Occurrence Of Clinical Events Research Articles

Periprocedural myocardial infarction enhances the predictive value of inflammatory biomarkers for patients with obstructive coronary artery disease after implantation of drug-eluting stent

Periprocedural myocardial infarction enhances the predictive value of inflammatory biomarkers for patients with obstructive coronary artery disease after implantation of drug-eluting stent Anastasia Jesika,1 Zuo-Ying Hu,2 Jing Kan,3 Shao-Liang Chen2 1Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China; 3Nanjing Heart Center, Nanjing, People’s Republic of China Objective: The present study aims to clarify the long-term clinical importance of interleukin (IL)-6 in predicting major adverse cardiac events (MACE) for an entire cohort of patients with coronary artery disease after implantation of a drug-eluting stent (DES), and its interplay with periprocedural myocardial infarction (PMI). Background: The correlation of proinflammatory biomarkers with occurrence of clinical events, including PMI and mortality, is controversial. Methods: IL-6 was measured in 1,991 patients at admission. The participants were then assigned to two groups: IL-6 level 9 pg/mL and IL-6 level

Cytokines Polymorphisms and Relationship with Cytokine Expression in Sickle Cell Disease

Sickle cell disease (SCD) is a chronic inflammatory condition, even in steady state, as indicated by elevated levels of inflammatory cytokines and increased Th17 responses, compared with healthy controls. These inflammatory pathways may be directly regulated by genetic polymorphisms and could be associated to different outcomes of the disease. High levels of a number of different circulating cytokines were found in SCD patients in several studies, and changes in the cytokine balance in SCD patients are an important risk factor for the occurrence of clinical events. Moreover, inter-patient variations in cytokine levels could be attributed to gene polymorphisms. To investigate cytokine polymorphisms and their association with cytokines expression we evaluated the IL4 intron3 VNTR (genotypes 1.1, 1.2, 2.2, 2.3), IL4T590C/T, IL6174G/C and TNFA308A/G polymorphisms and their correlation with TGFB, IL-4, IL-6 and IL-10 expression in steady-state SCD patients.Methods. Fourth-nine patients (24 male and 25 female; 39.8 ± 9.59 years) with SCD and 28 (22 male and 6 female; 35.5 ± 10.2 years) healthy blood donors were evaluated. The polymorphisms were performed by PCR-RFLP analysis described as [individuals (genotype frequencies)] and the expression of TGFB, IL-4, IL-6 and IL-10 by q-PCR expressed as [median (max-min)].Results. A higher frequency of 1.2, 2.2 and 2.3 genotypes was found in SCD patients compared with normal controls [34(0.69) vs 12 (0.44), P=0.03]; higher expression of IL-4 was found in the ones carrying the 1.1 genotype [0.31 (2.53-0.01) vs 0.05 (0.95-0.0), P=0.047] and although no differences were found in the IL4T590C/T, IL6174G/C and TNFA308A/G polymorphism frequencies, a significantly greater expression of TGFB, IL6 and IL10 was observed in the patients cohort compared to normal individuals [1.55 (9.02-0.0) vs 0.97 (5.46-0.0), P=0.019]; [0.18 (45.45-0.0) vs 0.0 (8.14-0.0), P=0.03] and [0.98 (22.84-0.0) vs 0.0 (9.95-0.0), P<0.001, respectively]. All the genotype frequencies are consistent with Hardy-Weinberg equilibrium.Conclusion: A unique distribution of IL-4 genotypes was observed in our cohort of patients and controls, probably related to the miscellaneous ethnic background of our population. The highest prevalence of the IL4intron3 polymorphism in sickle cell patients suggests a less secretory phenotype associated with increased expression of inflammatory cytokines. IL-4 plays an important role in tissue adhesion and inflammation, including induction of adhesion molecules on vascular endothelial cells and could be responsible for a more “inflammatory” phenotype. Despite the small number of patients enrolled, our study brings insights and new data regarding the deregulation in immune system affecting SCD patients and this information must be investigated in larger cohorts, and may help to better characterize individual variations in immune responses and new markers for disease morbidity. DisclosuresNo relevant conflicts of interest to declare.

Cost-effectiveness of DTG+ABC/3TC versus EFV/TDF/FTC for first-line treatment of HIV-1 in the United States.

