Oral anticoagulants for nonvalvular atrial fibrillation in frail elderly patients: insights from the ARISTOPHANES study.

BACKGROUND: Patient frailty amongst patients with nonvalvular atrial fibrillation (NVAF) is associated with adverse health outcomes and increased risk of mortality. Additional evidence is needed to evaluate effective and safe NVAF treatment in this patient population. OBJECTIVES: This subgroup analysis of the ARISTOPHANES study compared the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) amongst frail NVAF patients prescribed nonvitamin K antagonist oral anticoagulants (NOACs) or warfarin. METHODS: This comparative retrospective observational study of frail, older NVAF patients who initiated apixaban, dabigatran, rivaroxaban or warfarin from 01JAN2013-30SEP2015 was conducted using Medicare and 3 US commercial claims databases. To compare each drug, 6 propensity score-matched (PSM) cohorts were created. Patient cohorts were pooled from 4 databases after PSM. Cox models were used to estimate hazard ratios (HR) of S/SE and MB. RESULTS: Amongst NVAF patients, 34% (N = 150 487) met frailty criteria. Apixaban and rivaroxaban were associated with a lower risk of S/SE vs warfarin (apixaban: HR: 0.61, 95% CI: 0.55-0.69; rivaroxaban: HR: 0.79, 95% CI: 0.72-0.87). For MB, apixaban (HR: 0.62, 95% CI: 0.57-0.66) and dabigatran (HR: 0.79, 95% CI: 0.70-0.89) were associated with a lower risk and rivaroxaban (HR: 1.14, 95% CI: 1.08-1.21) was associated with a higher risk vs warfarin. CONCLUSION: Amongst this cohort of frail NVAF patients, NOACs were associated with varying rates of stroke/SE and MB compared with warfarin. Due to the lack of real-world data regarding OAC treatment in frail patients, these results may inform clinical practice in the treatment of this patient population.

Comparison of major bleeding risk in patients with non-valvular atrial fibrillation receiving direct oral anticoagulants in the real-world setting: a network meta-analysis.

OBJECTIVE: To conduct a systematic literature review (SLR) and network meta-analysis (NMA) of real-world studies comparing major bleeding risk among patients with non-valvular atrial fibrillation (NVAF) on direct oral anticoagulants (DOACs) or warfarin. METHODS: Systematic searches were conducted in MEDLINE and Embase for full-text articles published between January 1, 2003 and March 18, 2017. Eligible studies compared at least two of the following in a real-world setting: warfarin, apixaban, dabigatran, rivaroxaban, or edoxaban. A Bayesian NMA was conducted to estimate hazard ratios (HRs) for major bleeding using a random-effects model. RESULTS: Eleven studies were included in the NMA. Nine studies included DOACs vs Warfarin comparisons, and four studies included DOACs vs DOACs comparisons (two studies included both comparisons). Median follow-up duration ranged from 2.6-31.2 months. No evidence was identified for edoxaban. Apixaban was associated with a significantly lower risk of major bleeding compared to other oral anticoagulants (warfarin HR = 0.58; 95% credible interval [CrI] = 0.48-0.69; dabigatran = 0.73; 0.61-0.87; rivaroxaban = 0.55; 0.46-0.66). Dabigatran was associated with a significantly lower risk than warfarin (0.79; 0.71-0.88) and rivaroxaban (0.76; 0.67-0.85), and rivaroxaban was not statistically different from warfarin (1.05; 0.91-1.19). Sensitivity analyses with standard dose and sponsorship showed consistent results. CONCLUSION: DOACs were associated with lower or similar risk of major bleeding compared with warfarin in NVAF patients. Apixaban was associated with a significantly lower risk of major bleeding than other DOACs. Dabigatran was associated with a significantly lower risk of major bleeding compared to rivaroxaban and warfarin.

Impact of apixaban vs low molecular weight heparin/vitamin k antagonist on hospital resource use in patients with venous thromboembolism.

