BACKGROUND: Increased long-term prescription of opioids and/or benzodiazepines necessitates evaluating risks associated with their receipt. We sought to evaluate the association between long-term opioids and/or benzodiazepines and mortality in HIV-infected patients receiving antiretroviral therapy and uninfected patients.
METHODS: Prospective analysis of all-cause mortality using multivariable methods and propensity score matching among HIV-infected patients receiving antiretroviral therapy and uninfected patients.
RESULTS: Of 64,602 available patients (16,989 HIV-infected and 47,613 uninfected), 27,128 (exposed and unexposed to long-term opioids and/or benzodiazepines) were 1:1 matched by propensity score. The hazard ratio for death was 1.40 [95% confidence interval (CI): 1.22 to 1.61] for long-term opioid receipt, 1.26 (95% CI: 1.08 to 1.48) for long-term benzodiazepine receipt, and 1.56 (95% CI: 1.26 to 1.92) for long-term opioid and benzodiazepine receipt. There was an interaction (P = 0.01) between long-term opioid receipt and HIV status with mortality. For long-term opioid receipt, the hazard ratio was 1.46 (95% CI: 1.15 to 1.87) among HIV-infected patients, and 1.25 (95% CI: 1.05 to 1.49) among uninfected patients. Mortality risk was increased for patients receiving both long-term opioids and benzodiazepines when opioid doses were ≥ 20 mg morphine-equivalent daily dose and for patients receiving long-term opioids alone when doses were ≥ 50 mg morphine-equivalent daily dose.
CONCLUSIONS: Long-term opioid receipt was associated with an increased risk of death; especially with long-term benzodiazepine receipt, higher opioid doses, and among HIV-infected patients. Long-term benzodiazepine receipt was associated with an increased risk of death regardless of opioid receipt. Strategies to mitigate risks associated with these medications, and caution when they are coprescribed, are needed particularly in HIV-infected populations.
OBJECTIVES: Gastrointestinal (GI) bleeding may impose a serious threat in patients undergoing total hip or knee replacement (THR/TKR). The objectives of this study are to evaluate the timing of GI bleeding following THR/TKR and to determine the effect modification by proton pump inhibitor (PPI) use.
METHODS: In a nationwide Danish cohort study, we selected all patients with a primary THR/TKR between 1998 and 2007 (n=95,115). Three control subjects without THR/TKR were matched by age, sex, and region. We calculated disease and medication adjusted (adj.) Hazard ratios (HRs) for GI bleeding with THR/TKR vs. controls. PPI use was assessed in the previous 3 months (in a time-dependent manner).
RESULTS: We identified a 6-fold increased risk of GI bleeding during the first 2 weeks following THR (adj. HR, 6.02; 95% confidence interval (CI), 4.06-8.92) and a 2.3-fold increased risk for TKR patients (adj. HR, 2.30; 95% CI, 1.17-4.54), both vs. matched controls. The elevated risk lasted longer in THR patients (12 weeks) as compared with TKR patients (6 weeks). PPI use lowered the HR for GI bleeding by 74% during the first 6 weeks following THR, but not TKR.
CONCLUSIONS: This study demonstrated an increased risk of GI bleeding during the first 2 weeks following THR (6-fold) and TKR (2.3-fold), and remained increased for up to 6 (TKR) to 12 weeks (THR) after surgery. PPI use substantially lowered this elevated risk in THR patients, but not in TKR patients.
Glucosamine and chondroitin are products commonly used by older adults in the US and Europe. There is limited evidence that they have anti-inflammatory properties, which could provide risk reduction of several diseases. However, data on their long-term health effects is lacking. To evaluate whether use of glucosamine and chondroitin are associated with cause-specific and total mortality. Participants (n = 77,510) were members of a cohort study of Washington State (US) residents aged 50-76 years who entered the cohort in 2000-2002 by completing a baseline questionnaire that included questions on glucosamine and chondroitin use. Participants were followed for mortality through 2008 (n = 5,362 deaths). Hazard ratios (HR) for death adjusted for multiple covariates were estimated using Cox models. Current (baseline) glucosamine and chondroitin use were associated with a decreased risk of total mortality compared to never use. The adjusted HR associated with current use of glucosamine (with or without chondroitin) was 0.82 (95 % CI 0.75-0.90) and 0.86 (95 % CI 0.78-0.96) for chondroitin (included in two-thirds of glucosamine supplements). Current use of glucosamine was associated with a significant decreased risk of death from cancer (HR 0.87 95 % CI 0.76-0.98) and with a large risk reduction for death from respiratory diseases (HR 0.59 95 % CI 0.41-0.83). Use of glucosamine with or without chondroitin was associated with reduced total mortality and with reductions of several broad causes of death. Although bias cannot be ruled out, these results suggest that glucosamine may provide some mortality benefit.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Previous studies have found varying impact of exposure to COX-2 selective and non-selective NSAIDs.
