Postoperative use of sleep aids and delirium in older adults after major surgery: A retrospective cohort study.

BACKGROUND: Sleep aids are commonly prescribed to treat sleep disturbance, a modifiable risk factor for postoperative delirium in older patients. The use of melatonin receptor agonists in the postoperative period has been increasing. The comparative safety of melatonin receptor agonists, zolpidem, and temazepam remains uncertain. METHODS: This retrospective study included 22,083 patients ≥65 years old who initiated melatonin receptor agonists, zolpidem, or temazepam after major surgery in the Premier Healthcare Database 2009-2018. We performed propensity score-based overlap weighting and estimated the risk ratio (RR) and risk difference (RD) of postoperative delirium as the primary outcome and a composite of delirium or new antipsychotic initiation, pneumonia, and in-hospital mortality as secondary outcomes. RESULTS: The mean age of the study population was 78 (SD, 7) years and 50% were female. There was no significant difference in the risk of postoperative delirium among patients treated with melatonin receptor agonists (3.4%, reference group), zolpidem (2.9%; RR [95% CI], 0.9 [0.7-1.2]; RD [95% CI] per 100 persons, -0.3 [-1.1 to 0.6]), and temazepam (3.1%; 0.9 [0.7-1.1]; RD [95% CI] per 100 persons, -0.5 [-1.2 to 0.3]). The risks of delirium or new antipsychotic initiation, pneumonia, and in-hospital mortality were also similar among all groups. CONCLUSIONS: Melatonin receptor agonists were not associated with a lower risk of postoperative delirium and other adverse outcomes compared with zolpidem and temazepam in older adults after major surgery.

Trends in use of antipsychotics and psychoactive drugs in older patients after major surgery.

BACKGROUND: Professional society guidelines recommend limiting the use of antipsychotics in older patients with postoperative delirium. How these recommendations affected the use of antipsychotics and other psychoactive drugs in the postoperative period has not been studied. METHODS: This retrospective cohort study included patients 65 years or older without psychiatric diagnoses who underwent major surgery in community hospitals (CHs) and academic medical centers (AMCs) in the United States. The outcome was the rate of hospital days exposed to antipsychotics, antidepressants, antiepileptics, benzodiazepines, hypnotics, and selective alpha-2 receptor agonist dexmedetomidine in the postoperative period by hospital type. RESULTS: The study included 4,098,431 surgical admissions from CHs (mean age 75.0 [standard deviation, 7.1] years; 50.8% female) during 2008-2018 and 2,310,529 surgical admissions from AMCs (75.0 [7.4] years; 49.4% female) during 2009-2018. In the intensive care unit (ICU) setting, the number of exposed days per 1000 hospital-days declined for haloperidol (CHs: 33-21 days [p < 0.01]; AMCs: 24-15 days [p < 0.01]) and benzodiazepines (CHs: 261-136 days [p < 0.01]; AMCs: 150-77 days [p < 0.01]). The use of atypical antipsychotics, antidepressants, antiepileptics, and dexmedetomidine increased, while hypnotic use varied by the hospital type. In the non-ICU setting, the rate declined for haloperidol in CHs but not in AMCs (CHs: 10-6 days [p < 0.01]; AMCs: 4-3 days [p = 0.52]) and for benzodiazepines in both settings (CHs: 126-56 days [p < 0.01]; AMCs: 30-27 days [p < 0.01]). The use of antiepileptics and antidepressants increased, while the use of atypical antipsychotics and hypnotics varied by the hospital type. CONCLUSIONS: The use of haloperidol and benzodiazepines in the postoperative period declined at both CHs and AMCs. These trends coincided with the increasing use of other psychoactive drugs.

Comparative Safety Analysis of Oral Antipsychotics for In-Hospital Adverse Clinical Events in Older Adults After Major Surgery : A Nationwide Cohort Study.

