Rajeev Ayyagari

Indirect tolerability comparison of Deutetrabenazine and Tetrabenazine for Huntington disease

BackgroundVesicular monoamine transporter 2 (VMAT2) inhibitors can improve hyperkinetic movements, and are effective treatment options for chorea of Huntington disease (HD). Tetrabenazine was assessed for treating chorea in the TETRA-HD trial, and while efficacious, there are tolerability concerns possibly due to its pharmacokinetic properties. Deutetrabenazine is a novel VMAT2 inhibitor that contains deuterium, which extends active metabolite half-lives and minimizes drug concentration fluctuations. In the First-HD trial, deutetrabenazine was efficacious in treating chorea and was generally well tolerated. In the absence of a head-to-head trial, we performed an indirect treatment comparison (ITC) of the tolerability of deutetrabenazine and tetrabenazine for the treatment of HD-associated chorea, as observed in the First-HD and TETRA-HD trials, using well-established comparison methods.MethodsData from the Phase III, 12-week, parallel-group, clinical trials First-HD (N = 90) and TETRA-HD (N = 84) were used to conduct an ITC of the tolerability of deutetrabenazine versus tetrabenazine using two anchor-based methods: Bucher comparison for unadjusted ITCs, and matching indirect comparison for adjusted ITCs. Overall adverse events (AEs; mild, moderate, and severe), serious AEs, specific AEs occurring in ≥10% of patients, and discontinuations (all-cause and AE-related) were included in the analysis. The risk differences of these outcomes for deutetrabenazine and tetrabenazine were estimated by subtracting the applicable placebo-adjusted risk in First-HD from that of TETRA-HD. Sensitivity analyses were performed to address differences between trials, and p-values were obtained from z-tests.ResultsCompared with tetrabenazine, deutetrabenazine was associated with a significantly lower risk of moderate to severe AEs and neuropsychiatric AEs including agitation, akathisia, depression, depression/agitated depression, drowsiness/somnolence, insomnia, and parkinsonism in both adjusted and unadjusted analyses (p < 0.05 for each). Deutetrabenazine had a significantly lower rate of dose reduction or dose reduction/suspension in the unadjusted and adjusted analyses (p < 0.001 for each). Deutetrabenazine resulted in numerically more mild AEs, such as diarrhea and coughing; however, these results were not statistically significant.ConclusionsThis indirect treatment comparison demonstrates that for the treatment of HD chorea, deutetrabenazine has a favorable tolerability profile compared to tetrabenazine.Trial registrationClinicalTrials.gov NCT01795859 and NCT00219804.

Major molecular response during the first year of dasatinib, imatinib or nilotinib treatment for newly diagnosed chronic myeloid leukemia: A network meta-analysis

OBJECTIVE No randomized trials have directly compared dasatinib with nilotinib for the treatment of newly diagnosed chronic myeloid leukemia in the chronic phase. The objective of this study was to indirectly compare these therapies using evidence from randomized trials versus imatinib, the current standard of care. METHODS Randomized trials that included either dasatinib or nilotinib as first-line treatment for chronic myeloid leukemia were identified in a systematic review. Inclusion and exclusion criteria, baseline characteristics and endpoint definitions were compared across trials. The outcome of interest was major molecular response by or at 12 months. A network meta-analysis was conducted to compare rates of major molecular response among therapies while adjusting for measurement of response by or at 12 months. RESULTS One trial of nilotinib versus imatinib (ENESTnd) and two trials of dasatinib versus imatinib (DASISION and the S0325 Intergroup Trial) were identified. Major molecular response was reported by and at 12 months in ENESTnd, by 12 months in DASISION, and at 12 months in the S0325 Intergroup Trial. In the network meta-analysis, nilotinib had a 97% chance of having the highest rate of major molecular response compared to dasatinib and imatinib, corresponding to absolute rates of major molecular response by month 12 of 55.2%, 44.8% and 26.7%, respectively. CONCLUSIONS In this network meta-analysis, nilotinib was associated with the highest rate of major molecular response, compared to dasatinib and imatinib, during the first year of treatment in patients with newly diagnosed chronic myeloid leukemia in the chronic phase.

A pulmonary exacerbation risk score among cystic fibrosis patients not receiving recommended care

Pulmonary exacerbations (PEx) lead to substantial morbidity in cystic fibrosis (CF), and guidelines recommend chronic medication including dornase alfa and inhaled tobramycin. However PEx risk and medication use vary across patients.

Pulse pressure and stroke risk: development and validation of a new stroke risk model.

