~ Pergamon 0163-7258(94)E0016-U

Pharmac. Ther. Vol. 62, pp. 175-191, 1994 Copyright © 1994 Elsevier Science Ltd

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Specialist Subject Editor: C. J. HAWKEY

COMPARATIVE TOXICITY OF NON-STEROIDAL ANTI-INFLAMMATORY AGENTS

GURKIRPAL SINGH,* DENA R. RAMEY, DIANNE MORFELD a n d JAMES F. FRIES

Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, 1000 Welch Road, Suite 203, Palo Alto, CA 94304, U.S.A.

Abstract--Comparative toxicity of non-steroidal anti-inflammatory drugs was assessed using the Stanford Toxicity Index consisting of weighted symptoms, laboratory abnormalities and hospitalizations in 2976 consecutively enrolled rheumatoid arthritis patients from eight data bank centers with 27,936 patient-years of observation. Scores ranged from 1.77 (SE 0.20) for aspirin to 5.94 (SE 0.92) for meclofenamate, with many differences between drugs being 2- to 3-fold and highly statistically significant. Results are consistent with our prior data, persist when assessed by several different scoring algorithms, are consistent across data bank centers and are consistent with data of others. There are major and reproducible differences in the overall toxicity of different non-steroidal anti-inflammatory drugs.

Keywords---Non-steroidal anti-inflammatory drugs, toxicity, rheumatoid arthritis, adverse drug reactions, post-marketing surveillance, pharmacoepidemiology.

CONTENTS 1. Introduction 175

1.1. Overall side effects 176 1.2. Gastrointestinal side effects 178 1.3. Renal side effects 180 1.4. Hepatic toxicity 180 1.5. Cutaneous toxicity 180 1.6. CNS toxicity 181 1.7. Miscellaneous toxicity 181 1.8. Toxicity profiles and summary toxicity measures 181

2. Methods 182 2.1. Subjects 182 2.2. Validation 182 2.3. Statistical Methods 183

3. Results 183 3.1. Patient characteristics 183 3.2. Incidence of major symptoms 183 3.3. Toxicity Index scores 183

4. Discussion 188 References 188

1. I N T R O D U C T I O N

Non-s tero ida l an t i - in f lammatory drugs (NSAIDs) are used daily by approx imate ly 30 million people worldwide (O'Brien and Bagby, 1985a). In 1991, nearly 70.3 million prescriptions for N S A I D s were filled in the United States alone, at an est imated retail cost exceeding 2.2 billion

*Corresponding author. Abbreviations: ADR, adverse drug reactions; ARAMIS, arthritis, rheumatism and aging medical infor-

mation system; DMARDs, disease-modifying anti-rheumatic drugs; NSAIDs, non-steroidal anti-inflamma- tory drugs; PMS, post-marketing surveillance; RA, rheumatoid arthritis; TI, toxicity index.

175

176 G. SINGH et al.

dollars (Metropolitan Life Insurance Co., 1992)--and this estimate does not take into account the costs of over-the-counter aspirin and ibuprofen preparations. The number and utilization of non-aspirin NSAIDs has increased dramatically over the past 30 years, and along with the benefits these drugs convey has come a concomitant increase in the associated adverse drug reactions (ADR). The Committee on Safety of Medicines (1986a) reported that one quarter of all ADR reported in the United Kingdom several years ago were due to NSAIDs. The magnitude of the problem of NSAID toxicity is also underscored by the fact that 17 NSAIDs have been withdrawn from the market worldwide due to unacceptable levels of toxicity (Brooks and Buchanan, 1991).

Very few studies are available that directly compare the 20 or more NSAIDs currently available worldwide for either efficacy or toxicity. With regard to relative efficacy, there is a consensus that there is inadequate data in the literature to suggest the superiority of any one or one class of NSAIDs in rheumatoid arthritis (RA) (Bollet, 1985; Buchanan and Kean, 1987; Hardin and Longenecker, 1992; Hart, 1987). In general, only minor mean differences in efficacy, as measured by a variety of clinical, laboratory and health status parameters, have been found. Larger differences have been found in individual patient responses and patient and physician preferences (Day, 1985; Gall et al., 1982; Huskisson et al., 1976; Orme et al., 1981; Scott et al., 1982; Wasner et al., 1981), and Paulus (1989) indicates that patient preference may vary within the same patient from time to time. At the present time, there is no established method to predict which NSAID will be most effective for an individual patient.

1.1. OVERALL SIDE EFFECTS

While there is much information available in the literature regarding specific adverse reactions to NSAIDs in the form of individual case reports, reports based on voluntary ADR reporting to regulatory agencies, and studies of the relative frequency of individual side effects (e.g. tinnitus or gastric mucosal ulcerations), there are few studies available that compare the toxicity of various NSAIDs across a broad range of drug side effects. Case reports and voluntary ADR reporting tend to accentuate rare, serious side effects and do not facilitate comparison across drugs because neither the numerator (the total number of adverse drug reactions in a given time frame) nor the denominator--the total exposure (total number of prescriptions in that time frame or total period of time all patients took the drug within that time frame)--is well specified. It is estimated that only 20% or fewer of adverse reactions are actually reported using spontaneous reporting systems in the United States and the United Kingdom (Rogers, 1987; Gordon and Sachs, 1987). In addition, Weber (1984) has noted that more side effects tend to be reported for new drugs. He found that the rate of reporting of adverse reactions usually increases until the end of the second calendar year of marketing and thereafter declines.

Given those caveats, there is emerging evidence that substantial differences in toxicity may exist between NSAIDs. Indomethacin may be associated with more side effects than some other NSAIDs (Hardin and Longenecker, 1992; Wijnands et al., 1991), particularly CNS reactions (Hardin and Longenecker, 1992; O'Brien, 1968; Goldenberg and Cohen, 1986), gastrointestinal side effects (Goldenberg and Cohen, 1986) and renal complications (Hardin and Longenecker, 1992; Golden- berg and Cohen, 1986).

