Preadmission Opioid Use and 1-Year Mortality Following Incident Myocardial Infarction: A Danish Population-Based Cohort Study (1997-2016).

Background Opioid use has been linked to an increased risk of myocardial infarction and cardiovascular mortality, but the prognostic impact of opioid use before an incident myocardial infarction is largely unknown. Methods and Results We conducted a nationwide population-based cohort study including all patients hospitalized for an incident myocardial infarction in Denmark (1997-2016). Based on their last redeemed opioid prescription before admission, patients were categorized as current users (0-30 days), recent users (31-365 days), former users (>365 days), and nonusers. One-year all-cause mortality was calculated using the Kaplan-Meier method. Hazard ratios (HRs) were computed using Cox proportional hazards regression analyses, adjusting for age, sex, comorbidity, any preceding surgery within 6 months before the myocardial infarction admission, and medication use before the myocardial infarction admission. We identified 162 861 patients with an incident myocardial infarction. Of these, 8% were current opioid users, 10% were recent opioid users, 24% were former opioid users, and 58% were nonusers of opioids. One-year mortality was highest among current users (42.5% [95% CI, 41.7%-43.3%]) and lowest among nonusers (20.5% [95% CI, 20.2%-20.7%]). Compared with nonusers, current users had an elevated 1-year all-cause mortality risk (adjusted HR, 1.26 [95% CI, 1.22-1.30]). Following adjustment, neither recent users nor former users of opioids were at elevated risk. Conclusions Preadmission opioid use was associated with an increased 1-year all-cause mortality risk following an incident myocardial infarction. Opioid users thus represent a high-risk subgroup of patients with myocardial infarction.

Impact of Preadmission Opioid Treatment on 1-Year Mortality Following Nonsurgical Intensive Care.

OBJECTIVES: Compare all-cause mortality following nonsurgical ICU admission for opioid users with nonusers. DESIGN: Nationwide register-based cohort study. SETTING: All 43 ICUs in Denmark (7,028,668 citizens cumulatively during the study period). The Danish National Health Service provides universal healthcare, guaranteeing equal access to healthcare along with partial reimbursement for prescribed drugs. PATIENTS: All 118,388 nonsurgical patients admitted to an ICU from 2005 to 2014. INTERVENTION: Patients were categorized according to timing of last redeemed opioid prescription before admission: current user (prior 0-30 d), recent user (prior 31-365 d), former user (prior 365+ d), or nonuser (no prescription since 1994). MEASUREMENTS: All-cause mortality 0-30 days and 31-365 days following ICU admission was calculated using the Kaplan-Meier method. Crude and adjusted hazard ratios with 95% CIs were computed using Cox regression, comparing users with nonusers. Adjusted models included age, gender, socioeconomic factors, comedications, and comorbidity. MAIN RESULTS: Fifteen percent of the patients were current opioid users, 15% recent users, 30% former users, and 40% nonusers. Zero- to 30-day mortality was 35% for current users, 29% for recent users, 24% for former users, and 21% for nonusers. After confounder adjustment, current users remained at elevated risk during the first 30 days following ICU admission (hazard ratio, 1.20; 95% CI, 1.15-1.24). No association remained for recent or former users. A similar pattern was evident for 31-365-day all-cause mortality: 24% for current users, 19% for recent users, 13% for former users, and 10% for nonusers. During 31-365 days of follow-up, both current users and recent users remained at elevated risk of mortality after adjustment (hazard ratio, 1.47; 95% CI, 1.39-1.55 and hazard ratio, 1.20; 95% CI, 1.13-1.27, respectively). CONCLUSIONS: Current opioid users experience increased mortality during the first year following ICU admission.

Natural history of pain associated with melanoma surgery.

