[Show abstract][Hide abstract] ABSTRACT: Little is known about the respective healing responses and clinical efficacy and safety of drug-eluting balloons (DEB) and the second generation of drug-eluting stents (DES) when used to treat in-stent restenosis (ISR). In this study, we set out to compare prospectively the healing characteristics, as assessed by optical coherence tomography (OCT), of DEB versus DES after treatment of ISR in bare metal stents (BMS).
EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 08/2014; 10(4):439-48. · 3.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To date, accurate quantification and localization of malapposed and uncovered struts needs manual and time consuming analysis of large datasets. To develop an algorithm for automated detection and quantification of clusters of malapposed and uncovered struts in optical coherence tomography (OCT) pullbacks, including comprehensive information about their three-dimensional spatial distribution. 64 lesions in 64 patients treated with drug-eluting stent underwent assessment with OCT immediately after implantation and at 9-month follow-up (55 patients). An automated algorithm was used to detect and quantify stent strut malapposition at baseline and coverage at follow-up on an individual strut level. We subsequently applied an algorithm for the automated clustering of malapposed and uncovered struts and for the quantification of clusters' properties. In the 64 baseline examinations, a total of 24,013 struts were analyzed, of which 1,519 (6 %) were malapposed. Most malapposed struts (78 %) occurred in clusters and more than half of patients had malapposition clusters. The mean number of struts per cluster was 19.7 ± 11.8 with a mean malapposition distance of 213 ± 66 μm. In the 55 follow-up pullbacks, a total of 20,484 struts were analyzed, of which 1,320 (6 %) were uncovered. Again, most uncovered struts (85 %) occurred in clusters. The mean number of struts per cluster was 21.1 ± 14.7. We developed an automated algorithm for studying clustering of malapposed or uncovered struts. This algorithm might facilitate future investigations of the prognostic impact of clusters of malapposed or uncovered struts.
The international journal of cardiovascular imaging 03/2014; · 2.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vessel wall injury after drug-eluting stent (DES) implantation can be characterized in detail by optical coherence tomography (OCT). Little is known about the healing course of these phenomena.
In 62 lesions (62 patients), the incidence of acute vessel trauma was assessed in the stented region and the edge segments immediately after DES implantation. The healing course of these injuries was assessed at 9-month OCT follow-up using a software algorithm allowing for reliable spatial comparison of baseline and follow-up cross-sectional images. Tissue prolapse (TP) and tissue protrusions were detected in 81 and 35% of lesions, respectively. A total of 342 intra-stent dissection flaps (ISD) and 114 intra-stent dissection cavities (ISC) were visualized in 98 and 81% of lesions, respectively. Thirty-five lesions (56%) showed edge dissections (EDs). No residual TP or protrusion was observed at follow-up. Incomplete healing was seen in 8% of ISD and in 20% of ISC. For ED, a residual flap was observed in one-third of the initially dissected stent edges. Incomplete healing of acute vessel injury was associated with the presence of underlying atherosclerotic disease at baseline. Uncovered and malapposed stent struts were observed more often with incomplete healing of vessel injury at follow-up.
Acute vessel wall trauma is highly prevalent immediately after DES implantation. Most of these injuries are minor and resolve at mid-term follow-up. Incomplete healing of ISDs seems to be associated with other OCT findings suggesting delayed arterial healing.
[Show abstract][Hide abstract] ABSTRACT: Tamoxifen remains important in the treatment and prevention of estrogen receptor-positive breast cancer. In postmenopausal women, it can lead to endometrial changes such as cystic appearances, hyperplasia, polyps and endometrial cancer. Tamoxifen is metabolized by cytochrome P450 (CYP450) enzymes to the more active metabolite endoxifen. Several genetic variants in the CYP450 enzymes reduce tamoxifen metabolism, leading to reduced endoxifen levels. We hypothesize that carriers of these variants, which are established poor metabolizers of tamoxifen, do not have the typical tamoxifen-induced increase in endometrial thickness. We test the association between genetic variability in CYP450 enzymes and the increase in double endometrial thickness (DET) as measured through transvaginal ultrasound (TVU).
