Adjuvant Systemic Therapies for Resected Stages III and IV Melanoma: A Multi-Center Retrospective Clinical Study.

BACKGROUND: Adjuvant therapies have been approved for resected melanoma based on improved recurrence-free survival. We present early findings from a real-world study on adjuvant treatments for melanoma. METHODS: A comprehensive chart review was conducted for patients receiving adjuvant systemic therapy for resected high-risk stages III and IV melanoma. Statistical analysis was performed to assess recurrence-free survival and subgroup differences. RESULTS: A total of 149 patients (median age = 58.0 years, 61.1% men, 49.7% with BRAF V600E/K genotypes) were included, with 94.6% having resected stage III melanoma. Anti-PD-1 immunotherapy was received by 86.5% of patients, while 13.4% received BRAF-targeted therapy. At a median follow-up of 22.4 months, the recurrence rate was 31.5%, with 1-year and 2-year recurrence-free survival rates of 79% and 62%, respectively. Similar recurrence rates were observed between anti-PD-1 immunotherapy and BRAF-targeted therapy. Long-term toxicity affected 27.4% of patients, with endocrinopathies and late-emergent immune-related adverse events being common. CONCLUSIONS: Real-world adjuvant systemic therapy aligns with clinical trial practice. Recurrence rates remain high despite treatment, and long-term toxicities, including endocrinopathies and chronic inflammatory conditions, are not uncommon.

Effectiveness of Immune Checkpoint Inhibitor with Anti-PD-1 Monotherapy or in Combination with Ipilimumab in Younger versus Older Adults with Advanced Melanoma.

Background: The majority of melanoma is diagnosed in individuals between 55 and 84 years old. Current data varied in reporting differences in survival outcomes amongst different age groups. Methods: A retrospective, multi-center, provincial cohort database was used to investigate the relationship between age (<65 or ≥65 years old) and overall survival. Patients must have had histologically confirmed locally advanced or metastatic melanoma and had to have received at least one cycle of immunotherapy (single agent nivolumab, pembrolizumab, or combination ipilimumab plus nivolumab). Results: From August 2013 to May 2020, we identified 497 patients (median age = 64 [range 12-96 years]; 65.2% men; 36.4% with a BRAF mutation (V600E and V600K)). Of these, 260 were < 65 years old, and 237 were ≥65 years old. A total of 39.1% of the patients in the younger cohort received combination ICI compared with 10.2% in the older cohort, and the difference was statistically significant. Median survival amongst individuals aged ≥65 years old was shorter compared to individuals <65 years old, with a median overall survival of 17.1 (95% CI 12.3-22.9 months) months and 22.2 months (95% CI 18.7-33.8 months), respectively (p = 0.04), at a median follow-up of 34.4 months (range: 1.84-81.4 months). The survival difference was present in the cutaneous melanoma cohort where median OS was 18.2 months (95% CI 12.3-30.4 months) in patients ≥65 years old and 23.8 months (95% CI 19.2-48.2 months) in patients <65 years old, p = 0.04. There were no significant differences by age in the non-cutaneous melanoma cohort. A combination of nivolumab plus ipilimumab was associated with an improved overall survival hazard ratio of 0.48 (95% CI 0.36-0.65) as compared to anti-PD-1 monotherapy alone (p < 0.001). In the cutaneous cohort treated with anti-PD-1 monotherapy (n = 306), no significant differences were seen with median OS at 16.1 months (95% CI 11.4-25.7 months) in patients ≥65 years old and 17.1 months (95% CI 12.0-22.2 months) in patients <65 years old (p = 0.84). Tumor response to anti-PD-1 was higher in the older patients compared with the response in younger patients with cutaneous melanoma. Conclusions: Older melanoma patients have similar survival compared with younger patients after receiving the same treatment with anti-PD-1 monotherapy. The superior survival observed in the younger patients is possibly related to the higher utilization of combination ICI. Tumor response to immunotherapy is superior in older patients with cutaneous melanoma; however, younger patients may improve their survival by using combination ICI.

