Michele M. Spence

Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study

BACKGROUND Controversy has surrounded the question about whether high-dose rofecoxib increases or naproxen decreases the risk of serious coronary heart disease. We sought to establish if risk was enhanced with rofecoxib at either high or standard doses compared with remote non-steroidal anti-inflammatory drug (NSAID) use or celecoxib use, because celecoxib was the most common alternative to rofecoxib. METHODS We used data from Kaiser Permanente in California to assemble a cohort of all patients age 18-84 years treated with a NSAID between Jan 1, 1999, and Dec 31, 2001, within which we did a nested case-control study. Cases of serious coronary heart disease (acute myocardial infarction and sudden cardiac death) were risk-set matched with four controls for age, sex, and health plan region. Current exposure to cyclo-oxygenase 2 selective and non-selective NSAIDs was compared with remote exposure to any NSAID, and rofecoxib was compared with celecoxib. FINDINGS During 2302029 person-years of follow-up, 8143 cases of serious coronary heart disease occurred, of which 2210 (27.1%) were fatal. Multivariate adjusted odds ratios versus celecoxib were: for rofecoxib (all doses), 1.59 (95% CI 1.10-2.32, p=0.015); for rofecoxib 25 mg/day or less, 1.47 (0.99-2.17, p=0.054); and for rofecoxib greater than 25 mg/day, 3.58 (1.27-10.11, p=0.016). For naproxen versus remote NSAID use the adjusted odds ratio was 1.14 (1.00-1.30, p=0.05). INTERPRETATION Rofecoxib use increases the risk of serious coronary heart disease compared with celecoxib use. Naproxen use does not protect against serious coronary heart disease.

Direct-to-Consumer Advertising of COX-2 Inhibitors: Effect on Appropriateness of Prescribing

Spending on direct-to-consumer advertising (DTCA) of prescription drugs has increased dramatically in the past several years. An unresolved question is whether such advertising leads to inappropriate prescribing. In this study, the authors use survey and administrative data to determine the association of DTCA with the appropriate prescribing of cyclooxygenase-2 (COX-2) inhibitors for 1,382 patients. Treatment with either a COX-2 or a traditional nonsteroidal anti-inflammatory drug (NSAID) was defined as appropriate or not according to three different definitions of gastrointestinal risk. Patients who saw or heard a COX-2 advertisement and asked their physician about the advertised drug were significantly more likely to be prescribed a COX-2 (versus a NSAID, as recommended by evidence-based guidelines) than all other patients. Findings also suggest that some patients may benefit from DTCA. The authors discuss the need for balanced drug information for consumers, increased physician vigilance in prescribing appropriately, and further study of DTCA.

Evaluation of Clinical and Safety Outcomes Associated with Conversion from Brand-Name to Generic Tacrolimus in Transplant Recipients Enrolled in an Integrated Health Care System

To evaluate clinical and safety outcomes among transplant recipients whose tacrolimus was converted from the brand‐name formulation to a generic formulation.

Risk of Injury Associated with Skeletal Muscle Relaxant Use in Older Adults

BACKGROUND The use of skeletal muscle relaxants (SMRs) among older adults is associated with sedation and confusion, which may lead to an increased risk of falls and injuries. SMRs continue to be used among older adults, although they are on the Beers list as drugs to avoid in the elderly. OBJECTIVE To investigate the relationship between SMR use and subsequent risk of injury. METHODS This was a retrospective case-control study of members aged 65 years or older enrolled in an integrated health care system. Cases were defined as patients with a documented injury resulting in either a hospitalization or an emergency department or urgent care visit from January 2009 through December 2010. Cases were matched to controls in a 1:4 ratio by age and sex. Patients had to be enrolled and alive on the date of an injury (index date). SMR exposure for all cases and controls was evaluated within 60 days prior to the index date. Conditional logistic regression adjusted for covariates was performed, with risk estimates presented as odds ratios with 95% confidence intervals. RESULTS From a base population of 322,806 older adults, we identified 27,974 cases of injury and 104,303 matched controls. Among the cases, 365 (1.30%) used an SMR; among the controls, 801 (0.77%) used an SMR in the 60 days prior to the index date. After adjustment for demographic and clinical covariates, risk of injury was significantly increased for patients using an SMR compared to no use (OR 1.32, 95% CI 1.16–1.50; p < 0.001). Carisoprodol was associated with an increased risk of injury (OR 1.73, 95% CI 1.04–2.88; p = 0.036), as were methocarbamol (OR 1.42, 95% CI 1.16–1.75; p = 0.001) and cyclobenzaprine (OR 1.22, 95% CI 1.02–1.45; p = 0.029). CONCLUSIONS Older adults using SMRs have an increased risk of injury. These findings provide evidence to support current recommendations to avoid the use of SMRs in elderly patients.

