Economic evaluation of everolimus and mycophenolate mofetil versus azathioprine in de novo heart transplantation.

UNLABELLED: Both the proliferation signal inhibitor everolimus (1.5 mg/day) and mycophenolate mofetil (MMF) (3 g/day) have shown superior efficacy versus azathioprine in de novo heart transplantation. The cost-effectiveness of everolimus and MMF versus azathioprine was assessed to 6 months posttransplantation. METHODS: The evaluation was performed from the German health insurance payer perspective. The composite efficacy endpoint in the everolimus trial was death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR) grade>or=3A, rejection with hemodynamic compromise, and loss to follow-up. The composite endpoint in the MMF trial included only death, retransplantation, and BPAR with hemodynamic compromise. To mimic the everolimus endpoint, an estimated number of patients with BPAR>or=3A was added to the MMF trial results, using two mapping scenarios. RESULTS: The incremental 6-month cost versus azathioprine was euro2535 for everolimus and euro3007 for MMF. The absolute reduction in efficacy failure versus azathioprine was 10.4% for everolimus and 9.8% and 10.1% for MMF, respectively, using scenarios 1 and 2. The incremental cost per efficacy failure avoided (ie, the incremental cost versus azathioprine divided by the reduction in efficacy failure) was euro24,457 for everolimus, and euro30,628 and euro29,912 for MMF in scenarios 1 and 2. CONCLUSION: This analysis, based on findings from two clinical trials, suggested that everolimus was more cost-effective than MMF versus azathioprine in the first 6 months after heart transplantation. Data from a head-to-head trial are required to confirm these results.

Myocardial viability assessment in patients with highly impaired left ventricular function: comparison of delayed enhancement, dobutamine stress MRI, end-diastolic wall thickness, and TI201-SPECT with functional recovery after revascularization.

This study compared different magnetic resonance imaging (MRI) methods with Tl(201) single photon emission computerized tomography (SPECT) and the "gold standard" for viability assessment, functional recovery after coronary artery bypass grafting (CABG). Twenty patients (64+/-7.3 years) with severely impaired left ventricular function (ejection fraction [EF] 28.6+/-8.7%) underwent MRI and SPECT before and 6 months after CABG. Wall-motion abnormalities were assessed by stress cine MRI using low-dose dobutamine. A segment with a nonreversible defect in Tl(201)-SPECT and a delayed enhancement (DE) in an area >50% of the entire segment, as well as an end-diastolic wall thickness <6 mm, was defined as nonviable. The mean postoperative EF (n=20) improved slightly from 28.6+/-8.7% to 32.2+/-12.4% (not significant). Using the Tl(201)-SPECT as the reference method, end-diastolic wall thickness, MRI-DE, and stress MRI showed high sensitivity of 94%, 93%, and 84%, respectively, but low specificities. Using the recovery of contractile function 6 months after CABG as the gold standard, MRI-DE showed an even higher sensitivity of 99%, end-diastolic wall thickness 96%, stress MRI 88%, and Tl(201)-SPECT 86%. MRI-DE showed advantages compared with the widely used Tl(201)-SPECT and all other MRI methods for predicting myocardial recovery after CABG.

Assessment of the vasodilator response in primary pulmonary hypertension. Comparing prostacyclin and iloprost administered by either infusion or inhalation.

AIMS: To directly compare the differential effects of oxygen, prostacyclin and iloprost (aerosolized and intravenous) in primary pulmonary hypertension. METHODS AND RESULTS: Twenty-one patients with severe primary pulmonary hypertension underwent right heart catheterization following oxygen inhalation, inhalation of aerosolized iloprost, intravenous prostacyclin or intravenous iloprost. The stability of the iloprost solution was tested for up to 4 weeks. Oxygen slightly decreased pulmonary vascular resistance. Intravenous prostacyclin (7.2+/-3.4 ng kg(-1) min(-1)) reduced pulmonary (1772+/-844 vs 1325+/-615 dyn s cm(-5), P<0.001) and systemic vascular resistance, and arterial and right atrial pressure, while cardiac output increased. Iloprost inhalation diminished pulmonary (1813+/-827 vs 1323+/-614 dyn s cm(-5), P<0.001) and systemic vascular resistance, and pulmonary artery (58+/-12 vs 50+/-12 mmHg,P<0.001) and right atrial pressure, while cardiac output increased. With intravenous iloprost (1.2+/-0.5 ng kg(-1) min(-1), n=8) a decrease in pulmonary (2202+/-529 vs 1515+/-356 dyn s cm(-5), P<0.05) and systemic vascular resistance and right a trial pressure occurred while cardiac output increased. Iloprost solution remained stable for 33 days while losing <10% (4 degrees C) of its active drug concentration.Conclusions Intravenous iloprost and prostacyclin have very similar haemodynamic profiles. In contrast, only inhaled iloprost exerted selective pulmonary vasodilation, reducing pulmonary vascular resistance and pulmonary artery pressure without systemic vasodilation. The longer half-life and extended stability despite lower costs render iloprost an attractive alternative to chronic prostacyclin treatment in primary pulmonary hypertension.

