R. J. de Winter

Early Invasive vs Conservative Treatment Strategies in Women and Men With Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction: A Meta-analysis

CONTEXT Although an invasive strategy is frequently used in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS), data from some trials suggest that this strategy may not benefit women. OBJECTIVE To conduct a meta-analysis of randomized trials to compare the effects of an invasive vs conservative strategy in women and men with NSTE ACS. DATA SOURCES Trials were identified through a computerized literature search of the MEDLINE and Cochrane databases (1970-April 2008) using the search terms invasive strategy, conservative strategy, selective invasive strategy, acute coronary syndromes, non-ST-elevation myocardial infarction, and unstable angina. STUDY SELECTION Randomized clinical trials comparing an invasive vs conservative treatment strategy in patients with NSTE ACS. DATA EXTRACTION The principal investigators for each trial provided the sex-specific incidences of death, myocardial infarction (MI), and rehospitalization with ACS through 12 months of follow-up. DATA SYNTHESIS Data were combined across 8 trials (3075 women and 7075 men). The odds ratio (OR) for the composite of death, MI, or ACS for invasive vs conservative strategy in women was 0.81 (95% confidence interval [CI], 0.65-1.01; 21.1% vs 25.0%) and in men was 0.73 (95% CI, 0.55-0.98; 21.2% vs 26.3%) without significant heterogeneity between sexes (P for interaction = .26). Among biomarker-positive women, an invasive strategy was associated with a 33% lower odds of death, MI, or ACS (OR, 0.67; 95% CI, 0.50-0.88) and a nonsignificant 23% lower odds of death or MI (OR, 0.77; 95% CI, 0.47-1.25). In contrast, an invasive strategy was not associated with a significant reduction in the triple composite end point in biomarker-negative women (OR, 0.94; 95% CI, 0.61-1.44; P for interaction = .36) and was associated with a nonsignificant 35% higher odds of death or MI (OR, 1.35; 95% CI, 0.78-2.35; P for interaction = .08). Among men, the OR for death, MI, or ACS was 0.56 (95% CI, 0.46-0.67) if biomarker-positive and 0.72 (95% CI, 0.51-1.01) if biomarker-negative (P for interaction = .09). CONCLUSIONS In NSTE ACS, an invasive strategy has a comparable benefit in men and high-risk women for reducing the composite end point of death, MI, or rehospitalization with ACS. In contrast, our data provide evidence supporting the new guideline recommendation for a conservative strategy in low-risk women.

Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial†

Aim High-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo. Objective To investigate the effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA). Design and setting A prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2–5) weeks after the last study infusion. Patients Five hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively. Intervention Patients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001. Main outcome measures The primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints. Results The nominal change in the total atheroma volume (adjusted means) was −2.71, −3.13, −1.50, and −3.05 mm3 with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, −0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was −0.022, −0.036, −0.022, and −0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was −0.51, 2.65, 0.71, and −0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups. Conclusion CER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study. Name of the trial registry: Clinicaltrials.gov; Registrys URL: http://clinicaltrials.gov/ct2/show/NCT01201837?term=cer-001&rank=2; Trial registration number: NCT01201837.

Colocalisation of intraplaque C reactive protein, complement, oxidised low density lipoprotein, and macrophages in stable and unstable angina and acute myocardial infarction