BACKGROUND: Antipsychotics are commonly used to manage postoperative delirium. Recent studies reported that haloperidol use has declined, and atypical antipsychotic use has increased over time. OBJECTIVE: To compare the risk for in-hospital adverse events associated with oral haloperidol, olanzapine, quetiapine, and risperidone in older patients after major surgery. DESIGN: Retrospective cohort study. SETTING: U.S. hospitals in the Premier Healthcare Database. PATIENTS: 17 115 patients aged 65 years and older without psychiatric disorders who were prescribed an oral antipsychotic drug after major surgery from 2009 to 2018. INTERVENTIONS: Haloperidol (≤4 mg on the day of initiation), olanzapine (≤10 mg), quetiapine (≤150 mg), and risperidone (≤4 mg). MEASUREMENTS: The risk ratios (RRs) for in-hospital death, cardiac arrhythmia events, pneumonia, and stroke or transient ischemic attack (TIA) were estimated after propensity score overlap weighting. RESULTS: The weighted population had a mean age of 79.6 years, was 60.5% female, and had in-hospital death of 3.1%. Among the 4 antipsychotics, quetiapine was the most prescribed (53.0% of total exposure). There was no statistically significant difference in the risk for in-hospital death among patients treated with haloperidol (3.7%, reference group), olanzapine (2.8%; RR, 0.74 [95% CI, 0.42 to 1.27]), quetiapine (2.6%; RR, 0.70 [CI, 0.47 to 1.04]), and risperidone (3.3%; RR, 0.90 [CI, 0.53 to 1.41]). The risk for nonfatal clinical events ranged from 2.0% to 2.6% for a cardiac arrhythmia event, 4.2% to 4.6% for pneumonia, and 0.6% to 1.2% for stroke or TIA, with no statistically significant differences by treatment group. LIMITATION: Residual confounding by delirium severity; lack of untreated group; restriction to oral low-to-moderate dose treatment. CONCLUSION: These results suggest that atypical antipsychotics and haloperidol have similar rates of in-hospital adverse clinical events in older patients with postoperative delirium who receive an oral low-to-moderate dose antipsychotic drug. PRIMARY FUNDING SOURCE: National Institute on Aging.

Perioperative Gabapentin Use and In-Hospital Adverse Clinical Events Among Older Adults After Major Surgery.

Importance: Gabapentin has been increasingly used as part of a multimodal analgesia regimen to reduce opioid use in perioperative pain management. However, the safety of perioperative gabapentin use among older patients remains uncertain. Objective: To examine in-hospital adverse clinical events associated with perioperative gabapentin use among older patients undergoing major surgery. Design, Setting, and Participants: This retrospective cohort study using data from the Premier Healthcare Database included patients aged 65 years or older who underwent major surgery at US hospitals within 7 days of hospital admission from January 1, 2009, to March 31, 2018, and did not use gabapentin before surgery. Data were analyzed from June 14, 2021, to May 23, 2022. Exposures: Gabapentin use within 2 days after surgery. Main Outcomes and Measures: The primary outcome was delirium, identified using diagnosis codes, and secondary outcomes were new antipsychotic use, pneumonia, and in-hospital death between postoperative day 3 and hospital discharge. To reduce confounding, 1:1 propensity score matching was performed. Risk ratios (RRs) and risk differences (RDs) with 95% CIs were estimated. Results: Among 967 547 patients before propensity score matching (mean [SD] age, 76.2 [7.4] years; 59.6% female), the rate of perioperative gabapentin use was 12.3% (119 087 patients). After propensity score matching, 237 872 (118 936 pairs) gabapentin users and nonusers (mean [SD] age, 74.5 [6.7] years; 62.7% female) were identified. Compared with nonusers, gabapentin users had increased risk of delirium (4040 [3.4%] vs 3148 [2.6%]; RR, 1.28 [95% CI, 1.23-1.34]; RD, 0.75 [95% CI, 0.75 [0.61-0.89] per 100 persons), new antipsychotic use (944 [0.8%] vs 805 [0.7%]; RR, 1.17 [95% CI, 1.07-1.29]; RD, 0.12 [95% CI, 0.05-0.19] per 100 persons), and pneumonia (1521 [1.3%] vs 1368 [1.2%]; RR, 1.11 [95% CI, 1.03-1.20]; RD, 0.13 [95% CI, 0.04-0.22] per 100 persons), but there was no difference in in-hospital death (362 [0.3%] vs 354 [0.2%]; RR, 1.02 [95% CI, 0.88-1.18]; RD, 0.00 [95% CI, -0.04 to 0.05] per 100 persons). Risk of delirium among gabapentin users was greater in subgroups with high comorbidity burden than in those with low comorbidity burden (combined comorbidity index <4 vs ≥4: RR, 1.20 [95% CI, 1.13-1.27] vs 1.40 [95% CI, 1.30-1.51]; RD, 0.41 [95% CI, 0.28-0.53] vs 2.66 [95% CI, 2.08-3.24] per 100 persons) and chronic kidney disease (absence vs presence: RR, 1.26 [95% CI, 1.19-1.33] vs 1.38 [95% CI, 1.27-1.49]; RD, 0.56 [95% CI, 0.42-0.69] vs 1.97 [95% CI, 1.49-2.46] per 100 persons). Conclusion and Relevance: In this cohort study, perioperative gabapentin use was associated with increased risk of delirium, new antipsychotic use, and pneumonia among older patients after major surgery. These results suggest careful risk-benefit assessment before prescribing gabapentin for perioperative pain management.

