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Prevalence of Contraindications and Prescription of Pharmacologic Therapies for Gout

      Abstract

      Background

      Patients with gout have comorbidities, but the impact of these comorbidities on treatment has not been studied.

      Methods

      A total of 575 patients with gout were stratified according to certainty of diagnosis according to International Classification of Diseases, 9th Revision, Clinical Modification code alone (cohort I), American College of Radiology criteria (cohort II), and crystal diagnosis (cohort III). Comorbid conditions were defined according to International Classification of Diseases, 9th Revision, Clinical Modification codes, and stratified as either moderate or severe. Drug contraindications were defined as moderate or strong, based on Food and Drug Administration criteria and severity of disease.

      Results

      The most common comorbidity was hypertension (prevalence 0.89). The presence of comorbidities resulted in a high frequency of contraindications to approved gout medications. More than 90% of patients had at least 1 contraindication to nonsteroidal anti-inflammatory drugs. Many patients demonstrated multiple contraindications to 1 or more gout medications. Frequently, patients were prescribed medications to which they harbored contraindications. The prevalence of patients prescribed colchicine despite having at least 1 strong contraindication was 30% (cohort I), 37% (cohort II), and 39.6% (cohort III).

      Conclusion

      Patients with gout typically harbor multiple comorbidities that result in contraindications to many of the medications available to treat gout. Frequently, despite contraindications to gout therapies, patients are frequently prescribed these medications.

      Keywords

      Gout is the most common inflammatory arthropathy and an increasing public health problem.
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      Gout and mortality.
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      Epidemiology of hyperuricemia and gout.
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      Epidemiology of gout: is the incidence rising?.
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      The association between gout and nephrolithiasis: the National Health and Nutrition Examination Survey III, 1988-1994.
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      Estimates of the prevalence of arthritis and other rheumatic conditions in the United States Part II.
      The most important risk factor for developing gout is hyperuricemia. Conditions promoting hyperuricemia (eg, diuretic use, renal failure, obesity) are increasing, posing a challenge for gout management.
      • Kramer H.M.
      • Curhan G.
      The association between gout and nephrolithiasis: the National Health and Nutrition Examination Survey III, 1988-1994.
      • Wallace K.L.
      • Riedel A.A.
      • Joseph-Ridge N.
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      Increasing prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population.
      • Choi H.K.
      • Ford E.S.
      Prevalence of the metabolic syndrome in individuals with hyperuricemia.
      • Choi H.K.
      • Ford E.S.
      • Li C.
      • Curhan G.
      Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey.
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      • Dong Y.
      • et al.
      The prevalence of hyperuricemia in a population of the coastal city of Qingdao, China.
      Currently, gout treatment options are currently limited.
      • Singh J.A.
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      • Toscano J.P.
      • Asch S.M.
      Quality of care for gout in the US needs improvement.
      • Zell S.C.
      • Carmichael J.M.
      Evaluation of allopurinol use in patients with gout.
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      • Saag K.G.
      Medication errors with the use of allopurinol and colchicine: a retrospective study of a national, anonymous Internet-accessible error reporting system.
      • Neogi T.
      • Hunter D.J.
      • Chaisson C.E.
      • Allensworth-Davies D.
      • Zhang Y.
      Frequency and predictors of inappropriate management of recurrent gout attacks in a longitudinal study.
      Anti-inflammatory therapies (colchicine, nonsteroidal anti-inflammatory drugs, and glucocorticoids) treat and prevent acute gout flares.
      • Burke A.
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      • Fitzgerald G.A.
      Analgesic-Antipyretic Agents: Pharmacotherapy of Gout.
      Allopurinol and febuxostat block urate production, and probenecid stimulates renal urate excretion, to lower serum urate.
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      • Goldfinger S.E.
      • Seegmiller J.E.
      The effectiveness of the xanthine oxidase inhibitor allopurinol in the treatment of gout.
      Use of these agents may be limited by contraindications that commonly manifest in patients with gout. For example, nonsteroidal anti-inflammatory drugs may exacerbate renal failure,
      • Hoskison K.T.
      • Wortmann R.L.
      Management of gout in older adults: barriers to optimal control.
      • Cheng H.F.
      • Harris R.C.
      Renal effects of non-steroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors.
      hypertension,
      • Hoskison K.T.
      • Wortmann R.L.
      Management of gout in older adults: barriers to optimal control.
      • White W.B.
      Cardiovascular risk, hypertension, and NSAIDs.
      and cardiovascular disease,
      • Hoskison K.T.
      • Wortmann R.L.
      Management of gout in older adults: barriers to optimal control.
      • White W.B.
      Cardiovascular risk, hypertension, and NSAIDs.
      all reportedly common in patients with gout. Similarly, glucocorticoids may exacerbate diabetes and hyperlipidemia,
      • Schimmer B.P.
      • Parker K.L.
      Adrenocorticotropic Hormone: Adrenocortical Steroids and Their Synthetic Analogs: Inhibitors of the Synthesis and Actions of Adrenocortical Hormones.
      also reportedly common in these individuals.
      • Choi H.K.
      • Ford E.S.
      • Li C.
      • Curhan G.
      Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey.
      • Choi H.K.
      • De Vera M.A.
      • Krishnan E.
      Gout and the risk of type 2 diabetes among men with a high cardiovascular risk profile.
      Because patients with gout may simultaneously have multiple comorbidities,
      • Choi H.K.
      • Ford E.S.
      Prevalence of the metabolic syndrome in individuals with hyperuricemia.
      • Hak A.E.
      • Choi H.K.
      Lifestyle and gout.
      • Choi H.K.
      • Mount D.B.
      • Reginato A.M.
      Pathogenesis of gout.
      • Becker M.A.
      • Chohan S.
      We can make gout management more successful now.
      the management of the individual patient can be complex and require a customized approach. However, the extent to which patients with gout harbor therapeutic contraindications to their possible treatments and physician responses to these contraindications have not been studied.
      • Patients with gout have multiple comorbid conditions.
      • Patients with gout frequently have contraindications to acute and chronic gout medications.
      • Therapeutic decisions should be based on individualized risks and benefits.
      • Potential adverse effects may be averted with heightened clinician and patient education.
      The Department of Veterans Affairs (VA) is the largest health care delivery system in the United States, providing services to a population that includes a large proportion of middle-aged and elderly men
      • Singh J.A.
      • Hodges J.S.
      • Toscano J.P.
      • Asch S.M.
      Quality of care for gout in the US needs improvement.
      • Agha Z.
      • Lofgren R.P.
      • VanRuiswyk J.V.
      • Layde P.M.
      Are patients at Veterans Affairs medical centers sicker? A comparative analysis of health status and medical resource use.
      well suited for the study of patients with gout. The VA also is distinguished by an extensive and searchable electronic medical record system. We used the electronic medical record at the New York Harbor Health Care System, New York campus of the VA (NY VA) to examine contraindications to therapy and physician-prescribing patterns among a cohort of patients with gout.

