Balance of benefit and risk of ticagrelor in patients with diabetes and stable coronary artery disease according to bleeding risk assessment with the CRUSADE score: Data from THEMIS and THEMIS PCI.

BACKGROUND: The THEMIS trial demonstrated that in high-risk patients with stable coronary artery disease and diabetes without previous myocardial infarction or stroke, ticagrelor, in addition to aspirin, reduced the incidence of ischemic events but increased major bleeding. Identification of patients who could derive the greatest net benefit from the addition of ticagrelor appears important. We used the CRUSADE bleeding risk score to risk stratify the THEMIS population. METHODS: The population was divided into tertiles: score ≤22, 23 to 33, and ≥34. In each tertile, primary efficacy (composite of cardiovascular death, myocardial infarction, or stroke) and safety (TIMI major bleeding) outcomes were analyzed. NACE (net adverse clinical events) was defined as the irreversible harm composite, in which all-cause death, myocardial infarction, stroke, amputations, fatal bleeds, and intracranial hemorrhage were counted. RESULTS: Patients in the lower risk tertile experienced fewer ischemic events with ticagrelor than placebo, whereas there was no significant benefit from ticagrelor in the other tertiles (Pinteraction = .008). Bleeding rates were consistently increased with ticagrelor across all tertiles (Pinteraction = .79). Ticagrelor reduced NACE in the first tertile (HR = 0.74, 95% CI = 0.61-0.90) but not in the others (HR = 1.03, 95% CI = 0.86-1.23 and HR = 1.05, 95% CI = 0.91-1.22, respectively; Pinteraction = .012). CONCLUSIONS: In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, only those at the lower end of the bleeding risk spectrum according to the CRUSADE score derived net benefit from ticagrelor.

Impact of prior oral anticoagulant use and outcomes on patients from secondary analysis in the AUGUSTUS trial.

OBJECTIVE: Managing antithrombotic therapy in patients with atrial fibrillation (AF) and an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) is challenging and can be affected by prior oral anticoagulant (OAC) treatment. We examined the relationship between prior OAC use and outcomes in the AUGUSTUS trial. METHODS: This prespecified secondary analysis is from AUGUSTUS, an open-label, 2-by-2 factorial, RCT to evaluate the safety of apixaban versus vitamin K antagonist (VKA) and aspirin versus placebo in patients with AF and ACS and/or PCI. The primary endpoint, major or clinically relevant non-major bleeding and clinical outcomes were compared in patients receiving (n=2262) or not receiving (n=2352) an OAC prior to enrolment. RESULTS: Patients with prior OAC use had more comorbidities, higher CHA2DS2-VASC and HAS-BLED scores, and were more likely enrolled following elective PCI. There was no difference in major or clinically relevant non-major bleeding with or without prior OAC (30 days: 5.1% vs 5.9% (adjusted HR (aHR) 0.82, 95% CI 0.63 to 1.06); 180 days: 13.5% vs 13.5% (aHR 0.98, 95% CI 0.83 to 1.16)). Patients with prior OAC use had a lower risk of death or ischaemic events (30 days: 1.7% vs 2.8% (aHR 0.61, 95% CI 0.41 to 0.92); 180 days: 5.4% vs 7.6% (aHR 0.70, 95% CI 0.55 to 0.88)). No interactions between randomised treatment (apixaban vs VKA, aspirin vs placebo) and prior OAC status were observed for outcomes, apart from apixaban (vs VKA) being associated with a lower risk of myocardial infarction with prior OAC use (180 days: 2.0% vs 3.7% (aHR 0.56, 95% CI 0.33 to 0.91(). CONCLUSIONS: In AUGUSTUS, prior OAC use was associated with fewer ischaemic events but not more bleeding. In patients with AF and ACS and/or undergoing PCI, clinicians can be assured that the trial results can be applied to patients regardless of their prior OAC status. TRIAL REGISTRATION NUMBER: NCT02415400.

