Ariel Finkelstein

Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis.

Background— Aspirin and clopidogrel are recommended for patients with acute coronary syndromes (ACS) or undergoing coronary stenting. Ticagrelor, a reversible oral P2Y12-receptor antagonist, provides faster, greater, and more consistent platelet inhibition than clopidogrel and may be useful for patients with acute ST-segment elevation (STE) ACS and planned primary percutaneous coronary intervention. Methods and Result— Platelet Inhibition and Patient Outcomes (PLATO), a randomized, double-blind trial, compared ticagrelor with clopidogrel for the prevention of vascular events in 18 624 ACS patients. This report concerns the 7544 ACS patients with STE or left bundle-branch block allocated to either ticagrelor 180-mg loading dose followed by 90 mg twice daily or clopidogrel 300-mg loading dose (with provision for 300 mg clopidogrel at percutaneous coronary intervention) followed by 75 mg daily for 6 to 12 months. The reduction of the primary end point (myocardial infarction, stroke, or cardiovascular death) with ticagrelor versus clopidogrel (10.8% versus 9.4%; hazard ratio [HR], 0.87; 95% confidence interval, 0.75 to 1.01; P=0.07) was consistent with the overall PLATO results. There was no interaction between presentation with STE/left bundle-branch block and randomized treatment (interaction P=0.29). Ticagrelor reduced several secondary end points, including myocardial infarction alone (HR, 0.80; P=0.03), total mortality (HR, 0.82; P=0.05), and definite stent thrombosis (HR, 0.66; P=0.03). The risk of stroke, low in both groups, was higher with ticagrelor (1.7% versus 1.0%; HR,1.63; 95% confidence interval, 1.07 to 2.48; P=0.02). Ticagrelor did not affect major bleeding (HR, 0.98; P=0.76). Conclusion— In patients with STE-ACS and planned primary percutaneous coronary intervention, the effects of ticagrelor were consistent with those observed in the overall PLATO trial. Clinical Trial Registration— URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00391872.

Intensive home-care surveillance prevents hospitalization and improves morbidity rates among elderly patients with severe congestive heart failure

The purpose of this study was to examine the impact of intensive home-care surveillance on morbidity rates of elderly patients with severe congestive heart failure. Forty-two patients aged 78 +/- 8 years who had severe congestive heart failure (New York Heart Association functional classes III through IV, mean ejection fraction 27% +/- 6%), were examined at least once a week at home by internists from the district hospital and by a trained paramedical team. The year before entry to the home-care program was compared to the first year of home surveillance. The mean total hospitalization (hosp) rate was reduced from 3.2 +/- 1.5 hosp/yr to 1.2 +/- 1.6 hosp/yr and duration from 26 +/- 14 days/yr to 6 +/- 7 days/yr (p < 0.001 for both). Cardiovascular admissions decreased from 2.9 +/- 1.5 hosp/yr to 0.8 +/- 1.1 hosp/yr and duration from 23 +/- 13 days/yr to 4 +/- 4 days/yr (p < 0.001). The vital status (ability to perform daily activities, expressed in a 1 to 4 scale) was improved from 1.4 +/- 0.9 to 2.3 +/- 0.7 (p < 0.001). In conclusion, an intensive home-care program was associated with a marked decrease in the need for hospitalization and improved the functional status of elderly patients with severe congestive heart failure. Such a service might also have a cost-effective advantage and a major impact on health expenditure.

The effects of hormone replacement therapy in normal postmenopausal women: Measurements of Doppler-derived parameters of aortic flow

In this study the effects of hormone replacement therapy on cardiac function in healthy postmenopausal women were evaluated by Doppler echocardiography that was performed before (T1) and 2.5 months after the initiation of hormone replacement therapy (T2) in the peak estrogenic phase. The following parameters of aortic flow were measured: peak flow velocity, acceleration time, and ejection time. Additional parameters were calculated: flow velocity integral and mean acceleration. The study group included 24 postmenopausal women aged 43 to 60 years (mean 51.6 years). The control group consisted of 19 postmenopausal women aged 46 to 60 years (mean 53.5 years) who were not receiving hormone replacement therapy and who underwent the same evaluation. There were no changes in all Doppler parameters between T1 and T2 in the control group. However, in the study group there were significant increases in peak flow velocity (108.3 +/- 16.7 cm/sec at T1 vs 123 +/- 20.7 cm/sec at T2; p = 0.002), flow velocity integral (17.7 +/- 3.9 vs 21.5 +/- 4.7 cm; p = 0.0003), mean acceleration (11.5 +/- 1.9 vs 13.1 +/- 2.6 m/sec/sec; p = 0.001), and ejection time (324 +/- 37.6 vs 348.8 +/- 40.7 msec; p = 0.002). There was no change in acceleration time (94.8 +/- 6.6 vs 95 +/- 10.9 msec). These results demonstrate that estrogens increase both stroke volume and flow acceleration. The latter probably reflects a combination of enhanced inotropism and vasodilatation. We assume that the cardioprotective effect of hormone replacement therapy in postmenopausal women may be due not only to changes in lipid profile but also to direct effects of estrogens on central and peripheral hemodynamic parameters.