      Materials and Methods

      Patient Enrollment

      Patients with gout were identified from all patients in the NY VA electronic medical record, ages 18 to 100 years, as having any International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code (274.xx) for gout. Patients from this initial screen were excluded from further analysis if their records lacked documentation of a clinic or hospital visit during the 18-month period of our review (July 2007 to December 2008) or if the patient had died within the first 6 months of the review period. The resulting group was designated cohort I (Figure 1). Baseline demographic information was collected according to NY VA electronic medical record designation, including patient self-designations for race and ethnicity.
      Figure thumbnail gr1
      Figure 1Flow of study design. ACR=American College of Radiology; ICD-9-CM=International Classification of Diseases, 9th Revision, Clinical Modification.
      To identify a cohort of patients with gout at a higher level of definitional stringency (cohort II), we individually reviewed the charts of cohort I patients to identify those meeting American College of Rheumatology (ACR) criteria for gout.
      • Wallace S.L.
      • Robinson H.
      • Masi A.T.
      • Decker J.L.
      • McCarty D.J.
      • Yu T.F.
      Preliminary criteria for the classification of the acute arthritis of primary gout.
      Patients from cohort I were included in cohort II if their electronic medical record also contained evidence of current use of a gout medication (allopurinol, colchicine, or probenecid); microscopic identification of urate crystals; clinical or radiologic evidence of1 tophus; or 6 of 12 clinical criteria for the diagnosis of acute arthritis of primary gout.
      • Wallace S.L.
      • Robinson H.
      • Masi A.T.
      • Decker J.L.
      • McCarty D.J.
      • Yu T.F.
      Preliminary criteria for the classification of the acute arthritis of primary gout.
      Patients taking allopurinol for hyperuricemia of malignancy/tumor lysis syndrome or with diagnoses of lymphoma, leukemia, myeloma, or other malignancy were excluded. A third, more rigorously defined group of patients with gout (cohort III) included only cohort II patients whose record included polarizing microscopic documentation of monosodium urate crystals in synovial fluid or tophi.

