Elizabeth V. Lawler

Proton pump inhibitors and risk for recurrent Clostridium difficile infection.

BACKGROUND Proton pump inhibitors (PPIs) are widely used gastric acid suppressants, but they are often prescribed without clear indications and may increase risk of Clostridium difficile infection (CDI). We sought to determine the association between PPI use and the risk of recurrent CDI. METHODS Retrospective, cohort study using administrative databases of the New England Veterans Healthcare System from October 1, 2003, through September 30, 2008. We identified 1166 inpatients and outpatients with metronidazole- or vancomycin hydrochloride-treated incident CDI, of whom 527 (45.2%) received oral PPIs within 14 days of diagnosis and 639 (54.8%) did not. We determined the hazard ratio (HR) for recurrent CDI, defined by a positive toxin finding in the 15 to 90 days after incident CDI. RESULTS Recurrent CDI was more common in those exposed to PPIs than in those not exposed (25.2% vs 18.5%). Using Cox proportional survival methods, we determined that the adjusted HR of recurrent CDI was greater in those exposed to PPIs during treatment (1.42; 95% confidence interval [CI], 1.11-1.82). Risks among exposed patients were highest among those older than 80 years (HR, 1.86; 95% CI, 1.15-3.01) and those receiving antibiotics not targeted to C difficile during follow-up (HR, 1.71; 95% CI, 1.11-2.64). [corrected] CONCLUSIONS Proton pump inhibitor use during incident CDI treatment was associated with a 42% increased risk of recurrence. Our findings warrant further studies to examine this association and careful consideration of the indications for prescribing PPIs during treatment of CDI.

The Association Between Statins and Cancer Incidence in a Veterans Population

BACKGROUND Meta-analyses of trials of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors or statins for cardiovascular disease prevention have failed to show any statistically significant benefit of statins for cancer prevention. However, these trials included relatively young participants, who develop few cancers, and their follow-up periods may have been too short to detect an association between statin use and cancer incidence. We investigated this association in a population of veterans. METHODS We identified patients using antihypertensive medications but no cholesterol-lowering medications (n = 25,594) and patients using statins (n = 37,248) who were enrolled in the Veterans Affairs New England Healthcare System between January 1, 1997, and December 31, 2005. Age- and multivariable-adjusted Cox proportional hazards models were used to calculate the hazard ratio (HR) and its 95% confidence interval (CI) for cancer incidence, excluding nonmelanoma skin cancer, among patients taking statins compared with patients taking antihypertensive medications and among patients grouped by statin dose (as equivalent simvastatin dose). All statistical tests were two-sided. RESULTS The absolute incidence of total cancers was 9.4% among statin users and 13.2% among nonusers (difference = 3.8%, 95% CI = 3.3% to 4.3%, P(difference) < .001). Statin users had a statistically significant lower risk for total cancer than nonusers after adjustment for age (HR = 0.76, 95% CI = 0.73 to 0.80) and multiple potential confounders (HR = 0.74, 95% CI = 0.70 to 0.78). After multivariable adjustment, a statistically significantly decreased risk of all cancers was also associated with increasing statin use (P(trend) < .001). CONCLUSIONS Patients using statins may be at lower risk for developing cancer. Additional observational studies and randomized trials of statins for cancer prevention are warranted.

Posttraumatic Stress Disorder and Completed Suicide

Most research regarding posttraumatic stress disorder (PTSD) and suicide has focused on suicidal ideation or attempts; no known study of the association between PTSD and completed suicide in a population-based sample has been reported. This study examined the association between PTSD and completed suicide in a population-based sample. Data were obtained from the nationwide Danish health and administrative registries, which include data on all 5.4 million residents of Denmark. All suicides between January 1, 1994, and December 31, 2006, were included, and controls were selected from a sample of all Danish residents. Using this nested case-control design, the authors examined 9,612 suicide cases and 199,306 controls matched to cases on gender, date of birth, and time. Thirty-eight suicide cases (0.40%) and 95 controls (0.05%) were diagnosed with PTSD. The odds ratio associating PTSD with suicide was 9.8 (95% confidence interval: 6.7, 15). The association between PTSD and completed suicide remained after controlling for psychiatric and demographic confounders (odds ratio = 5.3, 95% confidence interval: 3.4, 8.1). Additionally, persons with PTSD and depression had a greater rate of suicide than expected based on their independent effects. In conclusion, a registry-based diagnosis of PTSD based on International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, is a risk factor for completed suicide.

Cholinesterase inhibitors and incidence of bradycardia in patients with dementia in the veterans affairs new England healthcare system.

OBJECTIVES: To quantify the association between cholinesterase inhibitors (ChE‐Is) and a new diagnosis of bradycardia and to evaluate the clinical significance of bradycardia.

