Delayed timing of physical therapy initiation increases the risk of future opioid use in individuals with knee osteoarthritis: a real-world cohort study.

OBJECTIVE: We assessed whether late versus early initiation of physical therapy (PT) was related to greater risk of future opioid use in people with knee osteoarthritis (OA) who receive PT. METHODS: We used Commercial and Medicare Advantage claims data from 1999 to 2018 from American adults with incident knee OA referred for PT within 1 year of diagnosis. We categorised people as opioid naïve or opioid experienced based on prior prescriptions. We examined the association of timing of PT initiation with any and chronic opioid use over 1 year. RESULTS: Of the 67 245 individuals with incident knee OA, 35 899 were opioid naïve and 31 346 were opioid experienced. In the opioid naïve group, compared with PT within 1 month, PT 1 to <3, 3 to <6, 6 to <9, 9-12 months from diagnosis was associated with adjusted risk ratio (aRR (95% CIs)) for any opioid use of 1.18 (1.10 to 1.28), 1.49 (1.37 to 1.61), 1.73 (1.58 to 1.89) and 1.93 (1.76 to 2.12), respectively; aRRs (95% CIs) for chronic opioid use were 1.25 (1.01 to 1.54), 1.83 (1.48 to 2.26), 2.29 (1.82 to 2.89) and 2.50 (1.96 to 3.19). Results were similar among opioid experienced; aRRs (95% CIs) for any opioid use were 1.19 (1.14 to 1.24), 1.32 (1.26 to 1.37), 1.39 (1.32 to 1.45) and 1.54 (1.46 to 1.61); aRRs (95% CIs) for chronic opioid use were 1.25 (1.17 to1.34), 1.43 (1.33 to 1.54), 1.53 (1.41 to 1.66) and 1.65 (1.51 to 1.80). CONCLUSION: Compared with PT initiation within 1 month, delayed PT initiation was associated with higher risk of opioid use in people with incident knee OA. The longer the delay in PT initiation, the greater was the risk.

Validation of knee osteoarthritis case identification algorithms in a large electronic health record database.

Purpose: To facilitate studies of knee osteoarthritis (OA) in large databases, case finding algorithms with high levels of diagnostic performance are needed. Methods: From a UK general practitioner (GP) practice derived database, we selected adults ages 40-90 years meeting algorithms that included various combinations of codes for knee OA or knee pain and imaging. The GP for each patient was mailed a questionnaire to assess the cause of knee pain and provide knee x-ray and/or MRI findings. We considered knee pain with x-ray and/or MRI findings consistent with OA the gold standard. We calculated positive predictive values (PPV) and sensitivity for case identification algorithms. Results: Of 100 questionnaires sent, 93 were returned; we excluded 8 subjects who had other rheumatic disorders or total knee replacements. Among those with one code for OA, the PPV was 64% (95% CI = 49%-79%) and it increased to 92% (95% CI = 76%-100%) when two or more OA codes over six months were required. The increase in PPV was accompanied by a drop in sensitivity from 44% (95% CI = 31%-57%) to 19% (95% CI = 9%-30%). Use of one pain code yielded similar results to use of one OA code. Requiring two or more knee pain codes over six months yielded a PPV of 68% (95% CI = 49%-88%) and sensitivity of 26% (95% CI = 15%-38%). Discussion: A case identification algorithm requiring two or more knee OA codes yielded the highest PPV at the cost of reduced sensitivity. Tradeoffs between PPV and sensitivity will need to be weighed alongside study goals when selecting a case identification algorithm.

Proton-Pump Inhibitors and Risk of Calcium Pyrophosphate Deposition in a Population-Based Study.