      Comorbidities

      Comorbidities were identified by the presence of physician-assigned ICD-9-CM codes and confirmed by chart review. On the basis of a review of the literature and consensus opinion of the authors, clinically relevant gout-associated comorbidities were defined as hypertension (ICD-9-CM code 401.xx), chronic kidney disease (585.xx), coronary artery disease (414.xx), hyperlipidemia (272.xx), chronic hepatitis (571.xx), gastroesophageal disease (530.xx, 533.xx), diabetes (250.xx), osteoporosis (733.xx), chronic infection (011.xx-018.xx, 730.xx), and allopurinol hypersensitivity. Comorbidity severities were determined on the basis of clinical and laboratory results documented in the electronic medical record. Most comorbidities were defined within 2 ranges of disease activity (moderate vs severe) (Table 1), depending on whether the comorbidity was controlled successfully by medical management. Coronary artery disease, osteoporosis, and chronic infection were designated as present or absent only. In addition to ICD-9-CM code, chronic kidney disease was confirmed according to the criteria of the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative.
      • Levey A.S.
      • Coresh J.
      • Balk E.
      • et al.
      National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification.
      • Bailie G.R.
      • Johnson C.A.
      • Mason N.A.
      • St Peter W.L.
      Chronic Kidney Disease 2006: A Guide to Select NKF-KDOQI Guidelines and Recommendations.
      Table 1Comorbidities and Disease Severity Defined
      DiseaseMild-to-Moderate or ControlledModerate-to-Severe or Uncontrolled
      HypertensionControlled prescribed anti-HTN medications with SBP<140 mm Hg or DBP<90 mm HgUncontrolled with or without prescribed anti-HTN medications and SBP140 mm Hg or DBP90 mm Hg
      HyperlipidemiaDocumentation of HL controlled with medical therapy (TC240 mg/dL, TG150 mg/dL, LDL150 mg/dL)Documentation of HL uncontrolled with or without medical therapy (TC240 mg/dL, TG150 mg/dL, LDL150 mg/dL)
      Chronic kidney disease
      Calculated by the 4 variable Modification of Diet in Renal Disease equations.
      Creatinine>1.2 mg/dL and eGFR60 mL/min/1.73 m2eGFR<60 mL/min/1.73 m2
      Chronic hepatitisSerologically proven chronic hepatitis with normal LFTs: AST<42, ALT<40; and no detectable viral load (hepatitis B and C)Serologically proven chronic hepatitis with abnormal LFTs or detectable viral load (hepatitis B and C)
      Diabetes mellitusHbA1c7.0 mg/dL with or without medical therapyHbA1c>7.0 mg/dL with or without treatment, or history of DKA/hyperosmolar hyperglycemic state
      astroesophageal diseasesGERD with prescribed histamine2 receptor antagonist blocker or proton pump inhibitorDocumented PUD or history of upper GI bleed regardless of prescribed histamine2 receptor antagonist blocker or proton pump inhibitor
      Present
      Coronary artery diseaseDocumentation of angina, ischemia, positive stress test, or myocardial infarction
      Osteoporosis
      Per World Health Organization 2000 Prevention and Management of Osteoporosis Technical Report Series 921 World Health Organization, Geneva, Switzerland.
      Documentation by DEXA (T-score−2.5) on medical therapy or osteopenia (T-scores between −2.0 and −2.5) documented by DEXA not on therapy
      Chronic infectionDocumented presence of untreated or partially treated osteomyelitis or tuberculosis
      HTN=hypertension; SBP=systolic blood pressure; DBP=diastolic blood pressure; NA=not applicable; HL=hyperlipidemia; TC=total cholesterol; TG=triglycerides; LDL=low-density lipids; eGFR=estimated glomerular filtration rate; LFT=liver function test; AST=aspartate aminotransferase; ALT=alanine transaminase; HgA1c=glycosylated hemoglobin; HbA1c=hemoglobin A1c; GERD=gastroesophageal reflux disease; PUD=peptic ulcer disease; DEXA=dual-energy x-ray absorptiometry; GI=gastrointestinal.
      low asterisk Calculated by the 4 variable Modification of Diet in Renal Disease equations.
      Per World Health Organization 2000 Prevention and Management of Osteoporosis Technical Report Series 921 World Health Organization, Geneva, Switzerland.