Abstract Objective: This study aims to develop and validate a stroke risk model incorporating pulse pressure (PP) as a potential risk factor. Recent evidence suggests that PP, defined as the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP), could be an incremental risk factor beyond SBP. Methods: Electronic health records (EHRs) of hypertensive patients from a US integrated health delivery system were analyzed (January 2004 to May 2012). Patients with ≥1 PP reading and ≥6 months of observation prior to the first diagnosis of hypertension were randomly split into development (two-thirds of sample) and validation (one-third of sample) datasets. Stroke events were identified using ICD-9-CM 433.xx–436.xx. Cox proportional hazards models assessed time to first stroke event within 3 years of first hypertension diagnosis based on baseline risk factors, including PP, age, gender, diabetes, and cardiac comorbidities. The optimal model was selected using the least absolute shrinkage and selection operator (LASSO); performance was evaluated by the c-statistic. Results: Among 34,797 patients selected (mean age 59.3 years, 48% male), 4272 patients (12.3%) had a stroke. PP was higher among patients who developed stroke (mean [SD] PP, stroke: 02.0 [15.3] mmHg; non-stroke: 58.1 [14.0] mmHg, p < 0.001). The best performing risk model (c-statistic, development: 0.730; validation: 0.729) included PP (hazard ratio per mmHg increase: 1.0037, p < 0.001) as a significant risk factor. Limitations: This study was subject to limitations similar to other studies using EHRs. Only patient encounters occurring within the single healthcare network were captured in the data source. Though the model was tested internally, external validation (using a separate data source) would help assess the model’s generalizability and calibration. Conclusions: This stroke risk model shows that greater PP is a significant predictive factor for increased stroke risk, even in the presence of known risk factors. PP should be considered by practitioners along with established risk factors in stroke treatment strategies.

A cost-effectiveness analysis of lisdexamfetamine dimesylate in the treatment of adults with attention-deficit/hyperactivity disorder in the UK:

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder in children that may persist into adulthood. Lisdexamfetamine dimesylate (LDX) is approved in many countries for ADHD treatment in children, adolescents, and adults.ObjectivesEstimate the cost-effectiveness of LDX as a first- or second-line treatment for adults with ADHD from the United Kingdom (UK) National Health Service (NHS) perspective compared with methylphenidate extended release (MPH-ER) and atomoxetine (ATX).MethodsA 1-year decision-analytic model was developed. Health outcomes included response, non-response and inability to tolerate. Efficacy data were obtained from a mixed-treatment comparison (MTC). Response was a score of 1 or 2 on the Clinical Global Impression–Improvement scale. Tolerability was assessed by discontinuation rates due to adverse events. Utilities were identified via a systematic literature review. Health care resource use estimates were obtained via a survey of clinicians. Daily drug costs were estimated from mean doses reported in the trials used in the MTC. One-way and probabilistic sensitivity analyses (PSAs) were performed.ResultsLDX dominated MPH-ER and ATX; reducing mean per-patient annual cost by £5 and £200, and increasing mean quality-adjusted life years (QALYs) by 0.005 and 0.009, respectively. In the PSA, the probability of cost-effectiveness for LDX vs. MPH-ER and ATX at a threshold of £20,000 per QALY was 61% and 80%, respectively.ConclusionsFrom the perspective of the UK NHS, LDX is likely to provide a cost-effective treatment for adults with ADHD. This conclusion may be drawn with more certainty in comparison with ATX than with MPH-ER.

A retrospective study evaluating the tolerability and effectiveness of adjunctive antihypertensive drugs in patients with inadequate response to initial treatment

Real‐world tolerability and effectiveness of nebivolol as first add‐on therapy were compared with hydrochlorothiazide, metoprolol, and amlodipine. Medical records of hypertensive adults initiating nebivolol, hydrochlorothiazide, metoprolol, or amlodipine as first add‐on therapy between December 16, 2010 and July 21, 2011 were retrospectively abstracted (N = 1600; 400/treatment). Outcomes included medication‐related side‐effect rates and blood pressure (BP) reduction and control. Compared with nebivolol, metoprolol and amlodipine had significantly higher side‐effect rates (incidence rate ratio [95% CI]: 1.82 [1.14‐2.92] and 2.67 [1.69‐4.21]), respectively); the hydrochlorothiazide‐nebivolol rate ratio was not significant (1.61 [0.95‐2.71]). All treatments reduced BP at 2 months. Metoprolol, amlodipine, and hydrochlorothiazide were associated with significantly lower odds of achieving 2‐month BP control than nebivolol (odds ratios [95% CI]: 0.34 [0.23‐0.51], 0.51 [0.35‐0.75] and 0.66 [0.44‐0.99], respectively). In a real‐world setting, nebivolol as first add‐on therapy was associated with fewer side effects than metoprolol or amlodipine and with a higher BP control rate than hydrochlorothiazide, metoprolol, or amlodipine.

