Shahar Lavi

Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events

AIMS There is growing need for the identification of novel non-invasive methodologies for the identification of individuals at risk for adverse cardiovascular (CV) events. We examined whether endothelial dysfunction, as detected by non-invasive peripheral arterial tonometry (EndoPAT), can predict late CV events. METHODS AND RESULTS Reactive hyperaemia (RH) was induced following upper arm occlusion of systolic blood pressure in 270 outpatients (54 +/- 12 years, 48% female). The natural logarithmic scaled RH index (L_RHI) was calculated from the ratio between the digital pulse volume during RH and at baseline. The patients were followed for CV adverse events (AE: cardiac death, myocardial infarction, revascularization or cardiac hospitalization) during a 7-year follow-up (inter-quartile range = 4.4-8). Cox models were used to estimate the association of EndoPAT results with AE adjusted for age. During the follow-up, AE occurred in 86 patients (31%). Seven-year AE rate was 48% in patients with L_RHI < 0.4 vs. 28% in those with L_RHI >or= 0.4 (P = 0.03). Additional univariate predictors of AE were advancing age (P = 0.02) and prior coronary bypass surgery (P = 0.01). The traditional Framingham risk score was not higher in patients with AE. Multivariate analysis identified L_RHI < 0.4 as an independent predictor of AE (P = 0.03). CONCLUSION A low RH signal detected by EndoPAT, consistent with endothelial dysfunction, was associated with higher AE rate during follow-up. L_RHI was an independent predictor of AE. Non-invasive assessment of peripheral vascular function may be useful for the identification of patients at risk for cardiac AEs.

Randomized Trial of Primary PCI with or without Routine Manual Thrombectomy

BACKGROUND During primary percutaneous coronary intervention (PCI), manual thrombectomy may reduce distal embolization and thus improve microvascular perfusion. Small trials have suggested that thrombectomy improves surrogate and clinical outcomes, but a larger trial has reported conflicting results. METHODS We randomly assigned 10,732 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI to a strategy of routine upfront manual thrombectomy versus PCI alone. The primary outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or New York Heart Association (NYHA) class IV heart failure within 180 days. The key safety outcome was stroke within 30 days. RESULTS The primary outcome occurred in 347 of 5033 patients (6.9%) in the thrombectomy group versus 351 of 5030 patients (7.0%) in the PCI-alone group (hazard ratio in the thrombectomy group, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P=0.86). The rates of cardiovascular death (3.1% with thrombectomy vs. 3.5% with PCI alone; hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P=0.34) and the primary outcome plus stent thrombosis or target-vessel revascularization (9.9% vs. 9.8%; hazard ratio, 1.00; 95% CI, 0.89 to 1.14; P=0.95) were also similar. Stroke within 30 days occurred in 33 patients (0.7%) in the thrombectomy group versus 16 patients (0.3%) in the PCI-alone group (hazard ratio, 2.06; 95% CI, 1.13 to 3.75; P=0.02). CONCLUSIONS In patients with STEMI who were undergoing primary PCI, routine manual thrombectomy, as compared with PCI alone, did not reduce the risk of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heart failure within 180 days but was associated with an increased rate of stroke within 30 days. (Funded by Medtronic and the Canadian Institutes of Health Research; TOTAL ClinicalTrials.gov number, NCT01149044.).

Smoking Is Associated With Epicardial Coronary Endothelial Dysfunction and Elevated White Blood Cell Count in Patients With Chest Pain and Early Coronary Artery Disease

Background— Smoking is a major risk factor for cardiovascular events. One of the potential mechanisms may be related to both coronary endothelial dysfunction and increased inflammatory response. The present study was designed to test the hypothesis that smoking is associated with epicardial coronary endothelial dysfunction and inflammation. Methods and Results— Coronary endothelial function in response to acetylcholine was assessed in 881 patients (115 current smokers and 766 nonsmokers, including 314 previous smokers). Smokers were significantly younger than nonsmokers (43±1 versus 51±1 years, P<0.0001), had more epicardial vasoconstriction in response to intracoronary acetylcholine (−19±2% versus −14±1% change in coronary artery diameter, P=0.03), and were more likely than nonsmokers to have epicardial endothelial dysfunction (46% versus 35%, P=0.005), but their microvascular endothelial function was intact. Smokers had higher white blood cell counts than nonsmokers (7.7±0.2 versus 6.6±0.1×109/L, P<0.0001), higher myeloperoxidase (156±19 versus 89±8 ng/mL), higher lipoprotein-associated phospholipase A2 (242±12 versus 215±5 ng/mL), and higher levels of intracellular adhesion molecule (283±14 versus 252±5 ng/mL). There were no differences in the levels of C-reactive protein, fibrinogen, or vascular cell adhesion molecule between the groups. Conclusion— Young smokers are characterized by epicardial coronary endothelial dysfunction, preserved microvascular endothelial function, and increased levels of inflammatory biomarkers and oxidative stress. The present study provides further information regarding the potential mechanisms by which smoking contributes to cardiovascular events.