Effectiveness of angiotensin-neprilysin inhibitor treatment versus renin-angiotensin system blockade in older adults with heart failure in clinical care.

OBJECTIVE: To evaluate the effectiveness of angiotensin receptor-neprilysin inhibitor (ARNI) versus renin-angiotensin system (RAS) blockade alone in older adults with heart failure with reduced ejection fraction (HFrEF). METHODS: We conducted a cohort study using US Medicare fee-for-service claims data (2014-2017). Patients with HFrEF ≥65 years were identified in two cohorts: (1) initiators of ARNI or RAS blockade alone (ACE inhibitor, ACEI; or angiotensin receptor blocker, ARB) and (2) switchers from an ACEI to either ARNI or ARB. HR with 95% CI from Cox proportional hazard regression and 1-year restricted mean survival time (RMST) difference with 95% CI were calculated for a composite outcome of time to first worsening heart failure event or all-cause mortality after adjustment for 71 pre-exposure characteristics through propensity score fine-stratification weighting. All analyses of initiator and switcher cohorts were conducted separately and then combined using fixed effects. RESULTS: 51 208 patients with a mean age of 76 years were included, with 16 193 in the ARNI group. Adjusted HRs comparing ARNI with RAS blockade alone were 0.92 (95% CI 0.84 to 1.00) among initiators and 0.79 (95% CI 0.74 to 0.85) among switchers, with a combined estimate of 0.84 (95% CI 0.80 to 0.89). Adjusted 1-year RMST difference (95% CI) was 4 days in the initiator cohort (-1 to 9) and 12 days (8 to 17) in the switcher cohort, resulting in a pooled estimate of 9 days (6 to 12) favouring ARNI. CONCLUSION: ARNI treatment was associated with lower risk of a composite effectiveness endpoint compared with RAS blockade alone in older adults with HFrEF.

The Risk of Overdose With Concomitant Use of Z-Drugs and Prescription Opioids: A Population-Based Cohort Study.

OBJECTIVE: The Z-drugs (zolpidem, zopiclone, zaleplon) are widely used to treat insomnia in patients receiving prescription opioids, and the risk of overdose resulting from this coprescription has not been explored. The authors compared the rates of overdose among patients using opioids plus Z-drugs and patients using opioids alone. METHODS: All individuals 15 to 85 years of age receiving prescription opioids, regardless of underlying indication and without evidence of cancer, were identified in the IBM MarketScan database (2004-2017). Patients with concomitant exposure to Z-drugs were matched 1:1 to patients with exposure to prescription opioids alone based on opioid prescribed, morphine equivalents, number of days' supply, and hospitalization within the past 30 days. The primary outcome was any hospitalization or emergency department visit due to an overdose within 30 days, using an intention-to-treat approach. Fine stratification on the propensity score was used to control for confounding. RESULTS: A total of 510,529 exposed patients and an equal number of matched reference patients were analyzed. There were 217 overdose events among the exposed patients (52.5 events per 10,000 person-years) and 57 events among the reference patients (14.4 events per 10,000 person-years), corresponding to an unadjusted hazard ratio of 3.67 (95% CI=2.75, 4.90). Using fine stratification on the propensity score (c-statistic: 0.66), the adjusted hazard ratio was 2.29 (95% CI=1.79, 2.91). Results were consistent across sensitivity analyses. CONCLUSIONS: Among patients receiving prescription opioids, after controlling for all confounding factors, concomitant treatment with Z-drugs was associated with a substantial relative increase in the risk of overdose. The potential implications are significant given the large number of opioid-treated patients receiving Z-drugs.

Clinical outcomes following bone marrow transplantation in patients with sickle cell disease: A cohort study of US Medicaid enrollees.

