Can osteoprotegerin be used to identify the presence and severity of coronary artery disease in different clinical settings?

PURPOSE: The biomarker Osteoprotegerin (OPG) is associated with coronary artery disease (CAD). The main purpose of this study was to evaluate the diagnostic value of OPG in healthy subjects and in patients with suspected angina pectoris (AP). METHODS: A total of 1805 persons were enrolled: 1152 healthy subjects and 493 patients with suspected AP. For comparison 160 patients with acute myocardial infarction (MI) were included. To uncover subclinical coronary atherosclerosis, a non-contrast cardiac-CT scan was performed in healthy subjects; while in patients with suspected AP a contrast coronary angiography was used to detect significant stenosis. OPG concentrations were analyzed and compared between groups. ROC-analyses were performed to estimate OPG cut-off values. RESULTS: OPG concentrations increased according to disease severity with the highest levels found in patients with acute MI. No significant difference (p = 0.97) in OPG concentrations was observed between subgroups of healthy subjects according to severity of coronary calcifications. A significant difference (p < 0.0001) in OPG concentrations was found between subgroups of patients with suspected stable AP according to severity of CAD. ROC-analysis showed an AUC of 0.62 (95% CI: 0.57-0.67). The optimal cut-off value of OPG (<2.29 ng/mL) had a sensitivity of 56.2% (95% CI: 49.2-63.0%) and a specificity of 62.9% (95% CI: 57.3-68.2%). CONCLUSION: OPG cannot be used to differentiate between healthy subjects with low versus high levels of coronary calcifications. In patients with suspected AP a single OPG measurement is of limited use in the diagnosis of CAD.

Optimal cut-off value for cardiac troponin I in ruling out Type 5 myocardial infarction.

OBJECTIVES: The clinical classification of myocardial infarction (MI) into five types was introduced in 2007 as a component of the universal definition. A Type 5 MI was defined as a MI related to coronary artery bypass surgery. In a setting of patients undergoing elective coronary artery bypass grafting, we set out (i) to describe the pattern of multiple serial cardiac troponin I (cTnI) measurements within 72 h postoperatively and (ii) to determine the optimal cardiac troponin I cut-off value in ruling in or ruling out a Type 5 MI. METHODS: In 2011-2012, patients with two- and three-vessel disease scheduled for elective on-pump coronary artery bypass grafting were considered. Samples for cTnI were drawn before and 0, 2, 4, 6, 12, 24, 48 and 72 h after surgery. Analysis for cardiac troponin I was performed by use of the Abbott Architect c16000 system with an upper reference limit (URL) of 30 ng/l. The diagnosis of a Type 5 MI was prospectively made by a consultant cardiologist and was based on clinical, electrocardiographic and imaging data together with routine sampling and measurements of cTnI, but without knowledge of the results of serial study cTnI measurements. RESULTS: Of the 141 eligible patients, 99 (70%) qualified for final enrollment. In 8 patients (8%), the clinical diagnosis of a Type 5 MI was made. Patients without Type 5 MI (n = 91) had a median cTnI peak value of 7675 ng/l compared with 20 500 ng/l in Type 5 MI patients (P = 0.01). By use of receiver operating characteristic curves, optimal cut-off values for identifying Type 5 MI were defined as 7970 ng/l (corresponding to 266 times the URL) 12 h postoperatively and 9950 ng/l (corresponding to 331 times the URL) 24 h postoperatively. These cut-off values resulted in negative predictive values of 0.99 (12 h) and 0.99 (24 h). Positive predictive values were 0.23 (12 h) and 0.35 (24 h). CONCLUSIONS: In clinically stable patients undergoing elective coronary artery bypass grafting, measurements of cTnI are useful in ruling out a Type 5 MI.

Mortality rate in type 2 myocardial infarction: observations from an unselected hospital cohort.