Decitabine/Cedazuridine in the Management of Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia in Canada.

The management of myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) is limited and remains an unmet need. Decitabine/cedazuridine (DEC-C, ASTX727) is Canada's first and only approved oral hypomethylating agent for MDS and CMML. We characterized the real-world use of DEC-C through a Canadian compassionate use program. Demographic and clinical data from 769 patients enrolled in Taiho Pharma Canada's Patient Support Program were collected and analyzed. These patients represent a collection period from 10 November 2020 to 31 August 2022 with a median age of 76 years. Among 651 patients who started DEC-C, the median treatment duration was 4.2 cycles. The median overall and progression-free survival were 21.6 and 10.7 months, respectively. Among 427 patients who discontinued treatment, the majority (69.5%) stopped due to death (n = 164) or disease progression (n = 133). Multivariable cox regression showed that age, province of residence, blast counts, antibiotic prophylaxis, and number of dose reductions and delays were not significantly associated with overall and progression-free survival. DEC-C is a promising alternative to parenteral hypomethylating agent therapy, and it likely addresses an important unmet need for effective and convenient therapies in this setting.

Cost-Effectiveness of Surveillance after Metastasectomy of Stage IV Colorectal Cancer.

Surveillance of stage IV colorectal cancer (CRC) after curative-intent metastasectomy can be effective for detecting asymptomatic recurrence. Guidelines for various forms of surveillance exist but are supported by limited evidence. We aimed to determine the most cost-effective strategy for surveillance following curative-intent metastasectomy of stage IV CRC. We performed a decision analysis to compare four active surveillance strategies involving clinic visits and investigations elicited from National Comprehensive Cancer Network (NCCN) recommendations. Markov model inputs included data from a population-based cohort and literature-derived costs, utilities, and probabilities. The primary outcomes were costs (2021 Canadian dollars) and quality-adjusted life years (QALYs) gained. Over a 10-year base-case time horizon, surveillance with follow-ups every 12 months for 5 years was most economically favourable at a willingness-to-pay threshold of CAD 50,000 per QALY. These patterns were generally robust in the sensitivity analysis. A more intensive surveillance strategy was only favourable with a much higher willingness-to-pay threshold of approximately CAD 425,000 per QALY, with follow-ups every 3 months for 2 years then every 12 months for 3 additional years. Our findings are consistent with NCCN guidelines and justify the need for additional research to determine the impact of surveillance on CRC outcomes.

Palliative care for people who use drugs during communicable disease epidemics and pandemics: A scoping review on access, policies, and programs and guidelines.

BACKGROUND: People who use drugs with life-limiting illnesses experience substantial barriers to accessing palliative care. Demand for palliative care is expected to increase during communicable disease epidemics and pandemics. Understanding how epidemics and pandemics affect palliative care for people who use drugs is important from a service delivery perspective and for reducing population health inequities. AIM: To explore what is known about communicable disease epidemics and pandemics, palliative care, and people who use drugs. DESIGN: Scoping review. DATA SOURCES: We searched six bibliographic databases from inception to April 2021 as well as the grey literature. We included English and French records about palliative care access, programs, and policies and guidelines for people ⩾18 years old who use drugs during communicable disease epidemics and pandemics. RESULTS: Forty-four articles were included in our analysis. We identified limited knowledge about palliative care for people who use drugs during epidemics and pandemics other than HIV/AIDS. Through our thematic synthesis of the records, we generated the following themes: enablers and barriers to access, organizational barriers, structural inequity, access to opioids and other psychoactive substances, and stigma. CONCLUSIONS: Our findings underscore the need for further research about how best to provide palliative care for people who use drugs during epidemics and pandemics. We suggest four ways that health systems can be better prepared to help alleviate the structural barriers that limit access as well as support the provision of high-quality palliative care during future epidemics and pandemics.

Real-World Use of Granulocyte-Colony Stimulating Factor in Patients with Breast Cancer from Alberta, Canada.