Risk of Stroke After Transcatheter Aortic Valve Implantation: Epidemiology, Mechanism, and Management.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has become an established and increasingly used approach for management of severe symptomatic aortic stenosis, showing similar or even superior outcomes compared with standard surgical aortic valve replacement (SAVR). Stroke after TAVI is a relatively rare, but serious complication, associated with potential prolonged disability and increased mortality. AREAS OF UNCERTAINTY: The overall incidence of 30-day stroke in TAVI patients is 3%-4%, but varies between different trials. Initial data suggested a higher risk of stroke after TAVI when compared with SAVR. The association between subclinical leaflet thrombosis and cerebral embolism, presented as stroke, transient ischemic accident, or silent cerebral ischemia is not entirely elucidated yet. Moreover, TAVI for severe bicuspid aortic stenosis is a relatively new issue, bicuspid anatomy being initially excluded from the pivotal clinical trials investigating TAVI procedure. Efficient stroke prevention strategies are under investigation. DATA SOURCES: In the present manuscript, we used the available published data from the most relevant clinical trials, registries, and meta-analysis of patients from different risk categories who underwent TAVI or SAVR. THERAPEUTIC ADVANCES: Predictors of acute stroke are mainly procedure related. Technological development, improvements in bioprosthesis valve delivery catheters, and implantation technique may explain the decrease of stroke over the years since the beginning of TAVI procedures. CONCLUSIONS: The overall evidences confirm similar or lower rate of stroke in TAVI versus SAVR. Risk predictors for acute stroke after TAVI are generally related to procedural factors, whereas late stroke is mainly associated with patient characteristics, with a variable impact on cognitive function. The optimal choice for the antithrombotic treatment in TAVI for stroke prevention is yet to be determined. Current data do not support routine use of cerebral embolic protection devices during TAVI.

Systematic investment in the delivery of guideline-coherent therapy reduces mortality and overall costs in patients with ST-elevation myocardial infarction: Results from the Stent for Life economic model for Romania, Portugal, Basque Country and Kemerovo region.

AIMS: The Stent for Life initiative aims at the reduction of mortality in patients with ST-elevation myocardial infarction by enhancing timely access to primary percutaneous coronary intervention. To assess the associated health and socioeconomic impact, the Stent for Life economic project was launched and applied to four model regions: Romania, Portugal, the Basque Country in Spain, and the Kemerovo region in the Russian Federation. METHODS AND RESULTS: The Stent for Life economic model is based on a decision tree that incorporates primary percutaneous coronary intervention rates and mortality. Healthcare costs and indirect costs caused by loss of productivity were estimated. A baseline scenario simulating the status quo was compared to the Stent for Life scenario which integrated changes initiated by the Stent for Life programme. In the four model regions, primary percutaneous coronary intervention numbers rose substantially between 29-303%, while ST-elevation myocardial infarction mortality was reduced between 3-10%. Healthcare costs increased by 8% to 70%. Indirect cost savings ranged from 2-7%. Net societal costs were reduced in all model regions by 2-4%. CONCLUSION: The joint effort of the Stent for Life initiative and their local partners successfully saves lives. Moreover, the increase in healthcare costs was outweighed by indirect cost savings, leading to a net cost reduction in all four model regions. These findings demonstrate that systematic investments to improve the access of ST-elevation myocardial infarction patients to guideline-coherent therapy is beneficial, not only for the individual, but also for the society at large.

The role of ventricular-arterial coupling in cardiac disease and heart failure: assessment, clinical implications and therapeutic interventions. A consensus document of the European Society of Cardiology Working Group on Aorta & Peripheral Vascular Diseases, European Association of Cardiovascular Imaging, and Heart Failure Association.

Ventricular-arterial coupling (VAC) plays a major role in the physiology of cardiac and aortic mechanics, as well as in the pathophysiology of cardiac disease. VAC assessment possesses independent diagnostic and prognostic value and may be used to refine riskstratification and monitor therapeutic interventions. Traditionally, VAC is assessed by the non-invasive measurement of the ratio of arterial (Ea) to ventricular end-systolic elastance (Ees). With disease progression, both Ea and Ees may become abnormal and the Ea/Ees ratio may approximate its normal values. Therefore, the measurement of each component of this ratio or of novel more sensitive markers of myocardial (e.g. global longitudinal strain) and arterial function (e.g. pulse wave velocity) may better characterize VAC. In valvular heart disease, systemic arterial compliance and valvulo-arterial impedance have an established diagnostic and prognostic value and may monitor the effects of valve replacement on vascular and cardiac function. Treatment guided to improve VAC through improvement of both or each one of its components may delay incidence of heart failure and possibly improve prognosis in heart failure. In this consensus document, we describe the pathophysiology, the methods of assessment as well as the clinical implications of VAC in cardiac diseases and heart failure. Finally, we focus on interventions that may improve VAC and thus modify prognosis.