Progression-free survival with endocrine-based therapies following progression on non-steroidal aromatase inhibitor among postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative metastatic breast cancer: a network meta-analysis

Abstract Objective: To quantify the comparative efficacy of currently available endocrine-based therapies (ETs) for postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2−) metastatic breast cancer (mBC) after non-steroidal aromatase inhibitor (NSAI) progression. Design: Network meta-analysis (NMA). Methods: Randomized clinical trials of ETs for HR+/HER2− mBC were identified via a systematic literature review using MEDLINE, Embase, Cochrane Library and key conference proceedings. All trials met the following inclusion criteria: (1) included women with HR+/HER2− mBC; (2) previous treatment with ETs or chemotherapy as first-line therapy; (3) treatment with ET as monotherapy or in combination with targeted therapy; (4) progression-free survival (PFS) was reported; and (5) published in 2007 (when HER2 testing became standardized) or later. Regimens were compared using pairwise hazard ratios (HRs) and 95% credible intervals (CrIs) of PFS obtained from a Bayesian NMA. Treatments with different approved dosages were pooled into the same arm; anastrozole and exemestane were pooled as aromatase inhibitors (AIs) due to clinical similarities. Results: A total of 4 trials and 6 regimens (palbociclib + fulvestrant, everolimus + fulvestrant, everolimus + AI, fulvestrant + AI, fulvestrant and AI) were eligible for inclusion. Palbociclib + fulvestrant and everolimus + AI had 50% and 55% reduced hazard of progression or death vs. AI (95% CrI upper bound ≤1), respectively. Palbociclib + fulvestrant, everolimus + AI and everolimus + fulvestrant had 54%, 58% and 40% reduced hazard vs. fulvestrant (95% CrI upper bound ≤1), while palbociclib + fulvestrant and everolimus + AI had 52% and 55% reduced hazard vs. fulvestrant + AI (95% CrI upper bound ≤1), respectively. Conclusion: Postmenopausal women with HR+/HER2− mBC who had previously failed an NSAI and received palbociclib + fulvestrant, everolimus + AI or everolimus + fulvestrant had longer PFS compared to those who received fulvestrant or AI alone.

Progression-free Survival With First-line Endocrine-based Therapies Among Postmenopausal Women With HR+/HER2– Metastatic Breast Cancer:: A Network Meta-analysis

PURPOSE The comparative efficacy of endocrine-based therapies (ETs) for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) is not well characterized. This network meta-analysis (NMA) synthesized available evidence on progression-free survival (PFS) with first-line ETs for postmenopausal HR+/HER2- mBC. METHODS A systematic literature review identified randomized controlled trials of first-line ETs. Pairwise hazard ratios and 95% credible intervals (CrIs) were obtained via a Bayesian NMA model. Subgroup NMAs were conducted among late progressors (disease-free interval ≥12 months from completion of [neo] adjuvant therapy with letrozole or anastrozole at the time of randomization) and de novo patients, defined as patients whose initial BC diagnosis is mBC. FINDINGS Five trials and 5 regimens (ribociclib + an aromatase inhibitor [AI] [LEE + AI], palbociclib + AI [Pal + AI], fulvestrant 250 mg + AI [Ful250 + AI], fulvestrant 500 mg [Ful500], and AI) were selected. LEE + AI, Pal + AI, Ful250 + AI, and Ful500 had significantly longer PFS versus AI (95% CrI upper-bound ≤1). LEE + AI had a 30% and 29%, and Pal + AI had a 31% and 30%, reduced hazard of progression or death versus Ful250 + AI and Ful500 (95% CrI upper-bound ≤1), respectively. The probability of being the most efficacious was 46% for LEE + AI and 54% for Pal + AI. In subgroup analyses among late progressors, LEE + AI had a 4% reduced hazard of progression or death versus Pal + AI but was not statistically significant. In the de novo analysis, Pal + AI and LEE + AI had a 29% and 40% reduced hazard of progression or death versus Ful500, respectively, but were not statistically significant. In both subgroup analyses, all therapies had significantly longer PFS compared with AI. IMPLICATIONS Pal + AI, LEE + AI, Ful250 + AI, or Ful500 as first-line treatment for HR+/HER2- mBC had longer PFS than AI alone. Given the lack of head-to-head clinical trials comparing the efficacy of recently approved first-line ETs for HR+/HER2- mBC, these results have important clinical implications for the treatment of HR+/HER2- mBC in the first-line setting.

