard.
Keywords: Body mass index, cardio-vascular risk, cyclooxygenase inhibitors, lipid profile
|How to cite this article:|
Bhosale UA, Quraishi N, Yegnanarayan R, Devasthale D. A cohort study to evaluate cardiovascular risk of selective and nonselective cyclooxygenase inhibitors (COX-Is) in arthritic patients attending orthopedic department of a tertiary care hospital. Niger Med J 2014;55:417-22
|How to cite this URL:|
Bhosale UA, Quraishi N, Yegnanarayan R, Devasthale D. A cohort study to evaluate cardiovascular risk of selective and nonselective cyclooxygenase inhibitors (COX-Is) in arthritic patients attending orthopedic department of a tertiary care hospital. Niger Med J [serial online] 2014 [cited 2019 Nov 12];55:417-22. Available from: http://www.nigeriamedj.com/text.asp?2014/55/5/417/140386
| Introduction|| |
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely prescribed group of therapeutic drugs worldwide, and include many common analgesics and anti-inflammatory agents.  Selective COX-2-Is have demonstrated improved gastrointestinal tract (GI) safety over nonselective NSAIDs. , The clinical trials have evidenced that, compared to nonselective COX -Is, COX-2-Is associated with a reduced rate of serious GI events as well as a reduced requirement for concomitant gastro-protective therapies.  This relative benefit may be due to a lack of COX-1-mediated inhibition of gastric mucous production and a lack of effect on platelet thromboxane production. However, the differential effects of COX-2-Is on platelet aggregation, prostacyclin/thromboxane balance, and inflammatory mediators involved in the development of atherosclerosis have also led to concerns that COX-2-Is increase the CV events. ,
Evidence from large prospective clinical trials on CV risks has been largely limited as those trials were designed to evaluate primarily GI events. The VIOXX Gastrointestinal Outcomes Research Study (VIGOR) revealed an increased rate of thrombotic events in patients receiving COX-2 inhibitor (rofecoxib).  Mukherjee and colleagues have compared rate of CV events in rofecoxib and celecoxib in VIGOR and Celecoxib Long-term Arthritis Safety Study (CLASS) trials with four aspirin studies viz., the US Physicians Health Study, the UK Doctors Study, the Thrombosis Prevention Trial, and the Hypertension Optimal Treatment Trial and revealed significantly higher CV event rate in COX-2-Is treatment groups. ,
In contrast to this, Konstam and colleagues  have analysed the results of multiple clinical studies involving rofecoxib and have not demonstrated any increased risk for CV events comparing COX-2 inhibitors and nonselective NSAIDs. Observational studies also have found mixed results when comparing select COX-2 Is and nonselective NSAIDs. , Hence, we chose to research this question with an observational prospective cohort study of CV risk of selective and nonselective COX-Is in adult arthritic patients. Many of the observational studies rely on case-control designs. In our cohort study, we evaluated the risk of cardiovascular events with COX-2 Is versus nonselective NSAIDs.
| Materials and methods|| |
In this observational prospective cohort study adult arthritic patients of either sex those were freshly diagnosed or taking COX-Is for < 3 months; were included. Patients those with history of any other disease (e.g., diabetes, hypertension, stroke, IHD, etc.) and medical treatment for the same were excluded. Initial ECG screening of every patient was done to rule out the cardiovascular disease. After getting the protocol approved by institutional ethics committee (Ref: SKNMC NO/Ethics/Corr/2011/103) patients were grouped into nonselective and selective COX-2-Is groups with reference to treatment they received (n = 34). Their CV risk factors i.e. BMI, BP, BSL, lipid profile, etc., were assessed at enrollment and recorded as baseline. All arthritic patients were followed up and CV risk factors were assessed at 6 th and 12 th month of treatment [see [Figure 1]. Parameters were compared with their baseline records and among the groups. Demographics of CV risk factors (i.e., age, sex, smoking, alcohol, heredity) were also studied. BMI calculated by online BMI calculator while, 10-year CV risk was calculated using Framingham's calculator. Statistical test used was Student's 't'-test using OpenEpi statistical software package version 2.
