Jacek Godlewski

Intracoronary Abciximab and Aspiration Thrombectomy in Patients With Large Anterior Myocardial Infarction The INFUSE-AMI Randomized Trial

CONTEXT Thrombus embolization during percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) is common and results in suboptimal myocardial perfusion and increased infarct size. Two strategies proposed to reduce distal embolization and improve outcomes after primary PCI are bolus intracoronary abciximab and manual aspiration thrombectomy. OBJECTIVE To determine whether bolus intracoronary abciximab, manual aspiration thrombectomy, or both reduce infarct size in high-risk patients with STEMI. DESIGN, SETTING, AND PATIENTS Between November 28, 2009, and December 2, 2011, 452 patients presenting at 37 sites in 6 countries within 4 hours of STEMI due to proximal or mid left anterior descending artery occlusion undergoing primary PCI with bivalirudin anticoagulation were randomized in an open-label, 2 x 2 factorial design to bolus intracoronary abciximab delivered locally at the infarct lesion site vs no abciximab and to manual aspiration thrombectomy vs no thrombectomy. INTERVENTIONS A 0.25-mg/kg bolus of abciximab was administered at the site of the infarct lesion via a local drug delivery catheter. Manual aspiration thrombectomy was performed with a 6 F aspiration catheter. MAIN OUTCOME MEASURES Primary end point: infarct size (percentage of total left ventricular mass) at 30 days assessed by cardiac magnetic resonance imaging (cMRI) in the abciximab vs no abciximab groups (pooled across the aspiration randomization); major secondary end point: 30-day infarct size in the aspiration vs no aspiration groups (pooled across the abciximab randomization). RESULTS Evaluable cMRI results at 30 days were present in 181 and 172 patients randomized to intracoronary abciximab vs no abciximab, respectively, and in 174 and 179 patients randomized to manual aspiration vs no aspiration, respectively. Patients randomized to intracoronary abciximab compared with no abciximab had a significant reduction in 30-day infarct size (median, 15.1%; interquartile range [IQR], 6.8%-22.7%; n = 181, vs 17.9% [IQR, 10.3%-25.4%]; n = 172; P = .03). Patients randomized to intracoronary abciximab also had a significant reduction in absolute infarct mass (median, 18.7 g [IQR, 7.4-31.3 g]; n = 184, vs 24.0 g [IQR, 12.1-34.2 g]; n = 175; P = .03) but not abnormal wall motion score (median, 7.0 [IQR, 2.0-10.0]; n = 188, vs 8.0 [IQR, 3.0-10.0]; n = 184; P = .08). Patients randomized to aspiration thrombectomy vs no aspiration had no significant difference in infarct size at 30 days (median, 17.0% [IQR, 9.0%-22.8%]; n = 174, vs 17.3% [IQR, 7.1%-25.5%]; n = 179; P = .51), absolute infarct mass (median, 20.3 g [IQR, 9.7-31.7 g]; n = 178, vs 21.0 g [IQR, 9.1-34.1 g]; n = 181; P = .36), or abnormal wall motion score (median, 7.5 [IQR, 2.0-10.0]; n = 186, vs 7.5 [IQR, 2.0-10.0]; n = 186; P = .89). CONCLUSION In patients with large anterior STEMI presenting early after symptom onset and undergoing primary PCI with bivalirudin anticoagulation, infarct size at 30 days was significantly reduced by bolus intracoronary abciximab delivered to the infarct lesion site but not by manual aspiration thrombectomy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00976521.

Rationale and design of the EMBRACE STEMI Study: A phase 2a, randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability and efficacy of intravenous Bendavia on reperfusion injury in patients treated with standard therapy including primary percutaneous coronary intervention and stenting for ST-segment elevation myocardial infarction

BACKGROUND Although significant efforts have been made to improve ST-segment elevation myocardial infarction (STEMI) outcomes by reducing symptom-onset-to-reperfusion times, strategies to decrease the clinical impact of ischemic reperfusion injury have demonstrated limited success. Bendavia, an intravenously administered mitochondrial targeting peptide, has been shown to reduce myocardial infarct size and attenuate coronary no-reflow in experimental modelswhen given before reperfusion. DESIGN The EMBRACE STEMI study is a phase 2a, randomized, double-blind, placebo-controlled trial enrolling 300 patients with a first-time anterior STEMI and an occluded proximal or mid-left anterior descending artery undergoing primary percutaneous coronary intervention (PCI) within 4 hours of symptom onset. Patients will be randomized to receive either Bendavia at 0.05 mg/kg per hour or an identically appearing placebo administered as an intravenous infusion at 60 mL/h. The primary end point is infarct size measured by the area under the creatine kinase-MB enzyme curve calculated from measurements from the central clinical chemistry laboratory obtained over the initial 72 hours after the primary PCI procedure, and the major secondary end point is infarct size calculated by the volume of infarcted myocardium (late contrast gadolinium enhancement) on the day 4±1 cardiac magnetic resonance imaging. SUMMARY EMBRACE-STEMI is testing the hypothesis that Bendavia, in conjunction with standard-of-care therapy, is superior to placebo for the reduction of myocardial infarction size among patients with first time, acute, anterior wall STEMI who undergo successful reperfusion with primary PCI and stenting.

