Studies have identified increased cancer risk among patients undergoing total hip arthroplasty (THA) compared to the general population. However, evidence of all-cause and site-specific cancer risk ...associated with different bearing surfaces has varied, with previous studies having short latency periods with respect to use of modern Metal-on-Metal (MoM) bearings. Using the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) linked to Australasian Association of Cancer Registries data, our aim was to evaluate risk of all-cause and site-specific cancer according to bearing surfaces in patients undergoing THA for osteoarthritis and whether risk increased with MoM bearings.
Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated by comparing number of observed cancer cases to expected number based on incidence rate in the Australian population. All-cause and site-specific cancer rates were calculated for all conventional stemmed THA (csTHA) and resurfacing THA (rsTHA) procedures performed for osteoarthritis. Cox proportional hazards models were used to compare cancer rates for MoM, ceramic-on-ceramic (CoC) and resurfacing procedures with a comparison group comprising metal-on-polyethylene (MoP) or ceramic-on-polyethylene (CoP) procedures.
There were 156,516 patients with csTHA procedures and 11,321 with rsTHA procedures for osteoarthritis performed between 1999 and 2012. Incidence of all-cause cancer was significantly higher for csTHA (SIR 1.24, 95% CI 1.22-1.26) and rsTHA (SIR 1.74, 95% CI 1.39-2.04) compared to the Australian population. For csTHA, there was no significant difference in all-site cancer rates for MoM (Hazard Ratio (HR) 1.01, 95%CI 0.96-1.07) or CoC (HR 0.98, 95%CI 0.94-1.02) compared to MoP and CoP bearings. Significantly increased risk of melanoma, non-Hodgkins lymphoma, myeloma, leukaemia, prostate, colon, bladder and kidney cancer was found for csTHA and, prostate cancer, melanoma for rsTHA procedures when compared to the Australian population, although risk was not significantly different across bearing surfaces.
csTHA and rsTHA procedures were associated with increased cancer incidence compared to the Australian population. However, no excess risk was observed for MoM or CoC procedures compared to other bearing surfaces.
Uncertainty remains about the optimal monotherapy for hypertension, with current guidelines recommending any primary agent among the first-line drug classes thiazide or thiazide-like diuretics, ...angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers, and non-dihydropyridine calcium channel blockers, in the absence of comorbid indications. Randomised trials have not further refined this choice.
We developed a comprehensive framework for real-world evidence that enables comparative effectiveness and safety evaluation across many drugs and outcomes from observational data encompassing millions of patients, while minimising inherent bias. Using this framework, we did a systematic, large-scale study under a new-user cohort design to estimate the relative risks of three primary (acute myocardial infarction, hospitalisation for heart failure, and stroke) and six secondary effectiveness and 46 safety outcomes comparing all first-line classes across a global network of six administrative claims and three electronic health record databases. The framework addressed residual confounding, publication bias, and p-hacking using large-scale propensity adjustment, a large set of control outcomes, and full disclosure of hypotheses tested.
Using 4·9 million patients, we generated 22 000 calibrated, propensity-score-adjusted hazard ratios (HRs) comparing all classes and outcomes across databases. Most estimates revealed no effectiveness differences between classes; however, thiazide or thiazide-like diuretics showed better primary effectiveness than angiotensin-converting enzyme inhibitors: acute myocardial infarction (HR 0·84, 95% CI 0·75–0·95), hospitalisation for heart failure (0·83, 0·74–0·95), and stroke (0·83, 0·74–0·95) risk while on initial treatment. Safety profiles also favoured thiazide or thiazide-like diuretics over angiotensin-converting enzyme inhibitors. The non-dihydropyridine calcium channel blockers were significantly inferior to the other four classes.
This comprehensive framework introduces a new way of doing observational health-care science at scale. The approach supports equivalence between drug classes for initiating monotherapy for hypertension—in keeping with current guidelines, with the exception of thiazide or thiazide-like diuretics superiority to angiotensin-converting enzyme inhibitors and the inferiority of non-dihydropyridine calcium channel blockers.
US National Science Foundation, US National Institutes of Health, Janssen Research & Development, IQVIA, South Korean Ministry of Health & Welfare, Australian National Health and Medical Research Council.