OBJECTIVES: Bone marrow transplantation (BMT) is currently the only curative therapy available for patients with sickle cell disease (SCD), but clinical outcomes in routine care are not well understood. We describe the rates of vaso-occlusive crises (VOCs), transplant complications, and mortality in SCD patients after BMT. METHODS: A cohort study of SCD patients who underwent BMT was designed using US Medicaid claims data (2000-2013). RESULTS: A total of 204 SCD patients undergoing BMT were identified with a mean (SD) age of 10.6 (7.3) years, with 52.9% male and 67.6% African American. The overall VOC rate was 0.99 per person-year (95% CI: 0.91-1.07) over a median follow-up time of 2.1 years (IQR: 0.8-4.3 years). A total of 138 (67.6%) remained free of VOCs. The mortality rate was 1.7 (95% CI: 0.9-3.1) per 100 person-years, transplant-related complications occurred among 113 (55.4%) patients with an incidence rate of 38.2 (95% CI: 31.7-45.9) per 100 person-years, while 47 (23%) patients had GvHD with an incidence rate of 8.0 (95% CI: 6.0-10.7) per 100 person-years. CONCLUSION: Two thirds of the BMT recipients remained VOC-free over 2 years of follow-up, but transplant-related complications, including GvHD occurred with high frequency. This highlights a continuing unmet need for alternative curative interventions in SCD.

Using Data From Routine Care to Estimate the Effectiveness and Potential Limitations of Outcomes-Based Contracts for Diabetes Medications.

OBJECTIVES: Outcomes-based contracts tie rebates and discounts for expensive drugs to outcomes. The objective was to estimate the utility of outcomes-based contracts for diabetes medications using real-world data and to identify methodologic limitations of this approach. METHODS: A population-based cohort study of adults newly prescribed a medication for diabetes with a publicly announced outcomes-based contract (ie, exenatide microspheres ["exenatide"], dulaglutide, or sitagliptin) was conducted. The comparison group included patients receiving canagliflozin or glipizide. The primary outcome was announced in the outcomes-based contract: the percentage of adults with a follow-up hemoglobin A1C <8% up to 1 year later. Secondary outcomes included the percentage of patients diagnosed with hypoglycemia and the cost of a 1-month supply. RESULTS: Thousands of adults newly filled prescriptions for exenatide (n = 5079), dulaglutide (n = 6966), sitagliptin (n = 40 752), canagliflozin (n = 16 404), or glipizide (n = 59 985). The percentage of adults subsequently achieving a hemoglobin A1C below 8% ranged from 83% (dulaglutide, sitagliptin) to 71% (canagliflozin). The rate of hypoglycemia was 25 per 1000 person-years for exenatide, 37 per 1000 person-years for dulaglutide, 28 per 1000 person-years for sitagliptin, 18 per 1000 person-years for canagliflozin, and 34 per 1000 person-years for glipizide. The cash price for a 1-month supply was $847 for exenatide, $859 for dulaglutide, $550 for sitagliptin, $608 for canagliflozin, and $14 for glipizide. CONCLUSION: Outcomes-based pricing of diabetes medications has the potential to lower the cost of medications, but using outcomes such as hemoglobin A1C may not be clinically meaningful because similar changes in A1C can be achieved with generic medications at a far lower cost.

Longitudinal Trends and Variation in Antipsychotic Use in Older Adults After Cardiac Surgery.

OBJECTIVES: To evaluate temporal trends and between-hospital variation in off-label antipsychotic medication (APM) use in older adults undergoing cardiac surgery. DESIGN: Retrospective cohort study. SETTING: National administrative database including 465 U.S. hospitals. PARTICIPANTS: Individuals aged 65 and older without known indications for APMs who underwent cardiac surgery from 2004 to 2014 (N=293,212). MEASUREMENTS: Postoperative exposure to any APMs and potentially excessive dosing were examined. Hospital-level APM prescribing intensity was defined as the proportion of individuals newly treated with APMs in the postoperative period. RESULTS: The rate of APM use declined from 8.8% in 2004 to 6.2% in 2014 (p<.001). Use of haloperidol (parenteral 7.0% to 4.5%, p<.001; oral: 1.9% to 0.5%, p<.001), and risperidone (1.1% to 0.3%, p<.001) declined, whereas quetiapine use tripled (0.6% to 1.9%, p=.03). Hospital APM prescribing intensity varied widely, from 0.3% to 35.6%, across 465 hospitals. Treated individuals at higher-prescribing hospitals were more likely to receive APMs on the day of discharge (highest vs lowest quintile: 15.1% vs 9.6%; p<.001) and for a longer duration (4.8 vs 3.7 days; p<.001) than those at lower-prescribing hospitals. Delirium was the strongest risk factor for APM exposure (odds ratio=9.73, 95% confidence interval=9.02-10.5), whereas none of the hospital characteristics were significantly associated. The rate of potentially excessive dosing declined (60.7% to 44.9%, p<.001), and risk factors for potentially excessive dosing were similar to those for any APM exposure. CONCLUSIONS: Our findings suggest highly variable prescribing cultures and raise concerns about inappropriate use, highlighting the need for better evidence to guide APM prescribing in hospitalized older adults after cardiac surgery.