We carried out a retrospective study on postmenopausal tamoxifen users for which germline DNA was available and at least one DET measurement was made between January 2000 and October 2011. Genotyping of 33 single nucleotide polymorphisms in CYP450 genes involved in tamoxifen metabolism was carried out using Sequenom MassARRAY. The association between these variants and TVU outcome (DET ≥5 mm) was assessed by proportional hazards regression.
Data were available for 184 women: 47 with a DET of <5 mm on all ultrasounds and 137 with a DET of ≥5 mm on at least one ultrasound. The rs1800716 variant in CYP2D6 showed a statistically significant association with DET. In particular, mutant carriers of rs1800716 had an increased chance of having a DET of ≥5 mm (P = 0.0022, false discovery rate 0.0179). None of the other variants were associated with DET.
Although mutant carriers of rs1800716 are characterized by reduced CYP2D6 enzyme activity and by low levels of endoxifen, we observed that mutant alleles of rs1800716 were associated with an increased chance of having a DET of ≥5 mm in postmenopausal women on tamoxifen. We conclude that the increase in endometrial thickness seen under tamoxifen cannot be used as a marker for favorable genotypes.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES
Transcatheter aortic valve implantation (TAVI) has been proposed as a treatment alternative for patients with aortic valve stenosis (AS) at high or prohibitive risk for surgical aortic valve replacement (AVR). We aimed to assess real-world outcomes after treatment according to the decisions of the multidisciplinary heart team.METHODS
At a tertiary centre, all high-risk patients referred between 1 March 2008 and 31 October 2011 for symptomatic AS were screened and planned to undergo AVR, TAVI or medical treatment. We report clinical outcomes as defined by the Valve Academic Research Consortium.RESULTSOf 163 high-risk patients, those selected for AVR had lower logistic EuroSCORE and STS scores when compared with TAVI or medical treatment (median [interquartile range] 18 [12-26]; 26 [17-36]; 21 [14-32]% (P = 0.015) and 6.5 [5.1-10.7]; 7.6 [5.8-10.5]; 7.6 [6.1-15.7]% (P = 0.056)). All-cause mortalities at 1 year in 35, 73 and 55 patients effectively undergoing AVR, TAVI and medical treatment were 20, 21 and 38%, respectively (P = 0.051). Cardiovascular death and major stroke occurred in 9, 8 and 33% (P < 0.001) and 6, 4 and 2% (P = 0.62), respectively. For patients undergoing valve implantation, device success was 91 and 92% for AVR and TAVI, respectively. The combined safety endpoint at 30 days was in favour of TAVI (29%) vs AVR (63%) (P = 0.001). In contrast, the combined efficacy endpoint at 1 year tended to be more favourable for AVR (10 vs 24% for TAVI, P = 0.12).CONCLUSION
Patients who are less suitable for AVR can be treated safely and effectively with TAVI with similar outcomes when compared with patients with a lower-risk profile undergoing AVR. Patients with TAVI or AVR have better survival than those undergoing medical treatment only.
Interactive Cardiovascular and Thoracic Surgery 05/2013; · 1.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
To assess the impact of single-nucleotide polymorphisms (SNPs) on predefined severe adverse events in breast cancer (BC) patients receiving (neo-)adjuvant 5-fluorouracil (FU), epirubicin and cyclophosphamide (FEC) chemotherapy.Patients and methodsTwenty-six SNPs in 16 genes of interest, including the drug transporter gene ABCC1/MRP1, were selected based on a literature survey. An additional 33 SNPs were selected in these genes, as well as in 12 other genes known to be involved in the metabolism of the studied chemotherapeutics. One thousand and twelve female patients treated between 2000 and 2010 with 3-6 cycles of (neo-)adjuvant FEC were genotyped for these SNPs using Sequenom MassARRAY. Severe adverse events were evaluated through an electronic chart review for febrile neutropenia (FN, primary end point), FN first cycle, prolonged grade 4 or deep (<100/µl) neutropenia, anemia grade 3-4, thrombocytopenia grade 3-4 and non-hematological grade 3-4 events (secondary end points).ResultsCarriers of the rs4148350 variant T-allele in ABCC1/MRP1 were associated with FN relative to homozygous carriers of the G-allele [P = 0.0006; false discovery rate (FDR) = 0.026]. Strong correlations with secondary end points such as prolonged grade 4 neutropenia (P = 0.002, FDR = 0.046) were also observed. Additionally, two other SNPs in ABCC1/MRP1 (rs45511401 and rs246221) correlated with FN (P = 0.007 and P = 0.01, respectively; FDR = 0.16 and 0.19), as well as two SNPs in UGT2B7 and FGFR4 (P = 0.024 and P = 0.04; FDR = 0.28 and 0.38).Conclusion
Genetic variability in ABCC1/MRP1 was associated with severe hematological toxicity of FEC.
