Sex Differences in the Effectiveness of Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Sacubitril-Valsartan for the Treatment of Heart Failure.

Background PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) suggested a potential benefit of sacubitril-valsartan in women with preserved ejection fraction. Among patients with heart failure previously treated with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), we studied whether effectiveness of treatment with sacubitril-valsartan compared with ACEI/ARB monotherapy differed between men and women for both preserved and reduced ejection fraction. Methods and Results Data were derived from the Truven Health MarketScan Databases between January 1, 2011, and December 31, 2018. We included patients with a primary diagnosis of heart failure on treatment with ACEIs, ARBs, or sacubitril-valsartan on the basis of the first prescription after diagnosis. A total of 7181 patients treated with sacubitril-valsartan, 25 408 patients using an ACEI, and 16 177 patients treated with ARBs were included. A total of 790 readmissions or deaths occurred among 7181 patients in the sacubitril-valsartan group and 11 901 events in 41 585 patients treated with an ACEI/ARB. Adjusted for covariates, the hazard ratio (HR) for treatment with sacubitril-valsartan compared with an ACEI or ARB was 0.74 (95% CI, 0.68-0.80). The protective effect of sacubitril-valsartan was evident for men and women (women: HR, 0.75 [95% CI, 0.66-0.86]; P<0.01; men: HR, 0.71 [95% CI, 0.64-0.79]; P<0.01; P interaction 0.03). A protective effect for both sexes was seen only among those with systolic dysfunction. Conclusions Treatment with sacubitril-valsartan is more effective at reducing death and admission to the hospital for heart failure compared with ACEIs/ARBs similarly among men and women with systolic dysfunction; sex differences in the effectiveness of sacubitril-valsartan in diastolic dysfunction requires further investigation.

Trimethoprim-sulfamethoxazole prophylaxis during treatment of granulomatosis with polyangiitis with rituximab in the United States of America: a retrospective cohort study.

BACKGROUND: Antibiotic prophylaxis is recommended during ANCA-associated vasculitis (AAV) induction. We aimed to describe the frequency, persistence, and factors associated with trimethoprim-sulfamethoxazole (TMP-SMX) use in an adult population sample with granulomatosis with polyangiitis (GPA) treated with rituximab (RTX). METHODS: We identified adults with GPA treated with RTX within the Merative™ Marketscan® Research Databases (2011-2020). TMP-SMX prophylaxis was defined as a [Formula: see text] 28-day prescription dispensed within a month of starting RTX. We estimated TMP-SMX persistence, allowing prescription refill gaps of 30 days. Multivariable logistic regression and Cox proportional hazards regression assessed the factors associated with baseline TMP-SMX use and persistence, respectively. Covariates included age, sex, calendar year, insurance type, immunosuppressant use, hospitalization, and co-morbidities. RESULTS: Among 1877 RTX-treated GPA patients, the mean age was 50.9, and 54% were female. A minority (n = 426, 23%) received TMP-SMX with a median persistence of 141 (IQR 83-248) days. In multivariable analyses, prophylaxis was associated with prednisone use in the month prior to RTX ([Formula: see text] 20 mg/day vs none, OR 3.96; 95% CI 3.0-5.2; 1-19 mg/day vs none, OR 2.63; 95% CI 1.8-3.8), and methotrexate use (OR 1.48, 95% CI 1.04-2.1), intensive care (OR 1.95; 95% CI 1.4-2.7), and non-intensive care hospitalization (OR 1.56; 95% CI 1.2-2.1) in the 6 months prior to RTX. Female sex (OR 0.63; 95% CI 0.5-0.8) was negatively associated with TMP-SMX use. CONCLUSIONS: TMP-SMX was dispensed to a minority of RTX-treated GPA patients, more often to those on glucocorticoids and with recent hospitalization. Further research is needed to determine the optimal use and duration of TMP-SMX prophylaxis following RTX in AAV.

Predictors of long-term use of prescription opioids in the community-dwelling population of adults without a cancer diagnosis: a retrospective cohort study.

