Bevacizumab and the risk of arterial and venous thromboembolism in patients with metastatic, castration-resistant prostate cancer treated on Cancer and Leukemia Group B (CALGB) 90401 (Alliance).

BACKGROUND: Bevacizumab is associated with an increased risk of arterial thromboembolism (ATE); however, its effect on venous thromboembolism (VTE) remains controversial. Scant data exist on the factors that increase the risk of ATE/VTE in patients with prostate cancer. The authors investigated the association of bevacizumab treatment and clinical factors with ATE/VTE risk in patients who were treated on Cancer and Leukemia Group B (CALGB) trial 90401. METHODS: Patients with metastatic, castration-resistant prostate cancer were randomized to receive docetaxel and prednisone with or without bevacizumab once every 21 days. Cycle-to-event Cox regression models were used to investigate the association of bevacizumab with the incidence of grade 3 or greater (≥ 3) ATE and VTE. Age, prior ATE/VTE, baseline antiplatelet/anticoagulant use, and VTE risk score (based on leukocyte count, hemoglobin, platelet count, body mass index, and tumor location) were evaluated in univariate and multivariable analyses. RESULTS: Of 1008 randomized patients, the odds of experiencing grade ≥ 3 ATE were significantly greater in those who received bevacizumab compared with those who received placebo (odds ratio, 2.79; P = .02), whereas an opposite trend was noted for grade ≥ 3 VTE (odds ratio, 0.60; P = .08). In the multivariable analysis, bevacizumab treatment (hazard ratio [HR], 3.00; P = .01) and age (HR, 1.06; P = .02) were significantly associated with the risk of ATE; whereas age (HR, 1.05; P = .01) and VTE risk score (HR, 1.83; P = .03) were significantly associated with the risk of VTE. CONCLUSIONS: Bevacizumab was significantly associated with a greater risk of ATE in patients with metastatic, castration-resistant prostate cancer, but it was not significantly associated with the risk of VTE. Understanding clinical factors that increase the risk for experiencing ATE/VTE is essential to mitigate the risks and reduce the burden of these prevalent complications in cancer care.

Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism.

The clinical significance of subsegmental pulmonary embolism (SSPE) remains to be determined. This study aimed to investigate whether SSPE forms a distinct subset of thromboembolic disease compared with more proximally located pulmonary embolism (PE). We analyzed 3728 consecutive patients with clinically suspected PE. SSPE patients were contrasted to patients with more proximal PE and to patients in whom suspected PE was ruled out, in regards of the prevalence of thromboembolic risk factors and the 3-month risks of recurrent venous thromboembolism (VTE) and mortality. PE was confirmed in 748 patients, of whom 116 (16%) had SSPE; PE was ruled out in 2980 patients. No differences were seen in the prevalence of VTE risk factors, the 3-month risk of recurrent VTE (3.6% vs 2.5%; P = .42), and mortality (10.7% vs 6.5%; P = .17) between patients with SSPE and those with more proximal PE. When compared with patients without PE, aged >60 years, recent surgery, estrogen use, and male gender were found to be independent predictors for SSPE, and patients with SSPE were at an increased risk of VTE during follow-up (hazard ratio: 3.8; 95% CI: 1.3-11.1). This study indicates that patients with SSPE mimic those with more proximally located PE in regards to their risk profile and clinical outcome.

ASPIRE registry: assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre.

Pulmonary hypertension (PH) is a heterogeneous condition. To date, no registry data exists reflecting the spectrum of disease across the five diagnostic groups encountered in a specialist referral centre. Data was retrieved for consecutive, treatment-naïve cases diagnosed between 2001 and 2010 using a catheter-based approach. 1,344 patients were enrolled, with a mean follow-up of 2.9 yrs. The 3-yr survival was 68% for pulmonary arterial hypertension (PAH), 73% for PH associated with left heart disease, 44% for PH associated with lung disease (PH-lung), 71% for chronic thromboembolic PH (CTEPH) and 59% for miscellaneous PH. Compared with PAH, survival was inferior in PH-lung and superior in CTEPH (p<0.05). Multivariate analysis demonstrated that diagnostic group independently predicted survival. Within PAH, Eisenmenger's survival was superior to idiopathic PAH, which was superior to PAH associated with systemic sclerosis (p<0.005). Within PH-lung, 3-yr survival in sleep disorders/alveolar hypoventilation (90%) was superior to PH-lung with chronic obstructive pulmonary disease (41%) and interstitial lung disease (16%) (p<0.05). In CTEPH, long-term survival was best in patients with surgically accessible disease undergoing pulmonary endarterectomy. In this large registry of consecutive, treatment-naïve patients identified at a specialist PH centre, outcomes and characteristics differed between and within PH groups. The current system of classification of PH has prognostic value even when adjusted for age and disease severity, emphasising the importance of systematic evaluation and precise classification.