IntroductionData from the SINGLE trial demonstrated that 88% of treatment-naive HIV-1 patients treated with dolutegravir and abacavir/lamivudine (DTG+ABC/3TC) achieved viral suppression at 48 weeks compared with 81% of patients treated with efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC). It is unclear how this difference in short-term efficacy impacts long-term cost-effectiveness of these regimens. This study sought to evaluate the long-term cost-effectiveness of DTG+ABC/3TC versus EFV/TDF/FTC from a US payer perspective.Materials and MethodsAn individual discrete-event simulation model tracked the disease status and treatment pathway of HIV-1 patients. The model simulated treatment over a lifetime horizon by tracking change in patients’ CD4 count, occurrence of clinical events (opportunistic infections, cancer and cardiovascular events), treatment switch and death. The model included up to four lines of treatment. Baseline patient characteristics, efficacy and safety of DTG+ABC/3TC and EFV/TDF/FTC were informed by data from the SINGLE trial. The efficacy of subsequent lines of treatment, clinical event risks, mortality, cost and utility inputs were based on literature and expert opinion. Outcomes were lifetime medical costs, quality-adjusted life-years (QALYs) (both discounted at 3% per annum) and the incremental cost-effectiveness ratio (ICER).ResultsCompared with EFV/TDF/FTC, DTG+ABC/3TC increased lifetime costs by $58,188 and per-person survival by 0.12 QALYs, resulting in an ICER of $482,717/QALY. In sensitivity analyses testing conservative assumptions about EFV/TDF/FTC's efficacy beyond the trial period, ICERs comparing DTG+ABC/3TC to EFV/TDF/FTC remained high (lowest reported ICER of $365,662/QALY). In a scenario in which the price of EFV/TDF/FTC was reduced by 10% to reflect the potential for price reduction as EFV goes off patent, DTG+ABC/3TC's ICER compared to EFV/TDF/FTC was $600,916/QALY. When DTG+ABC/3TC's price was reduced by 10%, the resulting ICER comparing DTG+ABC/3TC to EFV/TDF/FTC was $302,171/QALY.ConclusionsCompared with EFV/TDF/FTC, DTG+ABC/3TC resulted in substantially higher cost, slightly better QALY over lifetime, and ICERs far exceeding standard cost-effectiveness thresholds, indicating that the incremental benefit in efficacy associated with DTG+ABC/3TC may not be worth the incremental increase in costs.

HIV-1 superinfection is associated with an accelerated viral load increase but has a limited impact on disease progression.

HIV-1 superinfection occurs frequently in high-risk populations, but its clinical consequences remain poorly characterized. We undertook this study to determine the impact of HIV-1 superinfection on disease progression. In the largest prospective cohort study of superinfection to date, we compared measures of HIV-1 progression in women who acquired superinfection with those who did not. Clinical and laboratory data were collected at quarterly intervals. Linear mixed effects models were used to compare postacute viral load and CD4 T-cell counts over time in singly infected and superinfected women. Cox proportional hazards analysis was used to determine the effect of superinfection on time to clinical progression [CD4 cell count <200 cells/μl, antiretroviral therapy (ART) initiation or death]. Among 144 women, 21 of whom acquired superinfection during follow-up, the rate of viral load increase was higher in superinfected than in singly infected women (P = 0.0008). In adjusted analysis, superinfected women had lower baseline viral load before superinfection (P = 0.05) and a trend for increased viral load at superinfection acquisition (P = 0.09). We also observed a borderline association of superinfection with accelerated CD4 cell count decline (P = 0.06). However, there was no significant difference in time to clinical progression events. These data suggest that superinfection is associated with accelerated progression in laboratory measures of HIV-1 disease, but has a limited impact on the occurrence of clinical events. Our observation that superinfected individuals have lower baseline viral load prior to superinfection suggests that there may be host or viral determinants of susceptibility to superinfection.

Semi-automatic MRI segmentation and volume quantification of intra-plaque hemorrhage.