Abstract Background Opioids are commonly used for the management of preoperative and postoperative pain among patients undergoing total knee arthroplasty (TKA). There is limited literature on the ...chronic use of opioids pre-TKA and post-TKA. The aim of this study was to characterize the use of opioids in TKA patients before and after surgery and identify risk factors of chronic opioid use. Methods Opioid use among 15,020 patients undergoing TKA (01/01/2001-31/12/2012) was examined. Generalized estimating equations assessed change in total oral morphine equivalents pre-TKA and post-TKA, and logistic regression estimated risk factors of chronic opioid use. Results Of the total sample, 7782 (52.0%) patients had at least 1 opioid (38.6% pre-TKA and 34.4% post-TKA). The most commonly prescribed opioids were oxycodone, codeine + acetaminophen, and tramadol. Pre-TKA, 720 (4.8%) patients were chronic opioid users, of which 241 (33.5%) stopped being chronic users after surgery and 479 (66.5%) continued but had a 16% reduction (incidence rate ratio = 0.84; 95% confidence interval, 0.78-0.90) in total oral morphine equivalents. Of the 5077 (33.8%) occasional opioid user pre-TKA, 2407 (47.4%) stopped after surgery. Compared to nonopioid users, chronic users were younger, were female, had more comorbidity, and had longer hospital stays. Older age was associated with ceasing chronic opioid use post-TKA. Conclusion There was a reduction in opioid use following TKA. Almost 50% of occasional users and more than 30% of chronic users pre-TKA ceased opioids postoperatively. There was a reduction in use for those chronic users who continued to take opioids postsurgery.
Background
The incidence of joint arthroplasty is increasing worldwide. International estimates of future demand for joint arthroplasty have used models that propose either an exponential future ...increase, despite obvious system constraints, or static increases, which do not account for past trends. Country-specific projection estimates that address limitations of past projections are necessary. In Australia, a high-income country with the 7th highest incidence of TKA and 15th highest incidence of THA of the Organization for Economic Cooperation and Development (OECD) countries, the volume of TKAs and THAs increased 198% between 1994 and 2014.
Questions/purpose
To determine the projected incidence and volume of primary TKAs and THAs from 2014 to 2046 in the Australian population older than 40 years.
Methods
Australian State and Territory Health Department data were used to identify TKAs and THAs performed between 1994 and 1995 and 2013 and 2014. The Australian Bureau of Statistics was the source of the population estimates for the same periods and population-projected estimates until 2046. The incidence rate (IR), 95% CI, and prediction interval (PI) of TKAs and THAs per 100,000 Australian citizens older than 40 years were calculated. Future IRs were estimated using a logistic model, and volume was calculated from projected IR and population. The logistic growth model assumes the existence of an upper limit of the TKA and THA incidences and a growth rate directly related to this incidence. At the beginning, when the observed incidence is much lower than the asymptote, the increase is exponential, but it decreases as it approaches the upper limit.
Results
A 66% increase in the IR of primary THAs between 2013 and 2046 is projected for Australia (2013: IR = 307 per 100,000, 95% CI, 262-329 per 100,000 compared with 2046: IR= 510 per 100,000, 95% PI, 98-567 per 100,000), which translates to a 219% increase in the volume during this period. For TKAs the IR is expected to increase by 26% by 2046 (IR = 575 per 100,000; 95% PI, 402-717 per 100,000) compared with 2013 (IR = 437 per 100,000; 95% CI, 397-479 per 100,000) and the volume to increase by 142%.
Conclusion
A large increase in the volume of arthroplasties is expected using a conservative projection model that accounts for past surgical trends and future population changes in Australia. These findings have international implications, as they show that using country- specific, conservative projection approaches, a substantial increase in the number of these procedures is expected. This increase in joint arthroplasty volume will require appropriate workforce planning, resource allocation, and budget planning so that demand can be met.
Level of Evidence
Level II, economic and decision analysis.
Chlorthalidone is currently recommended as the preferred thiazide diuretic to treat hypertension, but no trials have directly compared risks and benefits.
To compare the effectiveness and safety of ...chlorthalidone and hydrochlorothiazide as first-line therapies for hypertension in real-world practice.
This is a Large-Scale Evidence Generation and Evaluation in a Network of Databases (LEGEND) observational comparative cohort study with large-scale propensity score stratification and negative-control and synthetic positive-control calibration on databases spanning January 2001 through December 2018. Outpatient and inpatient care episodes of first-time users of antihypertensive monotherapy in the United States based on 2 administrative claims databases and 1 collection of electronic health records were analyzed. Analysis began June 2018.
Chlorthalidone and hydrochlorothiazide.
The primary outcomes were acute myocardial infarction, hospitalization for heart failure, ischemic or hemorrhagic stroke, and a composite cardiovascular disease outcome including the first 3 outcomes and sudden cardiac death. Fifty-one safety outcomes were measured.