Predictive value of CHA2DS2-VASc scores regarding the risk of stroke and all-cause mortality in patients with atrial fibrillation (CONSORT compliant).

BACKGROUND: Patients with atrial fibrillation (AF) have a higher risk of fatal complications (e.g., stroke). This investigation was performed as an observational retrospective cohort study includes 137 patients (age 61 ±â€Š15; 34.3% women) with a primary diagnosis of AF (paroxysmal, persistent, and permanent). METHODS: We collected information about the drug therapy, comorbidities and survival of AF patients and determined their congestive heart failure, hypertension, age, diabetes mellitus, prior stroke or TIA or thromboembolism, vascular disease, age, sex category (CHA2DS2-VASc) scores. Statistical analysis identified patients with high CHA2DS2-VASc scores and defined the predictive value of individual parameters, or their combination, with regards to the outcomes of stroke and mortality. RESULTS: CHA2DS2-VASc scores identified 43.8% of the patients as low to intermediate risk (score 0-1) and 56.2% of the patients as high risk (score ≥2). Increasing CHA2DS2-VASc scores were not only accompanied by an increase in the incidence of stroke (Ptrend < .001) but also by an increase in the 3 to 5 years mortality (P = .005). Comparison of anticoagulation and anti-aggregation treatment between the 3 groups of AF did not show any significant statistical difference. Highly significant predictors of death were the CHA2DS2-VASc score (OR 1.71, 95% CI 1.10-2.67, P < .017) as well as other risk factors not included in the CHA2DS2-VASc score such as valvular heart disease (OR 5.04, 95% CI 1.10-23.10, P = .037), hyperlipidemia (OR 4.82, 95% CI 1.03-22.63, P = .046) and chronic renal failure (OR 14.21, 95% CI 2.41-83.91, P = .003). The type of AF type did not affect survival (P = .158) nor the incidence of stroke (P = .466). Patients with paroxysmal AF were linked to significantly lower frequencies of ischemic heart disease (P < .0001), vascular disease (P = .002), diabetes mellitus (P = .047), valvular heart disease (P = .03) and heart failure/left ventricular dysfunction (P = .015). CONCLUSION: The CHA2DS2-VASc score correctly predicted the patients at high-risk for 3 to 5 years mortality and confirmed its significant predictive value in the patients with AF.

Stroke, thromboembolism and bleeding in patients with atrial fibrillation according to the EHRA valvular heart disease classification.

AIMS: We compared thromboembolic (TE) and bleeding risks in patients with atrial fibrillation (AF) according to the new 'Evaluated Heartvalves, Rheumatic or Artificial' (EHRA) valve classification. METHODS: Patients were divided into 3 categories: (i) EHRA type 1 corresponds to the previous 'valvular' AF patients, with either rheumatic mitral valve stenosis or mechanical prosthetic heart valves; (ii) EHRA type 2 includes AF patients with other valvular heart disease (VHD) and valve bioprosthesis or repair; and (iii) 'non-VHD controls' i.e. all AF patients with neither VHD nor post-surgical valve disease. RESULTS: Among 8962 AF patients seen between 2000 and 2010, 357 (4%) were EHRA type 1, 1754 (20%) were EHRA type 2 and 6851 (76%) non-VHD controls. EHRA type 2 patients were older and had a higher CHA2DS2-VASc and HAS-BLED scores than either type 1 and non-VHD patients. After a mean follow-up of 1264 ±â€¯1160 days, the occurrence of TE events was higher in EHRA type 2 than non-VHD patients (HR (95%CI): 1.30 1.09-1.54), p = 0.003; also, p = 0.31 for type 1 vs 2, p = 0.68 for type 1 vs non-VHD controls). The rate of major BARC bleeding events for AF patients was higher in either EHRA type 1 (HR (95%CI): 3.16(2.11-4.72), p < 0.0001) or type 2 (HR (95%CI): 2.19(1.69-2.84), p < 0.0001) compared to non-VHD controls. CONCLUSION: The EHRA valve classification of AF patients with VHD appears useful in categorizing these patients, in terms of TE and bleeding risks. This classification can be used in clinical practice for appropriate choices of oral anticoagulation therapy and follow-up.

The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism.

