Cancer effect on periprocedural thromboembolism and bleeding in anticoagulated patients.

BACKGROUND: Patients with active cancer are often on chronic anticoagulation and frequently require interruption of this treatment for invasive procedures. The impact of cancer on periprocedural thromboembolism (TE) and major bleeding is not known. PATIENTS AND METHODS: Two thousand one hundred and eighty-two consecutive patients referred for periprocedural anticoagulation (2484 procedures) using a standardized protocol were followed forward in time to estimate the 3-month incidence of TE, major bleeding and survival stratified by anticoagulation indication. For each indication, we tested active cancer and bridging heparin therapy as potential predictors of TE and major bleeding. RESULTS: Compared with patients without cancer, active cancer patients (n=493) had more venous thromboembolism (VTE) complications (1.2% versus 0.2%; P=0.001), major bleeding (3.4% versus 1.7%; P=0.02) and reduced survival (95% versus 99%; P<0.001). Among active cancer patients, only those chronically anticoagulated for VTE had higher rates of periprocedural VTE (2% versus 0.16%; P=0.002) and major bleeding (3.7% versus 0.6%; P<0.001). Bridging with heparin increased the rate of major bleeding in cancer patients (5% versus 1%; P=0.03) without impacting the VTE rate (0.7% versus 1.4%, P=0.50). CONCLUSIONS: Cancer patients anticoagulated for VTE experience higher rates of periprocedural VTE and major bleeding. Periprocedural anticoagulation for these patients requires particular attention to reduce these complications.

The spectrum of haemostatic characteristics of women with unexplained menorrhagia.

While an estimated 13% of women with unexplained menorrhagia have von Willebrand disease (VWD), the frequency of other potential bleeding disorders has been uncertain. This study describes the relatively wide range of laboratory characteristics of women with unexplained menorrhagia and presents issues affecting diagnosis in this population. Women with pictorial blood assessment chart (PBAC) score > 100 were identified at six U.S. sites and asked to remain drug free for 10 days prior to testing. Blood was collected on one of the first four menstrual cycle days and tested at a central laboratory for procoagulant factors, VWD and fibrinolytic factors. Platelet function testing by PFA-100® (PFA) and platelet aggregation with ATP release (PAGG/ATPR) were performed locally using standardized methods. Among 232 subjects, a laboratory abnormality was found in 170 (73.3%), including 124 of 182 White (68.1%) and 34 of 37 Black (91.9%) subjects; 6.0% had VWD, 56.0% had abnormal PAGG/ATPR, 4.7% had a non-VWD coagulation defect (NVCD) and 6.5% had an abnormal PFA only. AGG/ATPR was reduced in 58.9% of subjects, with multiple agonists in 28.6%, a single agonist in 6.1% and ristocetin alone in 24.2%. Frequencies of PAGG/ATPR defects varied by study site and race; frequencies of VWD and NVCD were similar. Laboratory abnormalities of haemostasis, especially platelet function defects, were common among women with unexplained menorrhagia across multiple U.S. sites. To what degree these abnormalities are clinically significant requires further study.

The association of anti-platelet factor 4/heparin antibodies with early and delayed thromboembolism after cardiac surgery.