Intra-plaque hemorrhage (IPH) is associated with plaque instability. Therefore, the presence and volume of IPH in carotid arteries may be relevant in predicting the progression of atherosclerotic disease and the occurrence of clinical events. The aim of our work was to develop and evaluate a method for semi-automatic IPH segmentation in T1-weighted (T1w)-magnetic resonance imaging (MRI). IPH segmentation is performed by a regional level set method that models the intensity of the IPH and the background in T1w-MRI to be smoothly varying. The method only requires minimal user interaction, i.e., one or more mouse clicks inside the hemorrhage serve as initialization. The parameters of the method are optimized using a leave-one-out strategy by maximizing the Dice similarity coefficient (DSC) between manual and semi-automatic segmentations. We evaluated the IPH segmentation method on 22 carotid arteries; 10 of which were annotated by two observers and 12 were scanned twice within a 2 week period. We obtained a DSC of 0.52 between the manual and level set segmentations on all 22 carotids. The inter-observer DSC on 10 arteries is 0.57, which is comparable to the DSC between the method and the manual segmentation (0.55). The correlation between the IPH volumes extracted from the level set segmentation and the manual segmentation is 0.88, which is close to the inter-observer volume correlation of 0.92. The reproducibility after rescanning 12 carotids yield an IPH volume correlation of 0.97. The robustness with respect to the initialization by manually clicking two sets of seed points in these 12 carotid artery pairs yields a volume correlation of 0.99. Semi-automatic segmentation and quantification of IPHs are feasible with an accuracy in the range of the inter-observer variability. The method has excellent reproducibility with respect to rescanning and manual initialization.

Abdominal aortic calcification and its distribution in normal-sized and aneurysmatic abdominal aortas

Multi-detector computed tomography (MDCT) is more and more used for evaluation and quantification of coronary artery calcification, but correlation between the degree of calcification and occurrence of clinical events is also known for other vascular beds such as the aorta. To assess possible differences in amount and pattern of calcification in aneurysmatic and non-aneurysmatic abdominal aortas. Thirty-four subjects displayed infrarenal abdominal aneurysm (AAA) and were compared to 33 patients with normal-sized aortas using MDCT. Quantitative and qualitative analysis was performed by two radiologists. Calcium scores were assessed for the whole abdominal aorta as well as separately for the supra- and infrarenal segments. Moreover, plaque patterns were evaluated and classified according to their thickness and size. Furthermore, calcium scores were correlated with a number of cardiovascular risk factors. Total calcium scores were comparable in patients with and without AAA (1,213 ± 1,351 and 1,211 ± 1,535, respectively), but significant differences were found regarding plaque density that was considerably higher both in the supra- and infrarenal segments in the non-aneurysmatic group (AAA: suprarenal, 0.01, infrarenal, 0.07; non-AAA: suprarenal, 0.06, infrarenal, 0.16). Plaque pattern were considerably different in the infrarenal segments in aneurysmatic aortas: they were thinner (1 and 2 mm) and smaller (< 100 mm2) than in normal-sized aortas (mainly > 3mm and > 100 mm2). Distribution of risk factors was similar in both groups with the highest mean calcium score being present in patients with 4 risk factors. Pearson's correlation coefficient indicating correlation between total calcium score and number of risk factors was almost the same in both groups: AAA, r = 0.67; non-AAA, r = 0.65. Compared to normal-sized aortas thinner and smaller plaques are present in AAA, which may be due to degenerative processes.

