Safety Profile of Nonsteroidal Antiflammatory Drugs (NSAID) R. Stoilov: University Hospital St Ivan Rilski, Clinic of Rheumatology Contact: Rumen Stoilov, Clinic of Rheumatology, University Hospital St Ivan Rilski, 15 Acad. Ivan Geshov Blvd, 1431 Sofia, e-mail: rmstoilov@abv.bg Key words: Nonsteroidal Anti-Inflammatory Drugs, Gastrointestinal toxicity, Cardiovascular toxicity, COX 2 inhibitors Abstract: NSAIDs are among the most frequently used medicinal products in medical practice. They are in great use for managing pain and other symptoms of inflammation, but they can also cause a number of adverse effects on gastrointestinal tract, cardiovascular or kidney and urinary systems, etc. The leading mechanism which defines their efficiency as well as their toxicity is the suppression of cyclooxigenesis. COX-1 inhibition is related with the manifestation of adverse drug reaction. COX-2 inhibitors have smaller gastrointestinal toxicity, though some researches suggest that long-term treatment with coxibs in high doses can increase the risk from cardiovascular incidents. This review article shows that the efficiency of coxibs is comparable to that of nonselective NSAIDs, though considerably more sparing to gastrointestinal tract, while some of them can increase the risk from cardiovascular incidents. Review Article The rheumatic diseases are characteristic with high frequency. Every 7 th inhabitant on the Earth has some rheumatic disorders, in every 3 rd family there is a member with a rheumatic problem. More than 200 rheumatic diseases are known. About 300 million in the world are only those suffering from arthritis and osteoporosis. In Europe their number is about 100 million. Most of these diseases are chronic. The rheumatic diseases are one of the most frequent causes for temporal working incapacity as well as permanent disability. The ageing of the population and the changes of the way of life of the contemporary people will increase the relative part of these chronic diseases such as osteoarthritis, osteoporosis, and various types of arthritis etc, which become more frequent in the late decades of people s lives (see Graph 1). The demographic prognosis show definite increase of the number of people of over 60 and over 80 years of age in the forthcoming decades. In Europe only the joint diseases constitute about 50% of all chronic diseases of people over 65 years of age (4). The chronic course of these diseases requires constant or intermittent treatment as well as periodical medical and laboratory control. This is connected with considerable financial funds for drugs, consumables, medical equipment, doctors labour etc. In Europe the economic burden for only rheumatic diseases is more that 200 billion euro a year (4). In many cases the working capacity may be preserved but the discomfort caused by them has influence on the quality of the professional activity of the sufferers and their quality of life in the leisure time. (Graph 1) Frequency of most common rheumatic diseases by age The most widely used medicines for the treatment of rheumatic diseases are the Nonsteroidal antiflammatory drugs. They combine antiflammatory, analgetic and antipyretic effect. Daily more than 30 million people all over the world use nonsteroidal antiflammatory drugs. 10% of the total population in most of the European countries take nonselective NSAID, whereas this percentage reaches 25 with the adults (14). With this kind of drugs symptomatic influence can be achieved on the joint pains, on the stiffness and the swelling as well as on the functional capacity of the loco- 15
