Transportation to primary percutaneous coronary intervention, compared with on-site fibrinolysis, is a strong independent predictor of functional status after myocardial infarction: 5-year follow-up of the PRAGUE-2 trial.

AIMS: Subjective symptoms represent significant criteria of a patient's health condition; therefore, we focused on the long-term prevalence of heart failure symptoms and angina pectoris after myocardial infarction between two groups of patients in which two different therapeutic strategies were used during the acute phase of ST-elevation myocardial infarction (STEMI). METHODS: The PRAGUE-2 study enrolled 850 patients with STEMI. The patients were randomized into two groups - transport to a primary percutaneous coronary intervention (PCI) centre (n=429) vs. fibrinolysis in community hospitals (n=421). The data were collected from either primary hospitals or PCI centres, as well as via questionnaires. RESULTS: The mean follow-up was 58 months. At 5 years, 45.4% of patients were in New York Heart Association class I following primary PCI vs. 31.8% of those treated with fibrinolysis (OR 2.02, 95% CI 1.37-2.97, p<0.002). At 5 years, 83.6% of patients had no symptoms of angina pectoris following invasive therapy vs. 58% of patients treated with fibrinolysis (OR 4.47, 95% CI 2.79-7.18, p<0.001). CONCLUSIONS: The symptoms of angina pectoris and heart failure were significantly lower in patients assigned to primary PCI in the acute stage of myocardial infarction compared with patients treated with fibrinolysis at the 5-year follow up.

Comparison of outcomes in ST-segment depression and ST-segment elevation myocardial infarction patients treated with emergency PCI: data from a multicentre registry.

BACKGROUND: Traditionally, acute myocardial infarction (AMI) has been described as either STEMI (ST-elevation myocardial infarction) or non-STEMI myocardial infarction. This classification is historically related to the use of thrombolytic therapy, which is effective in STEMI. The current era of widespread use of coronary angiography (CAG), usually followed by primary percutaneous coronary intervention (PCI) puts this classification system into question. OBJECTIVES: To compare the outcomes of patients with STEMI and ST-depression myocardial infarction (STDMI) who were treated with emergency PCI. METHODS: This multicentre registry enrolled a total of 6 602 consecutive patients with AMI. Patients were divided into the following subgroups: STEMI (n = 3446), STDMI (n = 907), left bundle branch block (LBBB) AMI (n = 241), right bundle branch block (RBBB) AMI (n = 338) and other electrocardiographic (ECG) AMI (n = 1670). Baseline and angiographic characteristics were studied, and revascularisation therapies and in-hospital mortality were analysed. RESULTS: Acute heart failure was present in 29.5% of the STDMI vs 27.4% of the STEMI patients (p < 0.001). STDMI patients had more extensive coronary atherosclerosis than patients with STEMI (three-vessel disease: 53.1 vs 30%, p < 0.001). The left main coronary artery was an infract-related artery (IRA) in 6.0% of STDMI vs 1.1% of STEMI patients (p < 0.001). TIMI flow 0-1 was found in 35.0% of STDMI vs 66.0% of STEMI patients (p < 0.001). Primary PCI was performed in 88.1% of STEMI (with a success rate of 90.8%) vs 61.8% of STDMI patients (with a success rate of 94.5%) (p = 0.012 for PCI success rates). In-hospital mortality was not significantly different (STDMI 6.3 vs STEMI 5.4%, p = 0.330). CONCLUSION: These data suggest that similar strategies (emergency CAG with PCI whenever feasible) should be applied to both these types of AMI.

Primary angioplasty in acute myocardial infarction with right bundle branch block: should new onset right bundle branch block be added to future guidelines as an indication for reperfusion therapy?

