Raji Shameem

Disadvantages of VKA and requirements for novel anticoagulants

Vitamin K antagonists have been in wide use for over 70 years. Warfarin, the most commonly used vitamin K antagonist, has been shown to be highly effective in treating and preventing thrombosis. Despite this, warfarin has many disadvantages, which has led to the development of a new class of oral anticoagulants targeted to specific coagulation factors designated as target-specific oral anticoagulants (TSOAs). TSOAs include the thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban). This chapter reviews the disadvantages of warfarin and evaluates both the advantages and disadvantages of the new oral anticoagulants.

A new paradigm shift in antithrombotic therapy

Decades after the introduction of oral anti-coagulants namely the vitamin K antagonist (VKA) Warfarin and antiplatelet agents such as Aspirin and Plavix, new classes of direct, small molecule, novel oral anti-coagulant medications and antiplatelet P2Y12 receptor inhibitors have recently become available. For the novel oral anticoagulants (NOAC), these agents can be separated by direct thrombin inhibitors such as Dabigatran and direct Factor Xa inhibitors such as Rivaroxaban and Apixaban. For next generation antiplatelet agents such as Ticagrelor and Prasugrel, these new P2Y12 receptor inhibitors form the cornerstone of therapy for patients with acute coronary syndrome (ACS) or undergoing percutaneous interventions. These novel oral antithrombotics are revolutionizing the field of stroke prevention, atrial fibrillation (AF), the management of venous thromboembolism (VTE) and treatment of ACS. This article reviews the current research developed in order to identify therapeutic effects and establish net clinical benefits of these new oral antithrombotics.

Comparative analysis of the effectiveness of abiraterone before and after docetaxel in patients with metastatic castration-resistant prostate cancer.

AIM To study the efficacy and safety of abiraterone in patients with and without prior chemotherapy. METHODS The databases including PubMed and abstracts presented at the American Society of Clinical Oncology meetings up to April 2014 were systematically searched. Eligible studies included randomized controlled trials (RCTs) in which abiraterone plus prednisone was compared to placebo plus prednisone in metastatic castration-resistant prostate cancer (CRPC) patients. The summary incidence, relative risk, hazard ratio and 95%CI were calculated using random or fixed-effects models. Heterogeneity test was performed to test between-study differences in efficacy and toxicity. RESULTS A total of two phase III RCTs were included in our analysis, with metastatic CPRC patients before (n = 1088) and after chemotherapy (n = 1195). Prior chemotherapy did not significantly alter the effect of abiraterone on overall survival (P = 0.92) and prostate-specific antigen (PSA) progression-free survival (P = 0.13), but reduced its effect on radiographic-progression-free survival (P = 0.04), objective response rate (P < 0.001), and PSA response rate (P < 0.001). Prior chemotherapy significantly increased the specific risk of fluid retention and edema (P < 0.001) and hypokalemia (P < 0.001), but decreased the risk of all-grade hypertension (P < 0.001) attributable to abiraterone. There was no significant difference of cardiac disorders associated with abiraterone between the two settings (P = 0.58). CONCLUSION Prior chemotherapy may reduce the effectiveness of abiraterone in patients with metastatic CRPC.

Incidence and risk of rash to mTOR inhibitors in cancer patients - a meta-analysis of randomized controlled trials

Abstract Background. Inhibitors of the mammalian target of rapamycin (mTOR) are currently approved for the treatment of several cancers, and their use is associated with serious rash, which affects patients quality of life and leads to undesirable dose reductions or interruptions. A meta-analysis of randomized controlled trials (RCTs) was performed to determine the overall risk of developing high-grade rash with mTOR inhibitors in cancer patients. Methods. We searched the PubMed database and abstracts presented at the American Society of Clinical Oncology (ASCO) meetings up to December 2013 for relevant studies. Eligible studies included RCTs in which everolimus or temsirolimus was compared to controls in cancer patients. The summary incidence, relative risk (RR), and 95% confidence intervals (CI) were calculated using a random- or fixed-effects model depending on the heterogeneity of the included trials. Results. A total of 11 RCTs with 4752 patients (mTORs: 2725, controls: 2027) with a variety of solid tumors were included in the analysis. The incidences of all-grade (grade 1–4) and high-grade rash (grade 3–4) were 27.3% (95% CI 21.0–34.7%) and 1.0% (95% CI 0.6–1.4%), respectively. In comparison with controls, mTOR inhibitors significantly increased the risk for developing all-grade rash (RR = 3.55, 95% CI 3.0–4.20, p < 0.001) and high-grade rash (RR = 4.25, 95% CI 1.63–11.10, p = 0.003). The increased risk of high-grade rash did not vary significantly among different tumors (p = 0.91). There was no significant difference between everolimus and temsirolimus (p = 0.60). There was also no significant difference between mTOR inhibitors alone and in combination with other agents (p = 0.57). Conclusions. Everolimus and temsirolimus significantly increased the risk of high-grade rash in cancer patients. Early recognition and appropriate treatment is recommended.

Non-Small-Cell Lung Cancer Clinicopathologic Features and Survival Outcomes in Asian Pacific Islanders Residing in the United States: A SEER Analysis.

Background. The objective of our study was to ascertain racial/ethnic disparities in Asian/Pacific Islanders (API) for non-small-cell lung cancer (NSCLC) clinicopathologic features and survival outcomes based on various tumor characteristics and treatment modalities. Method. SEER database identified invasive NSCLC cases from 2004 to 2010. Variables included American Joint Committee on Cancer (AJCC) stage 7, tumor grade, tumor size, histology, age, marital status, radiation, surgery, and reason for no surgery. The Kruskall-Wallis test and the Z test were used to examine differences between races/ethnicities and the referent, non-Hispanic white (NHW). Multivariate Cox proportional analyses were used to establish the weight of the prognostic significance contributing to disease-specific survival (DSS) in each AJCC stage. Result. Improved DSS was seen in API across stage I (HR: 0.78), stage II (HR: 0.79), and stage IV (HR: 0.86), respectively, compared to the referent NHW (P < 0.01). Prognosis was improved by being married, being female gender, AIS histology, and birth outside the US (P < 0.01). Conclusion. We have demonstrated improved survival among API in early stage and stage IV NSCLC. Further research is necessary to clarify the role of lifestyle and tumor biology for these differences.

Risk of hyperglycemia attributable to everolimus in renal cell and non–renal cell carcinoma patients: A meta-analysis.

515 Background: Everolimus has been used widely in cancer patients and is associated with the development of hyperglycemia. Due to confounding factors, everolimus’ specific impact on hyperglycemia has not been well understood. We performed a meta-analysis to determine the risk of hyperglycemia attributable to everolimus in cancer patients of varying tumor types. Methods: PubMed and ASCO conference abstracts up to June 2015 were systematically searched. Eligible studies included randomized controlled trials (RCTs) in which everolimus was compared to placebo in cancer patients with or without additional cancer therapies. Heterogeneity tests were performed to examine between-study differences in hyperglycemia. The incidence and relative risk of all-grade and high-grade hyperglycemia attributable to everolimus were determined using random- or fixed-effects models. Results: A total of 7 phase III and 2 phase II RCTs with various tumors were included in our analysis. Everolimus significantly increased the risk ...