BACKGROUND: The classification of myocardial infarction into 5 types was introduced in 2007. The prognostic impact of this universal definition, with particular focus on type 2 myocardial infarction, has not been studied prospectively in unselected hospital patients. METHODS: During a 1-year period, all hospitalized patients having cardiac troponin I measured were considered. The diagnosis of a myocardial infarction was according to the universal definition, and specified criteria were used in the classification of type 2 myocardial infarction. Follow-up was at least 1 year, with mortality as the end point. RESULTS: A total of 3762 consecutive patients were studied, of whom 488 (13%) had a myocardial infarction. In 119 patients a type 2 myocardial infarction was diagnosed. After a median of 2.1 years (interquartile range, 1.6-2.5 years), 150 patients had died, with a mortality rate of 49% (58/119) in those with type 2 myocardial infarction and 26% (92/360) in those with type 1 myocardial infarction (P < .0001). In a multivariable Cox regression analysis the following variables were independently associated with mortality: current or prior smoker, high age, prior myocardial infarction, type 2 myocardial infarction, hypercholesterolemia, high p-creatinine, and diabetes mellitus. The multivariable-adjusted hazard ratio for type 2 myocardial infarction was 2.0 (95% confidence interval, 1.3-3.0). With shock as the only exception, mortality was independent of the triggering conditions leading to type 2 myocardial infarction. CONCLUSIONS: Mortality in patients with type 2 myocardial infarction is high, reaching approximately 50% after 2 years. Further descriptive and survival studies are needed to improve the scientific evidence on which treatment of type 2 myocardial infarction is based.

Localization of microfibrillar-associated protein 4 (MFAP4) in human tissues: clinical evaluation of serum MFAP4 and its association with various cardiovascular conditions.

Microfibrillar-associated protein 4 (MFAP4) is located in the extracellular matrix (ECM). We sought to identify tissues with high levels of MFAP4 mRNA and MFAP4 protein expression. Moreover, we aimed to evaluate the significance of MFAP4 as a marker of cardiovascular disease (CVD) and to correlate MFAP4 with other known ECM markers, such as fibulin-1, osteoprotegerin (OPG), and osteopontin (OPN). Quantitative real-time PCR demonstrated that MFAP4 mRNA was more highly expressed in the heart, lung, and intestine than in other elastic tissues. Immunohistochemical studies demonstrated high levels of MFAP4 protein mainly at sites rich in elastic fibers and within blood vessels in all tissues investigated. The AlphaLISA technique was used to determine serum MFAP4 levels in a clinical cohort of 172 patients consisting of 5 matched groups with varying degrees of CVD: 1: patients with ST elevation myocardial infarction (STEMI), 2: patients with non-STEMI, 3: patients destined for vascular surgery because of various atherosclerotic diseases (stable atherosclerotic disease), 4: apparently healthy individuals with documented coronary artery calcification (CAC-positive), and 5: apparently healthy individuals without signs of coronary artery calcification (CAC-negative). Serum MFAP4 levels were significantly lower in patients with stable atherosclerotic disease than CAC-negative individuals (p<0.05). Furthermore, lower serum MFAP4 levels were present in patients with stable atherosclerotic disease compared with STEMI and non-STEMI patients (p<0.05). In patients with stable atherosclerotic disease, positive correlations between MFAP4 and both fibulin-1 (ρ = 0.50; p = 0.0244) and OPG (ρ = 0.62; p = 0.0014) were found. Together, these results indicate that MFAP4 is mainly located in elastic fibers and is highly expressed in blood vessels. The present study suggests that serum MFAP4 varies in groups of patients with different cardiovascular conditions. Further studies are warranted to describe the role of serum MFAP4 as a biomarker of stable atherosclerotic disease.

Classification of myocardial infarction: frequency and features of type 2 myocardial infarction.

BACKGROUND: The classification of myocardial infarction into 5 types was introduced in 2007 as an important component of the universal definition. In contrast to the plaque rupture-related type 1 myocardial infarction, type 2 myocardial infarction is considered to be caused by an imbalance between demand and supply of oxygen in the myocardium. However, no specific criteria for type 2 myocardial infarction have been established. METHODS: We prospectively studied unselected hospital patients who had cardiac troponin I measured on clinical indication. The diagnosis and classification of myocardial infarction were established, and the frequency and features of type 2 myocardial infarction were investigated by use of novel developed criteria. RESULTS: From January 2010 to January 2011, a total of 7230 consecutive patients who had cardiac troponin I measured were evaluated, and 4499 patients qualified for inclusion. The diagnosis of myocardial infarction was established in 553 patients, of whom 386 (72%) had a type 1 myocardial infarction and 144 (26%) had a type 2 myocardial infarction. Patients in the group with type 2 myocardial infarction were older and more likely to be female, and had more comorbidities. The proportion of patients without significant coronary artery disease was higher in those with type 2 myocardial infarction (45%) than in those with type 1 myocardial infarction (12%) (P < .001). Tachyarrhythmias, anemia, and respiratory failure were the most prevalent mechanisms causing type 2 myocardial infarction. CONCLUSIONS: In a cohort of patients with myocardial infarction who were admitted consecutively through 1 year, the category of type 2 myocardial infarction comprised one fourth when diagnosed by the use of newly developed criteria. Approximately half of patients with type 2 myocardial infarction had no significant coronary artery disease.

