Gains and losses of warfarin therapy as performed in an anticoagulation clinic.

BACKGROUND: Knowledge of the net benefit of warfarin therapy in routine care is needed to define realistic management recommendations, but lack of randomized controls precludes conventional risk-benefit analysis. OBJECTIVE: Assess risk and benefit of routine warfarin therapy in an anticoagulation clinic. DESIGN: Retrospective observational analysis. PATIENTS: A total of 1435 outpatients on warfarin for a total of 1613 patient years, treated to prevent the target events recurrent venous thromboembolism (VTE) or myocardial infarction (MI), and stroke in patients with atrial fibrillation (AF) or mechanical heart valves. MEASUREMENTS: Major bleeding and thromboembolic (TE) events and all deaths. CALCULATIONS: Expected annual target event rates without warfarin were from published data. Differences between combined major events observed with warfarin, and expected without warfarin were calculated. RESULTS: In the total material, annual rates were 3.0% major TE events, 1.1% major bleeding events, 0.12% fatal bleeding, and a benefit/risk ratio of 3.8. The net gain, expressed in reduced combined bleeding and target TE annual event rate, was 9.9% in secondary prophylaxis in AF, 4.4% in VTE patients, 2.7% in post-MI patients, 2.4% in primary prophylaxis in AF and 0.6 in patients with mechanical heart valves. The apparent benefit/risk ratio was 3.9 in VTE patients, 5.8 in AF patients and 1.1 in patients with mechanical heart valves. CONCLUSION: Net effects of prolonged warfarin therapy in patients with VTE and AF performed in an anticoagulation clinic have an acceptable risk/benefit ratio, comparable with what has been obtained in elective clinical trials.

On-pump versus off-pump coronary artery bypass: independent risk factors and off-pump graft patency.

OBJECTIVE: Current knowledge on off-pump coronary artery bypass (OPCAB) generally stems from single surgeons' experience or from series where OPCABs constituted a minor fraction of coronary operations. The present center decided to venture as far into OPCAB as possible during 1999. The present series thus represents the average surgeon's experience. METHODS: During 1999, 533 patients underwent coronary artery bypass grafting using cardiopulmonary bypass (CPB) in 368 and OPCAB in 165 including the circumflex artery (CX) area in 91. Coronary arteriography was performed before discharge in the first 103 OPCAB patients. RESULTS: The CPB and OPCAB groups differed as regards left ventricular ejection fraction (53+/-13 versus 57+/-11, P < 0.0001) and frequency of triple-vessel or left main stem disease (84 versus 32%, P < 0.0001) but were comparable as regards diabetes (12%), prior myocardial infarct (57%), unstable angina (21%), and previous heart surgery (3%). Using multivariate analyses, 30-day mortality (1.3%), P-creatine kinase myocardial band (CKMB) > 80 microg/l (11.1%), re-sternotomy for bleeding (4.5%) or dehiscense (1.7%), transitory cerebral ischemia and stroke (1.7%), supraventricular tachycardia (27.4%), and hospital stay (mean 8 days) were unrelated to off- versus on-pump surgery as well as to OPCAB in triple-vessel disease. CX branches < or = 1mm, > or = 5 distal anastomoses, prior heart surgery, right coronary artery (RCA) branches < or = 1.5mm, 8-21 days old myocardial infarct, female gender, and preoperative acute arrhythmia (among others) were identified as independent risk factors for mortality or increased CKMB in all 533 patients. The latter five risk factors were reproduced in the OPCAB group isolated. The patency in the 103 OPCABs was 95.3, 91.8, and 85.3% in the left anterior descending artery (LAD), CX, and RCA, respectively. Patency was inversely related to diameter of the grafted vessel in the LAD and CX areas, unlike the RCA area. CONCLUSIONS: The results after beating heart surgery were good also in patients with triple-vessel disease, but specific gains relative to on-pump surgery could not be shown. The independent risk factors in the OPCAB group may indicate relative contraindications for OPCAB grafting.

[Olav Egeberg--hereditary antithrombin deficiency and thrombophilia]. / Olav Egeberg--arvelig antitrombinmangel og trombofili.

In 1965 Olav Egeberg (1916-77) presented the first report that linked a defined, hereditary defect in the control of blood coagulation to thrombotic disease. Having examined a family in which several members had sustained venous thrombosis, he demonstrated that antithrombin activity was clearly subnormal in the affected members. Heparin cofactor activity was also subnormal in these persons. This supported the hypothesis that the two activities might reside in a single protein. The condition was inherited as an autosomal dominant trait. Egeberg's publication initiated thrombophilia as a rewarding research area, and also as an important clinical discipline.

Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease.

BACKGROUND: Low-molecular-weight heparins administered subcutaneously once or twice daily have been reported to be as safe and efficacious as intravenous unfractionated heparin in the treatment of acute venous thromboembolic disease. OBJECTIVE: To determine whether subcutaneous enoxaparin administered once or twice daily is as effective as continuously infused unfractionated heparin in acute symptomatic venous thromboembolic disease. DESIGN: Randomized, controlled, partially blinded equivalence trial. SETTING: 74 hospitals in 16 countries. PATIENTS: 900 patients with symptomatic lower-extremity deep venous thrombosis, including 287 (32%) with confirmed pulmonary embolism. INTERVENTIONS: Initial therapy with dose-adjusted intravenous unfractionated heparin compared with subcutaneous enoxaparin at fixed dosages of 1.0 mg/kg of body weight twice daily or 1.5 mg/kg once daily. Long-term oral anticoagulation was started in all patients within 72 hours of randomization. MEASUREMENTS: Clinical end points assessed during a 3-month follow-up period. RESULTS: Equivalent efficacy was seen in the heparin group and both enoxaparin groups. Symptomatic venous thromboembolism recurred in 12 of 290 patients receiving unfractionated heparin (4.1%), 13 of 298 patients receiving once-daily enoxaparin (4.4%), and 9 of 312 patients receiving twice-daily enoxaparin (2.9%). Compared with unfractionated heparin, the treatment difference was 0.2% (95% CI, -3.04% to 3.49%) for once-daily enoxaparin and -1.2% (CI, -4.2% to 1.7%) for twice-daily enoxaparin. Incidence of major hemorrhage did not differ among the three treatment groups. Major hemorrhage occurred in 6 of 290 patients (2.1%) in the unfractionated heparin group, 5 of 298 patients (1.7%) in the once-daily enoxaparin group, and 4 of 312 patients (1.3%) in the twice-daily enoxaparin group. CONCLUSIONS: Subcutaneous enoxaparin once or twice daily is as effective and safe as dose-adjusted, continuously infused unfractionated heparin in the prevention of recurrent symptomatic venous thromboembolic disease.

[Contrast echocardiography. Basic principles and clinical applications]. / Kontrastekkokardiografi. Basale principper og kliniske applikationer.

Recent advances in ultrasound technology and intravenous contrast agents have made it possible for contrast echocardiography to move from bench to bedside. Ultrasound contrast agents enhance endocardial border delineation and the Doppler signal, which may improve the diagnostic accuracy of echocardiography in selected patients. The most exciting feature of contrast echocardiography is its capability to achieve a quantitative assessment of myocardial perfusion, and the method may thus provide a range of clinical applications in patients with ischaemic heart disease.

Tissue factor pathway inhibitor (TFPI) in disseminated intravascular coagulation: low levels of the activated factor X-TFPI complex.

Tissue factor pathway inhibitor (TFPI) fractions and coagulation markers were determined in 26 patients with disseminated intravascular coagulation (DIC). Thrombin-antithrombin complex and fibrin monomer values were markedly elevated in all patients (P < 0.01). The median TFPI activity level (2.1 nmol/l) was lower than in normal controls (2.6 nmol/l; P < 0.01). The median free TFPI level was within the normal reference range, but seven patients had levels above and nine patients had levels below normal range. The median activated factor X (FXa)-TFPI complex level in patients (0.13 nmol/l) was lower than in controls (0.18 nmol/l; P < 0.01). Only one patient had a FXa-TFPI complex level above the normal range, while eight patients had levels below. In conclusion, TFPI activity, free TFPI antigen and FXa-TFPI complex levels vary considerably in DIC. Activation of coagulation may increase TFPI levels, as reported by other workers and supported by a positive correlation between tissue factor and free TFPI in the present material. A negative correlation between fibrin monomer and free TFPI (r = -0.46, P = 0.019) might indicate that hyperactive coagulation leads to consumption of TFPI. Subnormal FXa-TFPI levels in DIC, possibly caused by consumption, may imply a reduced capacity to inactivate the triggering factor VIIa-tissue factor complex.

Lipoprotein(a), other lipoproteins and hemostatic profiles in patients with ischemic stroke: the relation to cardiogenic embolism.