Single Versus Standard Multiview Assessment of Global Longitudinal Strain for the Diagnosis of Cardiotoxicity During Cancer Therapy.

OBJECTIVES: The goal of this study was to compare echocardiographic measurements of global longitudinal strain (GLS) (using 3 apical views) with single-view longitudinal strain (LS, 4- or 2-chamber [4CV_LS and 2CV_LS, respectively]) for detection of cancer-therapy related cardiotoxicity. BACKGROUND: GLS is useful for the detection of cardiotoxicity, but the need for repeated measurements poses a significant burden on busy echocardiography laboratories. A single-view LS measurement, possibly at point of care, could improve efficiency. METHODS: Seventeen international centers prospectively recruited 108 patients (mean age 54 ± 13 years) at high risk for cardiotoxicity as part of the ongoing SUCCOUR (Strain Surveillance for Improving Cardiovascular Outcomes During Chemotherapy) randomized controlled trial. Echocardiography performed at baseline and follow-up were analyzed in a core laboratory setting blinded to clinical information. Peak systolic GLS and LS were measured from raw data. Cardiotoxicity was defined by reduction in left ventricular ejection fraction >0.10 to <0.55 or a relative drop in GLS by ≥12%. RESULTS: Cardiotoxicity developed in 46 patients by either criteria. Baseline and follow-up 2-dimensional left ventricular ejection fraction were 61 ± 4% and 58 ± 5%, respectively (p < 0.001). The baseline GLS (-20.9 ± 2.4%) was not different from 4CV_LS (-20.7 ± 2.5%; p = 0.09) or 2CV_LS (-21.1 ± 3.1%; p = 0.25). The follow-up GLS (-19.5 ± 2.4%) was also similar to 4CV_LS (-19.5 ± 2.6%; p = 0.80) and 2CV_LS (-19.7 ± 3.1%; p = 0.19). There was good correlation between GLS and 4CV_LS at baseline (r = 0.86; p < 0.001) and follow-up (r = 0.89; p < 0.001) and with 2CV_LS at baseline (r = 0.87; p < 0.001) and follow-up (r = 0.88; p < 0.001). However, there was 15% to 22% disagreement between GLS and 4CV_LS or 2CV_LS for the detection of cardiotoxicity. The interobserver and intraobserver reproducibility was higher for GLS (intraclass correlation: 0.93 to 0.95; coefficient of variance: 2.9% to 3.7%) compared with either single-chamber-based LS measurement (intraclass correlation: 0.85 to 0.91; coefficient of variance: 4.1% to 4.8%). CONCLUSIONS: Although there was good correlation between GLS and single-view LS measurements, single-view LS measurement led to disagreement in the diagnosis of cardiotoxicity in up to 22% of patients. GLS measurements were more reproducible than single-view LS. GLS based on 3 apical views should remain the preferred technique for detection of cardiotoxicity. (Strain Surveillance for Improving Cardiovascular Outcomes During Chemotherapy [SUCCOUR]; ACTRN12614000341628).

Epidemiology, pathophysiology, and in-hospital management of pulmonary edema: data from the Romanian Acute Heart Failure Syndromes registry.

