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Aim: Biliary tract cancers are aggressive, with poor prognosis. This study describes clinical characteristics, treatment patterns and healthcare resource utilization in patients with metastatic biliary tract cancer in Japan. Materials & methods: This cohort-based study collected data from the Japan Medical Data Center claims database (2014-2018). Results: A total of 325 patients were included; 65.2% were male and the mean age was 59.2 years. A 47.6% had an Elixhauser Comorbidity Index score ≥5. Most frequent regimens were gemcitabine + cisplatin (52.9%) for first-line therapy and tegafur + gimeracil + oteracil for second-line therapy (48.6%) and third-line therapy (27.2%). Approximately 77% of patients had ≥1 hospital admission, with a median length of 57 days. Conclusion: This study provides insights on the characteristics and burden of metastatic biliary tract cancer in Japan, highlighting high disease burden in a younger population.
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BACKGROUND: Limited data are available regarding second-line (2 L) treatment for advanced or metastatic biliary tract cancers (BTC) in the US real-world setting. This study explores the rapidly evolving and growing treatment landscape in the 2 L setting for advanced or metastatic BTC with a large cohort of patients treated in a community oncology setting. METHODS: Adult patients with BTC initiating 2 L treatment after a platinum-containing first-line between 1/1/10- and 6/30/19 were identified from the US Oncology Network electronic healthcare record database and followed through 12/31/19. Baseline patient and treatment characteristics were analyzed descriptively, including overall response rate (ORR) in the real-world clinical setting. Kaplan-Meier methods were used to measure duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS: The overall population (N = 160) included 74 patients (46.3%) with intrahepatic cholangiocarcinoma, 41 (25.6%) with extrahepatic cholangiocarcinoma, and 45 (28.1%) with gallbladder cancer. Thirty unique 2 L regimens were recorded for the study population, with folinic acid, fluorouracil and oxaliplatin (FOLFOX, 34.4%) and capecitabine monotherapy (20.0%) being the most common. ORR was 7.5% (95% CI, 3.9%-12.7%). From 2 L initiation, median PFS was 2.8 months (95% CI, 2.4-3.3 months), and median OS was 5.2 months (95% CI, 4.2-6.7 months). CONCLUSION: Results from this study provide real-world evidence that although patients treated in the community oncology setting receive a wide variety of 2 L treatments, the regimens are consistent with those recommended by guidelines. Although responses are observed with 2 L treatment, duration is brief and associated with poor OS in patients with advanced or metastatic disease.
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Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Colangiocarcinoma , Adulto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de los Conductos Biliares/patología , Fluorouracilo/uso terapéutico , Conductos Biliares Intrahepáticos/patología , Neoplasias del Sistema Biliar/patologíaRESUMEN
Background: A systematic review was conducted to understand clinical, economic and health-related quality-of-life outcomes in second-line biliary tract cancer. Materials & methods: The review followed established recommendations. The feasibility of network meta-analysis revealed limited networks, thus synthesis was limited to a summary of reported ranges, percentiles and medians. Results: The review included 62 trials and observational studies highly variable with respect to key baseline characteristics. Commonly evaluated second-line treatments included fluoropyrimidine-, gemcitabine- and S-1-based regimens. Across active treatment arms, median overall survival ranged from 3.5 to 15.0 months (median: 6.9), median progression-free survival from 1.4 to 6.5 months (median: 2.9) and objective response from 0 to 36.4%. Outcomes were similar between study types, with a few notable outliers. Treatment-related/emergent adverse events were infrequently reported; no studies reported economic or health-related quality-of-life outcomes. Conclusions: Biliary tract cancer is a difficult-to-treat disease with poor prognosis. Despite evolving treatment landscapes, more recent studies did not show clinical outcome improvement, highlighting an unmet need among advanced/metastatic patients.
A systematic review of published literature was undertaken to understand the clinical, economic and health-related quality-of-life impact of second-line biliary tract cancer (BTC). A total of 62 relevant studies were identified. The patient populations included across these studies were highly variable with respect to key patient characteristics (i.e., age, sex, physical functioning and tumor type). Commonly evaluated treatments included fluoropyrimidine-, gemcitabine- and S-1-based regimens. Reported values for key outcomes varied substantially, somewhat explained by a few outlier studies. Median overall survival ranged from 3.5 to 15.0 months, median progression-free survival from 1.4 to 6.5 months and objective response from 0 to 36.4%. Treatment-related/emergent adverse events were infrequently reported; no studies reported economic or health-related quality-of-life outcomes. The results demonstrate that BTC is a difficult-to-treat disease with poor prognosis. Despite evolving treatment landscapes, more recent studies did not show clinical outcome improvement, highlighting an unmet need among advanced/metastatic second-line BTC patients.