OBJECTIVE: There are no proven effective medical treatments to prevent calcium pyrophosphate crystal deposition (CPPD). Hypomagnesemia is a known CPPD risk factor. The present study was undertaken to carry out a real-world epidemiologic study on proton-pump inhibitor (PPI) use, which can cause hypomagnesemia, and CPPD risk. METHODS: We conducted a time-stratified, propensity score (PS)-matched cohort study using the UK-based IQVIA Medical Research Data. We compared risk of incident CPPD among PPI users versus H2 blocker users using Cox proportional hazards models. We used greedy matching of incident PPI users 1:1 to incident histamine receptor 2 (H2 ) blocker users in 1-year cohort accrual blocks. Subjects were censored at time of drug switch. We evaluated incident use of PPI and H2 blockers prior to incident CPPD using a nested case-control study within the same cohort, matched 1:4 by age and sex using risk-set sampling. RESULTS: We identified 81,102 PPI and H2 blocker initiators, with 113 and 63 incident cases of CPPD, respectively. In the case-control study when compared with nonusers, both PPI and H2 B users had higher risk of incident CPPD, with odds ratios (ORs) of 1.79 (95% confidence interval [95% CI] 1.55-2.07) and 1.52 (95% CI 1.14-2.03), respectively. Incident PPI use was nonsignificantly associated with incident CPPD (hazard ratio 1.03 [95% CI 0.75-1.41]) compared with H2 blocker use. CONCLUSION: In this study using real-world data, incident use of PPIs was not associated with a higher risk of CPPD compared with incident H2 blocker use, although use of PPI and H2 blockers had higher risk compared with nonuse.

Association of Physical Therapy Interventions With Long-term Opioid Use After Total Knee Replacement.

Importance: Many individuals who undergo total knee replacement (TKR) become long-term opioid users after TKR. Associations of physical therapy (PT) interventions before or after TKR with long-term use of opioids are not known. Objectives: To evaluate associations of PT interventions before and after TKR with long-term opioid use after TKR. Design, Setting, and Participants: This cohort study used data from the OptumLabs Data Warehouse on 67 322 individuals aged 40 years or older who underwent TKR from January 1, 2001, to December 31, 2016, stratified by history of opioid use. The analyses for the study included data from January 1, 1999, to December 31, 2018. Exposures: Any PT interventions within 90 days before or after TKR, post-TKR PT dose as number of sessions (ie, 1-5, 6-12, and ≥13 sessions), post-TKR PT timing as number of days to initiation of care (ie, <30 days, 31-60 days, or 61-90 days after TKR), and post-TKR PT type (ie, active vs passive). Main Outcomes and Measures: The association of pre- and post-TKR PT with risk of long-term opioid use occurring more than 90 days after TKR was assessed using logistic regression while adjusting for confounders, including age, sex, race and ethnicity (Asian, Black, Hispanic, or White), obesity, type of insurance, geographical location, and physical and mental health comorbidities. Results: A total of 38 408 opioid-naive individuals (21 336 women [55.6%]; mean [SD] age, 66.2 [9.2] years) and 28 914 opioid-experienced individuals (18 426 women [63.7%]; mean [SD] age, 64.4 [9.3] years) were included. Receipt of any PT before TKR was associated with lower odds of long-term opioid use in the opioid-naive (adjusted odds ratio [aOR], 0.75 [95% CI, 0.60-0.95]) and opioid-experienced (aOR, 0.75 [95% CI, 0.70-0.80]) cohorts. Receipt of any post-TKR PT was associated with lower odds of long-term use of opioids in the opioid-experienced cohort (aOR, 0.75 [95% CI, 0.70-0.79]). Compared with 1 to 5 sessions of PT after TKR, 6 to 12 sessions (aOR, 0.82 [95% CI, 0.75-0.90]) and 13 or more sessions (aOR, 0.71 [95% CI, 0.65-0.77) were associated with lower odds in the opioid-experienced cohort. Compared with initiation of PT within 30 days after TKR, initiation 31 to 60 days or 61 to 90 days after TKR were associated with greater odds in the opioid-naive (31-60 days: aOR, 1.45 [95% CI, 1.19-1.77]; 61-90 days: aOR, 2.15 [95% CI, 1.43-3.22]) and opioid-experienced (31-60 days: aOR, 1.10 [95% CI, 1.02-1.18]; 61-90 days: aOR, 1.32 [95% CI, 1.12-1.55]) cohorts. Compared with passive PT, active PT was not associated with long-term opioid use in the opioid-naive (aOR, 1.00 [95% CI, 0.81-1.24]) or opioid-experienced (aOR, 0.99 [95% CI, 0.92-1.07]) cohorts. Conclusions and Relevance: This cohort study suggests that receipt of PT intervention before and after TKR, receipt of 6 or more sessions of PT care after TKR, and initiation of PT care within 30 days after TKR were associated with lower odds of long-term opioid use. These findings suggest that PT may help reduce the risk of long-term opioid use after TKR.

