[Computer aided dosage management of phenprocoumon anticoagulation therapy. Clinical validation]. / Rechnergestützte Dosierung in der Antikoagulationstherapie mit Phenprocoumon. Validierung für den klinischen Einsatz.

UNLABELLED: A recently developed multiparameter computer-aided expert system (TheMa) for guiding anticoagulation with phenprocoumon (PPC) was validated by a prospective investigation in 22 patients. The PPC-INR-response curve resulting from physician guided dosage was compared to INR values calculated by "twin calculation" from TheMa recommended dosage. Additionally, TheMa was used to predict the optimal time to perform surgery or invasive procedures after interruption of anticogulation therapy. RESULTS: Comparison of physician and TheMa guided anticoagulation showed almost identical accuracy by three quantitative measures: Polygon integration method (area around INR target) 616.17 vs. 607.86, INR hits in the target range 166 vs. 161, and TTR (time in therapeutic range) 63.91 vs. 62.40 %. After discontinuation of anticoagulation therapy, calculating the INR phase-out curve with TheMa INR prognosis of 1.8 was possible with a standard deviation of 0.50 ± 0.59 days. CONCLUSION: Guiding anticoagulation with TheMa was as accurate as Physician guided therapy. After interruption of anticoagulant therapy, TheMa may be used for calculating the optimal time performing operations or initiating bridging therapy.

Computer-aided dosage in oral anticoagulation therapy using phenprocoumon. Problems and approaches.

Oral anticoagulation using vitamin K antagonists has been established for over 50 years. Although it is highly effective in preventing thromboembolic incidents, its therapeutic control still remains problematic. Therefore, a computer-aided approach is recommended for deriving dosages. Up to now, the dosage is often based on the visual inspection of previous INR measurements, average weekly doses, and the INR target range. Statistical variations of measurement results and time-delayed effects of dosages, however, frequently result in the misinterpretation of data and suggest pseudo-trends. Treating physicians are not only responsible for determining the patient-specific maintenance dose, but must also respond to deviating INR values, overdosage or underdosage, initiate the oral anticoagulation therapy, and control the INR level in case of a new target range (bridging). Instructive examples are provided to illustrate the described difficulties. A computer-aided expert system is currently developed to ensure the therapeutic safety under the specified conditions. We present preliminary results from a study designed to validate mathematical models underlying such expert systems.

A prospective multicentre study on the safety of long-term intensive plasmapheresis in donors (SIPLA).

BACKGROUND AND OBJECTIVES: The safety of chronic intensive donor plasmapheresis has not been determined in large prospective studies examining dropout rates, dropout reasons and predictors of withdrawals. MATERIALS AND METHODS: Twenty-one plasma centres recruited 3783 donors who were switched from a moderate to an intensive plasmapheresis programme and observed over a 3-year period. Individuals weighing < 70 kg and > or = 70 kg donated 750 ml and 850 ml of plasma per session, respectively. The maximum of annual donations was limited to 60. Total serum protein (TSP) and haemoglobin (Hb) or haematocrit (Hct) were determined at each donation, and immunoglobulin G (IgG) at every fifth donation. Dropout rates, dropout reasons and potential predictors of withdrawal were analysed. RESULTS: Dropouts were predominantly due to socioeconomic (49.2% of all donors) or medical reasons not related to plasma donations (10.4% of all donors). Sixteen per cent of donors dropped out when IgG, TSP or Hb levels fell below threshold values. Severe clinical adverse events related to plasmapheresis were observed in five subjects. The incidence in severe cardiovascular diseases was lower in donors than in the general population. The risk factors that led to dropping out as a result of low IgG, TSP or Hb levels included younger age, female gender, low initial IgG levels and a high donation frequency. Neither body weight nor the amounts of plasma donated per kilogram of body weight per session were associated with ceasing due to medical reasons, whether related or unrelated to plasma donations. Females and males within the respective lowest body weight category were not at higher risk of dropping out. CONCLUSION: Long-term intensive donor plasmapheresis under conditions investigated in this study is safe. All donors weighing > or = 70 kg are safely able to donate 850 ml of plasma in each session up to 60 times per year, provided that they are carefully monitored.

Reduction of gaseous microembolism during aortic valve replacement using a dynamic bubble trap.