[Show abstract][Hide abstract] ABSTRACT: We retrospectively followed 250 patients who started dialysis between 2005 and 2009 to clarify the prevalence, the prognosis and the prescribed heart failure treatment of systolic heart failure patients on dialysis.
This cohort was divided according to left ventricular ejection fraction (LVEF): group A with a reduced LVEF (< or = 45%, n = 45) versus group B with a preserved LVEF (> 45%, n = 205). Patients in group A had a significantly worse survival after 12 and 24 months (68.9% and 55.5% vs. 87.3% and 73.0%, respectively, P = 0.0001). Hazard ratio for all-cause mortality was 2.70 (C.I. 95% 1.6 - 4.56, P = 0.0002). In the subgroup of patients with a LVEF < 30% the hazard ratio increased to 3.45 (C.I. 95% 1.71 - 6.94, P = 0.0005). The cumulative incidence of cardiovascular death was significantly higher in group A (hazard ratio: 4.78 (C.I. 95% 1.99- 11.50, P = 0.0005), especially in the subgroup with a LVEF < 30%. In group A 71%, 31% and 9% of the patients received a beta blocker, an ACE inhibitor and an angiotensin-receptor blocker, respectively. Only 27% were treated with the combination of a beta blocker and a RAAS inhibitor, while 18% did not receive any heart failure therapy. Most patients only received a low dose of neurohormonal blockers (< or = 25% of the recommended daily dose). The use of these heart failure medications was not significantly different between group A and B.
After initiation of dialysis, patients with heart failure and reduced LVEF have a bad prognosis. Only a minority of these patients receive adequate specific heart failure treatment.
[Show abstract][Hide abstract] ABSTRACT: The significance of nodal metastasis in breast cancer is under discussion. We investigated the impact of variables of tumor chronology and tumor biology on the presence of lymph node metastases.
Lymph node involvement is the main prognostic factor in breast cancer. However, it is under discussion whether nodal metastasis in breast cancer only reflects the chronological age of the tumor or whether it is also a marker of tumor biology. The goal of our study was to investigate the impact of variables of tumor chronology and biology on the presence of lymph node metastases.
We performed a retrospective analysis of data from 3002 patients with an early invasive breast carcinoma. All patients underwent primary surgery at the University Hospitals Leuven between 2001 and 2009. First, the impact of tumor size on the presence of lymph node metastasis was evaluated as the chronological age of a tumor is supposed to be reflected in its size. Next, the impact of tumor grade, lymphovascular invasion and the hormone receptor status, which are all variables of tumor biology, was studied. Logistic regression analyses were performed and the area under the ROC curve (AUC) was calculated as a measure of discrimination between logistic regression models.
Using pathological tumor size the AUC of prediction was 0.67. Based on variables of tumor biology, axillary lymph node positivity could be predicted with an AUC of 0.68. Combining variables of tumor chronology and biology an AUC of 0.74 for the prediction of axillary lymph node (ALN) positivity was calculated.
According to our data variables of tumor chronology and tumor biology have a similar impact on the presence of lymph node metastasis.