BACKGROUND: The clinical and economic benefits associated with apixaban treatment have been established in clinical trials and published economic evaluations. The benefits associated with apixaban could extend to improving hospital efficiencies, potentially influencing hospital resource use, and bed days. The objective of this study is to estimate the impact of 6-month treatment with apixaban vs low molecular weight heparin/vitamin k antagonist (LMWH/VKA) on hospital resource use among patients with venous thromboembolism (VTE). METHODS: A model was developed to assess the impact of apixaban vs LMWH/VKA for treatment of VTE and prevention of recurrences on hospital resource use and costs. Resource use items included total hospitalizations, length of stay (LOS), and emergency department (ED) visits, estimated for all incident VTE patients in the UK over a 5-year time horizon. Rates of hospitalizations, ED visits, and LOS associated with recurrent VTE, major, and clinically relevant non-major bleeding were obtained from the AMPLIFY trial; costs were obtained from UK published sources. RESULTS: Over a 5-year time horizon, the model predicted that, compared to 6 months of LMWH/VKA, 6 months of apixaban led to 3,954 fewer hospitalizations (consisting of 2,341 fewer new admissions and 1,613 fewer re-admissions) and 32,214 fewer bed days, among 332,607 incident VTE patients. ED visits were reduced by 1,582. The reduction in hospital resource use led to a cost saving of ∼£4.5 million in a market of patients treated with apixaban as compared to a market treated with LMWH/VKA. Sensitivity analysis indicated these findings were robust over a wide range of inputs. CONCLUSIONS: 6-month treatment with apixaban for treatment of VTE and prevention of recurrences on hospital resource use led to a reduction in hospitalizations and LOS in comparison to LMWH/VKA. These findings can help the efforts in reducing the growing burden of preventable re-admissions to hospitals.

Risk-adjusted relationship between voriconazole utilization and non-melanoma skin cancer among lung and heart/lung transplant patients.

BACKGROUND: We examined the relationship between voriconazole utilization and non-melanoma skin cancer (NMSC) development among adult lung and heart/lung transplant patients who were continuously enrolled in a large U.S. commercial health plan. METHODS: Cox proportional hazards regression models were constructed to assess both the crude and adjusted effect of voriconazole usage on NMSC development. Overall, 467 adult lung (98%) and heart/lung (2%) transplant patients (60% male) with median age of 58 years were analyzed. RESULTS: Fifty-seven (12%) patients developed NMSC over a median follow-up time of 610 days. At the crude level, patients with any (vs. none) claim for voriconazole were more likely to develop NMSC (19% vs. 12%, hazard ratio [HR]: 1.74, 95% confidence interval [CI]: 1.02, 2.96, P = 0.04). However, after statistical adjustment for demographic and clinical factors, the effect was largely diminished and no longer statistically significant (HR: 1.23, 95% CI: 0.71, 2.14, P = 0.45). Results were similar when modeling average and total dose of voriconazole. Risk factors significantly related to NMSC development were being male, older age, sun exposure, history of chronic obstructive pulmonary disorder, and history of immune disorder. CONCLUSION: Results suggest that the relationship between voriconazole utilization and NMSC among lung transplant patients may be a result of confounding by indication, and that controlling for underlying patient characteristics is paramount.

Pain-related pharmacotherapy, healthcare resource use and costs in spinal cord injury patients prescribed pregabalin.

