Ran Kornowski

ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM).

Authors/Task Force Members: Kenneth Dickstein (Chairperson) (Norway)*, Alain Cohen-Solal (France), Gerasimos Filippatos (Greece), John J.V. McMurray (UK), Piotr Ponikowski (Poland), Philip Alexander Poole-Wilson (UK), Anna Strömberg (Sweden), Dirk J. van Veldhuisen (The Netherlands), Dan Atar (Norway), Arno W. Hoes (The Netherlands), Andre Keren (Israel), Alexandre Mebazaa (France), Markku Nieminen (Finland), Silvia Giuliana Priori (Italy), Karl Swedberg (Sweden)

Bivalirudin during Primary PCI in Acute Myocardial Infarction

BACKGROUND Treatment with the direct thrombin inhibitor bivalirudin, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, results in similar suppression of ischemia while reducing hemorrhagic complications in patients with stable angina and non-ST-segment elevation acute coronary syndromes who are undergoing percutaneous coronary intervention (PCI). The safety and efficacy of bivalirudin in high-risk patients are unknown. METHODS We randomly assigned 3602 patients with ST-segment elevation myocardial infarction who presented within 12 hours after the onset of symptoms and who were undergoing primary PCI to treatment with heparin plus a glycoprotein IIb/IIIa inhibitor or to treatment with bivalirudin alone. The two primary end points of the study were major bleeding and combined adverse clinical events, defined as the combination of major bleeding or major adverse cardiovascular events, including death, reinfarction, target-vessel revascularization for ischemia, and stroke (hereinafter referred to as net adverse clinical events) within 30 days. RESULTS Anticoagulation with bivalirudin alone, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, resulted in a reduced 30-day rate of net adverse clinical events (9.2% vs. 12.1%; relative risk, 0.76; 95% confidence interval [CI] 0.63 to 0.92; P=0.005), owing to a lower rate of major bleeding (4.9% vs. 8.3%; relative risk, 0.60; 95% CI, 0.46 to 0.77; P<0.001). There was an increased risk of acute stent thrombosis within 24 hours in the bivalirudin group, but no significant increase was present by 30 days. Treatment with bivalirudin alone, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, resulted in significantly lower 30-day rates of death from cardiac causes (1.8% vs. 2.9%; relative risk, 0.62; 95% CI, 0.40 to 0.95; P=0.03) and death from all causes (2.1% vs. 3.1%; relative risk, 0.66; 95% CI, 0.44 to 1.00; P=0.047). CONCLUSIONS In patients with ST-segment elevation myocardial infarction who are undergoing primary PCI, anticoagulation with bivalirudin alone, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, results in significantly reduced 30-day rates of major bleeding and net adverse clinical events. (ClinicalTrials.gov number, NCT00433966 [ClinicalTrials.gov].).

In-stent restenosis: Contributions of inflammatory responses and arterial injury to neointimal hyperplasia

OBJECTIVES We examined the relative contributions of inflammation and arterial injury to neointimal formation in a porcine coronary overstretch restenosis model. BACKGROUND Previous studies established that stents cause neointimal proliferation proportional to injury. Although inflammation has been postulated to be a major contributor to restenosis after angioplasty, there is a paucity of data on the relation between inflammation and subsequent neointimal formation. METHODS Twenty-one pigs underwent balloon injury followed by implantation of oversized, tubular, slotted stents (stent/artery ratio 1.2:1) in the left anterior descending coronary artery. Morphometric analysis of the extent of injury (graded as injury score 0 to 3) and inflammation (graded as inflammation score 0 to 3) 1 month later was assessed and correlated with neointimal formation. RESULTS An inflammatory reaction was observed in 20 of 21 pigs, and significant positive correlations were found between the degree of arterial injury and the extent of the inflammatory reaction (r = 0.80, p < 0.01) and between the extent of inflammatory reaction and the neointimal thickness (r = 0.75, p < 0.01), neointimal area (r = 0.53, p = 0.01) and percent area stenosis (r = 0.66, p < 0.01) within the stents. Importantly, there were areas with inflammation only in the absence of injury, and vice versa, that were also associated with neointimal hyperplasia. CONCLUSIONS These data suggest that the inflammatory reaction plays an equally important role as arterial injury in neointimal formation after coronary stenting, and that anti-inflammatory approaches may be of value to reduce in-stent restenosis.

Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery

The American College of Cardiology, American Heart Association, and the European Society of Cardiology are all in the process of completing updated versions of our Guidelines for Perioperative Care. Our respective writing committees are undertaking a careful analysis of all relevant validated studies and always incorporate appropriate new trials and meta-analyses into our evidence review. In the interim, our current joint position is that the initiation of beta blockers in patients who will undergo non-cardiac surgery should not be considered routine, but should be considered carefully by each patients treating physician on a case-by-case basis. Please see the expression of concern which is free to view in Eur Heart J (2013) 34 (44): 3460; doi: 10.1093/eurheartj/eht431. AAA : abdominal aortic aneurysm ACC : American College of Cardiology ACE : angiotensin-converting enzyme ACS : acute coronary syndrome AHA : American Heart Association AR : aortic regurgitation ARB : angiotensin receptor blocker AS : aortic stenosis AF : atrial fibrillation BBSA : β-blocker in spinal anaesthesia BNP : brain natriuretic peptide CABG : coronary artery bypass grafting CARP : coronary artery revascularization prophylaxis CASS : coronary artery surgery study CI : confidence interval COX-2 : cyclooxygenase-2 COPD : chronic obstructive pulmonary disease CPET : cardiopulmonary exercise testing CPG : Committee for Practice Guidelines CRP : C-reactive protein CT : computed tomography cTnI : cardiac troponin I cTnT : cardiac troponin T CVD : cardiovascular disease DECREASE : Dutch Echocardiographic Cardiac Risk Evaluating Applying Stress Echo DES : drug-eluting stent DIPOM : Diabetes Postoperative Mortality and Morbidity DSE : dobutamine stress echocardiography ECG : electrocardiography ESC : European Society of Cardiology FEV1 : forced expiratory volume in 1 s FRISC : fast revascularization in instability in coronary disease HR : hazard ratio ICU : intensive care unit IHD : ischaemic heart disease INR : international normalized ratio LMWH : low molecular weight heparin LQTS : long QT syndrome LR : likelihood ratio LV : left ventricular MaVS : metoprolol after surgery MET : metabolic equivalent MI : myocardial infarction MR : mitral regurgitation MRI : magnetic resonance imaging MS : mitral stenosis NICE-SUGAR : normoglycaemia in intensive care evaluation and survival using glucose algorithm regulation NSTEMI : non-ST-segment elevation myocardial infarction NT-proBNP : N-terminal pro-brain natriuretic peptide NYHA : New York Heart Association OPUS : orbofiban in patients with unstable coronary syndromes OR : odds ratio PaCO2 : mixed expired volume of alveolar and dead space gas PAH : pulmonary arterial hypertension PETCO2 : end-tidal expiratory CO2 pressure PCI : percutaneous coronary intervention PDA : personal digital assistant POISE : PeriOperative ISchaemic Evaluation trial QUO-VADIS : QUinapril On Vascular ACE and Determinants of ISchemia ROC : receiver operating characteristic SD : standard deviation SMVT : sustained monomorphic ventricular tachycardia SPECT : single photon emission computed tomography SPVT : sustained polymorphic ventricular tachycardia STEMI : ST-segment elevation myocardial infarction SVT : supraventricular tachycardia SYNTAX : synergy between percutaneous coronary intervention with taxus and cardiac surgery TACTICS : treat angina with aggrastat and determine cost of therapy with an invasive or conservative strategy TIA : transient ischaemic attack TIMI : thrombolysis in myocardial infarction TOE : transoesophageal echocardiography UFH : unfractionated heparin VCO2 : carbon dioxide production VE : minute ventilation VHD : valvular heart disease VKA : vitamin K antagonist VO2 : oxygen consumption VPB : ventricular premature beat VT : ventricular tachycardia Guidelines and Expert Consensus Documents aim to present management and recommendations based on the relevant evidence on a particular subject in order to help physicians to select the best possible management strategies for the individual patient suffering from a specific condition, taking into account not only the impact on outcome, but also the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously.1 A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) and also by other organizations or related societies. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC guidelines and Expert Consensus Documents can be found on the ESC website in the guidelines section (www.escardio.org). In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. …

Comparison of zotarolimus-eluting and everolimus-eluting coronary stents.