[Show abstract][Hide abstract] ABSTRACT: AimsA pooled analysis of 14 genome-wide association studies revealed 23 susceptibility loci for coronary artery disease (CAD), thereby providing the most comprehensive genetic blueprint of CAD susceptibility. Here, we evaluated whether these 23 loci also predispose to recurrent myocardial infarction (MI) or cardiac death following an acute coronary syndrome (ACS).Methods and resultsA total of 2099 ACS patients enrolled in the Global Registry of Acute Coronary Events (GRACE) UK-Belgian study were prospectively followed for a median of 5 years (1668 days). C-allele carriers of the rs579459 variant, which is located upstream of the ABO gene and correlates with blood group A, were independently associated with recurrent MI [multivariable-adjusted hazard ratio (HR) 2.25, CI = 1.37-3.71; P = 0.001] and with recurrent MI or cardiac death [multivariable-adjusted (HR) 1.80, CI = 1.09-2.95; P = 0.021] within 5 years after an index ACS. The association of rs579459 was replicated in 1250 Polish patients with 6 months follow-up after an index ACS [multivariable-adjusted (HR) 2.70, CI = 1.26-5.82; P = 0.011 for recurrent MI]. Addition of rs579459 to a prediction model of 17 clinical risk factors improved risk classification for recurrent MI or cardiac death at 6 months as calculated by the integrated discrimination improvement method (P = 0.037), but not by C-statistics (P = 0.096).Conclusion
In this observational study, rs579459 was independently associated with adverse cardiac outcome after ACS. A weak improvement in clinical risk prediction was also observed, suggesting that rs579459 should be further tested as a potentially relevant contributor to risk prediction models for adverse outcome following ACS.
European Heart Journal 11/2012; · 14.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Elevated pulmonary artery systolic pressure (PASP) causes functional tricuspid valve insufficiency (TI). However, the differential contribution of pressure load and right ventricular (RV) dilatation is not well established. The study aim was to evaluate both variables in relation to TI.
A cross-sectional study was performed of consecutive transthoracic echocardiographic studies of patients with pre-capillary pulmonary hypertension (PH). Both, demographic data and echocardiographic RV parameters were reviewed. TI was graded semi-quantitatively with color Doppler flow imaging. Trend analyses for TI severity (TI grade 0/4, 1/4, 2/4, 3/4, or 4/4) were performed. A proportional odds logistic regression analysis was carried out to identify independent predictors of TI severity.
Eighty-one patients (56 females, 25 males; mean age 60 +/- 15 years) with pre-capillary PH were evaluated. Patients with more severe TI had a significantly lower body mass index, a lower mean systemic blood pressure, a shorter pulmonary acceleration time, a higher tricuspid regurgitant gradient, and a more dilated right ventricle. From the echocardiographic parameters, RV dilatation (p = 0.0143) and the tricuspid regurgitant gradient (p = 0.0026) were independently related to the degree of TI.
In patients with pre-capillary PH, PASP and RV dilatation were both related to the increasing severity of TI. When focusing on TI to improve the prognosis of patients with pre-capillary PH, both PASP and RV dimensions should be taken into consideration.
The Journal of heart valve disease 11/2012; 21(6):743-8. · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We performed an open-label, dose-ascending, single-centre, Phase IIa study to explore the safety and efficacy of catheter-directed thrombolysis (CDT) with microplasmin for infrainguinal arterial or bypass occlusions.
Patients who presented with acute occlusions were subsequently treated with an intrathrombus infusion of five ascending doses of microplasmin: 0.3 mg/kg/h for 4 hours; 0.45 mg/kg/h for 4 hours; 0.6 mg/kg/h for 4 hours; 0.9 mg/kg/h for 4 hours or 0.6 mg/kg/h for 6 hours. Repeat angiograms were obtained to assess the degree of clot lysis. The primary outcome was complete thrombolysis defined as >95% thrombus volume reduction at the end of the microplasmin infusion. Safety evaluation included bleedings, adverse events and coagulation biomarkers.
Complete thrombolysis was obtained in 3 of the 19 treated patients at the end of microplasmin infusion. Thrombus volume reduction between 50% and 95% was achieved with all dosing regimens. Clinically significant distal embolization occurred in 8 patients. One major and two non-major bleedings occurred. Microplasmin depleted α2-anti-plasmin and decreased fibrinogen.
