Background— Although most clinical trials of coronary stents have measured nominally identical safety and effectiveness end points, differences in definitions and timing of assessment have created confusion in interpretation. Methods and Results— The Academic Research Consortium is an informal collaboration between academic research organizations in the United States and Europe. Two meetings, in Washington, DC, in January 2006 and in Dublin, Ireland, in June 2006, sponsored by the Academic Research Consortium and including representatives of the US Food and Drug Administration and all device manufacturers who were working with the Food and Drug Administration on drug-eluting stent clinical trial programs, were focused on consensus end point definitions for drug-eluting stent evaluations. The effort was pursued with the objective to establish consistency among end point definitions and provide consensus recommendations. On the basis of considerations from historical legacy to key pathophysiological mechani...

Clinical End Points in Coronary Stent Trials A Case for Standardized Definitions

IN the 19th century there were two major hypotheses to explain the pathogenesis of atherosclerosis: the "incrustation" hypothesis and the "lipid" hypothesis. The incrustation hypothesis of von Rokitansky,1 proposed in 1852 and modified by Duguid,2 suggested that intimal thickening resulted from fibrin deposition, with subsequent organization by fibroblasts and secondary lipid accumulation. The lipid hypothesis, proposed by Virchow3 in 1856, suggested that lipid in the arterial wall represented a transduction of blood lipid, which subsequently formed complexes with acid mucopolysaccharides; lipid accumulated in arterial walls because mechanisms of lipid deposition predominated over those of removal. The two hypotheses are now . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199201233260406?articleTools=true

The pathogenesis of coronary artery disease and the acute coronary syndromes (1).

The nature of the pathologic lesion in sudden cardiac ischemic death is in dispute. Among 100 subjects who died of ischemic heart disease in less than six hours, coronary thrombi were found in 74. There was no difference in incidence between those who died in less than 15 minutes, those who died in 15 to 60 minutes, and those who died after one hour. Among 26 cases without an intraluminal thrombus, plaque fissuring was found in 21; thus, in only 5 cases was no acute arterial lesion demonstrated. No intraluminal thrombi were found in age-matched controls. Forty-eight of the 74 thrombi were found at sites of preexisting high-grade stenosis; 14 were found at points of previous stenosis of less than 50 per cent of the diameter of the lumen. Forty-seven per cent of the thrombi were found in the right coronary artery. Only 30 per cent were found in the left anterior descending coronary artery. The pathologic process in sudden ischemic death involves a rapidly evolving coronary-artery lesion in which plaque fissuring and resultant thrombus formation are present. These findings have implications for the prevention of sudden cardiac death by antithrombotic therapy.

Thrombosis and Acute Coronary-Artery Lesions in Sudden Cardiac Ischemic Death

The establishment of a prognosis and the approach to the treatment of many diseases is aided greatly by a logical classification. For example, classification of a wide variety of neoplasms by anatomic extent, microscopic appearance, and the presence of special markers now forms the basis for selecting appropriate therapy. In cardiology, the classification of patients with acute myocardial infarction and congestive heart failure has been of enormous value in following the progress and in selecting therapy of individual patients and in comparing the outcome of similar patients treated at different locations and at different times. The purpose of this article is to provide a classification of unstable angina. This classification is designed to facilitate communication about these patients, to aid in the decision regarding diagnostic measures and therapy of individual patients, and to provide a more precise basis for including patients in and for evaluating the outcome of clinical trials.

Unstable angina : a classification

Pathological and clinical studies have suggested that platelets have a role in the pathogenesis of unstable angina and myocardial infarction. However, the relation of platelet activation to episodic ischemia in patients with unstable angina is unknown. We assessed the biosynthesis of thromboxane and prostacyclin as indexes of platelet activation in patients with stable and unstable coronary disease by physicochemical analysis of metabolites in plasma and urine. Prostacyclin biosynthesis was markedly elevated in patients with acute myocardial infarction and correlated with plasma creatine kinase (r = 0.795; P less than 0.001). The largest rise in thromboxane synthesis was observed in patients with unstable angina, in whom 84 percent of the episodes of chest pain were associated with phasic increases in the excretion of thromboxane and prostacyclin metabolites. However, 50 percent of such increases were not associated with chest pain, possibly reflecting silent myocardial ischemia. These data indicate that platelet activation occurs during spontaneous ischemia in patients with unstable angina. The increment in prostacyclin biosynthesis during such episodes may be a compensatory response of vascular endothelium that limits the degree or effects of platelet activation. If so, biochemically selective inhibition of the synthesis or action of thromboxane A2 would be desirable in the treatment of unstable angina. In contrast, thromboxane inhibitors or antagonists would not be expected to be effective in patients with chronic stable angina, in whom there was no increase in the formation of thromboxane A2.