STUDY DESIGN: Retrospective database analysis. OBJECTIVES: To describe comorbidities, pain-related pharmacotherapy, healthcare resource use and costs among patients with spinal cord injury (SCI) newly prescribed pregabalin. SETTING: United Kingdom (UK). METHODS: Using The Health Improvement Network database, SCI patients newly prescribed (index event) pregabalin (N=72; average age 48 years; 53% female) were selected. Study measures were evaluated during both the 9-months pre-index and follow-up periods. RESULTS: Prevalent comorbidities included musculoskeletal disorders (51.4%), digestive disorders (23.6%) and urogenital disorders (20.8%). Opioids were the most frequently prescribed medications (pre-index, 58.3%; follow-up, 61.1%, P=not significant (NS)) followed by nonsteroidal anti-inflammatory drugs (43.1 and 45.8%, P=NS). Use of anti-epileptics (other than pregabalin) recommended for SCI neuropathic pain decreased (25.0 vs 12.5%, P=0.0290), whereas sedative/hypnotic use (18.1 vs 26.4%, P=0.034) increased during follow-up. Over 50% of patients had visits to specialists, and at least 1 in every 10 had laboratory/radiology-related visits. There were numerical decreases in proportions of patients with emergency room visits (22.2 vs 13.9%, P=NS) and hospitalizations (16.7 vs 12.5%, P=NS) during follow-up. Medication costs were higher during follow-up (median, £ 561.4 vs £ 889.5, P<0.0001). Costs of outpatient visits were similar during both study periods (£ 1082.1 vs £ 1066.1) as were total medical costs (£ 1689.0 vs £ 2169.4) when costs of pregabalin prescriptions were excluded. Inclusion of pregabalin costs resulted in higher (P<0.0001) total medical costs during follow-up. CONCLUSION: SCI patients had a high comorbidity, medication and healthcare resource use burden in clinical practice. Further research with larger sample sizes and more comprehensive data sources may serve to clarify study findings.

Raising orphans: how clinical development programs of drugs for rare and common diseases are different.

We compared clinical trials described in package inserts from noncancer orphan and nonorphan drugs from 1 January 2001 to 31 December 2011. Among the 37 orphan and 58 nonorphan drugs approved by the US Food and Drug Administration (US FDA) during this period, orphans had fewer clinical trials (2.8 vs. 3.5, P < 0.05) and fewer total participants (390 vs. 2,566, P < 0.001), but proportions with randomization, blinding, and placebo-controlled clinical end points were similar, as were development times. We conclude that small studies of appropriate design can support US FDA approval of new medicines for rare diseases.

Persistence with non-selective NSAIDs and celecoxib among patients with gastroesophageal reflux disease and osteoarthritis or rheumatoid arthritis.

OBJECTIVE: Gastrointestinal (GI) symptoms are common in patients taking nonselective, nonsteroidal anti-inflammatory drugs (nsNSAIDs) and are often a reason for therapy discontinuation. In osteoarthritis (OA) and rheumatoid arthritis (RA) patients requiring pain control, selective COX-2 NSAID use is typically associated with less dyspepsia than is nsNSAID use. Little is known about NSAID tolerance in patients with gastroesophageal reflux disease (GERD). This study assessed nsNSAID and celecoxib prescription patterns, in particular persistence, in OA/RA patients with concomitant diagnosis of GERD. METHODS: An observational study of GERD patients with a diagnosis of OA/RA using two separate databases, the IMS Lifelink Health Plan Claims Database (PharMetrics) and Market Scan Claims Database (Medstat) was conducted. In each database, parallel and separate analyses were performed in adult patients who had their first GERD diagnosis in 2006 and who were subsequently diagnosed with OA or RA in the same year. From this subset of patients, celecoxib-naïve and nsNSAID-naïve cohorts were identified and patients were selected. Patients with pre-existing GI conditions were excluded from the study. Persistence, measured as time to discontinuation, was evaluated by Kaplan-Meier survival curves and Cox proportional hazards models. Reasons for discontinuations were not available in these databases. RESULTS: Fewer patients discontinued celecoxib as compared to nsNSAIDs during the 60 days of the first prescription and throughout the entire follow-up period. After adjusting for baseline characteristics, celecoxib patients still had significantly decreased risk of discontinuation as compared to nsNSAID patients (p < 0.0001). Replication of these observations in two separate, large patient databases increases the confidence in this study's conclusion. LIMITATIONS: Limitations include those inherent to claims data analyses and retrospective review, e.g. these data do not provide clinical information related to reasons for medication discontinuation. CONCLUSION: In patients with concomitant GERD and OA or RA who require anti-inflammatory treatment, significantly more patients treated with celecoxib were persistent with their treatment than were patients treated with nsNSAIDs.