Local Drug Delivery via a Coronary Stent With Programmable Release Pharmacokinetics

Background—Fixed drug release kinetics and vessel wall partitioning may limit the effectiveness of drug-eluting stents. We report preliminary experience using a new coronary stent with programmable pharmacokinetics. Methods and Results—A newly designed metallic stent contains honeycombed strut elements with inlaid stacked layers of drug and polymer. In vitro studies evaluated recipes for loading paclitaxel to establish the parameters for controlling drug release. Manipulation of the layers of biodegradable polymer and drug allowed varying of the initial 24-hour burst release of paclitaxel from 69% to 8.6% (P <0.0001). Late release of drug could be adjusted dependently or independently of early burst release. A biphasic release profile was created by the addition of blank layers of polymer within the stack. In the 30-day porcine coronary model (n=17 pigs), there was a 70% reduction in late loss (0.3±0.5 versus 1.0±0.5 mm, P =0.04), a 28% increase in luminal volume (132±12 versus 103±21 mm3, P =0.02), and a 50% decrease in histological neointimal area (2.0±0.5 versus 4.0±1.6 mm2;P <0.001) compared with bare metal controls. Temporal and regional variations in vascular healing were seen histologically. Conclusions—Layered polymer/drug inlay stent technology permits flexible and controllable pharmacokinetic profiles. Programmable, complex chemotherapy using this approach may be feasible for the treatment of cardiovascular disease.

Number and Adhesive Properties of Circulating Endothelial Progenitor Cells in Patients With In-Stent Restenosis

Objective—Intact endothelialization machinery is essential to facilitate vessel healing after stent placement and to prevent restenosis. Circulating endothelial progenitor cells (EPC) have been demonstrated in the peripheral blood and shown to display endothelial functional properties, along with the ability to traffic to damaged vasculature. We reasoned that robust in-stent intimal growth could be partially related to impaired endothelialization resulting from reduced circulating EPC number or function. Methods and Results—Sixteen patients with angiographically-demonstrated in-stent restenosis were compared with patients with a similar clinical presentation that exhibited patent stents (n=11). Groups were similar with respect to the use of drugs that could potentially influence EPC numbers. Circulating EPC numbers were determined by the colony-forming unit assay, and their phenotype was characterized by endothelial-cell markers. Adhesiveness of EPC from both groups to extracellular matrix and to endothelial cells was also assayed. Patients with in-stent restenosis and with patent stents displayed a similar number of circulating EPC. Fibronectin-binding was compromised in patients with in-stent restenosis as compared with their controls exhibiting patent stents. Patients with diffuse in-stent restenosis exhibited reduced numbers of EPC in comparison with subjects with focal in-stent lesions. Conclusion—Reduced numbers of circulating EPC in patients with diffuse in-stent restenosis and impaired adhesion of EPC from patients with restenosis provides a potential mechanism mediating the exuberant proliferative process. These markers, if further validated, could provide means of risk stratifying patients for likelihood of developing in-stent restenosis.

Neutrophil/lymphocyte ratio is related to the severity of coronary artery disease and clinical outcome in patients undergoing angiography