There is also some evidence that ibuprofen may be associated with fewer reported ADRs than some other NSAIDs. The United Kingdom Committee on Safety of Medicines (1986b) estimated the relative risk of various NSAIDs by comparing the total number of serious reactions spontaneously reported per million prescriptions filled in the United Kingdom during the first five years of marketing of nineteen NSAIDs. They reported a group of five drugs appeared to be substantially more toxic than the others; all had been withdrawn from the market. Ibuprofen appered to be less toxic, at least at low dosage, than the remaining drugs, which could not be distinguished from each other. They also reported that the adverse reaction profiles of individual drugs varied widely, with some causing predominantly gastrointestinal reactions, while others have a greater effect on the blood, liver, kidney or skin. Fries et al. (1991a) presented toxicity index scores for different NSAIDs, identifying substantial differences. Table 1 summarizes the results of the major studies that have included many NSAIDs; the consistency of results across studies is striking.

With the exception of the above studies, most of the comparisons of ADRs across NSAIDs, until

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178 G. SINGH et al.

recently, have involved a specific side effect or organ system. The literature regarding comparative gastrointestinal, renal, hepatic, cutaneous, CNS and miscellaneous toxicity between various NSAIDs will be discussed in the following sections.

1.2. GASTROINTESTINAL SIDE EFFECTS

Gastrointestinal problems constitute the major source of ADRs to NSAIDs. The gastrointestinal side effects of NSAIDs can be classified into five categories: dyspepsia (epigastric pain, indigestion, heartburn), gastric mucosal damage, microbleeding and fecal blood loss, acute gastrointestinal hemorrhage and/or perforation and miscellaneous gastrointestinal side effects.

Without exception, all NSAIDs have been found to cause dyspepsia. Approximately 10-12% of patients will experience dyspepsia while taking an NSAID (Hardin and Longenecker, 1992; Goldenberg and Cohen, 1986), although the range is from 5 to 50%, depending on the drug, the patient population being studied and the study design (Goldenberg and Cohen, 1986). Five to 15% of RA patients can be expected to discontinue NSAID therapy with a given agent because of dyspepsia within a 6-month period (Buchanan and Brooks, 1991). No clinically significant differences appear to exist in the incidence of dyspepsia with different chemical classes of NSAIDs (Roth and Bennett, 1987), although some studies have found that dyspepsia is more likely with aspirin and indomethacin than with other NSAIDs (Goldenberg and Cohen, 1986). While dyspepsia is very common, it is, unfortunately, poorly correlated with bleeding and demonstrable lesions (Brooks and Day, 1991; Hardin and Longenecker, 1992). Many patients who present with acute and serious pathology (largely, bleeding gastric erosions or ulcers) will have had no significant prior symptoms (Hardin and Longenecker, 1992). Larkai and colleagues (1987) found that 41 of 45 patients with endoscopically documemted mucosal injury reported no gastrointestinal tract symptoms.

All NSAIDs have also been found to cause some degree of gastric mucosal damage (i.e. hyperemia, diffuse gastritis, superficial erosions or true ulcer craters), as demonstrated in endoscopic studies, and this damage tends to be dose dependent. One study reported that the overall prevalence of endoscopically confirmed gastric lesions during treatment with NSAIDs over a 1-year period was 31% (Caruso and Bianchi Porro, 1980). Hardin and Longenecker (1992) report that up to 20% of regular NSAID users can be expected to have an ulcer and an additional 20-40% can be expected to have erosions without frank ulceration. In one study of peptic ulcer disease in NSAID users, gastric ulcers were found in 13% of patients taking NSAIDs and in 0.28% of the untreated populations; duodenal ulcers were found in 1 i% of NSAID users and in 1.4% of the untreated population (McCarthy, 1989).

Mucosal adaptation does tend to occur over time. Studies of chronic NSAID use show less mucosai damage than studies of acute NSAID use (Graham et al., 1988; Shorrock et al., 1990). However, despite mucosal restitution and adaptation, continued NSAID use may result in decreased resistance to other injurious agents, delayed healing of injury, worsening mucosal damage and increased prominence of other risk factors for non-NSAID gastrointestinal ulcers (Earnest, 1990).

Comparisons of the mucosal damage caused by various drugs have tended to show marked differences among the various NSAIDs. Caruso and Bianchi Porro (1980) reported that aspirin caused the most damage and sulindac the least. Hardin and Longenecker (1992) indicate that non-enteric coated aspirin may cause more mucosal injury than other NSAIDs, while sulindac, enteric-coated aspirin and non-acetylated salicylates may cause less than other NSAIDs. In a series of five studies, Lanza and colleagues (Lanza, 1984; Lanza et al., 1981, 1983, 1987, 1989) found that anti-inflammatory doses of aspirin produced significantly more mucosal injury than did any of the newer NSAIDs, while sulindac, enteric-coated aspirin, and low-dose ibuprofen produced less. Ibuprofen and salsalate were also found to produce less damage than indomethacin and naproxen. Based on a review of many of the endoscopic studies done to date, Buchanan and Brooks (1991) concluded that no one chemical class of NSAIDs has been shown clearly to be less injurious than the others.

Most, if not all, NSAIDs have been found to cause some gastrointestinal blood loss (microbleed- ing or increased fecal blood loss). Aspirin tends to be associated with more bleeding than other

Comparative toxicity of NSAIDs 179

NSAIDs (Semble and Wu, 1987). In most cases, this blood loss is not clinically significant (Goldenberg and Cohen, 1986); however, it may make a significant contribution to the anemia often associated with RA (Hardin and Longenecker, 1992).

Gastrointestinal perforation and hemorrhage are the most serious of the gastrointestinal side effects associated with NSAIDs. NSAIDs have been associated with duodenal as well as gastric ulcers. The FDA estimates that gastrointestinal ulcers, bleeding and perforation occur in approximately 1-2% of patients using NSAIDs for 3 months and approximately 2-5% of those using them for 1 year (Paulus, 1987). The cumulative risk of these serious events appears to increase with the duration of therapy and to be greater in patients with previous peptic ulcer disease (Paulus, 1987). Hardin and Longenecker (1992) estimate that 1-4% of regular NSAID users will require hospitalization for perforation or bleeding, usually the latter, during each year of therapy.