INTRODUCTION: After excision of a primary malignant melanoma (MM), treatment of stage IB or higher MM consists of sentinel lymph node biopsy (SLNB). If malignant cells are identified, a complete lymph node dissection (CLND) can be performed. OBJECTIVE: To determine the natural history of pain and sensory changes after MM surgery. METHODS: We prospectively followed 39 patients (29 SLNB-only, 2 CLND-only, and 8 CLND preceded by SLNB) from before inguinal or axillary surgery through 6 months after surgery on measures of pain intensity, sensory symptoms, allodynia, and questionnaires of anxiety, depression, and catastrophizing. RESULTS: No patient had pain preoperatively. Ten days after surgery, 35% had surgical site pain after SLNB-only compared with 90% after CLND (P < 0.003); clinically meaningful pain (Visual Analogue Scale ≥ 30 mm/100 mm) was reported by 3% of patients after SLNB-only compared with 40% after CLND (P < 0.001). At 6 months, all SLNB-only patients were pain-free. By contrast, 4 of 7 in the SLNB + CLND group still had pain (P < 0.002). At 6 months, symptoms of altered sensation or numbness were reported by 32% and 42% of SLNB-only patients, and by 67% and 67% of patients undergoing CLND surgery (both P > 0.05). CONCLUSION: Acute pain is more common after CLND surgery. Undergoing SLNB followed by more invasive CLND surgery may increase the likelihood of pain at 6 months. Persistent sensory symptoms typical of those associated with nerve injury are more common after CLND. Surgery for MM is a good model for studying the natural history of postsurgical pain and sensory changes.

Positive predictive values of ICD-10 codes to identify incident acute pancreatitis and incident primary malignancy in the Scandinavian national patient registries among women with postmenopausal osteoporosis.

BACKGROUND: Validation of definitions used to identify conditions of interest is imperative to epidemiologic studies based on routinely collected data. The objective of the study was thus to estimate positive predictive values (PPVs) of International Classification of Diseases, 10th Revision (ICD-10) codes to identify cases of incident acute pancreatitis leading to hospitalization and incident primary malignancy in the Scandinavian (Denmark, Norway, and Sweden) national patient registries in women with postmenopausal osteoporosis (PMO). METHODS: This validation study included postmenopausal (defined as 55 years or older) women with osteoporosis, identified between 2005-2014. Potential cases were sampled based on ICD-10 codes from the three national patient registries. Cases were adjudicated by physicians, using medical record review as gold standard. PPVs with corresponding 95% CIs were computed. RESULTS: Medical records of 286 of 325 (retrieval rate 88%) women with PMO were available for adjudication. Acute pancreatitis leading to hospitalization had a PPV of 87.6% (95% CI: 80.8%-90.2%). Incident primary malignancy had a PPV of 88.1% (95% CI: 81.3%-92.7%). The PPVs did not vary substantially across the three countries. CONCLUSION: ICD-10 codes to identify acute pancreatitis leading to hospitalization, and incident primary malignancy in the Scandinavian national patient registries had high PPVs among women with PMO. This allows identification of cases of acute pancreatitis and incident primary malignancy with reasonable validity and to use these as outcomes in comparative analyses.

Thirty-Year Mortality After Coronary Artery Bypass Graft Surgery: A Danish Nationwide Population-Based Cohort Study.

