Comprehensive Comparative Effectiveness and Safety of First-Line β-Blocker Monotherapy in Hypertensive Patients: A Large-Scale Multicenter Observational Study.
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ABSTRACT:
SUBMITTER: Chan You S
PROVIDER: S-EPMC8035236 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
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Comprehensive Comparative Effectiveness and Safety of First-Line β-Blocker Monotherapy in Hypertensive Patients: A Large-Scale Multicenter Observational Study.
Chan You Seng S Krumholz Harlan M HM Suchard Marc A MA Schuemie Martijn J MJ Hripcsak George G Chen RuiJun R Shea Steven S Duke Jon J Pratt Nicole N Reich Christian G CG Madigan David D Ryan Patrick B PB Woong Park Rae R Park Sungha S
Hypertension (Dallas, Tex. : 1979) 20210329 5
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Project description:BACKGROUND:Uncertainty remains about the optimal monotherapy for hypertension, with current guidelines recommending any primary agent among the first-line drug classes thiazide or thiazide-like diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers, and non-dihydropyridine calcium channel blockers, in the absence of comorbid indications. Randomised trials have not further refined this choice. METHODS:We developed a comprehensive framework for real-world evidence that enables comparative effectiveness and safety evaluation across many drugs and outcomes from observational data encompassing millions of patients, while minimising inherent bias. Using this framework, we did a systematic, large-scale study under a new-user cohort design to estimate the relative risks of three primary (acute myocardial infarction, hospitalisation for heart failure, and stroke) and six secondary effectiveness and 46 safety outcomes comparing all first-line classes across a global network of six administrative claims and three electronic health record databases. The framework addressed residual confounding, publication bias, and p-hacking using large-scale propensity adjustment, a large set of control outcomes, and full disclosure of hypotheses tested. FINDINGS:Using 4·9 million patients, we generated 22 000 calibrated, propensity-score-adjusted hazard ratios (HRs) comparing all classes and outcomes across databases. Most estimates revealed no effectiveness differences between classes; however, thiazide or thiazide-like diuretics showed better primary effectiveness than angiotensin-converting enzyme inhibitors: acute myocardial infarction (HR 0·84, 95% CI 0·75-0·95), hospitalisation for heart failure (0·83, 0·74-0·95), and stroke (0·83, 0·74-0·95) risk while on initial treatment. Safety profiles also favoured thiazide or thiazide-like diuretics over angiotensin-converting enzyme inhibitors. The non-dihydropyridine calcium channel blockers were significantly inferior to the other four classes. INTERPRETATION:This comprehensive framework introduces a new way of doing observational health-care science at scale. The approach supports equivalence between drug classes for initiating monotherapy for hypertension-in keeping with current guidelines, with the exception of thiazide or thiazide-like diuretics superiority to angiotensin-converting enzyme inhibitors and the inferiority of non-dihydropyridine calcium channel blockers. FUNDING:US National Science Foundation, US National Institutes of Health, Janssen Research & Development, IQVIA, South Korean Ministry of Health & Welfare, Australian National Health and Medical Research Council.
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Project description:Lessons learnedFor patients with advanced hepatocellular carcinoma after failure of first-line sorafenib monotherapy, second-line axitinib provides modest efficacy with tolerable toxicity. The discrepant tumor responses and survival outcomes in trials using axitinib as salvage therapy highlight the importance of optimal patient selection with the aid of clinical biomarkers.BackgroundMultikinase inhibitors have been effective treatment for hepatocellular carcinoma (HCC). This multicenter phase II study explored the efficacy and safety of second-line axitinib for advanced HCC.MethodsPatients with advanced HCC and Child-Pugh A liver function, experiencing progression on first-line sorafenib monotherapy, were eligible. Axitinib 5 mg twice daily was given continuously with allowed dose escalation. Tumor assessment was performed according to RECIST version 1.1. The primary endpoint was rate of disease control.ResultsFrom April 2011 to March 2016, 45 patients were enrolled. Thirty-seven patients (82%) tested positive for hepatitis B surface antigen. The disease control rate was 62.2%, and the response rate was 6.7%, according to RECIST criteria. Median progression-free survival (PFS) and overall survival (OS) were 2.2 months and 10.1 months, respectively. Treatment-related adverse events were compatible with previous reports of axitinib.ConclusionSecond-line axitinib has moderate activity and acceptable toxicity for patients with advanced HCC after failing the first-line sorafenib monotherapy.