BACKGROUND: Long-term opioid use is a known risk factor for opioid-related harms. We aimed to identify risk factors for and predictors of long-term use of prescription opioids in the community-dwelling population of adults without a diagnosis of cancer, to inform practice change at the point of care. METHODS: Using Quebec administrative claims databases, we conducted a retrospective cohort study in a random sample of adult members (≥ 18 yr) of the public drug plan who did not have a cancer diagnosis and who initiated a prescription opioid in the outpatient setting between Jan. 1, 2012, and Dec. 31, 2016. The outcome of interest was long-term opioid use (≥ 90 consecutive days or ≥ 120 cumulative days over 12 mo). Potential predictors included sociodemographic factors, medical history, characteristics of the initial opioid prescription and prescriber's specialty. We used multivariable logistic regression to assess the association between each characteristic and long-term use. We used the area under the receiver operating characteristic curve to determine the predictive performance of full and parsimonious models. RESULTS: Of 124 664 eligible patients who initiated opioid therapy, 4172 (3.3%) progressed to long-term use of prescription opioids. The most important associated factors in the adjusted analysis were long-term prescription of acetaminophen-codeine (odds ratio [OR] 6.30, 95% confidence interval [CI] 4.99 to 7.96), prescription of a long-acting opioid at initiation (OR 6.02, 95% CI 5.31 to 6.84), initial supply of 30 days or more (OR 4.22, 95% CI 3.81 to 4.69), chronic pain (OR 2.41, 95% CI 2.16 to 2.69) and initial dose of at least 90 morphine milligram equivalents (MME) per day (OR 1.24, 95% CI 1.04 to 1.47). Our predictive model, including only the initial days' supply and chronic pain diagnosis, had area under the curve of 0.7618. INTERPRETATION: This study identified factors associated with long-term prescription opioid use. Limiting the initial supply to no more than 7 days and limiting doses to 90 MME/day or less are actions that could be undertaken at the point of care.

Real-world analyses of therapy discontinuation of checkpoint inhibitors in metastatic melanoma patients.

The 'real-world' patient population of metastatic melanoma is not fully represented in clinical trials investigating checkpoint inhibitors. We described therapy discontinuation in an unselected population-based cohort of adults with metastatic melanoma who started therapy with pembrolizumab, nivolumab, or nivolumab/ipilimumab from January 2015 to August 2017. Therapy discontinuation was defined as a gap between doses beyond 120 days, and/or initiation of another cancer therapy. We estimated drug-specific rate ratios for therapy discontinuation adjusted for age, sex, comorbidities, health care use, and past cancer therapies. We included 876 metastatic melanoma patients initiating pembrolizumab (44.3%), nivolumab/ipilimumab (31.2%), and nivolumab (24.5%). At 12 months of follow-up, the probabilities of therapy discontinuation were 49.9% (95% confidence interval, CI 43.6-56.5) for pembrolizumab, 58.8% (95% CI 50.5-67.3) for nivolumab, and 59.2% (95% CI 51.7-66.8) for nivolumab/ipilimumab. Stratified analyses based on prior cancer therapy, brain metastases at baseline, and sex showed similar trends. In multivariable analyses, compared with pembrolizumab, patients starting nivolumab (rate ratio 1.38, 95% CI 1.08-1.77) or nivolumab/ipilimumab (rate ratio 1.30, 95% CI 1.02-1.65) were more likely to discontinue therapy. Our findings indicate frequent discontinuations of checkpoint inhibitors at one year. The lower discontinuation associated with pembrolizumab should be confirmed in further studies.

A Systematic Review of Interventions and Programs Targeting Appropriate Prescribing of Opioids.

BACKGROUND: Canada and the United States have the highest levels of prescription opioid consumption in the world. In an attempt to curb the opioid epidemic, a variety of interventions have been implemented. Thus far, evidence regarding their effectiveness has not been consolidated. OBJECTIVES: The objectives of this study were to: 1) identify interventions that target opioid prescribing; 2) assess and compare the effectiveness of interventions on opioid prescription and related harms; 3) determine the methodological quality of evaluation studies. STUDY DESIGN: The study involved a systematic review of the literature including bibliographical databases and gray literature sources. SETTING: Systematic review including bibliographical databases and gray literature sources. METHODS: We searched MEDLINE, Embase, and LILACS databases from January 1, 2005 to September 23, 2016 for any intervention that targeted the prescription of opioids. We also examined websites of relevant organizations and scanned bibliographies of included articles and reviews for additional references. The target population was that of all health care providers (HCPs) or users of opioids with no restriction on indication. Endpoints were those related to process (implementation), outcomes (effectiveness), or impact. Sources were screened independently by 2 reviewers using pre-defined eligibility criteria. Synthesis of findings was qualitative; no pooling of results was conducted. RESULTS: Literature search yielded 12,278 unique sources. Of these, 142 were retained. During full-text review, 75 were further excluded. Searches of the gray literature and bibliographies yielded 49 additional sources. Thus, a total of 95 distinct interventions were identified. Over half consisted of prescription monitoring programs (PMPs) and mainly targeted HCPs. Evaluation studies addressed mainly opioid prescription rate (30.6%), opioid use (19.4%), or doctor shopping or diversion (9.7%). Fewer studies considered overdose death (9.7%), abuse (9.7%), misuse (4.2%), or diversion (5.6%). Study designs consisted of cross-sectional surveys (23.3%), pre-post intervention (26.7%), or time series without a comparison group (13.3%), which limit the robustness of the evidence. Although PMPs and policies have been associated with a reduction in opioid prescription, their impact on appropriateness of use according to clinical guidelines and restriction of access to patients in need is inconsistent. Continuing medical education (CME) and pain management programs were found effective in improving chronic pain management, but studies were conducted in specific settings. The impact of interventions on abuse and overdose-death is conflicting. LIMITATIONS: Due to the very large number of publications and programs found, it was difficult to compare interventions owing to the heterogeneity of the programs and to the methodologies of evaluation studies. No assessment of publication bias was done in the review. CONCLUSIONS: Evidence of effectiveness of interventions targeting the prescription of opioids is scarce in the literature. Although PMPs have been associated with a reduction in the overall prescription rates of Schedule II opioids, their impact on the appropriateness of use taking into consideration benefits, misuse, legal and illegal use remains elusive. Our review suggests that existing interventions have not addressed all determinants of inappropriate opioid prescribing and usage. A well-described theoretical framework would be the backdrop against which targeted interventions or policies may be developed. KEY WORDS: Opioid, prescription, abuse, misuse, diversion, interventions, prescription monitoring programs.

