Frederick A. Anderson

Risk Factors for Venous Thromboembolism

Abstract Until the 1990s, venous thromboembolism (VTE) was viewed primarily as a complication of hospitalization for major surgery (or associated with the late stage of terminal illness). However, recent trials in patients hospitalized with a wide variety of acute medical illnesses have demonstrated a risk of VTE in medical patients comparable with that seen after major general surgery. In addition, epidemiologic studies have shown that between one quarter and one half of all clinically recognized symptomatic VTEs occur in individuals who are neither hospitalized nor recovering from a major illness. This expanding understanding of the population at risk challenges physicians to carefully examine risk factors for VTE to identify high‐risk patients who could benefit from prophylaxis. Factors sufficient by themselves to prompt physicians to consider VTE prophylaxis include major surgery, multiple trauma, hip fracture, or lower extremity paralysis because of spinal cord injury. Additional risk factors, such as previous VTE, increasing age, cardiac or respiratory failure, prolonged immobility, presence of central venous lines, estrogens, and a wide variety of inherited and acquired hematological conditions contribute to an increased risk for VTE. These predisposing factors are seldom sufficient by themselves to justify the use of prophylaxis. Nevertheless, individual risk factors, or combinations thereof, can have important implications for the type and duration of appropriate prophylaxis and should be carefully reviewed to assess the overall risk of VTE in each patient. (Circulation. 2003;107:I‐9 ‐I‐16.)

Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE).

Objective To develop a clinical risk prediction tool for estimating the cumulative six month risk of death and death or myocardial infarction to facilitate triage and management of patients with acute coronary syndrome. Design Prospective multinational observational study in which we used multivariable regression to develop a final predictive model, with prospective and external validation. Setting Ninety four hospitals in 14 countries in Europe, North and South America, Australia, and New Zealand. Population 43 810 patients (21 688 in derivation set; 22 122 in validation set) presenting with acute coronary syndrome with or without ST segment elevation enrolled in the global registry of acute coronary events (GRACE) study between April 1999 and September 2005. Main outcome measures Death and myocardial infarction. Results 1989 patients died in hospital, 1466 died between discharge and six month follow-up, and 2793 sustained a new non-fatal myocardial infarction. Nine factors independently predicted death and the combined end point of death or myocardial infarction in the period from admission to six months after discharge: age, development (or history) of heart failure, peripheral vascular disease, systolic blood pressure, Killip class, initial serum creatinine concentration, elevated initial cardiac markers, cardiac arrest on admission, and ST segment deviation. The simplified model was robust, with prospectively validated C-statistics of 0.81 for predicting death and 0.73 for death or myocardial infarction from admission to six months after discharge. The external applicability of the model was validated in the dataset from GUSTO IIb (global use of strategies to open occluded coronary arteries). Conclusions This risk prediction tool uses readily identifiable variables to provide robust prediction of the cumulative six month risk of death or myocardial infarction. It is a rapid and widely applicable method for assessing cardiovascular risk to complement clinical assessment and can guide patient triage and management across the spectrum of patients with acute coronary syndrome.

Venous thromboembolism (VTE) in Europe - The number of VTE events and associated morbidity and mortality

Venous thromboembolism (VTE) is often asymptomatic, mis-diagnosed, and unrecognized at death, and there is a lack of routine postmortem examinations. These factors are thought to result in marked underestimates ofVTE incidence. The objective of our study was to estimate the total burden of VTE within the European Union (EU) per annum. An epidemiological model was constructed to estimate the number of community- and hospital-acquired incidents and recurrent cases (attack rate) of nonfatal VTE and VTE-related deaths, as well as incident and prevalent cases of post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (PH) occurring in the EU per annum. Individual models were developed for six EU countries. The models were populated with data from published literature and, where necessary, expert opinions. The findings were tested using probabilistic sensitivity analyses. The estimated total number of symptomaticVTE events (range based on probabilistic sensitivity analysis) per annum within the six EU countries was 465,715 (404,664-538,189) cases of deep-vein thrombosis, 295,982 (242,450-360,363) cases of pulmonary embolism (PE), and 370,012 (300,193-483,108) VTE-related deaths. Of these deaths, an estimated 27,473 (7%) were diagnosed as being antemortem; 126,145 (34%) were sudden fatal PE, and 217,394 (59%) followed undiagnosed PE. Almost three-quarters of all VTE-related deaths were from hospital-acquired VTE. VTE is a major health problem in the EU, with over one million VTE events or deaths per annum in the six countries examined. Given the availability of effective VTE prophylaxis, many of these events and deaths could have been prevented. These results have important implications for the allocation of healthcare resources.