Of 730 225 individuals (mean SD age, 51.5 13.3 years; 450 100 women 61.6%), 36 918 were dispensed or prescribed chlorthalidone and had 149 composite outcome events, and 693 337 were dispensed or prescribed hydrochlorothiazide and had 3089 composite outcome events. No significant difference was found in the associated risk of myocardial infarction, hospitalized heart failure, or stroke, with a calibrated hazard ratio for the composite cardiovascular outcome of 1.00 for chlorthalidone compared with hydrochlorothiazide (95% CI, 0.85-1.17). Chlorthalidone was associated with a significantly higher risk of hypokalemia (hazard ratio HR, 2.72; 95% CI, 2.38-3.12), hyponatremia (HR, 1.31; 95% CI, 1.16-1.47), acute renal failure (HR, 1.37; 95% CI, 1.15-1.63), chronic kidney disease (HR, 1.24; 95% CI, 1.09-1.42), and type 2 diabetes mellitus (HR, 1.21; 95% CI, 1.12-1.30). Chlorthalidone was associated with a significantly lower risk of diagnosed abnormal weight gain (HR, 0.73; 95% CI, 0.61-0.86).
This study found that chlorthalidone use was not associated with significant cardiovascular benefits when compared with hydrochlorothiazide, while its use was associated with greater risk of renal and electrolyte abnormalities. These findings do not support current recommendations to prefer chlorthalidone vs hydrochlorothiazide for hypertension treatment in first-time users was found. We used advanced methods, sensitivity analyses, and diagnostics, but given the possibility of residual confounding and the limited length of observation periods, further study is warranted.
ObjectivesTo provide a map of Anatomical Therapeutic Chemical (ATC) Classification System codes to individual Rx-Risk comorbidities and to validate the Rx-Risk Comorbidity Index.DesignThe 46 ...comorbidities in the Rx-Risk Index were mapped to dispensing’s indicative of each condition using ATC codes. Prescription dispensing claims in 2014 were used to calculate the Rx-Risk. A baseline logistic regression model was fitted using age and gender as covariates. Rx-Risk was added to the base model as an (1) unweighted score, (2) weighted score and as (3) individual comorbidity categories indicating the presence or absence of each condition. The Akaike information criterion and c-statistic were used to compare the models.SettingModels were developed in the Australian Government Department of Veterans’ Affairs health claims data, and external validation was undertaken in a 10% sample of the Australian Pharmaceutical Benefits Scheme Data.ParticipantsSubjects aged 65 years or older.Outcome measuresDeath within 1 year (eg, 2015).ResultsCompared with the base model (c-statistic 0.738, 95% CI 0.734 to 0.742), including Rx-Risk improved prediction of mortality; unweighted score 0.751, 95% CI 0.747 to 0.754, weighted score 0.786, 95% CI 0.782 to 0.789 and individual comorbidities 0.791, 95% CI 0.788 to 0.795. External validation confirmed the utility of the weighted index (c-statistic=0.833).ConclusionsThe updated Rx-Risk Comorbidity Score was predictive of 1-year mortality and may be useful in practice to adjust for confounding in observational studies using medication claims data.
Objective To determine whether treatment with methylphenidate in children and young people with attention-deficit/hyperactivity disorder (ADHD) was associated with cardiovascular events.Design Self ...controlled case series analysis.Setting Nationwide health insurance database, 1 January 2008 to 31 December 2011, in South Korea.Participants 1224 patients aged ≤17 who had experienced an incident cardiovascular event and had had at least one incident prescription for methylphenidate.Main outcome measures A recorded diagnosis (either a primary or secondary cause) of any of the following cardiovascular adverse events: arrhythmias (ICD-10 (international classification of diseases, 10th revision) codes I44, I45, I47, I48, I49), hypertension (codes I10-I15), myocardial infarction (code I21), ischemic stroke (code I63), or heart failure (code I50). Incidence rate ratios were calculated with conditional Poisson regression and adjusted for time varying comorbidity and comedication.Results Increased risk of arrhythmia was observed in all exposed time periods—that is, periods of treatment with methylphenidate—(incidence rate ratio 1.61, 95% confidence interval 1.48 to 1.74), and the risk was highest in the children who had congenital heart disease. No significant risk of myocardial infarction was observed for all exposed time periods (1.33, 0.90 to 1.98), though risk was higher in the early risk periods between eight and 56 days after the start of treatment with methylphenidate. No significant increased risk was observed for hypertension, ischemic stroke, or heart failure.Conclusion The relative risk of myocardial infarction and arrhythmias is increased in the early period after the start of methylphenidate treatment for ADHD in children and young people. Though the absolute risk is likely to be low, the risk-benefit balance of methylphenidate should be carefully considered, particularly in children with mild ADHD.