      Contraindications

      Contraindications to gout medications were defined, wherever possible, using criteria established by the US Food and Drug Administration (FDA).
      • Schlesinger N.
      • Moore D.F.
      • Sun J.D.
      • Schumacher Jr, H.R.
      A survey of current evaluation and treatment of gout.
      Contraindications included the following:
      • to nonsteroidal anti-inflammatory drugs—hypertension, cardiovascular disease, chronic kidney disease, gastroesophageal disease;
      • to glucocorticoids—hypertension, diabetes mellitus, cardiovascular disease, hyperlipidemia, gastroesophageal disease, osteoporosis;
      • to colchicine—chronic kidney disease, chronic hepatitis;
      • to allopurinol—chronic kidney disease, chronic hepatitis, allopurinol hypersensitivity;
      • to probenecid—chronic kidney disease, severe gastroesophageal disease.
      Categorization of the degree of contraindication was based, wherever possible, on the FDA definitions of “precaution” versus “contraindication,” which were operationalized as indicating that a particular drug was “moderately” or “strongly” contraindicated, respectively, in the setting of a particular comorbidity. In cases in which FDA guidelines did not provide guidance, medications were defined as “moderately” or “strongly” contraindicated based on the severity of the condition in question. For example, use of nonsteroidal anti-inflammatory drugs was defined as moderately contraindicated in patients with moderate chronic kidney disease, but strongly contraindicated in patients with severe chronic kidney disease. Allopurinol hypersensitivity was identified in subjects with a documented allopurinol allergy who had not undergone desensitization.

      Statistical Analyses

      All statistical analyses, including analysis of variance and Pearson chi-square, were done using R statistical software (version 2.8.1).

      Institutional Approval

      This study was approved by the Institutional Review Board and Research Committee of the NY Harbor Healthcare System, NY Campus of the Department of VA.

      Results

      Patients

      From among 32,888 patients in the NY Harbor VA Medical Center electronic medical record, 807 individuals age18 years (2.5%) were identified as having1 ICD-9-CM code diagnosis of gout. Exclusion of individuals who failed to meet other entry criteria resulted in an initial cohort for analysis (cohort I) of 575 patients (1.7%). As expected, this cohort was almost exclusively male. Mean age was 72±11.8 years. Mean and median serum urate levels for cohort I were 7.7 mg/dL and 7.6 mg/dL (range, 3-15.7 mg/dL), respectively (Table 2).
      Table 2Baseline Patient Characteristics
      CharacteristicsMean±SD (95% CI)
      Cohort 1 (N=575)Cohort 2 (N=478)Cohort 3 (N=41)
      Serum uric acid level, mg/dL7.67±2.06 (7.49-7.86)7.72±2.16 (7.51-7.93)7.91±2.33 (7.16-8.65)
      Body mass index, kg/m228.97±5.45 (28.52-29.42)29.11±5.60 (28.60-29.61)28.78±4.93 (27.22-30.34)
      Systolic BP, mm Hg127.47±17.73 (126.01-128.92)127.26±17.70 (125.67-128.86)125.75±20.16 (119.39-132.12)
      Diastolic BP, mm Hg71.25±12.68 (70.21-72.29)71.06±12.81 (69.91-72.22)69±15.27 (64.17-73.82)
      Creatinine, mg/dL1.45±0.93 (1.37-1.53)1.45±0.94 (1.37-1.54)1.55±0.62 (1.35-1.74)
      eGFR, mL/min/1.73 m266.64±27.40 (64.32-68.95)66.43±27.48 (63.91-68.95)58.79±20.57 (52.12-65.46)
      HgA1C, mg/dL6.44±3.94 (6.04-6.83)6.33±1.73 (6.14-6.52)6.43±1.35 (5.96-6.90)
      Total cholesterol, mg/dL169.29±47.67 (165.30-173.27)168.57±41.57 (164.79-172.35)158.75±30.63 (149.08-168.42)
      Triglycerides, mg/dL154.73±179.68 (139.71-169.75)158.35±191.91 (140.89-175.80)142.68±66.59 (121.66-163.70)
      Allopurinol dose, mg192.18±99.79 (179.90-204.47)192.18±99.79 (179.90-204.47)202.63±97.85 (155.46-249.79)
      Age, y71.75±11.64 (70.79-72.70)71.74±11.78 (70.67-72.79)71.73±9.96 (68.58-74.87)
      Race/ethnicity, %
       Black33.933.326.8
       White49.249.851.2
       Hispanic7.77.57.3
       South East Asian2.12.17.3
       Pacific Islander110
       Native American0.50.40
       Unknown4.94.64.9
      Sex, %
       Male99.399.297.6
       Female0.70.82.4
      SD=standard deviation; CI=confidence interval; BP=blood pressure; eGFR=estimated glomerular filtration rate; HgA1c=hemoglobin A1c.
      Of the patients in cohort I, 478 fulfilled ACR criteria for gout (cohort II) based on available data and were reanalyzed. Clinical parameters for cohort II were similar to those for cohort I (Table 2). Forty-one patients from cohort II had documentation of crystal-proven gout and were included in cohort III. Parameters were similar across all 3 cohorts (Table 2).

