M.J. de Boer

Randomized trial of a GPIIb/IIIa platelet receptor blocker in refractory unstable angina. European Cooperative Study Group.

BackgroundPatients with unstable angina despite intensive medical therapy, ie, refractory angina, are at high risk for developing thrombotic complications: myocardial infarction or coronary occlusion during percutaneous transluminal coronary angioplasty (PTCA). Chimeric 7E3 (c7E3) Fab is an antibody fragment that blocks the platelet glycoprotein (GP) Ib/IIIa receptor and potently inhibits platelet aggregation. Methods and ResultsTo evaluate whether potent platelet inhibition could reduce these complications, 60 patients with dynamic ST-T changes and recurrent pain despite intensive medical therapy were randomized to c7E3 Fab or placebo. After initial angiography had demonstrated a culprit lesion suitable for PTCA, placebo or c7E3 Fab was administered as 0.25 mg/kg bolus injection followed by 10 μg/min for 18 to 24 hours until 1 hour after completion of second angiography and PTCA. During study drug infusion, ischemia occurred in 9 c7E3 Fab and 16 placebo patients (P = .06). During hospital stay, 12 major events occurred in 7 placebo patients (23%), including 1 death, 4 infarcts, and 7 urgent interventions. In the c7E3 Fab group, only 1 event (an infarct) occurred (3%, P = .03). Angiography showed improved TIMI flow in 4 placebo and 6 c7E3 Fab patients and worsening of flow in 3 placebo patients but in none of the c7E3 Fab patients. Quantitative analysis showed significant improvement of the lesion in the patients treated with c7E3 Fab, which was not observed in the placebo group, although the difference between the two treatment groups was not significant. Measurement of platelet function and bleeding time demonstrated >90% blockade of GPIIb/IIIa receptors, >90% reduction of ex vivo platelet aggregation to ADP, and a significantly prolonged bleeding time during c7E3 Fab infusion, without excess bleeding. ConclusionsCombined therapy with c7E3 Fab, heparin, and aspirin appears safe. These pilot study results support the concept that effective blockade of the platelet GPIIb/IIIa receptors can reduce myocardial infarction and facilitate PTCA in patients with refractory unstable angina.

Limitation of infarct size and preservation of left ventricular function after primary coronary angioplasty compared with intravenous streptokinase in acute myocardial infarction.

BackgroundEarly and effective flow through the infarct-related vessel is probably of paramount importance for limitation of infarct size and preservation of left ventricular function in patients with acute myocardial infarction. Primary coronary angioplasty may offer advantages in these respects compared with thrombolytic therapy. The purpose of the present study was to assess the effects on estimated enzymatic infarct size and left ventricular function in patients with acute myocardial infarction randomly assigned to undergo primary angioplasty or to receive intravenous streptokinase. Methods and ResultsWe evaluated 301 patients with signs of acute myocardial infarction and without contraindications for thrombolysis who presented within 6 hours after onset of symptoms or between 6 and 24 hours if there was evidence of ongoing ischemia. One hundred fifty-two patients were randomly assigned to undergo primary angioplasty, and 149 patients were assigned to receive treatment with streptokinase (1.5 million U IV). Infarct size was estimated from enzyme release. Global left ventricular ejection fraction and regional wall motion, if possible in combination with exercise testing, were evaluated by radionuclide ventriculography before discharge. Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 through the infarct-related vessel within 120 minutes after admission was achieved in 92% of all patients assigned to receive primary angioplasty therapy. Myocardial infarct size was 23% smaller in the angioplasty group compared with patients assigned to receive streptokinase (1003±784 versus 1310±1198 U/L, P=.012). Global left ventricular ejection fraction (50±9% versus 45±11%, P<.001) and regional wall motion in the infarct-related zones (42±14% versus 34±13%, P<.001) were better in the angioplasty group, which could mainly be contributed to myocardial salvage in the infarct-related areas. The observed differences were more pronounced in patients with an anterior wall myocardial infarction, although patients with a nonanterior infarct location also showed a beneficial effect of primary coronary angioplasty on left ventricular function compared with streptokinase therapy. Furthermore, the observed differences appeared to be more pronounced in patients presenting relatively early (within 2 hours) after onset of symptoms. ConclusionsIn patients with acute myocardial infarction, primary angioplasty results in a smaller infarct size and a better preserved myocardial function compared with patients randomized to receive treatment with intravenous streptoki-nase. This is probably due to early and optimal blood flow through the infarct-related vessel, as can be accomplished in a very high percentage of patients undergoing primary coronary angioplasty.