motory system i.e. a considerable clinical improvement of the sick people. In clinical application of NSAID it is necessary to observe the following principles: adequate dosage; sufficient duration of the course of treatment; taking into consideration the individual sensitivity to NSAID; correct distribution of the prescribed dose in the twenty-four-hour period; usage of alternative forms of application (rectal, parenteral, percutanic) etc. Regardless of the fact that NSAID are extremely useful for supressing the inflammation and pain, their usage is often accompanied by adverse drug reactions. In the recent years, more and more attention is paid to the correlation benefit/risk in the clinical application of NSAID. Particular attention is worth paying to gastrointestinal adverse events (1), and recently the cardiovascular, too (8). According to the data of the Spanish system of Pharmacovigilance (SSPV) for the period 1983 1991, 18 348 reports of adverse drug reactions were made and 8.8% out of them were caused by NSAID, thus taking the second place after the antibiotics (15.1%). The most frequently quoted NSAID are: Diclofenac (364 reports), Piroxicam (282), Indometacin (197), Naproxen (155) and Ketoprofen (137). The nonselective NSAID exert their effects by blocking, approximately to the same extent, the two isoenzymes of cyclooxygenase - COX-1 and COX-2. The suppression of the inducible COX-2 is connected with the therapeutic effects of NSAID antiflammatory, analgetic and antipyretic. The inhibition of the constitutive COX-1 which supports the homeostasis leads to adverse drug reactions from the gastro-intestinal tract, the kidneys and the cardio-vascular system.(fig. 1) The basic factors, associated with the higher risk of gastro-intestinal adverse drug reactions are: - high dose or combination of NSAID; - age over 65; - anamnesis data of the ulcer in the past; - continuous usage of NSAID; - simultaneous application of other drugs (anticoagulants, glucocorticosteroid and others); - serious concomitant illnesses; - others: presence of infection with Helicobacter Pylori, smoking, alcohol abuse and others; We must particularly be vigilant at the presence of one or several of the above factors. People using NSAID have three times higher relative risk of development of serious gastro-intestinal adverse drug reactions and two times higher relative risk of bleeding compared to those who do not use NSAID. Patients who are treated with NSAID at an older age are exposed to three times higher risk of developing gastro-intestinal complications compared to those who use NSAID at an earlier age. The serious gastro-intestinal complications due to the usage of NSAID in a number of cases can have a lethal issue. Graph 2 shows that the mortality cause due to usage of NSAID in the USA for a year is juxtaposable to that of the sufferers from AIDS. (Graph 2) The adverse effects of NSAID on the GIT are a significant cause for morbidity and mortality (11). About 60% of the patients on chronic treatment with NSAID have dyspeptic complaints: abdominal pain, sickness, vomiting, burning behind the sternum; whereas 15 30% have gastroduodenal ulcers proven by endoscopy. Most clinically significant ADR, connected with the usage of NSAID, are ulcer complications perforation, obstruction or bleeding (POB). The clinical studies show that about 1.5% of the patients with RA and OA, treated with NSAID have POB (1, 13, 14). (Fig. 2). The NSAID suppress the synthesis of the cytoprotective prostaglandines, reduce the mucous and bicarbonate secretion in the stomach, injure the surface phospholipids layer, reduce the blood circulation in the mucous membranes, and increase the acid secretion. All this upsets the balance between the protective and aggressive factors in the stomach and the duodenum 16
Conventional NSAIDs mechanism of action ARACHIDONIC ACID Conventional NSAIDs Prostaglandins Thromboxane Prostaglandins Gastrointestinal Toxicity Malfunction of plateles Inflammation, pain, fever Figure 1. Nonselective NSAID mechanism of action Figure 2 Adverse NSAID effects on gastric mucous membrane. 17