      Comorbidities

      Patients in cohort I had substantial comorbidity (Figure 2). The most prevalent comorbidity was hypertension (88.7%). Coronary artery disease, chronic kidney disease, and hyperlipidemia affected 37.4%, 47.1%, and 62.6% of patients, respectively. Diabetes was present in 28.9% of the cohort I population. Only 2.4% of the patients in cohort I had no listed comorbidity. Most patients in cohort I had multiple comorbidities: 17.4%, 22.3%, and 25.2% had 2, 3, and 4 comorbidities, respectively (Figure 3). Approximately 1.0% of the patients had7 comorbidities.
      Figure thumbnail gr2
      Figure 2Prevalence of comorbidities in patients with gout. For each cohort defined in , the prevalence of specific comorbidities (y axis) was redetermined. In some instances, specific comorbidities were further subcategorized as severe (black bars) or moderate (white bars). In other cases (hatched bars), the comorbidities were defined only as absent versus present. HTN=hypertension; HL=hyperlipidemia; CKD=chronic kidney disease: hepatitis=chronic hepatitis; DM=diabetes mellitus; GED=gastroesophageal disease; CAD=coronary artery disease; OP=osteoporosis; infection=chronic infection. See text for additional details.
      Figure thumbnail gr3
      Figure 3Patients with gout typically harbor multiple comorbidities. The prevalence of having 0 to>7 associated comorbidities was determined among patients with gout in each of the 3 defined cohorts.
      Trends in cohort II were similar to those observed in cohort I. Patients with 0, 2, 3, and 4 comorbidities comprised 2.7%, 28.2%, 21.8%, and 24.3% of cohort II, respectively; 1.0% of the patients had7 comorbidities. All patients in cohort III had1 comorbidity, and the majority had2 comorbidities. Patients with 3, 4, and 5 comorbidities accounted for 24.0%, 12.2%, and 19.5% of cohort III, respectively. More than 12% of the patients in this cohort had7 comorbidities (Figure 2, Figure 3).
      To determine whether comorbidity rates among patients with gout were greater than those seen in patients without gout, we determined the rates of comorbidities in a randomly selected cohort of 190 patients with osteoarthritis but no gout (mean age 71.3 years). Rates of comorbidity in the osteoarthritis group were lower than those in the gout group. In the osteoarthritis group, 63% had hypertension, 12.5% had coronary artery disease, 7.3% had chronic kidney disease, 17.3% had gastroesophageal disease, 4.2% had osteoporosis, and 8.9% had hepatitis.
      We further stratified the frequencies of gout comorbidities into moderate versus severe disease (Figure 2). In cohort I, 64.0% of patients had moderate hypertension and 24.7% had severe hypertension. In cohorts II and III, 65.0% and 73.2% had moderate hypertension, respectively, and 21.9% and 17.1% had severe disease, respectively. Hyperlipidemia was moderate in 35.5%, 35.6%, and 39.0% and severe in 27.1%, 27.8%, and 29.3% of the patients in cohorts I, II, and III, respectively. According to our definition, the majority of patients with chronic kidney disease in each cohort had severe disease.

