Lifelong Oral Anticoagulation Research Articles

Thromboembolic and Bleeding Complications Following St. Jude Medical Valve Replacement: Results of the German Experience With Low-Intensity Anticoagulation Study

Study objectives Due to their inherent thrombogenicity, mechanical cardiac valves necessitate lifelong oral anticoagulation. Less intensive oral anticoagulation than recommended earlier might result in a lower incidence of bleeding complications without increasing the embolic hazard significantly. Design Comparison of three different intensities of oral anticoagulation in a prospective, randomized multicenter design. Three months after valve replacement, patients were randomly assigned to stratum A, international normalized ratio (INR) 3.0 to 4.5; stratum B, INR 2.5 to 4.0; or stratum C, INR 2.0 to 3.5. Patients Data from 2,735 patients following aortic valve replacement (AVR; n = 2,024), mitral valve replacement (MVR; n = 553), and combined AVR and MVR (n = 158) with the St. Jude Medical (SJM) valve (St. Jude Medical; St. Paul, MN) between July 1993 and May 1999 were analyzed, covering a total follow-up period of 6,801 patient-years. All complications were registered prospectively. Measurements and results Fifty-one thromboembolic events (TEs) were documented, resulting in a linearized incidence of 0.75 TEs per 100 patient-years, 22 of which were minor (0.32% per patient-year), 10 were moderate (0.15% per patient-year), and 19 were severe (0.28% per patient-year). Thromboembolism following AVR was significantly lower than after MVR (0.53% per patient-year vs 1.64% per patient-year). Patients reported 1,687 bleeding complications (24.8% per patient-year). The vast majority of bleeding complications (n = 1,509; 22.2% per patient-year) were classified as minor, 140 were classified as moderate (2.06% per patient-year), and 38 were classified as severe (0.56% per patient-year). The clinically relevant incidences of moderate and severe TEs and bleeding complications were not significantly different between the three prespecified INR strata. Conclusions The intention-to-treat analysis of the results of the German Experience With Low Intensity Anticoagulation study leads to the unexpected result that despite a sophisticated reporting system, the incidence of moderate and severe TE and bleeding complications was comparably low in all INR strata and more or less within the so-called background incidence reported for an age-related “normal” population. This study supports reexamination of the intensity of anticoagulation in patients with the SJM valve. Due to their inherent thrombogenicity, mechanical cardiac valves necessitate lifelong oral anticoagulation. Less intensive oral anticoagulation than recommended earlier might result in a lower incidence of bleeding complications without increasing the embolic hazard significantly. Comparison of three different intensities of oral anticoagulation in a prospective, randomized multicenter design. Three months after valve replacement, patients were randomly assigned to stratum A, international normalized ratio (INR) 3.0 to 4.5; stratum B, INR 2.5 to 4.0; or stratum C, INR 2.0 to 3.5. Data from 2,735 patients following aortic valve replacement (AVR; n = 2,024), mitral valve replacement (MVR; n = 553), and combined AVR and MVR (n = 158) with the St. Jude Medical (SJM) valve (St. Jude Medical; St. Paul, MN) between July 1993 and May 1999 were analyzed, covering a total follow-up period of 6,801 patient-years. All complications were registered prospectively. Fifty-one thromboembolic events (TEs) were documented, resulting in a linearized incidence of 0.75 TEs per 100 patient-years, 22 of which were minor (0.32% per patient-year), 10 were moderate (0.15% per patient-year), and 19 were severe (0.28% per patient-year). Thromboembolism following AVR was significantly lower than after MVR (0.53% per patient-year vs 1.64% per patient-year). Patients reported 1,687 bleeding complications (24.8% per patient-year). The vast majority of bleeding complications (n = 1,509; 22.2% per patient-year) were classified as minor, 140 were classified as moderate (2.06% per patient-year), and 38 were classified as severe (0.56% per patient-year). The clinically relevant incidences of moderate and severe TEs and bleeding complications were not significantly different between the three prespecified INR strata. The intention-to-treat analysis of the results of the German Experience With Low Intensity Anticoagulation study leads to the unexpected result that despite a sophisticated reporting system, the incidence of moderate and severe TE and bleeding complications was comparably low in all INR strata and more or less within the so-called background incidence reported for an age-related “normal” population. This study supports reexamination of the intensity of anticoagulation in patients with the SJM valve.

Do we Know which Patients with the Antiphospholipid Syndrome Should Receive Long-term High Dose Anti-coagulation?

The standard treatment of thrombosis related to antiphospholipid antibodies is lifelong high-intensity oral anticoagulation. This standard is primarily based on retrospective evaluations of such patients. In this paper we give a summary of current treatment of deep leg vein thrombosis, pulmonary embolism, ischaemic stroke and transient ischaemic events in the general population and relate this to studies performed in patients with the anti-phospholipid syndrome (APS). It is concluded that many patients with APS can be treated with convential doses of oral anticoagulants, and that anti-platelet drugs may have a role in the prevention of cerebral ischaemic events. Data from large scale prospective studies, which are underway, will ultimately identify the optimal treatment in individual patients.