AIMS: The current guidelines recommend reperfusion therapy in acute myocardial infarction (AMI) with ST-segment elevation or left bundle branch block (LBBB). Surprisingly, the right bundle branch block (RBBB) is not listed as an indication for reperfusion therapy. This study analysed patients with AMI presenting with RBBB [with or without left anterior hemiblock (LAH) or left posterior hemiblock (LPH)] and compared them with those presenting with LBBB or with other electrocardiographic (ECG) patterns. The aim was to describe angiographic patterns and primary angioplasty use in AMI patients with RBBB. METHODS AND RESULTS: A cohort of 6742 patients with AMI admitted to eight participating hospitals was analysed. Baseline clinical characteristics, ECG patterns, coronary angiographic, and echocardiographic data were correlated with the reperfusion therapies used and with in-hospital outcomes. Right bundle branch block was present in 6.3% of AMI patients: 2.8% had RBBB alone, 3.2% had RBBB + LAH, and 0.3% had RBBB + LPH. TIMI flow 0 in the infarct-related artery was present in 51.7% of RBBB patients vs. 39.4% of LBBB patients (P = 0.023). Primary percutaneous coronary intervention (PCI) was performed in 80.1% of RBBB patients vs. 68.3% of LBBB patients (P< 0.001). In-hospital mortality of RBBB patients was similar to LBBB (14.3 vs. 13.1%, P = 0.661). Patients with new or presumably new blocks had the highest (LBBB 15.8% and RBBB 15.4%) incidence of cardiogenic shock from all ECG subgroups. Percutaneous coronary intervention was done more frequently (84.8%) in patients with new or presumably new RBBB when compared with other patients with blocks (old RBBB 66.0%, old LBBB 62.3%, new or presumably new LBBB 73.0%). In-hospital mortality was highest (18.8%) among patients presenting with new or presumably new RBBB, followed by new or presumably new LBBB (13.2%), old LBBB (10.1%), and old RBBB (6.4%). Among 35 patients with acute left main coronary artery occlusion, 26% presented with RBBB (mostly with LAH) on the admission ECG. CONCLUSION: Acute myocardial infarction with RBBB is frequently caused by the complete occlusion of the infarct-related artery and is more frequently treated with primary PCI when compared with AMI + LBBB. In-hospital mortality of patients with AMI and RBBB is highest from all ECG presentations of AMI. Restoration of coronary flow by primary PCI may lead to resolution of the conduction delay on the discharge ECG. Right bundle branch block should strongly be considered for listing in future guidelines as a standard indication for reperfusion therapy, in the same way as LBBB.

Shock index: a simple clinical parameter for quick mortality risk assessment in acute myocardial infarction.

BACKGROUND: Primary percutaneous coronary intervention (PCI) has become the preferred reperfusion strategy in patients with ST-segment elevation myocardial infarction and cardiogenic shock. Early identification of patients at risk for developing cardiogenic shock allows rapid decision making to determine reperfusion and transportation to a PCI centre. The aim of this analysis was to evaluate shock index (SI) as a marker for patients at risk of cardiogenic shock. METHODS: A total of 644 consecutive patients (73% male) with acute myocardial infarction with ST elevations were analyzed retrospectively. Primary PCI was performed in 92% of patients, and 7% of patients underwent rescue PCI. The SI parameter was defined as the ratio of heart rate to systolic blood pressure at hospital admission. RESULTS: SI (odds ratio [OR], 81.26; 95% confidence interval [CI], 9.76-676.51; P<0.001), age (OR, 1.17; 95% CI, 1.08-1.26; P<0.001), and diabetes (OR, 4.94; 95% CI, 1.44-16.97; P<0.011) were independent predictors of mortality. In the group of patients with SI≥0.8, 20% died, whereas in the group with SI<0.8, 4% of patients died (P<0.01). CONCLUSIONS: The proposed clinical parameter SI correlates with patients' prognosis and could therefore be used as a simple indicator of mortality risk of acute myocardial infarction. The simplicity of this proposed index makes its use accessible in large-scale clinical practices for risk stratification during first contact with patients.

Platelet gene polymorphisms and risk of bleeding in patients undergoing elective coronary angiography: a genetic substudy of the PRAGUE-8 trial.

AIM: Utilization of cardiac catheterization has increased dramatically over time. Bleeding is a major prognostic predictor after percutaneous coronary catheterization procedures. This study aimed to assess the impact of eight polymorphisms of genes encoding platelet receptors and enzymes on the risk of bleeding in patients undergoing elective coronary angiography (CAG). METHODS: Polymorphisms of platelet receptors, GP Ia (807C>T, rs1126643), GP VI (13254T>C, rs1613662), GP IIIa (HPA-1, rs5918), PAR-1 (IVS-14A>T, rs168753), P2Y(12) (34C>T, rs6785930 and H1/H2 haplotype, rs2046934), and genetic variations of the gene coding for cyclooxygenase-1 (COX-1) (-842A>G, rs10306114 and 50C>T, rs3842787) were studied. The frequencies of gene polymorphisms carriers were investigated in 696 patients undergoing elective CAG because of suspected or proven stable coronary artery disease. Genotyping was done using PCR, followed by melting curve analysis with specific fluorescent hybridization probes. RESULTS: In patients undergoing elective CAG (without ad hoc percutaneous coronary intervention (PCI) and without clopidogrel pretreatment) a significant association was found between bleeding risk and variations in the gene coding for COX-1 (-842A>G and 50C>T) (both p=0.013). Six other investigated polymorphisms did not show any influence on bleeding complications. After controlling for potential bleeding confounders, the association between COX-1 gene polymorphisms (-842A>G and 50C>T) and bleeding risk remained statistically significant (both odds ratios 12.1, p=0.012). CONCLUSION: Cyclooxygenase-1 -842G and 50T alleles significantly contribute to the risk of bleeding complications in patients undergoing elective CAG. Genetic testing is able to influence the safety of diagnostic cardiac catheterization in large numbers of low risk patients with borderline indications.