      Prevalence of Contraindications to Gout Medications

      Rates of contraindication to approved gout therapies were high. In all 3 cohorts,1 contraindications to nonsteroidal anti-inflammatory drug use were present in>90% of the patients (Figure 4). A similarly high rate of contraindications to glucocorticoids also was observed. Allopurinol was contraindicated in 47.6% of cohort I, 43.0% of cohort II, and 65.9% of cohort III. Large percentages of patients also had contraindications to colchicine and probenecid. Among cohort I patients, approximately 50% had at least 1 contraindication to colchicine; this number increased to 66% in cohort III. The agents with the overall highest rate of contraindications in our study population were glucocorticoids (95.3%, 94.4%, and 97.6% in cohorts I, II, and III, respectively). The mean number of gout drugs to which each patient harbored contraindications was 3.47 (cohort I), 3.49 (cohort II), and 4.00 (cohort III).
      Figure thumbnail gr4
      Figure 4Patients with gout harbor contraindications to multiple gout medications. The prevalence of contraindications to allopurinol, colchicine, nonsteroidal anti-inflammatory drugs, and probenecid are shown among patients from cohorts 1, 2, and 3. The prevalence of contraindications to each drug was further subcategorized according to whether the agents were moderately (white portions of the bars) or strongly (black portions of the bars) contraindicated in the individual patients. For the purposes of this analysis, in cases in which a patient had multiple contraindications to a single agent, that situation was scored as a single patient contraindication to the drug. NSAID=nonsteroidal anti-inflammatory drug.
      Because some contraindications may be more important than others when making therapeutic decisions, we compared the percentage of patients with moderate contraindications with those with strong contraindications to particular medications (Figure 4). In each cohort, a large proportion of the patients had strong contraindications to multiple gout medications. For example, colchicine and probenecid were each strongly contraindicated for approximately 40% of the patients in both cohorts I and II. Similarly, nonsteroidal anti-inflammatory drugs were strongly contraindicated in approximately half of the subjects in the first 2 cohorts and in two thirds of cohort III. Glucocorticoid use was strongly contraindicated for 35.5%, 34.3%, and 39.0% of cohorts I, II, and III, respectively.

      Prescription of Gout Medications Despite Contraindications

      We next assessed the degree to which patients were being prescribed specific gout medicines in the setting of recognized contraindications (Figure 5). Prescribing of drugs in the presence of contraindications was common. For example, among the 538 patients in cohort I who were identified as having1 contraindication to nonsteroidal anti-inflammatory drugs, 98 (18.2%) had received 1 of these drugs. Of 293 patients with at1 contraindication to colchicine, 119 (40.6%) had received1 prescription. In cohort III, 12 of 25 patients (48%) in cohort III had been prescribed allopurinol despite1 contraindication to that medication. Notably, glucocorticoids were prescribed relatively rarely in our cohort, in both patients with and without contraindications to these agents.
      Figure thumbnail gr5
      Figure 5Prevalence of patients with gout in each study cohort who were prescribed a contraindicated medication, listed by individual medication. In circumstances in which the patient had multiple contraindications to a particular prescribed medication, the patient was scored as having received a single contraindicated medication. NSAID=nonsteroidal anti-inflammatory drug.
      Prescription of gout medications to patients with moderate versus strong contraindications also was evaluated (Figure 5). Although prescriptions were issued to patients with moderate contraindications to the specific agents in the majority of cases, a significant number of patients received prescriptions despite strong contraindication(s) to the medication prescribed. Among patients possessing1 strong contraindication to colchicine use, more than 30% in each of the 3 cohorts were nonetheless prescribed colchicine; 8% to 15% of patients with1 strong contraindication to nonsteroidal anti-inflammatory drugs received1 prescription for these agents. In cohort II, 17.4% of patients were prescribed allopurinol despite a strong contraindication to the drug.