Background: C reactive protein (CRP), an important serum marker of atherosclerotic vascular disease, has recently been reported to be active inside human atherosclerotic plaques. Aims: To investigate the simultaneous presence of macrophages, CRP, membrane attack complex C5b–9 (MAC), and oxidised low density lipoprotein (oxLDL) in atherectomy specimens from patients with different coronary syndromes. Methods: In total, 54 patients with stable angina (SA; n = 21), unstable angina (UA; n = 15), and myocardial infarction (MI; n = 18) underwent directional coronary atherectomy for coronary lesions. Cryostat sections of atherosclerotic plaques were immunohistochemically stained with monoclonal antibodies: anti-CD68 (macrophages), anti-5G4 (CRP), aE11 (MAC), and 12E7 (oxLDL). Immunopositive areas were evaluated in relation to fibrous and neointima tissues, atheroma, and media. Quantitative analysis was performed using image cytometry with systematic random sampling (percentage immunopositive/total tissue area). Results: Macrophages, CRP, MAC, and oxLDL were simultaneously present in a higher proportion of fibrous tissue and atheroma of atherectomy specimens from patients with UA and MI compared with SA (p<0.05). Quantitative analysis showed significantly higher mean percentages of macrophages in plaques from patients with MI (44%) than UA (30%; p<0.01) and SA (20%; p<0.001). Significantly higher mean percentages of CRP were also seen in MI (25%) and UA (25%) compared with SA (12%; p<0.05). Conclusions: The presence of CRP, complement, and oxLDL in a high proportion of plaque tissue from patients with unstable coronary artery disease implies that these surrogate markers have important proinflammatory effects inside atherosclerotic plaques. This may increase vulnerability to plaque rupture and thrombosis, with subsequent clinical sequelae.

Prognostic value of troponin T, myoglobin, and CK-MB mass in patients presenting with chest pain without acute myocardial infarction.

OBJECTIVE: To assess the prognostic value of minor myocardial damage in patients presenting with chest pain without myocardial infarction. DESIGN: The relative risk of suffering a cardiac event in the next six months was assessed in patients with minor myocardial damage assessed by the cardiac markers CK-MB, myoglobin, and troponin T. SETTING: Emergency department of a large university hospital. PATIENTS: In 128 consecutive patients with chest pain, acute myocardial infarction (by WHO criteria) was ruled out; of these, 39 had a rise and fall of one or more markers, indicating minor myocardial damage. The presence of a documented history of coronary artery disease was assessed on admission. RESULTS: 24 patients had a subsequent event (cardiac death, acute myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting) in the next six months. An abnormal troponin T predicted a subsequent event while abnormal CK-MB or myoglobin did not. The relative risk for troponin T was 2.8 (95% confidence interval: 1.0 to 7.9), for myoglobin 1.0 (0.3 to 3.2), and for CK-MB 0.9 (0.2 to 3.4). A documented history of coronary artery disease predicted subsequent events with a relative risk of 3.9 (1.3 to 11.3). CONCLUSIONS: Troponin T was the only marker that predicted future events, but a documented history of coronary artery disease was the best predictor in patients in whom an acute myocardial infarction had been ruled out.

Safety of low dose heparin in elective coronary angioplasty.

OBJECTIVES: To evaluate the safety of a low dose of heparin in consecutive stable patients undergoing elective percutaneous transluminal coronary angioplasty (PTCA). DESIGN: Open prospective study in a single centre. PATIENTS: 1375 consecutive patients had elective PTCA (1952 lesions: type A 11%, B1 34%, B2 36%, and C 19%). There were no angiographic exclusion criteria. INTERVENTIONS: A bolus of 5000 IU heparin was used as the standard anticoagulation regimen during PTCA. The sheaths were removed immediately after successful completion of the procedure. Prolongation of heparin treatment was left to the operators discretion. MAIN OUTCOME MEASURES: Procedural success was defined as < 50% residual stenosis without death from any cause, acute myocardial infarction, urgent coronary bypass surgery, or repeat angioplasty within 48 hours for acute recurrent ischaemia; the need for prolonged heparinisation; and the occurrence of puncture site complications. RESULTS: Procedural success without clinical events was achieved in 90% of patients. Mortality was 0.3%; coronary bypass surgery was performed in 1.7% of the procedures. The rate of myocardial infarction was 3.3%; repeat angioplasty within 48 hours was carried out in 0.7% of patients. A total of 89.1% of the patients were treated according to the protocol. Prolonged treatment with heparin was considered necessary in 123 patients (8.9%). Repeat angioplasty for abrupt closure was performed in two patients shortly after sheath removal and in two during prolonged heparinisation. Puncture site complications occurred in 2.1% of patients (low dose heparin 1.9% and prolonged heparinisation 4.9%). CONCLUSION: Elective PTCA can be safely performed using a low dose of heparin, with a negligible risk for subacute closure. Low dose heparin may reduce the incidence of puncture site complications, shorten hospitalisation, and enable out-patient angioplasty.

