clinicaltrials.gov Identifier: NCT00870298.

OBJECTIVELower-extremity amputation (LEA) is common among persons with diabetes. The goal of this study was to identify geographic variation and the influence of location on the incidence of LEA among U.S. Medicare beneficiaries with diabetes.RESEARCH DESIGN AND METHODSWe conducted a cohort study of beneficiaries of Medicare. The geographic unit of analysis was hospital referral regions (HRRs). Tests of spatial autocorrelation and geographically weighted regression were used to evaluate the incidence of LEA by HRRs as a function of geographic location in the U.S. Evaluated covariates covered sociodemographic factors, risk factors for LEA, diabetes severity, provider access, and cost of care.RESULTSAmong persons with diabetes, the annual incidence per 1,000 of LEA was 5.0 in 2006, 4.6 in 2007, and 4.5 in 2008 and varied by the HRR. The incidence of LEA was highly concentrated in neighboring HRRs. High rates of LEA clustered in contiguous portions of Texas, Oklahoma, Louisiana, Arkansas, and Mississippi. Accounting for geographic location greatly improved our ability to understand the variability in LEA. Additionally, covariates associated with LEA per HRR included socioeconomic status, prevalence of African Americans, age, diabetes, and mortality rate associated with having a foot ulcer.CONCLUSIONSThere is profound “region-correlated” variation in the rate of LEA among Medicare beneficiaries with diabetes. In other words, location matters and whereas the likelihood of an amputation varies dramatically across the U.S. overall, neighboring locations have unexpectedly similar amputation rates, some being uniformly high and others uniformly low.

Medical message boards are online resources where users with a particular condition exchange information, some of which they might not otherwise share with medical providers. Many of these boards contain a large number of posts and contain patient opinions and experiences that would be potentially useful to clinicians and researchers. We present an approach that is able to collect a corpus of medical message board posts, de-identify the corpus, and extract information on potential adverse drug effects discussed by users. Using a corpus of posts to breast cancer message boards, we identified drug event pairs using co-occurrence statistics. We then compared the identified drug event pairs with adverse effects listed on the package labels of tamoxifen, anastrozole, exemestane, and letrozole. Of the pairs identified by our system, 75–80% were documented on the drug labels. Some of the undocumented pairs may represent previously unidentified adverse drug effects.

Summary Purpose Sudden cardiac death (SD) and ventricular arrhythmias (VAs) caused by medications have arisen as an important public health concern in recent years. The validity of diagnostic codes in identifying SD/VA events originating in the ambulatory setting is not well known. This study examined the positive predictive value (PPV) of hospitalization and emergency department encounter diagnoses in identifying SD/VA events originating in the outpatient setting. Methods We selected random samples of hospitalizations and emergency department claims with principal or first-listed discharge diagnosis codes indicative of SD/VA in individuals contributing at least 6 months of baseline time within 1999–2002 Medicaid and Medicare data from five large states. We then obtained and reviewed medical records corresponding to these events to serve as the reference standard. Results We identified 5239 inpatient and 29 135 emergency department events, randomly selected 100 of each, and obtained 119 medical records, 116 of which were for the requested courses of care. The PPVs for an outpatient-originating SD/VA precipitating hospitalization or emergency department treatment were 85.3% (95% confidence interval [CI]=77.6–91.2) overall, 79.7% (95%CI=68.3–88.4) for hospitalization claims, and 93.6% (95%CI=82.5–98.7) for emergency department claims. Conclusions First-listed SD/VA diagnostic codes identified in inpatient or emergency department encounters had very good agreement with clinical diagnoses and functioned well to identify outpatient-originating events. Researchers using such codes can be confident of the PPV when conducting studies of SD/VA originating in the outpatient setting.

PURPOSE While patients often use the internet as a medium to search for and exchange health-related information, little is known about the extent to which patients use social media to discuss side effects related to medications. We aim to understand the frequency and content of side effects and associated adherence behaviors discussed by breast cancer patients related to using aromatase inhibitors (AIs), with particular emphasis on AI-related arthralgia. METHODS We performed a mixed methods study to examine content related to AI associated side effects posted by individuals on 12 message boards between 2002 and 2010. We quantitatively defined the frequency and association between side effects and AIs and identified common themes using content analysis. One thousand randomly selected messages related to arthralgia were coded by two independent raters. RESULTS Among 25,256 posts related to AIs, 4,589 (18.2%) mentioned at least one side effect. Top-cited side effects on message boards related to AIs were joint/musculoskeletal pain (N=5,093), hot flashes (1,498), osteoporosis (719), and weight gain (429). Among the authors posting messages who self-reported AI use, 12.8% mentioned discontinuing AIs, while another 28.1% mentioned switching AIs. Although patients often cited severe joint pain as the reason for discontinuing AIs, many also offered support and advice for coping with AI-associated arthralgia. CONCLUSIONS Online discussion of AI-related side effects was common and often related to drug switching and discontinuation. Physicians should be aware of these discussions and guide patients to effectively manage side effects of drugs and promote optimal adherence.