BACKGROUND: There are limited published data in the Canadian healthcare system on the use of granulocyte colony-stimulating factor (G-CSF) among patients with breast cancer. This study characterized real-world G-CSF use during the period surrounding the introduction of filgrastim biosimilar. METHODS: Electronic medical records were reviewed retrospectively for patients with breast cancer who received moderately or highly myelosuppressive (neo)adjuvant chemotherapy from 2008 to 2019 in Alberta, Canada. Trends in G-CSF usage were plotted to elucidate temporal variations and multivariable regression models were constructed to identify clinical factors associated with G-CSF use. RESULTS: We included 6662 patients in our analyses. G-CSF was used in 57.1% of patients during their treatment trajectory. Among the 3801 patients who were treated with G-CSF, the majority received pegfilgrastim only (91.5%; n = 3477) versus filgrastim only (5.7%; n = 217). G-CSF use increased linearly more than two-fold over the 11-year study period. Predictors of G-CSF use included younger age, south zone of residence, higher neighborhood education, inferior disease stage, highly neutropenic risk chemotherapy, and more recent chemotherapy initiation. CONCLUSIONS: Despite increasing G-CSF usage over time, an appreciable proportion of patients for whom G-CSF prophylaxis is recommended did not receive it. G-CSF use could be further optimized to align with supportive care clinical guidelines and reduce the impact of neutropenia and its associated complications.

The influence of adjuvant chemotherapy dose intensity on overall survival in resected colon cancer: a multicentered retrospective analysis.

BACKGROUND: Colorectal cancer remains the second leading cause of cancer death in North America. Fluorouracil and oxaliplatin based adjuvant chemotherapy for resected colon cancer (CC) reduces cancer recurrence, but also causes significant toxicity requiring dose reductions. The effect of dose intensity on survival outcomes is not fully understood and strengthening the evidence supports informed decision making between patients and oncologists. METHODS: Patients treated with adjuvant chemotherapy, between 2006 and 2011, for resected colon cancer at four Canadian academic cancer centers were retrospectively analyzed. All patients must have received oxaliplatin with either capecitabine (CAPOX) or 5-FU (FOLFOX). Dose intensity (DI) was calculated as total delivered dose of an individual chemotherapy agent divided by the cumulative intended dose of that agent. The influence of DI on overall survival was examined. RESULTS: Five hundred thirty-one patients with high-risk stage II or stage III resected CC were eligible and included in the analysis. FOLFOX was the most common regimen (69.6%) with 29.7% of patients receiving CAPOX and 0.7% receiving both therapies. Median follow-up was 36.7 months. The median DI for 5-FU and capecitabine was 100% and 100% with 13.6% and 9.8% of patients receiving ≤ 80% DI, respectively. The median DI of oxaliplatin was 70% with 56.8% of patients receiving ≤ 80% DI. A DI of > 80% for each chemotherapy component was associated with a significant improvement in overall survival compared to those with a DI of ≤ 80% (5-FU HR = 0.23, 95% CI = 0.08-0.65, p = 0.006; capecitabine HR = 0.56, 95% CI = 0.33-0.94, p = 0.026; oxaliplatin HR = 0.52, 95% CI = 0.33-0.82, p = 0.005). Patients with T2 and/or N2 disease with an oxaliplatin DI > 80% had a trend towards improved survival (HR = 0.62, 95% CI = 0.38-1.02, p = 0.06). CONCLUSIONS: In resected CC an adjuvant chemotherapy DI of > 80%, of each chemotherapy agent, is associated with improved overall survival.

Clinical Factors Associated with Long-Term Survival in Metastatic Melanoma Treated with Anti-PD1 Alone or in Combination with Ipilimumab.

