Risk Of Arterial Thromboembolic Events Research Articles

Increased risk of arterial thromboembolic events with combination lenalidomide/dexamethasone therapy for multiple myeloma

ABSTRACTIntroduction: Cancer associated thrombosis is a leading cause of morbidity and mortality. Research and guidelines have focused on venous thromboembolic events (VTE). Within the past decade, combination lenalidomide and dexamethasone has become a standard of therapy for multiple myeloma and is now widely used. In these patients, the risk of arterial thromboembolic events (ATE) has not been addressed to the same extent as VTE.Areas discussed: Presented is a targeted review of published data on ATE in MM patients on combination lenalidomide/dexamethasone therapy. Incidence, clinical presentations, prognosis, mechanisms and thromboprophylaxis are discussed. A framework for approaching ATE/VTE in these patients is suggested.Expert commentary: There is an increased incidence of ATE in this population, primarily cerebrovascular and cardiovascular events. ATE is associated with poorer prognosis and its prevention must be an important goal of management. It is suggested that on initiating treatment, a combined VTE/ATE risk assessment should be performed and thromboprophylaxis initiated for a minimum of 6 months. As newer immunomodulatory therapies are developed, thromboembolic risk must be assessed early on. Further studies are needed to determine the optimal strategy to reducing both VTE and ATE in this population.

Abstract 152: Risk of Arterial Thromboembolic Events After Intracerebral Hemorrhage

Introduction: Ischemic stroke and myocardial infarction (MI) have been reported as frequent complications after intracerebral hemorrhage (ICH), but the magnitude and duration of this risk is unclear. Methods: We performed a cohort-crossover study using inpatient and outpatient claims data from a nationally representative 5% sample of Medicare beneficiaries from 2008 through 2014. We included patients ≥66 years of age hospitalized for ICH. Our primary outcome was a composite of ischemic stroke or MI. We used validated ICD-9-CM diagnosis codes to identify predictors and outcomes. To avoid inclusion of patients with ICH as a complication of stroke or MI, we excluded ICH patients with a concurrent stroke or MI during the index ICH hospitalization. We compared the risk of stroke and MI during the 12 weeks after ICH versus the corresponding 12-week period 6 months later. To avoid immortal time bias, we limited our cohort to patients who remained alive and insured throughout the 9-month study period. Odds ratios (OR) and absolute risk differences were calculated using the Mantel-Haenszel estimator for matched data. Results: We included 1,817 ICH patients. In the 12-week period after discharge, 130 (7.1%) patients had a stroke or MI versus 13 (0.7%) in the corresponding 12-week period 6 months later. The absolute risk increase for ischemic stroke or MI was 6.4% (95% CI, 5.1-7.7%) during this period, with a corresponding OR of 10.0 (95% CI, 5.6-19.3). The absolute risk increase was 4.8% (95% CI, 3.7-5.8%) during the first 4 weeks, and 1.0% (95% CI, 0.3-1.7%) during weeks 5-8. Limitations: First, we lacked data on antithrombotic drug use, so further work is needed to distinguish how much of the heightened risk was due to the effect of ICH versus the effect of antithrombotic cessation. Second, we included only patients who survived at least 9 months; however, this would be expected to select for a less sick cohort and therefore decrease any apparent associations with these serious complications. Conclusions: There appears to be a heightened short-term risk of arterial thromboembolic events after acute ICH. This underlines the importance of studies and trials to identify optimal strategies for resuming antithrombotic medications in survivors of ICH.