      Discussion

      To our knowledge, this observational study is the first formal investigation of contraindications to traditional gout medications and of the use of such agents in the setting of such contraindications. Our principal findings were as follows: Patients with gout typically have multiple comorbid conditions; patients with gout frequently harbor multiple, often strong contraindications to the drugs available for gout management; and many patients with gout are prescribed medications for their gout despite contraindications to the agents in question.
      Overall, the incidence of comorbidities in our patients with gout was higher than in an age-matched cohort with osteoarthritis but no gout, consistent with several prior reports that patients with gout frequently have chronic comorbid conditions.
      • Choi H.K.
      • Ford E.S.
      • Li C.
      • Curhan G.
      Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey.
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      • Klag M.J.
      • Mead L.A.
      • Liang K.Y.
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      Incidence and risk factors for gout in white men.
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      Gout medication treatment patterns and adherence to standards of care from a managed care perspective.
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      • Bakst A.W.
      Serum urate levels and gout flares: analysis from managed care data.
      • Riedel A.A.
      • Nelson M.
      • Wallace K.
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      • Cleary M.
      • Fam A.G.
      Prevalence of comorbid conditions and prescription medication use among patients with gout and hyperuricemia in a managed care setting.
      Our cohort had a higher rate of comorbidity than patients with gout in some previous studies, probably reflecting the demographic of our VA population. For example, earlier studies typically included a greater representation of female subjects, who may have less severe or chronic gout than male subjects. Moreover, the mean age of our population (72 years) was 15 to 30 years older than that in previous gout comorbidity studies.
      • Choi H.K.
      • Ford E.S.
      • Li C.
      • Curhan G.
      Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey.
      • Choi H.K.
      • De Vera M.A.
      • Krishnan E.
      Gout and the risk of type 2 diabetes among men with a high cardiovascular risk profile.
      • Sarawate C.A.
      • Brewer K.K.
      • Yang W.
      • et al.
      Gout medication treatment patterns and adherence to standards of care from a managed care perspective.
      • Riedel A.A.
      • Nelson M.
      • Wallace K.
      • Joseph-Ridge N.
      • Cleary M.
      • Fam A.G.
      Prevalence of comorbid conditions and prescription medication use among patients with gout and hyperuricemia in a managed care setting.
      Given that the population of the United States is currently aging, our study cohort may more accurately reflect future trends in comorbidities than have prior studies.
      Medications used to treat acute and chronic gout generally have well-described contraindications.
      • Singh H.
      • Torralba K.D.
      Therapeutic challenges in the management of gout in the elderly.
      • Conaghan P.G.
      • Day R.O.
      Risks and benefits of drugs used in the management and prevention of gout.
      Not previously addressed, however, is the prevalence of these contraindications among those with gout. In our study, the majority of patients had1 contraindication to at least 1 of the commonly used gout therapies, and many had contraindications to multiple therapies. Moreover, a large proportion of patients had at least 1 strong contraindication to a gout medication. For example, colchicine use was strongly contraindicated in>40% of our study population.
      Management of gout in patients with multiple comorbidities remains a challenge even for experienced physicians.
      • Schlesinger N.
      • Moore D.F.
      • Sun J.D.
      • Schumacher Jr, H.R.
      A survey of current evaluation and treatment of gout.
      Clinicians and patients must make therapeutic decisions based on possible risks versus benefits of the individual treatment. Previous studies have evaluated gout medication treatment patterns, but none have addressed the extent to which patients receive gout medications in the face of drug contraindications.
      • Petersel D.
      • Schlesinger N.
      Treatment of acute gout in hospitalized patients.
      We observed a high rate of prescribing medications that were potentially contraindicated. For example, of the 93.6% of patients in cohort I who had at least 1 contraindication to nonsteroidal anti-inflammatory drug use, 18% were nonetheless prescribed these agents, including 9% with strong contraindications to their use. Approximately one fifth of patients in cohorts I, one fourth of patients in cohort II, and one third of patients in cohort III received allopurinol despite contraindications. To some extent, this may reflect the use of allopurinol in renal failure, a strategy with which rheumatologists may be more comfortable than primary care physicians; however (consistent with national trends), most of the patients in our cohort were cared for by primary care physicians.
      During chart review, we identified some reasons why physicians prescribed drugs despite contraindications. For example, one physician prescribed prednisone over colchicine or nonsteroidal anti-inflammatory drugs to treat an acute gout attack in a patient with diabetes and renal insufficiency, explicitly risking steroid-induced hyperglycemia rather than nonsteroidal anti-inflammatory drug-induced renal failure or colchicine toxicity. Thus, physicians may feel compelled to make the best drug choice from among a limited palette of available agents, based on clinical scenario. Other reasons why physicians prescribed contraindicated medications may include a failure to recognize the presence, nature, or severity of the contraindication(s). In any event, physician use of these agents in the face of contraindications testifies to a possible need for heightened professional and patient education, and for alternative gout therapies with fewer or different contraindications. In this regard, the recent approval of the non-purine xanthine oxidase inhibitor febuxostat, as well as pegylated uricase and a new dosing schedule for colchicine may provide useful alternative treatments.
      The strengths and limitations to our study are worth mentioning. The use of ICD-9-CM codes permitted us to identify a large cohort of patients with gout (cohort I), but may have intrinsic limitations in studying the epidemiology of gout.
      • Harrold L.R.
      • Saag K.G.
      • Yood R.A.
      • et al.
      Validity of gout diagnoses in administrative data.
      Pitfalls in basing a diagnosis of gout on physician-designated ICD-9-CM codes may result from several factors, including inadequate and incorrect coding.
      • Harrold L.R.
      • Saag K.G.
      • Yood R.A.
      • et al.
      Validity of gout diagnoses in administrative data.
      In addition, a diagnosis of gout based on a syndromic accumulation of features (as in our cohort II) is inherently less definitive than a diagnosis made on an unequivocal test.
      • Harrold L.R.
      • Saag K.G.
      • Yood R.A.
      • et al.
      Validity of gout diagnoses in administrative data.
      • Terkeltaub R.A.
      Gout: epidemiology, pathology and pathogenesis.
      Moreover, gout is episodic and physicians may make presumptive diagnoses during periods when findings are absent, based on patient-reported history alone.
      • Quam L.
      • Ellis L.B.
      • Venus P.
      • Clouse J.
      • Taylor C.G.
      • Leatherman S.
      Using claims data for epidemiologic research The concordance of claims-based criteria with the medical record and patient survey for identifying a hypertensive population.
      Strengths of our study included the rigorous methodology we used to addresses these limitations. We analyzed our enrollment cohort by ICD-9-CM groupings (cohort I), by the ACR's 12 clinical criteria for the diagnosis of gout (cohort II), and by the only universally accepted criterion for gout, a documented crystal diagnosis (cohort III).
      • Harrold L.R.
      • Saag K.G.
      • Yood R.A.
      • et al.
      Validity of gout diagnoses in administrative data.
      Patients in cohort III demonstrated a trend toward more comorbidities than those in cohorts I and II, suggesting that the data from the larger cohorts did not overestimate, and may actually have underestimated the frequency of comorbidities among patients with gout. However, in most cases the differences between cohorts I and II versus III did not achieve statistical significance. Thus, our ability to directly review charts allowed us to confirm the validity of our population-based approaches. Another strength of our study was the use of FDA criteria to define drug contraindications, allowing us to assess contraindications according to a rigorous external standard. On the other hand, our studies may have underestimated both the prevalence of drug contraindications and the use of medications in the face of contraindications. For example, in reviewing contraindications to gout medications, we did not address the issue of drug–drug interactions, and in assessing the severity of contraindications, we did not address the extent to which multiple moderate contraindications to a single drug might collectively constitute a strong contraindication to that agent.