Outcomes after thrombus aspiration for ST elevation myocardial infarction: 1-year follow-up of the prospective randomised TOTAL trial

BACKGROUND Two large trials have reported contradictory results at 1 year after thrombus aspiration in ST elevation myocardial infarction (STEMI). In a 1-year follow-up of the largest randomised trial of thrombus aspiration, we aimed to clarify the longer-term benefits, to help guide clinical practice. METHODS The trial of routine aspiration ThrOmbecTomy with PCI versus PCI ALone in Patients with STEMI (TOTAL) was a prospective, randomised, investigator-initiated trial of routine manual thrombectomy versus percutaneous coronary intervention (PCI) alone in 10,732 patients with STEMI. Eligible adult patients (aged ≥18 years) from 87 hospitals in 20 countries were enrolled and randomly assigned (1:1) within 12 h of symptom onset to receive routine manual thrombectomy with PCI or PCI alone. Permuted block randomisation (with variable block size) was done by a 24 h computerised central system, and was stratified by centre. Participants and investigators were not masked to treatment assignment. The trial did not show a difference at 180 days in the primary outcome of cardiovascular death, myocardial infarction, cardiogenic shock, or heart failure. However, the results showed improvements in the surrogate outcomes of ST segment resolution and distal embolisation, but whether or not this finding would translate into a longer term benefit remained unclear. In this longer-term follow-up of the TOTAL study, we report the results on the primary outcome (cardiovascular death, myocardial infarction, cardiogenic shock, or heart failure) and secondary outcomes at 1 year. Analyses of the primary outcome were by modified intention to treat and only included patients who underwent index PCI. This trial is registered with ClinicalTrials.gov, number NCT01149044. FINDINGS Between Aug 5, 2010, and July 25, 2014, 10,732 eligible patients were enrolled and randomly assigned to thrombectomy followed by PCI (n=5372) or to PCI alone (n=5360). After exclusions of patients who did not undergo PCI in each group (337 in the PCI and thrombectomy group and 331 in the PCI alone group), the final study population comprised 10,064 patients (5035 thrombectomy and 5029 PCI alone). The primary outcome at 1 year occurred in 395 (8%) of 5035 patients in the thrombectomy group compared with 394 (8%) of 5029 in the PCI alone group (hazard ratio [HR] 1·00 [95% CI 0·87-1·15], p=0·99). Cardiovascular death within 1 year occurred in 179 (4%) of the thrombectomy group and in 192 (4%) of 5029 in the PCI alone group (HR 0·93 [95% CI 0·76-1·14], p=0·48). The key safety outcome, stroke within 1 year, occurred in 60 patients (1·2%) in the thrombectomy group compared with 36 (0·7%) in the PCI alone group (HR 1·66 [95% CI 1·10-2·51], p=0·015). INTERPRETATION Routine thrombus aspiration during PCI for STEMI did not reduce longer-term clinical outcomes and might be associated with an increase in stroke. As a result, thrombus aspiration can no longer be recommended as a routine strategy in STEMI. FUNDING Canadian Institutes of Health Research, Canadian Network and Centre for Trials Internationally, and Medtronic Inc.

Cardiac catheterization is associated with superior outcomes for survivors of out of hospital cardiac arrest: review and meta-analysis.