BACKGROUND: While there have been marked advances in diagnostic and therapeutic strategies for venous thromboembolism, our understanding of its clinical epidemiology is based on studies conducted more than a decade ago. OBJECTIVE: The purpose of this observational study was to describe the incidence and attack rates of venous thromboembolism in residents of the Worcester Statistical Metropolitan Area in 1999. We also describe demographic and clinical characteristics, management strategies, and associated hospital and 30-day outcomes. DESIGN AND MEASUREMENTS: The medical records of all residents from Worcester, MA (2000 census=477,800), diagnosed with International Classification of Diseases, 9th revision (ICD-9) codes consistent with possible venous thromboembolism during 1999 were independently validated, classified, and reviewed by trained abstractors. RESULTS: A total of 587 subjects were enrolled with validated venous thromboembolism. The incidence and attack rates of venous thromboembolism were 104 and 128 per 100,000 population, respectively. Three quarters of patients developed their venous thromboembolism in the outpatient setting - a substantial proportion of these patients had undergone recent surgery or had a recent prior hospitalization. Less than half of the patients received anticoagulant prophylaxis during high-risk periods before their venous thromboembolism. Thirty-day rates of venous thromboembolism recurrence, major bleeding, and mortality were 4.8%, 7.7%, and 6.6%, respectively. CONCLUSION: These data provide insights into recent incidence and attack rates, changing patient profiles, management strategies, and subsequent outcomes in patients with venous thromboembolism. The underutilization of prophylaxis before venous thromboembolism, and relatively high 30-day recurrence rates, suggest a continued need for the improvement of venous thromboembolism prophylaxis and management in the community.

IgG and IgM isotypes of anti-cardiolipin and anti-beta2-glycoprotein i antibodies reflect different forms of recent thrombo-embolic events.

We correlated the distribution and levels of serum anti-cardiolipin (aCL) and anti-beta(2)-glycoprotein-1 antibodies (anti-beta(2)-GPI) of the IgG and IgM isotypes to the clinical spectrum of recent (<6 months) thrombo-embolic events in a cohort of 162 patients. Clinical information was obtained by questionnaires from the referring physicians. Cerebro-vascular infarction (CVI) had taken place in 82 patients, deep venous thrombosis (DVT) in 34, pulmonary embolism (PE) in 14, myocardial infarction (MI) in four, and other thromboses in 28 patients. SLE was the most commonly associated rheumatic disease and accounted for 20 (12%) patients. In 124 (77%) patients no underlying rheumatic disease was identified. Isolated IgG aCL was found in 31 of 48 patients with DVT/PE (65%), but in only 21 of 82 patients with CVI (26%); p<0.0001. IgG anti-beta(2)-GPI were detected in 23 (48%) DVT/PE patients, but in only 13 (16%) CVI patients; p<0.001. The IgG class anti-beta(2)-GPI positive patients had significantly higher levels of IgG aCL (mean 65 units) compared to IgG anti-beta(2)-GPI negative patients (mean 29 units); p<0.0001. In contrast, isolated IgM aCL was found in nine (19%) patients with DVT/PE, but in 46 (56%) CVI patients; p<0.0001. Only ten patients had IgM anti-beta(2)-GPI. The present study shows that the IgG and IgM aCL isotypes seem to define different clinical subsets of patients with thrombo-embolic events with IgG aCL being most prevalent in the group having DVT/PE, IgM aCL being found primarily among CVI patients.

Influence of two different reporting systems on counts of thromboembolic and bleeding complications after St. Jude medical valve replacement: results from the GELIA study.

BACKGROUND AND AIM OF THE STUDY: Different standards for the reporting of morbid events and different follow up techniques have a profound impact on reported morbidity after prosthetic valve replacement. Most studies follow the guidelines of The American Association of Thoracic Surgery (AATS) and The Society of Thoracic Surgeons (STS); the present authors' group has now developed an adapted Karnofsky scale which allows a more precise grading of the severity of morbid events. METHODS: The AATS/STS criteria and the adapted Karnofsky criteria were applied to the database of the German Experience with Low-Intensity Anticoagulation (GELIA) study. In a study population of 2,735 patients, GELIA compared three different intensities of oral anticoagulation in a prospective and randomized design. Patients registered morbid events prospectively by means of documentation cards. RESULTS: The overall rate of complications was comparable when utilizing the two classification systems. However, use of the AATS/STS criteria resulted in the counting of fewer bleeding complications, because only major bleedings were recorded. In contrast, the incidence of embolic complications was higher compared to the Karnofsky criteria because all events were counted, irrespective of their severity, while clinically insignificant (transient, reversible within 24 h) events were disregarded when using the Karnofsky grading. CONCLUSION: The adapted Karnofsky criteria provide a precise and easily understandable framework for the assessment of complications, with equal weighting of both hemorrhagic and embolic events.

Development of complications during rehabilitation.