Adverse Events Associated with Antipsychotic Use in Hospitalized Older Adults After Cardiac Surgery.

OBJECTIVES: To evaluate in-hospital adverse events associated with typical and atypical antipsychotic medications (APMs) after cardiac surgery. DESIGN: Retrospective cohort study. SETTING: Nationwide inpatient database, 2003 to 14. PARTICIPANTS: Individuals (mean age 70) newly treated with oral atypical (n = 2,580) or typical (n = 1,126 APMs) after coronary artery bypass grafting or valve surgery (N = 3,706). MEASUREMENTS: In-hospital mortality, arrhythmia, pneumonia, use of brain imaging (surrogate for oversedation and neurological events), and length of stay after drug initiation RESULTS: In the propensity score-matched cohort, median treatment duration was 3 days (interquartile range (IQR) 1-6 days) for atypical APMs and 2 days (IQR 1-3 days) for typical APMs. There were no large differences in in-hospital mortality (atypical 5.4%, typical 5.3%; risk difference (RD) = 0.1%, 95% confidence interval (CI) = -2.1 to 2.3%), arrhythmia (2.0% vs 2.2%; RD = 0.0%; 95% CI = -1.4 to 1.4%), pneumonia (16.1% vs 14.5%; RD = 1.6%, 95% CI = -1.9 to 5.0%), and length of stay (9.9 days vs 9.3 days; mean difference = 0.5 days, 95% CI = -1.2 to 2.2). Use of brain imaging was more common after initiating atypical APMs (17.3%) than after typical APMs (12.4%; RD = 4.9%, 95% CI = 1.4-8.4). CONCLUSION: In hospitalized individuals who underwent cardiac surgery, short-term use of typical APMs was associated with risks of adverse events similar to those with atypical APMs. Moreover, greater use of brain imaging associated with atypical APMs suggests that these drugs may cause oversedation or adverse neurological events. Because of the low event rates, the analysis could not exclude modest differences in adverse events between atypical and typical APMs.

Risk of mortality with concomitant use of tamoxifen and selective serotonin reuptake inhibitors: multi-database cohort study.

OBJECTIVE:  To compare differences in mortality between women concomitantly treated with tamoxifen and selective serotonin reuptake inhibitors (SSRIs) that are potent inhibitors of the cytochrome-P450 2D6 enzyme (CYP2D6) versus tamoxifen and other SSRIs. DESIGN:  Population based cohort study. SETTING:  Five US databases covering individuals enrolled in private and public health insurance programs from 1995 to 2013. PARTICIPANTS:  Two cohorts of women who started taking tamoxifen. In cohort 1, women started taking an SSRI during tamoxifen treatment. In cohort 2, women were already taking an SSRI when they started taking tamoxifen. MAIN OUTCOME MEASURES:  All cause mortality in each cohort in women taking SSRIs that are potent inhibitors of CYP2D6 (paroxetine, fluoxetine) versus other SSRIs. Propensity scores were used to match exposure groups in a variable ratio fashion. Results were measured separately for each cohort and combined hazard ratios calculated from Cox regression models across the two cohorts with random effects meta-analysis. RESULTS:  There were 6067 and 8465 new users of tamoxifen in cohorts 1 and 2, respectively. Mean age was 55. A total of 991 and 1014 deaths occurred in cohorts 1 and 2 during a median follow-up of 2.2 (interquartile range 0.9-4.5) and 2.0 (0.8-3.9) years, respectively. The pooled hazard ratio for death for potent inhibitors (rate 58.6/1000 person years) compared with other SSRIs (rate 57.9/1000 person years) across cohorts 1 and 2 was 0.96 (95% confidence interval 0.88 to 1.06). Results were consistent across sensitivity analyses. CONCLUSION:  Concomitant use of tamoxifen and potent CYP2D6 inhibiting SSRIs versus other SSRIs was not associated with an increased risk of death.

Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn.