Risk of Skeletal-Related Events in Patients with Advanced Prostate Cancer Treated with Pamidronate or Zoledronic Acid

Background: Pamidronate and zoledronic acid are used for the prevention of skeletal-related events (SREs) in patients with advanced solid tumors, particularly breast and prostate cancers. There have been no head-to-head clinical trials comparing Pamidronate and zoledronic acid among patients with advanced prostate cancer. Objective: To estimate the risk of developing an SRE among men with metastatic prostate cancer after being treated with either pamidronate or zoledronic acid. Methods: A retrospective cohort study was conducted, using data from Kaiser Permanentes Southern California Region. The cohort included men aged ≥18 years diagnosed with prostate cancer from 1998 to 2004 who received at least 1 infusion of either Pamidronate or zoledronic acid after their cancer diagnosis. Patients receiving both drugs and those with a documented SRE prior to diagnosis were excluded. The primary outcome of SREs was defined using diagnosis codes for fractures, spina) cord compression, radiation to bone, and hypercalcemia of malignancy. Secondary outcomes were deterioration in renal function, based on serum creatinine laboratory results, and mortality. Multivariate logistic regression was used to predict SREs and mortality risk for Pamidronate compared to zoledronic acid. The proportion of patients with renal function deterioration was analyzed using χ2 tests. Results: The cohort included 118 patients treated with Pamidronate and 274 treated with zoledronic acid. Results showed no significant difference in risk of SREs for Pamidronate versus zoledronic acid (OH 0.99; 95% CI 0.59 to 1.67; p = 0.98). No significant difference was found in renal function deterioration (χ2 2.08; p = 0.15) or mortality (OR 0.71; 95% CI 0.43 to 1.17; p = 0.18). Conclusions: For patients with prostate cancer, the choice between these 2 bisphosphonates must be balanced between the shorter infusion time of zoledronic acid versus its increased costs. We found no evidence for a difference in outcomes; therefore, pamidronate is an effective choice where clinic capacity permits.

Identifying Subsequent Therapies in Patients with Advanced Non–Small Cell Lung Cancer and Factors Associated with Overall Survival

To identify subsequent therapies used after first‐line therapies in patients with advanced non–small cell lung cancer (NSCLC), compare overall survival (OS) associated with subsequent therapies, and evaluate factors associated with OS in these patients.

Risk of injury in older adults using gastrointestinal antispasmodic and anticholinergic medications

To determine the risk of injury associated with gastrointestinal (GI) antispasmodic and anticholinergic use in elderly adults.

Treatment Patterns and Overall Survival Associated with First-Line Systemic Therapy for Patients with Advanced Non-Small Cell Lung Cancer

