Real-life clinical use of natalizumab and fingolimod in Austria.

OBJECTIVES: To compare the efficacy of natalizumab or fingolimod in a nationwide observational cohort using prospectively collected data. MATERIALS AND METHODS: We included all patients starting treatment with natalizumab or fingolimod documented in the Austrian MS Treatment Registry (AMSTR) from 2011 and staying on therapy for at least 24 months. We used propensity scores for several matching methods and as a covariate in multivariate models to correct for the bias of this non-randomized registry study. RESULTS: The study cohort includes 588 patients with RRMS. Ten patients did not produce a propensity score in the common support region, thus leaving 578 cases for final analyses, 332 in the fingolimod and 246 in the natalizumab group. Mean annualized relapse rates (ARR) during the 24 months observation period were 0.19 under fingolimod and 0.12 under natalizumab treatment (P = .005). No statistical significant differences were found analysing the log-transformed ARR, probability for experiencing a relapse, EDSS progression and EDSS regression. The hazard ratio for switching treatment from fingolimod comparing with natalizumab was 0.36 (95% CI: 0.247-0.523), P < .001. CONCLUSIONS: The generalized linear model (GLM) for relapse count as Poisson distributed dependent variable and propensity score as covariate showed a statistically significant reduction for the mean relapse count in the natalizumab group compared with fingolimod. This effect was smaller in the analyses of log-transformed ARR with propensity score matching, loosing statistical significance although showing the same direction for the effect. We assume that the GLM was the more sensitive model analysing this question.

Safety and efficacy of periprocedural anticoagulation with enoxaparin in patients undergoing peripheral endovascular revascularization.

BACKGROUND: Periprocedural anticoagulation is primarily used in endovascular procedures to prevent acute reocclusion of the target vessel, but periprocedural anticoagulation might also have an impact on long-term outcome. Consecutive bleeding events are feared complications. Despite changes in peripheral endovascular revascularizations (EVRs), the periprocedural management has remained unchanged for years. Unfractionated heparin is still the treatment of choice during and immediately after EVR. MATERIALS AND METHODS: We performed a prospective, single-center, open-label phase III study comparing 2 different regimes of enoxaparin peri-interventional to peripheral EVR stratified into low- and high-risk groups according to the acute and long-term reocclusion risk due to their vessel morphology. In both groups, 0.5 mg/kg of enoxaparin as a bolus was administered intravenously 10 to 15 minutes before the start of the procedure. In the low-risk group, 40 mg of enoxaparin were administered once daily for 7 days; whereas in the high-risk group, 1 mg/kg of enoxaparin was administered subcutaneously (sc) 2 times a day for 48 hours after the procedure and afterward 40 mg of enoxaparin was administered sc once daily for 5 days. RESULTS: For the analysis of the per protocol population, 44 patients remained in the low-risk group and 140 in the high-risk group. Concerning the primary safety end point, a total of 25 (13.59%) bleeding events occurred until day 30; 5 (11.36%) of them in the low-risk group and 20 (14.29%) in the high-risk group (P = .809 for low vs high risk). None of the bleeding events observed were major according to Thrombolysis In Myocardial Infarction criteria. Concerning our primary efficacy end point, none of the patients showed an acute reocclusion classified as a significant decrease in ankle-brachial index (ABI) or elevated peak systolic velocity ratio confirmed by duplex sonography until day 30. Concerning the second end point of prevention of chronic reobstruction, at day 180 ABI has decreased in the low-risk group from mean 0.94 at day 30 to mean 0.89 and from 1.28 at day 30 to 0.85 after 6 months in the high-risk group. No significant reobstruction was found in the low-risk group, whereas 5 significant reobstruction events were objectified in the high-risk group, all of them in the femoropopliteal arterial segment at day 180. CONCLUSION: We conclude that low-molecular-weight heparin either in a low-dose or high-dose regime during a peripheral EVR is safe concerning bleeding complications and acute reobstructions. The long-term follow-up showed no significant difference between our high- and low-risk groups concerning reobstruction. The periprocedural anticoagulation seems to have no influence on the long-term patency rate after peripheral EVR.

Socio-economic effects and cost saving potential of remote patient monitoring (SAVE-HM trial).