Essentials We evaluated antibody status, thromboembolism and survival after cardiac surgery. Positive antibody tests are common - over 50% are seropositive at 30 days. Seropositivity did not increase thromboembolism or impair survival after cardiac surgery. Results show heparin induced thrombocytopenia antibody screening after surgery is not warranted. SUMMARY: Background Heparin-induced thrombocytopenia (HIT) is a prothrombotic response to heparin therapy with platelet-activating, anti-platelet factor 4 (PF4)/heparin antibodies leading to thrombocytopenia associated with thromboembolism. Objective We tested the hypothesis that anti-PF4/heparin antibodies are associated with thromboembolism after cardiac surgery. Methods This multicenter, prospective cohort study collected laboratory and clinical data up to 30 days after surgery and longer-term clinical follow-up data. The primary outcome variable combined new arterial or venous thromboembolic complications (TECs) with all-cause death until 90 days after surgery. Laboratory analyses included platelet counts and anti-PF4/heparin antibody titers (GTI ELISA), with a confirmatory excess heparin step and serotonin release assay. Chi-square testing was used to test the relationship between our outcome and HIT antibody seropositivity. Results Initially, 1021 patients were enrolled between August 2006 and May 2009, and follow-up was completed in December 2014. Seropositivity defined by OD > 0.4 was common, being almost 20% preoperatively, > 30% by discharge, and > 60% by day 30. Death (1.7% within 30 days) or TECs (69 in total) were more likely if the partient was seronegative (OD < 0.4), but positivity defined by OD > 1.0 or including an excess heparin confirmatory step resulted in equal incidence of death or TECs, whether the patient was seronegative or seropositive. Incorporating the serotonin release assay for platelet-activating antibodies did not alter these findings. Conclusions Seropositivity for anti-PF4/heparin antibodies does not increase the risk of death or thromboembolism after cardiac surgery. Screening is not indicated, and seropositivity should only be interpreted in the context of clinical evidence for HIT. TRIAL REGISTRATION: Duke IRB Protocol #00010736.

Do incident and recurrent venous thromboembolism risks truly differ between heterozygous and homozygous Factor V Leiden carriers? A retrospective cohort study.

INTRODUCTION: While Factor V Leiden (F5 rs6025 A allele) is a known venous thromboembolism (VTE) risk factor, VTE risk among heterozygous vs. homozygous carriers is uncertain. MATERIALS AND METHODS: In a retrospective cohort study of Mayo Clinic patients referred for genotyping between 1996 and 2013, we tested Factor V Leiden genotype as a risk factor for incident and recurrent VTE. RESULTS: Among heterozygous (n=268) and homozygous (n=111) carriers, the prevalence of VTE was 54% and 68%, respectively (p=0.016). While mean patient age at first VTE event (43.9 vs. 42.9years; p=0.70) did not differ significantly, median VTE-free survival was modestly shorter for homozygous carriers (56.8 vs 59.5 years; p=0.04). Sixty-nine (48%) and 31 (42%) heterozygous and homozygous carriers had ≥1 VTE recurrence (p=0.42). In a multivariable model, idiopathic incident VTE and a second thrombophilia were associated with increased and anticoagulation duration >6months with reduced hazards of VTE recurrence; Factor V Leiden genotype was not an independent predictor of recurrence. CONCLUSIONS: Aside from a higher VTE prevalence and modestly reduced VTE-free survival, VTE penetrance and phenotype severity did not differ significantly among homozygous vs. heterozygous carriers, suggesting that VTE prophylaxis and management should not differ by Factor V Leiden genotype.

Recombinant tissue-type plasminogen activator versus a novel dosing regimen of urokinase in acute pulmonary embolism: a randomized controlled multicenter trial.

Thrombolysis of acute pulmonary embolism can be accomplished more rapidly and safely with 100 mg of recombinant human tissue-type plasminogen activator (rt-PA) (Activase) than with a conventional dose of urokinase (Abbokinase) given as a 4,400-U/kg bolus dose, followed by 4,400 U/kg per h for 24 h. To determine the effects of a more concentrated urokinase dose administered over a shorter time course, this trial enrolled 90 patients with baseline perfusion lung scans and angiographically documented pulmonary embolism. They were randomized to receive either 100 mg/2 h of rt-PA or a novel dosing regimen of urokinase: 3 million U/2 h with the initial 1 million U given as a bolus injection over 10 min. Both drugs were delivered through a peripheral vein. To assess efficacy after initiation of therapy, repeat pulmonary angiograms at 2 h were performed in 87 patients and then graded in a blinded manner by a panel of six investigators. Of the 42 patients allocated to rt-PA therapy, 79% showed angiographic improvement at 2 h, compared with 67% of the 45 patients randomized to urokinase therapy (95% confidence interval for the difference in these proportions [rt-PA minus urokinase] is -6.6% to 30.4%; p = 0.11). The mean change in perfusion lung scans between baseline and 24 h was similar for both treatments. Three patients (two treated with rt-PA and one with urokinase) had an intracranial hemorrhage, which was fatal in one. The results indicate that a 2-h regimen of rt-PA and a new dosing regimen of urokinase exhibit similar efficacy and safety for treatment of acute pulmonary embolism.