Value of cardiac troponin I and T for selection of heart donors and as predictors of early graft failure.

BACKGROUND: Cardiac troponin I and T (cTnI and cTnT) are sensitive and specific markers of myocardial damage. We evaluated them for the selection of heart donors and as predictors of early graft failure after heart transplantation. METHODS: cTnI, cTnT, myoglobin, and creatine kinase (CK) levels and its isoenzyme MB (CKMB) activity and mass were measured in serum samples immediately before opening the pericardium from 126 consecutive brain-dead multi-organ donors over 10 years of age inspected by our harvesting team. Donors with serum creatinine >2.0 mg/dL (n=6) were excluded from the analysis. Donors for high-urgency status recipients (n=2) were also excluded. The remaining donors were retrospectively divided into three groups: group I (n=68), grafts with good function; group II (n=11), grafts with impaired function; and group III (n=39), grafts not accepted for transplantation. RESULTS: No differences in donor and recipient characteristics were found among the groups. The mean values of cTnI (0.36+/-0.88 microg/L, 4.45+/-3.28 microg/L, and 3.02+/-7.88 micog/L, respectively) and cTnT (0.016+/-0.029 microg/L, 0.134+/-0.114 microg/L, and 0.123+/-0.245 microg/L, respectively) were lower in group I when compared with groups II or III (cTnI: P<0.0001, P=0.018; cTnT: P<0.0001, P=0.012). The cTnI value was higher in group II compared with group III (P=0.023). The cTnT values were similar in groups II and III. A cTnI value >1.6 microg/L as a predictor of early graft failure had a specificity of 94%, and a cTnT value of >0.1 microg/L had a specificity of 99%. The odds ratio for the development of acute graft failure after heart transplantation was 42.7 for donors with cTnI >1.6 microg/L and 56.9 for donors with cTnT >0.1 microg/L. No differences of myoglobin, CKMB activity, or CKMB/CK ratio were found among the groups. CONCLUSIONS: Significantly higher cTnI and cTnT values were found in peripheral blood at the time of explantation in donors of hearts with subsequently impaired graft function and in not accepted donors. cTnI and cTnT are useful as additional parameters for heart donor selection.

[Advances and perspectives in mechanical heart assist]. / Fortschritte und Perspektiven des mechanischen Herzersatzes.

Mechanical circulatory support devices were first developed to permanently replace the failing heart. Today, however, the majority of these devices are used as a mechanical bridge in patients awaiting heart transplantation. With this indication, important information on using mechanical assist devices has been assembled. We present our experience, which has been gained since 1987 in the area of patient selection, post-implant patient care and device maintenance. More than 450 patients have since been implanted with assist devices at our institution. Mechanical circulatory support may not only lead to recovery from secondary organ failure, but also to myocardial remodeling and recovery of the heart function in some patients. Additionally we report our experience with a newly developed implantable axial flow pump and discuss the possibility and costs of permanent support in some patients.

Elimination of recombinant hirudin by modified ultrafiltration during simulated cardiopulmonary bypass: assessment of different filter systems.

UNLABELLED: Recombinant hirudin (r-hirudin) is being used increasingly in patients with heparin-induced thrombocytopenia type II. Renal failure has been demonstrated to prolong the half-life of r-hirudin and to cause bleeding in patients who have undergone cardiopulmonary bypass (CPB). We assessed the ability of different filter systems for modified ultrafiltration to eliminate r-hirudin in vitro using simulated CPB. r-Hirudin concentration was measured (chromogenic laboratory standard plus ecarin clotting time) before and after filtration, and its elimination was calculated using both controlled system flow and arterial inflow (separate pump). Four hemofilters (Renoflow II, Baxter; Arylane H4, Cobe; Ultraflux AV 600, Fresenius; and BCS 110 Plus, Iostra) and two plasmapheresis filter systems (ASAHI Plasmaflow OP, Diamed; and PF 2000 N, Gambro) were assessed (5 filters of each brand = 30 filters) in a closed in vitro CPB system applying conditions usually occurring during CPB. Ten plasmapheresis filters showed a greater ability than 20 hemofilters to eliminate r-hirudin (60%-70% vs 15%-42%) within the shortest time (80 vs 180 s). Among the four hemofilter systems, the Arylane H4 filter provided the most effective (42%) r-hirudin elimination. Elimination of r-hirudin was markedly improved using plasmapheresis systems, compared with hemofilter systems. Our findings may be relevant to patients with impaired renal function, who have been administered r-hirudin during CPB. IMPLICATIONS: Modified ultrafiltration may enhance the elimination of recombinant-hirudin, although plasmapheresis systems provide the most rapid and complete elimination of recombinant-hirudin during simulated cardiopulmonary bypass. The decision to use a specific system will ultimately depend on the prevailing clinical situation and overall health of the patient.