OBJECTIVE: In the SAVE-trial we evaluated the safety, reliability and improvements of patient management using the BIOTRONIK Home Monitoring®-System (HM) in pacemaker (PM) and implanted cardioverter defibrillator (ICD) patients. DESIGN: 115 PM (Module A) and 36 ICD-patients (Module B) were recruited 3 months after implantation. PATIENTS: 65 patients in Module A were randomised to HM-OFF and had one scheduled outpatient clinic follow-up(FU) per year, whereas patients randomised to HM-ON were equipped with the mobile transmitter and discharged without any further scheduled in-office FU. In Module B 18 patients were randomised to HM-OFF and followed by standard outpatient clinic controls every 6 months; 18 patients were randomised to HM-ON receiving remote monitoring plus one outpatient clinic visit per year; unscheduled follow-ups were performed when necessary. RESULTS: The average follow-up period was 17.1 ± 9.2 months in Module A and 26.3 ± 8.6 months in Module B. In both modules, the number of FUs per year was significantly reduced (Module A HM-ON 0.29 ± 0.6 FUs/year vs HM-OFF 0.53 ± 0.5 FUs/year; p b 0.001; Module B HM-ON 0.87 ± 0.25 vs HM-OFF 1.73 ± 0.53 FU/year,p b 0.001). Cost analysis was significantly lower in the HM-ON group compared to the HM-OFF group (18.0 ± 41.3 and 22.4 ± 26.9 € respectively; p b 0.003). 93% of the unscheduled visits in Module B were clinically indicated,whereas 55% of the routine FUs were classified as clinically unnecessary. CONCLUSION: Remote home monitoring of pacemaker and ICD devices was safe, reduced overall hospital visits, and detected events that mandated unscheduled visits.

Plasma cholesteryl ester transfer protein concentrations predict cardiovascular events in patients with coronary artery disease treated with pravastatin.

OBJECTIVE: The B1B1 variant of the cholesteryl ester transfer protein (CETP) TaqIB polymorphism and high plasma CETP concentrations are associated with favourable angiographic outcomes in pravastatin-treated patients suffering from coronary artery disease (CAD). The purpose of the present study was to test whether CETP TaqIB genotypes and/or plasma CETP concentrations at baseline also predict clinical end-points in patients with CAD. DESIGN: Prospective longitudinal observational study. SETTING: Primary care doctors (n=88) and hospitals (n=7) in Austria. SUBJECTS: A total of 1620 men and women with preexisting CAD were recruited and plasma lipids were determined at study entry. 1389 hypercholesterolaemic patients were included and 1002 patients completed the follow-up. INTERVENTIONS: In all patients treatment with pravastatin was started and patients were followed up for 2 years. MAIN OUTCOME MEASURES: Cardiovascular events. RESULTS: One hundred patients suffered at least one cardiovascular event. We observed significantly more events in patients within the lowest compared with the highest quartile of plasma CETP concentrations (odds ratio 3.20, CI95 1.65-6.23; P=0.001, adjusted for known risk factors of CAD). No significantly different numbers of cardiovascular events were found between CETP TaqIB genotypes. CONCLUSIONS: Plasma CETP concentrations, but not CETP TaqIB genotypes, predict cardiovascular events in patients with CAD treated with pravastatin. Despite higher LDL cholesterol concentrations, high plasma CETP concentrations at baseline are associated with fewer cardiovascular events compared with low plasma CETP concentrations in CAD patients treated with pravastatin.

Prolonged mechanical systole and increased arterial wave reflections in diastolic dysfunction.