Venous thromboembolism: disease burden, outcomes and risk factors.

The epidemiology of venous thromboembolism (VTE) in the community has important implications for VTE prevention and management. This review describes the disease burden (incidence), outcomes (survival, recurrence and complications) and risk factors for deep vein thrombosis and pulmonary embolism occurring in the community. Recent comprehensive studies of the epidemiology of VTE that reported the racial demography and included the full spectrum of disease occurring within a well-defined geographic area over time, separated by event type, incident vs. recurrent event and level of diagnostic certainty, were reviewed. Studies of VTE outcomes had to include a relevant duration of follow-up. VTE incidence among whites of European origin exceeded 1 per 1000; the incidence among persons of African and Asian origin may be higher and lower, respectively. VTE incidence over recent time remains unchanged. Survival after VTE is worse than expected, especially for pulmonary embolism. Thirty percent of patients develop VTE recurrence and venous stasis syndrome. Exposures can identify populations at risk but have a low predictive value for the individual. An acquired or familial thrombophilia may predict the subset of exposed persons who actually develop symptomatic VTE. In conclusion, VTE is a common, lethal disease that recurs frequently and causes serious long-term complications. To improve survival and prevent complications, VTE occurrence must be reduced. Better individual risk stratification is needed in order to modify exposures and target primary and secondary prophylaxis to the person who would benefit most.

The incidence of venous thromboembolism among Factor V Leiden carriers: a community-based cohort study.

While Factor V (FV) Leiden is a risk factor for venous thromboembolism (VTE), the incidence of VTE among FV Leiden carriers is uncertain. The objective of the study was to estimate the overall age-specific and pregnancy-related VTE incidence and the relative risk among FV Leiden carriers. In a community-based sample of 3424 south-eastern Minnesota residents, 230 (6.7%) were genotyped as FV Leiden carriers; 220 carriers (mean age = 68 years) could be matched to a non-carrier on age, gender, ethnicity and length of medical history. We performed a retrospective cohort study of carriers and non-carriers by reviewing the complete medical records in the community for demographic and baseline characteristics, pregnancies and live births, and first lifetime VTE. Over 14 722 person-years, 24 (10.9%) carriers developed VTE [overall incidence = 163 (95% CI 104, 242) per 100,000 person-years]. VTE incidence rates for ages 15-29, 30-44, 45-59 and > or = 60 years were 0, 61, 244 and 764 per 100,000 person-years, respectively (cumulative VTE incidence at age 65 years = 6.3%). VTE incidence for carriers did not differ significantly from that for non-carriers except for those > or = 60 years old (relative risk = 3.6; 95% CI 2.0, 6.0). There were 311 live births among 130 women carriers; no VTE events occurred during pregnancy or postpartum [incidence = 0 (95% CI 0, 1186) per 100,000 women-years]. Most FV Leiden carriers do not develop VTE. Among all carriers, those > or = 60 years old are at the highest risk for VTE. The incidence of VTE among asymptomatic women carriers during pregnancy is low and insufficient to warrant prophylaxis.

Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study.