BACKGROUND: Data are sparse on long-term mortality after coronary artery bypass graft (CABG) surgery. We examined short-term and long-term mortality of patients undergoing CABG surgery and a general population comparison cohort. METHODS AND RESULTS: Linking data from Danish registries, we conducted a nationwide, population-based cohort study on 51 307 CABG patients and 513 070 individuals from the general population matched on age, sex, and calendar year (1980-2009). The mortality risk was higher in patients having isolated CABG surgery than in the general population, particularly during 0 to 30 days (3.2% versus 0.2%), 11 to 20 years (51.1% versus 35.6%), and 21 to 30 years (62.4% versus 44.8%), but not substantially higher during 31 to 364 days (2.9% versus 2.4%) or 1 to 10 years (30.7% versus 25.8%). The 30-day adjusted mortality rate ratio for isolated CABG surgery was 13.51 (95% confidence interval [CI], 12.59-14.49). Between 31 to 364 days and 1 to 10 years, the isolated CABG surgery cohort had a slightly higher mortality rate than the general population comparison cohort, adjusted mortality rate ratios of 1.15 (95% CI, 1.09-1.21) and 1.09 (95% CI, 1.08-1.11), respectively. Between 11 to 20 years and 21 to 30 years, the adjusted mortality rate ratios were 1.62 (95% CI, 1.58-1.66) and 1.76 (95% CI, 1.62-1.91). Within 30 days, CABG patients had a 25-fold, a 26-fold, and a 18-fold higher risk of dying from myocardial infarction, heart failure, or stroke, respectively, than members of the general population comparison cohort. We found substantial heterogeneity in absolute mortality rates according to baseline risk groups. CONCLUSIONS: The isolated CABG cohort had a higher mortality rate than the general population comparison cohort, especially within 30 days of and 10 years after surgery.

Positive predictive values of International Classification of Diseases, 10th revision codes for dermatologic events and hypersensitivity leading to hospitalization or emergency room visit among women with postmenopausal osteoporosis in the Danish and Swedish national patient registries.

BACKGROUND: Clinical epidemiology research studies, including pharmacoepidemiology and pharmacovigilance studies, use routinely collected health data, such as diagnoses recorded in national health and administrative registries, to assess clinical effectiveness and safety of treatments. We estimated positive predictive values (PPVs) of International Classification of Diseases, 10th revision (ICD-10) codes for primary diagnoses of dermatologic events and hypersensitivity recorded at hospitalization or emergency room visit in the national patient registries of Denmark and Sweden among women with postmenopausal osteoporosis (PMO). METHODS: This validation study included women with PMO identified from the Danish and Swedish national patient registries (2005-2014). Medical charts of the potential cases served as the gold standard for the diagnosis confirmation and were reviewed and adjudicated by physicians. RESULTS: We obtained and reviewed 189 of 221 sampled medical records (86%). The overall PPV was 92.4% (95% confidence interval [CI], 85.1%-96.3%) for dermatologic events, while the PPVs for bullous events and erythematous dermatologic events were 52.5% (95% CI, 37.5%-67.1%) and 12.5% (95% CI, 2.2%-47.1%), respectively. The PPV was 59.0% (95% CI, 48.3%-69.0%) for hypersensitivity; however, the PPV of hypersensitivity increased to 100.0% (95% CI, 67.6%-100.0%) when restricting to diagnostic codes for anaphylaxis. The overall results did not vary by country. CONCLUSION: Among women with PMO, the PPV for any dermatologic event recorded as the primary diagnosis at hospitalization or at an emergency room visit was high and acceptable for epidemiologic research in the Danish and Swedish national patient registries. The PPV was substantially lower for hypersensitivity leading to hospitalization or emergency room visit.

Positive predictive value of cardiac examination, procedure and surgery codes in the Danish National Patient Registry: a population-based validation study.

OBJECTIVE: Danish medical registries are widely used for cardiovascular research, but little is known about the data quality of cardiac interventions. We computed positive predictive values (PPVs) of codes for cardiac examinations, procedures and surgeries registered in the Danish National Patient Registry during 2010-2012. DESIGN: Population-based validation study. SETTING: We randomly sampled patients from 1 university hospital and 2 regional hospitals in the Central Denmark Region. PARTICIPANTS: 1239 patients undergoing different cardiac interventions. MAIN OUTCOME MEASURE: PPVs with medical record review as reference standard. RESULTS: A total of 1233 medical records (99% of the total sample) were available for review. PPVs ranged from 83% to 100%. For examinations, the PPV was overall 98%, reflecting PPVs of 97% for echocardiography, 97% for right heart catheterisation and 100% for coronary angiogram. For procedures, the PPV was 98% overall, with PPVs of 98% for thrombolysis, 92% for cardioversion, 100% for radiofrequency ablation, 98% for percutaneous coronary intervention, and 100% for both cardiac pacemakers and implantable cardiac defibrillators. For cardiac surgery, the overall PPVs was 99%, encompassing PPVs of 100% for mitral valve surgery, 99% for aortic valve surgery, 98% for coronary artery bypass graft surgery, and 100% for heart transplantation. The accuracy of coding was consistent within age, sex, and calendar year categories, and the agreement between independent reviewers was high (99%). CONCLUSIONS: Cardiac examinations, procedures and surgeries have high PPVs in the Danish National Patient Registry.