Serious postoperative psycho-neurological dysfunction is at least partially attributed to the occurrence of gaseous microbubbles in the arterial line of extracorporeal circulation (ECC). Therefore, we investigated in a prospective randomized double blind study whether the usage of dynamic bubble trap (DBT) will reduce microbubble load of patients undergoing aortic valve replacement. Patients (n = 41) were divided into group I (GI, n = 22) with DBT introduced into the arterial line of ECC and group II (GII, n = 19) with placebo-DBT instead. Doppler ultrasonography was used for detection of microbubbles before and after DBT, and for detection of high intensity transient signals (HITS) within the middle cerebral artery. The recording time during ECC was divided into period 1 (P1, until aortic clamp removal) and period 2 (P2, clamp removal until the end of ECC). A significant reduction of microbubble load was found in GI only (p < 0.0001 for ECC; p < 0.0001 for P1; p < 0.0025 for P2). A significant difference in number of HITS between the groups was observed in P1 only (p < 0.002 left middle cerebral artery, p < 0.005 right middle cerebral artery), since in P2 the trapped air in left chamber can go to the supraaortal vessels without passing ECC. In conclusion the use of DBT cannot substitute careful venting after aortic declamping. Nevertheless, reduction of HITS in the cross-clamped period of ECC justifies the use of DBT in patients undergoing open chamber surgery.

Trapidil decreases the aggregation of platelets from heart transplant recipients ex vivo.

Heart transplant recipients show platelet hyperaggregability, which may be related to the incidence of graft vasculopathy. We investigated whether trapidil can inhibit the aggregation of platelets from these patients. Platelet count, mean platelet volume (MPV), and adenosine diphosphate (ADP)-induced platelet aggregation were determined in 18 heart transplant recipients and 12 healthy subjects. Additionally, platelet-rich plasma from the patients was incubated with trapidil or with saline, prior to measuring ADP-induced aggregation. The MPV was significantly greater in patients compared to controls (9.4+/-1.1 vs 8.5+/-0.7 fL; P=.01), and ADP-induced platelet aggregation was significantly increased in patients compared to controls (81.2%+/-13.1% vs 69.6%+/-16.2%; P=.04, respectively). The trapidil-treated samples showed significantly decreased platelet aggregation compared to the control samples (24.2%+/-12.6% vs 66.7%+/-11.7%; P<.001). Platelets from heart transplant recipients showed an increased MPV and increased ADP-induced aggregation. Trapidil effectively reduced the ADP-induced aggregation ex vivo.

Self-management of oral anticoagulation in nonvalvular atrial fibrillation (SMAAF study).

UNLABELLED: Most patients with atrial fibrillation are at risk of suffering thromboembolic events. This risk can be reduced by twothirds by efficient anticoagulation. This prospective multi-center trial investigated whether the quality of treatment can be improved by self-management in patients with atrial fibrillations (SMAAF Study) compared to conventional patient management by the family doctor. METHODS: Two thousand patients suitable for self-management were to be randomized into the two arms of the study. In the period of investigation from December 1999 to July 2001, only 202 patients (64.3+/-9.2 years, 69.3% men) consented to participate. The study was discontinued prematurely since the number of patients was too low. As a consequence, the group comparison is confined to the evaluation of the INR values measured using the two-tailed t test. RESULTS: Of the 202 patients included, 101 were assigned to the self-management group (64.6+/-9.6 years, 71.4% men) and 101 (64.1+/-8.9 years, 61.4% men, n.s.) were assigned to the group managed by the family doctor. The total number of INR measurements was 2 865. This comprised 2 072 measurements in patients under self-management and 793 in the family doctor group. The values were within the target range significantly more frequently (p=0.0061) in patients under self-management (67.8%) as compared to the family doctor group (58.5%). There was a trend with regard to the time within target range, but the difference was not significant (178.8+/-126 days as compared to 155.9+/-118.4 days). In the self-management group, there were two severe hemorrhages, and there was one thromboembolic event in the family doctor group. CONCLUSION: Management of oral anticoagulation by INR self-management in patients with atrial fibrillation is not inferior to conventional care.

The dynamic air bubble trap reduces cerebral microembolism during cardiopulmonary bypass.