BACKGROUND: The appropriate duration of oral anticoagulation after a first episode of venous thromboembolism (VTE) is uncertain and depends upon VTE recurrence rates. OBJECTIVE: To estimate VTE recurrence rates and determine predictors of recurrence. METHODS: Patients in Olmsted County, Minnesota, with a first lifetime deep vein thrombosis or pulmonary embolism diagnosed during the 25-year period from 1966 through 1990 (N = 1,719) were followed forward in time through their complete medical records in the community for first VTE recurrence. RESULTS: Four hundred four patients developed recurrent VTE during 10,198 person-years of follow-up. The overall (probable/definite) cumulative percentages of VTE recurrence at 7, 30, and 180 days and 1 and 10 years were 1.6% (0.2%), 5.2% (1.4%), 10.1% (4.1%), 12.9% (5.6%), and 30.4% (17.6%), respectively. The risk of recurrence was greatest in the first 6 to 12 months after the initial event but never fell to zero. Independent predictors of first overall VTE recurrence included increasing age and body mass index, neurologic disease with paresis, malignant neoplasm, and neurosurgery during the period from 1966 through 1980. Independent predictors of first probable/definite recurrence included diagnostic certainty of the incident event and neurologic disease in patients with hospital-acquired VTE. Recurrence risk was increased by malignant neoplasm but varied with concomitant chemotherapy, patient age and sex, and study year. CONCLUSIONS: Venous thromboembolism recurs frequently, especially within the first 6 to 12 months, and continues to recur for at least 10 years after the initial VTE. Patients with VTE with neurologic disease and paresis or with malignant neoplasm are at increased risk for recurrence, while VTE patients with transient or reversible risk factors are at less risk.

Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study.

BACKGROUND: Reported risk factors for venous thromboembolism (VTE) vary widely, and the magnitude and independence of each are uncertain. OBJECTIVES: To identify independent risk factors for deep vein thrombosis and pulmonary embolism and to estimate the magnitude of risk for each. PATIENTS AND METHODS: We performed a population-based, nested, case-control study of 625 Olmsted County, Minnesota, patients with a first lifetime VTE diagnosed during the 15-year period from January 1, 1976, through December 31, 1990, and 625 Olmsted County patients without VTE. The 2 groups were matched on age, sex, calendar year, and medical record number. RESULTS: Independent risk factors for VTE included surgery (odds ratio [OR], 21.7; 95% confidence interval [CI], 9.4-49.9), trauma (OR, 12.7; 95% CI, 4.1-39.7), hospital or nursing home confinement (OR, 8.0; 95% CI, 4.5-14.2), malignant neoplasm with (OR, 6.5; 95% CI, 2.1-20.2) or without (OR, 4.1; 95% CI, 1.9-8.5) chemotherapy, central venous catheter or pacemaker (OR, 5.6; 95% CI, 1.6-19.6), superficial vein thrombosis (OR, 4.3; 95% CI, 1.8-10.6), and neurological disease with extremity paresis (OR, 3.0; 95% CI, 1.3-7.4). The risk associated with varicose veins diminished with age (for age 45 years: OR, 4.2; 95% CI, 1.6-11.3; for age 60 years: OR, 1.9; 95% CI, 1.0-3.6; for age 75 years: OR, 0.9; 95% CI, 0.6-1.4), while patients with liver disease had a reduced risk (OR, 0.1; 95% CI, 0.0-0.7). CONCLUSION: Hospital or nursing home confinement, surgery, trauma, malignant neoplasm, chemotherapy, neurologic disease with paresis, central venous catheter or pacemaker, varicose veins, and superficial vein thrombosis are independent and important risk factors for VTE.

Predictors of survival after deep vein thrombosis and pulmonary embolism: a population-based, cohort study.

BACKGROUND: Because reported survival after venous thromboembolism (VTE) varies widely, we performed a population-based retrospective cohort study to estimate survival, compare observed with expected survival, and determine predictors of short-term (< or =7 days) and long-term survival (>7 days) after VTE. METHODS: We followed the 25-year (1966-1990) inception cohort (n = 2218) of Olmsted County, Minnesota, patients with deep vein thrombosis alone (DVT) or pulmonary embolism with or without deep vein thrombosis (PE+/-DVT) forward in time until death or the last clinical contact. RESULTS: During 14 629 person-years of follow-up, 1333 patients died. Seven-day, 30-day, and 1-year VTE survival rates were 74.8% (DVT, 96.2%; PE+/-DVT, 59.1%), 72.0% (DVT, 94.5%; PE+/-DVT, 55.6%), and 63.6% (DVT, 85.4%; PE+/-DVT, 47.7%), respectively. Observed survival after DVT, PE+/-DVT, and overall was significantly worse than expected for Minnesota whites of similar age and sex (P<.001). More than one third of deaths occurred on the date of onset or after VTE that was unrecognized during life. Short-term survival improved during the 25-year study period, while long-term survival was unchanged. After adjusting for comorbid conditions, PE+/-DVT was an independent predictor of reduced survival for up to 3 months after onset compared with DVT alone. Other independent predictors of both short- and long-term survival included age, body mass index, patient location at onset, malignancy, congestive heart failure, neurologic disease, chronic lung disease, recent surgery, and hormone therapy. Additional independent predictors of long-term survival included tobacco smoking, other cardiac disease, and chronic renal disease. CONCLUSIONS: Survival after VTE, and especially after PE+/-DVT, is much worse than reported, and significantly less than expected survival. Compared with DVT alone, symptomatic PE+/-DVT is an independent predictor of reduced survival for up to 3 months after onset, implying that treatment for the 2 disorders should be different.

Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose-finding study.

BACKGROUND: Up to one third of patients who undergo total knee replacement develop deep vein thrombosis after surgery despite receiving low-molecular-weight heparin prophylaxis. Ximelagatran is a novel direct inhibitor of free and clot-bound thrombin. METHODS: We performed a randomized, parallel, dose-finding study of 600 adults undergoing elective total knee replacement at 68 North American hospitals to determine the optimum dose of ximelagatran to use as prophylaxis against venous thromboembolism after total knee replacement. Patients received either ximelagatran twice daily by mouth in blinded fixed doses of 8, 12, 18, or 24 mg or open-label enoxaparin sodium, 30 mg, subcutaneously twice daily, starting 12 to 24 hours after surgery and continuing for 6 to 12 days. We measured the 6- to 12-day cumulative incidence of symptomatic or venographic deep vein thrombosis, symptomatic pulmonary embolism, and bleeding. RESULTS: A total of 594 patients received at least 1 dose of the study drug; 443 patients were evaluable for efficacy. Rates of overall venous thromboembolism (and proximal deep vein thrombosis or pulmonary embolism) for the 8-, 12-, 18-, and 24-mg doses of ximelagatran were 27% (6.6%), 19.8% (2.0%), 28.7% (5.8%), and 15.8% (3.2%), respectively. Rates of overall venous thromboembolism (22.7%) and proximal deep vein thrombosis or pulmonary embolism (3.1%) for enoxaparin did not differ significantly compared with 24-mg ximelagatran (overall difference, -6.9%; 95% confidence interval, -18.0% to 4.2%; P=.3). There was no major bleeding with administration of 24 mg of ximelagatran twice daily. CONCLUSION: Fixed-dose, unmonitored ximelagatran, 24 mg twice daily, given after surgery appears to be safe and effective oral prophylaxis against venous thromboembolism after total knee replacement.

Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study.

BACKGROUND: The incidence of venous thromboembolism has not been well described, and there are no studies of long-term trends in the incidence of venous thromboembolism. OBJECTIVES: To estimate the incidence of deep vein thrombosis and pulmonary embolism and to describe trends in incidence. METHODS: We performed a retrospective review of the complete medical records from a population-based inception cohort of 2218 patients who resided within Olmsted County, Minnesota, and had an incident deep vein thrombosis or pulmonary embolism during the 25-year period from 1966 through 1990. RESULTS: The overall average age- and sex-adjusted annual incidence of venous thromboembolism was 117 per 100000 (deep vein thrombosis, 48 per 100000; pulmonary embolism, 69 per 100000), with higher age-adjusted rates among males than females (130 vs 110 per 100000, respectively). The incidence of venous thromboembolism rose markedly with increasing age for both sexes, with pulmonary embolism accounting for most of the increase. The incidence of pulmonary embolism was approximately 45% lower during the last 15 years of the study for both sexes and all age strata, while the incidence of deep vein thrombosis remained constant for males across all age strata, decreased for females younger than 55 years, and increased for women older than 60 years. CONCLUSIONS: Venous thromboembolism is a major national health problem, especially among the elderly. While the incidence of pulmonary embolism has decreased over time, the incidence of deep vein thrombosis remains unchanged for men and is increasing for older women. These findings emphasize the need for more accurate identification of patients at risk for venous thromboembolism, as well as a safe and effective prophylaxis.