Pharmacological Modulation of the Human Collateral Vascular Resistance in Acute and Chronic Coronary Occlusion Assessed by Intracoronary Blood Flow Velocity Analysis in an Angioplasty Model

BACKGROUND The pharmacological responsiveness of the coronary collateral circulation in humans has been studied only by indirect means. METHODS AND RESULTS Patients with one-vessel disease and recruitable (n = 14) or spontaneously visible (n = 24) collateral vessels were studied during coronary angioplasty. Collateral flow in the recipient coronary artery was determined with a 0.014-in Doppler guide wire during balloon coronary occlusion and expressed as the diastolic blood flow velocity integral (dVi). Collateral blood flow velocity, mean aortic pressure (Pao), and coronary wedge pressure (Pw) were used to calculate the collateral vascular resistance index: Rcoll = (Pao-Pw)/ dVi (mm Hg/cm) and the peripheral vascular resistance index of the recipient coronary artery: R4 = Pw/dVi (mm Hg/cm). Adenosine (12 to 18 micrograms) and nitroglycerin (0.2 mg) were injected as a bolus in the donor coronary artery during subsequent balloon inflations to assess their effect on these hemodynamic variables. The administration of adenosine or nitroglycerin in patients with recruitable collateral vessels did not induce a change in dVi and Pw/Pao ratio. In patients with spontaneously visible collateral vessels, dVi increased from 8.0 +/- 4.5 to 10.8 +/- 8.0 cm (P = .01) after adenosine and from 7.4 +/- 4.5 to 10.3 +/- 6.9 cm (P = .003) after nitroglycerin. The Pw/Pao ratio remained unchanged after adenosine and nitroglycerin. Rcoll decreased from 10.3 +/- 9.5 to 8.6 +/- 8.5 mm Hg/cm (P = .01) after adenosine and from 11.6 +/- 10.4 to 8.3 +/- 8.9 mm Hg/cm (P < .001) after nitroglycerin. R4 decreased from 7.7 +/- 5.5 to 5.9 +/- 5.1 mm Hg/cm (P < .001) after adenosine and from 8.4 +/- 6.6 to 7.1 +/- 7.2 mm Hg/cm (P = .01) after nitroglycerin. CONCLUSIONS Coronary collateral blood flow can be increased with adenosine and nitroglycerin in patients with one-vessel disease and spontaneously visible collateral vessels, which is in contrast to patients with recruitable collateral vessels. This effect is the result of a reduction in the collateral vascular resistance and peripheral vascular resistance of the recipient coronary artery.

Coronary atherosclerosis within a myocardial bridge, not a benign condition

In patients with myocardial bridging, the area within the bridge usually remains free from atherosclerotic disease. The case of a 47 year old man is described who had the rare combination of myocardial bridging with an atherosclerotic plaque within the area of bridging, which was detected with intravascular ultrasound but not with coronary angiography. The clinical history of the patient demonstrates that this is not a benign condition. In symptomatic patients the bridged segment should be screened for the presence of plaque with intracoronary ultrasound.

Persistent precordial “hyperacute” T-waves signify proximal left anterior descending artery occlusion

Objective: To describe patients with a distinct electrocardiogram (ECG) pattern without ST-segment elevation in the presence of an acute occlusion of the proximal left anterior descending (LAD) artery. Design: Single-centre observational study. Patients: Patients with acute anterior wall myocardial infarction who were referred for primary percutaneous coronary intervention (PCI) between 1998 and 2008. Results: We identified patients with a static, distinct ECG pattern without ST-segment elevation and an occlusion of the proximal LAD artery during urgent coronary angiography before PCI. Of 1890 patients who underwent primary PCI of the LAD artery, we could identify 35 patients (2%) with this distinct ECG pattern. The ECG showed ST-segment depression at the J-point of at least 1 mm in precordial leads with upsloping ST-segments continuing into tall, symmetrical T-waves. Patients with this distinct ECG pattern were younger, more often male and more often had hypercholesterolaemia compared to patients with anterior myocardial infarction and ST-segment elevation. Conclusions: In patients presenting with chest pain, ST-segment depression at the J-point with upsloping ST-segments and tall, symmetrical T-waves in the precordial leads of the 12-lead ECG signifies proximal LAD artery occlusion. It is important for cardiologists and emergency care physicians to recognise this distinct ECG pattern, so they can triage such patients for immediate reperfusion therapy.