OBJECTIVE: Neuropsychologic disorders are common after coronary artery bypass operations. Air microbubbles are identified as a contributing factor. A dynamic bubble trap might reduce the number of gaseous microemboli. METHODS: A total of 50 patients undergoing coronary artery bypass operation were recruited for this study. In 26 patients a dynamic bubble trap was placed between the arterial filter and the aortic cannula (group 1), and in 24 patients a placebo dynamic bubble trap was used (group 2). The number of high-intensity transient signals within the proximal middle cerebral artery was continuously measured on both sides during bypass, which was separated into 4 periods: phase 1, start of bypass until aortic clamping; phase 2, aortic clamping until rewarming; phase 3, rewarming until clamp removal; and phase 4, clamp removal until end of bypass. S100 beta values were measured before, immediately after, and 6 and 48 hours after the operation and before hospital discharge. RESULTS: The bubble elimination rate during bypass was 77% in group 1 and 28% in group 2 (P <.0001). The number of high-intensity signals was lower in group 1 during phase 1 (5.8 +/- 7.3 vs 16 +/- 15.4, P <.05 vs group 2) and phase 2 (6.9 +/- 7.3 vs 24.2 +/- 27.3, P <.05 vs group 2) but not during phases 3 and 4. Serum S100 beta values were equally increased in both groups immediately after the operation. Group 2 patients had higher S100 beta values 6 hours after the operation and significantly higher S100 beta values 48 hours after the operation (0.06 +/- 0.14 vs 0.18 +/- 0.24, P =.0133 vs group 2). Age and S100 beta values were correlated in group 2 but not in group 1. CONCLUSION: Gaseous microemboli can be removed with a dynamic bubble trap. Subclinical cerebral injury detectable by increases of S100 beta disappears earlier after surgical intervention.

INR self-management permits lower anticoagulation levels after mechanical heart valve replacement.

BACKGROUND: The Early Self Controlled Anticoagulation Trial (ESCAT I) showed that anticoagulation self-management after mechanical heart valve replacement decreased complication rates by maintaining INR levels closer to the target range than International Normalized Ratio (INR) home doctor management. The therapeutic range for the INR in that study was between 2.5 and 4.5 for all positions of prosthetic valves. ESCAT II should find out whether lowering the target range for INR self-management would further reduce complication rates. METHODS: ESCAT II is a prospective controlled randomized (valves: St. Jude Medical Standard or Medtronic Hall, treatment: conventional/low-dose) multicenter study with 3,300 patients. We present interim results of 1,818 patients. 908 were categorized as having a low-dose target range, which was INR 1.8 to 2.8 for prostheses in aortic position and 2.5 to 3.5 for prostheses in mitral position or in combined valve replacement. The control group (conventional group) with 910 patients aimed at an INR of 2.5 to 4.5 for all valve positions. RESULTS: In the conventional group, 74% of INR values measured were within the therapeutic range. In the low-dose group, 72% of the values were within that range. The linearized thromboembolism rate (% per patient year) was 0.21% for both groups. The bleeding complication rate was 0.56% in the low-dose regimen group versus 0.91% in the conventional group. CONCLUSIONS: Early onset INR self-management under oral anticoagulation after mechanical heart valve replacement enables patients to keep within a lower and smaller INR target range. The reduced anticoagulation level resulted in fewer grade III bleeding complications without increasing thromboembolic event rates.

[Essential cryoglobulinemic vasculitis with severe peripheral neuropathy and neurogenic muscular atrophy -- inducing remission by cascade filtration]. / Essentielle kryoglobulinämische Vaskulitis mit hochgradiger peripherer Neuropathie und neurogener Muskelatrophie -- Remissionsinduktion mittels Differenzialfiltrationsapherese.

We report on a 60 year old patient with peripheral neuropathy, neurogenic muscular atrophy, skin ulcers, arthritis and weakness. Detection of cryoglobulins in association with typical clinical symptoms, exclusion of hepatitis C and any other disease led to a rare diagnosis: essential cryoglobulinemic vasculitis. The case demonstrates not only the difficult diagnostic process but also the problems of an adequate and effective therapy. Since the usual immunosuppressive treatments such as methotrexate, high dose corticosteroid and intermittent intravenous pulse cyclophosphamide therapy (Austin's scheme) failed, we performed plasmapheresis (cascade filtration), which brought about an immediate and long-term remission. Besides discussing various types of plasmapheresis procedures and potential pathophysiological mechanisms, we point out that this therapy could find an early use in severe essential cryoglobulinemic vasculitis because of its excellent risk/benefit ratio.