Direct-Acting Antivirals for Hepatitis C: Predictors of Early Discontinuation in the Real World.

BACKGROUND: The treatment for hepatitis C virus (HCV) infection has evolved over time, and direct-acting antivirals (DAA) have revolutionized HCV therapy. OBJECTIVES: To (a) assess early treatment discontinuation and (b) identify predictors of early discontinuation in a cohort of patients receiving second-generation DAAs. METHODS: We identified HCV patients newly prescribed simeprevir/sofosbuvir (SIM/SOF), ledipasvir/sofosbuvir (LDV/SOF), ombitasvir/paritaprevir/ritonavir + dasabuvir (OPrD), sofosbuvir/velpatasvir (SOF/VEL), elbasvir/grazoprevir (EBR/GZR), and glecaprevir/pibrentasvir (GLE/PIB) between 2014 and 2017. Early discontinuation was defined as duration of therapy less than 8 weeks. Multivariable logistic regression was performed to evaluate the association of drug regimens and potential predictive factors to early discontinuation. RESULTS: We identified 26,098 DAA-treated patients: 67.8% with LDV/SOF, 9.9% with OPrD, 8.5% with SIM/SOF, 7.8% with SOF/VEL, 5.2% with EBR/GZR, and 0.8% with GLE/PIB. With approval of new therapies in 2016 and 2017, use of OPrD, LDV/SOF, and SIM/SOF declined substantially. At baseline, there was some heterogeneity of past HCV drug use and comorbidity across groups; patients on SIM/SOF had the highest frequency of previous interferon, cirrhosis, and decompensated cirrhosis. Most HCV patients received therapy for 8-12 weeks; fewer patients went through 16-week and 24-week therapy courses. Early discontinuation rates (95% CI) were 7.1% (6.0-8.2) for SIM/SOF, 3.2% (2.9-3.5) for LDV/SOF, 9.6% (8.5-10.7) for OPrD, 3.1% (2.3-3.8) for SOF/VEL, 4.2% (3.1-5.3) for EBR/GZR, and 2.5% (0.3-4.7) for GLE/PIB. In multivariable analyses, versus OPrD, patients starting other drug regimens were less likely to discontinue therapy early. Early discontinuation was more common in women, patients with baseline anemia, and Medicare and Medicaid patients. CONCLUSIONS: These real-world data confirm low rates of early discontinuation in users of second-generation DAAs. Future research focusing on socio-economic and sex/gender issues may help further optimize care for patients with HCV. DISCLOSURES: This study was funded by the Canadian Institutes of Health Research. Klein has received grants for investigator-initiated trials from ViiV Healthcare, Janssen, Gilead, and Merck, as well as consulting fees from ViiV Healthcare, Merck, and AbbVie. Feld has received research support and/or scientific consulting fees from AbbVie, Contravir, Enanta, Gilead, Janssen, Merck, and Wako. All other authors have no conflicts of interest to declare. Results from this study were presented as a poster at the 34th International Conference of Phamacoepidemiology and Therapeutic Risk Management; August 22-26, 2018; Prague, Czech Republic.

Associations between low- and high-dose oral fluconazole and pregnancy outcomes: 3 nested case-control studies.