ObjectivesTo determine chronic opioid use pre-THA (total hip arthroplasty) and post-THA, and risk factors for persistent or new chronic opioid use post-THA.DesignRetrospective cohort ...study.SettingAustralian Government Department of Veterans' Affairs health claims database.Participants9525 patients who had an elective unilateral THA between 1/01/2001 and 12/31/2012.Primary outcome measureChronic opioid use. Defined as 90 days of continuous opioid use or 120 days of non-continuous use.ResultsPre-THA, 6.2% (n=593) of patients were chronic users, while 5.2% (n=492) were post-THA. Among the 492 postoperative chronic users, 302 (61%) were chronic users pre-THA and post-THA and 190 (39%) became new chronic users after surgery. Risk factors for persistent chronic use were younger age (OR=0.96, 95% CI 0.93 to 0.99/1-year increment), back pain (OR=1.99, 95% CI 1.20 to 3.23), diabetes (OR=3.52, 95% CI 1.05 to 11.8), hypnotics use (OR=2.52, 95% CI 1.48 to 4.30) and higher pre-THA opioid exposure (compared with opioid use for 94–157 days, 157–224 days (OR=3.75, 95% CI 2.28 to 6.18), 225+ days (OR=5.18, 95% CI 2.92 to 9.19). Risk factors for new chronic opioid use post-THA were being a woman (OR=1.40, 95% CI 1.00 to 1.96), back pain (OR=3.90, 95% CI 2.85 to 5.33), depression (OR=1.70, 95% CI 1.20 to 2.41), gastric acid disease (OR=1.62, 95% CI 1.16 to 2.25), migraine (OR=5.11, 95% CI 1.08 to 24.18), liver disease (OR=4.33, 95% CI 1.08 to 17.35), weight loss (OR=2.60, 95% CI 1.06 to 6.39), dementia (OR=2.19, 95% CI 1.04 to 4.61), hyperlipidaemia (OR=1.38, 95% CI 1.00 to 1.91), hypnotics (OR=1.56, 95% CI 1.13 to 2.16) and antineuropathic pain medication use (OR=3.11, 95% CI 2.05 to 4.72).ConclusionsPatients undergoing THA are exposed to opioids for long periods of time, putting them at high risk of harm related to opioid use. We identified groups at risk of chronic opioid use, including younger patients and women, as well as modifiable risk factors of chronic opioid use, including level of opioid exposure presurgery and hypnotic use. These indicators of chronic opioid use can be used by clinicians to target patient groups for suitable pain management interventions.
Highlights • MedicineInsight GP practice data can be used for risk management plan evaluation. • SGLT2 inhibitors did not increase the risk of UTIs compared to DPP4 SGLT2 inhibitors increased 3.5 ...times the risk of genital infection compared to DPP4. • Most people had one infection only in the first 12 weeks post SGLT2 initiation.
Purpose
The weighted cumulative exposure (WCE) method has been used in a number of fields including pharmacoepidemiology where it can account for intensity, duration and timing of exposures on the ...risk of an outcome. The method uses a data driven approach with flexible cubic B‐splines to assign weights to past doses and select an aetiologically appropriate time window. Predictions of risk are possible for common exposure patterns encountered in real‐world studies. The purpose of this study was to describe applications of the WCE method to pharmacoepidemiology and assess the strengths and limitations of the method.
Method
A literature search was undertaken to find studies applying the WCE method to the study of medicines. Articles published in PubMed using the search term ‘weighted cumulative exposure’ and articles citing Sylvestre et al. (2009) in Google Scholar or Scopus up to March 2023 were subsequently reviewed. Articles were selected based on title and review of s.
Results
Seventeen clinical applications using the data‐driven WCE method with flexible cubic splines were identified in the review. These included 3 case–control studies and 14 cohort studies, of which 12 were analysed with Cox proportional hazards models and 2 with logistic regression. Thirteen studies used time windows of 1 year or longer. Of 11 studies which compared conventional models with the WCE method, 10 (91%) studies found a better fit with WCE models while one had an equivalent fit. The freely available ‘WCE’ software package has facilitated the applications of the WCE method with flexible cubic splines.
Conclusions
The WCE method allows additional insights into the effect of cumulative exposure on outcomes, including the timing and intensity (dose) of the exposure on the risk. The flexibility of the method is particularly well suited to studies with long‐term exposures that vary over time or where the current risk of an event is affected by how far the exposure is in the past, which is difficult to model with conventional definitions of exposure. Interpretation of the results can be more complex than for conventional models and would be facilitated by a standardised reporting framework.
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