Positive predictive value of cardiovascular diagnoses in the Danish National Patient Registry: a validation study.

OBJECTIVE: The majority of cardiovascular diagnoses in the Danish National Patient Registry (DNPR) remain to be validated despite extensive use in epidemiological research. We therefore examined the positive predictive value (PPV) of cardiovascular diagnoses in the DNPR. DESIGN: Population-based validation study. SETTING: 1 university hospital and 2 regional hospitals in the Central Denmark Region, 2010-2012. PARTICIPANTS: For each cardiovascular diagnosis, up to 100 patients from participating hospitals were randomly sampled during the study period using the DNPR. MAIN OUTCOME MEASURE: Using medical record review as the reference standard, we examined the PPV for cardiovascular diagnoses in the DNPR, coded according to the International Classification of Diseases, 10th Revision. RESULTS: A total of 2153 medical records (97% of the total sample) were available for review. The PPVs ranged from 64% to 100%, with a mean PPV of 88%. The PPVs were ≥90% for first-time myocardial infarction, stent thrombosis, stable angina pectoris, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, takotsubo cardiomyopathy, arterial hypertension, atrial fibrillation or flutter, cardiac arrest, mitral valve regurgitation or stenosis, aortic valve regurgitation or stenosis, pericarditis, hypercholesterolaemia, aortic dissection, aortic aneurysm/dilation and arterial claudication. The PPVs were between 80% and 90% for recurrent myocardial infarction, first-time unstable angina pectoris, pulmonary hypertension, bradycardia, ventricular tachycardia/fibrillation, endocarditis, cardiac tumours, first-time venous thromboembolism and between 70% and 80% for first-time and recurrent admission due to heart failure, first-time dilated cardiomyopathy, restrictive cardiomyopathy and recurrent venous thromboembolism. The PPV for first-time myocarditis was 64%. The PPVs were consistent within age, sex, calendar year and hospital categories. CONCLUSIONS: The validity of cardiovascular diagnoses in the DNPR is overall high and sufficient for use in research since 2010.

Pain and falls and fractures in community-dwelling older men.

BACKGROUND: Pain may reduce stability and increase falls and subsequent fractures in older men. OBJECTIVES: To examine the association between joint pain and any pain with falls, hip and non-spine fractures in older community-dwelling men. DESIGN: A cohort study. SETTING AND PARTICIPANTS: Analyses included 5,993 community-dwelling men aged ≥65 years from the MrOS cohort. MEASUREMENTS: Pain at hip, knee and elsewhere (any) was assessed by self-report. Men reported falls via questionnaires mailed 3× per year during the year following the baseline visit. Fractures were verified centrally. Mean follow-up time for fractures was 9.7 (SD 3.1) years. Logistic regression models estimated likelihood of falls and proportional hazards models estimated risk of fractures. Models were adjusted for age, BMI, race, smoking, alcohol use, medications use, co-morbidities and arthritis; fracture models additionally adjusted for bone mineral density. RESULTS: One quarter (25%, n = 1,519) reported ≥1 fall; 710 reported ≥2 falls in the year after baseline. In multivariate models, baseline pain at hip, knee or any pain increased likelihood of ≥1 fall and ≥2 falls over the following year. For example, knee pain increased likelihood of ≥1 fall (odds ratio, OR 1.44; 95% confidence interval, CI 1.25-1.65) and ≥2 falls (OR 1.75; 95% CI 1.46-2.10). During follow-up, 936 (15.6%) men suffered a non-spine fracture (n = 217, 3.6% hip). In multivariate models, baseline pain was not associated with incident hip or non-spine fractures. CONCLUSIONS: Any pain, knee pain and hip pain were each strong independent risk factors for falls in older men. Increased risk of falls did not translate into an increased risk of fractures.