Long-term use of oral anticoagulants and the risk of fracture.

BACKGROUND: Vitamin K participates in bone metabolism and, since oral anticoagulants antagonize vitamin K, their use may increase the risk of osteoporosis. OBJECTIVE: To evaluate fracture risk at all skeletal sites following exposure to oral anticoagulants. METHODS: In a population-based retrospective cohort study, 572 Olmsted County, Minnesota, women 35 years or older at their first lifetime venous thromboembolism event between 1966 and 1990 were followed up for fractures. Risk was assessed by comparing new fractures with the number expected from sex- and age-specific fracture incidence rates for the general population (standardized incidence ratio [SIR]). RESULTS: Altogether, 480 fractures occurred during 6314 person-years of follow-up. Increasing exposure to oral anticoagulation was associated with an increased SIR for vertebral fractures: at less than 3 months of exposure, 2.4 (95% confidence interval [CI], 1.6-3.4); 3 to less than 12 months, 3.6 (95% CI, 2.5-4.9); and 12 months or more, 5.3 (95% CI, 3.4-8.0); and for rib fractures: at less than 3 months, 1.6 (95% CI, 0.9-2.7); 3 to less than 12 months, 1.6 (95% CI, 0.9-2.6); and 12 months or more, 3.4 (95% CI, 1.8-5.7). The data revealed no increased risk for other types of fractures. Oral anticoagulation for 12 months or more was an independent predictor of vertebral fractures (P = .009) and rib fractures (P = .02), but not other fractures. CONCLUSIONS: Long-term exposure to oral anticoagulation is associated with an increased risk of vertebral and rib fractures. The mechanism by which this occurs is still unclear and needs further investigation.

Familial segregation of venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) is postulated as a complex disease, but the heritability and mode of inheritance are uncertain. OBJECTIVE: To determine if VTE (i) segregates in families; (ii) is attributable to inheritance, shared environment, or both; and (iii) the possible mode of inheritance. PATIENTS AND METHODS: In a family-based study of relatives from 751 probands (60% female) with objectively diagnosed VTE (without cancer), we performed complex segregation analyses corrected for mode of ascertainment, considering age-specific, non-gender- and gender-specific liability classes under Mendelian and non-Mendelian assumptions. We tested 12 models categorized into four model sets: (i) sporadic (assumes no genetic effect); (ii) Mendelian inheritance of a major gene (including dominant, additive, recessive or codominant classes); (iii) mixed model (Mendelian inheritance including the same four classes plus the effect of polygenes); and (iv) non-Mendelian. RESULTS: Among the 16 650 relatives, 753 (48% female) were affected with VTE, of whom 62% were first-degree relatives. The sporadic model was rejected in both non-gender- and gender-specific liability class analyses. Among the remaining gender-specific models, the unrestricted (non-Mendelian) inheritance model was favored with an estimated heritability of 0.52. Among the Mendelian models, the dominant mixed model was preferred, with an estimated heritability and major disease allele frequency of 0.62 and 0.25, respectively, suggesting an effect of several minor genes. CONCLUSION: A multifactorial non-Mendelian inheritance model was favored as the cause for VTE, while a model postulating a purely environmental cause was rejected. VTE is probably a result of multigenic action as well as environmental exposures.

The epidemiology of venous thromboembolism in the community.

The incidence of venous thromboembolism exceeds 1 per 1000; over 200,000 new cases occur in the United States annually. Of these, 30% die within 30 days; one-fifth suffer sudden death due to pulmonary embolism. Despite improved prophylaxis, the incidence of venous thromboembolism has been constant since 1980. Independent risk factors for venous thromboembolism include increasing age, male gender, surgery, trauma, hospital or nursing home confinement, malignancy, neurologic disease with extremity paresis, central venous catheter/transvenous pacemaker, prior superficial vein thrombosis, and varicose veins; among women, risk factors include pregnancy, oral contraceptives, and hormone replacement therapy. About 30% of surviving cases develop recurrent venous thromboembolism within ten years. Independent predictors for recurrence include increasing age, obesity, malignant neoplasm, and extremity paresis. About 28% of cases develop venous stasis syndrome within 20 years. To reduce venous thromboembolism incidence, improve survival, and prevent recurrence and complications, patients with these characteristics should receive appropriate prophylaxis.