Strom et al. (1990) summarized the odds ratio or relative risk for upper gastrointestinal bleeding and/or peptic ulcer associated with the use of NSAIDs. They indicated that the estimates range from 2.3 to 13.9 in case-control studies depending on the study population, definition of a gastrointestinal event, potential confounders, etc. The estimates of odds ratios or relative risk in cohort studies range from 1.4 to 5.3. Fries et al. (1991b) found that the hazard ratio for hospitalization for gastrointestinal side effects of patients taking NSAIDs to those not taking NSAIDs was 5.2. Somerville and colleagues (1986) have shown that among patients hospitalized with bleeding peptic ulcers, the proportion of this group who were NSAID users increased from less than 10% in patients aged 15-29 years to almost 40% among patients aged 75 years or over. Brooks and Day (1991) reported "no striking evidence that clearly differentiates roughly equipotent anti-inflammatory doses of one NSAID from another with respect to the risk of serious upper gastrointestinal side effects"; there have been few comparative studies of the incidence of gastrointestinal ulcers, hemorrhage or perforation with various NSAIDs. Based on their review of the literature, Buchanan and Brooks (1991) concluded that aspirin may be associated with the highest incidence of gastrointestinal hemorrhage; however, there appears to be little difference among the newer NSAIDs. Inman (1987) studies the incidence of perforated ulcers and gastroin- testinal hemorrhages using the Prescription Event Monitoring System in the United Kingdom and found no difference among the five NSAIDs studied. Rossi et al. (1987) analyzed data based on the Food and Drug Administration spontaneous reporting system, and found that sulindac and tolmetin were associated with higher gastrointestinal hospitalization rates. Adjusting for time since marketing, they concluded that there is no decisive difference in the rate of reported gastrointestinal side effects among the NSAIDs. However, a number of recent studies do show differences, and the differences found are substantially similar between studies (Table 1). Griffin et al. (1991) studied the rate of hospitalizations because of ulcers in Tennessee Medicaid patients and found statistically different rates with different NSAIDs. The relative risks were ibuprofen 2.3, naproxen 4.3, piroxicam 6.4, tolmetin 8.5, and meclofenamate 8.7. Carson et al. (1987) studied billing and prescription data for Medicaid patients in Michigan and Minnesota and found higher hospitaliz- ation rates for gastrointestinal toxicity with sulindac and tolmetin.

The miscellaneous gastrointestinal side effects associated with NSAIDs include diarrhea, constipation, nausea, vomiting, esophageal stricture or hemorrhage, lower gastrointestinal prob- lems, such as inflammation and changes in the permeability of the intestine and lower bowel, ileal, duodenal and colonic hemorrhage, perforation and stricture formation (Buchanan and Brooks, 1991; Brooks and Day, 1991; Hardin and Longenecker, 1992; Paulus, 1989). For most of these side effects, no comparative information on the various NSAIDs is available. Salicylates may tend to cause more constipation than other NSAIDs (Hardin and Longenecker, 1992), and meclofenamate is associated with more diarrhea than any of the other NSAIDs (Paulus, 1989; Preston, 1978; Hardin and Longenecker, 1992). Eleven to 15% of patients can be expected to develop diarrhea while on meclofenamate (Paulus, 1989; Preston, 1978).

Two major risk factors for NSAID gastrointestinal side effects appear to be dose and age. Anti-inflammatory dosages of NSAIDs are associated with more gastrointestinal side effects than analgesic dosages. The elderly, especially those with multiple medical problems requiring polyphar- macy, appear to be at increased risk of gastrointestinal side effects. Fries et al. (1991b) found that the main risk factors for NSAID gastrointestinal hospitalizations in RA patients were age, use of

180 G. SINGH et al.

prednisone, previous NSAID gastrointestinal side effects or hospitalization, level of disability and NSAID dose.

1.3. RENAL SIDE EFFECTS

The primary renal side effects from NSAIDs can be classified into five categories: hemodynamic or functional acute renal failure, hyponatremia, hyperkalemia, acute interstitial nephritis and the nephrotic syndrome and analgesic nephropathy (Carmichael and Shankel, 1985; Schlegel, 1987; Buchanan and Brooks, 1991). The first three types of renal ADRs are due to the inhibition of prostaglandins by NSAIDs, while the latter two tend to be more idiosyncratic (Hardin and Longenecker, 1992; Buchanan and Brooks, 1991). The most common renal complication is reversible depression of renal function, and this is usually completely reversible within 24-72 hr following discontinuation of NSAID therapy (Schlegel, 1987).

Although all NSAIDs have been found to cause renal complications, there is some evidence that some NSAIDs are associated with more renal toxicity than others. There is some agreement that fenoprofen is the most nephrotoxic NSAID (Hardin and Longenecker, 1992; Schlegel, 1987; Carmichael and Shankel, 1985; Goldenberg and Cohen, 1986; Buchanan and Brooks, 1991), and indomethacin also causes more renal complications than other NSAIDs (Hardin and Longenecker, 1992; Goldenberg and Cohen, 1986). Fenoprofen has been implicated in, by far, the greatest number of cases of interstitial nephritis and nephrotic syndrome (Schlegel, 1987; Carmichael and Shankel, 1985; Garella and Matarese, 1984; Buchanan and Brooks, 1991). Non-acetylated salicylates have been reported to cause fewer renal complications (Hardin and Longenecker, 1991), as has piroxicam (Goldenberg and Cohen, 1986). Some studies seemed to indicate that sulindac was kidney-sparing (Nies, 1988). One study of ibuprofen, piroxicam and sulindac found that ibuprofen caused more renal toxicity than the other two drugs (Whelton et al., 1990).

According to Paulus (1989), the patients at highest risk for renal toxicity are patients with congestive heart failure, chronic glomerulonephritis or liver failure with ascites and those receiving diuretics. Buchanan and Brooks (1991) indicated that elderly patients with congestive heart failure, hypertension and renal insufficiency are at highest risk for all ADRs associated with NSAIDs.

1.4. HEPATIC TOXICITY

The major hepatic side effect associated with NSAID therapy is mild, usually asymptomatic elevation of one or more hepatic enzymes. Paulus (1982) reported that 5.4% of RA patients on aspirin developed persistent elevations of more than one liver function test result, while 2.9% of patients on NSAIDs developed similar elevations. This is usually reversible with a reduction in the dosage or discontinuation of NSAID therapy. The patients at highest risk for increased hepatic enzymes are the elderly, patients with decreased renal function, multiple drug use, higher drug doses and increased duration of therapy (Paulus, 1982). Recently, there has been some concern that diclofenac may be associated with more hepatotoxicity than the other NSAIDs and may cause more serious reactions (Brooks, 1988; Hardin and Longenecker, 1992; Furst and Paulus, 1993).