WHAT THIS STUDY ADDS: • Individuals receiving a COX-2 selective NSAID had an increased risk of all-cause mortality after correction for age, sex and cardiovascular risk as measured by co-prescription. • Despite differences in the pharmacokinetic properties of the COX-2 selective inhibitor drugs, our study lends no support to clinicians preferring any one COX-2 selective inhibitor drug, or substituting one for another on the grounds of mortality risk alone. • The Australian Department of Veterans' Affairs data sets make it possible to conduct timely record linkage studies of all-cause mortality from use of medicines in a large and clinically relevant population.
AIM: To determine hazard ratios for all-cause mortality in elderly Australian veterans taking COX-2 selective and non-selective NSAIDs.
METHODS: Patient cohorts were constructed from claims databases (1997 to 2007) for veterans and dependants with full treatment entitlement irrespective of military service. Patients were grouped by initial exposure: celecoxib, rofecoxib, meloxicam, diclofenac, non-selective NSAID. A reference group was constructed of patients receiving glaucoma/hypothyroid medications and none of the study medications. Univariate and multivariate analyses were performed using Cox proportional hazards regression models. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated for each exposure group against each of the reference group. The final model was adjusted for age, gender and co-prescription as a surrogate for cardiovascular risk. Patients were censored if the gap in supply of study prescription exceeded 30 days or if another study medication was initiated. The outcome measure in all analyses was death.
RESULTS: Hazard ratios and 95% CIs, adjusted for age, gender and cardiovascular risk, for each group relative to the reference group were: celecoxib 1.39 (1.25, 1.55), diclofenac 1.44 (1.28, 1.62), meloxicam 1.49 (1.25, 1.78), rofecoxib 1.58 (1.39, 1.79), non-selective NSAIDs 1.76 (1.59, 1.94).
CONCLUSIONS: In this large cohort of Australian veterans exposed to COX-2 selective and non-selective NSAIDs, there was a significant increased mortality risk for those exposed to either COX-2-selective or non-selective NSAIDs relative to those exposed to unrelated (glaucoma/hypothyroid) medications.
قمنا بتقييم المدى القصير من 0-90 يوما، وعلى المدى الطويل، وتصل إلى 12.7 سنة، وفيات المرضى الذين يخضعون الأساسي استبدال مفصل الورك (THR) في الدنمارك بالمقارنة مع السكان عموما. من خلال الدنماركي التسجيل هوب تقويم مفاصل حددنا كل THRs الأساسية التي تقوم لهشاشة العظام بين 1 يناير 1995 و 31 ديسمبر 2006 م. كل مريض (ن = 44 558) ويقابل في وقت الجراحة مع ثلاثة أشخاص من عامة السكان (ن = 133 674). قدرنا معدلات الوفيات ونسب ومعدلات الوفيات للفترات الثقة 95٪ لTHR المرضى مقارنة مع عموم السكان. وكان هناك فترة شهر واحد من تزايد وفيات على الفور بعد الجراحة لدى المرضى THR إلا أن وفيات قصير الأجل العلوي (0-90 أيام) أقل بكثير (وفيات نسبة نسبة 0.8؛ فاصل الثقة 95٪ 0،7-0،9). ومع ذلك، كان مرتبطا جراحة THR مع زيادة معدل الوفيات على المدى القصير في المواضيع تحت 60 سنة، وبين THR المرضى دون الاعتلال المشترك. كان معدل الوفيات على المدى الطويل أقل لدى المرضى الذين يعانون THR مقارنة بمجموعة التحكم (وفيات نسبة معدل 0.7؛ فاصل الثقة 95٪ 0،7-0،7). وعموما، كان مرتبطا مع انخفاض معدل وفيات THR قصيرة وطويلة الأجل بين المرضى الذين يعانون من هشاشة العظام. قد المرضى والمرضى الأصغر سنا دون الاعتلال المشترك قبل الجراحة أيضا تجربة زيادة معدل الوفيات بعد الجراحة THR، على الرغم من أن الخطر المطلق من الموت هو صغير.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are widely used analgesics in the prescription and non-prescription settings. Although both classes of drug are generally well tolerated, they can lead to well-characterized adverse effects. Both drugs are widely co-prescribed and it is of interest to understand better safety outcomes when the two drugs are taken concomitantly. WHAT THIS STUDY ADDS?: Relative rates and hazard ratio patterns of safety outcomes were broadly similar for patients prescribed ibuprofen alone, paracetamol alone and concomitant ibuprofen and paracetamol. The risks of the various safety outcomes examined do not appear to be modified by concomitant use of ibuprofen and paracetamol compared with paracetamol or ibuprofen alone.