AIM: The objective of this study was to evaluate the clinical presentation, inpatient management, and in-hospital outcome of patients hospitalized for acute heart failure syndromes (AHFS) and classified as pulmonary edema (PE). METHODS: The Romanian Acute Heart Failure Syndromes (RO-AHFS) study was a prospective, national, multicenter registry of all consecutive patients admitted with AHFS over a 12-month period. Patients were classified at initial presentation by clinician-investigators into the following clinical profiles: acute decompensated HF, cardiogenic shock, PE, right HF, or hypertensive HF. RESULTS: RO-AHFS enrolled 3224 patients and 28.7% (n = 924) were classified as PE. PE patients were more likely to present with pulmonary congestion, tachypnea, tachycardia, and elevated systolic blood pressure and less likely to have peripheral congestion and body weight increases. Mechanical ventilation was required in 8.8% of PE patients. PE patients received higher doses (i.e. 101.4 ±â€Š27.1 mg) of IV furosemide for a shorter duration (i.e. 69.3 ±â€Š22.3 hours). Vasodilators were given to 73.6% of PE patients. In-hospital all-cause mortality (ACM) in PE patients was 7.4%, and 57% of deaths occurred on day one. Increasing age, concurrent acute coronary syndromes, life-threatening ventricular arrhythmias, elevated BUN, left bundle branch block, inotrope therapy, and requirement for invasive mechanical ventilation were independent risk factors for ACM. CONCLUSIONS: In this national registry, the PE profile was found to be a high-acuity clinical presentation with distinctive treatment patterns and a poor short-term prognosis. Advances in the management of PE may necessitate both the development of novel targeted therapies as well as systems-based strategies to identify high-risk patients early in their course.

The Assessment of Subclinical Cardiovascular Dysfunction in Treated Rheumatoid Arthritis.

BACKGROUND AND PURPOSE: Rheumatoid arthritis (RA) causes frequently cardiovascular complications, probably determined by early atherosclerosis in connection to chronic systemic inflammation. Purpose of our study was to assess subclinical cardiac and vascular dysfunction, and to evaluate the mechanisms of ventriculo-arterial interaction, in patients with correctly treated RA vs. normal subjects. METHODS: We evaluated 46 subjects (55±10 years, 2 men): 29 patients with seropositive treated RA (mean duration of 11±9 years), without documented cardiovascular or pulmonary disease, and 17 control subjects, matched for age, sex, and distribution of conventional major risk factors. All RA patients were under long-term treatment (more than 6 months) with Methotrexat + Sulfasalasine (22 patients) or Methotrexat + Sulfasalasine + Infliximab (7 patients). We determined biomarkers of inflammation (P-selectin, interleukines 1, 6, 10, 18, seric amiloid A, á-TNF, ã-interferon, C-reactive protein, anti-oxidated LDL antibodies), myocardial fibrosis (â-crosslaps) and ventricular overload (BNP). We assessed the parameters of cardiac function by standard and tissue Doppler echocardiography, intima-media thickness and arterial stiffness by "e-tracking" and "wave intensity analysis" (at the level of the right carotid artery), endothelial function by flow mediated dilation (FMD), and carotid-femoral pulse wave velocity by the Complior method. RESULTS: Biological parameters of inflammation, markers of myocardial fibrosis and of ventricular overload were not different between the 2 study groups. Also, parameters of subclinical cardiac and vascular function were similar between the two groups. RA patients had subclinical RV dysfunction, correlated to the duration of the disease. They also tended to have higher values of systolic pulmonary artery pressure than normals. CONCLUSION: Correctly treated patients with RA, with controlled systemic inflammation, have normal LV, endothelial and arterial function. However, in the absence of documented pulmonary disease, they do have subclinical RV dysfunction, correlated with the duration of disease. This suggests an intrinsic RV myocardial involvement but, since pulmonary artery pressure was also higher, a secondary mechanism might be also involved.

New Echocardiographic Protocol for the Assessment of Experimental Myocardial Infarction in Rats.