Cardiovascular risks associated with the use of drospirenone-containing combined oral contraceptives

ObjectivesThe “Long-term Active Surveillance Study for Oral Contraceptives” investigated the risks of long-term use of a 21-day regimen of drospirenone and ethinylestradiol (DRSP) compared to established oral contraceptives (OCs) in a routine clinical setting. Study designProspective, controlled, non-interventional cohort study conducted in seven European countries with three main exposure groups: new users of DRSP, levonorgestrel-containing OCs (LNG), and OCs containing other progestogens (Other OCs). All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. Main OoI were serious clinical outcomes, in particular cardiovascular events. Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models. ResultsA total of 1,113 study centers enrolled 59,510 women. Overall 28%, 26% and 45% of these women used DRSP, LNG and Other OCs, respectively. Study participants were followed for up to ten years (mean value, 5.4years), which generated 318,784 woman-years (WY) of observation. Low loss to follow-up and drop-out rates of 2.9% and 16.8% were achieved. DRSP, LNG, and Other OCs showed similar incidence rates of venous thromboembolism. Corresponding hazard ratios (HRs) were close to unity. For arterial thromboembolic events (ATE) and initiation of antihypertensive treatment statistically significant lower risks were found for DRSP compared to LNG and Other OCs. ConclusionDRSP use was associated with similar general health risks and a low risk of ATE compared to OCs containing other progestogens. Implication statementThe 21-day regimen of drospirenone-containing combined oral contraceptives is associated with similar risk of VTE compared to other combined oral contraceptives as well as potentially with a lower risk of ATE.

Promoter Polymorphism (-174, G/C) of Interleukin-6 and Arterial Thromboembolic Events: A Meta-Analysis.

BackgroundIschemic stroke and myocardial infarction are fatal diseases and are among the top 10 causes of death in Korea, including arterial thromboembolic events. Many previous studies have described the function of interleukin-6 (IL-6) in arterial thromboembolic events and the association between promoter single-nucleotide polymorphism (SNP) (rs1800795; −174, G/C) of the IL-6 gene. However, these results were controversial. Therefore, we performed a meta-analysis to more precisely assess the association between the SNP of the IL-6 gene and susceptibility to arterial thromboembolic events.Material/MethodsWe used PubMed, Embase, Google Scholar, and Korean Studies Information Service System (KISS) electronic databases. Comprehensive Meta-analysis software (Corporation, NJ) was used to evaluate the relationship between rs1800795 SNP of IL-6 gene and risk of arterial thromboembolic events. Odds ratio (OR), 95% confidence interval (CI), and P value were also calculated. The 13 eligible studies were analyzed in the meta-analysis.ResultsThe present meta-analysis found that rs1800795 SNP of IL-6 gene is not significantly associated with susceptibility to arterial thromboembolic events (C allele vs. G allele, OR=1.04, 95% CI=0.91–1.19, P=0.619; CC vs. CG+GG, OR=1.09, 95% CI=0.91–1.31, P=0.364; CC+CG vs. GG, OR=0.97, 95% CI=0.78–1.21, P=0.763, respectively), and the SNP of IL-6 gene also did not show any significant association with ischemic stroke or myocardial infarction (P>0.05 in each model).ConclusionsWe found that rs1800795 SNP of IL-6 gene was not related to arterial thromboembolic events. However, further study will be needed to confirm these results.

Strategy of continued vs interrupted novel oral anticoagulant at time of device surgery in patients with moderate to high risk of arterial thromboembolic events: The BRUISE CONTROL-2 trial

Patients who require perioperative anticoagulation during cardiac implantable electronic device surgery are at increased risk for bleeding complications. The BRUISE CONTROL trial demonstrated that continuing warfarin was safer than heparin bridging, reducing the incidence of clinically significant pocket hematoma. Novel oral anticoagulants are being increasingly prescribed in place of warfarin. The best perioperative management of these new anticoagulants is unknown. A randomized controlled trial to investigate whether a strategy of continued vs interrupted novel oral anticoagulant (dabigatran, rivaroxaban, or apixaban) at the time of device surgery, in patients with moderate to high risk of arterial thromboembolic events, reduces the incidence of clinically significant hematoma (defined as a hematoma requiring reoperation and/or resulting in prolongation of hospitalization, and/or requiring interruption of anticoagulation). The secondary outcomes include components of the primary outcome, composite of all other major perioperative bleeding events, thromboembolic events, all-cause mortality, cost-effectiveness, patient quality of life, perioperative pain, and satisfaction. Planned analyses include descriptive statistics of all baseline variables. For the primary outcome, interrupted vs continued novel oral anticoagulant arms will be compared using the χ(2) test. If any clinically significant differences are identified, a logistic regression analysis will be conducted. Quality of life will be assessed using EuroQol-5D, and perioperative pain using a visual analog scale. BRUISE CONTROL-2 is a randomized trial evaluating the best strategy to manage novel oral anticoagulants at the time of device surgery. We hypothesize that device surgery can be performed safely without interruption of these medications.