OBJECTIVE: To evaluate whether left ventricular ejection time indexed for heart rate (left ventricular ejection time index (LVETI)) and arterial wave reflections (augmented pressure (AP)) are increased in patients with diastolic dysfunction (DD). DESIGN: Prospective observational study. SETTING: University teaching hospital providing primary and tertiary care. SUBJECTS: 235 consecutive patients undergoing left heart catheterisation were categorised as having definite DD, possible DD or no DD (controls) on the basis of their left ventricular end diastolic pressures and N-terminal brain natriuretic peptide concentrations. MAIN OUTCOME MEASURES: LVETI and AP were prospectively assessed non-invasively by radial applanation tonometry. In addition, all patients underwent comprehensive echocardiography, including tissue Doppler imaging of mitral annulus velocity in early diastole (E'). RESULTS: LVETI was longer in patients with definite DD than in patients with possible DD and in controls (433.6 (SD 17.2), 425.9 (17.9) and 414.3 (13.6) ms, respectively, p < 0.000001). Arterial wave reflections were higher in definite DD than in possible DD and control groups (AP was 19.4 (SD 8.9), 15.2 (8.0) and 10.7 (6.8) mm Hg, respectively, p < 0.000001). In receiver operating characteristic curve analysis, LVETI detected DD as well as echocardiography (E:E'). Area under the curve for LVETI to differentiate patients with definite DD from normal controls was 0.81 (95% CI 0.72 to 0.89, p < 0.0001). In multivariable logistic regression analysis, LVETI added significant independent power to clinical and echocardiographic variables for prediction of DD. CONCLUSIONS: Mechanical systole is prolonged and arterial wave reflections are increased in most patients with DD. Rapid non-invasive assessment of these parameters may aid in confirming or excluding DD.

Obesity, body fat and coronary atherosclerosis.

BACKGROUND: Recent prospective studies have provided compelling evidence that obesity is a risk factor for the occurrence of clinical coronary events. However, the link between angiographically determined coronary atherosclerosis and obesity still remains controversial. We conducted this cross-sectional study in a clinical setting to investigate the relation of the obesity and body fat (BF) with angiographically defined coronary atherosclerosis. PATIENTS AND METHODS: Six hundred and seventy-three men (median age 64 years) and four hundred and twenty-eight women (median age 69 years) who underwent coronary angiography for suspected or known coronary heart disease were analyzed. The body mass index (BMI) and the BF were used as main exposure variables, and either the presence of significant (> or =50%) coronary diameter stenosis or a coronary artery disease severity score were defined as outcome variables, in a sex-specific logistic regression analysis. RESULTS: Among male patients, BF was slightly higher with increasing number of vessels involved (adjusted P for trend <0.05). In contrast, BMI showed no association with presence and severity of coronary artery disease (CAD). The odds ratios (ORs) for the presence of significant stenosis across quartiles of BMI were 1.0 (reference), 0.9, 1.1 and 0.7 (adjusted P for trend 0.61). This result did not differ between younger and older men. Among females, however, both BF and BMI were not significantly associated with an increasing number of vessels involved. CONCLUSION: These results suggested that BF may be predictive of an increasing number of coronary vessels involved among male patients, but not among female patients. This study failed to detect a positive association of presence and severity of CAD with BMI.

Increased serum concentrations of soluble CD95/Fas and caspase 1/ICE in patients with acute angina.

OBJECTIVES: To investigate the expression of death inducing receptors in the sera of patients with stable and unstable angina. DESIGN: 80 consecutive patients with stable (n = 40) or unstable (n = 40) angina pectoris were studied. Serum concentrations of soluble CD95 (sCD95), soluble CD95 ligand (sCD95L; CD178), tumour necrosis factor (TNF) alpha, soluble TNFalpha receptor type 1 (sTNFR1), and interleukin 1beta converting enzyme (ICE; caspase 1) were measured by enzyme linked immunosorbent assay (ELISA). RESULTS: Significant increases in the concentrations of sCD95 and ICE (p < 0.001 and p < 0.023, respectively) were found in the serum from patients with unstable angina relative to those with stable angina. There were no significant differences in the concentrations of sCD95L, TNF alpha, and sTNFR1 between the groups. CONCLUSIONS: These data provide the first evidence that sCD95 and ICE are important serological markers that may help to discriminate between stable and unstable angina. This observation may warrant further clinical study to elucidate the clinical impact of sCD95 and ICE in acute coronary syndromes.

Smooth muscle cell migration promoting activity of plasma predicts restenosis in patients with peripheral arterial occlusive disease undergoing angioplasty.

BACKGROUND: Efficacy of percutaneous transluminal angioplasty (PTA) is limited by restenosis occurring in a large proportion of patients. Smooth muscle cell (SMC) migration is a major pathomechanism of restenosis. We studied SMC migration inducing activity of plasma from patients with peripheral arterial occlusive disease (PAOD) undergoing PTA. METHODS AND RESULTS: SMC migration was determined in a two-dimensional assay system after addition of 1/25 plasma dilutions. Mean increase in migration area was 65.5 +/- 33.8% in normal controls and 67.7 +/- 53.2% in patients with PAOD. 6 hours after PTA, plasmatic migration inducing activity was largely unchanged. In 19/30 patients with restenosis (6 months after PTA) migration promoting activity (82.7 +/- 60.0) was significantly higher than in 11/30 patients with patent vessels (41.8 +/- 21.0; p = 0.03). No correlation of clinical risk factors with outcome was observed. A weak correlation was found between plasmatic migration promoting activity and levels of epidermal growth factor and transforming growth factor-beta. CONCLUSION: The capacity of human plasma to stimulate SMC migration in tissue culture can be used to assess the risk for restenosis after PTA in patients with PAOD.

