Candesartan

Byline: M. Gupta, S. Malhotra, S. Jain, A. Aggarwal, P. Pandhi

Non-steroidal antiinflammatory drugs (NSAIDs) make up one of the largest groups of pharmaceutical agents used worldwide. In the past, NSAIDs are used by 20% or more of the population.[1] NSAIDs are also one of the most common causes of adverse drug reactions (ADRs) reported to drug regulatory agencies as well as in many clinical and epidemiological studies. The most common ADRs are those pertaining to gastrointestinal (GI) system, notably dyspepsia and bleeding. Clinical[2] and experimental[3] data as well as reviews[4] suggest that use of selective COX-2 inhibitors is associated with increase in systolic blood pressure and cardiovascular morbidity and mortality due to myocardial infarction. The risk of GI complications varies widely among individual NSAIDs and so does the cost. Since there are no important differences among these drugs with regard to efficacy, the choice of first line treatment should be based on their relative toxicity.

This was a drug utilization study conducted in the out patient clinic of the orthopedics department from December 2002 to June 2003. Prescriptions from newly registered patients were included in the study. Demographic characteristics such as age, sex and diagnosis were recorded. We also analysed the NSAID utilization that accounted for 90% of the use (drug utilization [DU] 90%) in order to determine the quality of prescribing. We further determined drug use indicators such as average number of drugs per prescription, concomitant medications, drugs on essential drug list and number of generics used. Lastly, average drug cost per encounter was determined by dividing the total cost of all drugs prescribed (for four weeks) by the number of encounters surveyed.

Out of the 800 prescriptions screened, 500 patients received NSAIDs (315 males, 185 females). Demographic characteristics and drug use indicators are shown in [Table 1]. Diclofenac was the only drug prescribed in generic form (8.4%). Rofecoxib was the most commonly prescribed NSAID (30.4%) followed by diclofenac, valdecoxib, ibuprofen + paracetamol, nimesulide, celecoxib, ibuprofen, piroxicam and indomethacin. [Table 2] Five out of nine NSAIDs were found in DU 90% segment. Ibuprofen + paracetamol was the most common fixed dose combination. Muscle relaxants like tizanidine in combination with analgesics made up only one percent of total prescriptions. There was no significant difference in analgesic prescription between males and females (data not shown). Further, coxibs (COX-2 inhibitors) accounted for the majority of prescriptions in elderly while diclofenac was more frequently prescribed in younger patients. Fracture was the most common condition for which NSAID was prescribed followed by osteoarthritis, cervical spondylosis, backache and sprain.

For patients with musculoskeletal disorders, conventional non-steroidal antiinflammatory drugs (NSAIDs) form mainstay of clinical care.[1] However, well-established limitations of NSAIDs include the risk causing significant injury to the upper gastrointestinal tract (GIT). The annualized incidence rate of symptomatic ulcers and ulcer complications in NSAID users ranges from 2 to 4%. It has been proposed that COX-2 inhibitors result in antiinflammatory and analgesic properties similar to what can be achieved with conventional NSAIDs. However, by sparing COX-1 activity; selective COX-2 inhibitors have greatly reduced toxicity, particularly, in GIT. Although, it seems quite clear that the COX-2 inhibitors are safer compared with other NSAIDs in high doses with regard to GI damage, it still remains an open question whether they are safer than other NSAIDs (in ordinary doses) such as ibuprofen 400 mg three times per day. Concerns have been raised from limited experimental studies that coxibs exacerbate inflammatory conditions in GIT as well as delay ulcer healing.

Established adverse effects of conventional NSAIDs might have accounted for such a high frequency of rofecoxib (30.4%) and valdecoxib (18%) prescription in our study. Moreover rofecoxib was more commonly prescribed in older patients with osteoarthritis. In younger patients diclofenac accounted for most of prescriptions. In a study conducted in elderly population with arthritis, patients receiving conventional NSAIDS had higher rates of GI events.[5] This justifies the higher use of coxibs in elderly patients in our study. Another interesting observation was a low frequency of prescription of nimesulide (6.3%). A wide publicity generated by controversy over the adverse drug reactions of nimesulide such as hepatotoxicity probably accounted for the above pattern.