Osteoprotegerin as a marker of atherosclerosis: a systematic update.

OBJECTIVE: Osteoprotegerin (OPG) may be involved in development of atherosclerosis. To evaluate plasma concentrations of OPG in individuals with stable coronary artery disease (CAD), acute coronary syndrome (ACS), peripheral artery disease (PAD), and cerebrovascular disease (CBVD) a systematic literature review was performed. DESIGN AND METHODS: Studies investigating OPG concentrations in stable CAD, ACS, PAD, and CBVD were extracted from PubMed and the Cochrane Library, retrieving 280 articles. Nonrelevant articles were excluded and after thorough evaluation, and only 14 studies with clearly defined cohorts qualified for this review. RESULTS: In 11 studies, OPG concentrations were elevated. Severity of atherosclerosis was significantly associated with higher OPG concentrations compared to healthy controls. No association between PAD and OPG concentrations was observed. CONCLUSION: OPG concentrations are associated with the presence and severity of stable CAD, ACS, and CBVD. Larger studies are needed to reach conclusions concerning OPG concentrations in PAD. Studies addressing a putative role for OPG in suspected CAD and CBVD are warranted.

Effect of exercise on platelet activation during aspirin or clopidogrel intake in healthy men.

Sudden strenuous exercise increases the risk of ischemic cardiac events in patients with coronary artery disease. The exact mechanism behind this observation is unknown, but platelet activation induced by exercise may be of importance. We hypothesized that brief strenuous exercise would activate platelets in healthy men, assessed by the Platelet Function Analyzer 100 and light transmittance aggregometry. Nearly all participants exhibited increased platelet reactivity after exercise measured by the Platelet Function Analyzer 100, whereas only minor changes were detected by light transmittance aggregometry. A significant increase in plasma von Willebrand Factor was also found in response to exercise. In conclusion, platelet activation occurs during exercise in healthy individuals. This activation is not prevented by use of aspirin or clopidogrel, and may partly be explained by an increase in plasma von Willebrand Factor.

[In-hospital resuscitation with automated external defibrilliator]. / Genoplivning med automatisk ekstern defibrillator på hospital.

Early defibrillation is a determinant of survival in cardiac arrest. We report a Danish case of successful in-hospital resuscitation using an automated external defibrillator (AED). This case illustrates important aspects of implementation of in-hospital use of an AED, i.e. location of the AED, education of the staff, systematic registration and data collection and technical aspects of AED use. If in-hospital AED implementation is carefully executed, its use may provide a safe and effective way of obtaining early defibrillation.

Lack of consensus in biomarker measurement to diagnose PCI-related myocardial infarction.

OBJECTIVE: To evaluate if biomarker sampling in PCI has adhered to the 2 000 consensus document for the diagnosis of procedure-related myocardial infarction (MI). DESIGN: Firstly, a review of relevant papers from 2000 to September 2007 was done. Secondly, in October 2007, a questionnaire addressing biomarker sampling in routine PCI was sent to Danish PCI centres. RESULTS: Fourteen papers fulfilled the selection criteria. In six studies serial sampling according to the consensus document had been done. Biomarker measuring before PCI was not performed in four studies. All centres answered the questionnaire. In none of six centres the proposed 3-sample testing of biomarkers had been followed. A pre-PCI sample was taken in one centre. In approximately half of the centres biomarkers were only measured on clinical indication. CONCLUSION: Biomarker sampling for procedure-related MI according to the 2 000 consensus document has not been universally adapted. In order to avoid hampering of epidemiologic data and the comparison of future clinical trials it is proposed that the 2007 MI re-definition consensus document will be rapidly and universally accepted.

Monitoring aspirin therapy with the Platelet Function Analyzer-100.