1.5. CUTANEOUS TOXICITY

Skin reactions in patients on NSAID therapy are fairly common, with pruritus and non-specific rashes occurring in 5-10% of patients (Hardin and Longenecker, 1992), although it is not clear how many of these are actually related to the NSAID therapy. The American Academy of Dermatology found that adverse cutaneous reactions to NSAIDs were most commonly reported with piroxicam, sulindac and meclofenamate (Stern and Bigby, 1984). Urticaria occurs most frequently with aspirin, indomethacin and ibuprofen (Stern and Bigby, 1984), while photosensi- tivity is more common with piroxicam.

Comparative toxicity of NSAIDs 181

1.6. CNS ToxIcITY

NSAIDs have been associated with a wide range of CNS side effects, including severe headache, cognitive dysfunction, dizziness, depression, sleeplessness, memory loss, inability to concentrate, confusion, personality change, forgetfulness, irritability, light-headedness, seizures and syncope (Schlegel, 1987; Hardin and Longenecker, 1992; Goodwin and Regan, 1982; Paulus, 1989; Goldenberg and Cohen, 1986). Severe headache is the most common CNS side effect. CNS reactions may occur in 1-4% of patients taking NSAIDs (Hardin and Longenecker, 1992). Elderly patients on NSAID therapy are at higher risk for cognitive dysfunction (Goodwin and Regan, 1982; Paulus, 1989) and this may be more common in patients on naproxen and ibuprofen (Goodwin and Regan, 1982). CNS reactions, in general, and headache, in particular, are more common in patients on indomethacin (O'Brien, 1968; Hardin and Longenecker, 1992; Goldenberg and Cohen, 1986), with 10-25% of patients on indomethacin affected (O'Brien, 1968). Headache may be less likely with ibuprofen and fenoprofen (Goldenberg and Cohen, 1986).

1.7 MISCELLANEOUS TOXICITY

NSAIDs, particularly salicylates (both aspirin and non-acetylated salicylates) are also associated with ototoxicity, primarily tinnitus (Hardin and Longenecker, 1992; Goldenberg and Cohen, 1986). This usually responds to a reduction in dosage. Tinnitus may be less common with ibuprofen than other NSAIDs (Goldenberg and Cohen, 1986).

Hypersensitivity reactions occur in 1-2% of patients taking NSAIDs (Hardin and Longenecker, 1992). These reactions tend to take the form of asthma or urticaria or both. The reactions may be more likely with indomethacin and less common with non-acetylated salicylates than with other NSAIDs (Hardin and Longenecker, 1992). Anaphylactoid reactions are more common with tolmetin than with other NSAIDs (Restivo and Paulus, 1978). Studies have also shown that a patient who is sensitive to one NSAID is generally sensitive to all (Gryglewski et al., 1975; Szczeklik, 1983).

Hematologic side effects of the NSAIDs include aplastic anemia, agranulocytosis, thrombocy- topenia and hemolytic anemia. While the hematologic toxicity of phenylbutazone is well docu- mented, recent studies suggest that indomethacin and diclofenac may also cause more hematologic toxicity than the other NSAIDs (The International Agranulocytosis and Aplastic Anemia Study, 1986; Paulus, 1987).

NSAIDs have been associated with a wide range of uncommon miscellaneous side effects; however, because these ADRs are so rare, it is not possible to make comparisons among the various NSAIDs. Miscellaneous NSAID side effects include acute pulmonary edema, hypersensitivity pneumonitis, stomatitis, sialoadenitis, febrile reactions, drug-induced lupus erythematosus, carditis, vasculitis, pancarditis, acute proctocolitis, aseptic meningitis, parotitis, congestive heart failure, gynecomastia and alopecia (Hardin and Longenecker, 1992; O'Brien and Bagby, 1985a,b,c,d; Goldenberg and Cohen, 1986; Paulus, 1989).

1.8. TOXICITY PROFILES AND SUMMARY TOXICITY MEASURES

From the evidence provided above, it is evident that the toxicity profiles of the various NSAIDs vary greatly with respect to the types of ADRs that occur, the clinical significance of those reactions, their relative frequency, the particular risk factors for each type of side effect, etc--not to mention the differences in patient populations. As a result, it is extremely difficult for a clinician to synthesize and evaluate all of the disparate information to make an optimal choice of therapy for a given patient. What is needed is a summary measure of drug toxicity, which would allow direct comparison of 'total toxicity' across the NSAIDs or any other class of drugs.

It is only recently that such a summary measure of drug toxicity has been developed (Fries et al., 1990) to help guide clinical choice. The Toxicity Index (TI) allows comparison among drugs based upon all ADRs (clinical symptoms, laboratory abnormalities and hospitalizations) in a defined population, taking into account their frequency, their clinical significance and their severity in each patient. Previous studies by our group have used the TI to compare the toxicity of NSAIDs and

182 G. SINGH et aL

of disease-modifying anti-rheumatic drugs (DMARDs) (Fries et al., 1991a, 1993a). In this study, we report the comparative toxicity of NSAIDs in our expanded longitudinal data bank experience, including an additional medication (diclofenac). We also present an alternative and improved statistical method for calculating the TI.

2. METHODS

2.1. SUBJECTS

ARAMIS (Arthritis, Rheumatism and Aging Medical Information System) is a chronic disease data bank system containing detailed clinical and outcome information on more than 23,000 patients with rheumatic diseases from 17 centers in the United States and Canada (Fries and McShane, 1986; Fries, 1985). The ARAMIS Post-Marketing Surveillance Program (PMS) has followed prospectively outcome status, drug side effects and economic impact in a cohort of 2976 consecutively enrolled RA patients from 8 patient populations (Stanford, Santa Clara County, Wichita, Phoenix, Saskatoon, Cincinnati, Baltimore and Montreal) with 27,936 patient-years of observation. The Stanford, Cincinnati and Montreal patients are drawn from referral institutional practices, Santa Clara County patients from the community, Saskatoon patients broadly from the patients in the province of Saskatchewan and Phoenix and Wichita patients from private practices of rheumatology in those cities. The Saskatchewan patients are believed to closely represent the general population of rheumatoid patients in that province, while the other patient groups are believed to have selection bias of some degree (Fries et al., 1990, 1991a).

Participants in the PMS program completed the Health Assessment Questionaire (HAQ) (Fries et al., 1980, 1982; Ramey et al., 1992) every 6 months. All drugs are assessed using identical procedures using the same populations. Patients are asked to report any side effects, attribute them to specific drugs and describe their severity. Patients also report on all hospitalizations. The protocol requires follow-up of non-responders, contacting patients for missing information and quality control of questionnaire coding and data entry. Detailed descriptions of the protocol and methods have been reported elsewhere (Fries et al., 1990, 1991a).