AIMS: To evaluate and compare the risk of specific safety outcomes in patients prescribed ibuprofen and paracetamol concomitantly with those in patients prescribed ibuprofen or paracetamol alone. The outcomes were evaluated according to dose, duration and exposure.
METHODS: The study used a retrospective longitudinal cohort design with data from the UK General Practice Research Database (GPRD). The study population included patients aged 18 years or over who were prescribed ibuprofen alone, paracetamol alone or concomitant ibuprofen and paracetamol (tablets or capsules only). The safety outcomes evaluated were upper gastrointestinal events, myocardial infarction, stroke, renal failure (excluding chronic), congestive heart failure, intentional or accidental overdose, suicidal behaviour and mortality. Time-dependent Cox regression was used to estimate relative rates for the safety outcomes, by treatment group. A further analysis evaluated whether the hazard rates (i.e. absolute risks) varied over time with changes in drug exposure.
RESULTS: The study population included 1.2 million patients. There was considerable heterogeneity in both patient and exposure characteristics. When comparing with past users, for most safety outcomes, current users of concomitant paracetamol and ibuprofen had relative rates between those for current users of ibuprofen alone and paracetamol alone. The hazard rates were generally proportional over time, from current to past exposure, following a prescription for concomitant paracetamol and ibuprofen compared with ibuprofen alone or paracetamol alone.
CONCLUSIONS: The known risk of the safety outcomes examined does not appear to be modified by concomitant use of ibuprofen and paracetamol compared with paracetamol or ibuprofen alone.
BACKGROUND: Severe nonmalignant pain affects a large proportion of adults. Optimal treatment is not clear, and opioids are an important option for analgesia. However, there is relatively little information about the comparative safety of opioids. Therefore, we sought to compare the safety of opioids commonly used for nonmalignant pain.
METHODS: We devised a propensity-matched cohort analysis that used health care utilization data collected from January 1, 1996, through December 31, 2005. Study participants were Medicare beneficiaries from 2 US states who were new initiators of opioid therapy for nonmalignant pain, including codeine phosphate, hydrocodone bitartrate, oxycodone hydrochloride, propoxyphene hydrochloride, and tramadol hydrochloride; none had a cancer diagnosis, and none were using hospice or nursing home care. Our main outcome measures were incidence rates and rate ratios (RRs) with 95% confidence intervals (CIs) for cardiovascular events, fractures, gastrointestinal events, and several composite end points.
RESULTS: We matched 6275 subjects in each of the 5 opioid groups. The groups were well matched on baseline characteristics. The risk of cardiovascular events was similar across opioid groups 30 days after the start of opioid therapy, but it was elevated for codeine (RR, 1.62; 95% CI, 1.27-2.06) after 180 days. Compared with hydrocodone, after 30 days of opioid exposure the risk of fracture was significantly reduced for tramadol (RR, 0.21; 95% CI, 0.16-0.28) and propoxyphene (0.54; 0.44-0.66) users. The risk of gastrointestinal safety events did not differ across opioid groups. All-cause mortality was elevated after 30 days for oxycodone (RR, 2.43; 95% CI, 1.47-4.00) and codeine (2.05; 1.22-3.45) users compared with hydrocodone users.
CONCLUSIONS: The rates of safety events among older adults using opioids for nonmalignant pain vary significantly by agent. Causal inference requires experimental designs, but these results should prompt caution and further study.
OBJECTIVE: To simultaneously assess cardiovascular (CV) and gastrointestinal (GI) risk with traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and cyclo-oxygenase 2 (COX-2) inhibitors.
METHODS: Using the PHARMO Record Linkage System, including drug-dispensing and hospitalisation data of >2 million residents of The Netherlands, subjects with first hospitalisation for acute myocardial infarction (AMI), CV and GI events were identified. Use of COX-2 inhibitors and traditional non-selective NSAIDs was classified into remote, recent and current. Cases were matched to controls in a 1:4 ratio on age and event date. Multivariate analyses adjusted for gender, history of hospitalisations and medications.