BACKGROUND New-generation coronary stents that release zotarolimus or everolimus have been shown to reduce the risk of restenosis. However, it is unclear whether there are differences in efficacy and safety between the two types of stents on the basis of prospectively adjudicated end points endorsed by the Food and Drug Administration. METHODS In this multicenter, noninferiority trial with minimal exclusion criteria, we randomly assigned 2292 patients to undergo treatment with coronary stents releasing either zotarolimus or everolimus. Twenty percent of patients were randomly selected for repeat angiography at 13 months. The primary end point was target-lesion failure, defined as a composite of death from cardiac causes, any myocardial infarction (not clearly attributable to a nontarget vessel), or clinically indicated target-lesion revascularization within 12 months. The secondary angiographic end point was the extent of in-stent stenosis at 13 months. RESULTS At least one off-label criterion for stent placement was present in 66% of patients. The zotarolimus-eluting stent was noninferior to the everolimus-eluting stent with respect to the primary end point, which occurred in 8.2% and 8.3% of patients, respectively (P<0.001 for noninferiority). There were no significant between-group differences in the rate of death from cardiac causes, any myocardial infarction, or revascularization. The rate of stent thrombosis was 2.3% in the zotarolimus-stent group and 1.5% in the everolimus-stent group (P=0.17). The zotarolimus-eluting stent was also noninferior regarding the degree (+/-SD) of in-stent stenosis (21.65+/-14.42% for zotarolimus vs. 19.76+/-14.64% for everolimus, P=0.04 for noninferiority). In-stent late lumen loss was 0.27+/-0.43 mm in the zotarolimus-stent group versus 0.19+/-0.40 mm in the everolimus-stent group (P=0.08). There were no significant between-group differences in the rate of adverse events. CONCLUSIONS At 13 months, the new-generation zotarolimus-eluting stent was found to be noninferior to the everolimus-eluting stent in a population of patients who had minimal exclusion criteria. (ClinicalTrials.gov number, NCT00617084.)

Transendocardial delivery of autologous Bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia

OBJECTIVES We tested the hypothesis that intramyocardial injection of autologous bone marrow (ABM) promotes collateral development in ischemic porcine myocardium. We also defined, in vitro, whether bone marrow (BM) cells secrete vascular endothelial growth factor (VEGF) and macrophage chemoattractant protein-1 (MCP-1). BACKGROUND The natural processes leading to collateral development are extremely complex, requiring multiple growth factors interacting in concert and in sequence. Because optimal angiogenesis may, therefore, require multiple angiogenic factors, we thought that injection of BM, which contains cells that secrete numerous angiogenic factors, might provide optimal therapeutic angiogenesis. METHODS Bone marrow was cultured four weeks in vitro. Conditioned medium was assayed for VEGF and MCP-1 and was added to cultured pig aortic endothelial cells (PAEC) to assess proliferation. Four weeks after left circumflex ameroid implantation, freshly aspirated ABM (n = 7) or heparinized saline (n = 7) was injected transendocardially into the ischemic zone (0.2 ml/injection at 12 sites). Echocardiography to assess myocardial thickening and microspheres to assess perfusion were performed at rest and during stress. RESULTS Vascular endothelial growth factor and MCP-1 concentrations increased in a time-related manner. The conditioned medium enhanced, in a dose-related manner, PAEC proliferation. Collateral flow (ischemic/normal zone X 100) improved in ABM-treated pigs (ABM: 98 +/- 14 vs. 83 +/- 12 at rest, p = 0.001; 89 +/- 18 vs. 78 +/- 12 during adenosine, p = 0.025; controls: 92 +/- 10 vs. 89 +/- 9 at rest, p = 0.49; 78 +/- 11 vs. 77 +/- 5 during adenosine, p = 0.75). Similarly, contractility increased in ABM-treated pigs (ABM: 83 +/- 21 vs. 60 +/- 32 at rest, p = 0.04; 91 +/- 44 vs. 36 +/- 43 during pacing, p = 0.056; controls: 69 +/- 48 vs. 64 +/- 46 at rest, p = 0.74; 65 +/- 56 vs. 37 +/- 56 during pacing, p = 0.23). CONCLUSIONS Bone marrow cells secrete angiogenic factors that induce endothelial cell proliferation and, when injected transendocardially, augment collateral perfusion and myocardial function in ischemic myocardium.

Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study.

OBJECTIVES We conducted a pilot study to evaluate the feasibility of transendocardial delivery of autologous bone marrow (ABM) strategy in patients with severe symptomatic chronic myocardial ischemia not amenable to conventional revascularization. BACKGROUND Transendocardial injection of ABM cells appears to enhance perfusion of ischemic porcine myocardium. METHODS Ten patients underwent transendocardial injection of freshly aspirated and filtered unfractionated ABM using left ventricular electromechanical guidance. Twelve injections of 0.2 ml each were successfully delivered into ischemic noninfarcted myocardium pre-identified by single-photon emission computed tomography perfusion imaging. RESULTS Autologous bone marrow injection was successful in all patients and was associated with no serious adverse effects; in particular, there was no arrhythmia, evidence of infection, myocardial inflammation, or increased scar formation. Two patients were readmitted for recurrent chest pain. At three months, Canadian Cardiovascular Society angina score significantly improved (3.1 +/- 0.3 vs. 2.0 +/- 0.94, p = 0.001), as well as stress-induced ischemia occurring within the injected territories (2.1 +/- 0.8 vs. 1.6 +/- 0.8, p < 0.001). Treadmill exercise duration, available in nine patients, increased, but the change was not significant (391 +/- 155 vs. 485 +/- 198, p = 0.11). CONCLUSIONS This study provides preliminary clinical data indicating feasibility of catheter-based transendocardial delivery of ABM to ischemic myocardium.

Increased Restenosis in Diabetes Mellitus After Coronary Interventions Is Due to Exaggerated Intimal Hyperplasia A Serial Intravascular Ultrasound Study

BACKGROUND The increased risk of restenosis after catheter-based coronary interventions in diabetic patients has not been determined. Intravascular ultrasound (IVUS) has shown that the decrease in arterial area is responsible for most of the late lumen loss in nonstented lesions and that intimal hyperplasia is responsible for all of the late lumen loss in stented lesions. METHODS AND RESULTS Serial (postintervention and follow-up at 5.6 +/- 3.3 months) IVUS was used to study 251 native coronary lesions in 241 patients; 63 patients had treated diabetes mellitus (oral hypoglycemic drugs or insulin). Interventional procedures included percutaneous transluminal coronary angioplasty, directional or rotational atherectomy, excimer laser angioplasty, or Palmaz-Schatz stents. The external elastic membrane (EEM), stent, and lumen areas were measured. The plaque+media (P+M) area in nonstented lesions was calculated as EEM minus lumen area, and the intimal hyperplasia (IH) area in stented lesions was calculated as stent minus lumen area. The anatomic slice selected for serial analysis had an axial location within the target lesion at the smallest follow-up lumen area. Nonstented lesions in diabetics and nondiabetics had a similar decrease in EEM cross-sectional area (CSA; 1.9 +/- 2.8 versus 1.8 +/- 4.2 mm2; P = .6350). However, nonstented lesions in diabetics had a greater increase in P+M CSA (1.3 +/- 2.8 versus 0.6 +/- 2.5 mm2, P = .0720), and the increase in P+M CSA contributed a greater percentage to the decrease in lumen CSA. In stented lesions, the decrease in lumen CSA (5.2 +/- 2.5 versus 2.0 +/- 2.3 mm2) and the increase in IH CSA (5.0 +/- 2.8 versus 1.8 +/- 2.0 mm2) were greater in diabetics than nondiabetics (P = .0009 and P = .0007, respectively). These findings were even more striking in (nonstented and stented) restenotic lesions. CONCLUSIONS Serial IVUS analysis showed that the main reason for increased restenosis in diabetes mellitus was exaggerated intimal hyperplasia in both stented and nonstented lesions.