2.2. VALIDATION

The data included in the PMS program has been validated at various levels. Patient recall and accuracy in reporting side effects were evaluated by repeat questionnaire administration, interview and review of physician records (Fries et al., 1990). To minimize patient under-reporting, those events that are severe enough to require hospitalization are also ascertained by record review of all hospitalizations.

The development and validation of the TI have been previously reported elsewhere (Fries et al., 1990, 1991a; Ramey et al., 1992). Briefly, the TI represents a summary index of all side effects of a particular medication. The index includes components of symptoms, laboratory abnormalities and hospitalizations. The side effects are weighted according to a previously described algorithm, based on physician judgements (Fries et al., 1990). Each side effect is also weighted for the severity of the symptom (mild, moderate or severe). Laboratory abnormalities are obtained from patient self-report and are underascertained to some extent. Hospitalizations are individually abstracted from discharge summaries. Events resulting in hospitalization are attributed to a drug if the attending physician made that attribution; if no such attribution was made, the events are fractionally attributed based on the attributable risk of the event while taking this class of medication (developed from ARAMIS data or from literature estimates). If more than one potential contributing drug is present, attribution is further fractionally allocated between the potential offending agents. Statistical adjustment procedures develop standardized scores, account- ing for differing patient characteristics with different medications, and standard errors are computed.

Comparative toxicity of NSAIDs 183

2.3. STATISTICAL METHODS

The standard procedure calculates the crude TI for each drug as the total toxicity units accrued across patients for that drug divided by the total years of exposure to the drug. The new procedure calculates a TI score for each patient consisting of the toxicity units for a drug divided by the length of time-on-drug, averages these scores across patients, and then statistically adjusts the crude index for patient characteristics, including age, sex, time-on-drug, previous side effects, disease duration, education level, disability level, concurrent medications and others, using analysis of covariance. The standard technique yields toxicity indexes that are statistically less variable, but differentially weights some patients; long-term patients contribute disproportionately more by this technique than do patients on a drug for shorter periods. With the new calculation, scores of all patients are equally weighted.

There are four differences in this study from the techniques used in our prior study. First, a new pool of patient data has been assembled, including three additional centers, with larger numbers of patients and with longer follow-up. Secondly, all hospitalizations were carefully reviewed to insure consistency (to our present standards) and a hospitalization data bank created for future use. This resulted in the finding of a number of additional hospitalizations. Third, we include data on diclofenac in this study. Fourth, as described above, we have calculated crude and adjusted toxicity scores using two different techniques, in part as a sensitivity analysis.

3. RESULTS

3.1. PATIENT CHARACTERISTICS

Table 2 summarizes the characteristics of the patients on different NSAIDs. In general, patient characteristics were similar among users of different non-steroidal medications and reflect the expected characteristics of RA populations: middle-aged women with established disease of substantial duration and with significant pain and disability. There were, however, some interesting differences. Aspirin and naproxen patients had been on prior prescription NSAIDs less frequently and, consequently, had reported fewer prior gastrointestinal side effects from NSAIDs. On the other hand, salsalate patients were more likely to have been on prior NSAID therapy, and had a substantially greater incidence of prior gastrointestinal side effects. These patients were also more likely to have used more DMARDs and steroids, and had a greater number of comorbid diseases (heart, lung, diabetes, other chronic).

3.2. INCIDENCE OF MAJOR SYMPTOMS

Table 3 lists the incidence of major symptoms, as events per 1000 patient-years. The algorithm for calculating incidence allowed only one occurrence per side effect (the first time a side effect was reported) per patient. There were substantial differences in side effect profiles between different agents. Tinnitus was more common with aspirin, diarrhea with meclofenamate and headache with indomethacin. Upper abdominal pain was most commonly seen with ketoprofen, meclofenamate, diclofenac and tolmetin, and was seen least frequently with salsalate and aspirin.

3.3. TOXICITY INDEX SCORES

The TI values for each drug are shown in Table 4, along with the scores for individual components. These scores were calculated by the 'new' methodology (see Sections 2.1-2.3). In general, the largest single component of the TI was clinical symptoms, consisting of the 36 standard symptoms usually coded ('Standard Symptoms'), as well as any additional symptoms not on the standard list. Hospital days made the next largest contribution, and laboratory abnormalities contributed only a relatively small amount. Since laboratory findings were not obtained by a standard monitoring protocol, there may be some underascertainment in this category.

Table 4 shows the adjusted TI obtained by analysis of covariance. Overall toxicity was greatest with meclofenamate, followed by indomethacin, sulindac and fenoprofen. Table 5 summarizes the

F*

Cha

ract

eris

tics

Asp

irin

(a

t fir

st v

isit

on d

rug)

n

= 15

16

Yea

rs a

t ris

k 30

56

Age

(yea

rs)

57.0

(0.3

) Se

x (%

fem

ale)

75

.9

Edu

catio

n le

vel (

year

s)

12.1

(0.0

8)

Dis

ease

dur

atio

n (y

ears

) 14

.5 (0

.3)

Dis

abili

ty in

dex

(0-3

) 1.

4 (0

.02)

Pa

in S

cale

(0-3

) 1.

3 (0

.02)

N

umbe

r of t

ende

r joi

nts

7.0

(0.2

) N

umbe

r of

swol

len j

oint

s 4.

3 (0

.2)

Prev

ious

use

of a

noth

er N

SA1D

(%)

46.9

Pr

ior N

SAID

gas

troi

ntes

tinal

sid

e ef

fect

(%, n

) 3.

0 (4

5)

Con

curr

ent u

se o

fDM

AR

D (%

) 35

.1

Prev

ious

use

of D

MA

RD

(%

) 32

.7

Con

curr

ent

Pred

niso

ne (

%)

23.1

Pr

edni

sone

dos

e (m

g/da

y)

6.4

(0.3

) Pr

evio

us P

redn

ison

e (%

) 22

.0

New

star

ts (%

) 22

.8

Com

orbi

dity

(%

) 27

.2

Dru

g do

se (m

g/da

y)

2665

(32.

5)

Dur

atio

n (p

erio

ds) o

n dr

ug a

t la

st v

isit

on d

rug

(%, n

):

I 31

.7 (4

81)

2-3

23.8

(36O

) 4-

8 24

.5 (3

71)

> 8

20.0

(304

)

T^m

~

2.