BACKGROUND: The rat infarct model was used extensively to study the pathophysiology of myocardial infarction and to evaluate different therapies. Transthoracic echocardiography is used in rats in order to assess cardiac anatomy and function, being a safe and reliable non-invasive technique. However, studies combining conventional with new echo techniques, such as tissue Doppler imaging (TDI) and speckletracking echocardiography (STE), are lacking. OBJECTIVES: To validate a protocol using the available conventional and new echocardiographic techniques (TDI and STE) for a comprehensive assessment of cardiac remodelling and function, after myocardial infarction in rats. METHODS: Ten Wistar (W) and five Sprague Dawley (SD) male rats (aged 21±2 weeks, mean weight 355±43 g) were evaluated by echocardiography, before and 24 hours post-ligation of the left coronary artery, with previous anaesthesia. Left ventricular (LV) structure was assessed by end-diastolic and endsystolic anterior wall thickness and LV diameters (from the SAX view), while LV function by fractional shortening (FS) and ejection fraction (EF) (by area-length formula), septal mitral annular plane systolic excursion (MAPSE), cardiac output (CO), myocardial performance index (MPI), septal mitral annular systolic velocity (S', by TDI), and global circumferential and radial systolic strain (GCS, GRS) and strain rate (GCSr, GRSr) by STE, from the SAX view at the level of papillary muscles. RESULTS: Feasibility of measuring the above mentioned parameters was 100%. Twenty-four hours after myocardial infarction, rats had lower heart rate (373±44 vs. 351±32 bpm, p<0.05) and thinner LV anterior wall, while LV diameters and volumes were significantly higher. FS (54±7 vs. 33±9%), EF (72±9vs. 47±10%), septal MAPSE (2.02±0.17 vs. 1.44±0.22 mm), CO (76±15 vs. 48±12 ml/min), MPI (0.33±0.11 vs. 0.50±0.14), S' (5.58±1.20 vs. 3.84±1.06 cm/s), and LV strain and strain rate (GCS: -23.52±2.44 vs. -13.33±1.51% and GRS: 50.45±13.11 vs. 17.27±5.2%, GCSr: -8.42±0.85 vs. -4.68±0.53; and GRSr: 11.93±2.39 vs. 4.89±1.18 1/s) were significantly lower, all p<0.01. CONCLUSIONS: Our echocardiographic protocol of experimental myocardial infarction in rats is feasible. The impact of myocardial infarction in rats could be more extensively assessed using a comprehensive echocardiographic protocol of conventional and specific myocardial parameters, measured by TDI and STE, in order to quantify better the LV structure and function. Therefore, we suggest that this protocol may be used in order to assess the effect of different regenerative therapies in experimental myocardial infarction in rats.

Methodological Gaps in Left Atrial Function Assessment by 2D Speckle Tracking Echocardiography.

The assessment of left atrial (LA) function is used in various cardiovascular diseases. LA plays a complementary role in cardiac performance by modulating left ventricular (LV) function. Transthoracic two-dimensional (2D) phasic volumes and Doppler echocardiography can measure LA function non­invasively. However, evaluation of LA deformation derived from 2D speckle tracking echocardiography (STE) is a new feasible and promising approach for assessment of LA mechanics. These parameters are able to detect subclinical LA dysfunction in different pathological condition. Normal ranges for LA deformation and cut-off values to diagnose LA dysfunction with different diseases have been reported, but data are still conflicting, probably because of some methodological and technical issues. This review highlights the importance of an unique standardized technique to assess the LA phasic functions by STE, and discusses recent studies on the most important clinical applications of this technique.

Cost-effectiveness of zofenopril in patients with left ventricular systolic dysfunction after acute myocardial infarction: a post hoc analysis of SMILE-4.

BACKGROUND: In SMILE-4 (the Survival of Myocardial Infarction Long-term Evaluation 4 study), zofenopril + acetylsalicylic acid (ASA) was superior to ramipril + ASA in reducing the occurrence of major cardiovascular events in patients with left ventricular dysfunction following acute myocardial infarction. The present post hoc analysis was performed to compare the cost-effectiveness of zofenopril and ramipril. METHODS: In total, 771 patients with left ventricular dysfunction and acute myocardial infarction were randomized in a double-blind manner to receive zofenopril 60 mg/day (n = 389) or ramipril 10 mg/day (n = 382) + ASA 100 mg/day and were followed up for one year. The primary study endpoint was the one-year combined occurrence of death or hospitalization for cardiovascular causes. The economic analysis was based on evaluation of cost of medications and hospitalizations and was applied to the intention-to-treat population (n = 716). Cost data were drawn from the National Health Service databases of the European countries participating in the study. The incremental cost-effectiveness ratio was used to quantify the cost per event prevented with zofenopril versus ramipril. RESULTS: Zofenopril significantly (P = 0.028) reduced the risk of the primary study endpoint by 30% as compared with ramipril (95% confidence interval, 4%-49%). The number needed to treat to prevent a major cardiovascular event with zofenopril was 13 less than with ramipril. The cost of drug therapies was higher with zofenopril (328.78 Euros per patient per year, n = 365) than with ramipril (165.12 Euros per patient per year, n = 351). The cost related to the occurrence of major cardiovascular events requiring hospitalization averaged 4983.64 Euros for zofenopril and 4850.01 Euros for ramipril. The incremental cost-effectiveness ratio for zofenopril versus ramipril was 2125.45 Euros per event prevented (worst and best case scenario in the sensitivity analysis was 3590.09 and 3243.96 Euros, respectively). CONCLUSION: Zofenopril is a viable and cost-effective treatment for managing patients with left ventricular dysfunction after acute myocardial infarction.