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Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias del Sistema Biliar/tratamiento farmacológico , HumanosRESUMEN
Administration of plerixafor with granulocyte-colony stimulating factor (G-CSF) mobilizes CD34+ cells much more effectively than G-CSF alone, but cost generally limits plerixafor use to patients at high risk of insufficient CD34+ cell collection based on low peripheral blood (PB) CD34+ counts following 4 days of G-CSF. We analyzed costs associated with administering plerixafor to patients with higher day 4 CD34+ cell counts to decrease apheresis days and explored the use of a fixed split dose of plerixafor instead of weight-based dosing. We analyzed 235 patients with plasma cell disorders or non-Hodgkin's lymphoma who underwent progenitor cell mobilization and autologous hematopoietic cell transplantation (AHCT) between March 2014 and December 2017. Two hundred ten (89%) received G-CSF plus Plerixafor and 25 (11%) received G-CSF alone. Overall, 180 patients (77%) collected in 1 day, 53 (22%) in 2 days and 2 (1%) in 3 days. Based on our data, we present a probabilistic algorithm to identify patients likely to require more than one day of collection using G-CSF alone. CD34+ cell yield, ANC and platelet recovery were not significantly different between fixed and standard dose plerixafor. Plerixafor enabled collection in 1 day and with estimated savings of $5000, compared to patients who did not receive plerixafor and required collection for three days. While collection and processing costs and patient populations vary among institutions, our results suggest re-evaluation of current algorithms.
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Movilización de Célula Madre Hematopoyética/economía , Trasplante de Células Madre Hematopoyéticas/economía , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre/química , Adulto , Anciano , Algoritmos , Ahorro de Costo , Femenino , Filgrastim/farmacología , Factor Estimulante de Colonias de Granulocitos , Costos de la Atención en Salud , Humanos , Linfoma no Hodgkin/economía , Trastornos Linfoproliferativos/economía , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Riesgo , Células Madre/citología , Trasplante Autólogo , Adulto JovenRESUMEN
INTRODUCTION: Daratumumab is approved for the treatment of multiple myeloma in both frontline and relapsed/refractory settings. Its major limitation is the long infusion time, especially with the first dose. Recent data demonstrated the feasibility of infusing daratumumab at an accelerated rate of 90 minutes starting from cycle 1 on day 15. Herein, we report the safety profile and cost associated with rapid daratumumab infusion protocol. PATIENTS AND METHODS: A chart review was performed to identify patients who completed at least 1 cycle of daratumumab (single agent or in combination) from April 2016 to October 2018. Patients were divided into 2 cohorts: cohort 1 received rapid daratumumab infusion after its implementation in March 2018, whereas cohort 2 included patients treated with daratumumab administered at the standard rate. The primary endpoint was to compare differences in rates of infusion-related reactions (IRRs). An Excel (Microsoft)-based model was developed to estimate cost and productivity. RESULTS: A total of 100 patients with relapsed/refractory disease were included in this study (53 in cohort 1 and 47 in cohort 2). Of the 53 patients in cohort 1, 18 (34%) received rapid daratumumab infusion starting with cycle 1. Overall, there was no statistically significant difference in rates of IRRs between cohort 1 and 2 (1.9% vs. 4.3%, P = .59); 1 patient in cohort 1 developed an IRR. The total costs estimated for a 52-week regimen of daratumumab infused at standard and rapid rates were $137,200 and $122,200 (P < .001), respectively. CONCLUSION: Our findings indicate that rapid daratumumab infusion is safe and tolerable and provides cost savings for patients with relapsed/refractory disease.