Different Effects of Ranibizumab and Bevacizumab on Platelet Activation Profile

Purpose: The aim of the study was to evaluate the potential influence of ranibizumab and bevacizumab on platelet activation and aggregation, which are critical processes in the pathogenesis of arterial thromboembolic events (ATEs). Methods: For the assessment of platelet function, flow cytometry and aggregometry were employed. Platelets were isolated from healthy volunteers and exposed to ranibizumab (1 mg/ml and 150 ng/ml) and bevacizumab (2.5 mg/ml and 3 μg/ml) or their solvents for 10 and 30 min prior to the addition of TRAP (25 μ<smlcap>M</smlcap>), PAR-4-AP (25 μ<smlcap>M</smlcap>) or thrombin (0.02 U/ml). The surface expression of activated GP IIb/IIIa, P-selectin (CD62P) and platelet-bound stromal cell-derived factor-1 (SDF-1) was measured on resting (nonactivated) and activated platelets by flow cytometry. The platelet aggregation capacity was examined using light transmission aggregometry. Results: The expression of surface activation markers did not differ significantly between nonstimulated and TRAP-, PAR-4-AP- or thrombin-activated platelets after incubating with ranibizumab. However, GP IIb/IIIa, CD62P and SDF-1 were significantly downregulated in PAR-4-AP- and thrombin-activated platelets after exposure to bevacizumab 2.5 mg/ml. In addition, ranibizumab- and bevacizumab-FITC were significantly increased in all activated platelets. No significant differences were observed in the aggregation of activated platelets after incubation with ranibizumab or bevacizumab. Conclusion: All ranibizumab concentrations as well as the bevacizumab concentration of 3 μg/ml had no influence on platelet activation and aggregation. Therefore, this in vitro study did not show any relationship between the exposition of activated platelets to ranibizumab or bevacizumab and the development of ATEs. However, the highest level of bevacizumab interfered with platelet activation, leading to downregulation of platelet activation markers. This observation might explain why the systemic treatment with high-dose bevacizumab could be associated with an increased risk of bleeding. Regarding the use of lower intravitreal dosages, further research should focus on the complex interactions between platelets and other cells, such as endothelial cells, which might stronger relate to a potentially increased risk of ATEs and depend on systemic vascular endothelial growth factor levels. Facing the different activation profiles, the diverse effects of the drugs on the cellular level have to be critically scrutinized for their clinical relevance.

Update on Cardiovascular Safety of Tyrosine Kinase Inhibitors: With a Special Focus on QT Interval, Left Ventricular Dysfunction and Overall Risk/Benefit.