Comparative reproducibility of the noninvasive ultrasound methods for the assessment of vascular function.

The aim of this work was to assess the reproducibility of ultrasound parameters of vascular function, since these measurements are currently recommended by the guidelines for the evaluation of the cardiovascular risk. Twenty subjects (51 ± 17 years, 11 men) had vascular ultrasound (Aloka Prosound α10) performed by two observers, at the level of the right common carotid artery for assessment of intima-media thickness (IMT), "wall tracking", and "wave-intensity analysis", and at the level of the right brachial artery for the assessment of flow-mediated dilation (FMD). Wave intensity is a hemodynamic index, evaluating ventriculo-arterial interaction and can be measured in real time by a double-beam ultrasound technique through simultaneous recording of carotid arterial blood flow velocity and diameter. Carotido-femoral pulse wave velocity (PWV) was determined using the Complior method. Intra- and inter-observer reproducibility was assessed during a first session, when three consecutive acquisitions were made (first observer → second observer → first observer); repeatability was evaluated 1 week later (second observer). The most reproducible and repeatable parameters were PWV (intraobserver ±3.3%, interobserver ±2.6%, repeatability ±5.6%) and IMT (±3.7, ±4.3, ±4.9%, respectively). Intraobserver reproducibility for arterial stiffness and ventriculo-arterial coupling parameters was the highest for the beta index (±3.8%), and the lowest for the second systolic peak (±22.4%). Interobserver reproducibility and repeatability varied between very good for the wave speed (±5.5 and ±4.3%), and unsatisfactory for the negative area (±31.8 and ±38.6%). FMD had good reproducibility (intraobserver ±11.6%, interobserver ±8%, repeatability ±7%), whereas augmentation index had only satisfactory results (±17.8, ±8.4, ±23.8%, respectively). Only some parameters of vascular function have good reproducibility and repeatability, better or similar to other ultrasound methods and, therefore, these are ready to be used in routine clinical practice.

Impact of the Romanian national programme for interventional therapy in ST-elevation myocardial infarction.

A national programme for PPCI in STEMI patients was started in Romania in August 2010, based on an integrated and well-trained pre-hospital emergency medical system. Ten national centres experienced in PPCI were organised in a 24/7 system in five regional networks, in order to assist STEMI patients from areas offering PPCI within the first two hours after the first medical contact. For centres located further away, a strategy of local thrombolysis followed by transfer to the closest PCI centre was recommended. The total number of PPCI procedures increased from 1,289 in 2010 to 4,209 in 2011. The percentage of PPCI increased from 25.0% in 2010 to 49.32% in 2011. From 40 PPCI/million inhabitants in 2009, we reached 64/million in 2010 and 210/ million in 2011. In the Bucharest area there were 640 PPCI/ million in 2011. The global in-hospital mortality decreased from 13.5% in 2009 to 9.93% in 2011. In 2011 in-hospital mortality was 4.39%, 8.32% and 17.11% for PPCI, thrombolysis and no-reperfusion, respectively. In-hospital mortality was 7.28% in the PCI centres but 14.20% in centres without PCI facilities. The national programme for PPCI had a major impact on STEMI in-hospital mortality in Romania.