Optimal pretreatment timing for high load dosing (600 mg) of clopidogrel before planned percutaneous coronary intervention for maximal antiplatelet effectiveness.

BACKGROUND: The optimal timing for 600 mg clopidogrel pre-treatment before planned PCI in patients with stable coronary artery disease has never been tested in a randomized trial. METHODS: The time course of platelet inhibition was investigated in 105 patients pre-treated with clopidogrel ≥ 6 h before the planned procedure. Flow cytometric analysis of the vasodilator stimulated phosphoprotein (VASP) phosphorylation state was done and a Platelet Reactivity Index (PRI) was calculated prior to treatment (baseline) and at 12, 28, 36, 60, 84 and 108 h after the clopidogrel loading dose administration. RESULTS: The maximal inhibition of platelet activation was seen at 28 h post administration (PRI mean 36 ± 23%), and 2/3 of patients had PRI value <50%. At 12 h 47% of patients had PRI value ≥ 50% (mean 45±21%). 600 mg of clopidogrel significantly suppressed platelet activation for 4 days. A correlation was between baseline PRI and its values by 28 h (r(S)=0.48, p<0.001), between 12 h-28 h the correlation was strong (r(S)=0.77, p<0.001). CONCLUSION: The time curve of clopidogrel efficacy was dependent on baseline platelet reactivity. Among stable CAD patients, pre-treatment with 600 mg of clopidogrel resulted in maximal antiplatelet efficacy 1 day after drug administration.

An embolus in the right atrium caught in the Chiari network and resistant to thrombolysis.

Case report is presented, which describes a patient with thromboemboli trapped in the Chiari network within the right heart and resistant to thrombolysis. The right atrial masses were completely removed under cardiopulmonary bypass. Histological evaluation confirmed a mixed thromboemboli, with thrombus structures showing signs of organization and surrounded by a fibrous capsule. A heterozygous methylenetetrahydrofolate reductase gene polymorphism was found, and the plasma level of the plasminogen activator inhibitor type-1 (PAI-1) was 50% higher than the normal upper limit. In this presented case, the Chiari network displayed a protective function, but the expansion and organization of the thromboembolus caught there made it resistant to lytic therapy. Another important factor which could have influenced the resistance to thrombolysis was the high level of PAI-1. PAI-1 is the primary physiologic inhibitor of plasminogen activation in blood. Elevated pre-treatment levels of PAI-1 may reduce the efficacy of thrombolytic therapy by preventing or retarding clot dissolution. The patient's DNA was tested for a common single-base-pair polymorphism (four or five guanine bases) in the promoter region of the gene (4G/5G), but the presence of this variant allele was not confirmed: the patient was homozygous for the 5G allele (5G/5G genotype).

High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism: a genetic substudy of PRAGUE-8 trial.

The study aimed to assess the impact of nine polymorphisms of genes encoding platelet receptors, enzymes, and hemostatic factors on clopidogrel efficacy to inhibit platelet reactivity in patients with stable coronary artery disease undergoing elective coronary angiography either with or without ad hoc percutaneous coronary intervention. The study was performed as a genetic substudy of the PRAGUE-8 trial. Ninety-five patients pretreated with 600 mg clopidogrel at least 6 h prior to coronary angiography were tested. Baseline platelet reactivity to ADP was assessed before the drug was administered. Clopidogrel efficacy was tested again at 12 and 28 h after administration. Polymorphisms of platelet receptors, glycoprotein (GP) Ia (807C/T), GPVI (13254C/T), GPIIIa (PlA1/PlA2), PAR-1 (IVSn-14A/T), P2Y12 (32C/T), P2Y12 (H1/H2) haplotype, gene variations of cyclooxygenase-1, Leiden, and factor II mutations were studied. Flow cytometric tests of vasodilator-stimulated phosphoprotein phosphorylation states were used as a measure of drug efficacy. None of the gene polymorphisms influenced baseline ADP-induced platelet reactivity significantly. Twenty-eight hours after drug administration, differences in suppression of ADP-induced platelet reactivity were observed between polymorphism-positive and polymorphism-negative patients. Inhibition of platelet reactivity, after 600 mg of clopidogrel, was significantly less in carriers of PlA2 (P=0.009) for mean decrease in platelet reactivity index. The proportion of clopidogrel nonresponders (platelet reactivity index >50%) was apparently higher in PlA2 carriers in comparison with PlA1/PlA1 patients (54 vs. 24%, P=0.082). A 600 mg loading dose of clopidogrel failed to acceptably inhibit platelet reactivity in patients who were positive for the PlA2 polymorphism.