Pat

ient

Cha

ract

eris

tics

(SE

in

Dic

lofe

nac

Feno

prof

en

Ibup

rofe

n ln

dom

etha

cin

n=41

5 n

=1

58

n=

577

n=41

8

337

221

826

613

60.1

(0.6

) 57

.7(I

.1)

57.5

(0.6

) 57

.2(0

.7)

82.2

81

.0

76.1

71

.5

12.5

(0.1

) 1

2.6

(0.2

) 12

.2(0

.1)

12.0

(0.2

) 16

.9 (0

.6)

13.3

(0.8

) 14

.1 (0

.5)

15.4

(0.6

) 1.

5 (0

.04)

1.

5 (0.

06)

1.4 (

0.04

) 1.

4 (0

.04)

1.4 (

0.04)

1.4 (

0.06)

1.4 (

0.03)

1.4 (

0.04)

8.1

(0.2

) 7.

7 (0

.6)

7.2

(0.3

) 7.

7 (0.4)

4.7 (0.2)

5.3 (0.5)

4.4 (0.2)

4.6 (0.3)

85.4

68.7

63.3

65.0

25.6

(100

) 11

.3(1

7)

10.1

(55)

8.

1 (3

0)

37.4

31

.0

31.5

27

.5

70.0

41

.3

43.3

40

.4

26.3

17

.7

22.2

18

.4

7.3

(0.5

) 6.

9 (0

.9)

6.9

(0.4

) 7.

5 (I

.3)

53.3

32

.0

30.9

25

.9

80.2

46

.8

50.3

43

.1

29.4

25.3

28

.9

26. I

13

8.0(

2.6)

16

10.7

(70.

0)

1711

.4(3

6.9)

10

3.2(

3.2)

Par

enth

eses

) K

etop

rofe

n M

eclo

fena

mat

e n

= 25

9 n

= 16

5

253

179

59.6

(0.8

) 57

.5 (1

.0)

88.9

78

.2

12.1

(0.2

) 13

.1 (0

.2)

18.7

(0.7

) 14

.3 (0

.9)

1.6

(0.0

5)

1.4

(0.0

6)

1.5

(0.0

5)

1.3

(0.0

6)

8.2

(0.3

) 7.

9 (0

.8)

5.1

(0.3

) 4.

9 (0

.6)

84.4

69

.0

22.5

(55)

13

.9 (2

2)

29.3

34

.5

62.3

50

.6

20.8

27

.9

7.1

(0.6

) 6.

4 (0

.7)

41.8

38

.0

76.1

53

.9

29.3

21

.2

179.

7 (5

.2)

278.

8

49.6

(206

) 41

.8 (6

6)

44.9

(259

) 47

. I (1

97)

52.1

(I 35

) 55

.8 (9

2)

37.1

(154

) 30

.4(4

8)

23.6

(136

) 21

.5(9

0)

29.0

(75)

21

.2(3

5)

13.3

(55)

17

.7 (2

8)

21.3

(123

) 19

,6 (8

2)

15.8

(41)

17

.6 (2

9)

0(0)

10

.1(1

6)

10.2

(59)

11

.7(4

9)

3.1

(8)

5.5(

9)

Nap

roxe

n n

= 10

62

1801

56

.8 (0

.4)

76.6

12

.4(0

.1)

12.5

(0.3

) 1.

3 (0

.02)

1.

3 (0

.02)

7.

3 (0

.2)

4.5

(0.2

) 50

.7

6.7 (65)

37.9

37

.4

20.9

6.

6 (0

.2)

24.3

36

.1

28.0

77

3.2

(9.2

)

27.8

(121

) 18

.8 (8

2)

24.1

(105

) 29

.4 0

28)

Piro

xica

m

n =

814

1167

56

.3 (0

.5)

78.9

12

.4 (O

.I)

13.8

(0.4

) 1.

4 (0.

03)

1.4 (

O.0

3)

7.3

(0.3

) 4.

5 (0

.3)

63.2

4.6

(35)

27

.3

40.4

19

.1

7.3

(0.4

) 28

.7

37.2

21

.3

19.7

(0.2

)

47.1

(383

) 24

.9 (2

03)

15.5

(126

) 12

.5 (1

02)

Sals

alat

e n

= 18

7

241 58

.5 (0

.9)

79.7

12

.9 (0

.2)

15.5

(0.7

) 1.

5 (0

.05)

1.

5 (0

.06)

7.

7 (0

.3)

4.7

(0.3

) 75

.4

23.5

49

.7

66.8

38

.5

6.9

(0.8

) 46

.5

77.5

47

.6

2671

.7 (4

6.7)

39.0

(73)

29

.4 (5

5)

24.1

(45)

7.

5 (1

4)

Sulin

dac

n =

562

860 57

.8 (0

.6)

73.5

12

.3 (0

.1)

13.2

(0.4

) 1.

3 (0

.03)

1.

3 (0

.03)

7.

1 (0

.3)

4.3

(0.2

) 60

.8

9.0

(48)

30

.1

43.0

22

.1

7.4(

0.7)

32

.7

45.6

23

.8

379.

8 (6

.3)

45.0

(253

) 23

.1 (1

30)

19.2

(108

) 12

.6 (7

1)

Tol

met

in

n =

243

306 56

.8 (0

.8)

79.8

12

.3 (0

.2)

13.5

(0.6

) 1.

4 (0

.05)

1.

5 (0

.05)

7.

3 (0

.5)

4.8

(0.4

) 69

.1

10.0

(23)

27

.7

46.1

21

.1

7.0

0.6)

30

.9

55.6

22

.3

1054

.7 (4

1.3)

50.2

(122

) 25

.9 (6

3)

16.1

(39)

7.