Panic disorder and response to sertraline: the effect of previous treatment with benzodiazepines.

More than 50% of patients who seek psychiatric care for panic disorder have previously received prescriptions for a benzodiazepine (BZ). Research on the treatment of generalized anxiety suggests that a history of BZ exposure might decrease the efficacy and tolerability of treatment with a serotonergic anxiolytic. This study examines the effect of prior BZ treatment on the efficacy and tolerability of sertraline treatment for panic disorder. Data were pooled (N = 705) from four double-blind, placebo-controlled studies of the efficacy of sertraline for the treatment of panic. Two of the studies were 12-week fixed-dose studies with starting doses of 50 mg, whereas 2 were flexible-dose studies of 10-week duration with starting doses of 25 mg. The effect of study treatment on the frequency of panic attacks, Clinical Global Impressions (CGI) Improvement Scale, and tolerability was examined for patients with or without prior BZ treatment. The efficacy of sertraline was not affected by prior treatment with BZs. The mean endpoint reduction in panic attack frequency was identical in patients with or without prior BZ use: 79% vs. 80% (not significant). A history of good versus poor response to prior BZ treatment did not significantly influence CGI responder rates for sertraline-treated patients (67% vs. 61%, respectively). Sertraline CGI responder rates were significantly greater than placebo response, which was 47% for the good-response prior-BZ subgroup (p = 0.007), and 36% for the poor-response BZ subgroup (p = 0.013). Placebo response was lower in patients with any prior BZ use by 10% on an intent-to-treat last-observation-carried-forward analysis (p = 0.106) and by 15% on a completer analysis (p = 0.045). Prior BZ use did not influence either rates of adverse events or discontinuation rates within the first 3 weeks in patients treated with either sertraline or placebo. Sertraline is both well-tolerated and has significant efficacy in patients with panic disorder, including the subset of patients with panic disorder who have previously been treated with BZs.

Is placebo response the same as drug response in panic disorder?

OBJECTIVE: The authors used seven definitions of response in panic disorder to compare patient-rated improvements in quality of life between patients with panic disorder who responded to sertraline and those who responded to placebo. METHOD: They combined and examined data from two multicenter, randomized, double-blind, parallel-group, flexible-dose studies of panic disorder (N=302). RESULTS: Significant differences in quality of life between patients who responded to sertraline and those who responded to placebo were apparent across all the definitions of clinical response. CONCLUSIONS: Patients who respond to placebo in panic disorder treatment studies may show symptom relief but may not experience improvement in quality of life. Determinations of quality of life should be included as components of both standard clinical assessment and clinical treatment studies of patients with panic disorder.

Sertraline treatment of panic disorder: response in patients at risk for poor outcome.