AIMS Survivors of out-of-hospital cardiac arrest (OHCA) have a high rate of morbidity and mortality. Invasive cardiac assessment with coronary angiography offers the potential for improving outcomes by facilitating early revascularization. The aim of the present study was to review the published data on early coronary angiography for survivors of OHCA, and its impact on survival and neurological outcomes. METHODS Medline, Embase and PubMed were searched with a structured search query. The primary outcome was in-hospital (or if not available, 30 day or 6 month) survival. Rates of survival with good neurological outcome were a secondary endpoint. The time period of the search was from 1 January 1980 to 1 January 2014. Data was pooled with means and 95% CI interval calculated. Meta-analysis of the main outcomes was performed using a weighted random effects model. RESULTS Following review of all identified records, 105 relevant full text articles were retrieved. Fifty had adequate outcome information stratified by the use of coronary angiography for analysis. In studies where a control group was available for comparison, the overall survival in the acute angiography group was 58.8% versus 30.9% in the control group (Odds ratio 2.77, 95% CI 2.06-3.72). Survival with good neurological outcome (as per the Utstein framework) in the early angiography group was 58% versus 35.8% in the control group (Odds ratio 2.20, 95% CI 1.46-3.32). CONCLUSIONS Early coronary angiography in patients following OHCA is associated with improved outcome and better survival.

Design and rationale of the TOTAL trial: A randomized trial of routine aspiration ThrOmbecTomy with percutaneous coronary intervention (PCI) versus PCI ALone in patients with ST-elevation myocardial infarction undergoing primary PCI

BACKGROUND A major limitation of primary percutaneous coronary intervention (PPCI) for the treatment of ST-elevation myocardial infarction (STEMI) is impaired microvascular perfusion due to embolization and obstruction of microcirculation with thrombus. Manual thrombectomy has the potential to reduce distal embolization and improve microvascular perfusion. Clinical trials have shown mixed results regarding thrombectomy. OBJECTIVE The objective of this study is to evaluate the efficacy of routine upfront manual aspiration thrombectomy during PPCI compared with percutaneous coronary intervention alone in patients with STEMI. DESIGN This is a multicenter, prospective, open, international, randomized trial with blinded assessment of outcomes. Patients with STEMI undergoing PPCI are randomized to upfront routine manual aspiration thrombectomy with the Export catheter (Medtronic CardioVascular, Santa Rosa, CA) or to percutaneous coronary intervention alone. The primary outcome is the composite of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or new or worsening New York Heart Association class IV heart failure up to 180 days. The trial uses an event-driven design and will recruit 10,700 patients. SUMMARY The TOTAL trial will determine the effect of routine manual aspiration thrombectomy during PPCI on clinically important outcomes.

The Adverse Long-Term Impact of Renal Impairment in Patients Undergoing Percutaneous Coronary Intervention in the Drug-Eluting Stent Era

Background—An observational study determining the long-term impact of chronic kidney disease (CKD) on patients undergoing percutaneous coronary intervention at a tertiary cardiac referral center. CKD is associated with poor in-hospital outcomes after percutaneous coronary intervention, but its effect beyond 1 year, particularly in the drug-eluting stent (DES) era, has not been reported. Methods and Results—Baseline creatinine was available for 11 953 patients entered into a prospective registry (April 2000 to September 2007). Patients were stratified: those with or without at least moderate CKD (creatinine clearance, <60 mL/min). Follow-up data were obtained through linkage to a provincial registry. Kaplan–Meier analysis was performed. Cox multiple-regression analysis identified independent predictors of late mortality and major adverse cardiac events (MACE) and examined the association between DES use and late outcomes in the presence or absence of CKD. CKD was present in 3070 patients (25.7%). In-hospital mortality and MACE were significantly increased in CKD (3.34% versus 0.44%, P<0.001 and 5.73% versus 2.2%, P<0.001). Survival and MACE-free survival at 7 years were reduced (64.5±1.4% versus 89.4±0.5%, P<0.001; 44.0±1.4% versus 63.4±0.8%, P<0.001). CKD was an independent predictor of late mortality and MACE (hazard ratio [HR]: 2.18, CI: 1.90 to 2.49, P<0.0001; HR: 1.37, CI: 1.25 to 1.49, P<0.0001). DES use was associated with a significant reduction in both (HR: 0.71, CI: 0.60 to 0.83, P<0.0001; HR: 0.70, CI: 0.63 to 0.78, P<0.0001). In patients with CKD, DES use was associated with reduced revascularization (HR: 0.68, CI: 0.53 to 0.88, P=0.004) and reduced MACE (HR: 0.81, CI: 0.69 to 0.95, P=0.011) but not reduced mortality (HR: 0.85, CI: 0.69 to 1.05, P=0.1). Conclusion—In a large registry of “all comers” for percutaneous coronary intervention, CKD was an independent predictor of adverse late outcomes. DES use may be associated with improved long-term outcomes in this high-risk cohort, but further prospective studies are required.