Immune checkpoint inhibitors (ICIs) for treatment of metastatic melanoma (MM) offer lasting overall survival (OS) benefit in a subset of patients. However, outcomes remain poor for non-responders. Clinical predictors of long-term survival remain elusive. We utilized the Alberta Immunotherapy Database to investigate the association of host and disease characteristics, and treatment factors with overall survival (OS) greater than 3 years. We identified patients treated between August 2013 and May 2020 with single-agent anti-PD1 or combination (anti-PD1 and anti-CTLA4) ICI regimens. A logistic regression model was used to assess for independent association between clinical factors captured and survival greater than 3 years. Statistically significant factors on univariable analysis were assessed using multivariable analysis. In total, 284 of 460 patients were identified to have short-term (<1 year) or long-term (>3 years) survival with 186 surviving <1 year and 98 surviving >3 years. The median age was 64 and 18.4% of patients were ECOG ≥ 2. On logistic regression, Breslow's Depth ≤ 4 mm, normal serum LDH, normal serum albumin and M-stage 1a/b were associated with OS > 3 years on univariable and multivariable analysis. ECOG < 2, dNLR ≤ 3, normal hemoglobin were only associated with survival on the univariable analysis but not in the multivariable analysis. The objective response rate in long-term survivors was 83.7% compared to 7.5% in the short-term survivors. Our study identifies four easily accessible predictors of long-term survival in a large real-world MM cohort treated with ICI.

Trifluridine/Tipiracil in the Real-World Management of Metastatic Gastric and Gastroesophageal Junction Cancers in Canada.

BACKGROUND: Gastric cancer mortality remains among the highest of all cancers. Trifluridine/tipiracil (FTD/TPI) represents Canada's first standard-of-care, third-line, systemic therapy for metastatic gastric/gastroesophageal cancer. We characterized real-world treatment patterns in patients enrolled to receive FTD/TPI through Taiho Pharma Canada's Patient Support Program. METHODS: Demographic and clinical information were collected from November 2019 to November 2021 for adult patients with refractory metastatic gastric/gastroesophageal cancer throughout Canada. We examined all variables using descriptive statistics and performed survival and association analyses. RESULTS: 162 patients enrolled to receive FTD/TPI with a median age of 65 years, 12 of whom had HER2 positive disease. Among 123 patients who started FTD/TPI, median follow-up was 3.1 months and median progression-free survival (PFS) was 3.5 months (95% CI 3.2-4.0). Among 121 patients who discontinued FTD/TPI, median treatment duration was 2.39 cycles (IQR 1.14-3.86). A total of 52% discontinued treatment due to disease progression, and 27% had a dose reduction or delay. On multivariable logistic regression, prior FOLFIRI was a statistically significant predictor of treatment modification. CONCLUSIONS: Through the Patient Support Program, FTD/TPI is an actively utilized treatment option in heavily pretreated metastatic gastric/gastroesophageal cancer, despite its recent introduction. With longer-than-expected treatment duration and PFS, FTD/TPI likely addresses an important unmet need for effective and tolerable therapies in this setting.

Real World Outcomes in Patients with Advanced Melanoma Treated in Alberta, Canada: A Time-Era Based Analysis.

Immune checkpoint and MAP kinase pathway inhibitors can significantly improve long-term survival for patients with melanoma. There is limited real-world data of these regimens' effectiveness. We retrospectively analyzed 402 patients with unresectable and metastatic melanoma between August 2013 and July 2020 treated with immune checkpoint inhibitors and MAP kinase pathway targeted therapy in Alberta, Canada. Overall survival (OS) was compared using Kaplan-Meier and Cox regression analyses. Subgroup survival outcomes were analyzed by first-line treatment regime and BRAF mutation status. Three treatment eras were defined based on drug access: prior to August 2013, August 2013 to November 2016, and November 2016 to July 2020. Across each era, there were improvements in median OS: 11.7 months, 15.9 months, and 33.6 months, respectively. Patients with BRAF mutant melanoma had improved median OS when they were treated with immunotherapy in the first line as opposed to targeted therapy (median OS not reached for immunotherapy versus 17.4 months with targeted treatment). Patients with BRAF wild-type melanomas had improved survival with ipilimumab and nivolumab versus those treated with a single-agent PD-1 inhibitor (median OS not reached and 21.2 months). Our real-world analysis confirms significant survival improvements with each subsequent introduction of novel therapies for advanced melanoma.

