Effects of tolvaptan discontinuation in patients with autosomal dominant polycystic kidney disease: a post hoc pooled analysis.

BACKGROUND: Tolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) who are at risk of rapid progression. Given that treatment requires commitment to long-term use, we evaluated the effects of tolvaptan discontinuation on the trajectory of ADPKD progression. METHODS: This was a post hoc analysis of pooled data from two clinical trials of tolvaptan (TEMPO 2:4 [NCT00413777] and TEMPO 3:4 [NCT00428948]), an extension trial (TEMPO 4:4 [NCT01214421]), and an observational study (OVERTURE [NCT01430494]) that enrolled patients from the other trials. Individual subject data were linked longitudinally across trials to construct analysis cohorts of subjects with a tolvaptan treatment duration > 180 days followed by an off-treatment observation period of > 180 days. For inclusion in Cohort 1, subjects were required have ≥ 2 outcome assessments during the tolvaptan treatment period and ≥ 2 assessments during the follow-up period. For Cohort 2, subjects were required to have ≥ 1 assessment during the tolvaptan treatment period and ≥ 1 assessment during the follow-up period. Outcomes were rates of change in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV). Piecewise-mixed models compared changes in eGFR or TKV in the on-treatment and post-treatment periods. RESULTS: In the Cohort 1 eGFR population (n = 20), the annual rate of eGFR change (in mL/min/1.73 m2) was -3.18 on treatment and -4.33 post-treatment, a difference that was not significant (P = 0.16), whereas in Cohort 2 (n = 82), the difference between on treatment (-1.89) and post-treatment (-4.94) was significant (P < 0.001). In the Cohort 1 TKV population (n = 11), TKV increased annually by 5.18% on treatment and 11.69% post-treatment (P = 0.06). In Cohort 2 (n = 88), the annual TKV growth rates were 5.15% on treatment and 8.16% post-treatment (P = 0.001). CONCLUSIONS: Although limited by small sample sizes, these analyses showed directionally consistent acceleration in measures of ADPKD progression following the discontinuation of tolvaptan.

Tolvaptan and Kidney Function Decline in Older Individuals With Autosomal Dominant Polycystic Kidney Disease: A Pooled Analysis of Randomized Clinical Trials and Observational Studies.

Rationale & Objective: Tolvaptan is indicated for treatment of patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. Participants aged 56-65 years constituted a small proportion of the Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trial population. We assessed effects of tolvaptan on estimated glomerular filtration rate (eGFR) decline in participants aged >55 years. Study Design: This was a pooled data analysis from 8 studies of tolvaptan or non-tolvaptan standard of care (SOC). Setting & Participants: Participants aged >55 years with ADPKD were included. Data on participants in >1 study were linked longitudinally for maximum follow-up duration, with matching for age, sex, eGFR, and chronic kidney disease (CKD) stage to minimize confounding. Interventions: Tolvaptan or non-tolvaptan SOC. Outcomes: Treatment effects on annualized eGFR decline were compared using mixed models with fixed effects for treatment, time, treatment-by-time interaction, and baseline eGFR. Results: In the pooled studies, 230 tolvaptan-treated and 907 SOC participants were aged >55 years at baseline. Ninety-five participant pairs from each treatment group were matched, all in CKD G3 or G4, ranging from 56.0 to 65.0 years (tolvaptan) or from 55.1 to 67.0 years (SOC). The eGFR annual decline rate was significantly reduced by 1.66 mL/min/1.73 m2 (95% CI, 0.43-2.90; P = 0.009) in the tolvaptan group compared with SOC (-2.33 versus -3.99 mL/min/1.73 m2) over 3 years. Limitations: Limitations include potential bias because of study population differences (bias risk was reduced through matching and multiple regression adjustment); vascular disease history data was not uniformly collected, and therefore not adjusted; and natural history of ADPKD precludes evaluating certain clinical endpoints within the study time frame. Conclusions: In individuals aged 56-65 years with CKD G3 or G4, compared to a SOC group with mean GFR rate of decline ≥3 mL/min/1.73 m2/year, tolvaptan was associated with efficacy similar to that observed in the overall indication. Funding: Otsuka Pharmaceutical Development & Commercialization, Inc (Rockville, MD). Trial Registration: TEMPO 2:4 (NCT00413777); phase 1 tolvaptan trial (no NCT number; trial number 156-06-260); phase 2 tolvaptan trial (NCT01336972); TEMPO 4:4 (NCT01214421); REPRISE (NCT02160145); long-term tolvaptan safety extension trial (NCT02251275); OVERTURE (NCT01430494); HALT Progression of Polycystic Kidney Disease (HALT-PKD) study B (NCT01885559).