Diagnostic and Prognostic Value of Multimodal MRI in Transient Ischemic Attack

The clinical diagnosis of transient ischemic attack is highly subjective, and the risk prediction after transient ischemic attack using the clinical parameters still remains unsatisfactory. We aimed to investigate the diagnostic and prognostic value of multimodal magnetic resonance imaging in transient ischemic attack patients. We prospectively performed diffusion-weighted imaging, perfusion-weighted imaging, and intracranial and extracranial magnetic resonance angiogram within 72 h of symptom onset in 162 transient ischemic attack patients defined by the classical time-based definition. Follow-up diffusion-weighted imaging was obtained three-days later in patients who did not exhibit lesions on the initial diffusion-weighted imaging. The occurrence of clinical events (transient ischemic attack or stroke) three-months after the initial transient ischemic attack was recorded, and the ABCD2 and ABCD3-I scores were calculated. The clinical and imaging parameters were compared between patients with and without initial diffusion-weighted imaging lesion, clinical events, and follow-up diffusion-weighted imaging lesions. Abnormalities were present on diffusion-weighted imaging, perfusion-weighted imaging, and magnetic resonance angiogram in 38·9%, 44·1%, and 51·9% of patients, respectively. Diffusion-weighted imaging plus perfusion-weighted imaging explained 64·8%, and the addition of magnetic resonance angiogram explained 74% of the transient ischemic attack symptoms. The initial diffusion-weighted imaging positivity was associated with longer time from symptom onset to magnetic resonance imaging examination (odds ratio, 1·039; 95% confidence interval, 1·008-1·071; P=0·013). On follow-up diffusion-weighted imaging, new lesions were found in 46·7% of the patients who initially showed normal diffusion-weighted imaging findings. Initial perfusion-weighted imaging abnormality predicted the appearance of follow-up diffusion-weighted imaging lesion (chi-square=7·774, P=0·005). During the three-months follow-up, 23 patients (14·2%) experienced subsequent transient ischemic attack (n=16) or stroke (n=7). Symptomatic magnetic resonance angiogram abnormality (odds ratio, 12·667; 95% confidence interval, 2·859-56·110; P=0·001) was the only independent factor associated with clinical events with a sensitivity of 91·3% and specificity of 54·7% (C statistics, 0·73). None with initially normal multimodal magnetic resonance imaging findings developed subsequent clinical events. Approximately three-quarter of transient ischemic attack is associated with multimodal magnetic resonance imaging abnormality. Initial perfusion-weighted imaging abnormality predicts newly developed diffusion-weighted imaging lesions, and symptomatic magnetic resonance angiogram abnormality seems to be the most important predictor for subsequent clinical events. Multimodal magnetic resonance imaging appears to be useful in assessing transient ischemic attack and predicting outcome in these patients.

Left Atrial and Left Ventricular Diastolic Function in Chronic Chagas Disease

Left atrial (LA) and left ventricular (LV) diastolic function analysis can yield new strategies to recognize early cardiac involvement and prognostic indicators in Chagas disease. Patients with Chagas disease with the indeterminate (n= 69) or with the cardiac form (32 with changes limited to electrocardiography [stage A], 25 with changes in LV systolic function but no heart failure [HF; stage B], and 26 with HF) underwent evaluation of LV diastolic function (mitral inflow, pulmonary vein flow, color M-mode echocardiography, and tissue Doppler analysis), and LA function by three-dimensional echocardiography and strain analysis and were prospectively followed for the occurrence of clinical events. Echocardiograms were also obtained from 32 controls. LV diastolic dysfunction was gradually more prevalent and severe across groups from patients with the indeterminate form of Chagas disease to patients with HF. Tissue Doppler was the best tool to demonstrate the worsening of LV diastolic function across the groups (E' velocity: controls, 12.6 ± 2.3 cm/sec; patients with the indeterminate form, 12.1 ± 3.1 cm/sec; stage A, 10.3 ± 2.9 cm/sec; stage B, 8.3 ± 2.8cm/sec; patients with HF, 5.6 ± 1.9; P < .0001). Although maximum LA volume was increased only in patients with HF, minimum LA volume (controls, 8 ± 2 mL/m(2); patients with the indeterminate form, 8 ± 2 mL/m(2); stage A, 9 ± 3 mL/m(2); stage B, 11 ± 4 mL/m(2); patients with HF, 27 ± 17 mL/m(2); P < .0001) and precontraction LA volume (controls, 11 ± 3 mL/m(2); patients with the indeterminate form, 12 ± 3 mL/m(2); stage A, 13 ± 4mL/m(2); stage B, 16 ± 5 mL/m(2); patients with HF, 32 ± 19 mL/m(2); P < .0001) were increased in all cardiac form groups. LA conductive function was depressed in all cardiac form groups, while LA contractile function was depressed only in patients with HF. Cox proportional-hazards regression analysis revealed that end-systolic LV diameter (hazard ratio, 1.6; 95% confidence interval, 0.9-2.8; P= .09), E' velocity (hazard ratio, 0.5; 95% confidence interval, 0.3-0.8; P= .001), and peak negative global LA strain (hazard ratio, 1.21; 95% confidence interval, 1.02-1.4; P= .03), were independent predictors of clinical events. LV diastolic dysfunction was found in all forms of chronic Chagas disease, including those without LV systolic dysfunction. LV diastolic dysfunction may contribute to changes in LA volume and conductive function found in early stages of the cardiac form. Both LV diastolic function and LA contractile function were independent predictors of clinical events.