Factors influencing clopidogrel efficacy in patients with stable coronary artery disease undergoing elective percutaneous coronary intervention: statin's advantage and the smoking "paradox".

PURPOSE: The aim was to identify factors that influence the efficacy of 600 mg of clopidogrel pretreatment in patients with stable coronary artery disease undergoing elective percutaneous coronary intervention. METHODS: In a laboratory substudy of the PRAGUE-8 trial, the influences of nonmodifiable (age and sex) and modifiable (body mass index and tobacco smoke) factors, comorbidity (hypertension, hyperlipidemia, diabetes mellitus, and renal insufficiency) and cotherapy (statin, aspirin, and heparin), on the course of clopidogrel efficacy were investigated in 105 patients pretreated with clopidogrel >or=6 hours before coronary angiography +/- percutaneous coronary intervention. Flow cytometric analysis of the vasodilator-stimulated phosphoprotein phosphorylation state was used. Independent predictors that influenced clopidogrel action were identified using linear regression. RESULTS: There was no correlation between baseline platelet reactivity index (PRI) and severity of coronary atherosclerosis; mean index of platelet reactivity for a nonsignificant lesion was 72% +/- 5.98% and for a significant lesion 70.08% +/- 8.43%. The highest proportion of low responders was patients with diabetes (50% at 28 hours). Among tobacco smokers, the response to clopidogrel occurred quickly and 80% of smokers had effective inhibition of PRI, 12 hours after drug use. After adjustments, tobacco smoking was an independent predictor for the most robust drop of PRI 12 hours after clopidogrel (P = 0.027). The magnitude of total decrease of PRI at 28 hours was not significantly influenced by cigarette smoking (P = 0.12). Linear regression showed that patients on statin therapy had a better response to clopidogrel than those without statins-the mean decrease of PRI at 28 hours was significantly higher (P = 0.02) among these patients (40.0 vs. 27.6). CONCLUSIONS: In stable coronary artery disease, no correlation exists between baseline PRI and the severity and extent of coronary atherosclerosis. A high loading dose of clopidogrel does not satisfactorily suppress enhanced PRI in patients with diabetes. Cigarette smoking is independently associated with a prompt antiplatelet response to clopidogrel. Ongoing statin therapy is an independent determinant of more effective clopidogrel-mediated inhibition of platelet reactivity.

The time has come for new, more precise guidelines in the treatment of high-risk acute coronary syndromes with heparin.

BACKGROUND: The aim of this analysis was to define the risk factors associated with the problematic dose titration of unfractionated heparin (UFH) in high-risk non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients. METHODS AND RESULTS: The study group comprised 267 patients with high-risk NSTE ACS managed with an early invasive strategy and treated with the recommended dose of UFH. The subsequent dose was adjusted after measurement of activated partial thromboplastin time (aPTT), using the nomogram. The goal for aPTT was 1.5-2.5-fold of the control value. At 6 h after starting therapy 29% of patients had a therapeutic initial aPTT value; half of them were over-anticoagulated, and 22% were undertreated. By continuing therapy, the proportion of optimally treated patients increased; after 12 h of treatment 40% of patients reached the therapeutic dose, and 58% after 24 h. Undertreatment was a problem in < or = 65-year-old men. Women and older patients have a higher risk of overdose. The patients with a therapeutic dose of UFH had the lowest occurrence of major ischemic adverse events. CONCLUSIONS: Expert consensus on more precise dose guidelines for UFH is needed. The dose needs to be not only weight, but also age and sex, adjusted.

Clopidogrel pre-treatment in stable angina: for all patients > 6 h before elective coronary angiography or only for angiographically selected patients a few minutes before PCI? A randomized multicentre trial PRAGUE-8.