We previously reviewed the cardiovascular safety of 16 tyrosine kinase inhibitors (TKIs), approved for use in oncology as of 30 September 2012. Since then, the indications for some of them have been widened and an additional nine TKIs have also been approved as of 30 April 2015. Eight of these nine are indicated for use in oncology and one (nintedanib) for idiopathic pulmonary fibrosis. This report is an update on the cardiovascular safety of those 16 TKIs, including the post-marketing data concerning their pro-arrhythmic effects, and reviews the cardiovascular safety of the nine new TKIs approved since (afatinib, cabozantinib, ceritinib, dabrafenib, ibrutinib, lenvatinib, nintedanib, ponatinib, and trametinib). As before, we focus on specific aspects of cardiovascular safety, namely their potential to induce QT interval prolongation, left ventricular (LV) dysfunction and hypertension but now also summarise the risks of arterial thromboembolic events (ATEs) associated with these agents. Of the newer TKIs, cabozantinib and ceritinib have been shown to induce a mild to moderate degree of QTc interval prolongation while cardiac dysfunction has been reported with the use of afatinib, dabrafenib, lenvatinib, ponatinib and trametinib. The label for axitinib was revised to include a new association with cardiac dysfunction. Hypertension is associated with cabozantinib, lenvatinib, nintedanib, ponatinib and trametinib. Ponatinib, within 10 months of its approval in December 2012, required voluntary (temporary) suspension of its marketing until significant safety revisions (restricted indication, additional warnings and precautions about the risk of arterial occlusion and thromboembolic events and amended dose) were made to its label. Compared with the previous 16 TKIs, more of the recently introduced TKIs are associated with the risk of LV dysfunction, and fewer with QT prolongation. Available data on morbidity and mortality associated with TKIs, together with post-marketing experience with lapatinib and ponatinib, emphasise the need for effective pharmacovigilance and ongoing re-assessment of their risk/benefit after approval of these novel agents. If not adequately managed, these cardiovascular effects significantly decrease the quality of life and increase the morbidity and mortality in a population already at high risk. Evidence accumulated over the last decade suggests that their clinical benefit, although worthwhile, is modest and extends only to progression-free survival and complete response without any effect on overall survival. During uncontrolled use in routine clinical practice, their risk/benefit is likely to be inferior to that perceived from highly controlled clinical trials.

Increased risk of arterial thromboembolic events after Staphylococcus aureus bacteremia: A matched cohort study

An association between infection and arterial thromboembolic events (ATE) has been suggested. Here we examined the risk of myocardial infarction (MI), stroke and other ATE after Staphylococcus aureus bacteremia (SAB). Danish register-based nation-wide observational cohort study between 1995 and 2008 with matched control subjects from the general population. Within a year, 278 of 15,669 SAB patients and 2570 of 156,690 controls developed MI, stroke or another ATE. The incidence rates among SAB patients were highest within the first 30 days and decreased over a year. The adjusted relative risk of MI, stroke and other ATE during the first 30 days after SAB in patients compared to controls were 2.2 (95% CI: 1.6-3.1), 5.5 (95% CI: 3.8-8.3) and 15.5 (95% CI: 6.9-35), respectively. Compared to controls, the increased adjusted relative risk persisted for 30 days for MI, 180 days for stroke and one year for other ATE. Increasing age, hypertension, atrial flutter/fibrillation, prior ATE and endocarditis in SAB patients were associated with an increased risk of ATE. SAB was associated with a short-term increased risk of ATE that persisted longer dependent on type of event. Studies are warranted to investigate treatment strategies to diminish ATE after SAB.

Activated recombinant factor VIIa should not be used in patients with refractory variceal bleeding: it is mostly ineffective, is expensive, and may rarely cause serious adverse events.

Activated recombinant factor VIIa should not be used in patients with refractory variceal bleeding: it is mostly ineffective, is expensive, and may rarely cause serious adverse events.

Intrinsic bleeding risk in patients with uninterrupted oral anticoagulation undergoing cardiac implantable electronic device procedures: A pilot study

The number of cardiac implantable electronic device (CIED) procedures is dramatically increasing worldwide [1]. Up to 37–46% of patients requiring device surgery are on chronic oral anticoagulation (OAC) therapy [2]. Perioperative anticoagulation management represents a dilemma for physicians, particularly in the subset of patients with moderate-to-high risk of arterial thromboembolic events. Current guidelines recommend interruption of anticoagulation and bridging with heparin [3]. However, such strategy has been associated with increased risk of pocket hematoma (up to 20%) [4].