Results availability for analgesic device, complex regional pain syndrome, and post-stroke pain trials: comparing the RReADS, RReACT, and RReMiT databases.

Evidence-based medicine rests on the assumption that treatment recommendations are robust, free from bias, and include results of all randomized clinical trials. The Repository of Registered Analgesic Clinical Trials search and analysis methodology was applied to create databases of complex regional pain syndrome (CRPS) and central post-stroke pain (CPSP) trials and adapted to create the Repository of Registered Analgesic Device Studies databases for trials of spinal cord stimulation (SCS), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS). We identified 34 CRPS trials, 18 CPSP trials, 72 trials of SCS, and 92 trials of rTMS/tDCS. Irrespective of time since study completion, 45% of eligible CRPS and CPSP trials and 46% of eligible SCS and rTMS/tDCS trials had available results (peer-reviewed literature, results entered on registry, or gray literature); peer-reviewed publications could be found for 38% and 39%, respectively. Examining almost 1000 trials across a spectrum of painful disorders (fibromyalgia, diabetic painful neuropathy, post-herpetic neuralgia, migraine, CRPS, CPSP) and types of treatment, no single study characteristic consistently predicts unavailability of results. Results availability is higher 12 months after study completion but remains below 60% for peer-reviewed publications. Recommendations to increase results availability include supporting organizations advocating for transparency, enforcing existing results reporting regulations, enabling all primary registries to post results, stating trial registration numbers in all publication abstracts, and reducing barriers to publishing "negative" trials. For all diseases and treatment modalities, evidence-based medicine must rigorously adjust for the sheer magnitude of missing results in formulating treatment recommendations.

RReACT goes global: perils and pitfalls of constructing a global open-access database of registered analgesic clinical trials and trial results.

Eliminating publication bias requires ensuring public awareness of studies and access to results. Clinical trial registries provide basic trial information, but access to unbiased trial results is inadequate. Nearly all studies of trial registration and results reporting have been limited to the ClinicalTrials.gov registry. We analyzed trial registration, registry functionality, cross-registry harmonization, and results reporting on all 15 primary registries in the World Health Organization International Clinical Trials Registry Platform (ICTRP) for postherpetic neuralgia, painful diabetic neuropathy, and fibromyalgia. A total of 447 unique trials were identified, with 86 trials listed on more than one registry. A comprehensive search algorithm was used to find trial results in the peer-reviewed literature and the grey literature. Creating a global database of registered trials and trial results proved surprisingly difficult for several reasons: (1) ICTRP does not reliably identify trials listed on multiple registries, manual searches are necessary; (2) Searching ICTRP yields different results than searching individual registries; (3) Outcome measure descriptions for multiply registered trials vary between registries; (4) Registry-publication pairings are often inaccurate or incomplete; (5) Grey literature results are not permanent. Overall, only 46% of all trials had results available. Trials registered on ClinicalTrials.gov were significantly more likely to have results (52% vs. 18%, P<0.001), partly due to the ability to post results directly to the registry. In addition to the simple remedy of including trial registration numbers on all meeting abstracts and peer-reviewed papers, specific strategies are offered to facilitate identifying multiply registered studies and ensuring accurate pairing of results and publications.

Effects of blood withdrawal and reinfusion on biomarkers of erythropoiesis in humans: Implications for anti-doping strategies.

To discriminate autologous blood doping procedures from normal conditions, we examined the hematological response to blood withdrawal and reinfusion. We found that biomarkers of erythropoiesis are primarily affected in the anemic period. Therefore, individual variations in [Hb] exceeding 15% between samples obtained shortly before any major competition would be indicative of autologous blood manipulation.