Warfarin use and risk of knee and hip replacements.

BACKGROUND: Identification of modifiable risk factors and treatments for osteoarthritis (OA) are needed. Warfarin, a vitamin K antagonist, causes fetal and animal model skeletal abnormalities. Vitamin K insufficiency has been associated with OA, but whether warfarin is also detrimental to OA is not known. METHODS: We conducted a nested case-control study using a UK general practitioner electronic medical records database. We identified cases of knee or hip replacement (KR or HR) from among adults with atrial fibrillation newly prescribed either warfarin or direct oral anticoagulants (DOACs). Cases were matched with four controls by age and sex. We assessed the relation of warfarin compared with DOAC use to risk of joint replacement using conditional logistic regression. We also evaluated different durations of warfarin use. RESULTS: We identified 857 subjects with KR or HR (cases), of whom 64.6% were warfarin users, and 3428 matched controls, of whom 56.1% were warfarin users (mean age 75, 47% female). Warfarin users had a 1.59 times higher risk of joint replacement than DOAC users (adjusted OR 1.59, 95% CI 1.31 to 1.92). Longer duration of warfarin use was associated with higher risk of joint replacement in comparison with <1 year of warfarin use. CONCLUSION: Warfarin, a vitamin K antagonist, was associated with greater risk of KR and HR (an indicator for end-stage knee OA) than DOAC use, supporting the importance of adequate vitamin K functioning in limiting OA progression.

Relation of therapies for ankylosing spondylitis and psoriatic arthritis to risk of myocardial infarction: a nested case control study.

BACKGROUND: Risk of myocardial infarction (MI) is elevated in ankylosing spondylitis and psoriatic arthritis (AS/PsA) compared to the general population. We evaluated the risk of MI related to the use of tumor necrosis factor inhibitor (TNFi) and other therapies in AS/PsA. METHODS: We conducted a nested case-control study using 1994-2018 data from OptumLabs® Data Warehouse, which includes de-identified medical and pharmacy claims, laboratory results, and enrollment records for commercial and Medicare Advantage enrollees. The database contains longitudinal health information on enrollees and patients, representing a diverse mixture of ages, ethnicities and geographical regions across the United States. Assessing AS/PsA separately, MI cases were matched to 4 controls by sex, age, diagnosis year and insurance type. We evaluated treatment within 6 months prior to MI including NSAIDs (AS referent), disease-modifying anti-rheumatic drug (DMARDs; PsA referent) and TNFi alone or in combinations. We evaluated the relation of treatment categories to MI risk using conditional logistical regression adjusting for confounders. RESULTS: Among 26,648 AS subjects, there were 237 MI cases and 894 matched controls. Among 43,734 PsA subjects, there were 404 cases and 1596 controls. In AS, relative to NSAID use, the adjusted odds ratio (aOR) for MI among TNFi only users was 0.85 (95% CI 0.39-1.85) and for DMARD only users was 1.04 (95% CI 0.65-1.68). In PsA, relative to DMARD use, the aOR among TNFi only was 1.09 (95% CI 0.74-1.60). Combination therapies also had no effect. CONCLUSIONS: Among AS/PsA, no combination of therapies appeared to be protective or harmful with regards to MI. Future studies should capture more AS and PsA patients and include longer term follow up to further investigate this question.

Knee osteonecrosis incidence from two real-world data sources.