IMPORTANCE: The association between selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and risk of persistent pulmonary hypertension of the newborn (PPHN) has been controversial since the US Food and Drug Administration issued a public health advisory in 2006. OBJECTIVE: To examine the risk of PPHN associated with exposure to different antidepressant medication classes late in pregnancy. DESIGN AND SETTING: Cohort study nested in the 2000-2010 Medicaid Analytic eXtract for 46 US states and Washington, DC. Last follow-up date was December 31, 2010. PARTICIPANTS: A total of 3,789,330 pregnant women enrolled in Medicaid from 2 months or fewer after the date of last menstrual period through at least 1 month after delivery. The source cohort was restricted to women with a depression diagnosis and logistic regression analysis with propensity score adjustment applied to control for potential confounders. EXPOSURES FOR OBSERVATIONAL STUDIES: SSRI and non-SSRI monotherapy use during the 90 days before delivery vs no use. MAIN OUTCOMES AND MEASURES: Recorded diagnosis of PPHN during the first 30 days after delivery. RESULTS: A total of 128,950 women (3.4%) filled at least 1 prescription for antidepressants late in pregnancy: 102,179 (2.7%) used an SSRI and 26,771 (0.7%) a non-SSRI. Overall, 7630 infants not exposed to antidepressants were diagnosed with PPHN (20.8; 95% CI, 20.4-21.3 per 10,000 births) compared with 322 infants exposed to SSRIs (31.5; 95% CI, 28.3-35.2 per 10,000 births), and 78 infants exposed to non-SSRIs (29.1; 95% CI, 23.3-36.4 per 10,000 births). Associations between antidepressant use and PPHN were attenuated with increasing levels of confounding adjustment. For SSRIs, odds ratios were 1.51 (95% CI, 1.35-1.69) unadjusted and 1.10 (95% CI, 0.94-1.29) after restricting to women with depression and adjusting for the high-dimensional propensity score. For non-SSRIs, the odds ratios were 1.40 (95% CI, 1.12-1.75) and 1.02 (95% CI, 0.77-1.35), respectively. Upon restriction of the outcome to primary PPHN, the adjusted odds ratio for SSRIs was 1.28 (95% CI, 1.01-1.64) and for non-SSRIs 1.14 (95% CI, 0.74-1.74). CONCLUSIONS AND RELEVANCE: Evidence from this large study of publicly insured pregnant women may be consistent with a potential increased risk of PPHN associated with maternal use of SSRIs in late pregnancy. However, the absolute risk was small, and the risk increase appears more modest than suggested in previous studies.

Full prescription coverage versus usual prescription coverage after coronary artery bypass graft surgery: analysis from the post-myocardial infarction free Rx event and economic evaluation (FREEE) randomized trial.

BACKGROUND: Eliminating out-of-pocket costs for patients after myocardial infarction (MI) improves adherence to preventive therapies and reduces clinical events. Because adherence to medical therapy is low among patients treated with coronary artery bypass graft surgery (CABG), we evaluated the impact of providing full prescription coverage to this patient subgroup. METHODS AND RESULTS: The MI Free Rx Event and Economic Evaluation (FREEE) trial randomly assigned 5855 patients with MI to full prescription coverage or usual formulary coverage for all statins, ß-blockers, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers. We assessed the impact of full prescription coverage on adherence, clinical outcomes, and healthcare costs using adjusted models among the 1052 patients who underwent CABG at the index hospitalization and 4803 who did not. CABG patients were older and had more comorbid illness (P<0.01). After MI, CABG patients were significantly more likely to receive ß-blockers and statins but were less likely to receive angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy (P<0.01). Receiving full drug coverage increased rates of adherence to all preventative medications after CABG (all P<0.05). Full coverage was also associated with nonsignificant reductions in the rate of major vascular events or revascularization for patients treated with CABG (hazard ratio, 0.91; 95% confidence interval, 0.66-1.25) or without CABG (hazard ratio, 0.93; 95% confidence interval, 0.82-1.06), with no interaction noted (Pint=NS). After CABG, full prescription coverage significantly reduced patient out-of-pocket spending for drugs (P=0.001) without increasing overall health expenditures (P=NS). CONCLUSIONS: Eliminating drug copayments after MI provides consistent benefits to patients treated with or without CABG, leading to increased medication adherence, trends toward improved clinical outcomes, and reduced patient out-of-pocket expenses.

Appropriateness of cardiovascular care in elderly adult cancer survivors.