In Great Britain, about 20% of the emergency cases with complication of the upper parts of the gastro-intestinal tract were due to nonselective NSAID in only one year (about 12 000 people). Seventy one percent of those using nonselective NSAID were with injured small intestines which was determined by capsule endoscopy. Only 10% of the people, who do not use this type of medicinal products, have similar injuries (7). The treatment of serious adverse drug events by GIT is connected with considerable economic losses. The total price of the treatment of one patient is from US$1800 in Switzerland to US$6500 in the Netherlands (3). (Graph 3) Graph 2. Mortality caused by gastrointestinal complications related to NSAIDs in comparison to other diseases in the USA 18
COX-2 conception gave rise to real hopes for optimisation of the balance between the therapeutic effectiveness and the adverse drug reactions of NSAID, i.e. between the benefit and the risk. This conception revealed the possibilities to create new generation of NSAID, called selective inhibitors of cyclooxigenase-2 (6). Today we have considerable experience in their application. The mechanism of the effect of the selective COX-2 inhibitors is presented in Figure 3. They block the inducible COX-2 and keep the constitutive COX-1. (Fig. 3) Graph 3. Direct costs associated with serious gastrointestinal adverse events (Chevat, C. et al Pharmacoeconomics, 2002 19, /Suppl.1/, 17-32). 19
Molecular basis of COX-2 inhibition Active place Active place Side pocket Figure 3. Mechanism of action of selective COX-2 inhibitors A number of studies showed, that the selective COX-2 inhibitors have anaesthetizing and antiflammatory effect, juxtaposed to that of the non-selective NSAID, but to a considerably larger extent protect the gastroduodenal mucous membrane (10, 13, 15, 16). Recently it has been found out that some representatives of COX-2 inhibitors with continuous usage lead to cardiovascular complications. This gave rise to prerequisites to shake the positive attitude to highly selective COX-2 inhibitors, called coxibis. 20
Prothrombotic hypothesis Vascular prostacyclin Platelet TXA2 Partial block COX-2 Specific inhibitors Conventional NSAIDs No block of TXA2 Vasodilation and endothelial function Platelet aggregation and vasoconstriction Misbalance can lead to prothrombotic state and can increase the cardiovascular risk Figure 4. Prothrombotic hypothesis It is admitted that COX-2 inhibition leads to increase of the potential risk of the thromboembolic cardiovascular events, as it was found out in the study VIGOR (9). The presumptive mechanism for this is connected with the suppression of the synthesis of the vascular prostacyclin (PgI2), without suppressing the synthesis of thromboxane A2 (TXA2) of the thrombocytes. COX-2 inhibitors do not influence the thrombocyte aggregation (12, 18). Fig. 4 presents the prothrombotic hypothesis (Fig. 4). 21
Figure 5. First and second generation coxibs chemical formulae of structure We have to underline that the patients participating in the study VIGOR are treated with Vioxx (rofecoxib), 50 mg/daily, in the course of one year (2). For the time being, there are no data that other COX-2 selective inhibitors bring to a higher risk of cardiovascular complications (9). Having in mind that COX-2 selective inhibitors are different chemical compounds, it seems more likely that the matter is about specific effect of a drug and not a class specific effect. Fig. 5 presents the chemical structural formulae of different coxibs in two basic groups sulfonamides and sulfonyls (Fig. 5). 22
Graph 4. Risk from acute MI related with COX-2 selective inhibitors and nonselective NSAIDs (~1.4 million patients) At present, we can consider that the clinical data causing the withdrawal of Vioxx (rofecoxib) are specifically connected with it and they should not be referred implicitly to the rest of the COX-2 selective inhibitors. With about 1.4 million patients in the USA, who use COX-2 selective and non-selective NSAID, the risk of acute myocardial infarction has been studied. It has been found out that with patients using celecoxib, the risk of acute myocardial infarction is commensurable with the control