OBJECTIVE: Low platelet response to aspirin has been reported to be associated with a high incidence of vascular events. The reported prevalence of aspirin low-responsiveness varies, which may be explained by poor reproducibility of the methods used to evaluate aspirin response and low compliance. The Platelet Function Analyzer-100 (PFA-100) is a commonly used platelet function test. We aimed to assess the reproducibility of the PFA-100 and the agreement with optical platelet aggregometry (OPA) in healthy volunteers and in patients with coronary artery disease (CAD) treated with low-dose aspirin. MATERIAL AND METHODS: Twenty-one healthy volunteers and 43 patients with CAD took part in the study. During treatment with aspirin 75 mg daily, all participants had platelet function assessed in duplicate with the PFA-100 and OPA on 4 consecutive days. Additionally, platelet function was assessed before aspirin treatment in healthy subjects. Serum-thromboxane B(2) (S-TxB(2)) was measured to assess compliance. RESULTS: In healthy volunteers not receiving aspirin, duplicate measurements resulted in coefficients of variation (CV) of 7.9 % for the PFA-100 and 5.2 % for OPA. During aspirin treatment, CVs were significantly higher (healthy volunteers: PFA-100: 15.6 %, OPA: 19.2 %; patients: PFA-100: 26.6 %, OPA: 16.8 %). Two of the 64 participants were classified as aspirin low-responders with both methods, indicating poor agreement (Kappa coefficient 0.05). Compliance was excellent, as S-TxB(2) was completely inhibited in all participants. CONCLUSIONS: Aspirin treatment affects the reproducibility of both PFA-100 and OPA. This imprecision should be considered carefully if the methods are used for monitoring aspirin treatment. Additionally, these methods do not identify the same individuals as being aspirin low-responders.

[Antithrombotic therapy in ischemic stroke and transient ischemic attack]. / Antitrombotisk behandling ved iskaemisk apopleksi og transitorisk cerebral iskaemi.

In acute ischemic stroke and transient ischemic attack (TIA), aspirin is recommended to all patients (except immediately following thrombolysis). Heparin and anticoagulant therapy using vitamin K antagonists should be avoided in the acute phase. Secondary preventive antithrombotic treatment includes anticoagulation in patients with cardioembolic stroke and antiplatelet agents aspirin possibly combined with dipyridamole or clopidogrel alone in patients with non-cardioembolic stroke. Other individual risks may modify this treatment regimen.

Prevalence of aspirin resistance in patients with an evolving acute myocardial infarction.

OBJECTIVE: To study the prevalence and importance of aspirin resistance in patients with an evolving acute myocardial infarction (AMI) by use of the Platelet Function Analyzer-100. INTRODUCTION: Previous studies have demonstrated the existence of aspirin resistance, but the clinical relevance of the phenomenon remains to be clarified. If aspirin resistant patients comprise a high-risk subgroup, it might be expected that the prevalence of aspirin resistance in patients with AMI would be higher than in patients without AMI. We hypothesized that the prevalence of aspirin resistance in patients with AMI was twice the prevalence in patients without AMI. METHODS: We included 298 consecutive patients with known cardiovascular disease who were admitted to hospital with symptoms suggestive of an AMI. All had been taking aspirin 150 mg/day for at least 7 days prior to hospital admission. Platelet function was measured immediately at admission, and aspirin resistance was defined as a collagen/epinephrine Closure Time (CT(CEPI))<165 s. RESULTS: We found that 70 (23.5%) patients were aspirin resistant, and 70 (23.5%) patients ended up with the diagnosis of an AMI. The prevalence of aspirin resistance was significantly higher in patients with AMI as compared to patients without (36% versus 20%, OR 2.26, CI 95% 1.19-4.22, p=0.0058). The CT(CEPI) measured at admission was an independent factor associated with an AMI. CONCLUSIONS: Aspirin resistance is present in almost one fourth of patients admitted to hospital with symptoms suggestive of an AMI, and aspirin resistance is significantly associated with the diagnosis of a definite AMI.

Using the Platelet Function Analyzer-100 for monitoring aspirin therapy.