Effectiveness and Safety of First-Line Pembrolizumab in Older Adults with PD-L1 Positive Non-Small Cell Lung Cancer: A Retrospective Cohort Study of the Alberta Immunotherapy Database.

The emergence of immunotherapy revolutionized the treatment of non-small-cell-lung cancer (NSCLC), with multiple landmark clinical trials establishing the efficacy of these agents. However, many patients who receive immunotherapy in clinical practice would be considered clinical trial ineligible. One such population that is often under-represented in clinical trials is older adults. In the current study, we evaluated clinical and safety outcomes in this population. Overall, older adults (>70 years of age) and younger adults had comparable clinical outcomes with an equivalent objective response rate (ORR), time to treatment failure (TTF), and median overall survival (p = 0.67, p = 0.98, and p = 0.91, respectively). Furthermore, the safety outcomes were equivalent between the cohorts with similar rates of immune-related adverse events (irAEs), irAE-related hospitalizations, and all-cause hospitalization (p = 0.99, p = 0.63, and p = 0.74, respectively). While older age was not found to impact overall survival, multivariant analysis revealed that a poor Eastern Cooperative Oncology Group (ECOG) status, low body-mass-index (BMI), and poor/intermediate lung immune prognostic index (LIPI) were all associated with worse survival. In conclusion, age does not impact the efficacy or safety of pembrolizumab in NSCLC, and therefore advanced age should not be a deterrent for treating these patients with pembrolizumab. Physicians and care providers can thus focus on other factors that may influence therapeutic outcomes.

Palliative care for people who use substances during communicable disease epidemics and pandemics: a scoping review protocol.

INTRODUCTION: Communicable disease epidemics and pandemics magnify the health inequities experienced by marginalised populations. People who use substances suffer from high rates of morbidity and mortality and should be a priority to receive palliative care, yet they encounter many barriers to palliative care access. Given the pre-existing inequities to palliative care access for people with life-limiting illnesses who use substances, it is important to understand the impact of communicable disease epidemics and pandemics such as COVID-19 on this population. METHODS AND ANALYSIS: We will conduct a scoping review and report according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews reporting guidelines. We conducted a comprehensive literature search in seven bibliographical databases from the inception of each database to August 2020. We also performed a grey literature search to identify the publications not indexed in the bibliographical databases. All the searches will be rerun in April 2021 to retrieve recently published information because the COVID-19 pandemic is ongoing at the time of this writing. We will extract the quantitative data using a standardised data extraction form and summarise it using descriptive statistics. Additionally, we will conduct thematic qualitative analyses and present our findings as narrative summaries. ETHICS AND DISSEMINATION: Ethics approval is not required for a scoping review. We will disseminate our findings to healthcare providers and policymakers through professional networks, digital communications through social media platforms, conference presentations and publication in a scientific journal.

Obesity and Its Impact on Outcomes in Patients With Stage III Colon Cancer Receiving Adjuvant Chemotherapy.

BACKGROUND: Even though obesity is a well-established risk factor for developing colon cancer, its prognostic value is not very well understood. The present study elucidated the effect of obesity, as measured by the body mass index (BMI) and body surface area (BSA), on colon cancer outcomes. PATIENTS AND METHODS: Patients with a diagnosis of stage III colon cancer from 2011 to 2016 who had undergone adjuvant chemotherapy in Alberta, Canada were identified. The demographic variables, treatment characteristics, and survival data were collected from the electronic medical records. Obesity was defined using the BMI in accordance with the World Health Organization criteria, and BSA was categorized as ≤ 2.0 m2 (low) and > 2.0 m2 (high). The effect of BMI and BSA on 5-year cancer-specific survival (CSS) and overall survival (OS) was analyzed using univariate and multivariate analysis. RESULTS: A total of 915 patients were identified with a median age of 64 years. Of these, 37% were overweight or obese, and the BSA was high in 42% of the patients. The survival outcomes for the obese and underweight patients were not significantly different from those with a normal BMI (P = .61 and P = .30 for OS and CSS, respectively). Similarly, no correlation was found between BSA and OS or CSS. Although 21% of patients experienced a > 10-week delay in receiving adjuvant chemotherapy, neither BMI nor BSA correlated significantly with chemotherapy timing (P = .45). CONCLUSIONS: Our results suggest that BMI and BSA do not correlate with survival outcomes in patients with stage III colon cancer. The role of a healthy lifestyle in an improved colon cancer prognosis might not be driven by its effects on obesity.