Statins and Prostate Cancer Diagnosis and Grade in a Veterans Population

BACKGROUND Although prostate cancer is commonly diagnosed, few risk factors for high-grade prostate cancer are known and few prevention strategies exist. Statins have been proposed as a possible treatment to prevent prostate cancer. METHODS Using electronic and administrative files from the Veterans Affairs New England Healthcare System, we identified 55,875 men taking either a statin or antihypertensive medication. We used age- and multivariable-adjusted Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer incidence among patients taking statins (n = 41,078) compared with patients taking antihypertensive medications (n = 14,797). We performed similar analyses for all lipid parameters including total cholesterol examining each lipid parameter as a continuous variable and by quartiles. All statistical tests were two-sided. RESULTS Compared with men taking an antihypertensive medication, statin users were 31% less likely (HR = 0.69, 95% CI = 0.52 to 0.90) to be diagnosed with prostate cancer. Furthermore, statin users were 14% less likely (HR = 0.86, 95% CI = 0.62 to 1.20) to be diagnosed with low-grade prostate cancer and 60% less likely (HR = 0.40, 95% CI = 0.24 to 0.65) to be diagnosed with high-grade prostate cancer compared with antihypertensive medication users. Increased levels of total cholesterol were also associated with both total (HR = 1.02, 95% CI = 1.00 to 1.05) and high-grade (HR = 1.06, 95% CI = 1.02 to 1.10) prostate cancer incidence but not with low-grade prostate cancer incidence (HR = 1.01, 95% CI = 0.98 to 1.04). CONCLUSIONS Statin use is associated with statistically significantly reduced risk for total and high-grade prostate cancer, and increased levels of serum cholesterol are associated with higher risk for total and high-grade prostate cancer. These findings indicate that clinical trials of statins for prostate cancer prevention are warranted.

A point-of-care clinical trial comparing insulin administered using a sliding scale versus a weight-based regimen

Background Clinical trials are widely considered the gold standard in comparative effectiveness research (CER) but the high cost and complexity of traditional trials and concerns about generalizability to broad patient populations and general clinical practice limit their appeal. Unsuccessful implementation of CER results limits the value of even the highest quality trials. Planning for a trial comparing two standard strategies of insulin administration for hospitalized patients led us to develop a new method for a clinical trial designed to be embedded directly into the clinical care setting thereby lowering the cost, increasing the pragmatic nature of the overall trial, strengthening implementation, and creating an integrated environment of research-based care. Purpose We describe a novel randomized clinical trial that uses the informatics and statistics infrastructure of the Veterans Affairs Healthcare System (VA) to illustrate one key component (called the point-of-care clinical trial – POC-CT) of a ‘learning healthcare system,’ and settles a clinical question of interest to the VA. Methods This study is an open-label, randomized trial comparing sliding scale regular insulin to a weight-based regimen for control of hyperglycemia, using the primary outcome length of stay, in non-ICU inpatients within the northeast region of the VA. All non-ICU patients who require in-hospital insulin therapy are eligible for the trial, and the VA’s automated systems will be used to assess eligibility and present the possibility of randomization to the clinician at the point of care. Clinicians will indicate their approval for informed consent to be obtained by study staff. Adaptive randomization will assign up to 3000 patients, preferentially to the currently ‘winning’ strategy, and all care will proceed according to usual practices. Based on a Bayesian stopping rule, the study has acceptable frequentist operating characteristics (Type I error 6%, power 86%) against a 12% reduction of median length of stay from 5 to 4.4 days. The adaptive stopping rule promotes implementation of a successful treatment strategy. Limitations Despite clinical equipoise, individual healthcare providers may have strong treatment preferences that jeopardize the success and implementation of the trial design, leading to low rates of randomization. Unblinded treatment assignment may bias results. In addition, generalization of clinical results to other healthcare systems may be limited by differences in patient population. Generalizability of the POC-CT method depends on the level of informatics and statistics infrastructure available to a healthcare system. Conclusions The methods proposed will demonstrate outcome-based evaluation of control of hyperglycemia in hospitalized veterans. By institutionalizing a process of statistically sound and efficient learning, and by integrating that learning with automatic implementation of best practice, the participating VA Healthcare Systems will accelerate improvements in the effectiveness of care.

Translational breast cancer research consortium (TBCRC) 022: A phase II trial of neratinib for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases

PURPOSE Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. PATIENTS AND METHODS Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥ 50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression--the threshold for success was five of 40 responders. RESULTS Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. CONCLUSION Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.