RESULTS: Compared to remote use, AMI risk was increased among current users of COX-2 inhibitors combined (adjusted odds ratio (OR) 1.73, 95% CI 1.37 to 2.19) and tNSAIDs combined (OR 1.41, 95% CI 1.23 to 1.61). AMI risk with celecoxib (OR 2.53, 95% CI 1.53 to 4.18), rofecoxib (OR 1.60, 95% CI 1.22 to 2.10), ibuprofen (OR 1.56, 95% CI 1.19 to 2.05) and diclofenac (OR 1.51, 95% CI 1.22 to 1.87) was significantly increased. CV risk with current use of individual COX-2 inhibitors and tNSAIDs was significantly increased (OR from 1.17 to 1.64), as was GI risk with current use of rofecoxib (OR 1.99, 95% CI 1.51 to 2.63), naproxen (OR 4.44, 95% CI 3.36 to 5.86), ibuprofen (OR 1.90, 95% CI 1.40 to 2.58), diclofenac (OR 4.77, 95% CI 3.94 to 5.76), other tNSAIDs (OR 2.59, 95% CI 2.08 to 3.21), but not celecoxib (OR 1.36, 95% CI 0.70 to 2.66). Compared to current use of celecoxib and AMI risk was significantly decreased with current use of naproxen (OR 0.48, 95% CI 0.26 to 0.87) only. GI risk was increased with current naproxen (OR 3.26, 95% CI 1.59 to 6.70) and diclofenac (OR 3.50, 95% CI 1.76 to 6.98).
CONCLUSIONS: AMI and CV risk increased similarly with individual COX-2 inhibitors and tNSAIDs, whereas GI risk was found to be greater with naproxen and diclofenac. Residual confounding and "channelling" cannot be excluded.
BACKGROUND: Although randomized trials of cyclooxygenase-2 (COX-2) inhibitors have shown increased cardiovascular risk, studies of nonselective, nonsteroidal antiinflammatory drugs (NSAIDs) and acetaminophen have been inconsistent.
METHODS AND RESULTS: We examined the influence of NSAIDs and acetaminophen on the risk of major cardiovascular events (nonfatal myocardial infarction, fatal coronary heart disease, nonfatal and fatal stroke) in a prospective cohort of 70,971 women, aged 44 to 69 years at baseline, free of known cardiovascular disease or cancer, who provided medication data biennially since 1990. During 12 years of follow-up, we confirmed 2041 major cardiovascular events. Women who reported occasional (1 to 21 d/mo) use of NSAIDs or acetaminophen did not experience a significant increase in the risk of cardiovascular events. However, after adjustment for cardiovascular risk factors, women who frequently (> or =22 d/mo) used NSAIDs had a relative risk (RR) for a cardiovascular event of 1.44 (95% CI, 1.27 to 1.65) compared with nonusers, whereas those who frequently consumed acetaminophen had a RR of 1.35 (95% CI, 1.14 to 1.59). The elevated risk associated with frequent NSAID use was particularly evident among current smokers (RR=1.82; 95% CI, 1.38 to 2.42) and was absent among never smokers (Pinteraction=0.02). Moreover, we observed significant dose-response relations: Compared with nonusers, the RRs for a cardiovascular event among women who used > or =15 tablets per week were 1.86 (95% CI, 1.27 to 2.73) for NSAIDs and 1.68 (95% CI, 1.10 to 2.58) for acetaminophen.
CONCLUSIONS: Use of NSAIDs or acetaminophen at high frequency or dose is associated with a significantly increased risk for major cardiovascular events, although more moderate use did not confer substantial risk.
AIMS: لتحديد المخاطر المقارن من احتشاء عضلة القلب في المرضى الذين يتناولون أدوية أخرى غير الستيرويدية المضادة للالتهابات (المسكنات) في الرعاية الصحية الأولية بين عامي 2000 و 2004 سيكلوأكسجيناز-2 و. لتحديد هذه المخاطر في المرضى مع وبدون مرض القلب التاجي الموجود مسبقا والذين يتناولون وليس تناول الاسبرين.
تصميم: متداخلة دراسة الحالات والشواهد.
الإعداد: 367 ممارسات العامة المساهمة في قاعدة بيانات UK QRESEARCH وانتشار طوال كل سلطة الصحة الاستراتيجية ومجلس الصحة في إنجلترا، ويلز، واسكتلندا.