Estimation of central systolic blood pressure using an oscillometric blood pressure monitor.

Current noninvasive techniques for assessing central aortic pressure require the recording of an arterial pressure wave using a high-fidelity applanation tonometer. We therefore developed and validated a novel method to estimate the central aortic systolic pressure using an oscillometric blood pressure monitor alone. Invasive high-fidelity right brachial and central aortic pressure waves, and left-brachial pulse volume plethysmography from an oscillometric blood pressure monitor, were obtained at baseline and 3 min after administration of sublingual nitroglycerin in 100 patients during cardiac catheterization. In the initial 50 patients (Generation Group), Central systolic blood pressure was predicted by a multi-variate prediction model generated from the comprehensive analysis of the invasive brachial pressure wave, including brachial late-systolic shoulder pressure value and parameters related to wave reflection and arterial compliance. Another prediction model was similarly constructed from the noninvasively calibrated pulse volume plethysmography. Both models were validated in the subsequent 50 patients (Validation Group) with results: r=0.98 (P<0.001) and mean difference=0.5+/-4.5 (95% confidence interval -8.3 to 9.3) mm Hg for the invasive model, and r=0.93 (P<0.001) and mean difference=-0.1+/-7.6 (95% confidence interval -15.0 to 14.8) mm Hg for the noninvasive model. Thus, our results indicate that central aortic systolic blood pressure could be estimated by analysis of the noninvasive brachial pressure wave alone from an oscillometric blood pressure monitor.

Combined use of endothelial function assessed by brachial ultrasound and high-sensitive C-reactive protein in predicting cardiovascular events.

BACKGROUND: Endothelial function plays a key role in determining the clinical manifestations of atherosclerotic lesions. Elevated high-sensitive C-reactive protein (hsCRP) relates to long-term prognosis of cardiovascular disease. HYPOTHESIS: We test the hypothesis that combined use of endothelial function and hsCRP could increase predictive value of future cardiovascular events. METHODS AND RESULTS: 205 patients were followed up for a median period of 24 months. Endothelial function was assessed using brachial ultrasound to measure endothelium-dependent flow-mediated vasodilation (FMD). Cox regression analyses were conducted for the 205 subjects, with cardiovascular events being defined as myocardial infarction, hospitalization due to congestive heart failure, percutaneous coronary intervention, coronary artery bypass grafting, and ischemic stroke. Twenty nine (14%) developed cardiovascular events. Both FMD and hsCRP were significantly predictive of cardiovascular events (relative risk for patients with FMD<3% as compared to those with FMD>6%, 4.65, 95% confidence interval (CI): 1.30-16.66, p=0.018; relative risk for the highest as compared with the lowest tertile of hsCRP level, 3.59, 95% CI: 1.32-9.74, p=0.012, respectively). Further risk analysis was performed among four groups classified by FMD (FMD >or= 6% or<6%) and half percentile of hsCRP (hsCRP >or= 1 or<1 mg/dL). Relative risks for the FMD<6%/hsCRP >or= 1 mg/dL group compared to FMD >or= 6%/hsCRP<1 mg/dL group increased markedly to 12.598 (95% CI: 1.69 to 94.14, p=0.014) for cardiovascular events. CONCLUSIONS: Patients with suspected coronary artery disease may benefit from risk stratification based on both endothelium-dependent FMD and hsCRP, since combined these two factors contribute significantly toward the incidence of cardiovascular events.