BACKGROUND AND METHODS: Although studies have demonstrated that medical rehabilitation patients have many complications that warrant attention, none has attempted to categorize complications by severity. This retrospective cohort study examined the incidence, types, and severity of problems that interrupt rehabilitation and the major risk factors for these events. RESULTS: Of 1075 patients, 359 (33.4%) had acute medical complications on rehabilitation considered severe enough to interrupt treatment. Of the 359 patients, 158 (44%) required an unexpected transfer off rehabilitation. The most common reasons for unexpected transfer were surgical causes (22.8%), followed by infection or fever (17.1%) and by thromboembolic events (16.5%). Logistic regression revealed that major risk factors for complications requiring transfer were a primary diagnosis of deconditioning or nontraumatic spinal cord injury (adjusted odds ratio, 2.7; confidence interval, 1.8 to 4.2), severity of initial disability (adjusted odds ratio, 1.2; confidence interval, 1.1 to 1.3 for every 10-point drop in a Modified Barthel Index), and number of comorbid conditions (adjusted odds ratio, 1.1; confidence interval, 1.0 to 1.2). Risk factors for any complication were similar, but there was an interaction between comorbidity and the degree of functional impairment; in patients who were severely functionally impaired, the number of comorbidities was not as strongly associated with the risk of complications as it was in patients who were less functionally impaired. CONCLUSION: There is a complex relationship among the type of underlying medical impairment, severity of functional limitation, comorbidity, and unanticipated medical or surgical complications that interrupt rehabilitation. The interruptions vary both in type and in severity.

Validation of the obesity surgery mortality risk score in a multicenter study proves it stratifies mortality risk in patients undergoing gastric bypass for morbid obesity.

BACKGROUND: A scoring system for clinical assessment of mortality risk has been previously proposed for bariatric surgery (Demaria EJ, Portenier D, Wolfe L, Surg Obes Relat Dis. 2007;3:34-40.). The Obesity Surgery Mortality Risk Score (OS-MRS) was developed from a single institution experience of 2075 patients. The current study provides multicenter validation of the value of the OS-MRS. The OS-MRS assigns 1 point to each of 5 preoperative variables, including body mass index>or=50 kg/m2, male gender, hypertension, known risk factors for pulmonary embolism (previous thromboembolism, preoperative vena cava filter, hypoventilation, pulmonary hypertension), and age>or=45 years. Patients with total score of 0 to 1 are classified as 'A' (lowest) risk group, score 2 to 3 as 'B' (intermediate) risk group, and score 4 to 5 as 'C' (high) risk group. METHODS: Prospectively-collected data from 4431 consecutive patients undergoing a primary gastric bypass at 4 bariatric programs recruited to validate the proposed system were analyzed to assess OS-MRS as a means of stratifying surgical mortality risk. RESULTS: There were 33 total deaths for an overall mortality for the validation cohort of 0.7% consistent with published standards. Mortality for 2164 class A patients was 0.2%, for 2142 class B patients was 1.1%, and for 125 class C patients was 2.4%. Mortality was significantly different between each of the class A, B, and C groupings (P<0.05, chi2). Mortality was 5-fold greater in the class B group than in class A. Only 6 patients with all 5 risk factors were identified. Class C patients (n=125, 3% of total cohort) were characterized by a 12-fold greater mortality than the lowest risk group (A) and a disproportionate 9% of all mortalities. CONCLUSION: The OS-MRS was found to stratify mortality risk in 4431 patients from 4 validation centers that were nonparticipants in the original defining cohort study. The score represents the first validated scoring system for risk stratification in bariatric surgery and is anticipated to aid informed consent discussions, guide surgical decision-making, and allow standardization of outcome comparisons between treatment centers.

Analysis of pediatric thrombotic patients in Turkey.

This study analyzes the data of thrombotic children who were followed up in different pediatric referral centers of Turkey, to obtain more general data on the diagnosis, risk factors, management, and outcome of thrombosis in Turkish children. A simple two-page questionnaire was distributed among contact people from each center to standardize data collection. Thirteen pediatric referral centers responded to the invitation and the total number of cases was 271. All children were diagnosed with thromboembolic disease between January 1995 and October 2001. Median age at time of first thrombotic event was 7.0 years. Of the children 4% of the cases were neonates, 12% were infants less than 1 year old, and 17% were adolescents. Thromboembolic event was mostly located in the cerebral vascular system (32%), deep venous system of the limbs, femoral and iliac veins (24%), portal veins (10%), and intracardiac region (9%). Acquired risk factors were present in 86% of the children. Infection was the most common underlying risk factor. Inherited risk factors were present in 30% of the children. FVL was the most common inherited risk factor. Acquired and inherited risk factors were present simultaneously in 19% of the patients. Eleven children had a history of familial thrombosis. Due to the local treatment preferences, the treatment of the children varied greatly. Outcome of the 142 patients (52%) was reported: 88 (62%) patients had complete resolution, 47 (33%) had complications, 12 (9%) had recurrent thrombosis, and 34 (24%) died. Three children (2.1%) died as a direct consequence of their thromboembolic disease. The significant morbidity and mortality found in this study supports the need for multicentric prospective clinical trials to obtain more generalizable data on management and outcome of thrombosis in Turkish children.