Intrathrombus infusion of microplasmin for 4 or 6 hours resulted in significant clot lysis. Distal embolization appeared the most important limitation.
International angiology: a journal of the International Union of Angiology 06/2012; 31(3):289-96. · 1.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Single-lung transplantation (SLTx) is a valid treatment option for patients with non-suppurative end-stage pulmonary disease. This strategy helps to overcome current organ shortage. Side is usually chosen based on pre-transplant quantitative perfusion scan, unless specific recipient considerations or contralateral lung offer dictates opposite side. It remains largely unknown whether outcome differs between left (L) versus right (R) SLTx.
Between July 1991 and July 2009, 142 first SLTx (M/F=87/55; age=59 (29-69) years) were performed from 142 deceased donors (M/F=81/61; age=40 (14-66) years) with a median follow-up of 32 (0-202) months. Indications for SLTx were emphysema (55.6%), pulmonary fibrosis (36.6%), primary pulmonary hypertension (0.7%), and others (7.0%). Recipients of L-SLTx (n=72) and R-SLTx (n=70) were compared for donor and recipient characteristics and for early and late outcome.
Donors of L-SLTx were younger (37 (14-65) vs 43 (16-66) years; p=0.033). R-SLTx recipients had more often emphysema (67.1% vs 44.4%; p=0.046) and replacement of native lung with ≥ 50% perfusion (47.1% vs 23.6%; p=0.003). The need for bypass, time to extubation, intensive care unit (ICU) and hospital stay, and 30-day mortality did not differ between groups. Overall survival at 1, 3, and 5 years was 78.4%, 60.5%, and 49.4%, respectively, with a median survival of 60 months, with no significant differences between sides. Forced expiratory volume in 1s (FEV₁) improved (p<0.01) in both groups to comparable values up to 36 months. Complications overall (44.4% vs 50.0%) or in allograft (25.0% vs 24.3.0%) as well as time to bronchiolitis obliterans syndrome (BOS) (35 months) and 5-year freedom from BOS (68.9% vs 75.0%) were comparable after L-SLTx versus R-SLTx, respectively. There were no differences in all causes of death (p=0.766). On multivariate analysis, BOS was a strong negative predictor for survival (hazard ratio (HR) 6.78; p<0.001), whereas side and mismatch for perfusion were not.
The preferred side for SLTx differed between fibrotic versus emphysema recipients. Transplant side does not influence recipient survival, freedom from BOS, complications, or pulmonary function after SLTx. Besides surgical considerations in the recipient, offer of a donor lung opposite to the preferred side should not be a reason to postpone the transplantation until a better-matched donor is found.
European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 04/2011; 40(2):e83-92. · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It remains uncertain whether donor cause of brain death (DCBD) affects survival and freedom from bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). In addition, it is unknown whether the length of time interval from brain insult to brain death [BI-BD] and from brain death to cold preservation [BD-CP] has an impact on outcome.
Medical charts of isolated lung transplant recipients from 400 consecutive donors were reviewed and classified according to DCBD: 190 vascular [V], 185 traumatic [T], 25 others [O]. Demographics were compared between donor groups. Hospital outcome, survival, and freedom from BOS in recipients were analyzed in relation to DCBD and related time intervals.
Donor age, gender, and weight differed between donor groups (p<0.001, p<0.001, p<0.05; respectively). No differences in recipient hospital outcome, survival, and freedom from BOS were found between groups. [BD-CP] longer than 10h resulted in a survival advantage (69% vs 58% and 51% vs 42% at 5 and 10 years, respectively; p<0.05) and a reduced hazard risk (0.952) of dying after LTx; (p<0.05). Multivariable analysis failed to show a significant correlation between DCBD and [BI-BD] versus survival and BOS.
DCBD and [BI-BD] do not affect survival and freedom from BOS after LTx. Lung recipients from donors certified brain dead with a time interval longer than 10h prior to organ preservation showed improved survival unrelated to BOS. This may result from longer and better donor management with reduced lung injury.
