Pain is a distressing feeling and is the commonest symptom in clinical practice. It affects the quality of life. Sleep can be disturbed. The International Association of Pain defines pain as unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain can interfere with quality of life and general functioning. In elderly, musculo-skeletal pain is very common and demands pain relief with analgesics. NSAIDS are commonly prescribed. Elderly subjects usually have associated disorders like hypertension and diabetes, which are established risk factors for cardiovascular disease. Regular usage of NSAIDS can further increase this risk.
The increased risk of thrombotic events mediated by non-selective and selective COX-2 inhibitors has also been shown by large scale epidemiological studies. McGettigan and Henry(3) in their meta-analysis have summarized the results of 23 controlled observational studies (six cohort and 17 case control). The case control studies included 86,193 patients with cardiovascular events and 528,000 controls. In the cohort studies,75,520 coxib users and 375,619 users of nonselective NSAIDs were compared to 594,720 patients without exposure to NSAIDs. The Relative Risk values of cardiovascular events were analysed. From non-selective NSAIDs, the highest risk was present in the case of diclofenac (RR=1.40) and the safest was naproxen (RR=1.35). For rofecoxib (RR=1.35), the risk was significantly influenced by dose. Studies therefore suggest that there is an increased risk of thrombotic events with use of NSAIDs. Diclofenac poses a cardiovascular health risk compared with non-use, paracetamol use and use of other traditional non-steroidal anti-inflammatory drugs. (4)
Mechanisms for Thrombotic Events
Several theories have been put forward for this phenomenon. PGI-2 which has vasodilating and antithrombotic effects, is produced in the vessel wall. Selective Inhibition of COX -2 results in deficiency of PGI-2 while vasoconstricting and thrombogenic TXA-2 goes unchecked. This results in imbalance of pro-thrombotic and antithrombotic factors paving the path for thrombosis.
Though non- selective NSAIDs inhibit COX-1, significant suppression of platelet aggregation requires greater than 95% inhibition of COX-1. This is observed with aspirin and in certain situations with high dose of naproxen.(5) The overall strength of COX-2 inhibition appears to be the most important determinant of cardiovascular risk.(5)
The inhibition of PGI-2 production causes an increase in vascular tone, blood pressure elevation, thrombogenic state and likely atherosclerosis. COX-2 and PGI-2 also seem to play a key role in the resistance of the myocardium to ischemic – reperfusion injury observed after ischemic preconditioning or after administration of certain medications. (6,7)
Despite the above explanations the exact mechanisms responsible for high variability of the thrombotic risk with various NSAIDs remain unknown.
NSAIDs and Blood pressure
The rise in blood pressure with use of NSAIDs is possibly due to sodium & water retention and reduced formation of vasodilator prostacyclin. The risk of NSAID- mediated blood pressure increase in patients with controlled hypertension by use of anti-hypertensive drugs also depends upon the antihypertensive drug used. The effect of beta-blockers and various renin-angiotensin-aldosterone system (RAAS) inhibitors seems to be influenced the most. It appears that renin production is inhibited by NSAIDs as a compensatory mechanism to reduce the blood pressure raised due to sodium and water retention. However, this mechanism does not work in patients whose renin is chronically inhibited by drugs.
NSAIDs and Heart Failure
Inhibition of prostanoid production in the kidney may reduce the glomerular filtration and excretion of sodium and water. This paves the path for hypervolemia and worsening of heart failure. Presence of impaired renal or cardiac function also promote the development of heart failure. Heerdink et al(8) demonstrated that relative risk of hospitalization for heart failure to be 1.8 (95% CI=1.4-2.4) when NSAIDs were administered to patients treated with diuretics. There was no significant difference between individual NSAIDs, suggesting a class effect. The study further showed that the highest risk of heart failure decompensation was present within the first days of treatment initiation with NSAIDs.
Conclusions
Based on studies, the increased cardiovascular risk with use of NSAIDs, appears to be a class effect. Also, the absolute degree of COX-2 inhibition and not COX-2 selectivity is responsible for the increased risk. In clinical practice, musculo-skeletal disorders are common in the elderly population demanding prescriptions of NSAIDs. They usually suffer from hypertension, coronary artery disease and heart failure. Sleep disorders are also common and nocturnal musculoskeletal pain can be distressing. While addressing the issue of cardiovascular risk, it is also important to consider NSAIDs as a pharmacological risk factor.
The use of NSAIDs needs adequate monitoring of signs and symptoms of adverse effects and proper patient education to increase patient safety during NSAID therapy. Minimal dose with minimal duration of therapy needs to be stressed. Finally, pain management with physical and occupational therapies must be preferred to pharmacological agents.
References
1.Sharma S, Govind B, Rao K. The impact of non-steroidal anti-inflammatory drugs use in elderly cardiovascular patients- an observational study from tertiary care in South India. Int J Res Med Sci 2019; May;7(5):1787-1791.
2. Pawlosky N. Cardiovascular risk of all NSAIDS alike? Can Pharm J 2013;146(2):80-83.
3.McGettigan, Henry D: Cardiovascular risk and inhibition of cyclooxygenase- a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 2006; 296:1633-1644.
4. Schmidt M, Sorenson HF,Pedersen L. Diclofenac use and cardiovascular risks: series of nationwide cohort studies. BMJ 2018;362 doi: https://doi.org/10.1136/bmj.k.3426 (Publised 04 September 2018) Cite this as : BMJ 2018;362:K3426
5.Hinz B, Renner B, Brune K. Drug insight: cyclo-oxygenase -2 inhibitors- a critical appraisal. Nat Clin Pract Rheumatol 2007;3:552-560.
6.Shinmura K, Tang XL,Wang Y et al.Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits. P Natl Acad Sci. USA 2000;97: 10197-10202.
7.Birbaum Y, Ye Y, Rosanio S, et al. Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia-reperfusion injury. Cardiovasc Res.2005; 65:345-355.
8. Heerdink ER, Leufkens HG, Herings RMC,Ottervanger JP, Stricker BH, Bakker A: NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med. 1998; 158:1108-1112.
Dr.S.Ramnathan Iyer- MD (Medicine), FRCP (Glasgow),FICP,FGSI,FISDA,FISH, Consultant Physician- Sleep Medicine, Ambika Clinics- Dombivli (East), Dist. Thane and Kharghar, Navi Mumbai, Visiting Consultant-Sleep Medicine, Godrej Memorial Hospital, Vikhroli (East), Mumbai
Disclaimer: This website is primarily for healthcare professionals. The content here does not replace medical advice and should not be used as medical, diagnostic, endorsement, treatment, or prescription advice. Medical science evolves rapidly, and we strive to keep our information current. If you find any discrepancies, please contact us at corrections@medicaldialogues.in. Read our Correction Policy here. Nothing here should be used as a substitute for medical advice, diagnosis, or treatment. We do not endorse any healthcare advice that contradicts a physician's guidance. Use of this site is subject to our Terms of Use, Privacy Policy, and Advertisement Policy. For more details, read our Full Disclaimer here.
NOTE: Join us in combating medical misinformation. If you encounter a questionable health, medical, or medical education claim, email us at factcheck@medicaldialogues.in for evaluation.