AIMS: To compare two different clopidogrel regimens on the outcomes of patients undergoing elective coronary angiography (CAG)+/-ad hoc percutaneous coronary intervention (PCI). METHODS AND RESULTS: Open-trial randomized 1028 patients with stable angina to group A ('non-selective'-clopidogrel 600 mg > 6 h before CAG; n = 513) or group B ('selective'-clopidogrel 600 mg in the cath-lab after CAG, only in case of PCI; n = 515). Combined primary endpoint was death/periprocedural myocardial infarction (MI)/stroke/re-intervention within 7 days. Secondary endpoints were troponin elevation and bleeding complications. Primary endpoint occurred in 0.8% group A patients vs. 1% group B (P = 0.749; 90% CI for the percentage difference -1.2-0.8). Periprocedural troponin elevation (> 3 x ULN) was detected in 2.6% group A vs. 3.3% group B (P = 0.475; 90% CI -2.5-1.0). Bleeding complications occurred in 3.5% group A patients vs. 1.4% group B (P = 0.025). After adjustment for covariates and factors that may influence the bleeding risk, patients in group A were shown to have more likely bleeding complications when compared with group B (OR = 3.03; 95% CI 1.14-8.10; P = 0.027). CONCLUSION: High (600 mg) loading dose of clopidogrel before elective CAG increased the risk of minor bleeding complications, while the benefit on periprocedural infarction was not significant. Clopidogrel can be given safely in the catheterization laboratory between CAG and PCI in chronic stable angina patients.

Long-term outcomes of patients with acute myocardial infarction presenting to hospitals without catheterization laboratory and randomized to immediate thrombolysis or interhospital transport for primary percutaneous coronary intervention. Five years' follow-up of the PRAGUE-2 Trial.

AIM: Randomized trials in ST-elevation myocardial infarction (STEMI) showed improved early outcomes after primary percutaneous coronary intervention (p-PCI) compared with thrombolysis (TL). It is less known whether the early benefit is sustained during the long-term follow-up. METHODS AND RESULTS: The PRAGUE-2 trial enrolled 850 STEMI patients presenting to community hospitals without cath-labs within 12 h of symptom onset. Patients were randomized into the groups 'TL in community hospital' (n = 421) and 'interhospital transfer for p-PCI' (n = 429). Follow-up data were available in 416 (98.8%) patients in the TL group and 428 (99.8%) in the p-PCI group. At 5 year follow-up, the cumulative incidence of composite endpoint (death from any cause or recurrent infarction or stroke or revascularization) was 53% in TL patients compared with 40% in p-PCI patients (HR 1.8; 95% CI 1.38-2.33; P < 0.001). The respective cumulative incidence of death from any cause was 23 and 19% (HR 1.34; 95% CI 0.99-1.82; P = 0.06), recurrent infarction 19 vs. 12% (HR 1.72; 95% CI 1.15-2.58; P = 0.009), stroke 8 vs. 8% (HR 1.65; 95% CI 0.84-2.23; P = 0.18), revascularization 51 vs. 34% (HR 1.81; 95% CI 1.21-2.35; P < 0.001). CONCLUSION: The early benefit from the p-PCI strategy (over TL) is sustained during the 5 years' follow-up. It can be almost exclusively derived from differences in event rate during the first month.

The impact of age and Killip class on outcomes of primary percutaneous coronary intervention. Insight from the PRAGUE-1 and -2 trials and registry.

BACKGROUND: Primary PCI (p-PCI) was shown to be the most effective reperfusion strategy for ST segment elevation myocardial infarction (STEMI). However, its success rates and clinical outcomes among the elderly patients are less well defined. The aim of this work was to access, whether primary PCI, as compared to thrombolysis, improves the outcomes of elderly patients with STEMI to the same extent as in the younger patient groups and whether this holds true also for the elderly patients presenting in cardiogenic shock or acute heart failure. PATIENTS: A total of 2,073 patients were analysed: 1,050 were enrolled in the randomised trials PRAGUE-1 and -2 and 1,023 entered a p-PCI registry at our institution. The mean age was 64 years, 29% were females. Three hundred and ninety patients were in the elderly (> 75 years) age group, 605 patients were aged 65-74 years and 1,078 patients were <65 years old. Acute heart failure was more prevalent in the patients that entered in the registry as compared to the randomised patients: Killip class IV 10% vs 1% (p < 0.001), Killip II-III class 29% vs 18% (p < 0.001). RESULTS: An optimal PCI result was achieved in 81% of the elderly and 90% of the younger patients (p < 0.001). The absolute mortality reduction by p-PCI compared to thrombolysis was 5.7% in the elderly and 3.7% in the younger groups (n.s.). The in-hospital mortality of Killip IV patients was 69% (elderly group), 54% (group 65-74 years, p < 0.001) and 27% (group <65 years, p < 0.001). The in-hospital mortality of patients without cardiogenic shock was low in all age groups: 4% (elderly), 2.7% (65-74 years) and 0.8% (<65 years). CONCLUSION: Primary PCI is the most effective reperfusion strategy for the elderly patients presenting with STEMI.