Electron-beam computed tomography in the assessment of coronary artery disease after heart transplantation.

BACKGROUND: Our aim was to compare the electron-beam CT (EBCT) features of coronary arteries in heart transplant recipients with those of biplane coronary angiography and intracoronary ultrasound (ICUS). METHODS AND RESULTS: We examined 112 heart transplant recipients (25 female; age, 17 to 69 years; median, 52 years) 1 to 153 months (median, 46 months) after surgery by EBCT to detect coronary artery calcifications. Calcifications were quantified by the Agatston scoring system. EBCT scores were compared with coronary angiography in all patients and ICUS of the left anterior descending coronary artery (LAD) in 100 patients. Coronary artery calcifications were found in 84 patients (75%). Angiographically, 16 patients displayed >50% coronary artery stenoses, all of whom had some degree of coronary artery calcification and only 1 of whom had a score of <55 (P<0.0001). With this threshold, EBCT had a sensitivity of 94%, a specificity of 79%, a positive predictive value of 43%, and a negative predictive value of 99% for detecting stenosis. ICUS confirmed the presence of calcified plaques in all patients with an LAD score >9. EBCT total calcium score was associated with the degree of intimal proliferation in that patients without ICUS features of allograft vasculopathy had a median score of 0 (25th percentile, 0; 75th percentile, 0), whereas patients with Stanford class IV vasculopathy had a median score of 41 (9 to 98, P<0.0001). CONCLUSIONS: EBCT is a promising noninvasive test for the detection of coronary heart disease in cardiac transplant recipients.

Reduced atrial angiotensin receptor type 1 mRNA content in end-stage human heart failure: assessment by a novel quantitative PCR-ELISA technique.

The number of atrial angiotensin II binding sites is reduced in end-stage human heart failure. The goals of our study were the development of a quantitative polymerase chain reaction for angiotensin II receptor type 1 mRNA to determine the angiotensin receptor type 1 (AT1) mRNA content in the atria of patients with end-stage heart failure. We established a quantitative PCR based on coamplification of AT1 wild-type and an internal standard in the same PCR, followed by liquid-phase hybridization of PCR products in microtiter plates and quantitation by ELISA. Glyceraldehyde phosphate dehydrogenase mRNA in the same samples was used to relate the AT1 mRNA content to a stably expressed reference gene. Atrial samples from 11 patients with end-stage heart failure obtained at cardiac transplantation were compared with atrial samples from 11 patients with normal cardiac function undergoing routine cardiac surgery. A PCR/ELISA system with a variance of about 6% after reverse transcription and a linear measuring range was established. In the samples from 11 patients with end-stage heart failure a 58% decrease in AT1 mRNA content was found in comparison with 11 controls (heart failure: 185,680 +/- 196,912 AT1 mRNA copies/microgram RNA, controls: 440,555 +/- 268,456, P < 0.02). When AT1 mRNA content was related to glyceraldehyde phosphate dehydrogenase mRNA, a 65% decrease was detected (AT1/glyceraldehyde phosphate dehydrogenase: heart failure: 4.84 +/- 5.18; controls: 13.74 +/- 7.77; P < 0.005). Standardization of PCR resulting in a low coefficient of variance, high reproducibility, and large sample capacity is possible using optimal internal standardization and the liquid-phase hybridization/ELISA system for detection. The optimized PCR procedure indicated downregulation of atrial AT1 in end-stage human heart failure, suggesting a reduced capacity of the atria to respond to angiotensin II stimulation in end-stage heart failure.

[Coronary revascularization in end-stage coronary heart disease in relation to assessment of myocardial vitality]. / Koronarrevaskularisation im Endstadium der KHK in Abhängigkeit von Myokardvitalitätsprüfung.