Decreased heparin cofactor II activity is associated with impaired endothelial function determined by brachial ultrasonography and predicts cardiovascular events.

BACKGROUND: Heparin cofactor II (HCII) could inactivate thrombin after binding to dermatan sulfate at injured arterial walls, and has been shown to be a novel and independent antiatherosclerotic factor. However, the relation between plasma HCII activity and peripheral vascular endothelial function remains unclear. METHODS: A total of 199 patients (mean age, 63+/-14 years) were enrolled and followed up for a median period of 24 months. Endothelial function was assessed using brachial ultrasonography to determine endothelium dependent flow-mediated vasodilation (FMD). Cox regression analyses were conducted for the 199 subjects, with cardiovascular events being defined as myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), ischemic stroke, and peripheral artery revascularization. RESULTS: A total of 31 patients (16%) had cardiovascular events. Patients with cardiovascular events had significantly lower HCII activity (112+/-34 versus 127+/-34%, p=0.027) and lower antithrombin III (ATIII) activity (82+/-12 versus 88+/-13%, p=0.014) than those without events. By multivariate analysis, age (p=0.012), hsCRP (p=0.020) and HCII activity (p=0.035) were correlated with FMD. Kaplan-Meier analysis was performed and showed plasma HCII (p=0.036) and ATIII activities (p=0.005) were predictors of cardiovascular events. By Cox regression analysis, plasma HCII activity (p=0.026) could be an independent predictor of future cardiovascular events, but not ATIII. CONCLUSIONS: The present study demonstrates that plasma HCII activity is positively correlated with endothelial vasodilator function. Furthermore, plasma HCII activity could be a predictor of future cardiovascular events in patients with suspected coronary artery disease, suggesting its role in atherosclerosis.

Efficacy and safety of slow-release fluvastatin 80 mg daily in Chinese patients with hypercholesterolemia.

BACKGROUND: Before this study, the efficacy and safety of doubling the dosage of fluvastatin from 40 mg/day to 80 mg/day in Chinese patients with primary hypercholesterolemia remained to be determined. METHODS: In this open-label, active-controlled randomized 2-center study, patients with primary hypercholesterolemia were randomized to treatment with immediate-release fluvastatin 40 mg/day (n = 30) or slow-release fluvastatin 80 mg/day (n = 31) for 12 weeks. The primary efficacy variable was percent change in low-density lipoprotein (LDL) cholesterol level from baseline. Secondary efficacy variables were percent changes in total cholesterol, triglyceride, and high-density lipoprotein (HDL) cholesterol levels, and the percent of patients achieving LDL cholesterol goals of the US National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) II. RESULTS: Both fluvastatin dosages (40 mg/day vs 80 mg/day) effectively reduced LDL cholesterol (-22.5% vs -29.9%; p = 0.087), total cholesterol (-17.3% vs -22.5%; p = 0.140), and triglyceride levels (-14.0% vs -12.3%; p = 0.813) (all p < 0.0001 for comparison with baseline), and slightly increased HDL cholesterol levels (+5.2% vs +5.6%; p = 0.917), after 12 weeks of treatment. The percent of patients achieving LDL cholesterol goals of the NCEP ATP II was 37% versus 65% (p < 0.05). The adverse event profiles for the 2 fluvastatin dosages were similar. CONCLUSION: In Chinese patients with primary hypercholesterolemia, doubling the dosage of fluvastatin from 40 to 80 mg once daily was effective and safe regarding reduction of LDL cholesterol level, and allowed more patients to achieve LDL cholesterol goals of the NCEP ATP II.

Enhanced coronary calcification determined by electron beam CT is strongly related to endothelial dysfunction in patients with suspected coronary artery disease.