8 (1

9)

.o

z ~3

TA

BL

E 3

. In

cide

nce

of M

ajor

Sym

ptom

s (E

vent

s/lO

00 P

atie

nt-Y

ears

) W

ith

NSA

ID T

hera

py

Nu

mb

er

of

courses

Muc

osal

B

lurr

ed

Yea

rs a

t H

ives

P

ruri

tus

Ras

h E

dem

a ul

cers

vi

sion

V

erti

go

Hea

dach

e T

inn

itu

s H

eart

bu

rn

risk

(5

.4) ~

(3

.5) ~

(4

.7) l

(4

.6) ~

(5

.8) ~

(6

.2) l

(4

.8) ~

(4

.8) 1

(4

.3) 1

(3

.8) 1

Asp

irin

15

16

3056

2

3 3

0 l

l 5

2 39

12

S

alsa

late

18

7 24

1 0

0 8

0 0

0 12

12

37

12

Ib

upro

fen

577

826

1 6

10

10

6 6

11

8 8

21

Nap

roxe

n 10

62

! 801

4

11

14

10

7 3

8 7

8 20

S

ulin

dac

562

860

2 8

10

12

5 9

3 9

5 9

Pir

oxic

am

814

1167

3

21

31

10

6 3

9 9

4 15

T

olm

etin

24

3 30

6 3

0 7

10

13

7 20

16

7

26

Fen

op

rofe

n

158

221

9 18

23

5

14

9 5

9 5

9 D

iclo

fena

c 41

5 33

7 6

24

12

15

12

0 18

18

12

21

K

etop

rofe

n 25

9 25

3 8

12

16

4 12

4

20

12

12

28

Ind

om

eth

acin

41

8 61

3 0

3 5

10

2 11

34

55

5

13

Mec

lofe

nam

ate

165

179

11

22

39

11

0 0

17

6 6

28

O

Up

per

L

ower

T

rou

ble

L

iver

U

rin

e K

idn

ey

Low

L

ow

Nau

sea

Vom

itin

g ab

dom

, ab

dom

. D

iarr

hea

thin

kin

g

prob

lem

s pr

otei

n pr

oble

ms

WB

C

plat

elet

s A

nem

ia

(3.9

) t

(6.5

) I

pai

n (

5.7)

t p

ain

(5.

1) ~

(5

.4) I

(6

.0) I

(8

.5) I

(8

.8) ~

(8

.5) ~

(9

.5) 1

(8

.4) 1

(8

.6) I

5:

O

,..%

Asp

irin

14

2

Sal

sala

te

17

0 Ib

upro

fen

28

5 N

apro

xen

28

9 S

ulin

dac

33

3 P

irox

icam

39

4

Toi

met

in

43

3 F

enop

rofe

n 27

5

Dic

lofe

nac

42

9 K

etop

rofe

n 79

12

In

do

met

hac

in

52

11

Mee

lofe

nam

ate

56

6

31

4 5

2 0

0 0

0 1

1 33

8

0 0

0 0

4 0

0 0

44

7 11

0

0 0

2 0

0 1

51

8 7

1 1

1 4

0 1

3 36

8

14

l 2

l 1

0 0

2 59

9

12

3 0

2 3

1 2

3 62

16

16

0

3 3

3 3

0 3

59

18

14

0 0

5 0

0 0

0 65

21

33

3

14

3 6

6 3

18

99

36

24

0 0

4 4

0 0

8 59

15

l0

13

0

2 0

0 0

0 84

28

95

0

0 0

0 0

0 0

Z

0~

>

1Wei

ghts

app

lied

for

eac

h si

de e

ffec

t.

m

TAB

LE 4

. T

oxic

ity

Inde

x Sc

ores

by

NS

AID

and

Con

trib

utio

n o

f th

e C

ompo

nent

s o

f th

e ln

dex

to t

he O

vera

ll S

core

~

Tox

icit

y in

dex

Tox

icit

y in

dex

Num

ber

of

Yea

rs

Sta

ndar

d W

rite

-in

Lab

orat

ory

(new

) (n

ew)

cour

ses

at r

isk

sym

ptom

s sy

mpt

oms

abno

rmal

itie

s H

ospi

tali

zati

ons

mea

n (S

E)

adju

sted

(SE

)

Asp

irin

15

16

3056

1.

15

0.14

0.

02

0.45

1.

77 (

0.20

) 2.

25 (

0.27

) Sa

lsal

ate

187

241

1.52

0.

19

0.13

0.

16

2.00

(0.

46)

1.79

(0.

77)

Ibup

rofe

n 57

7 82

6 1.

72

0.19

0.

05

0.72

2.

68 (

0.44

) 1.

95 (

0.43

) N

apro

xen

1062

18

01

2.14

0.

20

0.11

0.

55

3.01

(0.

31)

3.29

(0.

32)

Suli

ndac

56

2 86

0 2.

58

0.28

0.

05

1.01

3.

92 (

0.78

) 3.

98 (

0.66

) Pi

roxi

cam

81

4 11

67

3.03

0.

32

0.14

0.

48

3.97

(0.

32)

3.83

(0.

37)

Tol

met

in

243

306

2.95

0.

35

0.21

0.

61

4.13

(0.

62)

3.77

(0.

67)

Fen

opro

fen

158

221

2.73

0.

32

0.15

1.

04

4.25

(0.

78)

3.96

(0.

83)

Dic

lofe

nac

415

337

3.10

0.

22

0.64

0.

52

4.48

(0.

56)

3.54

(0.

53)

Ket

opro

fen

259

253

3.83

0.

23

0.11

0.

53

4.69

(0.

70)

3.74

(0.

66)

Indo

met

haci

n 41

8 61

3 3.

64

0.38

0.

02

1.12

5.

15 (

0.62

) 5.

14 (

0.51

) M

eclo

fena

mat

e 16

5 17

9 5.

15

0.31

0.

00

0.49

5.

94 (

0.92

) 5.

40 (

0.81

)

1The

com

pone

nts

are

the

36 s

tand

ard

sym

ptom

s, a

ddit

iona

l 'w

rite

-in'

sym

ptom

s th

at a

re g

iven

an

aver

age

sym

ptom

wei

ght,

labo

rato

ry a

bnor

mal

itie

s an

d ho

spit

aliz

atio

ns.

Comparative toxicity of NSAIDs 187

TABLE 5. Statistical Significance of Differences Between Toxicity Index Scores (Based on Adjusted Scores using New Method)

Aspirin Salsalate Ibuprofen Naproxen Sulindac Piroxicam

I 2 3 4 5 6 n.s. n.s. 0.0064 0.0002 0.0001

n.s. n.s. 0.0174 0.0175 0.0218 0.0012 0.0007

l l .S. n . s .

n , s .