group, in contrast to those treated with rofecoxib, 50 mg/daily, and some other nonselective NSAID (8, 17). Graph 4 presents the data of Nested Case-Control Study published in Lancet 2005 (8) (Graph 4) The American Agency of Food and Drugs (FDA) recommends to the pharmaceutical companies to revise the medical indications of nonselective NSAID, as well as of COX-2 inhibitors. These should include special warning for higher risk of cardiovascular adverse events and life threatening gastro-intestinal hemorrhages (5). In the USA and Canada COX-2 inhibitors are counter-indicative in coronary-arterial bypass surgery and perioperative application in cardiac-surgery. In Europe (EMEA recommendation) COX-2 selective inhibitors and nonselective NSAID have different medical information. The contraindications about the application of COX-2 selective inhibitors are: cardiac insufficiency II-IV class by NYHA, determined ischemic heart disease peripheral artery diseases, cerebral artery diseases, uncontrolled hypertonia (only for Arcoxia [etoricoxib]) 23
REFERENCES 1. Armstrong CP, Blower AL. Non-Steroidal Anti-Inflammatory Drugs And Life Threatening Complications Of Peptic Ulceration. Gut. 1987; 28:527 532 2. Bombardier C. et al for the VIGOR Study Group. Comparison of Upper Gastrointestinal Toxicity of Rofecoxib And Naproxen In Patients With Rheumatoid Arthritis. N Engl J Med. 2000; 343:1520 1528. 3. Chevat C. et al. Healthcare Resourse Utilisation And Costs Of Treating NSAID-Associated Gastrointestinal Toxicity. A Multinational Perspective. Pharmacoeconomics, 2002; 19 /Suppl.1/:17-32. 4. European Science Foundation, 26; 2006:1-3. 5. FDA News, April 2005. 6. Goldstein J.L. et al. Reduced Risk of Upper Gastrointestinal Ulcers With Celexocib: a Novel COX 2 Inhibitors. Am J Gastroenterol. 2000; 95:1681 1690. 7. Graham D.J.et al Clin. Visible Small-Intestinal Injury in Chronic NSAID Users. Gastroenterol. Hepatol. 2005; 3:55-59. 8. Graham D.J. et al. Risk of Acute Myocardial Infarction and Sudden Cardiac Death in Patients Treated with Cyclo-Oxygenase 2 Selective and Non-Selective Non-Steroidal Anti-Inflammatory Drugs: Nested Case-Control Study. Lancet 2005; 365:475 481. 9. Mukherjee D. et al. Risk of Cardiovascular Events Associated with Selective COX-2 Inhibitors. JAMA.2001; 286:954 959. 10. Mckenna F. et al. Celecoxib Versus Diclofenac in the Management of Osteoarthritis of the Knee. Scand J Rheumatol. 2001; 30:11-18 11. National Center for Health Statistics, 1998. 12. Ray W. et al. Weighing the Risks and Benefits of Coxibs, NSAIDs and Antiplatelet Therapy: Where the Data Lead. Lancet. 2002; 360:1071-1073. 13. Singh G. et al. Gastrointestinal Tract Complications of Nonsteroidal Anti-Inflammatory Drug Treatment in Rheumatoid Arthritis. A Prospective Observational Cohort Study. Arch Intern Med. 1996; 156:1530 1536. 14. Singh G., Triadafilopoulos. Epidemiology of NSAID Induced Gastrointestinal Complications.J Rheumatol. 1999; 26(suppl 56):18-24. 15. Singh G., et al for the SUCCESS-I Investigators. Celecoxib Versus Naproxen and Diclofenac in Osteoarthritis Patients: SUCCESS-I Study. Am J Med. 2006; 119:255-266. 16. Silverstein F.F., et al. Gastrointestinal Toxicity with Celecoxib vs Nonsteroidal Anti-inflammatory Drugs for Osteoarthritis and Rheumatoid Arthritis. JAMA. 2000; 284:1247-1255. 17. White W.B. et al. Comparison of Thromboembolic Events in Patients Treated with Celecoxib, a Cyclooxygenase 2 Specific Inhibitor, Versus Ibuprofen or Diclofenac. Am J Cardiol. 2002; 89:425 430. 18. Wilner K.D. et al. Celecoxib Does not Affect the Antiplatelet Activity of Aspirin in Healthy Volunteers. J Clin Pharmacol. 2002; 42:1027 1030. Abbreviations: GIT gastrointestinal tract CVS cardiovascular system NSAID nonsteroid anatiflammatory drugs ADR adverse drug reactions COX-1 - cyclooxygenaseisoenzyme 1 COX-2 - cyclooxygenaseisoenzyme 2 POB - perforation, obstruction, bleeding RA rheumatoid arthritis OA - osteoartrosis AMI acute myocardial infarction 24