Triage of patients for short term observation after elective coronary angioplasty

OBJECTIVE To evaluate triage of patients for short term observation after elective percutaneous transluminal coronary angioplasty (PTCA), as appropriate selection of patients for short term observation after angioplasty may facilitate early discharge. METHODS 1015 consecutive patients scheduled for elective PTCA were prospectively included for short term observation. Patients with unstable angina Braunwald class III were excluded. There were no angiographic exclusion criteria. Patients were discharged from the interventional centre when considered stable during 4 hours of observation after PTCA. It was left to the operators discretion whether to prolong the observation period. Procedural complications were defined as death, coronary bypass surgery, early repeat PTCA, and myocardial infarction. OUTCOME MEASURES The need for prolonged observation (> 4 hours) and the occurrence of complications. Predictors for prolonged observation and the occurrence of complications after the 4 hours observation were assessed by univariate and multivariate analysis. RESULTS Two patients died, including one of six patients who underwent emergency bypass surgery. In all, 922 patients (90.8%) were triaged to short term observation and had an uncomplicated three day follow up. Observation was prolonged in 87 patients (8.6%), and 40 patients had a complicated course. Independent predictors of procedural complications were acute closure (odds ratio (OR) 9.7; 95% confidence interval 4.4 to 21.4), side branch occlusion (OR 8.9; 3.4 to 23.7), no angiographic success (OR 5.1; 2.4 to 11.0), female sex (OR 3.1, 1.7 to 5.7), any unplanned stent (OR 2.8, 1.4 to 5.9), and ostial lesion (OR 2.2, 1.0 to 4.7). CONCLUSIONS A 4 hour observation period is safe after elective coronary angioplasty. As procedural variables are the strongest predictors of postprocedural complications, the immediate procedural results allow effective triage of patients for short term or prolonged observation in order to anticipate complications.

Two hour ambulation after coronary angioplasty and stenting with 6 F guiding catheters and low dose heparin

Objective To evaluate the feasibility and safety of ambulation of patients two hours after elective coronary angioplasty or stenting, or both. Methods Coronary angioplasty and stenting were performed using 6 F guiding catheters by the femoral approach and a standard dose of heparin 5000 IU. There were no angiographic exclusion criteria except for planned atherectomy. Patients given oral anticoagulants or heparin were not eligible. All patients were given aspirin. Patients who underwent stent implantation also received ticlopidine 250 mg daily. The arterial sheath was removed immediately after the procedure. Haemostasis was achieved by manual compression and maintained with an inguinal compression bandage. Early ambulation was attempted after two hours of supine bed rest following removal of the bandage. Main outcome measures The incidence of bleeding at or during ambulation requiring compression and additional bed rest, and puncture site complications documented 48 hours after the procedure. Results 300 of 359 consecutive eligible patients were included for two hour ambulation. Stent implantation was performed in 32% of the procedures. The mean (SD) time to haemostasis was 9.6 (3.2) minutes. Bleeding at ambulation occurred in five patients (1.7%), and nine patients (3.0%) reached the secondary end point of haematoma > 5 × 5 cm at 48 hour follow up. All were treated conservatively without further sequelae. There was no late bleeding or vascular complications. Conclusion Ambulation two hours after elective balloon angioplasty or stent implantation with 6 F guiding catheters by the femoral route and low dose heparin is feasible and safe, with a low incidence of puncture site complications. This early ambulation protocol facilitates a short hospital stay.