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Anticuerpos Monoclonales/economía , Anticuerpos Monoclonales/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/farmacología , Análisis Costo-Beneficio , Femenino , Humanos , Bombas de Infusión , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
There is a high risk of voriconazole failure in those with subtherapeutic drug concentrations, which is more common in CYP2C19 (cytochrome P450 2C19) rapid/ultrarapid metabolizers (RMs/UMs). We evaluated CYP2C19 genotype-guided voriconazole dosing on drug concentrations and clinical outcomes in adult allogeneic hematopoietic cell transplant recipients. Poor (PMs), intermediate (IMs), and normal metabolizers (NMs) received voriconazole 200 mg twice daily; RMs/UMs received 300 mg twice daily. Steady-state trough concentrations were obtained after 5 days, targeting 1.0-5.5 mg/L. Of 89 evaluable patients, 29% had subtherapeutic concentrations compared with 50% in historical controls (P < 0.001). Zero, 26%, 50%, and 16% of PMs, IMs, NMs, and RMs/UMs were subtherapeutic. Voriconazole success rate was 78% compared with 54% in historical controls (P < 0.001). No patients experienced an invasive fungal infection (IFI). Genotype-guided dosing resulted in $4,700 estimated per patient savings as compared with simulated controls. CYP2C19 genotype-guided voriconazole dosing reduced subtherapeutic drug concentrations and effectively prevented IFIs.
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Antifúngicos/administración & dosificación , Citocromo P-450 CYP2C19/genética , Trasplante de Células Madre Hematopoyéticas , Infecciones Fúngicas Invasoras/prevención & control , Voriconazol/administración & dosificación , Adulto , Anciano , Antifúngicos/farmacocinética , Ahorro de Costo , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Humanos , Infecciones Fúngicas Invasoras/etiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Voriconazol/farmacocinéticaRESUMEN
BACKGROUND: Prolonged postoperative ileus (POI) is the predominant cause of extended hospitalization after bowel resection surgery. Alvimopan accelerates gastrointestinal recovery, potentially reducing health care costs. We examined the value of alvimopan in reducing prolonged POI and length of stay for patients undergoing abdominal surgery using different definitions of POI. STUDY DESIGN: We developed a decision analytic model to examine costs and outcomes associated with postoperative treatment with either an accelerated care pathway (ACP) only or alvimopan+ACP. To represent an overall perspective for alvimopan, data from four phase 3 bowel resection trials and one phase 4 radical cystectomy trial were used to populate the model with 3 different definitions of POI. The period analyzed included start of surgery to 7 days post discharge. Costs were obtained from standard US costing sources and are reported in 2015 US dollars. Due to variations in published definitions of POI, alternative definitions based on adverse event reports, NG tube insertion, and time to food toleration were examined. RESULTS: The combined clinical trial data included 1,003 ACP and 1,013 alvimopan+ACP patients. When POI was reported as an adverse event, the incidence of POI was significantly lower with alvimopan+ACP (n = 70 [7%]) vs ACP alone (n = 148 [15%]; p < 0.0001). Time to discharge order written was shorter for patients with POI who were treated with alvimopan+ACP than with ACP (202 ± 115 hours vs 266 ± 138 hours; p < 0.0001). As a result, costs were $731 lower with alvimopan+ACP ($17,835) vs ACP ($18,566). Alternative definitions of POI produced similar results. CONCLUSIONS: The addition of alvimopan to existing treatment pathways for patients undergoing abdominal surgery can reduce overall hospital costs.
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Fármacos Gastrointestinales/uso terapéutico , Costos de Hospital/estadística & datos numéricos , Ileus/tratamiento farmacológico , Piperidinas/uso terapéutico , Cuidados Posoperatorios/economía , Complicaciones Posoperatorias/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Cistectomía/economía , Árboles de Decisión , Procedimientos Quirúrgicos del Sistema Digestivo/economía , Femenino , Fármacos Gastrointestinales/economía , Humanos , Ileus/economía , Ileus/etiología , Ileus/terapia , Tiempo de Internación/economía , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Piperidinas/economía , Complicaciones Posoperatorias/economía , Complicaciones Posoperatorias/terapia , Estados Unidos , Adulto JovenRESUMEN
