Hypersensitivity cases associated with drug-eluting coronary stents: a review of available cases from the research on adverse drug events and reports (RADAR) project

Journal ArticleOBJECTIVES: We undertook the review of all available cases of hypersensitivity reactions after placement of a drug-eluting stent (DES) and classified potential causes. BACKGROUND: Six months after the approval of the first DES, the Food and Drug Administration (FDA) reported 50 hypersensitivity reactions after stent placement but later concluded these were due to concomitantly prescribed medications such as clopidogrel. Nevertheless, the FDA continued to receive reports of hypersensitivity. METHODS: Reports available from April 2003 through December 2004 for hypersensitivity-like reactions associated with the sirolimus-eluting stent (CYPHER, Cordis Corp., Miami Lakes, Florida) and paclitaxel-eluting stent (TAXUS, Boston Scientific Corp., Natick, Massachusetts) were reviewed. Sources of reports included the FDA's adverse-device-event database, the published literature, and investigators from the Research on Adverse Drug/Device events And Reports (RADAR) project. Causality was assessed using standardized World Health Organization criteria. RESULTS: Of 5,783 reports identified for the DES in the FDA database, 262 unique events included hypersensitivity symptoms. Of these reports, 2 were certainly and 39 unlikely caused by clopidogrel and 1 was certainly, 9 probably, and 13 unlikely caused by the DES. From all sources, we identified 17 distinct cases that were probably or certainly caused by the stent, of which 9 had symptoms that lasted longer than four weeks. Four autopsies confirmed intrastent eosinophilic inflammation, thrombosis, and lack of intimal healing. CONCLUSIONS: The FDA reports and autopsy findings suggest that DES may be a cause of systemic and intrastent hypersensitivity reactions that, in some cases, have been associated with late thrombosis and death

Preclinical restenosis models and drug-eluting stents Still important, still much to learn

Percutaneous coronary intervention continues to revolutionize the treatment of coronary atherosclerosis. Restenosis remains a significant problem but may at last be yielding to technologic advances. The examination of neointimal hyperplasia in injured animal artery models has helped in our understanding of angioplasty and stenting mechanisms, and as drug-eluting stent (DES) technologies have arrived, they too have been advanced through the study of animal models.These models are useful for predicting adverse clinical outcomes in patients with DESs because suboptimal animal model studies typically lead to problematic human trials. Similarly, stent thrombosis in animal models suggests stent thrombogenicity in human patients. Equivocal animal model results at six or nine months occasionally have been mirrored by excellent clinical outcomes in patients. The causes of such disparities are unclear but may result from differing methods, including less injury severity than originally described in the models. Ongoing research into animal models will reconcile apparent differences with clinical trials and advance our understanding of how to apply animal models to clinical stenting in the era of DESs

Endothelial and myocardial injury during ischemia and reperfusion: Pathogenesis and therapeutic implications

AbstractEarly reperfusion remains the most effective way of limiting myocardial necrosis and improving ventricular function in experimental models and human patients. However, the introduction of oxygen and cellular elements, especially the neutrophil, into the ischemic zone may initiate a deleterious cascade of events that limits myocardial salvage after reperfusion. Although the pathogenesis of reperfusion injury remains controversial, recent studies have suggested that the endothelium may play a critical role.Endothelial cells maintain flow in the microcirculation by secreting a number of vasodilatory compounds and substances that prevent plugging of capillaries by inhibiting neutrophil adherence and platelet aggregation. Reperfusion of ischemic myocardium accelerates structural and functional changes in endothelial cells, resulting in a progressive decrease in microcirculatory flow (“no reflow” phenomenon). Numerous studies suggest that activated neutrophils mediate vascular damage by releasing reactive oxygen species and potent proteolytic enzymes. The administration of therapeutic agents that limit endothelial disruption and neutrophil plugging has shown promising results in limiting myocardial reperfusion injury in experimental models

Myocardial infarct extension during reperfusion after coronary artery occlusion: Pathologic evidence

AbstractObjectives. The goal of this study was to demonstrate myocardial infarct extension during reperfusion within the same animal.Background. Whether myocardial reperfusion can result in the extension of myocardial necrosis remains controversial. The transformation of reversibly injured myocytes into irreversibly damaged cells after reperfusion has been difficult to demonstrate pathologically.Methods. New Zealand White rabbits (Group I, n = 10) were subjected to 30 min of coronary artery occlusion and 180 min of reperfusion. Horseradish peroxidase, a tracer protein that permeates the sarcolemma of irreversibly injured myocytes, was used to quantitate myocyte necrosis at the beginning of reperfusion. Within the same heart, infarct size was measured after 180 min of reperfusion by triphenyttetrazolium chloride (TTC) staining. In separate experiments to demonstrate the validity of the model, rabbits were subjected to 30 min of coronary occlusion, followed by intravenous infusion of horseradish peroxidase and rapid induction of death (Group II) or 30 min of occlusion, 180 min of reperfusion with horseradish peroxidase administered after 180 min of reperfusion and TTC staining after induced death (Group III).Results. In Group I, infarct size at the onset of reperfusion, delineated by horseradish peroxidase, measured 45.3 ± 2.8% of the area of risk and was significantly less than TTC-delineated infarct size after 189 min of re perfusion (59.8 ± 33%, p = 0.0002). By electron microscopy, border areas within the ischemic bed demonstrated irreversibly injured horseradish peroxidasepositive myocytes adjacent to irreversibly injured horseradish peroxidase-negative myocytes, suggesting that farther cell death occurred during reperfusion. In Group II, infarcts delineated by horseradish peroxidase after 30 min of coronary occlusion were similar in size to infarcts measured by this tracer in Group I. In Group III, infarcts delineated by horseradish peroxidase at 180 min of reperfusion were similar in size to infarcts measured by TTC and similar to TTC-delineated infarcts measured at 180 min of reperfusion in Group I.Conclusions. These results provide evidence that there is a subset of myocytes in border areas within the ischemic region that are viable at the beginning of reperfusion but subsequently progress to irreversible injury during the reperfusion period

Biological responses in stented arteries

Vascular walls change their dimension and mechanical properties in response to injury such as balloon angioplasty and endovascular stent implantation. Placement of bare metal stents induces neointimal proliferation/restenosis which progresses through different phases of repair with time involving a cascade of cellular reactions. These phases just like wound healing comprise distinct steps consisting of thrombosis, inflammation, proliferation, and migration followed by remodelling. It is noteworthy that animals show a rapid progression of healing after stent deployment compared with man. During stenting, endothelial cells are partially to completely destroyed or crushed along with medial wall injury and stretching promoting activation of platelets, and thrombus formation accompanied by inflammatory reaction. Macrophages and platelets play a central role through the release of cytokines and growth factors that induce vascular smooth muscle cell accumulation within the intima. Smooth muscle cells undergo complex phenotypic changes including migration and proliferation from the media towards the intima, and transition from a contractile to a synthetic phenotype; the molecular mechanisms responsible for this change are highlighted in this review. Since studies in animals and man show that smooth muscle cells play a dominant role in restenosis, drugs like rapamycin and paclitaxel have been coated on stent with polymers to allow local slow release of drugs, which have resulted in dramatic reduction of restenosis that was once the Achilles' heel of interventional cardiologist