BACKGROUND: Anti-nerve growth factor (NGF) has shown promise for osteoarthritis (OA) pain efficacy, but an unanticipated joint safety signal occurred in trials. To what extent this was related to OA natural history, or was a consequence of anti-NGF agents is unclear. Of the adverse joint safety events identified, osteonecrosis has specific diagnostic codes available in the medical record to enable assessment of its frequency in the general community. We therefore investigated the rates of knee osteonecrosis in three real-world cohorts using two data sources to place these trial data in context. METHODS: We used data from UK-based IQVIA Medical Research Data (IMRD) of adults diagnosed with incident knee OA between 2000-2018 to examine the incidence of knee osteonecrosis using different definitions. Additionally, we evaluated the incidence of knee osteonecrosis in the year prior to knee replacement in IMRD and among US Medicare beneficiaries who received a knee replacement in 2011-2014. RESULTS: In IMRD, among 122,343 subjects with incident knee OA (mean age 68 years, 58% female), incidence estimates for knee osteonecrosis were 0.006-0.10%, with incidence rates of 0.01-0.17 per 1000 person-years. Among the 81,807 who had a knee replacement, the incidence of knee osteonecrosis in the year prior to knee replacement was 0.004-0.06%. In Medicare, among 316,593 with knee replacement (mean age 74, 68% female), the incidence of knee osteonecrosis was 0.24-0.7%. CONCLUSION: Knee osteonecrosis is rare among people with knee OA, including in the year prior to knee replacement. These data provide context for interpreting osteonecrosis events in NGF trials.

Relation of NSAIDs, DMARDs, and TNF Inhibitors for Ankylosing Spondylitis and Psoriatic Arthritis to Risk of Total Hip and Knee Arthroplasty.

OBJECTIVE: Ankylosing spondylitis (AS) and psoriatic arthritis (PsA) often affect the hip and/or knee. If effective, treatments might reduce risk of total hip or total knee arthroplasty (THA/TKA). We evaluated risk of THA/TKA related to use of medical therapies in AS/PsA. METHODS: We conducted a nested case-control study using 1994-2018 data from the OptumLabs Data Warehouse, which includes deidentified medical and pharmacy claims, laboratory results, and enrollment records for commercial and Medicare Advantage enrollees. Among those with AS/PsA, THA/TKA cases were matched up to 4 controls by sex, age, AS/PsA diagnosis, diagnosis year, insurance type, obesity, and prior THA/TKA. We assessed AS/PsA treatment 6 months prior to THA/TKA, including disease-modifying antirheumatic drugs (DMARDs) and tumor necrosis factor inhibitors (TNFi), alone or in combination, stratified by nonsteroidal antiinflammatory drug (NSAID) use. We evaluated the relation of treatment to risk of THA/TKA using conditional logistical regression with adjustment for confounders. RESULTS: Among 16,748 adults with AS, there were 444 THA/TKA cases and 1613 matched controls. Among 34,512 adults with PsA, there were 1003 cases and 3793 controls. Adjusted ORs for treatment category and THA/TKA ranged from 0.60 to 1.92; however, none were statistically significant. Results were similarly null in several sensitivity analyses. CONCLUSION: Odds of THA/TKA were not reduced with any combinations of NSAIDs, DMARDs, or TNFi among persons with AS or PsA. Given current utilization patterns in this population of US adults with AS and PsA, these medical therapies did not appear to be associated with less end-stage peripheral joint damage.

Association of Chronic Kidney Disease With Allopurinol Use in Gout Treatment.

Importance: Clinicians are often cautious about use of allopurinol in patients with gout when renal function declines. Objective: To assess the association of allopurinol use in gout with the risk of developing chronic kidney disease stage 3 or higher. Design, Setting, and Participants: A time-stratified propensity score-matched, population-based, prospective cohort study of individuals with newly diagnosed gout who initiated allopurinol (≥300 mg/d) compared with those who did not initiate allopurinol, using the Health Improvement Network (THIN), a United Kingdom general practitioner electronic health records database, was carried out. The data were analyzed using Cox proportional hazards regression. Among adults aged 18 to 89 years with newly diagnosed gout, we propensity score matched 4760 initiators of allopurinol (≥300 mg/d) to the same number of noninitiators of allopurinol, excluding those with chronic kidney disease stage 3 or higher or urate-lowering therapy use before their gout diagnosis. Exposures: Allopurinol initiation at a dose of 300 mg or more per day. Main Outcomes and Measures: Development of chronic kidney disease stage 3 or higher. Results: Of the 4760 allopurinol initiators (3975 men, 785 women) and same number of noninitiators (3971 men, 789 women), 579 and 623, respectively, developed chronic kidney disease stage 3 or higher, with a mean follow-up time of 5 and 4 years, mean age of 57 years, and mean body mass index (calculated as weight in kilograms divided by height in meters squared) of 30 for both groups. Use of allopurinol of at least 300 mg/d was associated with lower risk of developing chronic kidney disease stage 3 or higher compared with nonusers, with a hazard ratio (HR) of 0.87 (95% CI, 0.77-0.97). Allopurinol initiation at less than 300 mg/d was not associated with renal function decline (HR, 1.00; 95% CI, 0.91-1.09). Conclusions and Relevance: In this large cohort, allopurinol initiation of at least 300 mg/d was associated with a lower risk of renal function deterioration. Because allopurinol does not appear to be associated with renal function decline, clinicians should consider evaluating other potential causes when patients with gout experience renal function decline.