Not only the quantity but also the quality and cost of NSAID prescribing is important for drug utilization studies. We determined the quality based on ranking of GI complications from a meta-analysis of controlled epidemiological studies.[6] A similar systematic review of case-control and cohort studies on serious GI complications came up to same ranking of "high-risk"(ketoprofen, piroxicam) and "low-risk" (ibuprofen, diclofenac) NSAIDs as we used in our comparison. In our study, piroxicam and indomethacin were not within the DU90% segment. This suggests that evidence-based medicine was an important factor while prescribing these drugs. Instead a previous study to assess quality of NSAID prescribing in Croatia and Sweden suggested higher use of piroxicam and ketoprofen.

As with all new drugs introduced in the market, COX-2 inhibitors are much more expensive than the earlier NSAIDs. However, for specific risk groups, they may turn out to be cost-effective, e.g. if one can avoid co-prescribing with expensive GI protective agents (i.e. proton pump inhibitors). We found that antacids accounted for only 4.4% of prescriptions in our study. The cost per prescription was US$4.5. The cost was calculated as average of total drugs prescribed per encounter. The average duration for which drugs were prescribed was 4 weeks. India has a per capita income of US$40. Hence, US$4.5 is quite affordable since these drugs have to be consumed for a long term.

Average number of drugs per prescription is an important index of prescription audit. In the present study, on an average three drugs were prescribed. Most of the musculoskeletal disorders like osteoarthritis and cervical spondylosis have chronic and progressive course. So, patients have to be prescribed concomitant medications such as calcium, glucosamine and rubefacients along with analgesics. Patients with fracture require antibiotics to prevent infection.

For a developing country like India, a national drug policy is needed to rationalize drug use. To achieve this, it is very important to determine drug use patterns and monitor drug-use profiles over time. Previous data regarding the utilization of analgesics in India is largely unknown. We used anatomic therapeutic classification (ATC) for the calculation of defined daily dose (DDD) and DU90% methodology to determine NSAID use.

In the ATC classification system, the drugs are divided into different groups according to the organ or system on which they act and their chemical, pharmacological and therapeutic groups at five levels. DDD is the estimated average maintenance dose per day of a drug when used in its major indication. DDD is established on the basis of assumed average use per day in adults and provides a rough estimate of drug consumption. However, drugs prescribed for a brief period can have their prevalence underestimated. DU 90% is the number of drugs responsible for 90% of the prescriptions. It has been proposed as a single method for assessing the general quality of drug prescribing. The principle of DU90% method is to focus on the bulk of prescribing (or uses). The DU90% methodology (combined by ATC/DDD) has not been widely used as a tool for measuring qualitative and quantitative drug consumption in India. Despite that, our study shows that it is simple, inexpensive, rational, understandable and easy to use. It provides pertinent information on drug usage in patients and could be widely applied as a basis for preparing prescription guidelines.

To conclude, our study shows that most commonly prescribed NSAID was rofecoxib. The higher use of rofecoxib, valdecoxib and diclofenac suggests that GI safety may have been an important concern while prescribing these drugs. The withdrawal of rofecoxib by the manufacturing company, in lieu of causing cardiovascular side effects, is likely to change the prescribing pattern of NSAIDs.

References

1. Pincus T, Swearingen C, Cummine P, Callahaw LP. Preference for non-steroidal anti-inflammatory drugs versus acetaminophen and concomitant use of both types of drugs in patients with osteoarthritis. J Rheumatol 2000;27:1020-7.

2. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286:954-9.

3. Jain S, Gupta M, Malhotra S, Pandhi P. Effect of rofecoxib on antihypertensive effects of candesartan in experimental models of hypertension. Meth Find Exp Clin Pharmacol 2005;27:11-6.

4. Malhotra S, Shafiq N, Pandhi P. COX-2 Inhibitors: A CLASS Act or Just VIGORously Promoted. Medscape General Medicine 2004;6:37.

5. Malhotra S, Karan RS ,Pandhi P, Jain S. Drug related medical emergencies in the elderly: Role of adverse drug reactions and non-compliance. Post Grad Med J 2001;913:703-7.

6. Henry D, Lim LL, Garcia Rodrignes LA, Perez Gutthann S, Carson JL, Griffsin M et al . Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. Br Med J 1996;312:1563-6.

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