Severe protein C deficiency and aseptic osteonecrosis of the hip joint: a case report

Homozygous congenital protein C deficiency is accompanied by severe thrombophilia. Thrombotic events can be reduced in number and severity by lifelong oral anticoagulation therapy. A 4-year-old boy was first diagnosed as having severe congenital homozygous protein C deficiency during the neonatal period when purpura fulminans occurred as the first manifestation of thrombosis. From this time he had been treated with phenprocoumon (INR 3.5-4.5). During an infection of the upper respiratory tract he developed signs of a new episode of purpura fulminans (INR 2.6). Additional anticoagulation therapy with LMW heparin (Clexane) and protein C concentrate was given while the oral anticoagulation therapy was continued. On the third day of this episode the boy suffered from pain of unknown origin. MRI of the abdomen and of the pelvis revealed nontraumatic osteonecrosis of the hip joint. After a few weeks of immobilisation no special treatment was necessary. One year later he was able to walk with no problem. Aseptic osteonecrosis of the hip joint is associated with a variety of disorders including vascular thrombosis and haemorrhage. Especially young children and handicapped patients with thrombophilia and pain of unknown origin are suspected to have thrombosis in atypical regions.

Oral anticoagulant treatment in patients with mechanical heart valves: how to reduce the risk of thromboembolic and bleeding complications.

Patients with mechanical heart valves have a high risk of thrombus formation on the valve and subsequent systemic embolism. These patients therefore need to receive life-long oral anticoagulation (OAC). Despite this treatment, the overall incidence rate of major thromboembolic complications is still about 1-2 per 100 patient-years. Additionally, these patients have an increased risk of bleeding complications, ranging between 1 and 7 per 100 patient-years. To reduce both types of often very serious complications, the optimal intensity of anticoagulation needs to be established. We found a fairly wide optimal range between 2.5 and 4.9 INR (international normalized ratio) at which the incidence of both untoward events was minimal. As a target intensity, we recommend opting for the middle of this range (INR 3.0-4.0), thereby providing a safe margin at both ends. In order to further reduce thromboembolic and bleeding complications, two approaches can be considered: first of all, the management of OAC treatment needs to be optimized in order to achieve a stable therapeutic effect in as many patients as possible. Secondly, patient characteristics need to be identified that increase the thromboembolic or bleeding risk. Subsequently, the optimal intensity may need to be adjusted accordingly, at an individual level. Possible risk factors for an increased thromboembolic risk are position and type of the prosthesis. Age may increase both the risk of thromboembolism and the risk of haemorrhage.

Anticoagulation after Artificial Valve Replacement with or without Atrial Fibrillation: How Much Is Really Needed?

Insertion of a mechanical artificial heart valve is an absolute indication for the use of lifelong oral anticoagulation, irrespective the presence or absence of atrial fibrillation. Depending on the type and position of the artificial valve the optimal International Normalized Ratio (INR) for these patients is between 2.5 and 4.5, although more prospective studies on the optimal range of oral anticoagulation are necessary. Addition of low dose antiplatelet therapy may further decrease the rate of thromboembolism, but also here more studies are needed. Patients with a bioprosthesis need only oral anticoagulation for the first three months following surgery in the absence of an indication for anticoagulation for other conditions. Atrial fibrillation is often seen in patients with artificial heart valves. Stroke prevention can be instituted by the mandatory oral anticoagulant therapy. The presence of atrial fibrillation and the use of oral anticoagulation prior to heart valve surgery support the indication for the insertion of a mechanical artificial heart valve. However, relative contraindications to oral anticoagulation and the presence of sinus rhythm may favor the use of a bioprosthesis.

Optimal Frequency of Patient Monitoring and Intensity of Oral Anticoagulation Therapy in Valvular Heart Disease.

The antithrombotic effect of oral anticoagulation therapy and the incidence of anticoagulant-related bleeding complications are both closely correlated with the intensity of treatment. The optimal intensity of oral anticoagulation for an individual patient is the target INR that results in the lowest incidence of thromboembolic plus bleeding complications. For patients with native valve lesions, one must consider the cardiac morphology and pathophysiology, for example, the etiology of the disease, left atrial diameters, loss of active atrial contraction (atrial fibrillation), left ventricular pump function, and left ventricular diameters, to determine an optimal INR target. In patients with prosthetic devices, the "thrombogenicity" of the heart valve prosthesis is an additional risk factor for intracardiac thrombus formation and thromboembolic episodes. This "thrombogenicity" may vary significantly from device to device. INR self-testing improves the overall prognosis of patients on lifelong oral anticoagulation therapy because patients remain more precisely within that target therapeutic INR range. For most patients under phenprocoumon, one to two INR measurements per week are a sufficient frequency to provide a stable intensity of anticoagulation.

Heterozygous Protein-S Deficiency: A Study of a Large Kindred

Another family with protein-S deficiency is described here. The defect is characterized by a reduced level of total protein-S antigen; in addition, a markedly reduced level of free protein-S antigen was found. We have studied 20 family members. Ten of them showed reduced levels of protein-S antigen. Five of the affected patients manifested 'thrombophilia'. All the symptomatic patients developed the first thrombotic event at a young age. Heparin and oral anticoagulants were useful for the treatment of the acute phase of the thrombotic events, and in 1 symptomatic patient, the life-long oral anticoagulation treatment was effective in preventing relapses. On the other hand, all the symptomatic but untreated family members developed several recurrent thrombotic episodes.