| Results|| |
In this prospective cohort study we have assessed the effects of NSAIDs on CV risk factors in arthritic patients over a period of time (1 yr). The demographic profiles of these arthritic patients were also studied and are presented in [Table 1]. There were 22 males and 46 females with mean age 50.7 yrs enrolled in this study. Subset arthritic patients with history of smoking were 10, alcohol consumption 6 and familial CVD 22. Arthritic patients with family history of CVD were maximum (15 out of 22) in selective COX-2-Is group. Arthritics in nonselective and selective COX-2-Is group received eight different NSAIDs [see [Figure 2]. Among nonselective NSAIDs, diclofenac sodium was received by majority of the patients (23%) followed by aceclofenac (10%) and only 2% were treated by indomethacin. In selective COX-2-Is 47% arthritics received etoricoxib and 3% received celecoxib.
|Figure 2: Distribution of cyclooxygenase inhibitors use in arthritic patients (n = 68)|
Click here to view
From the results of this study it becomes evident that all NSAIDs reason potential CV risk when taken over a period of time as in arthritic patients. However, selective COX-2-Is found to impart higher CV risk in this regard. BMI, BP, and lipid profile; the potential CV risk factors, showed statistically significant impairment in selective COX-2-Is-treated arthritic patients; P < 0.01, P < 0.001 (SBP) and P < 0.05, respectively, compared to baseline and P < 0.05 for BMI compared to nonselective COX-Is group at the end of 1yr treatment. Triglycerides (TGs) and cholesterol were apparently increased with apparent fall in HDL levels in COX-2-Is group after 6 month of treatment but this increase was statistically insignificant. No significant effect was observed on diastolic blood pressure and random BSL [see [Table 2], [Table 3] and [Figure 3].
|Table 2: Effects of cyclooxygenase inhibitors on physical cardiovascular risk factors|
Click here to view
|Table 3: Effects of cyclooxygenase inhibitors on biochemical cardiovascular risk factors|
Click here to view
When 10 year comparative CV Risk was assessed using Framingham's calculator; maximum over all CV risk percentage was reflected in selective COX-2-Is treated arthritics [see [Table 4]. While significantly higher risk of getting CHD and MI (P < 0.05) and apparently high risk of stroke, CVD, CHD death and CVD death (P > 0.05) over 10 years was also observed in arthritic patients treated with selective COX-2-Is and same was observed in subset arthritic patients [see [Table 5].
|Table 4: Comparative percentage 10-year risk of CHD, MI, stroke, CVD, CHD Death and CVD Death in arthritic patients|
Click here to view
| Discussion|| |
Arthritis is one of a 100 musculoskeletal conditions of varying etiologies and most prevalent disease involving middle age and elderly i.e., 50-65yrs and go on increasing in prevalence with age i.e. >65 yrs, the incident rate of arthritis is three times higher in females compared to males. , In this study also there were 22 men with 46 women with mean age 50.7 yrs, suggestive of high incidence rate in middle age women.
In present study arthritic patients received eight different NSAIDs; among nonselective COX-Is group 66% patients received diclofenac sodium and aceclofenac (i.e., phenylacetic acid derivatives) remaining patients were treated with other nonselective NSAIDs. In selective COX-2-Is group 94% patients received etoricoxib while only 6% treated with celecoxib.
Older age (≥ 45 years of age for men and ≥ 55 years for women), smoking, hypertension, low HDL concentration, hyperlipidaemia, hyperglycaemia and a family history of heart disease are major CV risk factors.  In present study we have evaluated CV risk of NSAIDs with reference to these risk factors. And the results have revealed that COX-2-Is cause significant increase in BMI, SBP and also significant impairment in lipid profile; the potential CV risk factors in arthritic patients. Nonselective COX-Is also showed impairment in lipid profile of the arthritics but except HDL this impairment was statistically insignificant. The effect of selective COX-2-Is on these CV risk factors could be attributed to etoricoxib as 94% of patients received etoricoxib while in nonselective COX-Is, these effects should be attributed to phenylacetic acid derivative with similar properties.