Purpose To examine the association between exposure to antidepressants and emergency department or inpatient admission for sudden cardiac death and ventricular arrhythmia (SD/VA), and to examine the impact of dose and cytochrome P-450 inhibition Methods A cohort study was conducted within 1999–2003 Medicaid claims data from beneficiaries of five large states, supplemented with Medicare claims for dually-eligible individuals. Exposures were prescription claims for antidepressants of interest or a reference antidepressant. Outcomes were incident first-listed emergency department or principal inpatient diagnoses indicative of SD/VA originating in the outpatient setting, an outcome previously found to have a positive predictive value of 85%. Results In 1.3 million person-years of antidepressant exposure, we identified 4,222 SD/VA outcomes for a rate of 3.3/1,000 person-years (95% CI, 3.2 – 3.4). Compared to paroxetine (a referent with a putatively favorable cardiovascular risk profile), adjusted hazard ratios (HRs) were 0.80 (0.67 – 0.95) for bupropion, 1.24 (0.93 – 1.65) for doxepin, 0.79 (0.55 – 1.15) for lithium, and 1.26 (1.11 – 1.42) for mirtazapine. HRs for amitriptyline, citalopram, fluoxetine, nefazodone, nortriptyline, sertraline, trazodone, and venlafaxine were near unity. For antidepressants having non-null risks (bupropion and mirtazapine), we observed no relationship with antidepressant dose and some relationships with concomitant cytochrome P-450 inhibition. Conclusions Of antidepressants studied, only mirtazapine had a statistically significantly greater SD/VA risk versus paroxetine. However, baseline differences between these users suggest that this finding may be attributable to residual confounding. Eleven other antidepressants had SD/VA risks no greater than that of paroxetine, thereby providing reassurance regarding the comparative cardiovascular safety of antidepressants.

Purpose This study aims to examine the associations between proton pump inhibitors (PPIs), traditional nonsteroidal anti-inflammatory drugs (tNSAIDs), PPI + tNSAID co-exposure, and the development of the following: (i) acute interstitial nephritis (AIN), a specific kidney injury often attributed to these drugs, and (ii) acute kidney injury (AKI), a general kidney injury encompassing AIN. Methods Two retrospective case-control studies were conducted, one for each outcome, within the General Practice Research Database. Cases were diagnostic-coded AIN (primary outcome) or AKI (secondary outcome) events. Controls were matched on age, sex, and general practitioner practice. Exposures were defined by the presence/absence of the following mutually exclusive therapies on the index date: (i) PPI alone; (ii) tNSAID alone; (iii) PPI + tNSAID; or (iv) neither PPI nor tNSAID (referent). Results Sixty-eight AIN cases and 3347 controls were identified. The adjusted odds ratios (ORs) for PPI and tNSAID exposures alone were 3.20 (0.80-12.79) and 1.90 (0.65-5.51), respectively. Numerous sensitivity analyses produced adjusted ORs for AIN between 3.0 and 7.7, and 1.6 and 1.9, respectively. We identified 27 982 AKI cases and 1 323 850 controls. The adjusted ORs for PPI alone, tNSAID alone, and PPI + tNSAID exposures were 1.05 (0.97-1.14), 1.31 (1.25-1.37), and 1.33 (1.07-1.64), respectively. Numerous sensitivity analyses produced adjusted ORs for AKI between 1.0 and 1.1, 1.1 and 1.3, and 1.3 and 1.4, respectively.Conclusions Proton pump inhibitor exposure may increase the odds of AIN, but this result was not definitive and should be confirmed in a dataset with more AIN cases to allow for increased statistical precision. tNSAIDs, yet not PPIs, were associated with a significantly increased odds of AKI.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Case reports have linked cisapride to ventricular arrhythmia and sudden cardiac death.• However, two prior epidemiological studies have failed to show an association between cisapride and serious arrhythmia. WHAT THIS STUDY ADDS• Overall, cisapride was associated with a doubling to tripling of the risk of hospitalization for sudden cardiac death and ventricular arrhythmia, and a near eightfold risk in the initial prescription period.• Although potentially arrhythmogenic CYP3A4 inhibitors were associated with an increased risk in cisapride users, this appears to be due to a direct effect of the drugs themselves rather than an interaction with cisapride. AIMSWe aimed to examine the association between cisapride and ventricular arrhythmia, and examine the relationship to dose and CYP3A4 inhibitors. METHODSA nested case-control study was conducted in Medicaid beneficiaries exposed to cisapride, metoclopramide or a proton pump inhibitor (PPI) from 1999 to 2000. Cases were hospitalized with a principal International Classification of Diseases-9 code indicating sudden cardiac death or ventricular arrhythmia. Controls had at least as much event-free person time following the study prescription as its matched case. RESULTSA total of 145 cases and 7250 controls were identified. The unadjusted rate ratio for cisapride vs. PPIs was 1.49 (95% confidence interval 0.96, 2.25). The adjusted odds ratio (OR) for cisapride vs. PPIs was 2.10 (1.34, 3.28). Excluding persons in managed care, the adjusted OR for cisapride was 2.92 (1.55, 5.49). In the initial prescription period, the adjusted OR for cisapride vs. PPIs was 7.85 (1.95, 31.60). Non-arrhythmogenic CYP3A4 inhibitors were not associated with an increased risk in users of cisapride or PPI inhibitors. The OR for potentially arrhythmogenic CYP3A4 inhibitors was 3.79 (1.76, 8.15) in cisapride users and 3.47 (2.06, 5.83) in PPI users. CONCLUSIONSCisapride was associated with a doubling to tripling of the risk of hospitalization for ventricular arrhythmia, and a nearly eightfold risk in the initial prescription period. Although use of potentially arrhythmogenic CYP3A4 inhibitors was associated with an increased risk, this appears to be due to a direct effect of the drugs themselves rather than an interaction with cisapride.