Lipid lowering therapy patterns and the risk of cardiovascular events in the 1-year after acute myocardial infarction in United Arab Emirates.

AIM: In United Arab Emirates, cardiovascular disease (CVD) is a leading cause of mortality and 22% of CVD deaths are attributable to acute myocardial infarction (MI). Adherence to guidelines for lipid management is incompletely described in the Middle East. This study aimed to characterize lipid lowering therapy (LLT) patterns and the risk of subsequent cardiovascular events (CVEs) in the first year after MI. METHODS: This was a retrospective cohort study using the Dubai Real-World Claims Database, including all patients discharged with MI between January 01, 2015 and December 31, 2018, followed-up until December 31, 2019. RESULTS: In the first year after MI, 8.42% of 4,595 patients included experienced at least one recurrent MI (rate 6.77 events/100 person-years [PYs]), 2.94% had one revascularization (cumulative rate 0.55 events/100 PYs) and 2.66% had one hospitalization due to unstable angina (cumulative rate 5.16 new events/100 PYs). The majority (60.40%) of the patients presented with LDL-C levels ≥ 70 mg/dL after MI. In the first year after MI, 93.45% of the patients received LLT, mainly high-intensity statin (67.79%); with a minority of patients receiving statin + ezetimibe (4.55%), PCSK9i (0.20%) or ezetimibe alone (0.07%). CONCLUSION: Patients hospitalized with MI in Dubai present an increased risk of CVEs in their first-year post-discharge. Majority of the patients presented with LDL-C levels above 70 mg/dL, which indicates suboptimal lipid control with existing LLT, particularly in high-risk patients.

Incidence of corneal adverse events in patients with multiple myeloma and their clinical and economic impact: A real-world retrospective cohort study.

AIMS: Ocular toxicities are common adverse events (AEs) associated with anticancer agents. There is a paucity of data documenting their impact on patient care. This study assessed the clinical and economic burden of corneal AEs and related symptoms (collectively termed corneal AEs) in patients receiving multiple myeloma (MM) treatment. MATERIALS AND METHODS: Adults with a newly diagnosed MM (MM cohort) were identified from PharMetrics Plus, a US insurance claims database. Incidence, outpatient (OP) care, emergency department (ED) visits, hospitalizations, and costs were assessed for corneal AEs of interest: keratopathy/keratitis, blurred vision/decreased acuity, dry eye, eye pain, and photophobia. Incidence of new corneal AEs, healthcare resource utilization (HCRU), corneal AE-related HCRU, and costs were assessed and benchmarked against a hematology cohort of patients. RESULTS: The MM cohort included 2,120 patients with a median follow-up of 734.5 days. Overall, 11.7% of patients in the MM cohort and 7.4% in the hematology cohort had ≥1 corneal AE of interest. In the MM cohort, dry eye (6.1%), blurred vision/decreased acuity (3.4%), and keratopathy/keratitis (2.5%) were the most frequent. The overall median corneal AE-related per-patient-per-month (PPPM) cost was $27, predominantly contributed by OP care (median $19 PPPM). During follow-up, 4.8% of patients visited the ED, 3.6% were hospitalized, and 42.5% of patients visited an ophthalmologist/optometrist (∼1.69 visits/year). Costs of these visits were negligible (median PPPM $19) compared to total all-cause costs (median PPPM $17,286). LIMITATIONS: The results can only be generalized to commercially insured and Medicare Advantage patients. Claims-based diagnosis of corneal AEs may underestimate true incidences. CONCLUSIONS: Corneal AEs were observed in ∼12% of patients in the MM cohort, the most common were keratopathy/keratitis, dry eye, and blurred vision. Most of them required only OP care. The clinical and economic burden for treating corneal AEs was low when compared with total all-cause or MM-related PPPM costs.

Patient characteristics and acute cardiovascular event rates among patients with very high-risk and non-very high-risk atherosclerotic cardiovascular disease.

