J. W. Deckers

Diagnostic interpretation of electrocardiograms in population-based research : Computer program research physicians, or cardiologists?

We assessed the performance of diagnostic electrocardiogram (ECG) interpretation by the computer program MEANS and by research physicians, compared to cardiologists, in a physician-based study. To establish a strategy for ECG interpretation in health surveys, we also studied the diagnostic capacity of three scenarios: use of the computer program alone (A), computer program and cardiologist (B), and computer program, research physician, and cardiologist (C). A stratified random sample of 381 ECGs was drawn from ECGs collected in the Rotterdam Study (n = 3057), which were interpreted both by a trained research physician using a form for structured clinical evaluation and by MEANS. All ECGs were interpreted independently by two cardiologists; if they disagreed (n = 175) the ECG was judged by a third cardiologist. Five ECG diagnoses were considered: anterior and inferior myocardial infarction (MI), left and right bundle branch block (LBBB and RBBB), and left ventricular hypertrophy (LVH). Overall, sensitivities and specificities of MEANS and the research physicians were high. The sensitivity of MEANS ranged from 73.8% to 92.9% and of the research physician ranged from 71.8% to 96.9%. The specificity of MEANS ranged from 97.5% to 99.8% and of the research physician from 96.3% to 99.6%. To diagnose LVH, LBBB, and RBBB, use of the computer program alone gives satisfactory results. Preferably, all positive findings of anterior and inferior MI by the program should be verified by a cardiologist. We conclude that diagnostic ECG interpretation by computer can be very helpful in population-based research, being at least as good as ECG interpretation by a trained research physician, but much more efficient and therefore less expensive.

Efficacy of long-term anticoagulant treatment in subgroups of patients after myocardial infarction.

OBJECTIVE--To investigate the efficacy of long term oral anticoagulant treatment in subgroups of patients after myocardial infarction. DESIGN--Analysis of the effect of anticoagulant treatment in subgroups of hospital survivors of myocardial infarction based upon age, gender, history of hypertension, previous myocardial infarction, smoking habits, diabetes mellitus, Killip class, anterior location of infarction, thrombolytic therapy, and use of beta blockers. SUBJECTS--Participants of a multicentre, randomised, double blind, placebo controlled trial that assessed the effect of oral anticoagulant treatment on mortality as well as cerebrovascular and cardiovascular morbidity in 3404 hospital survivors of acute myocardial infarction. MAIN OUTCOME MEASURES--The effect of anticoagulant treatment on recurrent myocardial infarction, cerebrovascular events, and vascular events (the composite endpoint of reinfarction, cerebrovascular event, and vascular death). RESULTS--Long term anticoagulant treatment was associated with a reduction in mortality of 10% (95% confidence interval -11% to 27%), recurrent myocardial infarction of 53% (41% to 62%), cerebrovascular events of 40% (10% to 60%) and vascular events of 35% (24% to 45%). Treatment effect with respect to recurrent myocardial infarction was comparable among all subgroups of patients. Although treatment effect appeared to be somewhat smaller in females than in males (-11% v -45%), and in patients with diabetes compared to those without (-14% v -42%) with respect to vascular events, none of these differences reached statistical significance. In multivariate analysis, more advanced age, previous myocardial infarction, diabetes mellitus, and heart failure during admission were independently associated with increased incidence of cardiovascular complications. CONCLUSIONS--The relative benefit of long term anticoagulant therapy in survivors of myocardial infarction is not modified by known prognostic factors for cardiovascular disease.

Characteristics and prognosis of non-participants of a multi-centre trial of long-term anticoagulant treatment after myocardial infarction

Participants of a randomised trial may differ from eligible non-participants as a result of selection. We studied the distribution of prognostic factors and survival in eligible patients of a multi-centre trial of long-term oral anticoagulant treatment after myocardial infarction. All hospital survivors of myocardial infarction in one participating clinical centre of a multi-centre, randomised, double-blind, placebo-controlled trial of long-term anticoagulant treatment after myocardial infarction were screened for entry criteria. Subsequently, prognostic factors and survival of participants were compared with eligible but not randomised patients. The 350 participants were younger and were more often of male gender and more often smokers compared with 587 non-participants. Non-participants had more frequently suffered a previous myocardial infarction and were treated more often with diuretics and ACE-inhibitors, suggesting a higher proportion of patients with chronic heart failure in this group. Age, previous myocardial infarction and the use of diuretics at discharge were independent predictors of mortality, consent showed no association. Our findings indicate that participants of a clinical trial have a better prognosis during the first years following myocardial infarction compared to eligible non-participants as a result of a higher prevalence of cardiovascular risk factors associated with mortality in the non-participants.