Hospital utilization rates following antipsychotic dose reductions: implications for tardive dyskinesia

BackgroundData are limited on the benefits and risks of dose reduction in managing side effects associated with antipsychotic treatment. As an example, antipsychotic dose reduction has been recommended in the management of tardive dyskinesia (TD), yet the benefits of lowering doses are not well studied. However, stable maintenance treatment is essential to prevent deterioration and relapse in schizophrenia.MethodsA retrospective cohort study was conducted to analyze the healthcare burden of antipsychotic dose reduction in patients with schizophrenia. Medical claims from six US states spanning a six-year period were analyzed for ≥10% or ≥ 30% antipsychotic dose reductions compared with those from patients receiving a stable dose. Outcomes measured were inpatient admissions and emergency room (ER) visits for schizophrenia, all psychiatric disorders, and all causes, and TD claims.ResultsA total of 19,556 patients were identified with ≥10% dose reduction and 15,239 patients with ≥30% dose reduction. Following a ≥ 10% dose reduction, the risk of an all-cause inpatient admission increased (hazard ratio [HR] 1.17; 95% confidence interval [CI] 1.11, 1.23; P < 0.001), and the risk of an all-cause ER visit increased (HR 1.09; 95% CI 1.05, 1.14; P < 0.001) compared with controls. Patients with a ≥ 10% dose reduction had an increased risk of admission or ER visit for schizophrenia (HR 1.27; 95% CI 1.19, 1.36; P < 0.001) and for all psychiatric disorders (HR 1.16; 95% CI 1.10, 1.23; P < 0.001) compared with controls. A dose reduction of ≥30% also led to an increased risk of admission for all causes (HR 1.23; 95% CI 1.17, 1.31; P < 0.001), and for admission or ER visit for schizophrenia (HR 1.31; 95% CI 1.21, 1.41; P < 0.001) or for all psychiatric disorders (HR 1.21; 95% CI 1.14, 1.29; P < 0.001) compared with controls. Dose reductions had no significant effect on claims for TD.ConclusionPatients with antipsychotic dose reductions showed significant increases in both all-cause and mental health–related hospitalizations, suggesting that antipsychotic dose reductions may lead to increased overall healthcare burden in some schizophrenia patients. This highlights the need for alternative strategies for the management of side effects, including TD, in schizophrenia patients that allow for maintaining effective antipsychotic treatment.

I40 Number needed to harm (NNH) analysis of deutetrabenazine (DTB) and tetrabenazine (TBZ) from two pivotal trials: First-HD and Tetra-HD

Background DTB was efficacious and well tolerated in patients with Huntington’s disease (HD) chorea (First-HD). In the absence of a head-to-head trial with TBZ, we compared safety and tolerability outcomes of TBZ versus DTB using an indirect treatment comparison method and an NNH metric. Methods Safety data from First-HD and TETRA-HD were used to calculate the NNH, where serious adverse events (SAEs), discontinuation (all cause- and adverse event [AE]-related), and specific AEs (in > 10% of patients) were defined as undesirable outcomes. The difference between the proportions of undesirable outcomes was estimated by subtracting the applicable placebo-adjusted risk from both studies (TETRA-HD minus First-HD). NNH estimates, defined as the number of patients to be treated with TBZ instead of DTB for an average of one additional patient to experience an AE, were calculated as the inverses of the risk differences. P-values were obtained from z-tests, which approximate normal distribution. Results First-HD (N = 90) and TETRA-HD (N = 84) cohorts were of similar age (53.7 years vs 49.2 years) and gender (proportion of females 44% vs 62%), and baseline chorea scores were 12.7 vs 14.9. TBZ demonstrated a significant NNH vs DTB of 3 (95% CI: 1, 8; P < 0.01) for moderate to severe AEs, meaning that, if three patients were treated with TBZ instead of DTB, then one more patient, on average, would experience a moderate to severe AE. TBZ had a significant (all P ≤ 0.02) NNH vs DTB of 5 (95% CI: 3, 15) for depression, 5 (95% CI: 3, 15) for akathisia, 7 (95% CI: 4, 19) for Parkinsonism, 5 (95% CI: 3, 27) for somnolence, 4 (95% CI: 3, 12) for insomnia, and 8 (95% CI: 4, 46) for agitation. No other AEs analysed were significant. Conclusions In this NNH analysis, DTB demonstrated significantly better outcomes than TBZ on several safety measures. Further analysis adjusting for demographic differences between trials should be conducted to confirm these findings.