المواضيع: 9218 الحالات مع أول التشخيص من أي وقت مضى من احتشاء عضلة القلب أثناء فترة الدراسة أربع سنوات. 86 349 الضوابط الملائمة لعمر، السنة التقويمية، والجنس، والممارسة.
مقاييس النتائج: لم تتم تسويتها وتعديلها خلاف النسب مع فترات الثقة 95٪ عن احتشاء عضلة القلب المرتبطة Rofecoxi ب، السيليكوكسيب، نابروكسين، إيبوبروفين، ديكلوفيناك، وغيرها من NSAIDS انتقائية وغير انتقائية. تم تعديل نسب الأرجحية لحالة التدخين، الاعتلال المشترك، والحرمان، واستخدام الستاتين، والأسبرين، ومضادات الاكتئاب.
النتائج: كان مرتبطا وزيادة كبيرة في مخاطر احتشاء عضلة القلب مع الاستخدام الحالي للRofecoxi ب (تعديل نسبة الأرجحية 1.32، فاصل الثقة 95٪ 1،09-1،61) مقارنة مع عدم استخدام في غضون السنوات الثلاث السابقة؛ مع الاستخدام الحالي للديكلوفيناك (1.55، 1،39-1،72)؛ ومع الاستخدام الحالي للايبوبروفين (1.24، 1،11-1،39). وارتبطت زيادة المخاطر مع المسكنات الانتقائية أخرى، مع نابروكسين، ومع مضادات الالتهابات غير انتقائية. وكانت هذه المخاطر كبيرة في <0.05 بدلا من <0.01 للاستخدام الحالي ولكن كبيرة في <0.01 في اختبارات الاتجاه. لم تحدث التفاعلات الهامة بين أي من المسكنات والأسبرين أو أي مرض القلب التاجي.
الخلاصة: هذه النتائج تشير إلى زيادة مخاطر احتشاء عضلة القلب المرتبطة الاستخدام الحالي للRofecoxi ب، ديكلوفيناك، ايبوبروفين وعلى الرغم من تعديل لكثير من الإرباك المحتملة. تم العثور على أي دليل لدعم الحد من خطر احتشاء عضلة القلب المرتبطة الاستخدام الحالي للنابروكسين. هذا هو دراسة وصفية وقد تكون عرضة للالتباس المتبقية التي لا يمكن تصحيحها بالكامل. ومع ذلك، قد توجد مخاوف كافية لتبرير إعادة النظر في سلامة القلب والأوعية الدموية من جميع مضادات الالتهاب غير الستيروئيدية.
Increased long-term prescription of opioids and/or benzodiazepines necessitates evaluating risks associated with their receipt. We sought to evaluate the association between long-term opioids and/or benzodiazepines and mortality in HIV-infected patients receiving antiretroviral therapy and uninfected patients.
METHODS:
Prospective analysis of all-cause mortality using multivariable methods and propensity score matching among HIV-infected patients receiving antiretroviral therapy and uninfected patients.
RESULTS:
Of 64,602 available patients (16,989 HIV-infected and 47,613 uninfected), 27,128 (exposed and unexposed to long-term opioids and/or benzodiazepines) were 1:1 matched by propensity score. The hazard ratio for death was 1.40 [95% confidence interval (CI): 1.22 to 1.61] for long-term opioid receipt, 1.26 (95% CI.: 1.08 to 1.48) for long-term benzodiazepine receipt, and 1.56 (95% CI.: 1.26 to 1.92) for long-term opioid and benzodiazepine receipt. There was an interaction (P = 0.01) between long-term opioid receipt and HIV status with mortality. For long-term opioid receipt, the hazard ratio was 1.46 (95% CI.: 1.15 to 1.87) among HIV-infected patients, and 1.25 (95% CI.: 1.05 to 1.49) among uninfected patients. Mortality risk was increased for patients receiving both long-term opioids and benzodiazepines when opioid doses were ≥ 20 mg morphine-equivalent daily dose and for patients receiving long-term opioids alone when doses were ≥ 50 mg morphine-equivalent daily dose.
CONCLUSIONS:
Long-term opioid receipt was associated with an increased risk of death; especially with long-term benzodiazepine receipt, higher opioid doses, and among HIV-infected patients. Long-term benzodiazepine receipt was associated with an increased risk of death regardless of opioid receipt. Strategies to mitigate risks associated with these medications, and caution when they are coprescribed, are needed particularly in HIV-infected populations.