Significant reduction of air microbubbles with the dynamic bubble trap during cardiopulmonary bypass.

Air microbubbles mostly occur unnoticed during cardiopulmonary bypass and are predominantly responsible for serious postoperative psychoneurological dysfunction. A dynamic bubble trap (DBT), which removes air microbubbles from the arterial blood, was tested in a clinical study. The aim was to evaluate the efficiency of microbubble removal under clinical conditions. As blood passes through the DBT, which is placed in the arterial line between the arterial filter and arterial cannula, it is converted into a rotating stream. The bubbles are directed to the centre of the blood flow and are collected in the distal end of the DBT, from where they are returned to the cardiotomy reservoir. Doppler ultrasonography was used to detect the microbubbles before and after the DBT, and also the number of high-intensity transient signals (HITS) in the right and left middle cerebral artery during extracorporeal circulation. A significant reduction of microbubbles in the arterial line (3,990 before DBT, 537 after, p < 0.001) and HITS in the brain (51 in the DBT group, 77 in the placebo group, p = 0.04) was measured.

Lipid reductions by low-density lipoprotein apheresis: a comparison of three systems.

There are currently three established low-density lipoprotein (LDL) apheresis systems: immunoadsorption, heparin-induced extracorporeal LDL precipitation (HELP), and dextran sulfate. We treated the same patient with all three systems and compared the lipid reductions achieved. A total of 135 consecutive treatments were studied, 57 with immunoadsorption, followed by 30 with HELP and 48 with dextran sulfate adsorption. The mean plasma volume (mean +/- SD) treated was 4.9 +/- 0.05, 3.08 +/- 0.091, and 3.39 +/- 0.71 L, respectively. The LDL-cholesterol (LDL-C) reduction was 75.5% +/- 7.4%, 61.6% +/- 5.1%, and 57.1% +/- 12.4%, respectively (P < .001 for immunoadsorption vHELP and dextran sulfate). The mean removal efficiency (mass removed/plasma volume treated) for LDL-C was 1.0 +/- 0.12, 1.42 +/- 0.25, and 1.15 +/- 0.21 g/L, respectively (P < .001 for HELP v immunoadsorption and dextran sulfate). The mean LDL-C plasma concentration before apheresis was 199 +/- 23.9, 201 +/- 25.7, and 186 +/- 28 mg/dL, respectively (P < .001 for dextran sulfate adsorption v immunoadsorption and HELP). Among the three LDL apheresis systems, immunoadsorption caused the greatest percent reduction in LDL-C, while HELP eliminated LDL-C from the plasma most efficiently. Dextran sulfate was similar to HELP in terms of LDL-C reduction, and its removal efficiency was similar to immunoadsorption. Dextran sulfate was also associated with the lowest pretreatment plasma LDL-C concentration.

[Background and evaluation plan of a study on self-management of anticoagulation in patients with non-valvular atrial fibrillation (SMAAF Study)]. / Hintergrund und Prüfplan der Studie zum Selbstmanagement der Antikoagulation bei Patienten mit nichtvalvulärem Vorhofflimmern (SMAAF-Studie).

The objective of this open, randomized, multicenter study is to investigate the benefits and economic efficiency of self-management of oral anticoagulation in patients with atrial fibrillation (SMAAF study) in comparison with a group of patients given conventional care by a general practitioner or specialist. Two thousand patients suitable for self-management will be assigned at random to either the self-management group or the control group. The numbers of thromboembolic and hemorrhagic complications requiring treatment during the 2-year follow-up period will be recorded as the primary end point. The secondary endpoint variables will be maintenance of the INR value in the individual target range, INR variance, the course of complications over time, and the cost efficiency of self-management compared with the routine procedures. The last of these parameters will include the diagnostic and/or therapeutic measures carried out, the duration of inpatient hospital treatment, and the social consequences (subsequent rehabilitation treatment, inability to work, forced retirement). The estimate of the required number of patients was based on the assumption that during long-term anticoagulant therapy within the framework of primary and secondary prevention 4% of patients with chronic non-valvular atrial fibrillation would have severe thromboembolic of hemorrhagic complications each year. Since this rate can be halved by self-management, a one-tailed chi 2-test of 80% power and a 5% significance threshold would require n = 997 patients per group. The results of the SMAAF study will establish the socioeconomic benefits of self-management in patients with non-valvular atrial fibrillation.