Breast Cancer Prognosis and Occult Lymph Node Metastases, Isolated Tumor Cells, and Micrometastases

BACKGROUND The prognostic relevance of isolated tumor cells and micrometastases in lymph nodes from patients with breast cancer has become a major issue since the introduction of the sentinel lymph node procedure. We conducted a systematic review of this issue. METHODS Studies published from January 1, 1977, until August 11, 2008, were identified by use of MEDLINE, EMBASE, and the Cochrane Library. A total of 58 studies (total number of patients = 297,533) were included and divided into three categories according to the method for pathological assessment of the lymph nodes: cohort studies with single-section pathological examination of axillary lymph nodes (n = 285,638 patients), occult metastases studies with retrospective examination of negative lymph nodes by step sectioning and/or immunohistochemistry (n = 7740 patients), and sentinel lymph node biopsy studies with intensified work-up of the sentinel but not of the nonsentinel lymph nodes (n = 4155 patients). We used random-effects meta-analyses to calculate pooled estimates of the relative risks (RRs) of 5- and 10-year disease recurrence and death and the multivariably corrected pooled hazard ratio (HR) of overall survival of the cohort studies. RESULTS In the cohort studies, the presence (vs the absence) of metastases of 2 mm or less in diameter in axillary lymph nodes was associated with poorer overall survival (pooled HR of death = 1.44, 95% confidence interval [CI] = 1.29 to 1.62). In the occult metastases studies, the presence (vs the absence) of occult metastases was associated with poorer 5-year disease-free survival (pooled RR = 1.55, 95% CI = 1.32 to 1.82) and overall survival (pooled RR = 1.45, 95% CI = 1.11 to 1.88), although these endpoints were not consistently assessed in multivariable analyses. Sentinel lymph node biopsy studies were limited by small patient groups and short follow-up. CONCLUSION The presence (vs the absence) of metastases of 2 mm or less in diameter in axillary lymph nodes detected on single-section examination was associated with poorer disease-free and overall survival.

Non-culprit lesions detected during primary PCI: treat invasively or follow the guidelines?

AIMS: Evidence regarding the optimal treatment of non-culprit lesions detected during primary PCI is lacking. Our aim was to investigate whether early invasive treatment improves left ventricular ejection fraction (EF) and prevents major adverse cardiac events (MACE). METHODS AND RESULTS: Of 121 patients with at least one non-culprit lesion, 80 were randomised to early FFRguided PCI (invasive group), and 41 to medical treatment (conservative group). Primary endpoint was EF at six months, secondary endpoints included MACE. In the invasive group, early angiography was performed 7.5 days (5-20) after primary PCI. Forty percent of the non-culprit lesions did not show haemodynamic significance (FFR > 0.75). Subsequent PCI of at least one non-culprit lesion was performed in 52%, PCI without preceding FFR was performed in 8% and elective CABG was done in 4%. No in-hospital events occurred in the conservative group. After six months, EF was comparable (59+/-9% vs. 57+/-9%, p=0.362), and there was no difference in MACE between invasively and conservatively treated patients (21 vs. 22%, p=0.929). CONCLUSIONS: An invasive strategy towards non-culprit lesions does not lead to an increase in EF or a reduction in MACE. The functional stenosis severity of non-culprit lesions is frequently overestimated.

Elevated troponin T and C-reactive protein predict impaired outcome for 4 years in patients with refractory unstable angina, and troponin T predicts benefit of treatment with abciximab in combination with PTCA