Presently rofecoxib, valdecoxib and lumiracoxib have been withdrawn from the market worldwide on the basis of results of various trials viz. VIGOR, APPROVe and TARGET. ,,, Conflicting results of several clinical trials about CV safety of celecoxib created controversies. , Comparatively cardiovascular safety data about etoricoxib is scare although few clinical trials stated that etoricoxib exhibit less or comparable CV risk to nonselective NSAIDs and did not appear to significantly increase the risk for MI and stroke. ,, But in our study it has reasoned significant risk for CHD and MI (P < 0.05) whereas reflected apparent increase in risk of stroke, CVD and death due to CHD and CVD which was statistically insignificant compared to nonselective COX-Is. Hence though the results of our study confirm that selective COX-2-Is exhibit comparable CV risk to nonselective NSAIDs; our study results are in disagreement with the earlier studies that states selective COX-2-Is exhibit less CV risk and did not significantly increase the risk for MI and stroke.
Increased CV risk of selective COX-2-Is is said to be due inhibition of formation of the vasodilator PGI2, and leaving TXA2 unopposed, which facilitates vasoconstriction, platelet activation and smooth muscle cell proliferation but, their exact role on lipid profile, atherosclerosis and plaque formation is still unclear.  Recently molecular studies have identified cytochrome p-450 (CYP) pathway in arachidonic acid (AA) metabolism along with COX and lipooxygenase pathway (LOX). CYP epoxygenases are known to metabolise AA to four regioisomeric epoxyeicosatrienoic acids (5, 6-, 8, 9-, 11, 12-, and 14, 15-EET) and by CYP w -hydroxylases to 20-hydroxyeicosatetraenoic acid (20-HETE).  It is potent vasoconstrictor and induces oxidative stress. In clinical studies, it is associated with increased BMI and the metabolic syndrome.  COX pathway offer cardioprotection due to production of PGI2 by inducible COX 2 and blockade of this pathway may ultimately result into unopposed production of 20-HETE.  This could be the reason for increased BMI and impaired lipid profile in selective COX2-Is treated arthritic patients.
COX1 and COX2 exert opposite effects on systemic blood pressure and renal function. COX2 inhibitors reduce renal medullary blood flow, decrease urine flow, and enhance the pressor effect of Angiotensin II. In contrast, the pressor effect of Angiotensin II is blunted by COX1 inhibition.  Nonselective NSAIDs are said to increase blood pressure by nonselective blocking of COX1and 2 while selective NSAIDs by blocking of COX 2; hence nonselective NSAIDs are considered more renal toxic. But in our study significant increase was observed in COX-2-Is group and these findings are in agreement with various epidemiological studies that state hypertensive complications occur more commonly in patients treated with COX-2-Is.  LOX pathway has predominant role in insulin release and COX inhibition does not affect this release.  Our study also revealed no significant difference in BSL in both COX-Is groups compared to baseline.
In this study we have also explored the CV risk in subset arthritic patients i.e. with history of smoking, alcohol consumption and familial CVD which otherwise remained unexplored in majority of the earlier studies. History of familial CVD has positive correlation with CV risk as stated in earlier few studies; , our study results reflected higher CV risk in selective COX-2-Is group (9.6%). This high CV risk could be due to maximum number of arthritics (15 out of 22) with familial CVD were there in COX-2-Is group, which confirms this positive correlation.
Smoking is one of the most important CV risk factors for the development and progression of atherosclerosis. COX-derived prostanoids mediate the pathogenic effects of cigarette smoking on vascular health. Higher CV risk in smokers (23%) observed in arthritics treated with COX2-Is group could be explained on the basis of that all of these agents invariably cause an imbalance between PGI2 and TXA2; as they block COX2-derived prostacyclin (PGI2) keeping TXA2 biosynthesis unopposed by COX 1 in smokers.  Several epidemiological investigations have shown that a low to moderate level (i.e., 20 g-70/day) of alcohol intake has definitive protective role against CHD and stroke. Mechanisms for cardioprotective effects include increased HDL, decreased LDL, prevention of clot formation, reduction in platelet aggregation, and lowering of plasma apolipoprotein (a). In contrast to this heavy intake (i.e., <89 g-70/day) increase the CV risk due to increased homocysteine levels.  In this study CV risk was found to be high (20%) in COX2-Is group and alcohol consumption appears to compliment this.