EMBRACE STEMI study: a Phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention

AIMS Among patients with ST-elevation myocardial infarction (STEMI), reperfusion injury contributes to additional myocardial damage. MTP-131 is a cell-permeable peptide that preserves the integrity of cardiolipin, enhances mitochondrial energetics, and improves myocyte survival during reperfusion. METHODS AND RESULTS EMBRACE STEMI is a multicentre, randomized, double-blind Phase 2a trial that evaluated the efficacy and safety of MTP-131 vs. placebo infused at a rate of 0.05 mg/kg/h for 1 h among first-time anterior STEMI subjects undergoing primary percutaneous coronary intervention (PCI) for a proximal or mid left anterior descending (LAD) artery occlusion. Administration of MTP-131 was not associated with a significant reduction in the primary endpoint, infarct size by creatine kinase-myocardial band (CK-MB) area under the curve (AUC) over 72 h (5785 ± 426 ng h/mL in placebo vs. 5570 ± 486 ng h/mL in MTP-131; ITALIC! P = NS). MTP-131 was not associated with an improvement in pre-specified magnetic resonance imaging, angiographic, electrocardiographic, or clinical outcomes. CONCLUSION Among subjects with first-time anterior STEMI due to a proximal or mid LAD lesion who undergo successful PCI, administration of MTP-131 was safe and well tolerated. Treatment with MTP-131 was not associated with a decrease in myocardial infarct size as assessed by AUC0-72 of CK-MB.

Number of Microparticles Generated During Acute Myocardial Infarction and Stable Angina Correlates with Platelet Activation

BACKGROUND AND AIMS Elevated levels of circulating microparticles (MPs) have been reported in patients with acute myocardial infarction (AMI) and coronary artery disease. Platelet activation and inflammation have been recognized during AMI and stable angina (SA). We hypothesize that the origin and count of MPs in AMI and SA patients are related to markers of inflammation and platelet activation. METHODS Platelet, monocytes and endothelial MPs and surface P-selectin were determined in 12 AMI patients, 10 SA patients and 9 controls by flow cytometry. Plasma P-selectin, CD40 ligand (sCD40L) and interleukin 6 (IL-6) levels were evaluated by ELISA methods. RESULTS The total MP count was compared in control subjects, AMI, and SA patients: 12,765 (8465) vs. 38,750 (11,931) vs. 29,715 (12,072) counts/μl (p = 0.01), respectively. Patients with AMI displayed higher levels of total and platelet origin- tissue factor-positive (CD42/CD142) MPs than patients with SA: 72.8 (6.2) vs. 56.2 (6.4) %, p = 0.001. Levels of soluble P-selectin were significantly elevated in patients with AMI as compared to SA patients: 146 (6.5) vs. 107 (2.7) ng/mL, p = 0.005; significant correlation between total MP count and relative number of CD34, CD51, CD42-positive MPs, and the P-selectin expression was observed in patients with AMI. CONCLUSIONS Platelet activation in AMI is associated with increased generation of MPs not only from platelets, but also monocytes and endothelial cells. It suggests that interactions between platelets, monocytes and endothelial cells play an important role in the pathogenesis of myocardial ischemia.

Intralesional Abciximab and Thrombus Aspiration in Patients With Large Anterior Myocardial Infarction One-Year Results From the INFUSE-AMI Trial