The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation

OBJECTIVES We compared the clinical outcomes following coronary stent implantation in insulin-treated diabetes mellitus (IDDM), non-IDDM patients, and nondiabetic patients. BACKGROUND Diabetic patients have increased restenosis and late morbidity following balloon angioplasty. The impact of diabetes mellitus (DM), especially IDDM, on in-stent restenosis is not known. METHODS We studied 954 consecutive patients with native coronary artery lesions treated with elective Palmaz-Schatz stents implantation using conventional coronary angiographic and intravascular ultrasound methodology. Procedural success, major in-hospital complications, and 1-year clinical outcome were compared according to the diabetic status. RESULTS. In-hospital mortality was 2% in IDDM, significantly higher (p <0.02) compared with non-IDDM (0%) and nondiabetics (0.3%). Stent thrombosis did not differ among groups (0.9% in IDDM vs. 0% in non-IDDM and 0% in nondiabetics, p >0.1). During follow-up, target lesion revascularization (TLR) was 28% in IDDM, significantly higher (p <0.05) compared with non-IDDM (17.6%) and nondiabetics (16.3%). Late cardiac event-free survival (including death, myocardial infarction [MI], and any coronary revascularization procedure) was significantly lower (p=0.0004) in IDDM (60%) compared with non-IDDM (70%) and nondiabetic patients (76%). By multivariate analysis, IDDM was an independent predictor for any late cardiac event (OR=2.05, p=0.0002) in general and TLR (odds ratio=2.51, p=0.0001) in particular. CONCLUSIONS. In a large consecutive series of patients treated by elective stent implantation, IDDM patients were at higher risk for in-hospital mortality and subsequent TLR and, as a result, had a significantly lower cardiac event-free survival rate. On the other hand, acute and long-term procedural outcome was found to be similar for non-IDDM compared with nondiabetic patients.

Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial

BACKGROUND In the HORIZONS-AMI trial, patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) who were treated with the thrombin inhibitor bivalirudin had substantially lower 30-day rates of major haemorrhagic complications and net adverse clinical events than did patients assigned to heparin plus a glycoprotein IIb/IIIa inhibitor (GPI). Here, we assess whether these initial benefits were maintained at 1 year of follow-up. METHODS Patients aged 18 years or older were eligible for enrolment in this multicentre, open-label, randomised controlled trial if they had STEMI, presented within 12 h after the onset of symptoms, and were undergoing primary PCI. 3602 eligible patients were randomly assigned by interactive voice response system in a 1:1 ratio to receive bivalirudin (0.75 mg/kg intravenous bolus followed by 1.75 mg/kg per h infusion; n=1800) or heparin plus a GPI (control; 60 IU/kg intravenous bolus followed by boluses with target activated clotting time 200-250 s; n=1802). The two primary trial endpoints were major bleeding and net adverse clinical events (NACE; consisting of major bleeding or composite major adverse cardiovascular events [MACE; death, reinfarction, target vessel revascularisation for ischaemia, or stroke]). This prespecified analysis reports data for the 1-year follow-up. Analysis was by intention to treat. Patients with missing data were censored at the time of withdrawal from the study or at last follow-up. This trial is registered with ClinicalTrials.gov, number NCT00433966. FINDINGS 1-year data were available for 1696 patients in the bivalirudin group and 1702 patients in the control group. Reasons for participant dropout were loss to follow-up and withdrawal of consent. The rate of NACE was lower in the bivalirudin group than in the control group (15.6%vs 18.3%, hazard ratio [HR] 0.83, 95% CI 0.71-0.97, p=0.022), as a result of a lower rate of major bleeding in the bivalirudin group (5.8%vs 9.2%, HR 0.61, 0.48-0.78, p<0.0001). The rate of MACE was similar between groups (11.9%vs 11.9%, HR 1.00, 0.82-1.21, p=0.98). The 1-year rates of cardiac mortality (2.1%vs 3.8%, HR 0.57, 0.38-0.84, p=0.005) and all-cause mortality (3.5%vs 4.8%, HR 0.71, 0.51-0.98, p=0.037) were lower in the bivalirudin group than in the control group. INTERPRETATION In patients with STEMI undergoing primary PCI, anticoagulation with bivalirudin reduced the rates of net adverse clinical events and major bleeding at 1 year compared with treatment with heparin plus a GPI. This finding has important clinical implications for the selection of optimum treatment strategies for patients with STEMI. FUNDING Cardiovascular Research Foundation, with unrestricted grant support from Boston Scientific Corporation and The Medicines Company.