BACKGROUND: The risk for subsequent major cardiovascular (CV) events among patients with very high-risk (VHR) atherosclerotic CV disease (ASCVD) remains to be fully elucidated. HYPOTHESIS: We assessed the characteristics and major CV event rates of patients with VHR versus non-VHR ASCVD in a real-world setting in the United States (US), hypothesizing that patients with VHR ASCVD would have higher CV event rates. METHODS: This was a retrospective cohort study conducted from January 01, 2011, to June 30, 2018, in the US using the Prognos LDL-C database linked to the IQVIA PharMetrics Plus® database supplemented with the IQVIA prescription claims (Dx/LRx) databases. Patients were ≥18 years old and had ≥2 non-ancillary medical claims in the linked databases at least 30 days apart. The study was conducted in 2 stages: (1) identification of patients with ASCVD who met the definition of VHR ASCVD and a matched cohort of non-VHR ASCVD patients using the incidence density sampling (IDS) approach; (2) estimation of the occurrence of major CV events. RESULTS: Among patients with ≥1 major ASCVD event (N=147,679), most qualified as VHR ASCVD (79.5%). There were 115,460 patients each in IDS-matched VHR and non-VHR ASCVD cohorts. The composite myocardial infarction/ischemic stroke event rates in the VHR and non-VHR ASCVD cohorts were 8.04 (95% confidence interval [95% CI]: 7.87-8.22) and 0.82 (95% CI: 0.77-0.88) events per 100 patient-years, respectively, during the 1-year post-index period. CONCLUSIONS: Most patients with ≥1 previous major ASCVD event treated in real-world US clinical practice qualified as VHR ASCVD. Patients with VHR ASCVD had much higher rates of major CV events versus non-VHR ASCVD patients.

Impact of Lurasidone and Other Antipsychotics on Body Weight: Real-World, Retrospective, Comparative Study of 15,323 Adults with Schizophrenia.

PURPOSE: The primary objectives were to describe weight changes following initiation of lurasidone versus other antipsychotics and estimate the risk of clinically relevant (≥7%) weight changes. PATIENTS AND METHODS: This retrospective, longitudinal comparative cohort study was based on electronic medical records (EMRs) of United States (US) adult patients with schizophrenia who were prescribed lurasidone or other antipsychotics as monotherapy between 1 April 2013 and 30 June 2019. RESULTS: Overall, the study included 15,323 patients with a diagnosis of schizophrenia; 6.1% of patients received lurasidone, 60.4% received antipsychotics associated with a medium-high risk of weight gain (clozapine, olanzapine, quetiapine, risperidone, paliperidone) and 33.5% received antipsychotics with a low risk of weight gain (aripiprazole, first-generation antipsychotics, ziprasidone). Lurasidone was associated with the smallest proportion of patients experiencing clinically relevant weight gain and the greatest proportion of patients with clinically relevant weight loss. The risk of clinically relevant weight gain was numerically higher with all antipsychotics versus lurasidone and was statistically significant for olanzapine (hazard ratio [HR]=1.541; 95% confidence interval [CI]=1.121; 2.119; p=0.0078) versus lurasidone. The likelihood of ≥7% weight loss was significantly greater with lurasidone versus all antipsychotics (p<0.05), except ziprasidone. CONCLUSION: This real-world study suggests that lurasidone has a lower risk of clinically relevant weight gain and a higher likelihood of clinically relevant weight loss than other commonly used antipsychotics.

Geographic variations in lipid-lowering therapy utilization, LDL-C levels, and proportion retrospectively meeting the ACC/AHA very high-risk criteria in a real-world population of patients with major atherosclerotic cardiovascular disease events in the United States.