Effectiveness of a cardiac surgery–specific transfusion protocol

Cardiac surgery is often complicated by excessive bleeding that is commonly treated with blood products. In the year 2009 a transfusion protocol was introduced specifically designed for cardiac surgery procedures. This study aims to evaluate the effect of this protocol on transfusion of blood products and the occurrence of clinical events. This was a nonrandomized intervention study. The index group was transfused according to a tailor-made transfusion protocol (operation in 2009/2010) and the control group was transfused according to the Dutch national transfusion guideline (operation in 2007/2008). The primary outcome was mean number of units transfused and proportion of patients transfused. Secondary outcomes were in-hospital mortality, myocardial infarction, cerebrovascular accident or transient ischemic attack, renal injury or failure, rethoracotomy, and prolonged mechanical ventilation. The control group comprised 2685 patients and the index group 2534 patients. The tailor-made transfusion protocol resulted in a decrease of patients transfused with red blood cells (RBCs) and fresh-frozen plasma (FFP) during surgery with odds ratio of 0.69 (95% confidence interval [CI], 0.55-0.86) and 0.63 (95% CI, 0.46-0.86), respectively. Fewer myocardial infarctions were observed in the index group with OR of 0.67 (95% CI, 0.47-0.96). The cardiac surgery-specific transfusion protocol resulted in fewer patients transfused with RBCs and FFP and a lower incidence of myocardial infarction. This tailor-made protocol has led to a more judicious use of blood products and is a basis for further refinement of coagulation management during cardiac surgery procedures.

AB0202 Ultrasonografic carotid plaque morphology in women with rheumatoid arthritis without previous cardiovascular events

BackgroundPatients with inflammatory rheumatic diseases die prematurely, largely due to cardiovascular (CV) diseases. In rheumatoid arthritis (RA) patients subclinical atherosclerosis and cardiovascular events (CV) occur 2 to 3 times more...

PREDICTORS OF HIGH THROMBIN-INDUCED PLATELET-FIBRIN CLOT STRENGTH IN PATIENTS TREATED WITH PCI

High thrombin-induced platelet-fibrin clot strength (MATHROMBIN) measured by thrombelastography is associated with the risk of adverse clinical event occurrence. However, predictors and correlation with “HPR to ADP” of high MATHROMBIN are not undetermined. Among PCI patients (n=197), we

Cost-effectiveness of dabigatran for stroke prevention in atrial fibrillation in Switzerland

Atrial fibrillation is a major risk factor for ischemic stroke and anticoagulation therapy is indicated to reduce risk. Dabigatran is a new oral anticoagulant that does not require INR monitoring. This study evaluated the cost-effectiveness of dabigatran versus vitamin K antagonists for stroke prevention in atrial fibrillation in Switzerland. A Markov model simulating the course of treatment and occurrence of clinical events in two treatment arms over the lifetime of patients was adapted to the Swiss context. The adaptation included the cost of anticoagulation therapy and clinical events in Switzerland. The cost of inpatient care was estimated on data of all inpatient hospital stays in 2008. The calculation of outpatient care costs was based on peer reviewed studies, expert interviews and local tariffs. Patients treated with dabigatran had a higher life expectancy and experienced more quality adjusted life years (QALY) while incurring higher costs than patients treated with vitamin K antagonists. The estimated incremental cost-effectiveness ratio (ICER) was CHF 25,108.‒ per QALY with 110 mg and CHF 9,702 per QALY with 150 mg of dabigatran. A sequential dosage scheme, in which 150 mg are administered up to the age of 80 years and 110 mg thereafter, resulted in an ICER of CHF 10,215 per QALY. A sensitivity analysis confirmed that these results are robust. Dabigatran can be considered cost-effective in comparison with vitamin K antagonists in the Swiss context. The higher drug cost of dabigatran is compensated by savings in INR monitoring, lower cost of clinical events and QALY-gains.