INTRODUCTION: The aim of the study was to evaluate the test characteristics of the Platelet Function Analyzer-100 (PFA-100) in patients treated with aspirin. METHODS AND RESULTS: The study consisted of two sub-studies. In study 1, 10 patients with ischemic heart disease (IHD) and 10 controls had platelet function assessed by optical platelet aggregation and the PFA-100 method in two 5-week periods. Patients with IHD were treated with aspirin 150 mg/day (first 5-week period), and 300 mg/day (second 5-week period), whereas the controls only received aspirin (150 mg/day) during the second 5-week period. From the results of study 1, we found that a cut-off value for the PFA-100 collagen/epinephrine cartridge <165 s identified patients not taking aspirin (sensitivity 0.91, specificity 1.00). A good agreement between the PFA-100 method and optical platelet aggregation was found. Within-subject variation for the PFA-100 collagen/epinephrine cartridge was +/-28%, as compared to +/-17% for the optical platelet aggregation. Study 2 included 298 aspirin treated patients who were admitted with symptoms suggestive of an acute myocardial infarction. Platelet function was assessed in duplicate by the PFA-100 collagen/epinephrine cartridge, and a 95% Limit of Agreement interval at [-65%, 65%] indicated a limited precision. CONCLUSION: We defined a cut-off value below which patients not taking aspirin can be identified. However, due to imprecision of the PFA-100 method repeated duplicate assessment of the collagen/epinephrine Closure Time is recommended.

Variation and importance of aspirin resistance in patients with known cardiovascular disease.

AIM: To investigate whether aspirin resistance is a persistent condition, and to evaluate if aspirin resistance affects one-year clinical outcome. METHODS AND RESULTS: Previously we studied 298 patients admitted to hospital with symptoms suggestive of an acute myocardial infarction (MI) despite treatment with aspirin, and 70 patients (23.5%) were aspirin resistant. In the present study, platelet function was reassessed by use of a Platelet Function Analyzer-100 one year later. A total of 187 patients were re-examined, and 17 (9.1%) demonstrated aspirin resistance. Of these 17 patients, 12 also exhibited aspirin resistance at baseline resulting in a 6% (12/187) prevalence of persistent aspirin resistance. A total of 34 patients had changed from aspirin resistant at baseline to aspirin sensitive at follow-up. We found a significant decrease in the prevalence of aspirin resistance from baseline (43%) to follow-up (11%) in patients with MI at baseline (p=0.0018). Furthermore, a significant decrease was found for patients without MI at baseline (20% to 9%, p=0.0009). During follow-up, 17% (12/70) of the patients with aspirin resistance at baseline suffered death, MI or stroke compared to 16% (37/227) of aspirin sensitive patients (p=0.868). CONCLUSION: The prevalence of aspirin resistance varies with the clinical status of the patients, and indeed an acute MI is associated with temporary aspirin resistance. We also found that 6% of patients demonstrate persistent aspirin resistance. The presence of aspirin resistance did not affect one-year clinical outcome.

[Bleeding complications after treatment with clopidogrel and acetylsalicylic acid after acute coronary syndrome]. / Blødningskomplikationer ved behandling med clopidogrel og acetylsalicylsyre efter akut koronart syndrom.

INTRODUCTION: The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study showed that patients with unstable angina pectoris (UAP) and non-ST-elevation myocardial infarction (NSTEMI) benefit from combined therapy with acetylsalicylic acid (ASA) and clopidogrel. However, only patients entering clinical randomized trials were studied. We sought to assess whether the risk of bleeding increased after the introduction of the CURE criteria in an unselected population of Danish patients with NSTEMI or UAP. MATERIALS AND METHODS: The CURE criteria were implemented in the Department of Cardiology, Odense University Hospital, in December 2001. Two consecutive one-year periods were studied: period 1, December 2000-November 2001, and period 2, December 2001-November 2002. Patient charts were reviewed, and major bleeding complications and the primary clinical end point (non-fatal myocardial infarction, stroke or death) was registered. Follow-up took place one year later. RESULTS: In all, 290 patients were included in period 1 and 189 in period 2. During period 1, there were 12 (4.1%) and during period 2, 21 (11.1%) major bleeding events (odds ratio 3.07; 95% CI 1.42-6.65; p = 0.005). Compared with the patients treated with clopidogrel and ASA in the CURE study, we also found a three times greater risk of major bleeding in period 2. In particular, patients over 70 years of age and patients undergoing bypass surgery were at heightened risk. The incidence of the primary clinical end point was higher in both period 1 and period 2 than in the CURE study. CONCLUSION: Our study demonstrates an increased risk of major bleeding in unselected patients receiving combination therapy with ASA and clopidogrel after UAP or NSTEMI. Major bleeding complications most frequently occur in patients above 70 years of age and following bypass surgery.