AIMS Treatment with the glycoprotein IIb/IIIa receptor antagonist abciximab before and during coronary intervention in refractory unstable angina improves early outcome. We collected 4-year follow-up data to assess whether this benefit is sustained. Additionally, we investigated the predictive value of baseline troponin T and CRP for long-term cardiovascular events. METHODS AND RESULTS Of 1265 patients enrolled in the CAPTURE trial follow-up was available in 94% of the patients alive after 6 months (median 48 months). Survival was similar in both groups. Both elevated troponin T and CRP were associated with impaired outcome, independently of other established risk factors, but with a different time course. Elevated troponin was associated with increased procedure related risk, and elevated CRP with increased risk for subsequent events. Lower rates of the composite end-point of death or myocardial infarction with abciximab vs. placebo were sustained during long-term follow up: 15.7% vs 17.2% at 4 years (P=ns), particularly in patients with elevated troponin T: 16.9% with abciximab vs 28.4% with placebo: P=0.015. Elevated CRP was not associated with specific benefit of abciximab. CONCLUSION Troponin T as a marker of thrombosis and CRP as a marker of inflammation are independent predictors of impaired outcome at 4 years follow-up. The initial benefit from abciximab with regard to death and myocardial infarction was preserved at 4 years. No specific benefit with abciximab was observed for patients with elevated CRP, suggesting that a chronic inflammatory process is not affected by abciximab. In contrast the benefit of treatment in patients with elevated troponin T implies that the acute thrombotic process in refractory unstable angina is treated effectively.

Long term outcome and cost-effectiveness of stenting versus balloon angioplasty for acute myocardial infarction

OBJECTIVE To investigate the long term clinical outcome and cost-effectiveness of stenting compared with balloon angioplasty in patients with acute myocardial infarction. METHODS Patients with acute myocardial infarction were randomly allocated to primary stenting (112) or balloon angioplasty (115). The primary end point was the cumulative first event rate of death, non-fatal reinfarction, or target vessel revascularisation. Secondary end points were restenosis at six months and the cost-effectiveness at follow up. RESULTS After 24 months, the combined clinical end point of death/reinfarction was 4% after stenting and 11% after balloon angioplasty (p = 0.04). Subsequent target vessel revascularisation was necessary in 15 patients (13%) after stenting and in 39 (34%) after balloon angioplasty (p < 0.001). The cumulative cardiac event-free survival rate was also higher after stenting (84% v 62%, p < 0.001). The angiographic restenosis rate after stenting was less than after balloon angioplasty (12% v 34%, p < 0.001). Despite the higher initial costs of stenting (Dfl 21 484v Dfl 18 625, p < 0.001), the cumulative costs at 24 months were comparable with those of balloon angioplasty (Dfl 31 423 v Dfl 32 933, p = 0.83). CONCLUSIONS Compared with balloon angioplasty, primary stenting for acute myocardial infarction results in a better long term clinical outcome without increased cost.

Marked reduction of early stent thrombosis with pre-hospital initiation of high-dose Tirofiban in ST-segment elevation myocardial infarction.

Summary.  Background: No randomized comparisons are yet available evaluating the effect of pre‐hospital high dose tirofiban on the incidence of early stent thrombosis after primary percutaneous coronary intervention (PCI). Objectives: The aim of this analysis was to evaluate whether routine pre‐hospital administration of high‐dose tirofiban in ST‐segment elevation myocardial infarction (STEMI) decreases the incidence of early stent thrombosis after primary PCI. Patients/methods: The Ongoing Tirofiban in Myocardial Evaluation (On‐TIME) 2 trial was a prospective multicenter study of consecutive STEMI patients referred for primary PCI in which patients were randomized to pre‐hospital no high‐dose tirofiban/placebo. We examined the incidence of Academic Research Consortium definite and probable early stent thrombosis and determined predictors and outcome of early stent thrombosis. Results: Primary PCI was performed in 1203 out of 1398 patients (86.1%). In 1073 patients (89.2%) a coronary stent was placed. Early stent thrombosis occurred in 39 patients (3.6%). Pre‐hospital initiation of high‐dose tirofiban significantly reduced early stent thrombosis (2.1% vs. 5.2%, P = 0.006) and was associated with a lower incidence of urgent repeat PCI (1.9% vs. 5.2%, P = 0.005). Early stent thrombosis, as well as pre‐hospital initiation of high‐dose tirofiban, was independently associated with 30‐day mortality. Conclusions: Pre‐hospital initiation of high‐dose tirofiban reduces the 30‐day incidence of stent thrombosis in STEMI patients treated with primary PCI and stenting. Early stent thrombosis and pre‐hospital initiation of high‐dose tirofiban were independent predictors of 30‐day mortality.