Analysis of Draining Leukocytes from the Abdominal Fluid to Monitor Immune Events after Intestinal Transplantation. Follow Up Report

Introduction: During intestinal transplant (ITx) operation, intestinal lymphatics are not reconstituted. Consequently, lymph containing trafficking leukocytes drains freely into the abdominal cavity, where this fluid is absorbed by an open drainage system. We have previously reported that the abdominal drainage sample is different from the blood sample in composition of the three major leukocyte populations, lymphocytes, monocytes, and granulocytes and therefore might be useful for monitoring immune events during the first post-operative weeks. In this follow up study, our aim was to correlate changes in fluid cellularity with the occurrence of clinical events. Methods: Seventeen consecutive ITx patients (12 pediatric, 5 adult; 1 liver/intestine, 2 multivisceral, 14 isolated) were included in this retrospective cohort study. Cell composition of the abdominal drainage sample was analyzed by flow cytometry during the first 15 post-ITx days. The correlation between cell parameters (FSC-SSC pattern, CD4/CD8 ratio, CD69 expression in T cells, NK and NKT cells appearance) and clinical complications was evaluated. Results: Cellular pattern varied along the post-ITx period in non-complicated recipients (n = 6) from a mixed leukocyte pattern to an exclusively lymphocytic pattern from the fourth day onwards with predominance of CD4+ T cells (50-80%). In contrary, in samples of patients with intra-abdominal clinical complications, such as bacterial infections (n = 3), rejection (n = 3), or non-infectious inflammatory events (n = 5), we could correlate appearance of granulocytes and natural killer cells with clinical events. In addition, the expression of the early activation marker CD69 was significantly increased on CD4 and CD8 T cells from samples with clinical events. No clear differences in cellular composition or CD69 expression between the different clinical complications could be detected. Conclusions: Our results indicate that cell analysis of the draining fluid from intestinal transplant recipients might be useful as a tool to support diagnosis and clinical patient management during the first post-Tx weeks, that are critical due to high incidence of complications. Furthermore, this follow-up study ensures the utility of this method to gain insight into intestinal transplant immunobiology.

Análisis coste-efectividad de dabigatrán para la prevención de ictus y embolia sistémica en fibrilación auricular no valvular en España

Introduction and objectivesAssessment of the cost-effectiveness of dabigatran for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in Spain, from the perspective of the National Health System. MethodsAdaptation of a Markov chain model that simulates the natural history of the disease over the lifetime of a cohort of 10 000 patients with non-valvular atrial fibrillation. Model comparators were warfarin in a first scenario, and a real world prescribing pattern in a second scenario, in which 60% of the patients were treated with vitamin K antagonists, 30% with acetylsalicylic acid, and 10% received no treatment. Deterministic and probabilistic sensitivity analyses were performed. ResultsDabigatran reduced the occurrence of clinical events in both scenarios, providing gains in quantity and quality of life. The incremental cost-effectiveness ratio for dabigatran compared to warfarin was 17 581 euros/quality-adjusted life year gained and 14 118 euros/quality-adjusted life year gained when compared to the real world prescribing pattern. Efficiency in subgroups was demonstrated. When the social costs were incorporated into the analysis, dabigatran was found to be a dominant strategy (ie, more effective and less costly). The model proved to be robust. ConclusionsFrom the perspective of the Spanish National Health System, dabigatran is an efficient strategy for the prevention of stroke in patients with non-valvular atrial fibrillation compared to warfarin and to the real-world prescribing pattern; incremental cost-effectiveness ratios were below the 30 000 euros/quality-adjusted life year threshold in both scenarios. Dabigatran would also be a dominant strategy from the societal perspective, providing society with a more effective therapy at a lower cost compared to the other 2 alternatives.Full English text available from:www.revespcardiol.org

Cost-effectiveness of Dabigatran for Stroke Prevention in Non-valvular Atrial Fibrillation in Spain