[Coronary angioplasty and coronary artery bypass surgery in older patients. Incidence, complications and mortality, 1999-2003]. / Ballonbehandling og koronar bypasskirurgi hos aeldre. Forekomst, komplikationer og mortalitet 1999-2003.

INTRODUCTION: Persons over 70 years of age are the fastest-growing segment of the population. A major proportion of these elderly have ischemic heart disease and may need treatment. We describe the development of mechanical coronary revascularization in patients aged 70-79 years versus those 80 years of age or older over a five-year period. MATERIALS AND METHODS: During 1999, 2001 and 2003, a total of 774 patients over 70 years of age had coronary angioplasty (PCI) or coronary artery bypass surgery (CABG) performed at Odense University Hospital. The patients were separated according to type of intervention and age: 70-79 versus > or = 80 years of age. Retrospectively, descriptive characteristics, complication rates and six-month mortality rates were compiled. RESULTS: During the study period, the number of interventions increased from 182 to 374 per year. In the patients > or = 80 years of age, a tenfold increase in the number of procedures was noted, whereas the frequency in the younger patients was approximately doubled. During the five-year period, the proportion of CABGs performed was stable, but the frequency of PCIs increased by a factor of five. Over time, the number of acute interventions increased. Patients > or = 80 years of age more frequently had complications than did patients 70-79 years of age. The six-month mortality rate increased throughout the study period and was highest in patients > or = 80 years of age. CONCLUSION: During the five-year period from 1999 to 2003, the total number of coronary revascularizations in the elderly increased. The main reason for this was a marked increment in the use of PCIs and a general increase in the use of revascularizations in patients 80 years of age or older. PCI in the elderly is associated with a lower frequency of complications.

The antiplatelet effect of clopidogrel is not attenuated by statin treatment in stable patients with ischemic heart disease.

Recent studies suggest that cytochrome P450 (CYP) 3A4 metabolized statins attenuate the antiaggregatory effect of clopidogrel. We evaluated how CYP3A4 metabolized statins and non-CYP3A4 metabolized statins influence platelet aggregation when given concomitantly with clopidogrel. Sixty-six stable patients with ischemic heart disease were included in this parallel group study. All patients were on clopidogrel and aspirin. Thirty-three patients received a CYP3A4 metabolized statin (simvastatin or atorvastatin), and 33 were treated with a non-CYP3A4 metabolized statin (pravastatin). The antiplatelet effect of clopidogrel was assessed at inclusion and 21 days after statin discontinuation. Platelet function was evaluated by two methods 1) optical platelet aggregometry after stimulation with 20 and 30 microM ADP, and 2 and 4 mg/l collagen, respectively, 2) a Platelet FunctionAnalyzer-100. The primary effect measure was final platelet aggregation after stimulation with 20 microM ADP. No difference was observed between patients treated with a CYP3A4 metabolized statin and patients receiving a non-CYP3A4 metabolized statin (30% point (7-42) versus 20% point (9-32), p = 0.83). Platelet aggregation was not improved by discontinuation of statins for 21 days. Indeed, we found that statin treatment given concomitantly with clopidogrel resulted in an improved platelet inhibition when compared to clopidogrel given alone. The antiplatelet effect of clopidogrel is not attenuated by concomitant treatment with a CYP3A4 metabolized statin in patients with clinical stable ischemic heart disease.

Existence of a clinically relevant interaction between clopidogrel and HMG-CoA reductase inhibitors? Re-evaluating the evidence.

Clopidogrel is an inactive prodrug, which requires activation by the cytochrome P450 3A4 system in order to exert its antiplatelet action. Some statins (atorvastatin, lovastatin and simvastatin) also requires metabolism by the cytochrome P450 3A4 system. From a theoretical point of view, a clinical relevant interaction may exist between clopidogrel and cytochrome P450 3A4 metabolized statins. Nine studies have investigated the existence of this potential interaction. Seven studies have used results based on platelet function as surrogate endpoints and two studies have dealt with objective clinical events including mortality, acute myocardial infarction and stroke. However the studies have yielded conflicting results. This controversy is primarily caused by substantial differences in study design and methods used for assessment of the antiaggregatory effect of clopidogrel. Most studies have included too few patients, and there appears to be no consensus regarding the definition of and optimal way of measuring the platelet inhibitory effect of clopidogrel. Therefore an adequately powered prospective study, ensuring elimination of identified possible confounders and with the use of a well-defined surrogate ex vivo parameter should be performed.