OBJECTIVE: We assessed national- and state-level geographic variations among patients with a history of ≥1 major atherosclerotic cardiovascular disease (ASCVD) event in: (1) the proportion of patients with retrospectively identified 2018 American College of Cardiology/American Heart Association guideline very high-risk (VHR) ASCVD criteria; (2) utilization of guideline-directed lipid-lowering therapy (LLT); and (3) the proportion of patients with persistent low-density lipoprotein cholesterol (LDL-C) elevations despite statin and/or ezetimibe use. METHODS: A retrospective cohort study using the Prognos LDL-C database linked to IQVIA longitudinal medical and prescription claims databases. The study period was from January 01, 2011, to November 30, 2019 and the index period was from January 01, 2016, to November 30, 2019; the index date was defined as the most recent LDL-C test during the index period. The study included patients aged ≥18 years at index who had a measured LDL-C level during the index period and had ≥1 inpatient/outpatient claim for ASCVD during the 5-year pre-index period. RESULTS: Of patients with any ASCVD (N=4652,468), 1537,514 (33.1%) patients had ≥1 major ASCVD event. Among patients with ≥1 major ASCVD event, the VHR ASCVD criteria were retrospectively identified in 1139,018 (74.1%) patients; Hawaii had the highest (81.7%) and Colorado the lowest (65.0%) proportion of these patients. Nationally, 48.8% and 50.2% of patients with ≥1 major ASCVD event and retrospectively identified VHR ASCVD criteria, respectively, had current LLT use; Massachusetts and Colorado had the highest and lowest proportions, respectively. After standardizing for age and sex, 57.3% and 58.8% of patients with ≥1 major ASCVD event and retrospectively identified VHR ASCVD criteria, respectively, had LDL-C ≥70 mg/dL (≥1.8 mmol/L) despite statin and/or ezetimibe use, with substantial state-level variations observed. CONCLUSIONS: The study highlights high rates of elevated LDL-C and pervasive underuse of LLT in health-insured patients with a history of major ASCVD events treated in the United States, with state-level geographic variations observed.

Low-density lipoprotein cholesterol lowering in real-world patients treated with evolocumab.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is a risk factor for atherosclerotic cardiovascular disease (ASCVD). There are limited real-world data on LDL-C lowering with evolocumab in United States clinical practice. HYPOTHESIS: We assessed LDL-C lowering during 1 year of evolocumab therapy. METHODS: This retrospective cohort study used linked laboratory (Prognos) and medical claims (IQVIA Dx/LRx and PharMetrics Plus® ) data. Patients with a first fill for evolocumab between 7/1/2015 and 10/31/2019 (index event) and LDL-C ≥ 70 mg/dL were included (overall cohort; N = 5897). Additionally, a patient subgroup with a recent myocardial infarction (MI) within 12 months (median 130 days) before the first evolocumab fill was identified (N = 152). Reduction from baseline LDL-C was calculated based on the lowest LDL-C value recorded during a 12-month follow-up period. RESULTS: The mean (SD) age was 65 (10) years; 61.9% of patients had ASCVD diagnoses and 70.7% of patients were in receipt of lipid-lowering therapy. Following evolocumab treatment, changes in LDL-C from baseline were -60% in the overall cohort (median [interquartile range (IQR)] 146 [115-180] mg/dL to 58 [36-84] mg/dL) and -65% in the recent MI subgroup (median [IQR] 137 [109-165] mg/dL to 48 [30-78] mg/dL). In the overall cohort and recent MI subgroup, 62.1% and 69.7% of patients achieved LDL-C < 70 mg/dL, respectively. CONCLUSIONS: In this real-world analysis, evolocumab was associated with significant reductions in LDL-C comparable to that seen in the FOURIER clinical trial, which were durable over 1 year of treatment.

Demographic And Clinical Characteristics Of Patients Prescribed Proprotein Convertase Subtilisin/kexin Type 9 Inhibitor Therapy And Patients Whose Current Lipid-Lowering Therapy Was Modified.

PURPOSE: Our objective was to describe the demographic and clinical characteristics of real-world patients in the US with elevated low-density lipoprotein cholesterol (LDL-C) whose lipid-lowering therapy (LLT) ─ both proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor and non-PCSK9 inhibitor ─ was actively modified. METHODS: This retrospective cohort study used linked laboratory (Prognos), pharmacy (IMS Formulary Impact Analyzer), and medical claims (IQVIA Dx/LRx or PharMetrics Plus) data. PCSK9 inhibitor-prescribed patients with LDL-C ≥70 mg/dL (multiply by 0.02586 for mmol/L) at the time of prescription were matched by LDL-C test date to patients whose non-PCSK9 inhibitor therapy was modified by intensifying statin therapy, switching statins without intensification, or augmenting with ezetimibe (N=12,345 in each cohort). Baseline demographics, use of LLT, LDL-C values, atherosclerotic cardiovascular disease (ASCVD) diagnoses and cardiovascular comorbidities, and occurrence of major adverse cardiovascular events (MACE) were assessed during the 2-year pre-index period. RESULTS: Mean age was 66.2 years in the PCSK9 inhibitor cohort and 64.1 years in the cohort whose LLT regimen was otherwise modified. Respectively, mean baseline LDL-C values were 150 and 121 mg/dL; 60.3% and 39.0% of patients had ASCVD diagnoses, and 9.6% and 5.1% had experienced a recent MACE. Prevalence of ASCVD diagnoses in the PCSK9 inhibitor and modified non-PCSK9 inhibitor cohorts, respectively, was 15.5% vs 9.1% for acute coronary syndrome, 20.7% vs 8.7% for coronary revascularization, and 22.2% vs 5.1% for possible familial hypercholesterolemia. In addition, 19.8% of patients in the PCSK9 inhibitor cohort were receiving both statins and ezetimibe vs 5.0% in the modified LLT cohort. CONCLUSION: Physicians are prescribing PCSK9 inhibitor therapy to patients with markedly elevated LDL-C levels who also have comorbid risk factors for adverse cardiovascular events. These results may be of interest to payers and policymakers involved in devising access strategies for PCSK9 inhibitors.