Introduction and objectivesAssessment of the cost-effectiveness of dabigatran for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in Spain, from the perspective of the National Health System. MethodsAdaptation of a Markov chain model that simulates the natural history of the disease over the lifetime of a cohort of 10 000 patients with non-valvular atrial fibrillation. Model comparators were warfarin in a first scenario, and a real world prescribing pattern in a second scenario, in which 60% of the patients were treated with vitamin K antagonists, 30% with acetylsalicylic acid, and 10% received no treatment. Deterministic and probabilistic sensitivity analyses were performed. ResultsDabigatran reduced the occurrence of clinical events in both scenarios, providing gains in quantity and quality of life. The incremental cost-effectiveness ratio for dabigatran compared to warfarin was 17581 euros/quality-adjusted life year gained and 14118 euros/quality-adjusted life year gained when compared to the real world prescribing pattern. Efficiency in subgroups was demonstrated. When the social costs were incorporated into the analysis, dabigatran was found to be a dominant strategy (ie, more effective and less costly). The model proved to be robust. ConclusionsFrom the perspective of the Spanish National Health System, dabigatran is an efficient strategy for the prevention of stroke in patients with non-valvular atrial fibrillation compared to warfarin and to the real-world prescribing pattern; incremental cost-effectiveness ratios were below the 30 000 euros/quality-adjusted life year threshold in both scenarios. Dabigatran would also be a dominant strategy from the societal perspective, providing society with a more effective therapy at a lower cost compared to the other 2 alternatives.

RAS mutations are frequent in FAB type M4 and M5 of acute myeloid leukemia, and related to late relapse: a study of the Japanese Childhood AML Cooperative Study Group

Mutations in RAS are frequent in acute myeloid leukemia (AML), and are thought to contribute to leukemogenesis in a subset of patients; however, their prognostic significance has not been firmly established. One hundred and fifty-seven pediatric patients with AML were analyzed for NRAS and KRAS mutations around hot spots at codons 12, 13, and 61. Twenty-nine patients (18.5%) had an activating mutation of RAS. We found KRAS mutations to be more frequent than NRAS mutations (18/29, 62.1% of patients with RAS mutation), in contrast to previous reports (18-40%). The frequency of RAS mutation was higher in French-American-British types M4 and M5 than other types (P=0.02). There were no significant differences in other clinical manifestations or distribution in cytogenetic subgroups, or aberrations of other genes, including KIT mutation, FLT3-ITD, and MLL-PTD, between patients with and without RAS mutations. No significant differences were observed in the 3-year overall survival and disease-free survival; however, the presence of RAS mutation was related to late relapse. The occurrence of clinical events at relatively late period should be monitored for in AML patients with mutations in RAS.

Impact of First-Line Sildenafil Monotreatment for Pulmonary Arterial Hypertension

Sildenafil has been demonstrated as effective for the treatment of pulmonary arterial hypertension (PAH). The purpose of this study was to investigate the occurrence of clinical events after sildenafil monotreatment as a first-line therapy in patients with PAH over a long-term observation period. Sildenafil was administered as a first-line drug to 46 patients with PAH (including 24 patients with idiopathic PAH) during 2003-2010. We investigated subsequent clinical events such as the addition of epoprostenol, hospitalization for right-side heart failure, and death. All the hemodynamic parameters and the 6-min walk distance improved significantly in the enrolled patients as a whole receiving sildenafil treatment; 15 (33%) of the 46 patients required the addition of epoprostenol during follow-up. Kaplan-Meier analysis demonstrated that more than 60% of the patients receiving first-line sildenafil treatment did not require the addition of epoprostenol for a 5-year period. Furthermore, the 5-year survival rate after first-line sildenafil treatment was 81%. Finally, more than 75% of the enrolled patients did not reach the composite endpoint of hospitalization for right-side heart failure and death for a 5-year period. This study describes the long-term outcome of patients with PAH receiving sildenafil monotreatment as a first-line therapy and suggests that it is a promising therapeutic strategy.

Flow Visualization and Characterization of an Artery Model with Stenosis

Cardiovascular diseases, principally atherosclerosis, are responsible for 30% of world deaths. Atherosclerosis is due to the formation of plaque. The fatty plaque may be at risk of rupture, leading typically to stroke and heart attack. The plaque is usually associated with a high degree of lumen reduction, called a stenosis.It is increasingly recognized that the initiation and progression of disease and the occurrence of clinical events is a complex interplay between the local biomechanical environment and the local vascular biology. The aim of this study is to investigate the flow behavior through a stenosed artery. A physical experiment was performed using an artery model and blood analogue fluid. An axisymmetric model constructed consists of contraction and expansion region that follow a mathematical form of cosine function. A 30% diameter reduction was used in this study. The flow field was measured using particle image velocimetry (PIV). Spherical particles with 20µm diameter were seeded in a water-glycerol-NaCl mixture. Steady flow Reynolds numbers are 250. The area of interest is the region after the stenosis where the flow separation occurs. The velocity field was measured and the velocity gradient was investigated. There was high particle concentration in the recirculation zone. High velocity gradient formed immediately after the stenosis throat created a lift force that enhanced particle migration to the flow separation area. Keywords—Stenosis artery, Biofluid mechanics, PIV

Abstract 18022: High On-Treatment Platelet Reactivity Measured by Various Platelet Function Tests: Is the Current VASP-PRI Cutoff Too Low?