Risk of myocardial infarction with use of selected non-steroidal anti-inflammatory drugs in patients with spondyloarthritis and osteoarthritis.

OBJECTIVES: Spondyloarthritis (SpA) is associated with an increased risk of myocardial infarction (MI) due to underlying inflammation and possibly due to medications such as certain non-steroidal anti-inflammatory drugs (NSAIDs). We sought to describe MI risk among patients with SpA who were prescribed NSAIDs, and to compare the pattern of risk in SpA with that in osteoarthritis (OA). METHODS: Nested case-control studies were performed using The Health Improvement Network (THIN). Underlying cohorts included adults with incident SpA or OA who had >1 NSAID prescription and no history of MI. Within each cohort, we matched each MI case to four controls without MI. NSAID use was categorised as: (a) current (prescription date 0-180 days prior to index date), (b) recent (181-365 days) or (c) remote (>365 days). We performed conditional logistic regression to compare the odds of current or recent NSAID use relative to remote use of any NSAID, considering diclofenac and naproxen specifically. RESULTS: Within the SpA cohort of 8140 and the OA cohort of 244 339, there were 115 and 6287 MI cases, respectively. After adjustment, current diclofenac use in SpA was associated with an OR of 3.32 (95% CI 1.57 to 7.03) for MI. Naproxen was not associated with any increase (adjusted OR 1.19, 95% CI 0.53 to 2.68). A ratio of ORs for SpA/diclofenac relative to OA/diclofenac was 2.64 (95% CI 1.24 to 5.58). CONCLUSIONS: MI risk in SpA is increased among current users of diclofenac, but not naproxen. The MI risk with diclofenac in SpA appears to differ from that in OA.

Effect of bisphosphonates on knee replacement surgery.

PURPOSE: Bone remodelling as a therapeutic target in knee osteoarthritis (OA) has gained much interest, but the effects of antiresorptive agents on knee OA have been conflicting, with no studies to date examining the effects of bisphosphonate use on the clinically relevant endpoint of knee replacement (KR) surgery. METHODS: We used data from The Health Improvement Network (THIN), a general practitioner electronic medical records representative of the general UK population. We identified older women who had initiated bisphosphonate use after their incident knee OA diagnosis. Each bisphosphonate initiator was propensity score-matched with a non-initiator within each 1-year cohort accrual block. The effect of bisphosphonates on the risk of KR was assessed using Cox proportional hazard regression. Sensitivity analyses to address residual confounding were also conducted. RESULTS: We identified 2006 bisphosphonate initiators, who were matched to 2006 non-initiators(mean age 76, mean body mass index 27), with mean follow-up time of 3 years. The crude incidence rate of KR was 22.0 per 1000 person-years among the initiators, and 29.1 among the non-initiators. Bisphosphonate initiators had 26% lower risk of KR than non-initiators(HR 0.74, 95% CI 0.59 to 0.93); these results were similar when additionally adjusted for potential confounders in the propensity score (HR 0.76, 95% CI 0.60 to 0.95). Results of sensitivity analyses supported this protective effect. CONCLUSIONS: In this population-based cohort of older women with incident knee OA, those with incident bisphosphonate users had lower risk of KR than non-users of bisphosphonates, suggesting a potential beneficial effect of bisphosphonates on knee OA.

Meloxicam and risk of myocardial infarction: a population-based nested case-control study.