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Project description:The efficacy and safety of olmesartan medoxomil (OM) vs active control (AC) monotherapy among elderly patients aged 60-79 years (N = 4487) was evaluated by meta-analysis (25 studies). In all patients, change from baseline to end point in blood pressure (BP) was significantly greater with OM vs AC (-19.5/-11.9 vs -16.8/-10.7 mm Hg). Greater proportions of OM- vs AC-treated patients achieved BP goals. In patients with impaired renal function (estimated glomerular filtration rate <60 mL/min/1.73 m2 ), OM treatment resulted in a greater mean change from baseline in systolic BP vs AC (-21.2 vs -18.7 mm Hg, respectively) and a greater proportion of patients achieving BP goals. These parameters were similar in both groups for elderly patients with diabetes. OM was well tolerated with few adverse events. OM monotherapy can be used as an initial treatment for hypertension in elderly patients, including those with renal impairment or diabetes.
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Project description:BackgroundCombining an antiangiogenic agent with an anti-PD-1 agent is a promising strategy for unresectable hepatocellular carcinoma (HCC).AimsTo explore the effectiveness and tolerability of lenvatinib plus camrelizumab vs. lenvatinib monotherapy as a first-line treatment for unresectable HCC.MethodsThis multicenter, retrospective cohort study included patients with unresectable HCC treated with oral lenvatinib 8 mg daily and intravenous camrelizumab 200 mg every 3 weeks (L+C group) or lenvatinib 12 mg or 8 mg daily (L group) in four Chinese centers between September 2018 and February 2020. Tumor response was evaluated according to RECIST 1.1 and mRECIST. The outcomes included objective response rate (ORR), overall survival (OS), 1-year OS rate, progression-free survival (PFS), and safety.ResultsBy March 31, 2021, 92 patients were finally included, with 48 and 44 in the L+C and L groups, respectively. ORR was significantly higher in the L+C group than in the L group (RECIST 1.1: 37.5% vs. 13.6%, P=0.009; mRECIST: 41.7% vs. 20.5%, P=0.029). Median OS and 95% confidence interval (CI) was 13.9 (13.3-18.3) months in the L group and not reached in the L+C group (P=0.015). The 1-year survival rate was 79.2% and 56.8% in the L+C and L groups, respectively. Median PFS was 10.3 (6.6-14.0) months and 7.5 (5.7-9.3) months in the L+C and L groups, respectively (P=0.0098). Combined therapy vs. monotherapy was independently associated with a prolonged OS (hazard ratio=0.380, 95% CI=: 0.196-0.739, P=0.004) and a prolonged PFS (hazard ratio=0.454, 95%CI=0.282-0.731, P=0.001). The safety profile was comparable between the two groups. The most common adverse event in the L+C and L groups was loss of appetite (41.7% vs. 40.9%, P=0.941). Three patients in the L+C group and two in the L group terminated treatment owing to adverse events.ConclusionFirst-line lenvatinib plus camrelizumab showed better effectiveness than lenvatinib alone in patients with unresectable HCC.
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Project description:For secondary prevention of coronary artery disease (CAD) antiplatelet therapy is essential. For patients undergoing a percutaneous coronary intervention (PCI) temporary dual antiplatelet platelet therapy (DAPT: aspirin combined with a P2Y12 blocker) is mandatory, but leads to more bleeding than single antiplatelet therapy with aspirin. Therefore, to reduce bleeding after a PCI the duration of DAPT is usually kept as short as clinically acceptable; thereafter aspirin monotherapy is administered. Another option to reduce bleeding is to discontinue aspirin at the time of DAPT cessation and thereafter to administer P2Y12 blocker monotherapy. To date, five randomised trials have been published comparing DAPT with P2Y12 blocker monotherapy in 32,181 stented patients. Also two meta-analyses addressing this novel therapy have been presented. P2Y12 blocker monotherapy showed a 50-60% reduction in major bleeding when compared to DAPT without a significant increase in ischaemic outcomes, including stent thrombosis. This survey reviews the findings in the current literature concerning P2Y12 blocker monotherapy after PCI.