From 4/1986-12/1990, 177 pts. with endstage coronary artery disease (CAD) and left ventricular ejection fraction 10-30% received coronary artery bypass grafting (CABG). Preoperatively myocardial infarction rate was 1.5 (mean). Presupposition for CABGs was myocardial ischaemia at present demonstrated in myocardial viability test. 66.1% of the pts. had signs of ischaemia at e.c.g. after work. Additionally 97.6% of the pts. had myocardial ischaemia defined as redistribution in myocardial scintigraphy. Angina pectoris was present in 93.8% of the pts. preoperatively. 1-5 (mean 2.9) CABG per pt. were performed. 35 pts. received an internal mammaria bypass to the left coronary artery also. Operative mortality was 11.3% (1986-1990) and in 1990 alone 7.3%. Actuarial survival rate was calculated after one year to 87.4% after two years to 86.1% and after three years to 84.8%. Postoperatively all pts. were free from angina pectoris. 5 months after the operation e.c.g. after work was performed. The physical stress bearing area was increased to 82.7 Watt (mean) compared to 51.7 Watt (mean) preoperatively (p less than 0.001 s.). In conclusion pts. with endstage CAD and left ventricular ejection fraction 10-30% appeared to be good candidates for CABG with good prognosis and significant symptomatic improvement when signs of myocardial ischaemia are present preoperatively.

[Patients with late-life vision damage in occupational rehabilitation. Preliminary ophthalmologic treatment, concomitant manifestations and an illustration provided by the growing number of patients with juvenile diabetes]. / Spätsehgeschädigte in der beruflichen Rehabilitation. Augenärztliche Vorbehandlung, Begleiterscheinungen und Vorbildung am Beispiel der steigenden Zahl von Patienten mit juvenilem Diabetes mellitus.

The rehabilitation centre in Veitshöchheim (near Würzburg) offers different kinds of training programs for the adult visually handicapped. This is usually preceded by a long time of unemployment. Diabetes mellitus was the third most common disease at the centre and 25% of the patients with diabetes mellitus were already legally blind. In a retrospective study we looked at the medical and ophthalmological treatment and the education the 76 patients with diabetes mellitus had received before coming to the rehabilitation center. All charts from February, 87, to September, 90, were included in the study. According to the classification of visual acuities by the WHO we formed four groups (less than or equal to 1/50; 1/35-0.1; 0.125-0.3; greater than 0.3) and compared them with each other. In the groups with the lowest visual acuity the medical management of the diabetes mellitus had been much poorer than in the better groups. Related to the bad visual acuity was the higher incidence of proliferative diabetic retinopathy and the significantly lower percentage of panretinal lasercoagulations. 47% of the patients with diabetes mellitus had been trained in jobs that would not have been recommended to a potential visually disabled by an ophthalmologist or the office for labour exchange. Only in 10% of the cases could a job be maintained by the help of technical devices (including low vision aids). To ensure best medical treatment and counselling concerning the choice of an appropriate job a close team work between practising ophthalmologist, general practitioner, and the office for labour exchange is needed. Thereby the cost and psychological impact of a retraining program could hopefully be lowered.

Intraoperative assessment of the reconstructed mitral valve using a low pressure crystalloid infusion.

A technique to intraoperatively assess mitral valve function after reconstruction is described. Cold cardioplegic solution is infused into the left ventricle at low intraventricular pressure (less than 15 mm-Hg) via the cardioplegia infusion line. The infusion of a crystalloid solution, instead of blood, clearly demonstrates residual leaks. Additional pump lines are not required and hypothermic cardioplegic arrest is maintained, thus allowing for repeated testing and additional repair. In combined aortic and mitral valve procedures, a Foley catheter is used to seal the aortic annulus and to infuse the crystalloid solution into the left ventricle. This method has been found to simplify mitral valve testing after reconstruction in a series of 25 patients since September 1979. Testing prompted additional repair in 4 patients and subsequent valve replacement in 2 patients.

Thermocardiography--a method for continuous assessment of myocardial perfusion dynamics in the exposed animal and human heart.

In the exposed animal and human heart, coronary flow reduction results in a significant decrease of regional myocardial temperature. Epicardial temperature can be recorded instantaneously by the use of thermography. In contrast to other techniques, this method allows continuous assessment of rapid coronary flow changes and shows exactly the extent of myocardium involved. Value and limits of thermocardiography in animal experiments and during coronary bypass surgery are discussed and typical examples of myocardial thermograms obtained at various interventions are shown.