Lipoprotein and hemostatic profiles including coagulation inhibitors were determined in 136 patients with acute ischemic stroke. Based on clinical examination, cerebral computed tomography, Doppler ultrasonography of precerebral arteries and transthoracic echocardiography, the strokes were classified as cardioembolic (n = 38), non-cardioembolic (n = 92), and mixed cardioembolic/hypertensive (n = 6). Patients with cardioembolic stroke were older than patients with non-cardioembolic stroke. Lipoprotein(a) was higher in the cardioembolic than in the non-cardioembolic group. Lipoprotein(a) was not significantly correlated to the other lipid levels and may represent an independent lipid risk factor. The non-cardioembolic group had higher levels of total cholesterol, triglycerides, total cholesterol/high-density lipoprotein cholesterol ratio, low-density lipoprotein cholesterol, apolipoprotein A1, and apolipoprotein B. The cardioembolic group had higher concentrations of fibrinogen and D-dimer, and lower levels of antithrombin, protein C, protein S and heparin cofactor 2 than the non-cardioembolic group. The differences in the hemostatic profile are consistent with thrombosis due to activated coagulation being more involved in the pathogenesis of cardioembolic than of non-cardioembolic stroke. Lipoprotein(a) seems to be more associated with coagulation markers of thrombosis than with atherosclerosis, whereas the other lipids mainly seem to be risk factors for atherosclerosis.

Predictive value of coagulation markers concerning clinical outcome 90 days after anterior myocardial infarction.

To study the predictive value of coagulation markers concerning clinical outcome, prothrombin fragment F1.2 (F1.2), fibrin monomer antigen (FM), D-Dimer (DD), and fibrinogen were measured in plasma samples drawn 2 and 7 days after acute myocardial infarction (AMI) in 314 consecutive patients randomized in a clinical trial of low molecular weight heparin (Dalteparin) (the FRAMI trial). Placebo-treated patients suffering death or new AMI within 90 days had significantly higher levels at day 2 of FM (Enzymun-Test FM), and DD (TINAquant D-dimer) (p = 0.001 and 0.02, respectively), but not F1.2 (Enzygnost F1.2 micro), relative to those without serious clinical events. At day 7 all three coagulation activation markers were significantly higher in patients with subsequent adverse clinical outcome. The Dalteparin group had significantly lower levels of these markers as compared to the placebo group. Left ventricular (LV) thrombus formation was not associated with changes in coagulation activation. However, patients with thrombus had significantly higher fibrinogen levels than those without thrombus (p = 0.004 day 2), independent of treatment group. Thus, markers of coagulation activation may be useful in stratification of patients when estimating risk for adverse clinical outcome after AMI. Furthermore, elevated fibrinogen levels are associated with increased risk of LV thrombus formation.

Recurrent endocarditis in silver-coated heart valve prosthesis.

BACKGROUND AND AIM OF THE STUDY: In order to prevent prosthetic valve endocarditis (PVE), the implantation of a new silver-coated sewing ring has been introduced to provide peri- and postoperative protection against microbial infection. METHODS: A 56-year-old woman with aortic stenosis had elective replacement with a St. Jude Medical mechanical valve fitted with a silver-coated sewing ring (Silzone). The patient developed early PVE, which necessitated reoperation after one month. Despite a second Silzone prosthesis being implanted, the endocarditis recurred. During a third operation an aortic homograft was implanted, and after six months a fourth operation was performed for a pseudoaneurysm at the base of the homograft, in proximity to the anterior mitral valve leaflet. RESULTS: The diagnosis of PVE was confirmed by the presence of continuous fever, transesophageal echocardiography and growth of penicillin-resistant Staphylococcus epidermidis from the valve prosthesis. CONCLUSION: The implantation of all prosthetic valves is encumbered with a risk of endocarditis. Although silver has bacteriostatic actions, the advantages of silver-coated prostheses in the treatment of this condition have yet to be assessed in clinical trials.

Fibrin monomer antigen: a novel marker of mortality in acute myocardial infarction.

AIMS: A novel sensitive method for analyses of soluble fibrin monomer antigen was used to assess the predictive value of fibrin monomer when estimating mortality after acute myocardial infarction. METHODS AND RESULTS: Fibrin monomer was measured in plasma samples from 293 patients enrolled in a randomized clinical trial of low molecular weight heparin (dalteparin) in acute myocardial infarction (the FRAMI trial). Samples taken on days 2 and 7 were analysed using the Enzymun-Test FM(R)(Boehringer Mannheim, Germany). Non-survivors had significantly higher fibrin monomer levels relative to survivors (day 2, median (min-max): 1.8 mg. l-1(<0.01-73.1) vs 0.4 mg. l-1(<0. 01-103.5), P<0.0001). Fibrin monomer levels were significantly associated with congestive heart failure (P<0.001), enzymatic infarct size (P<0.0001), dalteparin treatment (P<0.001), and thrombolytic therapy (P=0.016). The relationship between fibrin monomer and mortality remained statistically significant after adjustment for these variables. In logistic regression analyses, fibrin monomer levels, age and congestive heart failure were all independent predictors of fatal outcome. CONCLUSIONS: Increased fibrin monomer level is an independent predictor of mortality in patients with myocardial infarction. It allows further risk stratification when combined with known risk factors such as age and presence of congestive heart failure.