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Project description:The approval of new immunotherapies has dramatically changed the treatment landscape of metastatic melanoma. These survival gains come with trade-offs in side effects and costs, as well as important considerations for third-party payer systems, physicians, and patients.To develop a Markov model to determine the cost-effectiveness of nivolumab, ipilimumab, and nivolumab-ipilimumab combination as firstline therapy in metastatic melanoma, while accounting for differential effectiveness in programmed death-ligand 1 (PD-L1) positive and negative patients.A 3-state Markov model (PD-L1 positive stable disease, PD-L1 negative stable disease, and progression and/or death) was developed using a U.S. societal perspective with a lifetime time horizon of 14.5 years. Transition probabilities were calculated from progression-free (PF) survival data reported in the CheckMate-067 trial. Costs were expressed in 2015 U.S. dollars and were determined using national sources. Adverse event (AE) management was determined using immune-related AE (irAE) data from CheckMate-067, irAE management guides for nivolumab and ipilimumab, and treatment guidelines. Utilities were obtained from published literature, using melanoma-specific studies when available, and were weighted based on incidence and duration of irAEs. Base case, one-way sensitivity, and probabilistic sensitivity analyses were conducted.Nivolumab-ipilimumab combination therapy was not the cost-effective choice ($454,092 per PF quality-adjusted life-year [QALY]) compared with nivolumab monotherapy in a base case analysis at a willingness-to-pay threshold of $100,000 per PFQALY. Combination therapy and nivolumab monotherapy were cost-effective choices compared with ipilimumab monotherapy. PD-L1 positive status, utility of nivolumab and combination therapy, and medication costs contributed the most uncertainty to the model. In a population of 100% PD-L1 negative patients, nivolumab was still the optimal treatment, but combination therapy had an improved incremental cost-effectiveness ratio (ICER) of $295,903 per PFQALY. Combination therapy became dominated by nivolumab, when 68% of the sample was PD-L1 positive. In addition, the cost of ipilimumab would have to decrease to < $21,555 per dose for combination therapy to have an ICER < $100,000 per PFQALY and to < $19,151 (a 42% reduction) to be more cost-effective than nivolumab monotherapy.Nivolumab-ipilimumab combination therapy was not cost-effective compared with nivolumab monotherapy, which was the most cost-effective option. Professionals in managed care settings should consider the pharmacoeconomic implications of these new immunotherapies as they make value-based formulary decisions, and future cost-effectiveness studies are completed.No funding supported this study. Merino was a contractor with EMD Serono at the time of this study but does not have any conflicts of interest and did not receive any funding related to this study. All other authors have no financial disclosures and no conflicts of interest. All the authors contributed to the study concept and design. Tran, McDowell, and Barcelon took the lead in data collection, along with Oh, Keyvani, and Merino. All authors except Merino contributed to data interpretation. The manuscript was written by Oh, Tran, McDowell, and Wilson and revised by Oh, Tran, McDowell, Wilson, and Keyvani. This analysis was presented at Academy of Managed Care Pharmacy Managed Care & Specialty Pharmacy Annual Meeting 2016, April 19-22, 2016, in San Francisco, California, and at the International Society for Pharmacoeconomics and Outcomes Research Annual International Meeting, May 21-25, 2016, in Washington DC.
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Project description:ObjectivesConventional synthetic DMARDs (csDMARDs) are the first-line treatment for PsA, but there is conflicting data regarding their efficacy and scarce reports describing the duration of use (drug retention) of csDMARD in this population. Their position in treatment recommendations is a matter of growing debate due to the availability of alternative treatment options with higher levels of evidence. We aimed to study drug retention and predictors for drug retention among PsA patients receiving first-line csDMARD monotherapy.MethodsRetrospective cohort study in DMARD-naïve adult PsA patients in whom a first csDMARD was prescribed as monotherapy primarily to treat PsA-related symptoms. The main outcome was time to failure of the csDMARD (i.e. stopping the csDMARD or adding another DMARD).ResultsA total of 187 patients were included, who were mainly prescribed MTX (n = 163) or SSZ (n = 21). The pooled median drug retention time was 31.8 months (interquartile range 9.04-110). Drug retention was significantly higher in MTX (median 34.5 months; interquartile range 9.60-123) as compared with SSZ-treated patients (median 12.0 months; interquartile range 4.80- 55.7) (P =0.016, log-rank test). In multivariable Cox regression, the use of MTX and older age were associated with increased retention. The main reasons for treatment failure were inefficacy (52%) and side effects (28%). Upon failure, MTX treated patients were more commonly, subsequently treated with a biologic DMARD compared with SSZ (P < 0.05).ConclusionMTX outperforms SSZ as a first-line csDMARD in DMARD-naïve PsA patients with respect to monotherapy drug retention in daily clinical practice.