Efficacy and safety of low molecular weight heparin (ardeparin sodium) compared to warfarin for the prevention of venous thromboembolism after total knee replacement surgery: a double-blind, dose-ranging study. Ardeparin Arthroplasty Study Group.

UNLABELLED: We performed a double-blind, randomized clinical trial to compare the efficacy and safety of three different subcutaneous (s.c.) low molecular weight heparin doses (ardeparin sodium 25, 35, or 50 anti-Xa U/kg twice daily [BID]) to adjusted-dose warfarin (international normalized ratio [INR] = 2.0 to 3.0), as venous thromboembolism prophylaxis after total knee replacement surgery. The primary endpoint was total venous thromboembolism prevalence, defined as deep vein thrombosis discovered at postoperative venography of the operated leg, or symptomatic, objectively-documented pulmonary embolism. Of 860 patients randomized, 680 (79%) had an evaluable venogram or pulmonary embolism. The total venous thromboembolism prevalence was significantly greater among patients prophylaxed with warfarin compared to ardeparin 50 BID (38% vs 27%, p = 0.019); the prevalence among ardeparin 25 BID (37%) and 35 BID (28%) patients was similar to warfarin and ardeparin 50 BID patients, respectively. Overt bleeding occurred in 22 (7.9%) ardeparin 50 BID patients compared to 12 (4.4%) warfarin patients (p = 0.08), and in seven ardeparin 25 and 35 BID patients each (5.2% and 5.0%, respectively). Compared to the warfarin group, blood loss was significantly greater in the ardeparin 50 and 25 BID groups, and not different in the ardeparin 35 BID group. CONCLUSIONS: Postoperative, unmonitored, fixed-dose ardeparin 50 anti-Xa U/kg s.c. BID is significantly more effective than adjusted-dose warfarin for this indication. Although overt bleeding among warfarin and ardeparin 50 BID patients did not differ significantly, ardeparin 50 BID patients had significantly greater blood loss. Ardeparin 35 anti-Xa U/kg s.c.BID may provide efficacy similar to ardeparin 50 anti-Xa U/kg s.c. BID but with reduced bleeding.

Use of low-molecular-weight heparin in the treatment of venous thromboembolic disease: answers to frequently asked questions. The Thrombophilia Center Investigators.

Low-molecular-weight heparins (LMWHs) represent an important therapeutic advance in the treatment of patients with venous thromboembolism. The use of LMWH has potential advantages in comparison with the use of standard unfractionated heparin (UH), including decreased binding to nonanticoagulant-related plasma proteins, greater bioavailability, longer half-life, and lower incidence of the heparin-induced thrombocytopenia syndrome. Because of the predictable anticoagulant response of LMWH when administered subcutaneously, laboratory monitoring is unnecessary, and the drug can be used to treat selected patients with venous thromboembolism in outpatient setting. Numerous studies have shown that the treatment of venous thromboembolism with LMWH is as safe and effective as that with standard UH when both are used appropriately. Allied health personnel can easily teach most patients to self-administer LMWH subcutaneously for home use. Transition of the treatment regimen to oral warfarin anticoagulation necessitates an overlap with heparin (UH or LMWH) for at least 4 to 5 days, and the international normalized ratio should ideally be 2.0 or higher for 2 consecutive days before heparin therapy is discontinued. A practical understanding of the pharmacology, risks, and benefits of LMWH in the treatment of venous thromboembolism will enhance the primary-care physician's ability to care for patients safely and cost-effectively.

Venous thromboembolism associated with hip and knee arthroplasty: current prophylactic practices and outcomes.