Background—Whether intralesional abciximab administration and thrombus aspiration confer clinical benefits to patients undergoing primary percutaneous coronary intervention for ST-segment–elevation myocardial infarction is controversial. Methods and Results—A total of 452 patients with ST-segment–elevation myocardial infarction caused by proximal or mid left anterior descending artery occlusion undergoing primary percutaneous coronary intervention with bivalirudin anticoagulation were randomized in a 2×2 factorial design to bolus abciximab delivered locally at the infarct lesion site versus no abciximab and to manual thrombus aspiration versus no aspiration. Treatment with intralesional abciximab, thrombus aspiration, or both therapies compared with no active therapy before stent implantation resulted in lower 1-year rates of death (4.5% versus 10.4%; P=0.03), severe heart failure (4.2% versus 10.3%; P=0.02), and stent thrombosis (0.9% versus 3.8%; P=0.046). Between 30 days and 1 year of follow-up, treatment with intralesional abciximab compared with no abciximab was associated with a lower rate of death (1.4% versus 4.9%; P=0.04) and composite major adverse ischemic events (3.3% versus 7.8%; P=0.04), with nonsignificantly different overall 1-year rates of mortality, composite ischemic events, and heart failure–related events. Thrombus aspiration compared with no aspiration was associated with lower rates of new-onset severe heart failure between 30 days and 1 year (0.9% versus 4.5%; P=0.02) and of rehospitalization for heart failure from randomization to 1 year (0.9% versus 5.4%; P=0.0008), with nonsignificantly different rates of mortality. Conclusions—Intralesional abciximab and thrombus aspiration may have long-term benefits in patients with anterior ST-segment–elevation myocardial infarction presenting early after symptom onset and undergoing primary percutaneous coronary intervention with bivalirudin anticoagulation. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00976521.

No-Reflow Phenomenon After Acute Myocardial Infarction Is Associated With Reduced Clot Permeability and Susceptibility to Lysis

Objective— We assessed the relationship between fibrin clot properties and the no-reflow phenomenon after primary coronary intervention (PCI). Methods and Results— Epicardial blood flow was assessed by TIMI scale and corrected TIMI frame count (cTFC), and perfusion by TIMI Myocardial Perfusion Grade (TMPG) after PCI during ST-segment elevation myocardial infarction (STEMI). Fibrin clot permeability (Ks) and susceptibility to lysis in assays using exogenous thrombin (t50%) and without thrombin (tTF) were determined in 30 no-reflow patients (TIMI ≤2) and in 31 controls (TIMI-3) after uneventful 6 to 14 months from PCI. Patients with TIMI ≤2 had lower Ks by 18% (P<0.0001) and prolonged fibrinolysis by 33% for t50% (P<0.0001) and by 45% for tTF (P<0.0001). cTFC was correlated with Ks (r=−0.56, P<0.0001), t50% (r=0.49, P<0.001), and tTF (r=0.54, P<0.001). Ks increased in a stepwise fashion with TIMI flow (P<0.0001) and TMPG (P<0.0001), whereas both fibrinolysis times decreased with TIMI flow (P<0.0001 for both) and TMPG (P<0.01 for both). Multiple regression models showed that only Ks and fibrinogen were independent predictors of cTFC (P<0.05 for both), TIMI ≤2 flow (P<0.05 for both) and TMPG-0/1 (P<0.05 for both). Conclusions— Survivors of myocardial infarction with a history of the no-reflow after PCI are characterized with more compact fibrin network and its resistance to lysis.

Relationship between ST-segment resolution and anterior infarct size after primary percutaneous coronary intervention: analysis from the INFUSE-AMI trial.

Aims: ST-segment resolution (STR) after reperfusion therapy has been shown to correlate with prognosis in patients with ST-segment elevation myocardial infarction (STEMI). We investigated whether acute ECG measurements also correlate with ultimate infarct size. Methods and Results: The INFUSE-AMI trial randomized 452 patients with anterior STEMI to intracoronary bolus abciximab vs. no abciximab, and to thrombus aspiration vs. no aspiration. Infarct size as percentage of total LV mass was calculated by cardiac magnetic resonance imaging (MRI) 30 days post intervention. Five ECG methods were analysed for their ability to predict MRI infarct mass: (1) summed STR across all infarct-related ECG leads (ΣSTR); (2) STR in the single lead with maximum baseline ST-segment elevation (maxSTR); (3) summed residual ST-segment elevation across all infarct-related leads at 60 min post intervention (ΣST residual); (4) maximum residual ST-segment elevation in the worst single lead at 60 min post intervention (maxST residual); (5) number of new significant Q-waves (Qwave) at 60 min. All ECG methods strongly correlated with 30-day MRI infarct mass (all p<0.003). Simpler ECG measurements such as maxSTresidual and Qwave were as predictive as more complex measurements. A subset analysis of 158 patients who had microvascular obstruction (MVO) determined by MRI 5 days post intervention also showed strong correlations of MVO with the ECG measures. Conclusions: ST-segment and Q-wave changes after primary PCI in anterior STEMI strongly correlated with 30-day infarct size by MRI. In particular, maxST residual and Qwave at 60 min are simple ECG parameters that offer rapid analysis for prognostication.