BACKGROUND White blood cell count is an independent predictor of cardiovascular events and mortality. Neutrophil/lymphocyte ratio (NLR) is a biomarker that can single out individuals at risk for vascular events. OBJECTIVE To evaluate whether NLR adds additional information beyond that provided by conventional risk factors and biomarkers for coronary artery disease (CAD) severity and adverse outcome, in a large cohort of consecutive patients referred for coronary angiography. MATERIALS AND METHODS NLR was computed from the absolute values of neutrophils and lymphocytes from the complete blood count of 3005 consecutive patients undergoing coronary angiography for various indications. CAD severity was determined by an interventional cardiologist unaware of the study aims. The association between NLR and CAD severity was assessed by logistic regression and the association between NLR and 3-years outcome were analyzed using Cox regression models, adjusting for potential clinical, metabolic, and inflammatory confounders. RESULTS The cohort was divided into 3 groups according to the NLR value (<2, 2-3, and >3). NLR was independently associated with CAD severity and it contributed significantly to the regression models. Patients with NLR >3 had more advanced obstructive CAD (OR = 2.45, CI 95% 1.76-3.42, p < 0.001) and worse prognosis, with a higher rate of major CVD events during up to 3 years of follow-up (HR = 1.55, CI 95% 1.09-2.2, p = 0.01). CONCLUSION Neutrophil/lymphocyte ratio is independently associated with CAD severity and 3-years outcome. NLR value appears additive to conventional risk factors and commonly used biomarkers.

Treatment and Clinical Outcomes of Transcatheter Heart Valve Thrombosis

Background—Valve thrombosis has yet to be fully evaluated after transcatheter aortic valve implantation. This study aimed to report the prevalence, timing, and treatment of transcatheter heart valve (THV) thrombosis. Methods and Results—THV thrombosis was defined as follows (1) THV dysfunction secondary to thrombosis diagnosed based on response to anticoagulation therapy, imaging modality or histopathology findings, or (2) mobile mass detected on THV suspicious of thrombus, irrespective of dysfunction and in absence of infection. Between January 2008 and September 2013, 26 (0.61%) THV thromboses were reported out of 4266 patients undergoing transcatheter aortic valve implantation in 12 centers. Of the 26 cases detected, 20 were detected in the Edwards Sapien/Sapien XT cohort and 6 in the Medtronic CoreValve cohort. In patients diagnosed with THV thrombosis, the median time to THV thrombosis post–transcatheter aortic valve implantation was 181 days (interquartile range, 45–313). The most common clinical presentation was exertional dyspnea (n=17; 65%), whereas 8 (31%) patients had no worsening symptoms. Echocardiographic findings included a markedly elevated mean aortic valve pressure gradient (40.5±14.0 mm Hg), presence of thickened leaflets or thrombotic apposition of leaflets in 20 (77%) and a thrombotic mass on the leaflets in the remaining 6 (23%) patients. In 23 (88%) patients, anticoagulation resulted in a significant decrease of the aortic valve pressure gradient within 2 months. Conclusions—THV thrombosis is a rare phenomenon that was detected within the first 2 years after transcatheter aortic valve implantation and usually presented with dyspnea and increased gradients. Anticoagulation seems to have been effective and should be considered even in patients without visible thrombus on echocardiography.

The Efficacy and Safety of Prasugrel With and Without a Glycoprotein IIb/IIIa Inhibitor in Patients With Acute Coronary Syndromes Undergoing Percutaneous Intervention: A TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction 38) Analysis

OBJECTIVES We evaluated the efficacy and safety of prasugrel and clopidogrel in the setting of a glycoprotein (GP) IIb/IIIa inhibitor. BACKGROUND Prasugrel reduced cardiovascular events as compared with clopidogrel in TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38) but with increased bleeding. METHODS Researchers in the TRITON-TIMI 38 randomized 13,608 subjects with acute coronary syndrome undergoing percutaneous coronary intervention to prasugrel versus clopidogrel. The use of a GP IIb/IIIa inhibitor was at the physicians discretion. For the current analysis, end points were examined at 30 days and were stratified by use of a GP IIb/IIIa inhibitor. RESULTS A total of 7,414 subjects (54.5%) received a GP IIb/IIIa inhibitor during their index hospitalization. There was a consistent benefit of prasugrel over clopidogrel for reducing cardiovascular death, myocardial infarction, or stroke in patients who did (hazard ratio: 0.76; 95% confidence interval: 0.64 to 0.90) or did not receive a GP IIb/IIIa inhibitor (hazard ratio: 0.78; 95% confidence interval: 0.63 to 0.97, p(interaction) = 0.83). Prasugrel significantly reduced myocardial infarction, urgent revascularization, and stent thrombosis irrespective of GP IIb/IIIa inhibitor use. Although subjects treated with a GP IIb/IIIa inhibitor had greater rates of bleeding, the risk of Thrombolysis in Myocardial Infarction major or minor bleeding with prasugrel versus clopidogrel was not significantly different in patients who were or were not treated with GP IIb/IIIa inhibitor (p(interaction) = 0.19). CONCLUSIONS Prasugrel significantly reduces the risk of cardiovascular events in patients with acute coronary syndromes after percutaneous coronary intervention regardless of whether or not a GP IIb/IIIa inhibitor is used. The use of a GP IIb/IIIa inhibitor does not accentuate the relative risk of bleeding with prasugrel as compared with clopidogrel.