Remote Ischemic Postconditioning During Percutaneous Coronary Interventions Remote Ischemic Postconditioning–Percutaneous Coronary Intervention Randomized Trial

Background—Remote ischemic preconditioning may result in reduction in infarct size during percutaneous coronary intervention (PCI). It is unclear whether remote ischemic postconditioning (RIPost) will reduce the incidence of myocardial injury after PCI, and whether ischemic conditioning of a larger remote organ (thigh versus arm) would provide further myocardial protection. Methods and Results—We randomized 360 patients presenting with stable or unstable angina (28% of patients) and negative Troponin T at baseline to 3 groups: 2 groups received RIPost (induced by ischemia to upper or lower limb), and a third was the control group. RIPost was applied during PCI immediately after stent deployment, by three 5-minute cycles of blood pressure cuff inflation to >200 mm Hg in the arm or thigh (20 mm Hg in the control) with 5-minute breaks between each cycle. The primary end-point was the proportion of patients with Troponin T levels >3×ULN postprocedure (at 6 or 18–24 hours), where ULN stands for upper limit of normal. A total of 120 patients were randomized to each group. There were no differences in baseline characteristics between the 3 groups. The primary outcome occurred in 30%, 35%, and 35% of the arm, thigh, and control groups, respectively (P=0.64). There were no differences in creatine kinase or high sensitivity C-reactive protein levels after PCI or in the incidence of acute kidney injury between the groups. Conclusions—RIPost during PCI did not reduce the incidence of periprocedural myocardial injury. Similar effect was obtained when remote ischemia was induced to the upper or lower limb. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00970827.

Culprit lesion thrombus burden after manual thrombectomy or percutaneous coronary intervention-alone in ST-segment elevation myocardial infarction: the optical coherence tomography sub-study of the TOTAL (ThrOmbecTomy versus PCI ALone) trial

AIMS Manual thrombectomy has been proposed as a strategy to reduce thrombus burden during primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). However, the effectiveness of manual thrombectomy in reducing thrombus burden is uncertain. In this substudy of the TOTAL (ThrOmbecTomy versus PCI ALone) trial, we compared the thrombus burden at the culprit lesion using optical coherence tomography (OCT) in patients treated with thrombectomy vs. PCI-alone. METHODS AND RESULTS The TOTAL trial (N = 10 732) was an international, multicentre, randomized trial of thrombectomy (using the Export catheter, Medtronic Cardiovascular, Santa Rosa, CA, USA) in STEMI patients treated with primary PCI. The OCT substudy prospectively enrolled 214 patients from 13 sites in 5 countries. Optical coherence tomography was performed immediately after thrombectomy or PCI-alone and then repeated after stent deployment. Thrombus quantification was performed by an independent core laboratory blinded to treatment assignment. The primary outcome of pre-stent thrombus burden as a percentage of segment analysed was 2.36% (95% CI: 1.73-3.22) in the thrombectomy group and 2.88% (95% CI: 2.12-3.90) in the PCI-alone group (P = 0.373). Absolute pre-stent thrombus volume was not different (2.99 vs. 3.74 mm(3), P = 0.329). Other secondary outcomes of pre-stent quadrants of thrombus, post-stent atherothrombotic burden, and post-stent atherothrombotic volume were not different between groups. CONCLUSION Manual thrombectomy did not reduce pre-stent thrombus burden at the culprit lesion compared with PCI-alone. Both strategies were associated with low thrombus burden at the lesion site after the initial intervention to restore flow.

Conditioning of the heart: from pharmacological interventions to local and remote protection: possible implications for clinical practice.

Ischemic preconditioning is a natural protective mechanism by which brief episodes of ischemia protect the heart or other organs from the deleterious effects of ischemia-reperfusion injury. Ischemic preconditioning was demonstrated in animals more than 20 years ago, and subsequent studies in humans showed a dramatic protective effect on the heart. This method did not translate into clinical practice partially due to difficulty in application of conditioning. At the same time, multiple drugs were assessed, but none proved to be beneficial in large scale studies for myocardial protection. Although multicenter studies are still lacking, it was recently demonstrated in reasonable sized studies that in patients undergoing percutaneous coronary interventions or suffering from myocardial infarction, remote ischemic conditioning has beneficial protective effect. With more studies we may see translation into clinical practice in the near future.