Effect of recombinant Factor VIIa on outcome of acute variceal bleeding: An individual patient based meta-analysis of two controlled trials

Two randomized controlled studies have evaluated the effect of recombinant Factor VIIa (rFVIIa) on variceal bleeding in cirrhosis without showing significant benefit. The aim of the present study was to perform a meta-analysis of the two trials on individual patient data with special focus on high risk patients. The primary outcome measure was the effect of rFVIIa on a composite five day endpoint: failure to control bleeding, 5-day rebleeding or death. Analysis was based on intention to treat. High risk was defined as active bleeding on endoscopy while under vasoactive drug infusion and Child-Pugh score >8. 497 patients were eligible for the meta-analysis; 308 (62%) had active variceal bleeding at endoscopy (oozing or spurting) and 283 of these had a Child-Pugh score >8. Analysis on the composite endpoint in all patients with bleeding from oesophageal varices did not show any beneficial treatment effect. However, failure rate for the primary composite end-point was significantly lower in treated patients with active bleeding at endoscopy (17%) compared to placebo (26%, p=0.049). This difference was highly significant in patients with Child-Pugh score >8 and active bleeding at endoscopy (rFVIIa 16%, placebo 27%; p=0.023). No significant treatment effect was found at 42 days. Five thromboembolic events occurred in rFVIIa treated patients compared to none in placebo treated patients. The current meta-analysis shows a beneficial effect of rFVIIa on the primary composite endpoint of control of acute bleeding, prevention of rebleeding day 1-5 and 5-day mortality in patients with advanced cirrhosis and active bleeding from oesophageal varices at endoscopy. A major drawback of the treatment is a potential increased risk of arterial thrombo-embolic events. This treatment might be considered in patients with lack of control of bleeding after standard treatment.

Thromboembolic Events in Women Exposed to Hormonal Contraception or Cyproterone Acetate in 2012: A Cross-Sectional Observational Study in 30 French Public Hospitals

In the context of the European reassessment of the benefit-risk balance of hormonal contraceptives, French data about thromboembolic events were requested. The aim of this study was to determine the number of patients exposed to hormonal contraception or cyproterone acetate among hospitalized females diagnosed with a thromboembolic event in 2012, to retrospectively analyze specific risk factors of venous and arterial thromboembolism and to assess the magnitude of the under-reporting of such events to the national pharmacovigilance system. This cross-sectional study included 15- to 49-year-old women with pulmonary embolism, venous cerebral thrombosis, ischemic stroke, or myocardial infarction, hospitalized in 2012, and identified within the computerized hospital databases of 30 French teaching hospitals. Among the 2,966 cases identified, 803 (27.1 %) patients had been exposed to a hormonal contraceptive (747) or to cyproterone acetate (56). Among these, there were 452 venous thromboembolic events (VTEs) and 351 arterial thromboembolic events (ATEs). Age ≥40 years and personal thrombophilia diagnosed after the event were the main VTE risk factors, while current smoking and age ≥40 years were the main ATE risk factors. The mean number of associated risk factors was significantly lower for VTE than for ATE (1.1 vs 2.3). The proportion of cases with no risk factors was higher for third- and fourth-generation than for first- and second-generation combined oral contraceptives. Overall, the under-reporting rate was 92.5 % (95 % CI 70.0-97.3). This study highlighted the need to strengthen the knowledge of patients and health professionals about thromboembolic risk factors at the first prescription and renewal of hormonal contraceptives.