With new agents entering the market, the sequencing of first-line (Tx1), second-line (Tx2), and subsequent chemotherapy/biologics regimens are being examined. We examined how Tx1 regimens impacted the likelihood of receiving Tx2 among metastatic colon cancer (mCC) patients. Surveillance, Epidemiology and End Results (SEER)-Medicare data were used to identify elderly mCC patients between 2003 and 2007. The inverse probability weighting Cox regression method was utilized to study the relationship between receipt of Tx2 and Tx1 regimens, controlling for patient-level factors. Of the 7895 elderly patients identified, 3211 (41%) received Tx1 of which 1440 proceeded to Tx2. The impact of Tx1 on receipt of Tx2 varied by the specific regimens utilized. As compared to 5FU/LV users, IROX (Hazard Ratio [HR] = 0.03; P < 0.01) and IROX + Biologics (HR = 0.20; P < 0.01) users were less likely to receive Tx2; (oxaliplatin) OX + Biologics (HR = 1.26; P < 0.01) users were more likely to receive Tx2. Significant patient-level factors included: Hispanic ethnicity (HR = 0.67; P < 0.01); being married (HR = 0.87; P = 0.01); proxy for poor performance status (HR = 0.82; P = 0.05); each 10-year age increment (HR = 1.14; P < 0.01); and State buy-in status (HR = 1.21; P = 0.01). The specific first-line regimen does impact mCC patients' likelihood of receiving Tx2 in clinical practice. Elderly mCC patients, their health care providers, and policy makers will benefit from new evidence about the impact of sequencing of treatment lines.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Neoplasias del Colon/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/patología , Neoplasias del Colon/radioterapia , Femenino , Humanos , Masculino , Medicare , Metástasis de la Neoplasia , Programa de VERF , Resultado del Tratamiento , Estados Unidos , Población BlancaRESUMEN
AIM: Heterogeneity of treatment effect (HTE) occurs when patient factors modify a treatment's effect on health outcomes due to interactions between these factors and the treatment. This article reviews evidence regarding HTE in stage IV prostate cancer (S4PC). METHOD: A systematic literature review was conducted in the MEDLINE and PubMed databases. Inclusion criteria required that articles examine the treatment-related impact of HTE factors on survival, adverse events or health-related quality of life in S4PC patients. The quality of evidence was graded good, fair or poor based on Agency for Healthcare Research and Quality guidelines. RESULTS: The search identified 2659 articles, of which 92 met the inclusion/exclusion criteria. HTE in S4PC was studied for biologic factors including age, race, clinical signs/symptoms, measures of S4PC disease severity, genetic factors, laboratory data, prior treatment, concurrent medications and comorbidities. Nonbiologic factors that were studied included social, geographic and dietary factors. Age and race seldom showed any correlation with S4PC outcomes. CONCLUSION: Diverse biologic and nonbiologic factors contribute to HTE in S4PC. This review in S4PC also provides an approach for examining HTE for other medical conditions. Ultimately, such knowledge can help oncologists prescribe more personalized medicine, help patients make more informed treatment choices, and inform policy-making and treatment coverage decisions.
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Neoplasias de la Próstata/mortalidad , Humanos , Masculino , Neoplasias de la Próstata/terapia , Factores de Riesgo , Resultado del TratamientoRESUMEN
Among older individuals diagnosed with metastatic colon cancer (mCC) there is limited evidence available that describes the characteristics associated with advancing to second- and subsequent lines of treatment with chemotherapy/biologics. Our objective was to describe the trends and lines of treatment received among elderly mCC patients. Elderly beneficiaries diagnosed with mCC from 2003 to 2007 were identified in the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset. Beneficiaries were followed up until death or censoring. Treatment lines were classified in combinations of chemotherapies and biologics. Modified Poisson regression was used to predict receipt of lines of treatment. Analyses controlled for age, race/ethnicity, gender, marital status, state buy-in during diagnosis year, SEER-registry site, Charlson comorbidity index (CCI), poor performance indicators, surgery of primary site, and surgery of regional/distal sites. Among 7951 Medicare beneficiaries identified with mCC, 3266 initiated therapy. Of these, 1440 advanced to second-line treatment. Of these, 274 advanced to a subsequent-line treatment. Surgeries of the primary tumor site and of the regional/distal sites and marital status were the most significant variables associated with advancing through second- and subsequent-line treatments. Greater than 80 years of age, African American race, SEER-registry area, less than 6 months state buy-in assistance in mCC diagnosis year, and having poor performance indicators were inversely associated with receipt of second- or subsequent-line treatments. Among elderly individuals diagnosed with mCC, we identified demographic, clinical, and regional factors associated with receipt of second- and subsequent-line chemotherapy/biologics. Additional research is warranted to understand the role of physician versus patient preferences as well as geographic differences explaining why patients advance through lines of chemotherapy.