Background: High on-treatment platelet reactivity (HPR) to ADP measured by multiple methods has been linked to adverse post-PCI clinical event occurrence. The correlation of HPR cutoffs is still a matter of debate, since the predictive value and HPR group size are different depending on platelet function assays. To determine the comparable cutpoint, we correlated cutpoints for HPR determined by various assays in the same patient cohort. Methods: Platelet measures [5µM ADP-induced light transmission aggregation (LTA5μ MADP); P2Y12 reaction units by VerifyNow (PRU), and platelet reactivity index by VASP assay (PRI)] were evaluated (n=936 pairs, cohort I) in stable CAD patients during P2Y12 receptor inhibitor treatment. These assays also performed in PCI-treated patients receiving standard aspirin and clopidogrel therapy (n=584, cohort II). The HPR cutpoints were defined as LTA 5μ MADP &gt;46%, PRU &gt;235, and PRI &gt;50%. Results: In the stable CAD patients, LTA 5μ MADP showed significant correlations with PRU and PRI (r ≥0.688). In ROC curve analysis using the cutpoint of LTA 5μ MADP (&gt;46%), the matched values of PRU and PRI were &gt;234 (AUC 0.943, p&lt;0.001, sensitivity 87.3% and specificity 87.8%) and &gt;60% (Figure A). Among PCI-treated patients, the prevalence of HPR was highest based on PRI &gt;50% (69%) compared with other criteria (≤55%). The comparable values for LTA 5μ MADP &gt;46% were PRU &gt;235 (AUC 0.850, p&lt;0.001, sensitivity 85.3% and specificity 70.4%) and PRI &gt;59% (Figure B). Conclusion: The published cutoff values for HPR by LTA 5μ MADP and PRU were well correlated, whereas published PRI &gt;50% cutoff value may overestimate the risk of HPR. Updated cutoff of PRI &gt; 60% may better stratify the risk for HPR and can be used in future trials.

Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia

Cell therapy is a novel experimental treatment modality for patients with critical limb ischemia (CLI) of the lower extremities and no other established treatment options. This study was conducted to assess the safety and clinical efficacy of intramuscular injection of autologous tissue repair cells (TRCs). A prospective, randomized double-blinded, placebo controlled, multicenter study (RESTORE-CLI) was conducted at 18 centers in the United States in patients with CLI and no option for revascularization. Enrollment of 86 patients began in April 2007 and ended in February 2010. For the prospectively planned interim analysis, conducted in February 2010, 33 patients had the opportunity to complete the trial (12 months of follow-up), and 46 patients had completed at least 6 months of follow-up. The interim analysis included analysis of both patient populations. An independent physician performed the bone marrow or sham control aspiration. The aspirate was processed in a closed, automated cell manufacturing system for approximately 12 days to generate the TRC population of stem and progenitor cells. An average of 136 ± 41 × 10(6) total viable cells or electrolyte (control) solution were injected into 20 sites in the ischemic lower extremity. The primary end point was safety as evaluated by adverse events, and serious adverse events as assessed at multiple follow-up time points. Clinical efficacy end points included major amputation-free survival and time to first occurrence of treatment failure (defined as any of the following: major amputation, death, de novo gangrene, or doubling of wound size), as well as major amputation rate and measures of wound healing. There was no difference in adverse or serious adverse events between the two groups. Statistical analysis revealed a significant increase in time to treatment failure (log-rank test, P = .0053) and amputation-free survival in patients receiving TRC treatment, (log-rank test, P = .038). Major amputation occurred in 19% of TRC-treated patients compared to 43% of controls (P = .14, Fisher exact test). There was evidence of improved wound healing in the TRC-treated patients when compared with controls at 12 months. Intramuscular injection of autologous bone marrow-derived TRCs is safe and decreases the occurrence of clinical events associated with disease progression when compared to placebo in patients with lower extremity CLI and no revascularization options.