Bevacizumab in elderly patients with metastatic colorectal cancer

The progressively ageing population combined with an increased availability of antitumoural agents has created a new, challenging therapeutic scenario for oncologists. Due to the lack of evidence-based data on elderly patients it is uncertain whether the criteria for assessing the risk/benefit ratio of treatment strategies in these patients coincide with those classically used for the general population. A critical reevaluation of the role and potential options of systemic chemotherapy in elderly patients with metastatic colorectal cancer (mCRC) is warranted as the historical conservative approach of oncologists may have resulted in undertreatment of this patient population. Bevacizumab was demonstrated to improve the outcome of mCRC patients when used in combination with standard first and second line chemotherapy. However, its toxicity profile including hypertension, thromboembolic events, haemorrhage and proteinuria may raise important concerns when this anti-angiogenic agent is used in elderly patients with comorbidities. In this review article we analyse the available evidence on the safety and effectiveness of bevacizumab in elderly mCRC patients. Based on the data from subgroup or pooled analysis of prospective trials, observational cohort studies, retrospective population-based studies and a single recent randomised phase III trial, we conclude that the clinical benefit and safety profile of bevacizumab in elderly patients are not significantly different from those reported in younger patients, with the exception of an increased risk of arterial thromboembolic events. Bevacizumab should therefore be considered as a potential therapeutic option for elderly patients with mCRC.

Bevacizumab use and risk of cardiovascular adverse events among elderly patients with colorectal cancer receiving chemotherapy: a population-based study

BackgroundCardiovascular risk attributable to bevacizumab (Avastin®, BEV) for treatment of metastatic colorectal cancer (CRC) remains unclear. We conducted a population-based cohort study to assess the safety of BEV use among patients aged ≥65. Patients and methodsWe identified CRC patients diagnosed from 2005 to 2007 who received chemotherapy and were followed until 31 December 2009. Outcomes were 3-year risk of arterial thromboembolic events (ATEs), cardiomyopathy or congestive heart failure (CM/CHF), and cardiac death (CD) after chemotherapy initiation. We fitted Cox-proportional hazards (PHs) models with inverse-probability-of-treatment-weights and calculated hazard ratios (HRs) for the risk of adverse events. ResultsWe identified 6803 CRC patients (median age: 73 years). Those with cardiac comorbidity were less likely to receive BEV (P < 0.0001). BEV is associated with an elevated risk of ATEs (HR = 1.82, 95% CI = 1.20–2.76, P < 0.001; rate difference: 3.5 additional cases/1000 person-years). We observed no association between BEV and CD or CM/CHF. ConclusionsIn general practice, the cardiovascular risk of BEV in elderly CRC is modest. The observed ATEs risk is lower than reported in clinical trials, which may be due to careful patient selection. Our findings may facilitate clinical decision-making of BEV use in elderly patients.

XELOX and bevacizumab followed by single-agent bevacizumab as maintenance therapy as first-line treatment in elderly patients with advanced colorectal cancer: the boxe study

The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved progression-free survival (PFS) in patients with metastatic colorectal cancer (CRC). An increased risk of arterial thromboembolic events has been observed in some trials in older patients, and the potential benefit of a maintenance therapy with bevacizumab alone has not been clearly demonstrated. This phase II study was designed to evaluate the efficacy and safety of XELOX (capecitabine plus oxaliplatin) plus bevacizumab followed by bevacizumab alone in elderly patients with advanced CRC. Treatment consisted of bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m(2) on day 1, plus capecitabine 1,000 mg/m(2) twice daily on days 1-14, every 3 weeks up to a maximum of 8 cycles. Patients then received maintenance therapy consisting of bevacizumab alone (7.5 mg/kg) once every 3 weeks up to disease progression. The primary study end-points were safety and response rate. A total of 44 patients were recruited. In an intention-to-treat analysis, the overall response rate was 52% [95% confidence interval (CI) 37 to 68%], with 86% of patients achieving disease control. Median PFS and overall survival were 11.5 months (95% CI 10.0-12.9 months) and 19.3 months (95% CI 16.5-22.1 months), respectively. In all, 10 patients (23%) had grade 3/4 adverse events (AEs), the most common being diarrhea (9%), neutropenia (7%), peripheral neuropathy (7%), and stomatitis (7%). No patients died because of treatment-related AEs. The rate of bevacizumab-related AEs (hypertension, thromboembolic events, and gastrointestinal perforation) was consistent with that reported earlier in the general CRC population. The combination of XELOX and bevacizumab is effective and has a manageable tolerability profile when administered to elderly patients with advanced CRC. Maintenance therapy with single-agent bevacizumab may be considered to extend PFS in this setting of patients.