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Antineoplásicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Factores de Edad , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/epidemiología , Demografía , Femenino , Humanos , Masculino , Medicare , Metástasis de la Neoplasia , Programa de VERF , Estados Unidos/epidemiologíaRESUMEN
STUDY OBJECTIVE: To estimate the cost-effectiveness of genotype-guided selection of antiplatelet therapy compared with selecting clopidogrel or prasugrel irrespective of genotype. DESIGN: Decision model based on event occurrence in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38. PATIENTS: Simulated cohort of patients with acute coronary syndrome scheduled to undergo percutaneous coronary intervention (PCI), consisting of three arms: those receiving genotype-guided antiplatelet therapy with clopidogrel or prasugrel, those receiving clopidogrel regardless of genotype, and those receiving prasugrel regardless of genotype. MEASUREMENTS AND MAIN RESULTS: All three arms of the model incorporated the probability that patients would experience a cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke), a bleeding event (major or minor bleeding), or no event while receiving antiplatelet therapy during the 15 months after the scheduled PCI. The cytochrome P450 (CYP) 2C19 genotype determined antiplatelet drug selection in the genotyping group. Cost-effectiveness was expressed as the incremental cost-effectiveness ratio (ICER) for each event avoided in the genotype-guided therapy arm versus the other two arms. Genotype-guided antiplatelet therapy was dominant, or more effective and less costly, when compared with the selection of clopidogrel (ICER -$6760 [95% confidence interval (CI) -$6720 to -$6790]) or prasugrel (ICER -$11,710 [95% CI -$11,480 to -$11,950]) for all patients without regard to genotype. Genotype-guided therapy that included generic clopidogrel was dominant to prasugrel for all patients (ICER -$27,160 [95% CI -$27,890 to -$26,420]). Cost savings were not evident when genotype-guided therapy that included generic clopidogrel was compared with generic clopidogrel for all patients (ICER $2300 [95% CI $2290 to $2320]). [Correction added after online publication 12-Mar-2012: In the previous sentence -$2300 has been corrected as $2300.]. CONCLUSION: Genotype-guided antiplatelet therapy selection may be more cost-effective and may provide more clinical value due to fewer adverse outcomes.
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Hidrocarburo de Aril Hidroxilasas/genética , Piperazinas/economía , Piperazinas/uso terapéutico , Inhibidores de Agregación Plaquetaria/economía , Inhibidores de Agregación Plaquetaria/uso terapéutico , Tiofenos/economía , Tiofenos/uso terapéutico , Terapia Trombolítica/economía , Ticlopidina/análogos & derivados , Síndrome Coronario Agudo/tratamiento farmacológico , Enfermedades Cardiovasculares/tratamiento farmacológico , Clopidogrel , Simulación por Computador , Análisis Costo-Beneficio , Citocromo P-450 CYP2C19 , Árboles de Decisión , Medicamentos Genéricos/economía , Genotipo , Hemorragia/inducido químicamente , Hemorragia/economía , Humanos , Modelos Económicos , Modelos Estadísticos , Infarto del Miocardio/tratamiento farmacológico , Piperazinas/efectos adversos , Inhibidores de Agregación Plaquetaria/efectos adversos , Clorhidrato de Prasugrel , Tiofenos/efectos adversos , Ticlopidina/efectos adversos , Ticlopidina/economía , Ticlopidina/uso terapéuticoRESUMEN
Comparative effectiveness research (CER), or research design to meet the needs of post-regulatory decision makers, has been brought into the spotlight with the introduction of the American Recovery and Reinvestment Act, which provided $US1.1 billion over 2 years to support CER. In the short run, the majority of this money will be invested in observational studies and building of infrastructure; however, in the long run, we will likely see an increase in the number of randomized controlled trials (RCTs), as this method is arguably the most unbiased approach for establishing causal effect between treatments and health outcomes. RCTs are an integral component of CER for generating credible evidence on the relative value of alternative interventions in order to meet the needs of post-regulatory decision makers (patients, physicians, payers and policy makers). Explanatory phase III RCTs are fit for purpose; researchers make use of guidance documents produced by the US FDA to inform the design of these clinical trials. Historically, without explicit FDA guidance, broad patient populations, including women and minorities, often were not considered in trial design. In addition, attempts to minimize cost and maximize efficiency have led to smaller sample sizes, as is clear from the increase in 'creeping phase II-ism'. To demonstrate effectiveness, RCTs must be reflective of how an intervention will be used in the healthcare market. The concept of pragmatic clinical trials has emerged to describe those trials that are designed explicitly with this need in mind. Use of pragmatic trials will be most impactful if post-regulatory decision makers are engaged in the development of recommendations for trial design features, such as indicating outcomes measures and articulating patient populations of interest, which clearly express their evidence needs.