Circumflex artery-related acute myocardial infarction : limited ECG abnormalities but poor outcome

Background. Circumflex (CX) artery-related myocardial infarction (MI) is less well represented in trials on ST-elevation acute myocardial infarction (STEMI), most often due to the absence of significant ST-segment elevation, and therefore the outcome of these patients is less well known. We aimed to compare the outcome of patients with CX versus right coronary artery (RCA) related STEMI in a large cohort of patients treated with primary angioplasty.Methods. A total of 1683 consecutive patients with STEMI were studied. Patients who lacked STsegment elevation were also included if they had persistent chest pain with signs of ischaemia or regional wall motion abnormalities on echocardiography. Coronary angioplasty was performed according to standard procedures. After the intervention, all patients received aspirin and clopidogrel or ticlopidine.Results. The infarct-related vessel was the CX in 229 patients (14%) and the RCA in 600 patients (36%). No differences in baseline characteristics were present. Mean extent of ST-segment elevation or deviation was significantly higher in patients with the RCA as infarct-related vessel. Enzymatic infarct size was significantly higher in the CXrelated MI (1338±1117 IU/l vs. 1806±1498 IU/l, p<0.001). Left ventricular ejection fraction <45% was more often present in patients with CXrelated MI (37 vs. 26%, p<0.01). Both short- and long-term mortality were significantly higher in the CX-related MI.Conclusion. This study emphasises the fact that CX-related infarction has a worse prognosis compared with RCA-related infarction. (Neth Heart J 2007;15:286-90.)

Incidence, predictors and prognostic importance of bleeding after primary PCI for ST-elevation myocardial infarction

AIMS: To investigate incidence, predictors and prognosis of bleeding in ST elevation myocardial infarction (STEMI) patients who underwent primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: A large scale, prospective, observational study was performed between 1991 and 2004 in a single teaching hospital in The Netherlands including all consecutive STEMI patients who underwent primary PCI. The independent association between both major and minor bleeding and one year mortality was evaluated using Cox proportional hazard models. A total of 5,030 patients were included, of whom 109 patients (2%) had cardiac surgery within 48 hours. Data on bleeding or = 2 on admission, anterior MI location and TIMI 0 flow before PCI. Killip class > or = 2 on admission was an independent predictor of major bleeding. Major bleeding (HR 3.5 [95% CI 2.3-5.4]) was associated with an increased risk of death at one year. CONCLUSIONS: After primary PCI, the incidence of major bleeding is less than 2%. Although relatively infrequent, major bleeding complications are strongly and independently related to short- and midterm mortality.

Cardiac operative risk evaluation: The EuroSCORE II, does it make a real difference?

BackgroundThe EuroSCORE, worldwide used as a model for prediction of mortality after cardiac surgery, has recently been renewed. Since October 2011, the EuroSCORE II calculator is available at the EuroSCORE website and recommended for clinical use. The intention of this paper is to compare the use of the initial EuroSCORE and EuroSCORE II as a risk evaluation tool.Methods100 consecutive patients who underwent combined mitral valve and coronary bypass surgery (MVR + CABG) and 100 consecutive patients undergoing combined aortic valve surgery and coronary bypass surgery (AVR + CABG) at the Radboud University Nijmegen Medical Center before 10 October 2011 were included. For both groups the initial EuroSCORE and the EuroSCORE II model were used for risk calculation and based on the calculated risks, cumulative sum charts (CUSUM) were constructed to evaluate the impact on performance monitoring.ResultsFor the MVR + CABG group the calculated risk using the initial logistic EuroSCORE was 9.95 ± 8.47 (1.51–45.37) versus 5.08 ± 4.03 (0.67–19.76) for the EuroSCORE II. For the AVR + CABG group 9.50 ± 8.6 (1.51–69.5) versus 4.77 ± 6.6 (0.96–64.24), respectively. For both groups the calculated risk by the EuroSCORE II was statistically lower compared with the initial EuroSCORE (p < 0.001). This lower expected risk has influence on performance monitoring, using risk-adjusted CUSUM analysis.ConclusionThe EuroSCORE II, based on a recently updated database, reduces the overestimation of the calculated risk by the initial EuroSCORE. This difference is statistically significant and the EuroSCORE II may also reflect better current surgical performance.