Determinants and prognostic impact of heart failure complicating acute coronary syndromes: observations from the Global Registry of Acute Coronary Events (GRACE)

Background—Few data are available on the impact of heart failure (HF) across all types of acute coronary syndromes (ACS). Methods and Results—The Global Registry of Acute Coronary Events (GRACE) is a prospective study of patients hospitalized with ACS. Data from 16 166 patients were analyzed: 13 707 patients without prior HF or cardiogenic shock at presentation were identified. Of these, 1778 (13%) had an admission diagnosis of HF (Killip class II or III). HF on admission was associated with a marked increase in mortality rates during hospitalization (12.0% versus 2.9% [with versus without HF], P <0.0001) and at 6 months after discharge (8.5% versus 2.8%, P <0.0001). Of note, HF increased mortality rates in patients with unstable angina (defined as ACS with normal biochemical markers of necrosis; mortality rates: 6.7% with versus 1.6% without HF at admission, P <0.0001). By logistic regression analysis, admission HF was an independent predictor of hospital death (odds ratio, 2.2; P <0.0001). Admission HF was associated with longer hospital stay and higher readmission rates. Patients with HF had lower rates of catheterization and percutaneous cardiac intervention, and fewer received &bgr;-blockers and statins. Hospital development of HF (versus HF on presentation) was associated with an even higher in-hospital mortality rate (17.8% versus 12.0%, P <0.0001). In patients with HF, in-hospital revascularization was associated with lower 6-month death rates (14.0% versus 23.7%, P <0.0001; adjusted hazard ratio, 0.5; 95% CI, 0.37 to 0.68, P <0.0001). Conclusions—In this observational registry, heart failure was associated with reduced hospital and 6-month survival across all ACS subsets, including patients with normal markers of necrosis. More aggressive treatment of these patients may be warranted to improve prognosis.

Receptor Activator of NF-κB and Osteoprotegerin Expression by Human Microvascular Endothelial Cells, Regulation by Inflammatory Cytokines, and Role in Human Osteoclastogenesis

The receptor activator of NF-κB (RANKL) is the essential signal required for full osteoclast (OC) development, activation, and survival. RANKL is highly expressed in areas of trabecular bone remodeling and inflammatory bone loss, is increased on marrow stromal cells or osteoblasts by osteotropic hormones or cytokines, and is neutralized by osteoprotegerin (OPG), a soluble decoy receptor also crucial for preventing arterial calcification. Vascular endothelial cells (VEC) are critically involved in bone development and remodeling and influence OC recruitment, formation, and activity. Although OCs develop and function in close association with bone VEC and sinusoids, signals mediating their interactions are not well known. Here, we show for the first time that human microvascular endothelial cells (HMVEC) express transcripts for both RANKL and OPG; inflammatory cytokines tumor necrosis factor-α and interleukin-1α elevate RANKL and OPG expression 5–40-fold in HMVEC (with an early OPG peak that declines as RANKL rises), and RANKL protein increases on the surface of tumor necrosis factor-α-activated HMVEC. Cytokine-activated HMVEC promoted the formation, fusion, and bone resorption of OCs formed in co-cultures with circulating human monocytic precursors via a RANKL-mediated mechanism fully antagonized by exogenous OPG. Furthermore, paraffin sections of human osteoporotic fractured bone exhibited increased RANKL immunostaining in vivo on VEC located near resorbing OCs in regions undergoing active bone turnover. Therefore, cytokine-activated VEC may contribute to inflammatory-mediated bone loss via regulated production of RANKL and OPG. VEC-derived OPG may also serve as an autocrine signal to inhibit blood vessel calcification.

Perioperative Mortality for Pancreatectomy: A National Perspective

Objective:To analyze in-hospital mortality after pancreatectomy using a large national database. Summary and Background Data:Pancreatic resections, including pancreaticoduodenectomy, distal pancreatectomy, and total pancreatectomy, remain the only potentially curative interventions for pancreatic cancer. The goal of this study was to define factors affecting outcomes after pancreatectomy for neoplasm. Methods:A retrospective analysis was performed using all patients undergoing pancreatic resections for neoplastic disease identified from the Nationwide Inpatient Sample from 1998 to 2003. Crude in-hospital mortality was analyzed by χ2. A multivariable model was constructed to adjust for age, sex, hospital teaching status, hospital surgical volume, year of resection, payer status, and selected comorbid conditions. Results:In all, 279,445 patient discharges were identified with a primary diagnosis of pancreatic neoplasm. A total of 39,463 (14%) patients underwent resection during that hospitalization. In-hospital mortality was 5.9% with a significant decrease from 7.8% to 4.6% from 1998 to 2003 by trend analysis (P < 0.0001). Resections done at low (<5 procedures/year)- and medium (5–18/year)-volume centers had higher mortality compared with those at high (>18/year)-volume centers (low-volume odds ratio = 3.3; 95% confidence interval, 2.3–4.; medium-volume, odds ratio = 2.1; 95% confidence interval, 1.5–3.0). The proportion of procedures performed at high volume centers increased from 30% to 39% over the 6-year time period (P < 0.0001) by trend test. Conclusions:This large observational study demonstrates an improvement in operative mortality for patients undergoing pancreatectomy for neoplastic disease from 1998 to 2003. In addition, a greater proportion of pancreatectomies were performed at high-volume centers in 2003. The regionalization of pancreatic surgery may have partially contributed to the observed decrease in mortality rates.

The Worcester Venous Thromboembolism Study: A Population‐Based Study of the Clinical Epidemiology of Venous Thromboembolism

AbstractBACKGROUND: 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.