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Investigación sobre la Eficacia Comparativa , Toma de Decisiones , Proyectos de Investigación , Ensayos Clínicos como Asunto , Análisis Costo-Beneficio , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
Hyperkalemic cardioplegic arrest (HCA) and rewarming evokes postoperative myocyte contractile dysfunction, a phenomenon of particular importance in settings of preexisting left ventricular (LV) failure. Caspases are intracellular proteolytic enzymes recently demonstrated to degrade myocardial contractile proteins. This study tested the hypothesis that myocyte contractile dysfunction induced by HCA could be ameliorated with caspase inhibition in the setting of compromised myocardial function. LV myocytes were isolated from control pigs (n = 9, 30 kg) or pigs with LV failure induced by rapid pacing (n = 6, 240 bpm for 21 days) and were randomized to the following: (1) normothermia (2003 myocytes), incubation in cell culture medium for 2 hours at 37 degrees C; (2) HCA only (506 myocytes), incubation for 2 hours in hypothermic HCA solution (4 degrees C, 24 mEq K); or (3) HCA + z-VAD, incubation in hypothermic HCA solution supplemented with 10 microM of the caspase inhibitor z-VAD (z-Val-Ala-Asp-fluoromethyl-ketone, 415 myocytes). Inotropic responsiveness was examined using beta-adrenergic stimulation (25 nM isoproterenol). Ambient normothermic myocyte shortening velocity (microm/s) was reduced with LV failure compared with control values (54 +/- 2 versus 75 +/- 2, respectively, P < 0.05). Following HCA, shortening velocity decreased in the LV failure and control groups (27 +/- 5 and 45 +/- 3, P < 0.05). Institution of z-VAD increased myocyte shortening velocity following HCA in both the LV failure and control groups (49 +/- 5 and 65 +/- 5, P < 0.05). Moreover, HCA supplementation with z-VAD increased beta-adrenergic responsiveness in both groups compared with HCA-only values. This study provides proof of concept that caspase activity contributes to myocyte contractile dysfunction following simulated HCA. Pharmacologic caspase inhibition may hold particular relevance in the execution of cardiac surgical procedures requiring HCA in the context of preexisting LV failure.
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Soluciones Cardiopléjicas , Inhibidores de Caspasas , Inhibidores Enzimáticos/farmacología , Paro Cardíaco Inducido , Insuficiencia Cardíaca/tratamiento farmacológico , Contracción Miocárdica/efectos de los fármacos , Recalentamiento , Disfunción Ventricular Izquierda/tratamiento farmacológico , Agonistas Adrenérgicos beta/farmacología , Animales , Cardiotónicos/farmacología , Separación Celular , Insuficiencia Cardíaca/fisiopatología , Hiperpotasemia/fisiopatología , Técnicas In Vitro , Miocitos Cardíacos/efectos de los fármacos , Porcinos , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
BACKGROUND: Exposure of left ventricular (LV) myocytes to simulated hyperkalemic cardioplegic arrest (HCA) has been demonstrated to perturb ionic homeostasis and adversely affect myocyte contractility on rewarming. Altered ionic homeostasis can cause cytosolic activation of the caspases. While caspases participate in apoptosis, these proteases can degrade myocyte contractile proteins, and thereby alter myocyte contractility. Accordingly, this study tested the hypothesis that caspase inhibition during HCA would attenuate the degree of myocyte contractile dysfunction upon rewarming, independent of a loss in myocyte viability. METHODS: Porcine (n = 8) LV myocytes were isolated and assigned to the following treatment groups: normothermic control: incubation in cell culture media for 2 hours at 37 degrees C; HCA only: incubation for 2 hours in hypothermic HCA solution (4 degrees C, 24 mEq K(+)); or incubation in hypothermic HCA solution supplemented with 10 microM of the caspase inhibitor, z-VAD (z-Val-Ala-Asp-fluoromethyl-ketone, HCA+zVAD). Myocyte viability, assayed as a function of mitochondrial function, was determined to be similar in the normothermic and both HCA groups. RESULTS: The HCA caused a significant reduction in myocyte shortening velocity compared with normothermic control values (41 +/- 6 versus 86 +/- 8 microm/s, p < 0.05). The HCA+zVAD group had significantly improved myocyte shortening velocity compared with the HCA only group (63 +/- 7 microm/s, p < 0.05). CONCLUSIONS: Independent of changes in viability, caspase inhibition attenuated myocyte contractile dysfunction after HCA and rewarming. Thus, caspase activation during HCA contributes, at least in part, to impaired myocyte contractility with rewarming. Supplementation of HCA with caspase inhibitors may provide a means to preserve myocyte contractile function after cardioplegic arrest.