Frequency of the von Willebrand factor Tyr1584Cys polymorphism in arterial thrombosis

A recent review on von Willebrand factor (VWF) proteolysis (Bowen & Collins, 2006) extensively discussed the Tyr1584Cys polymorphism. The Tyr1584Cys polymorphism, located in exon 28 of the VWF gene (VWF), is associated with an increased proteolysis of VWF by ADAMTS13. A strongly increased frequency of this polymorphism was first reported in Canadian patients with Von Willebrand Disease type 1 (O’Brien et al, 2003). A functional study then reported an increased proteolysis of VWF in heterozygotes (Bowen et al, 2005). As VWF is essential in clot formation it is expected that decreased proteolysis of VWF would increase the risk of thrombosis. Upon endothelial activation, ultra large VWF is released from Weibel-Palade bodies into the circulation, where it binds platelets, which can then form aggregates. In the circulation VWF is vulnerable to proteolysis by ADAMTS13. The proteolysis cleaves the ultra large multimers in smaller, less active multimers, resulting in decreased platelet aggregation and thereby in a decreased thrombus growth. In coronary heart disease high levels of VWF are associated with an increased risk of arterial thrombosis (Jansson et al, 1991). We recently confirmed the association between levels of VWF antigen and activity and risk for ischemic stroke (Bongers et al, 2006). It has not yet been studied whether the Tyr1584Cys polymorphism is associated with the risk of arterial thrombosis. Therefore we investigated the Tyr1584Cys polymorphism in two different case-control studies in patients with well-documented arterial thrombosis. The first study, the COCOS-study, has been described in detail previously (Leebeek et al, 2005). Briefly, this study comprised 124 patients with a first-ever ischemic stroke and 125 controls without a history of stroke with an age range between 18–75 years. The second study, the ATTAC-study, was a case-control study that comprised 374 young patients (males £ 45 years and females £ 55 years) with a first-ever arterial thrombotic event, including unstable angina pectoris, acute myocardial infarction, transient ischemic attack, ischemic stroke or peripheral arterial disease and 332 young population controls without a cardiovascular event (unpublished observations). The Tyr1584Cys polymorphism in VWF results from an A/G Single Nucleotide Polymorphism at 24/1282 (rs1800386). The relevant region of exon 28 was amplified by polymerase chain reaction (PCR), using the forward primers: 5-’AAGCCGGATTAGAACC-’3 and reverse primer: 5’-AACTCCATGGTTGTGGAT-’3. The primers contain three mismatches to avoid amplifying the VWF pseudogene. The PCR comprised 95 C for 4 min followed by 35 cycles of 94 C for 30 s, 65 C for 1 min, 72 C for 1 min and finally 72 C for 4 min. The PCR product (682bp) was digested with Kpn1, which cleaves the A-allele in two fragments of 276 and 406, while the G-allele was not cleaved. The fragments were separated using 2% agarose gels and visualized using ultra violet light. The COCOS study (mean age 56 years ± 12 SD) showed similar carrier frequencies of 1584Cys carriers in cases and controls, [one patient (0.8%) and four (3.2%) controls were heterozygote, P = 0.48]. No homozygotes for the 1584Cys allele were present. In the ATTAC population (mean age 43 ± 7 years,) we observed no differences in 1584Cys carrier frequency between patients and controls [two patients (0.5%)

Pharmacodynamics and safety of lefradafiban, an oral platelet glycoprotein IIb/IIIa receptor antagonist, in patients with stable coronary artery disease undergoing elective angioplasty

OBJECTIVE Lefradafiban is the orally active prodrug of fradafiban, a glycoprotein IIb/IIIa receptor antagonist. The present phase II study aimed to determine the dose of lefradafiban that provides 80% blockade of the glycoprotein IIb/IIIa receptors by fradafiban, and to study the pharmacodynamics and safety of different doses in patients with stable angina undergoing angioplasty. DESIGN A double blind, placebo controlled, dose finding study. SETTING Four academic and community hospitals in the Netherlands. PATIENTS 64 patients with stable coronary artery disease undergoing elective percutaneous transluminal coronary angioplasty. INTERVENTIONS 30 mg, 45 mg, and 60 mg of lefradafiban three times daily or placebo was given for 48 hours. MAIN OUTCOME MEASURES The primary safety end point was the occurrence of bleeding, classified as major, minor, or insignificant according to the thrombolysis in myocardial infarction (TIMI) criteria. Efficacy indices included per cent fibrinogen receptor occupancy (FRO), ex vivo platelet aggregation, and plasma concentrations of fradafiban. RESULTS Administration of lefradafiban 30, 45, and 60 mg three times daily resulted in a dose dependent increase in median FRO levels of 71%, 85%, and 88%, respectively. Inhibition of platelet aggregation was closely related to FRO. There were no major bleeding events. The 60 mg lefradafiban group had a high (71%) incidence of minor and insignificant bleeding. The incidence of bleeding was 44% in the 30 mg and 45 mg groups, compared with 9% in placebo patients. Puncture site bleeding was the most common event. The odds of bleeding increased by 3% for every 1% increase in FRO. CONCLUSIONS Lefradafiban is an effective oral glycoprotein IIb/IIIa receptor blocker. The clinical effectiveness of doses up to 45 mg three times daily should be investigated.

Medium- and long-term outcome after coronary balloon angioplasty

E VEN THOUGH percutaneous transluminal coronary angioplasty (PTCA) was introduced 15 years ago, 1 data on the long-term follow-up of patients who have undergone the procedure remains incomplete. So far, only nonrandomized long-term studies have been published. In this review the available information on medium and long-term outcome is examined. We have analyzed the data on the intention to treat principle and, thus, have only included studies providing follow-up data of all patients who underwent balloon angioplasty, including those with unsuccessful as well as successful procedures. We sought to answer the following questions: (1) how many patients underwent successful PTCA and were symptomfree at last follow-up after attempted balloon angioplasty and (2) what was the price they had to pay in terms of major adverse cardiac events.