| Conclusions|| |
Several earlier studies have affirmed CV risk of Selective COX-2-Is like rofecoxib, valdecoxib, lumiracoxib and celecoxib. Our study mainly emphasizes the potential CV risk of etoricoxib; CV safety data of which is scare and continued to be used in therapeutics. The results of this study encourage the proclamation that CV risk of COX-2-Is could be expressed as a class effect, derived from earlier studies in this regard. Although COX-2-Is preferred over nonselective COX-Is due to cardiovascular, GI and renal toxicity of these agents and are said to be safe, the use of selective COX-2-Is must be constrained to the arthritic patients with absolute contraindications (i.e., peptic ulcer, asthma and renal disease) for nonselective NSAIDs as arthritics need to take them over a long period of time and they impart substantial CV risk over a period of time. Thus this study could be a rewarding accumulation in CV safety data of selective COX-2-Is.
| Acknowledgement|| |
The authors are thankful to Dr. A.V. Bhore, Dean SKNMC and Dr. Madhav Khadilkar, HOD Orthopaedics and Dr. Dnyaneshwari Ghadage CCL I/C for providing facilities to carry out the experiments of this work.
| References|| |
|1.||Ritter JM, Harding I, Warren JB. Precaution, cyclooxygenase inhibition, and cardiovascular risk. Trends Pharmacol Sci 2009;30:503-8. |
|2.||Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520-8. |
|3.||Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284:1247-55. |
|4.||Weir MR, Sperling RS, Reicin A, Gertz BJ. Selective COX-2 inhibition and cardiovascular effects: A review of the rofecoxib development program. Am Heart J 2003;146:591-604. |
|5.||Sperling R, Braunstein N, Melin J, Reicin A. Cyclooxygenase 2 inhibitors and thrombogenicity production: Comment on the article by Crofford et al. Arthritis Rheum 2001;44:1229-30. |
|6.||Ehrich EW, Dallob A, de Lepeleire I, van Hecken A, Riendeau D, Yuan W, et al. Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model. Clin Pharmacol Ther 1999;65:336-47. |
|7.||Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286:954-9. |
|8.||Konstam MA, Weir MR, Reicin A, Shapiro D, Sperling RS, Barr E, et al. Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib. Circulation 2001;104:2280-8. |
|9.||Solomon DH, Schneeweiss S, Glynn RJ, Kiyota Y, Levin R, Mogun H, et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 2004;109:2068-73. |
|10.||Mamdani M, Juurlink DN, Lee DS, Rochon PA, Kopp A, Naglie G, et al. Cyclo-oxygenase-2 inhibitors versus nonselective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: A population-based cohort study. Lancet 2004;363:1751-6. |
|11.||Hootman JM, Helmick CG, Brady TJ. A public health approach to addressing arthritis in older adults: the most common cause of disability. Am J Public Health 2012;102:426-33. |
|12.||Kuo CF, Luo SF, See LC, Chou IJ, Chang HC, Yu KH. Rheumatoid arthritis prevalence, incidence, and mortality rates: A nationwide population study in Taiwan. Rheumatol Int 2013;33:355-60. |
|13.||Irons BK, Snella KA, McCall K, MacLaughlin EJ, Villarreal M. Update on the management of dyslipidemia. Am J Health Syst Pharm 2002;59:1615-25. |
|14.||Topol EJ. Failing the public health--rofecoxib, Merck, and the FDA. N Engl J Med 2004;351:1707-9. |
|15.||Davies NM, Jamali F. COX-2 selective inhibitors cardiac toxicity: Getting to the heart of the matter. J Pharm Pharm Sci 2004;7:332-6. |