      Conclusions

      Our study demonstrates that gout is associated with an increased risk for multiple comorbidities, that patients with gout typically harbor contraindications to multiple medications available to treat their condition, and that patients with gout frequently are prescribed medications despite contraindications. Collectively, these data illuminate the limitations of the currently available therapies for gout management.

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      Linked Article

      • Steroid for Gout: Myth or Elixir?
        The American Journal of MedicineVol. 124Issue 10
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          In their excellent study of gout prescription and contraindication within the Veterans Affairs system, Keenan et al1 found that less than 10% of patients receive corticosteroids, contrary to a 2-fold higher use of nonsteroidal anti-inflammatory agents, but more than 90% of patients have a contraindication to both medications. This surely reflects our practice pattern: We would prefer to prescribe nonsteroidal anti-inflammatory drugs than corticosteroids, despite the advanced age of the population in Keenan et al's study.
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      • Contraindications to Pharmacologic Therapies for Gout
        The American Journal of MedicineVol. 124Issue 10
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          Keenan et al highlight the potential hazards of prescribing in patients with multiple comorbidities, using the example of gout.1 As nephrologists, we have to consider these issues in many consultations, but we rarely encounter significant limitations when prescribing treatment for gout in our patients with chronic kidney disease (CKD). In contrast to the suggested contraindications, prescription information from the US National Library of Medicine does not list CKD as an absolute contraindication for either allopurinol and/or colchicine;2 rather, these drugs can be prescribed to patients with CKD, with appropriate dose reduction and additional monitoring of renal function.
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        • PDF