European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 01/2011; 39(4):e68-76. · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies have suggested that intravenous administration of adenosine improves myocardial reperfusion and reduces infarct size in ST-elevation myocardial infarction (STEMI) patients. Intracoronary administration of adenosine has shown conflicting results.
In a prospective, single-centre, double-blind, placebo-controlled clinical study, we assessed whether selective intracoronary administration of adenosine distal to the occlusion site immediately before initial balloon inflation results in myocardial salvage and decreased microvascular obstruction (MVO) as assessed with cardiac magnetic resonance imaging (MRI). Using a combination of T(2)-weighted and contrast-enhanced sequences, myocardial salvage index (MSI) was defined as the percentage of the area at risk that did not become necrotic. We randomized 112 patients presenting with STEMI within 12 h from symptom onset to selective intracoronary administration of adenosine 4 mg or matching placebo. In 100/110 (91%) patients receiving study drug, MRI was performed on Days 2-3. No significant difference in MSI was found between adenosine- and placebo-treated patients: 41.3% (20.8, 66.7) vs. 47.8% (39.8, 60.9) [median (Q1, Q3)] (P = 0.52). The extent of MVO was comparable in both groups, with a trend favouring the placebo group: 2.4 g (0.0, 6.8) vs. 5.9 g (0.0, 12.8) after adenosine (P = 0.07). TIMI flow grade, TIMI frame count, myocardial blush grade, and ST-segment resolution after primary percutaneous coronary intervention were similar between groups. After 4 months, infarct size was similar in both treatment groups.
We found no evidence that selective high-dose intracoronary administration of adenosine distal to the occlusion site of the culprit lesion in STEMI patients results in incremental myocardial salvage or a decrease in microvascular obstruction.
European Heart Journal 12/2010; 32(7):867-77. · 14.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Over the past decades, the life expectancy of individuals with congenital heart disease (CHD) has increased significantly. However, precise estimates for survival to adulthood are scarce for patients with CHD. We investigated the proportion of CHD patients born between 1990 and 1992 who survived into adulthood. We also compared their survival with that of CHD patients born in earlier eras and evaluated survival as a function of the type of heart defect.
We reviewed the CHD program administrative and clinical database at the University Hospitals Leuven (Leuven, Belgium) and analyzed the records of 7497 CHD patients born from 1970 to 1992. Survival to 18 years of age in patients born between 1990 and 1992 was 88.6% (95% confidence interval [CI], 86.3% to 90.5%), which was significantly greater than that of patients born in previous decades (P<0.0001). For patients born between 1990 and 1992, survival into adulthood for those with mild heart defects was 98.0% (95% CI, 95.8% to 99.1%), whereas survival for those with moderate- and severe-complexity heart defects was 90.0% (95% CI, 86.8% to 92.5%) and 56.4% (95% CI, 47.4% to 64.5%), respectively. Analysis per heart defect confirmed these findings, demonstrating that patients with univentricular heart (49.1% [95% CI, 30.8% to 65.1%]) and hypoplastic left heart syndrome (7.5% [95% CI, 0.6% to 26.6%]) had the poorest survival rate.
This study demonstrates that almost 90% of children with CHD have the prospect of surviving into adulthood.
[Show abstract][Hide abstract] ABSTRACT: Triple valve surgery remains a challenge, although with an improved survival rate compared to historical data. Aws assessment was made as to whether the type of valve surgery, underlying valve lesion and pathology were independent predictors of outcome. The patient characteristics were also described according to the type of surgery performed.
A total of 166 consecutive patients underwent triple valve surgery and were followed up between October 1972 and June 2006. The clinical and operative variables were obtained retrospectively by physicians. The median follow up was 6.11 years (interquartile range 2.13-10.43).