Research suggests that the quality of non-cancer-related care among cancer survivors (CS) is suboptimal. Secondary disease prevention is an important component of survivorship care that has not been previously evaluated. Our aims were (1) to assess the utilization of and adherence to medications and treatments for the secondary prevention of myocardial infarction (MI) in CS versus non-cancer patients (NCP) and (2) to compare temporal trends in cardiovascular care between these two patient cohorts. Linking data from Medicare, pharmacy assistance programs, and cancer registries, we calculated the percentage of individuals receiving preventive medications (statins, ß-blockers, angiotensin-converting enzyme inhibitors) and revascularization interventions (angioplasty, stent, bypass surgery) within 90 days after acute MI in CS and propensity score-matched NCP. We assessed trends over time and determined predictors of appropriate preventive care using modified Poisson regression. We identified 1,119 CS and 7,886 NCP. Compared to NCP, more survivors received statins (38 vs. 31 %) and ß-blockers (67 vs. 59 %), but fewer underwent bypass surgery (1.5 vs. 2.8 %) after MI. From 1997 to 2004, both survivors and NCP were increasingly prescribed medications to prevent future coronary events. Over the same time period, receipt of bypass surgery was significantly lower among survivors. Co-morbidities, such as depression and lung disease, and demographic factors, such as advanced age and female, were associated with underuse of preventive care among survivors when compared to NCP. Use of preventive medications and procedures has generally improved, but uptake of bypass surgery among CS still lags behind NCP.

The prevalence and cost of unapproved uses of top-selling orphan drugs.

INTRODUCTION: The Orphan Drug Act encourages drug development for rare conditions. However, some orphan drugs become top sellers for unclear reasons. We sought to evaluate the extent and cost of approved and unapproved uses of orphan drugs with the highest unit sales. METHODS: We assessed prescription patterns for four top-selling orphan drugs: lidocaine patch (Lidoderm) approved for post-herpetic neuralgia, modafinil (Provigil) approved for narcolepsy, cinacalcet (Sensipar) approved for hypercalcemia of parathyroid carcinoma, and imatinib (Gleevec) approved for chronic myelogenous leukemia and gastrointestinal stromal tumor. We pooled patient-specific diagnosis and prescription data from two large US state pharmaceutical benefit programs for the elderly. We analyzed the number of new and total patients using each drug and patterns of reimbursement for approved and unapproved uses. For lidocaine patch, we subcategorized approved prescriptions into two subtypes of unapproved uses: neuropathic pain, for which some evidence of efficacy exists, and non-neuropathic pain. RESULTS: We found that prescriptions for lidocaine patch, modafinil, and cinacalcet associated with non-orphan diagnoses rose at substantially higher rates (average monthly increases in number of patients of 14.6, 1.45, and 1.58) than prescriptions associated with their orphan diagnoses (3.12, 0.24, and 0.03, respectively (p<0.001 for all)). By contrast, for imatinib, approved uses increased significantly over off-label (0.97 vs. 0.47 patients, p<0.001). Spending on off-label uses was highest for lidocaine patch and modafinil (>75%). Increases in lidocaine patch use for non-neuropathic pain far exceeded neuropathic pain (10.2 vs. 3.6 patients, p<0.001). DISCUSSION: In our sample, three of four top-selling orphan drugs were used more commonly for non-orphan indications. These orphan drugs treated common clinical symptoms (pain and fatigue) or laboratory abnormalities. We should continue to monitor orphan drug use after approval to identify products that come to be widely used for non-FDA approved indications, particularly those without adequate evidence of efficacy.

Adherence to statin therapy in elderly patients after hospitalization for coronary revascularization.

Low levels of statin adherence have been documented in patients with coronary artery disease (CAD), but whether coronary revascularization is associated with improved adherence rates has yet to be evaluated. We identified all Medicare beneficiaries enrolled in 2 statewide pharmacy assistance programs who were ≥65 years old, who had been hospitalized for CAD from 1995 through 2004, and who had been prescribed statin therapy within 90 days of discharge (n = 13,130). Statin adherence was measured based on the proportion of days covered with statin therapy after hospital discharge, and full adherence was defined as proportion of days covered ≥80%. Statin adherence was compared in patients with CAD treated with medical therapy (n = 3,714), percutaneous coronary intervention (n = 6,309), or coronary artery bypass graft surgery (n = 3,107). Statin adherence significantly increased over the period of the study from 70.5% to 75.4% (p <0.0001). After hospitalization for CAD, patients treated with percutaneous coronary intervention and coronary artery bypass graft surgery had full adherence rates of 70.6% and 70.2%, respectively. Full adherence rates were significantly lower for patients treated with coronary revascularization compared to patients treated with medical therapy (79.4%, p <0.0001). Independent predictors of higher statin adherence included treatment with medical therapy, later year of hospital admission, white race, previous statin use, and use of other cardiac medications after CAD hospitalization (p <0.01 for all comparisons). In conclusion, in patients receiving invasive coronary treatment, statin adherence remains suboptimal, despite strong evidence supporting their use. Given the health and economic consequences of nonadherence, these findings highlight the need for developing cost-effective strategies to improve medication adherence after coronary revascularization.