Analysis of the long-term efficacy and selectivity of immunoadsorption columns for low density lipoprotein apheresis.

Immunoadsorption low density lipoprotein (LDL) apheresis is performed with reusable columns containing anti-apolipoprotein B(ApoB) antibodies. We analyzed their long-term efficacy and selectivity. Performance over 60 treatment sessions of six pairs of immunoadsorption LDL apheresis columns was evaluated by analysis of variance using the removal of total cholesterol and ApoB to assess efficacy and the ratio of total cholesterol/high density cholesterol removed to assess selectivity. The removal of cholesterol did not vary significantly with treatment number. The mass of ApoB removed increased significantly (p = 0.002), and the mass of ApoB removed per volume unit of processed plasma showed a trend (p = 0.065) toward an increase with treatment number. Both parameters correlated with the serum ApoB concentration before treatment, which also increased significantly (p = 0.0007) with treatment number. No significant variation of selectivity was found. The efficacy of the LDL apheresis immunoadsorption columns did not decrease after 60 treatment sessions. The columns' selectivity also remained unchanged.

A dynamic bubble trap reduces microbubbles during cardiopulmonary bypass: a case study.

Microemboli passing to the cerebral circulation during cardiopulmonary bypass can contribute to postoperative neurologic dysfunction. Many studies conclude that air microbubbles predominantly are responsible for this problem. A dynamic bubble trap (DBT) was developed to diminish the number of microbubbles in the arterial line of extracorporeal circulation. The DBT is able to substantially reduce the number of air microbubbles, as shown in two patients undergoing coronary artery bypass grafting, where a high number of microbubbles was assessed. Although a 40-micron arterial filter was used, many bubbles larger than 40 microns occurred in the arterial line. The DBT reduced the number of large microbubbles from 2,267 to 67 in patient 1 and from 897 to 61 in patient 2.

State-of-the-art patient self-management for control of oral anticoagulation.

Currently, in Germany, there is a successful program where patients monitor their own coagulation status through self-testing. The advent of a new generation of coagulometers has allowed more and more patients to use self-testing to monitor their coagulation status. The development of a structured training program by the Association of Self-Management of Anticoagulation (ASA), and the effective cost reimbursement system by health insurance companies has furthered the success of this program. The reliability of the coagulometers is quite important to the success of this program, and has been extensively evaluated. These systems are characterized by high accuracy and precision, and low intra-/interassay variation. They also exhibit excellent recovery of the therapeutic range. Several clinical studies have shown that patients performing self-management remain in the therapeutic range a greater percentage of the time when compared to conventional testing, and tended to have less incidences of bleeding or thromboembolic complications. It is estimated that about 50 to 60% of all patients on anticoagulant therapy in Germany are suitable candidates for self-management.

Cost-effectiveness of self-managed anticoagulant therapy in Germany.

In this study, the cost-effectiveness of anticoagulation self-management--which is now established in Germany--was compared with the conventional method of monitoring oral anticoagulant therapy by the patient's family physician or by a specialist. Costs were determined based on the usual conditions in Germany such as frequency of testing and control testing, scope of the tests, and diagnostic and therapeutic standards for thromboembolic or bleeding complications. In addition to direct monitoring costs, we determined the costs for treating minor and serious complications and used them to calculate overall therapy costs. The incidence of complications was estimated based on the results of more recent studies. The only costs considered in this study were those covered by the primary cost carrier--the government-controlled health insurance funds--and included outpatient visits and, in cases of serious complications, acute inpatient treatment and rehabilitation. It was shown that the costs to treat minor complications only slightly affected annual, overall treatment costs. The potential reduction in incidences of serious bleeding and thromboembolic complications due to anticoagulation self-management--which is independent of the indication for oral anticoagulation--reduced overall therapy costs from DM 2,061.48/patient-year for conventional therapeutic methods to DM 1,342.46/patient-year for patients under self-management of anticoagulation.