Extranasal Methicillin-Resistant Staphylococcus aureus Colonization at Admission to an Acute Care Veterans Affairs Hospital

OBJECTIVE To evaluate the prevalence of and risk factors for extranasal methicillin-resistant Staphylococcus aureus (MRSA) colonization and its relationship to nasal colonization among veterans hospitalized for acute care. DESIGN Prospective observational study. SETTING Veterans Affairs (VA) acute care hospital in Boston, Massachusetts. PATIENTS Convenience sample of 150 patients hospitalized within the previous 36 hours and screened for nasal MRSA who were not known to have an active MRSA infection or MRSA isolates recovered from a wound during the past 12 months. METHODS Potential risk factors for MRSA colonization were assessed, and oropharynx, axilla, hand, perirectal, wound, and catheter insertion site samples were obtained for culture. MRSA was identified in chromogenic agar and confirmed by use of routine culture techniques. Nasal MRSA colonization was detected by means of polymerase chain reaction (PCR). RESULTS Nasal swab samples analyzed by use of PCR yielded results positive for MRSA in 16 (11%) of 150 patients. Extranasal cultures yielded positive results for 3 (2%) of 134 patients who tested negative for nasal MRSA colonization and for 9 (56%) of 16 patients who tested positive for nasal MRSA colonization (odds ratio [OR], 56.1 [95% confidence interval {CI}, 12.4-254.6]; p < .001). The oropharynx was the most commonly colonized extranasal site (10 patients [7%]). Independent risk factors for extranasal MRSA colonization included nasal MRSA colonization (OR, 66.9 [95% CI, 11.8-379.7]; P < .001) and end-stage hepatic disease (OR, 98.5 [95% CI, 3.1-3,112.4]; P = .01). CONCLUSIONS Extranasal MRSA colonization is infrequent among veterans admitted for acute care to VA Boston Healthcare System. Extranasal MRSA colonization was strongly associated with nasal MRSA colonization, which suggests that the VA MRSA Prevention Initiative is not missing a large number of MRSA-colonized patients by focusing on nasal-only screening.

Suicide Among US Veterans: A Prospective Study of 500,000 Middle-aged and Elderly Men

Expert opinion is divided about whether US military veterans, the vast majority of whom are middle-aged or older, are at increased risk of suicide. To assess the risk of suicide associated with veteran status, the authors conducted a prospective cohort study of 499,356 male participants in the Cancer Prevention Study II. Participants reported their veteran status and other characteristics in 1982 and were followed for mortality through 2004. The relative risk of mortality from suicide according to veteran status at baseline was estimated by using Cox proportional hazards models. During follow-up, 1,248 veterans and 614 nonveterans died by suicide. In age-adjusted analyses, the risk of suicide did not differ by veteran status. Additional adjustment for several sociodemographic, behavioral, and clinical factors had little effect on hazard ratios. The authors concluded that the risk of death from suicide among middle-aged and older US males is independent of veteran status and suggest that policies to prevent veteran suicide should focus on factors that may heighten suicide risk rather than on veteran status per se.

Risk of Community-Acquired Pneumonia in Veteran Patients to Whom Proton Pump Inhibitors Were Dispensed

BACKGROUND Observational studies linking proton pump inhibitor (PPI) exposure with community-acquired pneumonia (CAP) have reported either modest or no associations. Accordingly, we studied PPI exposure and CAP in veteran patients, using a retrospective, nested case-control design. METHODS From linked pharmacy and administrative databases of the New England Veterans Healthcare System, we identified 71985 outpatients newly prescribed PPIs between 1998 and 2007; 1544 patients met criteria for CAP subsequent to PPI initiation; 15440 controls were matched through risk-set sampling by age and time under observation. Crude and adjusted odds ratios comparing current with past PPI exposures, as well as tests for interactions, were conducted for the entire and stratified samples. RESULTS Current PPI use associated with CAP (adjusted odds ratio [OR], 1.29 [95% confidence interval {CI}, 1.15-1.45]). Risks were not substantially altered by age or year of diagnosis. Dementia (n = 85; P = .062 for interaction) and sedative/tranquilizer use (n = 224; P = .049 for interaction) were likely effect modifiers increasing a PPI-CAP association; conversely, for some chronic medical conditions, PPI-associated CAP risks were reversed. PPI exposures between 1 and 15 days increased CAP risks, compared with longer exposures, but PPI initiation also frequently occurred shortly after CAP diagnoses. Prescribed PPI doses >1 dose/day also increased PPI-associated CAP risks. CONCLUSIONS Among the veterans studied, current compared with past PPI exposures associated modestly with increased risks of CAP. However, our observations that recent treatment initiation and higher PPI doses were associated with greater risks, and the inconsistent PPI-CAP associations between patient subgroups, indicate that further inquiries are needed to separate out coincidental patterns of associations.