The comparative safety of opioids for nonmalignant pain in older adults.

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.

Hospice, opiates, and acute care service use among the elderly before death from heart failure or cancer.

BACKGROUND: Advances in heart failure (HF) treatments have prolonged survival, but more patients die of HF than of any type of cancer. Little is known about the current practice in end-of-life (EOL) care in HF. METHODS: Two EOL cohorts (HF and cancer) were identified using Medicare data linked with pharmacy and cancer registry data. We assessed use of hospice, opiates, and acute care services (hospitalizations, emergency department [ED] visits, intensive care unit [ICU] admissions, and death in acute care). Time trends and predictors of use were assessed using multivariate regression including demographics and cardiovascular and noncardiovasuclar comorbidities. RESULTS: Among 5,836 HF patients with median age of 85, 77% female and 4% black, 20% were referred to hospice compared to 51% of 7,565 cancer patients. A modest rise in hospice use over time was parallel in the 2 groups. Twenty-two percent of HF patients filled opiate prescriptions during 60 days before death compared to 46% of cancer patients. Use of acute care services in the 30 days before death was higher for HF (64% vs 39% for ED visits, 60% vs 45% for hospitalizations, and 19% vs 7% for ICU admission). More HF patients died during acute hospitalizations than cancer patients (39% vs 21%). CONCLUSION: Patients dying of HF were less likely to be supported by hospice and opiates but more likely to die in hospitals than patients with cancer. Our study suggests that opportunities may exist to improve hospice and opiate use in HF patients.

Impact of statin use on outcomes after coronary artery bypass graft surgery.

BACKGROUND: The benefits of statins have been demonstrated for patients with a remote history of coronary artery bypass grafting (CABG); however, no investigation to date has evaluated whether initiation of statin therapy in the early months after surgery improves clinical outcomes. METHODS AND RESULTS: A retrospective cohort of 7503 Medicare patients >/=65 years of age who underwent CABG (1995-2003) was assembled by use of linked hospital and pharmacy claims data. Rates of all-cause mortality and major adverse cardiovascular events were compared between patients who were (n=1745) and were not (n=5788) prescribed statins within 1 month of CABG discharge. Additional analyses evaluated the impact of statin initiation between 1 and 6 months after surgery. Multivariable and propensity score analysis demonstrated that statin use within 1 month of CABG discharge independently reduced the risk of all-cause mortality (adjusted hazard ratio 0.82, 95% confidence interval 0.72 to 0.94) compared with no statin use. Similarly, statin use within 1 month of CABG discharge independently reduced the risk of major adverse cardiovascular events (adjusted hazard ratio 0.89, 95% confidence interval 0.81 to 0.98). Initiation of statin therapy between 1 and 6 months after CABG discharge was also associated with reductions in major adverse cardiovascular events and mortality; however, outcome rates between early (

Tumor necrosis factor-alpha antagonist use and heart failure in elderly patients with rheumatoid arthritis.

BACKGROUND: Clinical trials have shown that tumor necrosis factor-alpha antagonists (TNFAs) confer little benefit, and some may cause potential harm in advanced heart failure (HF). Although TNFAs had significant benefits in treating rheumatoid arthritis (RA), little is known whether the drugs pose an increased risk of HF in older patients with RA. METHODS: A cohort study was conducted using data from Medicare and drug benefit programs in 2 states (1994-2004). We identified patients with RA aged > or =65 who received TNFA or methotrexate (MTX). The cohort was divided into patients with and without previous HF. We considered demographic variables, cardiovascular risk factors, RA severity-related measures, and other comorbidities. The primary end point was hospitalization with HF. We used stratified Cox proportional hazards regression to estimate the adjusted effect of TNFAs on HF hospitalization. RESULTS: The cohort consisted of 1,002 TNFA users and 5,593 MTX users. There were 59 HF admissions during 1,680 person-years of TNFA use and 227 HF admissions during 10,623 person-years of MTX use. Comparing TNFA with MTX users, the adjusted hazard ratio for HF hospitalization was 1.70 (95% confidence interval 1.07-2.69). We found similar results in patients with and without previous HF. Among patients with previous HF, the adjusted hazard ratio for death was 4.19 (95% confidence interval 1.48-11.89). CONCLUSIONS: TNFAs may increase the risk of both first hospitalization and exacerbation of HF in elderly patients with RA. The potential for residual confounding in our study cannot be ruled out; larger and more detailed studies are needed to confirm the findings.