BACKGROUND A variety of regimens are used as first-line treatment in patients with advanced non-small cell lung cancer (NSCLC), which may include combination regimens and single agents, depending on histology, molecular profile, and performance status. OBJECTIVE To describe the types of first-line therapies and compare overall survival between therapies used for patients with advanced NSCLC in an integrated health care system. METHODS This retrospective cohort study included patients aged 18 years or older from Kaiser Permanente California with a diagnosis of stage IIIB/IV NSCLC. First systemic treatment date occurred from January 1, 2008, through September 30, 2013. Overall survival was measured as the number of months from initial treatment until death, end of enrollment, or September 30, 2014. Treatment regimens were categorized into 6 mutually exclusive groups: platinum doublets; pemetrexed-based, bevacizumab-based, and pemetrexed + bevacizumab-based combinations; singlets; and tyrosine-kinase inhibitors (TKIs). Survival was compared using Kaplan-Meier curves and adjusted Cox proportional hazard models. Subgroup analyses were performed by age group and by nonsquamous histology. RESULTS Of 2,081 patients, approximately half (52.3%) received platinum doublets, followed by TKIs (19.0%), pemetrexed-based regimens (13.4%), bevacizumab-regimens (8.0%), singlets (5.5%), and pemetrexed + bevacizumab-based combinations (1.8%). Median survival was longest for pemetrexed + bevacizumab-based combinations (18.5 months), followed by bevacizumab-based regimens (14.5), TKIs (12.7), pemetrexed-based regimens (10.4), doublets (9.2), and singlets (5.3). There was a significantly reduced risk of mortality for pemetrexed + bevacizumab-based combinations (HR = 0.64; 95% CI = 0.42-0.94) and TKIs (HR = 0.83; 95% CI = 0.73-0.94) compared with doublets. Singlets were associated with an increased risk of mortality (HR = 1.50; 95% CI = 1.22-1.84). Subgroup analysis among patients aged 65 years and over found no significant differences among treatment groups, with the exception of singlets, which were associated with an increased risk of mortality compared with doublets (HR = 1.51; 95% CI = 1.20-1.90). Among patients under aged 65 years, pemetrexed + bevacizumab-based combinations (HR = 0.36; 95% CI = 0.21-0.64) and TKIs (HR = 0.76; 95% CI = 0.59-0.97) were associated with a reduced risk of mortality, and singlets were associated with an increased risk (HR = 1.85; 95% CI = 1.17-2.92). CONCLUSIONS In this cohort of patients with advanced NSCLC, patients received a platinum agent with or without bevacizumab or pemetrexed, a TKI, or a single agent. Younger patients (aged < 65 years) receiving bevacizumab + pemetrexed-based combinations had a survival advantage over those receiving platinum doublets, and this finding merits further investigation. Younger patients receiving TKIs also had longer survival. Compared with platinum doublets, we found no survival advantage for older patients receiving bevacizumab or pemetrexed, which suggests that combination therapy of a platinum agent and taxane, such as carboplatin and paclitaxel, could be a reasonable option for older patients who are not candidates for targeted therapy. DISCLOSURES No outside funding supported this study. Rashid has received past funding from Bristol-Myers Squibb, Astellas, Novartis, and Pfizer. No other authors report any potential financial conflicts of interest. Study concept and design were primarily contributed by Spence and Hui, with input from the other authors. Hui, Spence, and Rashid took the lead in data collection, and data interpretation was performed by Schottinger, Millares, and Spence, assisted by the other authors. The manuscript was written primarily by Spence, along with Chang, and revised by Spence, with input from the other authors.