Certain non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with an increased risk of myocardial infarction (MI), a risk linked to cyclo-oxygenase-2 inhibition. There are limited studies assessing the risk of MI associated with meloxicam, an increasingly popular drug with COX-2 inhibiting properties. A nested matched case-control study using The Health Improvement Network, a UK population-based database was conducted. NSAID users between 35 and 89 years of age with at least 1 year enrollment in the cohort were included. Incident MI cases were matched on age, sex, practice and event date with up to 4 controls. NSAID exposure was categorized as remote (between 60 days and 1 year), recent (between 1 and 60 days) or current relative to the event date. Current users were further classified as naproxen (negative control), diclofenac (positive control), meloxicam or other NSAID users. Multivariable conditional logistic regression was conducted to determine the risk of MI for each NSAID use categories compared with that of remote users. 9291 MI cases were matched with 30,676 controls. The cases had a higher prevalence of traditional cardiac risk factors, chronic kidney disease and inflammatory arthritis and cardioprotective drug utilization. The adjusted odds ratio of MI for current user compared to remote users were: meloxicam 1.38 (1.17-1.63), naproxen 1.12 (0.96-1.30) and diclofenac 1.37 (1.25-1.50). In this large population-based study, meloxicam increased the risk of MI by 38%. This study warrants cautious use of this increasingly popular drug.

Primary Prevention of Myocardial Infarction in Rheumatoid Arthritis Using Aspirin: A Case-crossover Study and a Propensity Score-matched Cohort Study.

OBJECTIVE: Subjects with rheumatoid arthritis (RA) are at higher risk of developing cardiovascular disease, which is their leading cause of death. Conflicting evidence exists regarding the efficacy of aspirin (ASA) as primary prevention. We evaluated whether a protective association exists between ASA and myocardial infarction (MI) in RA subjects. METHODS: In the United Kingdom, persons age ≥ 60 years receive free ASA by prescription and 75% of use is by prescription. Subjects ≥ 60 years with RA in the population-based The Health Improvement Network database constituted our study population. We excluded patients with history of MI, angina, stroke, peripheral vascular disease, or coronary artery procedures. Our main outcome was the occurrence of fatal and nonfatal MI. We performed a case-crossover study with each subject contributing a hazard period and a control period 90 days prior to the MI. In addition, to minimize confounding by indication, a propensity score (PS)-matched cohort study was performed, considering all patients with RA with an incident prescription of low-dose ASA as our exposed group. RESULTS: We did not find a protective effect in the case-crossover study (OR 1.83, 95% CI 0.71-4.71), with 55 subjects exposed in the hazard period and 44 in the control period. Similarly, among 1836 subjects included in the PS-matched cohort study (918 ASA users and 918 ASA non-users), we did not find a protective effect of low ASA on MI (HR 1.39, 95% CI 0.87-2.23). CONCLUSION: We did not find a protective effect of ASA on MI in patients with RA when used as primary prophylaxis.

Improved survival in rheumatoid arthritis: a general population-based cohort study.

OBJECTIVE: Mortality trends of rheumatoid arthritis (RA) are largely unknown over the past decade when new drugs and management strategies have been adopted to effectively treat RA. METHODS: Using The Health Improvement Network, an electronic medical record database representative of the UK general population, we identified patients with incident RA and up to five individuals without RA matched for age, sex and year of diagnosis between 1999 and 2014. The RA cohort was divided in two sub-cohorts based on the year of RA diagnosis: the early cohort (1999-2006) and the late cohort (2007-2014). We compared mortality rates, HRs (using a Cox proportional hazard model) and rate differences (using an additive hazard model) between RA and non-RA cohorts adjusting for potential confounders. RESULTS: Patients with RA diagnosed between 1999 and 2006 had a considerably higher mortality rate than their comparison cohort (ie, 29.1 vs 18.0 deaths/1000 person-years), as compared with a moderate difference in patients with RA diagnosed between 2007 and 2014 and their comparison cohort (17.0 vs 12.9 deaths/1000 years). The corresponding absolute mortality rate differences were 9.5 deaths/1000 person-years (95% CIs 7.5 to 11.6) and 3.1 deaths/1000 person-years (95% CI 1.5 to 4.6) and the mortality HRs were 1.56 (95% CI 1.44 to 1.69) and 1.29 (95% CI 1.17 to 1.42), respectively (both p values for interaction <0.01). CONCLUSION: This general population-based cohort study indicates that the survival of patients with RA has improved over the past decade to a greater degree than in the general population. Improved management of RA and its associated comorbidities over recent years may be providing a survival benefit.