BACKGROUND: While topical azoles are the first-line treatment for fungal infections, oral fluconazole is frequently used during pregnancy. We aimed to assess the effect of exposure to low and high doses of fluconazole during pregnancy on the occurrence of spontaneous abortions, major congenital malformations and stillbirths. METHODS: Within the Quebec Pregnancy Cohort (1998-2015), we identified women exposed to low- (≤ 150 mg) and high-dose (> 150 mg) fluconazole, and women who were not exposed. For each case of spontaneous abortion or stillbirth, up to 5 controls were randomly selected using an incidence density sampling method matched on gestational age at diagnosis of spontaneous abortion or stillbirth (index date) and the year of the last menstrual period. For cases of major congenital malformation, we considered all liveborn babies as controls. Generalized estimation equation models were used to analyze the 3 main outcomes separately. RESULTS: Within a cohort of 441 949 pregnancies, 320 868 pregnancies were included in the analyses of spontaneous abortions, 226 599 of major congenital malformations and 7832 of stillbirths. Most (69.5%) women exposed to fluconazole in pregnancy received the common single therapeutic dose of 150 mg (low dose); the remainder received a dose of > 150 mg (high dose). Use of oral fluconazole during early pregnancy was associated with an increased risk of spontaneous abortion compared with no exposure (adjusted odds ratio [OR] for 345 cases exposed to low-dose treatment 2.23, 95% confidence interval [CI] 1.96-2.54; adjusted OR for 249 cases exposed to high-dose treatment 3.20, 95% CI 2.73-3.75). Exposure to fluconazole during the first trimester did not increase the risk of overall major congenital malformations; however, exposure to a high dose during the first trimester was associated with an increased risk of cardiac septal closure anomalies (adjusted OR 1.81, 95% CI 1.04-3.14; 13 exposed cases) compared with no exposure. No association was found between exposure to fluconazole during pregnancy and the risk of stillbirth. INTERPRETATION: Any maternal exposure to fluconazole during pregnancy may increase risk of spontaneous abortion and doses higher than 150 mg during the first trimester may increase risk of cardiac septal closure anomalies.

Comparative effectiveness of antihypertensive drugs in nondiabetic patients with hypertension: A population-based study.

The authors compared the effectiveness of thiazide diuretic (TD), angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), and calcium channel blocker (CCB) monotherapies for the treatment of nondiabetic hypertension using MarketScan Databases 2010-2014. Multivariable Cox regression models assessed whether the addition of a new antihypertensive drug, treatment discontinuation, or switch and major cardiovascular or cerebrovascular events varied across groups. A total of 565 009 patients started monotherapy with ACEIs (43.6%), CCBs (23.6%), TDs (18.8%), or ARBs (14.0%). Patients who took TDs had a higher risk for either drug addition or discontinuation than patients who took ACEIs (hazard ratio [HR], 0.69 [95% CI, 0.68-0.70] vs HR, 0.81 [95% CI, 0.80-0.81]), ARBs (HR, 0.67 [95% CI, 0.66-0.68] vs HR, 0.66 [95% CI, 0.65-0.67]), and CCBs (HR, 0.85 [95% CI, 0.84-0.87] vs HR, 0.94 [95% CI, 0.93-0.95]). Conversely, patients who took TDs experienced a lower risk of clinical events compared with patients who took ACEIs (HR, 1.24 [95% CI, 1.15-1.33]), ARBs (HR, 1.28 [95% CI, 1.18-1.39]), and CCBs (HR, 1.35 [95% CI, 1.25-1.46]). Our results provide a strong rationale for choosing TDs as first-line monotherapy for the control of hypertension.

[Evaluation of potential drug interactions in primary health care prescriptions in Vitória da Conquista, Bahia (Brazil)]. / Avaliação de interações medicamentosas potenciais em prescrições da atenção primária de Vitória da Conquista (BA), Brasil.

Drug interactions are risk factors for the occurrence of adverse drug reactions. The risk for drug interactions includes factors related to prescription that are intrinsic to the patient. This study sought to evaluate the potential drug interactions in primary care prescriptions in Vitória da Conquista in the state of Bahia to fill the knowledge gap on this topic in Brazil. Information about several variables derived from the primary health care prescriptions was collected and drug interactions were evaluated based on information from Medscape and Micromedex(R) databases. Polypharmacy frequency and its association with the occurrence of drug interactions were also evaluated. Results revealed a 48,9% frequency of drug interactions, 74,9% of moderate or greater severity, 8,6% of prescriptions in polypharmacy that in the chi-square test showed a positive association with the occurrence of drug interactions (p < 0,001). Prescriptions from primary care in Vitória da Conquista in the state of Bahia showed a high frequency of drug interactions, however it is necessary to analyze other risk factors for their occurrence at this level of health care.