The Risk of Pneumonia in Older Adults Using Nonbenzodiazepine Hypnotics

BACKGROUND Previous studies have shown an increased risk of pneumonia with benzodiazepines (BZD) and an increased risk of any infection with non-BZD hypnotics, but no analysis has specifically investigated the risk of pneumonia with non-BZD hypnotic use. OBJECTIVE To evaluate the risk of pneumonia associated with non-BZD hypnotic use in the elderly. METHODS This was a retrospective case-control study of members aged 65 years and older enrolled in an integrated health care system. Cases were identified as patients aged 65 years and older with a diagnosis of pneumonia from January 2011 to December 2012. Controls were matched in a 4:1 ratio to cases based on age, gender, and active enrollment. Non-BZD hypnotic exposure was evaluated for all cases and controls 1 year before the index date. Proximity of exposure to index date and duration of use were analyzed. Conditional logistic regression adjusted for covariates was performed. RESULTS We identified 51,029 cases with pneumonia and matched 188,391 controls without pneumonia. Of the cases with pneumonia, 5.5% (2,790) of cases had exposure to a non-BZD hypnotic, compared with 3.4% (6,345) of controls. Non-BZD hypnotic exposure was associated with an increased risk of pneumonia (OR = 1.14; 95% CI = 1.08-1.20). When exposure was stratified by proximity to index date, only current exposure was associated with an increased risk of pneumonia (OR = 1.27; 95% CI = 1.18-1.36). Short-term exposure was associated with a relatively higher risk of pneumonia (OR = 1.57; 95% CI = 1.39-1.77) compared with long-term use (OR = 1.16; 95% CI = 1.06-1.25). CONCLUSIONS Current use of non-BZD hypnotics in older adults is associated with an increased risk of pneumonia. The findings of this study provide additional support for reducing the use of non-BZD hypnotics in older adults and for pursuing safer alternatives for treating insomnia. DISCLOSURES No outside funding supported this study. At the time of this study, Jung was a PGY2 resident in drug information at Kaiser Permanente Drug Information Services. All authors are employed by Kaiser Permanente and report no other potential financial conflicts of interest. Study concept and design were contributed by Jung, Spence, Lee, and Gibbs. Jung, Spence, and Hui were responsible for data collection, and data interpretation was performed by Jung and Spence, with assistance from Escasa, Lee, and Hui. The manuscript was primarily written by Jung, along with Spence and Escasa, and revised by Spence, Escasa, and Lee, along with the other authors.

Evaluation of a Pharmacist-Managed Diabetes Program in a Primary Care Setting Within an Integrated Health Care System

BACKGROUND Pharmacists have important roles in managing the therapy of patients with type 2 diabetes and improving patient care. Pharmacists titrate medications; reinforce patient education; and address care gaps, such as medication adherence, vaccinations, and overdue health screenings. Through these efforts and more, pharmacists help to improve patient care and achieve Healthcare Effectiveness Data and Information Set (HEDIS) measures. Thus, it is important to demonstrate improved health outcomes through pharmacist contributions to diabetes management, which can then provide an opportunity to expand the role of clinical pharmacists in other medical centers and practice settings within an integrated health care system. OBJECTIVE To evaluate the effect of a pharmacist-managed program within a primary care setting by determining the percentage of patients who reached the HEDIS goal of hemoglobin A1c (A1c) < 8.0%, the time needed to reach this goal, and A1c reduction in patients with type 2 diabetes. METHODS This retrospective cohort study identified patients aged 18-74 years who had uncontrolled A1c ≥ 8.0%. Patients in the Complete Care Program (CCP) had their diabetes therapy managed by a pharmacist and were propensity score matched to a comparison group of usual care (UC) patients. Multivariate regression analyses and a Cox proportional hazards model compared the change in A1c from baseline and the time to A1c goal between the 2 groups. RESULTS There were no significant differences in baseline characteristics between the CCP and UC patients (n = 980 patients per group). CCP patients were significantly more likely to achieve the HEDIS goal of A1c < 8% at 3 months (OR = 2.44, 95% CI = 1.93-3.10, P < 0.0001) and at 6 months (OR = 1.32, 95% CI = 1.08-1.61, P = 0.007) compared with the UC patients. CCP patients also reached the A1c goal significantly faster: 3.4 months versus 4.6 months (P < 0.0001), even after controlling for covariates (HR = 1.24, 95% CI = 1.09-1.41, P = 0.001). Change in baseline A1c was -0.95% versus -0.54% (P < 0.0001) at 3 months and -1.19% versus -0.99% (P = 0.008) at 6 months for CCP versus UC patients, respectively. CONCLUSIONS Type 2 diabetes therapy management by clinical pharmacists was associated with a greater percentage of patients achieving the HEDIS goal of A1c < 8.0%, reaching the A1c goal faster, and a greater A1c reduction from baseline at 3 and 6 months of follow-up compared with patients receiving usual care. DISCLOSURES No funding was provided to support this research study. The authors report no potential conflicts of interest relevant to this article. All authors contributed to the study concept and design. Benedict and Spence performed data analysis and interpretation. The manuscript was written by Benedict, with assistance from Spence and Rashid. All authors reviewed and contributed to manuscript revisions. Spence is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Parts of this study were presented at the AMCP Managed Care and Specialty Pharmacy Annual Meeting; San Francisco, California; April 19-22, 2016.