The overall 30-day mortality was 10%, five-year survival 70%, and 10-year survival 60%. In patients with three mechanical valves, survival at five years was 90%, and 85% at 10 years, compared to 40% at five years and 30% at 10 years in patients with three bioprostheses. Among all patients with a mechanical valve in the aortic and mitral positions, those with a tricuspid bioprosthesis were compared to patients with tricuspid repair. The survival rate at 10 years was 60%, and similar between groups. The survival rate of patients with aortic and mitral bioprostheses and tricuspid repair was comparable to that in patients with three bioprostheses. Multivariable analyses showed that the type of tricuspid surgery, age, and NYHA functional class were each significant and independent predictors of survival, with a tricuspid mechanical prosthesis favoring survival. According to the type of surgery, the patient groups differed in their cardiovascular and non-cardiovascular risk profiles.
Triple-valve surgery is a difficult procedure, with greatly improved survival rates compared to historically reported data. The decision of prosthetic valve type and repair should be tailored to the individual patient, as both patient characteristics and chosen surgery appear to determine survival and morbidity. In young patients, a mechanical prosthesis should also be considered in the tricuspid position.
The Journal of heart valve disease 09/2010; 19(5):644-51; discussion 652. · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: TB-402, a human monoclonal antibody that partially inhibits Factor VIII activity (FVIII:C), is being developed as a long-acting antithrombotic agent.
The primary goal of this study was to investigate the tolerability of TB-402 in healthy male volunteers. Secondary objectives were to determine the pharmacokinetics and pharmacodynamics of TB-402.
In this ascending-dose study, healthy subjects aged 18 to 45 years were randomly assigned in a 2:1 ratio to receive TB-402 administered as a single intravenous bolus at 0.015, 0.1, 0.5, 2.5, 12.5, 37.5, 188, 620, or 1860 microg/kg or matching inactive vehicle (placebo). An older group (55-75 years) was also administered the highest dose that was well tolerated in the younger group (1860 microg/kg). Adverse events (AEs) were obtained from spontaneous reporting and from answers to nonleading questions asked by the principal investigator and study staff during follow-up visits on days 4, 7 (+/-1 day), 14 (+/-1 day), 21 (+/-2 days), 28 (+/-3 days), 42 (+/-3 days), and 56 (+/-3 days) after TB-402 administration. AEs were monitored up to the last study visit on day 56 after the administration of TB-402 or placebo, with special attention to bleeding events. The pharma-codynamic assessment of TB-402 included changes in FVIII:C, activated partial thromboplastin time (APTT), and prothrombin time (PT).
The study enrolled 56 subjects (mean ages: younger group, 28 years [range, 20-45 years]; older group, 65 years [range, 58-76 years]; weight, 79 kg [range, 60-104 kg] and 81 kg [range, 64-94 kg], re-spectively). Thirty-one of the 38 subjects who received TB-402 (82%) experienced a total of 85 treatment-emergent AEs (TEAEs), and 14 of 18 subjects who received placebo (78%) experienced 35 TEAEs. A total of 34 bleeding events were reported in 13 of 38 subjects (34%) who received TB-402 and 7 of 18 subjects (39%) who received placebo. Most common AEs reported in subjects who received TB-402 were headache (11 [29%]), vessel puncture-site hematoma (7 [18%]), and traumatic hematoma (5 [13%]); with placebo, these AEs were vessel puncture-site hematoma (4 [22%]), headache (3 [17%]), vasovagal reaction (3 [17%]), and hematuria (3 [17%]). No serious AEs considered to be related to TB-402 were reported, and no dose-dependent increases in bleeding events were observed. On pharmacokinetic analysis of TB-402, the t(1/2) values across doses were 22.9 days (age 18-45 years) and 19.5 days (age 55-75 years). TB-402 was associated with a reduction in FVIII:C over a period of approximately 48 hours in the d37.5-microg/kg dose groups. TB-402 was associated with a prolonged APTT at doses >or=2.5 microg/kg approximately 1.1-1.2-fold predose APTT). Administration of a higher dose of TB-402 was associated with an extended duration of APTT prolongation. No significant effect on PT was found.
In this study in healthy male volunteers, TB-402 was well tolerated in the population studied. Based on the findings from this study, the long t(1/2) of TB-402 may allow a pharmacodynamic effect over a prolonged period after single-dose administration. Further trials are needed to address the tolerability and efficacy of this agent in preventing thromboembolism. Clinicaltrials.gov identifier: NCT00612196.