Changes in the fibrinolytic system in patients with peripheral arterial occlusive disease undergoing percutaneous transluminal angioplasty.

We have investigated fibrinolytic parameters in 33 patients with peripheral arterial occlusive disease (PAOD) before and 6, 24, and 48 hours after percutaneous transluminal angioplasty (PTA) as well as in 35 gender-matched healthy controls, whose mean age was not significantly different from the mean age of the patients. PAOD patients had significantly higher plasma levels of t-PA antigen (12.0+/-4.9 vs. 9.2+/-5.5 ng/ml), PAI-1 antigen (34.8+/-22.1 vs. 27.2+/-23.6 ng/ml), PAI-1 activity (10.0+/-6.5 vs. 8.0+/-8.0 U/ml), PCI (188.2+/-55.6 vs. 134.1+/-75.5% as compared with normal human plasma), and fibrinogen (420.2+/-92.6 vs. 261.9+/-32.7 mg/dl) as compared with controls. After angioplasty, fibrinolytic parameters and fibrinogen levels increased, reaching higher than preintervention levels 24 and 48 hours after the intervention. Six months after initially successful PTA, restenosis was demonstrated in 14 out of 33 patients (42%). Patients with late restenosis had significantly higher levels of PAI-1 activity 24 and 48 hours after PTA, as compared with patients with late patency (24 hours: 16.1+/-8.0 vs. 10.0+/-7.4; 48 hours: 16.5+/-7.9 vs. 12.0+/-7.0; p<0.05 for both time points). The results suggest that impaired fibrinolysis early after PTA might be a cause or marker of a disturbed repair process of vascular injury, leading to restenosis.

Plasma hyaluronan concentration: no circadian rhythm but large effect of food intake in humans.

This study was designed to determine if a circadian rhythm in plasma hyaluronan concentration [HA] exists in the absence of physical activity, and if plasma [HA] is associated with feeding in human subjects. Five persons were studied under standardized conditions, blood samples being taken between 0600 and 2200 hours at 30-min intervals. Any orthostatic challenge and muscle activity was abolished by immobilization by a 6 degrees head-down bed-rest, and the effect of a quasi-continuous ingestion of energy compared a normal, three-portion diet of equivalent energy content or to fasting. Reproducibility of HA profiles on two consecutive half-days was also studied. A highly sensitive immunoassay was used to determine plasma [HA]. The data indicated that without physical activity and without food ingestion, [HA] was unchanged and displayed no diurnal rhythm. In addition, we observed that [HA] increased after the first food intake, peaking after 60 min, and concluded from our results that without ingestion of a larger meal, and sessions of postural or muscle activity, no circadian plasma [HA] rhythm exists.

Changes in psychopathology of parents of NOFT (non-organic failure to thrive) infants during treatment.

This clinical case-study of 50 infants suffering from NOFT (non-organic failure to thrive) and their parents supports the idea that the feeding problem is intimately related to parental disorders. We find a high rate (70%) of parental psychopathology (axis I diagnosis applying DSM-III-R) at the time of referral and a significant reduction (to 37%) during treatment of the infants and their parents. After a year only 12% of the parents were diagnosed with psychiatric disorders. In contrast personality disorders (axis II diagnosis applying DSM-III-R) show more stability and can be regarded as a trait variable, whereas the psychiatric disorders are of a more reactive nature. These conclusions may be influenced somewhat by the strictly hospital based design of our pilot study (infants and parents contacted only after clinical referral) and by inclusion only of firstborn infants. Nevertheless, they point to the psychopathology of parents as a main cause for non-organic failure to thrive. Psychopathological traits such as severe attachment behavior problems and primary bonding difficulties may have been latent and only became manifest due to the task of nurturing an infant for the first time.