Intervention in acute coronary syndromes: do patients undergo intervention on the basis of their risk characteristics? The Global Registry of Acute Coronary Events (GRACE)

Objective: To determine whether revascularisation is more likely to be performed in higher-risk patients and whether the findings are influenced by hospitals adopting more or less aggressive revascularisation strategies. Methods: GRACE (Global Registry of Acute Coronary Events) is a multinational, observational cohort study. This study involved 24 189 patients enrolled at 73 hospitals with on-site angiographic facilities. Results: Overall, 32.5% of patients with a non-ST elevation acute coronary syndrome (ACS) underwent percutaneous coronary intervention (PCI; 53.7% in ST segment elevation myocardial infarction (STEMI)) and 7.2% underwent coronary artery bypass grafting (CABG; 4.0% in STEMI). The cumulative rate of in-hospital death rose correspondingly with the GRACE risk score (variables: age, Killip class, systolic blood pressure, ST segment deviation, cardiac arrest at admission, serum creatinine, raised cardiac markers, heart rate), from 1.2% in low-risk to 3.3% in medium-risk and 13.0% in high-risk patients (c statistic  =  0.83). PCI procedures were more likely to be performed in low- (40% non-STEMI, 60% STEMI) than medium- (35%, 54%) or high-risk patients (25%, 41%). No such gradient was apparent for patients undergoing CABG. These findings were seen in STEMI and non-ST elevation ACS, in all geographical regions and irrespective of whether hospitals adopted low (4.2−33.7%, n  =  7210 observations), medium (35.7−51.4%, n  =  7913 observations) or high rates (52.6−77.0%, n  =  8942 observations) of intervention. Conclusions: A risk-averse strategy to angiography appears to be widely adopted. Proceeding to PCI relates to referral practice and angiographic findings rather than the patient’s risk status. Systematic and accurate risk stratification may allow higher-risk patients to be selected for revascularisation procedures, in contrast to current international practice.

From guidelines to clinical practice: the impact of hospital and geographical characteristics on temporal trends in the management of acute coronary syndromes. The Global Registry of Acute Coronary Events (GRACE).

Aims The extent to which hospital and geographic characteristics influence the time course of uptake of evidence from key clinical trials and practice guidelines is unknown. The gap between evidence and practice is well recognized but the factors influencing this disjunction, and the extent to which such factors are modifiable, remain uncertain. Methods and results Using chronological data from the GRACE registry ( n =12 666, July 1999 to December 2001), we test the hypothesis that hospital and geographic characteristics influence the time course of uptake of evidence-based guideline recommendations for acute coronary syndromes (ACS) with and without ST elevation. Certain therapies were widely adopted in both ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) patients (aspirin >94% of all patients; beta-blockers 85–95%) and changed only modestly over time. Significant increases in the use of low-molecular-weight heparins and glycoprotein IIb/IIIa inhibitors occurred in STEMI and NSTEMI patients in advance of published practice guidelines (September/November 2000) with marked geographical differences. The highest use of LMWH was in Europe in NSTEMI (86.8%) and the lowest in the USA (24.0%). Contrasting geographical variations were seen in the use of percutaneous coronary intervention (PCI) in NSTEMI: 39.5% USA, 34.6% Europe, 33.5% Argentina/Brazil, 25.0% Australia/New Zealand/Canada (July–December 2001). Theuse of PCI was more than five times greater in hospitals with an on-site catheterization laboratory compared to centres without these facilities, and geographic differences remained after correction for available facilities. Conclusions Hospital and geographical factors appear to have a marked influence on the uptake of evidence-based therapies in ACS management. The presentation and publication of major international guidelines was not associated with a measurable change in the temporal pattern of practice. In contrast, antithrombotic and interventional therapies changed markedly over time and were profoundly influenced by hospital and geographic characteristics.

Physician practices in the prevention of venous thromboembolism

OBJECTIVE To determine the rate of use of prophylaxis for venous thromboembolism in high-risk hospital patients. DESIGN A retrospective medical record review. SETTING A community-wide study in 16 short-stay hospitals in central Massachusetts. PATIENTS A total of 2017 patients with multiple risk factors for venous thromboembolism. MEASUREMENTS AND MAIN RESULTS On the basis of age, length of hospitalization, and the presence of at least one additional major risk factor, 17% of 151,349 discharges (25,410 patients) were identified as being at high risk for venous thromboembolism. Eight percent of these discharges were randomly selected for medical record review. Prophylaxis for venous thromboembolism was received by 32% of these high-risk patients. Prophylaxis use among the 16 study hospitals varied widely, ranging from 9% to 56%, and was higher in teaching hospitals than in nonteaching hospitals (44% compared with 19%; P less than 0.001). One or more of the following methods of prophylaxis was used: low-dose heparin (78%), intermittent calf compression (13%), warfarin (12%), and inferior vena caval filter (3%). Use of prophylaxis increased with the number of risk factors identified (P less than 0.001). CONCLUSION Prophylaxis for venous thromboemobolism is underused, particularly in nonteaching hospitals.