Effects of combined oral contraceptives containing levonorgestrel or chlormadinone on the endothelium

BackgroundAlthough the use of combined oral contraceptives (COCs) is associated with an increased risk of arterial and venous thromboembolic events, less is known about the impact of COCs on endothelial function. The present study evaluated the effects on the endothelium of healthy women of combinations of 30 mcg ethinylestradiol (EE)/2 mg chlormadinone acetate (CMA) and 30 mcg EE/150 mcg levonorgestrel (LNG). Study DesignSixty-four healthy women were evaluated, 21 using a nonhormonal contraceptive method (control) and 43 using COCs, randomized to EE 30 mcg /CMA 2 mg or to EE 30 mcg/LNG 150 mcg. Anthropometric parameters, systolic arterial pressure (SAP), diastolic arterial pressure (DAP), ultrasound markers of endothelial function, flow-mediated dilation (FMD) of the brachial artery, intima–media thickness (IMT) and common carotid artery stiffness were measured at randomization and 6 months later. ResultsRelative to baseline, EE/CMA users showed a significant reduction in mean DAP at 6 months (p=.02), and EE/LNG users showed a significant increase in mean IMT (p=.02) and a significant reduction in mean FMD (p=.01) at 6 months. DAP at 6 months was significantly lower in COC users than in controls (p=.01). Intergroup evaluations showed that, at 6 months, mean SAP (p=.02) was significantly lower in EE/LNG users than in controls (p=.02) and that mean DAP was significantly lower in EE/CMA (p<.01) and EE/LNG (p=.01) users than in controls. EE/LNG users experienced a mean FMD reduction almost threefold greater than that of EE/CMA users. Compared to controls, EE/LNG users experienced a 7.5-fold greater reduction in mean FMD. ConclusionsCOC containing LNG is associated with more pronounced changes in the FMD and IMT of healthy women than a COC containing CMA and nonhormonal contraception. Further studies are needed to determine whether these differences may lead to higher risk of arterial thromboembolic events.

Arterial Thromboembolism in Cancer Patients Treated With Cisplatin: A Systematic Review and Meta-analysis

Cisplatin has been associated with an increased risk of arterial thromboembolic events (ATEs). However, because this association is mostly based on case reports and retrospective studies, we conducted a systemic review and meta-analysis of randomized controlled trials evaluating the incidence and risk of ATEs associated with cisplatin. Eligible studies included prospective randomized phase II and III trials evaluating cisplatin-based vs non-cisplatin-based chemotherapy in patients with solid tumors, which were identified from PubMed articles published between 1990 and 2010. Incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using a random effects model. A total of 8216 patients from 38 trials were included. Among patients treated with cisplatin-based chemotherapy, the summary incidence of ATEs was 0.67% (95% CI = 0.40% to 0.95%), and the RR of ATEs was 1.36 (95% CI = 0.86 to 2.17; P = .19). No increase in ATEs was detected in any prespecified subgroup.

Effect of intravitreal anti-vascular endothelial growth factor therapy on the risk of arterial thromboembolic events: a meta-analysis.

BackgroundIntravitreal anti-vascular endothelial growth factor (VEGF) monoclonal antibodies are used in ocular neovascular diseases. A consensus has emerged that intravenous anti-VEGF can increase the risk of arterial thromboembolic events. However, the role of intravitreal anti-VEGF in arterial thromboembolism is controversial. Therefore, we did a systematic review and meta-analysis to investigate the effects of intravitreal anti-VEGF on the risk of arterial thromboembolic events.MethodsElectronic databases were searched to identify relevant randomized clinical trials comparing intravitreal anti-VEGF with controls. Criteria for inclusion in our meta-analysis included a study duration of no less than 12 months, the use of a randomized control group not receiving any intravitreal active agent, and the availability of outcome data for arterial thromboembolic events, myocardial infarction, cerebrovascular accidents, and vascular death. The risk ratios and 95% CIs were calculated using a fixed-effects or random-effects model, depending on the heterogeneity of the included studies.ResultsA total of 4942 patients with a variety of ocular neovascular diseases from 13 randomized controlled trials were identified and included for analysis. There was no significant difference between intravitreal anti-VEGF and control in the risk of all events, with risk ratios of 0.87 (95% CI, 0.64 to 1.19) for arterial thromboembolic events, 0.96 (95% CI, 0.55–1.68) for cerebrovascular accidents, 0.69 (95% CI 0.40–1.21) for myocardial infarctions, and 0.68 (95% CI, 0.37–1.27) for vascular death.ConclusionsThe strength evidence suggests that the intravitreal use of anti-VEGF antibodies is not associated with an increased risk of arterial thromboembolic events.