Platelet activation in unstable coronary disease.

Pseudoaneurysm of the ascending aorta following cardiac surgery.

Although intracoronary thrombus formation plays a major role in acute transmural myocardial infarction (MI), its occurrence in unstable angina (UA) and nontransmural MI has not clearly been established. To determine whether intracoronary thrombus does occur in these syndromes, coronary arteriography was performed before, during, and after intracoronary nitroglycerin and streptokinase infusion in 17 patients. None of the 8 patients with nontransmural MI and 1 of the 9 patients with UA responded to intracoronary nitroglycerin. Seven of 8 patients with nontransmural MI and 4 of 9 patients with UA responded to streptokinase infusion with opening of an occluded vessel, an increase in stenotic diameter, dissolution of an intracoronary filling defect, or a combination of these. Serial opening and closing of ischemia-related vessels occurred spontaneously and in response to streptokinase in some patients in whom thrombolysis was demonstrated. Evidence of thrombolysis was not seen in any patient studied longer than 1 week from the onset of the rest pain syndrome. The finding of thrombolysis in several patients with nontransmural MI and UA suggests that intracoronary thrombus formation plays a pathogenetic role in some patients with these ischemic syndromes.

Intracoronary thrombus in nontransmural myocardial infarction and in unstable angina pectoris

Recent studies have shown that pain at rest in patients with unstable angina pectoris is often caused by transient reduction in regional myocardial perfusion. Coronary spasm has been implicated as a mechanism of this phenomenon. Recent reports have documented the occurrence of intracoronary thrombus in patients with unstable angina. Previous surveys have estimated a 6 to 12% frequency of intracoronary thrombus in this syndrome, but have not examined whether this incidence is related to how recent the angina at rest was. Angiograms of 119 patients with unstable angina who had rest pain within 14 days of angiography and 35 patients with stable angina were surveyed. Patients with unstable angina were subgrouped according to how recent angina at rest was at the time of angiography. Group I consisted of 44 patients in whom rest pain occurred within 24 hours before angiography. The 75 patients in group II had angina at rest between 1 and 14 days before angiography. Patients in group II had stable angina. The angiographic criterion for intracoronary thrombus was an intraluminal filling defect, surrounded by contrast medium on 3 sides, located just distal to or within a coronary stenosis, as assessed by each of 2 independent observers blinded to the nature of the anginal syndrome and its temporal proximity. Intracoronary thrombi were found in 44 of 119 patients with unstable angina (37%) and 0 of 35 patients with stable angina (p

Frequency of intracoronary filling defects by angiography in angina pectoris at rest.

Many different laboratory tests have been used to screen patients for pulmonary embolism. The sensitivity of certain laboratory tests was assessed in a prospective study of 50 patients wit...

Diagnostic Sensitivity of Laboratory Findings in Acute Pulmonary Embolism

The "R-on-T phenomenon" is the superimposition of an ectopic beat on the T wave of a preceding beat. Early observations suggested that R-on-T was likely to initiate sustained ventricular tachyarrhythmias. More recent experimental and clinical observations suggest that R-on-T is not a critical determinant of primary ventricular fibrillation in acute myocardial infarction; represents few of the initiating beats of paroxysmal ventricular tachycardia; and represents at worst only a small risk in terms of sudden death. Apparently when the capacity for sustained repetitive beating has not been clinically obvious, R-on-T is quite unlikely to result in ventricular tachyarrhythmias, even in the presence of coronary heart disease. However, in the setting of acute myocardial infarction, inability to always identify the precursors of tachyarrhythmias strengthens the argument for prophylactic treatment of patients.

Steven G. Meister

Papers

Pseudoaneurysm of the ascending aorta following cardiac surgery.

Intracoronary thrombus in nontransmural myocardial infarction and in unstable angina pectoris

Frequency of intracoronary filling defects by angiography in angina pectoris at rest.

Diagnostic Sensitivity of Laboratory Findings in Acute Pulmonary Embolism

The R-on-T Phenomenon: An Update and Critical Review