Improvement of cardiac performance by intravenous infusion of l-arginine in patients with moderate congestive heart failure

OBJECTIVES The aim of this study was to evaluate the hemodynamic effect of L-arginine infusion in patients with congestive heart failure. BACKGROUND Endothelium-dependent vasodilation is impaired in patients with congestive heart failure. Nitric oxide, which was identified as endothelium-derived relaxing factor, is generated by nitric oxide synthase from L-arginine. Our hypothesis was that administration of L-arginine in patients with congestive heart failure may increase nitric oxide production and have a beneficial hemodynamic effect. METHODS Twelve patients with congestive heart failure (New York Heart Association class II or III) due to coronary artery disease (left ventricular ejection fraction < 35%) were given 20 g of L-arginine by intravenous infusion over 1 h at a constant rate. Stroke volume, cardiac output and left ventricular ejection fraction were determined with Doppler echocardiography at baseline and at 30 and 60 min and 1 h after the end of infusion. Blood and urinary levels of nitrite/nitrate (NO2/NO3), stable metabolites of nitric oxide, were measured and clearance was calculated. RESULTS One hour of infusion of L-arginine resulted in a significant increase in stroke volume (from 68 +/- 18 ml to 76 +/- 23 ml [mean +/- SD], p = 0.014) and cardiac output (from 4.07 +/- 1.22 liters/min to 4.7 +/- 1.42 liters/min, p = 0.006) without a change in heart rate. Mean arterial blood pressure decreased (from 102 +/- 11 mm Hg to 89 +/- 9.5 mm Hg, p < 0.002), and systemic vascular resistance decreased significantly. Within 1 h after cessation of L-arginine infusion, blood pressure, stroke volume, cardiac output and systemic vascular resistance were statistically not different from baseline values. Clearance of NO2/NO3 increased significantly during L-arginine administration (from 13.28 +/- 0.42 ml/min to 29.97 +/- 1.09 ml/min, p < 0.001). CONCLUSIONS Infusion of L-arginine in patients with congestive heart failure results in increased production of nitric oxide, peripheral vasodilation and increased cardiac output, suggesting a beneficial hemodynamic and possibly therapeutic profile.

Transcatheter Replacement of Failed Bioprosthetic Valves: Large Multicenter Assessment of the Effect of Implantation Depth on Hemodynamics After Aortic Valve-in-Valve

Background—Transcatheter valve implantation inside failed bioprosthetic surgical valves (valve-in-valve [ViV]) may offer an advantage over reoperation. Supra-annular transcatheter valve position may be advantageous in achieving better hemodynamics after ViV. Our objective was to define targets for implantation that would improve hemodynamics after ViV. Methods and Results—Cases from the Valve-in-Valve International Data (VIVID) registry were analyzed using centralized core laboratory assessment blinded to clinical events. Multivariate analysis was performed to identify independent predictors of elevated postprocedural gradients (mean ≥20 mm Hg). Optimal implantation depths were defined by receiver operating characteristic curve. A total of 292 consecutive patients (age, 78.9±8.7 years; 60.3% male; 157 CoreValve Evolut and 135 Sapien XT) were evaluated. High implantation was associated with significantly lower rates of elevated gradients in comparison with low implantation (CoreValve Evolut, 15% versus 34.2%; P=0.03 and Sapien XT, 18.5% versus 43.5%; P=0.03, respectively). Optimal implantation depths were defined: CoreValve Evolut, 0 to 5 mm; Sapien XT, 0 to 2 mm (0–10% frame height); sensitivities, 91.3% and 88.5%, respectively. The strongest independent correlate for elevated gradients after ViV was device position (high: odds ratio, 0.22; confidence interval, 0.1–0.52; P=0.001), in addition to type of device used (CoreValve Evolut: odds ratio, 0.5; confidence interval, 0.28–0.88; P=0.02) and surgical valve mechanism of failure (stenosis/mixed baseline failure: odds ratio, 3.12; confidence interval, 1.51–6.45; P=0.002). Conclusions—High implantation inside failed bioprosthetic valves is a strong independent correlate of lower postprocedural gradients in both self- and balloon-expandable transcatheter valves. These clinical evaluations support specific implantation targets to optimize hemodynamics after ViV.