BACKGROUND: More than one third of panic disorder patients have a chronic and/or recurrent form of the disorder, accounting for much of the individual and societal cost associated with the illness. Six clinical variables have been most consistently identified as high-risk predictors of poor outcome: (1) panic severity, (2) presence of agoraphobia, (3) comorbid depression, (4) comorbid personality disorder, (5) duration of illness, and (6) female sex. No published research has systematically examined the differential antipanic efficacy of selective serotonin reuptake inhibitors in patients at high risk for poor outcome. METHOD: Data were pooled (N = 664) from 4 double-blind, placebo-controlled studies of the efficacy of sertraline for the treatment of DSM-III-R panic disorder. Two of the studies were 12-week fixed-dose studies with starting daily doses of sertraline, 50 mg, and 2 were 10-week flexible-dose studies with starting daily doses of sertraline, 25 mg. All other study design features were the same, except for the exclusion of women of childbearing potential in the 2 fixed-dose studies. Exclusion of patients with marked personality disorders and depression meant that only 4 of the poor-outcome variables could be evaluated. RESULTS: Clinical improvement was similar for patients treated with sertraline whether or not they carried an agoraphobia diagnosis, had a duration of illness > 2 years, or were female. Patients with high baseline panic severity had significantly (p = .01) less improvement on the endpoint Clinical Global Impressions-Improvement (CGI-I) scale than patients with moderate severity, although the Clinical Global Impressions-Severity of Illness scale change score was higher in the patients with high severity (-2.00 vs. -1.31). For patients with 3 or more high-risk variables, there was a modest, but statistically significant, tendency for reduced global improvement (endpoint CGI-I score of 2.7 for the high-risk vs. 2.4 for the non-high-risk group; p = .017), although the high-risk group actually had a similar endpoint reduction in frequency of panic attacks (82%) compared with the non-high-risk group (78%). CONCLUSION: Treatment of panic disorder with sertraline was generally effective, even in the presence of baseline clinical variables that have been associated with poor treatment response. The main limitations of the analysis were the reliance on pooled data from 4 studies (even if the designs were similar) and our inability to examine the impact of depression and personality disorders on response to treatment because of the exclusion criteria of the clinical trials.

Sertraline in children and adolescents with obsessive-compulsive disorder: a multicenter randomized controlled trial.

CONTEXT: The serotonin reuptake inhibitors are the treatment of choice for patients with obsessive-compulsive disorder; however, empirical support for this assertion has been weaker for children and adolescents than for adults. OBJECTIVE: To evaluate the safety and efficacy of the selective serotonin reuptake inhibitor sertraline hydrochloride in children and adolescents with obsessive-compulsive disorder. DESIGN: Randomized, double-blind, placebo-controlled trial. PATIENTS: One hundred eighty-seven patients: 107 children aged 6 to 12 years and 80 adolescents aged 13 to 17 years randomized to receive either sertraline (53 children, 39 adolescents) or placebo (54 children, 41 adolescents). SETTING: Twelve US academic and community clinics with experience conducting randomized controlled trials. INTERVENTION: Sertraline hydrochloride was titrated to a maximum of 200 mg/d during the first 4 weeks of double-blind therapy, after which patients continued to receive this dosage of medication for 8 more weeks. Control patients received placebo. MAIN OUTCOME MEASURES: The Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), the National Institute of Mental Health Global Obsessive Compulsive Scale (NIMH GOCS), and the NIMH Clinical Global Impressions of Severity of Illness (CGI-S) and Improvement (CGI-I) rating scales. RESULTS: In intent-to-treat analyses, patients treated with sertraline showed significantly greater improvement than did placebo-treated patients on the CY-BOCS (adjusted mean, -6.8vs -3.4, respectively; P=.005), the NIMH GOCS (-2.2 vs -1.3, respectively; P=.02), and the CGI-I (2.7 vs 3.3, respectively; P=.002) scales. Significant differences in efficacy between sertraline and placebo emerged at week 3 and persisted for the duration of the study. Based on CGI-I ratings at end point, 42% of patients receiving sertraline and 26% of patients receiving placebo were very much or much improved. Neither age nor sex predicted response to treatment. The incidence of insomnia, nausea, agitation, and tremor were significantly greater in patients receiving sertraline; 12 (13%) of 92 sertraline-treated patients and 3 (3.2%) of 95 placebo-treated patients discontinued prematurely because of adverse medical events (P=.02). No clinically meaningful abnormalities were apparent on vital sign determinations, laboratory findings, or electrocardiographic measurements. CONCLUSION: Sertraline appears to be a safe and effective short-term treatment for children and adolescents with obsessive-compulsive disorder.