BACKGROUND: Coronary artery calcification determined by electron beam CT (EBCT) is strongly associated with total plaque burden but is not related to systemic vascular inflammation. AIMS: We sought to test the hypothesis that enhanced coronary artery calcification, a marker of atherosclerosis and plaque burden, was related to endothelial dysfunction in patients with suspected coronary artery disease (CAD). METHODS AND RESULTS: One hundred twenty-four subjects with suspected CAD were enrolled. Coronary artery calcification was detected by EBCT. A noninvasive method of brachial ultrasound was used to measure endothelium-dependent flow-mediated vasodilation (FMD) and endothelium-independent nitroglycerin-mediated vasodilation (NMD). Serum high-sensitivity C-reactive protein (hsCRP) and monocyte chemoattractant protein-1 (MCP-1) levels were also determined. Of the 124 patients, the calcium scores ranged from 0 to 4,394. All subjects were classified into three groups according to coronary calcium scores: group 1, score 0 (n = 26); group 2, scores 1 to 199 (n = 50); group 3, scores > or = 200 (n = 48). There was an inverse association between the degree of coronary artery calcification and the endothelium-dependent FMD in the three groups (6.9 +/- 0.6% vs 5.3 +/- 0.3% vs 3.7 +/- 0.3%, respectively; p < 0.001) but not the endothelium-independent NMD. Besides, no significant difference in serum levels of hsCRP and MCP-1 were found among the three groups. However, both the serum levels of hsCRP and MCP-1 were correlated significantly with endothelium-dependent FMD (r = - 0.211, p = 0.019; and r = - 0.188, p = 0.037, respectively). By multivariate analysis, enhanced coronary calcification was a strong independent predictor of endothelial dysfunction (p < 0.001). CONCLUSION: Enhanced coronary artery calcification strongly predicted endothelial dysfunction in patients with suspected CAD. Also, serum levels of hsCRP and MCP-1 were significantly correlated with endothelial function. These findings suggested that both calcium deposition and inflammation were involved in endothelial dysfunction.

A double blind randomized trial to compare the effects of eprosartan and enalapril on blood pressure, platelets, and endothelium function in patients with essential hypertension.

The renin-angiotensin system is the major contributor to development of hypertension, atherosclerosis, and many other cardiovascular diseases. Angiotensin II, one of the main effectors of this system, contributes to the pathogenesis of hypertension and plays an important role in monocyte, platelet, and endothelium interactions. The effects on platelet and endothelial function, either by angiotensin converting enzyme inhibitors or angiotensin receptor antagonists, are still not well understood. A double-blind, randomized, prospective trial of either enalapril (10-20 mg daily) or eprosartan (400-800 mg daily) over a 10-week period was conducted in 42 patients (27 males, 15 females). Platelet activation was evaluated by measuring platelet factor 4 (PF-4), beta-thromboglobulin (beta-TG), the ratio of platelet factor 4 to beta-thromboglobulin, and endothelial function by measuring total plasma nitrate levels, von Willebrand factor (vWF) levels, and blood flow using venous occlusive plethysmography. After a 10-week treatment with enalapril or eprosartan, the sitting blood pressure in both the enalapril group (from 152.2 +/- 18.7 mmHg to 141.9 +/- 23.5 mmHg, P < 0.05) and eprosartan group (from 151 +/- 10.0 mmHg to 142.3 +/- 12.9 mmHg, P < 0.05) was significantly reduced. Significant diastolic blood pressure (DPB) reduction (from 94 +/- 8.7 to 84.5 +/- 9.6 mmHg, P < 0.05) and a greater DBP reduction response were found in the eprosartan group (63% in eprosartan versus 25% in enalapril). Additionally, dose-dependent reductions in the indices of platelet activation and endothelial dysfunction were observed in patients administered high dose treatments of eprosartan and enalapril, and the beneficial effects of these agents were not correlated with the reduction of blood pressure using both agents. Eprosartan is effective and well-tolerated in the treatment of mid-to-moderate hypertension, and the DBP response reduction to eprosartin was better than that to enalapril. A high dose of either eprosartan or enalapril significantly decreased the indices of platelet activation and endothelial dysfunction in hypertensive patients. The benefits of both agents cannot be explained solely by their antihypertensive effects and possibly may be mediated through their unique effect on angiotensin blockade.