Aspirin 1 Salsalate 2 Ibuprofen 3 Naproxen 4 Sulindac 5 Piroxicam 6 Tolmetin 7 Fenoprofen 8 Diclofenac 9 Ketoprofen 10 Indomethacin 11 Meclofenamate 12

Tolmetin Fenoprofen Diclofenac Ketoprofen Indomethacin Meclofenamate

i/j 7 8 9 10 11 12 Aspirin 1 0.0133 0.0257 0.0032 0.0085 0.0001 0.0001 Salsalate 2 0.0492 0.0566 0.0305 0.0362 0.0003 0.0008 Ibuprofen 3 0.0175 0.0287 0.0057 0.0113 0.0001 0.0001 Naproxen 4 n.s. n.s. n.s. n.s. 0.0011 0.0059 Sulindac 5 n.s. n.s. n.s. n.s. 0.0736 0.0753 Piroxicam 6 n.s. n.s. n.s. n.s. 0.0416 0.0544 Tolmetin 7 n.s. n.s. n.s. n.s. 0.0958 Fenoprofen 8 n.s. n.s. n.s. n.s. Diclofenac 9 n.s. 0.0696 0.0663 Ketoprofen 10 n.s. n.s. Indomethacin 11 n.s. Meciofenamate 12

n.s. not significant.

statistical significance o f the differences in adjusted TI scores calculated using the new method. In general, there were consistent differences between the four drugs with the highest scores and the three with the lowest (salsalate, ibuprofen and aspirin), while differences in the middle class o f agents were less readily distinguishable. A total o f 66 comparisons are made in this table (Table 6). One would expect three or four o f these to be statistically significant at P < 0.05 level by chance alone. Instead, 28 o f the 66 values were statistically significant at P < 0.05, and 12 o f these were significant at P < 0.005 level, Thus, differences between the most toxic and least toxic drugs are highly clinically significant (2 or 3 times as toxic) and often highly statistically significant.

Table 6 contrasts results f rom the s tandard TI calculation previously reported (Fries et al., 1991 a)

TABLE 6. Toxicity Index Scores: Standard and New Methods

Toxicity index Toxicity index Number of Years (standard) (new)

courses at risk mean (SE) mean (SE)

Aspirin 1516 3056 1.26 (0.10) 1.77 (0.20) Salsalate 187 241 i.28 (0.25) 2.00 (0.46) Ibuprofen 577 826 1.87 (0.30) 2.68 (0.44) Naproxen 1062 1801 1.87 (0.10) 3.01 (0.31) Sulindac 562 860 1.91 (0.28) 3.92 (0.78) Piroxicam 814 1167 2.36 (0.18) 3.97 (0.32) Tolmetin 243 306 2.91 (0.43) 4.13 (0.62) Fenoprofen 158 221 2.62 (0.54) 4.25 (0.78) Diclofenac 415 337 3.45 (0.44) 4.48 (0.56) Ketoprofen 259 253 3.80 (0.65) 4.69 (0.70) Indomethacin 418 613 3.17 (0.35) 5.15 (0.62) Meclofenamate 165 179 3.54 (0.50) 5.94 (0.92)

188 G. SINGH et al.

with the new calculation described above. The standard method differentially weights patients with longer drug courses, while the new method weights all patients equally. With the new technique, the standard error terms are larger, but the TI values are also higher and more widely spread. The rank order of drug toxicity remains essentially unchanged by these two techniques.

4. DISCUSSION

NSAIDs are one of the most frequently prescribed classes of therapeutic agents. In this review, we have presented data on the comparative toxicity profiles of the most commonly used NSAIDs and a summary TI to compare these toxicities. We confirm our previous finding (Fries et al., 1991 a) of substantial differences in overall toxicity between different NSAIDs. The differences are often highly statistically significant, and are often even greater after statistical adjustment for confound- ing variables.

We confirm the relatively benign toxicity profile of aspirin. In a recent study (Fries et al., 1993b), we found that the safety advantage is explained primarily by a dose effect (aspirin is used in lower doses in clinical practice as compared with the doses previously used in clinical trials) and secondarily, by differences between aspirin formulations, with coated aspirin the least toxic. The lowest toxicity, however, was seen with salsalate, reflecting the low incidence of gastrointestinal toxicity with this agent. Of note, individuals on salsalate were more likely to have been on prior NSAID and concurrent DMARD and steroid therapy. It appears that salsalate, because of its benign toxicity profile, is increasingly being used in relatively sicker patients with a more frequent history of side effects to prior NSAID therapy. Meclofenamate and indomethacin have the highest TI scores, in agreement with clinical practice and previous studies (Table 1).

Some of these differences are likely due to dosages employed, and dosage is not adjusted for in this study, since there are no available data from which to calculate an equally effective dose for each drug. Average dosage ranged from 50% to nearly 100% of the highest dose recommended by the manufacturer; the highest percentages were for piroxicam and sulindac. The most toxic drugs, moreover, were taken at only 50-70% of the highest recommended doset Aspirin was taken at an average dose of 2665 mg/day, and this accounts for the differences in toxicity compared with pre-marketing trials where the dose was 4000-4800 rag/day (Fries et al., 1993b). We believe that the most appropriate dosage for comparison between drugs is that dose actually used in practice, since this speaks directly to the question of actual toxicity experienced by a patient, and represents a titration of dose by patient and physician to a level that best represents the compromise between effectiveness and toxicity in the individual patient.

The choice of a particular NSAID does not depend on toxicity alone. Efficacy of these agents has been shown to vary widely among individual patients, with some patients faring better on one agent and some on another (Day, 1985; Gall et al., 1982; Huskisson et al., 1976; Orme et al., 1981; Scott et al., 1982; Wasner et al., 1981). However, there is inadequate quantitative data in the literature to suggest the consistent superiority of any one or one class of NSAIDs (Bollet, 1985; Buchanan and Kean, 1987; Hardin and Longenecker, 1992; Hart, 1987). Therefore, it may not be possible, at this time, to calculate and compare the toxic: therapeutic ratios for individual NSAIDs. Nevertheless, the large differences in average toxicity between different NSAIDs need to be taken into consideration when making therapeutic decisions. If one agent is twice as toxic as another, then the first drug must be twice as efficacious as the second for the toxic:therapeutic ratio to be equivalent. Although there may be large differences in individual patient responses, clinical experience suggests that large differences in average efficacy are not likely. On the other hand, the differences in toxicities can be several-fold when the most toxic drugs are compared with the least toxic drugs. Thus, comparative data on drug toxicity, as presented in this paper, can assist the clinician in selecting more appropriate drugs.

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