Joint registry and hospital data bases for 5,024 total hip and total knee arthroplasties done between 1986 and 1988 at the Mayo Clinic were used to study prophylactic measures and frequency of symptomatic deep venous thrombosis and pulmonary embolism. In virtually all patients, graduated compression stockings were used, with or without another type of prophylaxis. Only 44 of 3,115 patients who underwent hip arthroplasty (1.4%) and 32 of 1,909 patients who underwent knee arthroplasty (1.7%) had definite or probable deep venous thrombosis or pulmonary embolism. Death definitely or possibly attributable to pulmonary embolism occurred in 11 patients who underwent hip arthroplasty (0.35%) and 1 patient who underwent knee arthroplasty (0.05%). Although patients with a history of deep venous thrombosis or pulmonary embolism were more likely to receive warfarin than were patients without such a history, the relative risk of symptomatic deep venous thrombosis or pulmonary embolism in patients who underwent hip arthroplasty and received warfarin postoperatively was approximately half that in patients who received other types of prophylaxis. The risk of death from pulmonary embolism was similarly diminished in the group that received warfarin. The lower rates of these complications in the patients who received warfarin support the prophylactic use of this agent after total hip arthroplasty.

Efficacy and safety of intravenous phytonadione (vitamin K1) in patients on long-term oral anticoagulant therapy.

OBJECTIVES: To determine the safety and efficacy of intravenously administered phytonadione (vitamin K1) in patients on routine oral warfarin anticoagulation. PATIENTS AND METHODS: This retrospective cohort study comprised adults who were taking warfarin, were not bleeding, and received intravenous phytonadione anticoagulation therapy before a diagnostic or therapeutic procedure between September 1, 1994, and March 31, 1996. The main outcome measures were adverse reactions to intravenously administered phytonadione, prothrombin-international normalized ratio time values, the incidence of bleeding and thrombosis after the procedure, and the time between the procedure and return to anticoagulation after resumption of warfarin treatment. RESULTS: Two (1.9%) of the 105 patients studied had suspected adverse reactions to intravenous phytonadione (dyspnea and chest tightness during infusion in both). For the 82 patients who underwent a procedure, the median time from phytonadione to procedure onset was 27 hours (range, 0.7-147 hours), which was significantly less for patients receiving an initial phytonadione dose of more than 1 mg (P=.009). None had thromboembolism after surgery, although 2 (2.4%) of the 82 patients had procedure-associated major bleeding. For the 60 patients resuming warfarin therapy after a procedure, the median time to return to therapeutic anticoagulation was 4.1 days (range, 0.8-31.7 days) and was unaffected by the phytonadione dosage. CONCLUSIONS: Intravenous phytonadione appears to be safe and is effective for semiurgent correction of long-term oral anticoagulation therapy before surgery. In small doses, it does not prolong the patient's time to return to therapeutic anticoagulation.

Incidence of venous thromboembolism in hospitalized patients vs community residents.

OBJECTIVE: To estimate the incidence rates of deep venous thrombosis (DVT) and pulmonary embolism (PE) in hospitalized patients and to compare these with incidence rates in community residents. PATIENTS AND METHODS: We performed a retrospective review of the complete medical records from a population-based inception cohort of patients who resided in Olmsted County, Minnesota, and had an incident DVT or PE from 1980 through 1990. RESULTS: From 1980 through 1990, 911 Olmsted County residents experienced their first lifetime event of definite, probable, or possible venous thromboembolism. Of these residents, 253 had been hospitalized for some reason other than a diagnosis of DVT or PE (in-hospital cases), and 658 were not hospitalized at onset of venous thromboembolism (community residents). The average annual age- and sex-adjusted incidence of in-hospital venous thromboembolism was 960.5 (95% confidence interval, 795.1-1125.9) per 10,000 person-years and was more than 100 times greater than the incidence among community residents at 7.1 (95% confidence interval, 6.5-7.6) per 10,000 person-years. The incidence of venous thromboembolism rose markedly with increasing age for both groups, with PE accounting for most of the age-related increase among in-hospital cases. Incidence rates in the 2 groups changed little over time despite a reduction in the average length of hospital stay between 1980 and 1990. CONCLUSIONS: Venous thromboembolism is a major national health problem, especially among elderly hospitalized patients. This finding emphasizes the need for accurate identification of hospitalized patients at risk for venous thromboembolism and a better understanding of the mechanisms involved so that safe and effective prophylaxis can be implemented.