|16.||Farkouh ME, Kirshner H, Harrington RA, Ruland S, Verheugt FW, Schnitzer TJ, et al, TARGET Study Group. Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET), cardiovascular outcomes: Randomized controlled trial. Lancet 2004;364:675-84. |
|17.||Mackenzie IS, Wei L, MacDonald TM. Cardiovascular safety of lumiracoxib: A meta-analysis of randomized controlled trials in patients with osteoarthritis. Eur J Clin Pharmacol 2013;69:133-41. |
|18.||Giorgi M, Kim TW, Saba A, Rouini MR, Yun H, Ryschanova R, et al. Detection and quantification of cimicoxib, a novel COX-2 inhibitor, in canine plasma by HPLC with spectrofluorimetric detection: Development and validation of a new methodology. J Pharm Biomed Anal 2013;83:28-33. |
|19.||Combe B, Swergold G, McLay J, McCarthy T, Zerbini C, Emery P, et al. Cardiovascular safety and gastrointestinal tolerability of etoricoxib vs diclofenac in a randomized controlled clinical trial (The MEDAL study). Rheumatology (Oxford). 2009;48:425-32. |
|20.||Cannon CP, Curtis SP, FitzGerald GA, Krum H, Kaur A, Bolognese JA, et al, MEDAL Steering Committee. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: A randomised comparison. Lancet 2006;368:1771-81. |
|21.||Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: Network meta-analysis. BMJ 2011;342:c7086. |
|22.||Gross GJ, Falck JR, Gross ER, Isbell M, Moore J, Nithipatikom K. Cytochrome P450 and arachidonic acid metabolites: Role in myocardial ischemia/reperfusion injury revisited Cardiovasc Res 2005;68:18-25. |
|23.||Qi Z, Hao CM, Langenbach RI, Breyer RM, Redha R, Morrow JD, et al. Opposite effects of cyclooxygenase-1 and-2 activity on the pressor response to angiotensin II. J Clin Invest 2002;110:61-9. |
|24.||Grosser T, Smyth EM, FitzGerald GA. Anti-inflammatory, antipyretic & analgesic agents; pharmacotherapy of gout. In: Brunton LL, Chabner BA, Knollmann BC, editors. Goodman & Gillman's The Pharmacological Basics of Therapeutics. 12 th ed. China,: McGraw Hill; 2011. p. 962-76. |
|25.||Walsh MF, Pek SB. Effects of lipoxygenase and cyclooxygenase inhibitors on glucose-stimulated insulin secretion from the isolated perfused rat pancreas. Life Sci 1984;34:1699-706. |
|26.||TMT Review: Cardiovascular safety of Celebrex. Available from: www.fda.gov/ohrms/dockets/dockets/04n0559/04N-0559 [Last accessed on 2013 Dec]. |
|27.||Hermann M, Krum H, Ruschitzka F. To the heart of the matter: Coxibs, smoking, and cardiovascular risk. Circulation 2005;112:941-5. |
|28.||Agarwal DP. Cardioprotective effects of light-moderate consumption of alcohol: A review of putative mechanisms. Alcohol Alcohol 2002;37:409-15. |
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
|This article has been cited by|
||Omega-3 PUFA vs. NSAIDs for Preventing Cardiac Inflammation
| ||Jiayu Ye,Sanjoy Ghosh |
| ||Frontiers in Cardiovascular Medicine. 2018; 5 |
|[Pubmed] | [DOI]|
||Combination effect of anti-rheumatic medications for coronary artery diseases risk in rheumatoid arthritis: a nationwide population-based cohort study
| ||Yao-Min Hung,Lichi Lin,Yu-Hsun Wang,James Cheng-Chung Wei,Paul Yung-Pou Wang,Jeng-Yuan Chiou |
| ||Current Medical Research and Opinion. 2018; : 1 |
|[Pubmed] | [DOI]|
||The effect of anti-rheumatic medications for coronary artery diseases risk in patients with rheumatoid arthritis might be changed over time: A nationwide population-based cohort study
| ||Yao-Min Hung,Lichi Lin,Chyong-Mei Chen,Jeng-Yuan Chiou,Yu-Hsun Wang,Paul Yung-Pou Wang,James Cheng-Chung Wei,Graham R. Wallace |
| ||PLOS ONE. 2017; 12(6): e0179081 |
|[Pubmed] | [DOI]|