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Project description:PurposeNivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has demonstrated improved survival over docetaxel in previously treated advanced non-small-cell lung cancer (NSCLC). First-line monotherapy with nivolumab for advanced NSCLC was evaluated in the phase I, multicohort, Checkmate 012 trial.MethodsFifty-two patients received nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity; postprogression treatment was permitted per protocol. The primary objective was to assess safety; secondary objectives included objective response rate (ORR) and 24-week progression-free survival (PFS) rate; overall survival (OS) was an exploratory end point.ResultsAny-grade treatment-related adverse events (AEs) occurred in 71% of patients, most commonly: fatigue (29%), rash (19%), nausea (14%), diarrhea (12%), pruritus (12%), and arthralgia (10%). Ten patients (19%) reported grade 3 to 4 treatment-related AEs; grade 3 rash was the only grade 3 to 4 event occurring in more than one patient (n = 2; 4%). Six patients (12%) discontinued because of a treatment-related AE. The confirmed ORR was 23% (12 of 52), including four ongoing complete responses. Nine of 12 responses (75%) occurred by first tumor assessment (week 11); eight (67%) were ongoing (range, 5.3+ to 25.8+ months) at the time of data lock. ORR was 28% (nine of 32) in patients with any degree of tumor PD-ligand 1 expression and 14% (two of 14) in patients with no PD-ligand 1 expression. Median PFS was 3.6 months, and the 24-week PFS rate was 41% (95% CI, 27 to 54). Median OS was 19.4 months, and the 1-year and 18-month OS rates were 73% (95% CI, 59 to 83) and 57% (95% CI, 42 to 70), respectively.ConclusionFirst-line nivolumab monotherapy demonstrated a tolerable safety profile and durable responses in first-line advanced NSCLC.
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Project description:IntroductionThe efficacy and safety of atezolizumab in previously treated patients with NSCLC have been established in the registrational phase 3 OAK trial. In this study, we evaluated the effectiveness and safety of atezolizumab monotherapy in a large real-world cohort to confirm the reproducibility of the results of the registrational trial.MethodsThis was a multicenter, prospective, single-arm observational study. Consecutive patients with previously treated NSCLC scheduled to receive atezolizumab monotherapy were enrolled. The primary end point was the 18-month overall survival (OS) rate. The incidence of adverse events (AEs) and immune-related AEs was evaluated.ResultsOverall, 1002 patients were included in the safety analysis set and 1000 in the full analysis set. Median follow-up was 11.5 months. Of the full analysis set, 62% were ineligible for the OAK trial (OAK-unlike subpopulation). The 18-month OS rate was 41.1%, with a median OS of 13.0 months (95% confidence interval: 12.2-15.1). The 18-month OS rate was 49.4% and 36.1% in OAK-like and OAK-unlike subpopulations, respectively; that in patients with Eastern Cooperative Oncology Group performance status greater than or equal to 2 was 14.3%. The incidence of AEs overall, in the OAK-like, and OAK-unlike subpopulations was 43.9%, 46.2%, and 42.5%; that of immune-related AEs was 19.0%, 20.1%, and 18.3%, respectively.ConclusionsThe findings suggest that atezolizumab may be effective and safe for previously treated patients with NSCLC in real-world settings; however, atezolizumab administration should be considered carefully regarding the benefit-risk balance for the OAK-unlike subpopulation, especially in patients with Eastern Cooperative Oncology Group performance status greater than or equal to 2.
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Project description:BackgroundPembrolizumab monotherapy significantly extends progression-free and overall survival compared to platinum-based chemotherapy for advanced non-small cell lung cancer (NSCLC), but also has a significant impact on medical costs.AimTo clarify the health economic evidence for selecting the first-line treatment for patients with stage IV advanced NSCLC with a programmed cell death ligand 1 tumor proportion score of 50% or greater in Japan, we assessed the cost-effectiveness of pembrolizumab monotherapy compared with that of platinum-based chemotherapy.MethodUsing a Markov model, the study simulated three health states for patients, based on clinical data and utility values from KEYNOTE-024. Transition probabilities were estimated exponentially. Direct medical costs were calculated according to the 2022 National Health Insurance Medical Fee Points and Drug Price Standards. The outcomes measured included life years, quality-adjusted life years, and incremental cost-effectiveness ratio, with sensitivity analysis performed to evaluate the effect of uncertainties.ResultsPembrolizumab led to an additional 1.58 life years and 1.23 quality-adjusted life years at an additional cost of 7,009,888 Japanese yen (48,448 U.S. dollars [USD]), resulting in incremental cost-effectiveness ratio of 4,436,638 Japanese yen (30,663 USD) per life year and 5,699,096 Japanese yen (39,388 USD) per quality-adjusted life year. Pembrolizumab was deemed cost-effective under a threshold of 7.5 million Japanese yen (51,835 USD) per quality-adjusted life year.ConclusionPembrolizumab monotherapy is a cost-effective option for the first-line treatment of advanced NSCLC with high programmed cell death ligand 1 expression in Japan, providing valuable health economic evidence for treatment selection.
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