Denervation of nerve terminals in renal arteries: one-year follow-up of interventional treatment of arterial hypertension

BACKGROUND Arterial hypertension is the most common cardiovascular system disease, affecting nearly one billion people worldwide. Despite the widespread use of antihypertensive medications, in some groups of patients an optimal blood pressure (BP) cannot be achieved. AIM To assess BP reduction in patients with resistant hypertension after a catheter-based renal sympathetic denervation procedure and to report vascular and kidney safety in one-year follow-up. METHODS Twenty eight patients with diagnosed resistant hypertension (median age 52.02 years, range 42-72) underwent percutaneous catheter-based renal denervation of nerve terminals in renal arteries. Arterial angiography and procedure of ablation was performed by Symplicity catheters and generator provided by Ardian (currently Medtronic Inc., USA). RESULTS Mean BP value before ablation was [mm Hg]: systolic 176.6, diastolic 100.28 and pulse pressure 73.4. After the procedure, reductions in the value of BP were reported [mm Hg]: systolic 154.8/152.54; diastolic 90.2/89.8, pulse pressure 64.66/62.73, respectively in nine-month and one-year follow-up. All results were statistically significant. No complications during one year observation were observed. CONCLUSIONS Percutaneous renal artery ablation procedure effectively reduces systolic BP, diastolic BP, and pulse pressure. No vascular or renal complications in any of the patients were observed. The results of a Polish research group showed no significant differences compared to the results obtained in the international studies Symplicity I and Symplicity II.

Denervation (ablation) of nerve terminalis in renal arteries: early results of interventional treatment of arterial hypertension in Poland

BACKGROUND Arterial hypertension is one of the main causes of cardiovascular disease morbidity and overall mortality. AIM To report the single centre experiences with changes in arterial blood pressure (BP) in patients after intra-arterial application of radiofrequency (RF) energy to cause renal sympathetic efferent and somatic afferent nerve and report vascular and kidney safety in a six month follow up. METHODS Twenty-eight patients, with hypertension despite medical therapy (median age 52.02 years, range 42-72 years) consented to therapeutic renal nerve ablation. SIMPLICITY RF catheters and generator provided by Ardian (currently Medtronic Inc., USA) were used to perform renal artery angiography and ablation. RESULTS The mean BP at baseline, and after one month, three months and six months were measured [mm Hg]: systolic 176.6; 162.3 (p = 0.004); 150.6 (p < 0.001); 147.2 (p < 0.001); diastolic 100.2; 90.3 (p < 0.001); 91.79 (p = 0.03); 88.5 (p < 0.001); pulse pressure 76.57; 75.18 (p = NS); 65.80 (p < 0.001); 62.15 (p < 0.001). Neither procedure-related nor therapy-related complications were reported in the six month follow up. CONCLUSIONS In our cohort of patients, intra-arterial renal nerve denervation was not associated with either vascular or renal complications out to six months. Nerve ablation of renal arteries led to significant reduction of mean values of arterial systolic, diastolic BP and significant reduction of pulse pressure. The Polish experience is not significantly different compared to that reported in the Symplicity I and Symplicity II international cohorts. The long term durability of this therapy and its application to earlier stages of hypertension or other disease states will require further investigation.

Polymorphism rs7023923 and monocyte count in blood donors and coronary artery disease patients

BACKGROUND The importance of the role of monocytes in coronary artery disease (CAD) is well documented. An increased number of circulating monocytes is associated with higher incidence of CAD. Both environmental and genetic factors influence monocytosis. The latter have been extensively studied since the development of high-throughput genome-wide association studies. Several associations between polymorphisms and monocytosis were found among healthy individuals; the first example was rs7023923. The magnitude of the association of studied polymorphisms with the trait of interest is often confounded by environmental factors and may therefore differ between patient and healthy populations. It is very important to determine the magnitude of the association among patients to predict outcome of the disease, e.g. myocardial infarction. AIM To determine whether the magnitude of association of rs7023923 with monocytosis, previously reported among healthy volunteers, is similar in patients in whom diagnosis of CAD was determined during elective coronarography. METHODS AND RESULTS Leucocytosis and neutrophilocytosis were higher among patients with CAD, while thrombocytosis was lower. Monocyte count did not differ among the studied groups (p = 0.25). We confirmed the association of rs7023923 with monocytosis among healthy blood donors (p = 0.0156) but not among patients admitted for elective coronarography (p = 0.61). Inclusion of the age and sex of patients in the statistical model did not modify the results. CONCLUSIONS Our data suggest that translation of the results of genetic association with the studied traits from healthy to patient population should be implemented with caution. It is possible that numerous environmental factors, which discriminate healthy volunteers from CAD patients, confound the magnitude of genetic associations and make interpretation of the data in patients less clear.