Obesity Among High School Students in the United States: Risk Factors and Their Population Attributable Fraction.

INTRODUCTION: The prevalence of obesity among children and adolescents in the United States is high. The aim of this study was to assess the association between modifiable risk factors and obesity and to estimate the population attributable fractions (PAFs) of modifiable risk factors among high school students in the United States. METHODS: For this retrospective study, we used a nationally representative sample of 15,624 students who participated in the 2015 Youth Risk Behavior Survey (YRBS). Obesity was defined as body mass index at or above the 95th percentile, based on sex- and age-specific data from the Centers for Disease Control and Prevention. We examined unhealthy dietary behaviors, physical inactivity, and other modifiable risk factors (tobacco use, alcohol consumption, and sleep). We used multivariable logistic regression, accounting for the complex survey design of YRBS, to assess the association between risk factors and obesity and to calculate PAFs. Confidence intervals of PAFs were estimated by using the jackknife repeated replication method. RESULTS: Among all students included in the study, 13.9% were classified as obese. Not being on a sports team (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.31-1.98), current tobacco use (OR, 1.42; 95% CI, 1.14-1.77), and watching television for 3 hours or more per day (OR, 1.38; 95% CI, 1.09-1.76) were significantly correlated with obesity. The combined PAF for all modifiable risk factors was 34.80% (95% CI, 32.09%-37.51%). The single modifiable risk factor with the largest PAF was not participating on a sports team (PAF, 16.57%; 95% CI, 15.30%-17.84%). CONCLUSION: Findings about PAFs help demonstrate the importance of promoting physical activity, healthy diet, and other healthy lifestyles in reducing obesity among high school students in the United States.

Confirming the timing of phase-based costing in oncology studies: a case example in advanced melanoma.

AIMS: The utilization of healthcare services and costs among patients with cancer is often estimated by the phase of care: initial, interim, or terminal. Although their durations are often set arbitrarily, we sought to establish data-driven phases of care using joinpoint regression in an advanced melanoma population as a case example. METHODS: A retrospective claims database study was conducted to assess the costs of advanced melanoma from distant metastasis diagnosis to death during January 2010-September 2014. Joinpoint regression analysis was applied to identify the best-fitting points, where statistically significant changes in the trend of average monthly costs occurred. To identify the initial phase, average monthly costs were modeled from metastasis diagnosis to death; and were modeled backward from death to metastasis diagnosis for the terminal phase. Points of monthly cost trend inflection denoted ending and starting points. The months between represented the interim phase. RESULTS: A total of 1,671 patients with advanced melanoma who died met the eligibility criteria. Initial phase was identified as the 5-month period starting with diagnosis of metastasis, after which there was a sharp, significant decline in monthly cost trend (monthly percent change [MPC] = -13.0%; 95% CI = -16.9% to -8.8%). Terminal phase was defined as the 5-month period before death (MPC = -14.0%; 95% CI = -17.6% to -10.2%). LIMITATIONS: The claims-based algorithm may under-estimate patients due to misclassifications, and may over-estimate terminal phase costs because hospital and emergency visits were used as a death proxy. Also, recently approved therapies were not included, which may under-estimate advanced melanoma costs. CONCLUSIONS: In this advanced melanoma population, optimal duration of the initial and terminal phases of care was 5 months immediately after diagnosis of metastasis and before death, respectively. Joinpoint regression can be used to provide data-supported phase of cancer care durations, but should be combined with clinical judgement.