Rate of serious adverse effects in a series of bevacizumab and ranibizumab injections

ObjectiveTo compare the rate of serious ocular and systemic adverse effects of intravitreal bevacizumab and ranibizumab in the treatment of a variety of eye diseases. DesignRetrospective chart review. ParticipantsConsecutive series of intravitreal injections of bevacizumab (n = 693) and ranibizumab (n = 891). MethodsMedical records of all patients receiving injections in the series were retrieved. We considered the rate of both serious ocular adverse effects (e.g., acute intraocular inflammation, infectious endophthalmitis, retinal detachment, vitreous hemorrhage) and of arterial thromboembolic events that occurred within 1 month of injection. ResultsSubjects who received bevacizumab were 12 times more likely to develop severe intraocular inflammation following each injection than were those who received ranibizumab (OR = 11.71; 95% CI 1.5–93). The 1 case of acute intraocular inflammation following ranibizumab injection was mild and not associated with vision loss. No other serious ocular complications were noted. A trend was also noted toward an increased risk for arterial thromboembolic events in patients receiving bevacizumab, although the confidence interval was wide (OR = 4.26; 95% CI 0.44–41). ConclusionsSignificant concern still exists regarding the safety of off-label use of intravitreal bevacizumab. Patients receiving bevacizumab should be counselled regarding a possible increased risk for serious adverse events.

P-0242 Xelox and Bevacizumab as First-Line Treatment in fit Elderly Patients with Metastatic Colorectal Cancer: The Boxe Study

ABSTRACT Introduction The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved progression-free survival (PFS) in patients with metastatic colorectal cancer (MCRC). However, clinical trials have been conducted primarily in younger patients with only a small proportion of elderly patients. Moreover, an increased risk of arterial thromboembolic events has been observed in some trials in older patients. This phase II study was designed to evaluate the efficacy and safety of XELOX (capecitabine plus oxaliplatin) plus bevacizumab in fit patients over 70 years of age with MCRC. Methods Treatment consisted of bevacizumab 7.5mg/Kg and oxaliplatin 130mg/m2 on day 1, plus capecitabine 1000mg/m2 twice daily on days 1-14, every 3 weeks up to a maximum of 8 cycles. Patients with a clinical response or stable disease could be maintained on bevacizumab monotherapy up to progressive disease. The primary study end-points were safety and response rate. Results A total of 44 patients were recruited. In an intention-to-treat analysis, the overall response rate was 52% [95% confidence interval (CI): 37% to 68%], with 86% of patients achieving disease control. Median PFS and overall survival were 11.5 months (95% CI: 10.0-12.9 months) and 19.3 months (95% CI: 16.5-22.1 months), respectively. Four patients (9%) underwent liver metastasectomy with curative intent. In all, 10 patients (23%) had grade 3/4 adverse events (AEs), the most common being peripheral neuropathy (7%), stomatitis (7%), diarrhoea (7%). No patients died because of treatment-related AEs. The low incidence of bevacizumab-associated AEs (hypertension, thromboembolic events and gastrointestinal perforation) was not consistent with that of previous reports in elderly patients. Conclusion XELOX plus bevacizumab is effective and has a manageable tolerability profile when administered to fit elderly patients with MCRC.