[Low molecular heparin in a pregnant women with heart valve prosthesis]. / Lavmolekylaert heparin ved mekanisk hjerteventil og graviditet.

Women with a prosthetic heart valve who wish to bear a child face a difficult choice. Continued medication with warfarin during pregnancy will offer her a reasonable good protection against thrombosis, but carries a considerable risk of teratogenic effects. Subcutaneously administered heparin is an alternative to warfarin. Standard (unfractionated) heparin has not offered sufficient protection against valve thrombosis, which may be a life-threatening complication. We were contacted by a woman who wished to become pregnant and who did not want to use warfarin if this implied a risk for the foetus. We followed a protocol using low molecular weight heparin in rather high doses. The dose was adjusted according to the results of blood test controls, which confirmed increased need for anticoagulation as the pregnancy evolved. Serial eccocardiography excluded valve thrombosis. The woman needed psychological support from her general practitioner. No complications occurred, and she gave birth to a normal child. We describe the various alternatives for anticoagulant treatment in pregnant women with mechanical heart valves. The choice of anticoagulant regimen and their consequences must be thoroughly discussed with the woman.

[Venous thromboembolism--incidence and risk factors in Oslo]. / Venøs tromboembolisme--insidens og risikofaktorer i Oslo.

Over a period of three years, 378 patients with objectively verified venous thromboembolism were treated at Aker University Hospital. Below the age of 60, men and women had about the same incidence of venous thromboembolism, but that age the incidence was significantly higher among men than among women. Incidence increased exponentially with age, from about 1:10,000 at age 20 to about 1:1,000 at age 50. The incidence found here is lower than in earlier Nordic studies. The great majority of the patients (93%) had deep venous thrombosis in the lower extremities, 11% had symptomatic and verified pulmonary embolism, and 1% had their thrombus in an inner organ vein. 23% of patients were previously treated for venous thromboembolism, and 22% had cancer. Seven women were on oral contraception, and 22 used postmenopausal hormone substitution. An obvious temporary precipitating factor was present in 42% of the patients, while 36% had a spontaneous venous thromboembolism. Hereditary thrombophilic disorder was found in 32% of patients below the age of 60.

Elevated TFPI in malignant disease: relation to cancer type and hypercoagulation.

We have previously reported high levels of the coagulation inhibitor TFPI in the blood of patients with gastrointestinal cancer. TFPI is not an acute-phase reactant, but high levels have also been reported in patients with septicaemia and disseminated intravascular coagulation (DIC). To study its relationship with other types of malignancy, TFPI activity was first determined in plasma samples from 214 patients with various malignancies. In a second cohort of 83 patients, total and free TFPI antigen, protein C, antithrombin, fibrin monomer and D-dimer were also measured. Elevated TFPI activity and antigens were found in about half of the patients with solid tumours. In contrast, elevated TFPI was rare in haematological malignancies (12%). In the 18 patients with acute nonlymphocytic leukaemia (ANLL), elevated free TFPI was found only in patients who also had DIC. No correlation was found between TFPI levels and fibrin monomer or D-dimer levels. Only four out of 20 patients with solid tumours had normal levels of fibrin monomer and D-dimer, yet three out of these four had elevated TFPI. In conclusion, elevated TFPI in ANLL is related to the coexistence of DIC. In solid tumour disease increased TFPI may reduce protective fibrin formation, but the pathogenic mechanism is as yet unknown.

[Prevention of thrombosis in medical patients--documentation is missing]. / Tromboseprofylakse til medisinske pasienter--dokumentasjon savnes.

A questionnaire regarding current routines for thromboprophylaxis was distributed to all 63 medical departments in Norwegian hospitals; 58 (92%) responded. All departments declared that they practiced prophylaxis against venous thromboembolism, and in most departments the decision (as to whether to practice prophylaxis) was left to the physicians. Written guidelines were used in only 12 departments, 21% of those who responded. The indications listed were those associated with a particular risk of thrombosis. Previous thrombosis and malignancy were listed less frequently than expected. There is a need for specific evidence regarding the efficacy and safety of thromboprophylaxis in medical patients. In our opinion this requires that further placebo-controlled studies be carried out.