Recurrent hemoptysis following thienopyridines and amiodarone administration. therapeutic dilemma

The authors describe a case of a 74-year-old man with advanced coronary heart disease in whom pulmonary hemorrhagic complications during therapy with ticlopidine and subsequently with clopidogrel and amiodarone were observed. Fever and massive hemoptysis following five days of ticlopidine treatment, before elective coronary angiography, were noticed. Transient interstitial X-ray changes of the right lung were visible. Three months later a new episode on the third day of clopidogrel administration was manifested. He was after PCI, performed because of ACS complicated with ventricular fibrillation. Two days following clopidogrel discontinuation hemoptysis remitted but after ten days occurred again (this time with bilateral X-ray changes). Amiodarone, given after VF, was stopped. Spectacular improvement with steroid treatment was observed. Indobufen (reversible COX- 1 inhibitor) as an antiplatelet therapy was availed. The authors discuss therapeutic dilemma concerning the patient with coexisting different diseases.     

The use of ticagrelor in a patient at increased risk of stent thrombosis resistant to multiple thienopyridines

Ticagrelor has been shown to be superior to clopidogrel in patients presenting with acute myocardial infarction who undergo early invasive treatment. We discuss a hitherto unreported use of ticagrelor in the management of a patient resistant to multiple thienopyridines at high risk of stent thrombosis.     

Stent thrombosis in patients treated with thienopyridines: clinical description of 10 cases

Subacute stent thrombosis (SAST) is a major thrombotic complication of coronary stenting. Its occurrence has been substantially reduced by thienopyridine treatment. However, information on clinical profile of patients with SAST in clopidogrel era is limited. In order to define the incidence and factors predisposing to stent thrombosis, we analyzed the computerized angiographic database of three interventional cardiology centers. Out of a total number of 5903 percutaneous coronary interventions (PCIs) with stent implantation, we found 10 patients with SAST (0.17%). The indication for PCI was usually an early invasive approach (90%) during an acute coronary syndrome. All patients were treated with an apparently optimal antithrombotic regimen (90% received heparin or LMWH and 70% received IIb/IIIa receptor inhibitors and all given aspirin). In each of the patients, we could identify high-risk angiographic findings. SAST presentation was always clinically significant with definite myocardial infarction in 100% of cases. 80% of cases occurred during the first six days post PCI. Two patients had a recurrent event. Finally, despite earlier reports of atorvastatin-mediated inhibition of clopidogrel activation we did not find any patient with SAST taking both drugs. Thus, patients with stent thrombosis during thienopyridine treatment usually exhibit high-risk angiographic features. Prospective studies should be performed to elucidate drug interactions that may reduce clopidogrel efficacy and contribute to stent thrombosis. (Int J Cardiovasc Intervent 2004; 6: 160-164)     

Neutropenia in patients treated with thienopyridines and high-dose oral prednisone after percutaneous coronary interventions

BACKGROUND: Oral treatment with prednisone has demonstrated efficacy in reducing restenosis after percutaneous coronary interventions (PCI). However, administration of steroids at high dose may raise concerns in terms of applicability and tolerability. Monitoring the occurrence of possible side-effects is therefore mandatory. METHODS: Secondary effects of oral prednisone in this setting is analyzed. The "expected" secondary effects of the steroid treatment are described, together with the "unexpected" occurrence of likely drug-induced neutropenia observed in patients prescribed prednisone and thienopyridines simultaneously after PCI. RESULTS: Two-hundred and twenty patients were monitored for the occurrence of side-effects of the prednisone therapy. Twenty-eight patients (14%) had side-effects likely related to the prednisone treatment: gastric pain (4%), increment of arterial pressure needing upgrading of antihypertensive treatment (4%), edema (1.8%), and concomitant infections (1.4%). In three patients (1.4%), agranulocytosis was detected at the time of the routine blood cell count scheduled 4 weeks after PCI in otherwise asymptomatic patients. Neutropenia subsided completely after withdrawal of prednisone and thienopyridine in all cases and the blood cell formula normalized within 3 weeks. CONCLUSIONS: Side-effects of oral prednisone given after PCI to reduce restenosis occur in less than 15% of patients. Complaints are mild and reversible and can be easily managed with adjunctive diuretic and antacid drugs. The occurrence of agranulocytosis after prednisone had never been reported before, but was observed in 1.4% of our patients receiving simultaneously a thienopyridine. To explain such an unusual event we propose the hypothesis of a possible metabolic interaction between prednisone and thienopyridines.     

Case report: use of thienopyridines in a patient with acquired idiopathic thrombotic thrombocytopenic purpura

Thienopyridines are commonly used anti-platelet drugs that may be associated with the development of secondary, drug-induced thrombotic thrombocytopenic purpura (TTP), a rare but potentially life threatening condition. We report the case of a 70?year-old man with a history of recurrent idiopathic TTP episodes who was treated with clopidogrel and then ticlopidine for thromboprophylaxis after percutaneous coronary intervention. Treatment was successful with no signs of TTP recurrence. Platelet counts and ADAMTS13 activity levels remained normal for months after the initiation of anti-platelet therapy, with no reappearance of anti-ADAMTS13 autoantibodies. This report demonstrates that thienopyridines do not necessarily induce TTP in patients with a history of TTP who are in disease remission.     

Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation.

We carried out a prospective evaluation of a new vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay in order to detect patients with high-risk coronary subacute stent thrombosis (SAT) despite thienopyridine regimen. Twenty healthy donors (group 1) without any medication were compared to 16 stented patients (group 2) treated by ticlopidin or clopidogrel initiated 2 days before stenting and aspirin (250 mg/day). No difference in platelet reactivity was noted between group 1 and group 2 treated only with aspirin (72.00% +/- 4.17% vs. 69.73% +/- 5.62%, respectively; P = NS). Significant differences were found between patients of group 2 treated with aspirin alone (69.73% +/- 5.62%), after 2.0 days (60.14% +/- 9.60%; P < 0.05), and after 4.8 +/- 1.3 days (48.37% +/- 11.19%; P < 0.05) with thienopyridine-aspirin. Among 1,684 consecutive stented patients, 16 patients who presented an SAT (group 3) were compared with 30 other stented patients free of SAT (group 4). We found a significant difference between group 3 (63.28% +/- 9.56%) and group 4 (39.80% +/- 10.9%; P < 0.0001). VASP phosphorylation analysis may be useful for the detection of coronary SAT.     

The expanding role of antiplatelet agents in coronary artery disease. A current review of aspirin, glycoprotein IIb/IIIa inhibitors, and the thienopyridines

The platelet has assumed an increasingly important role in cardiovascular medicine as our understanding of the pathophysiology of acute coronary syndromes (ACS) has evolved. Plaque rupture, platelet aggregation, and thrombus formation occur as a result of complex interaction between the platelet, the endothelium, and various inflammatory cells and circulating proteins. Aspirin continues to form the foundation of any anti-ischemic regimen, but cardiologists have long recognized the need for newer, more potent antiplatelet agents. Glycoprotein IIb/IIIa receptor antagonists and thienopryidines have been developed over the past decade and now serve as powerful complements to aspirin in the prevention and treatment of coronary events. The paper will begin with a review of aspirin as well as a discussion of the concept of aspirin resistance. The rapidly expanding body of knowledge supporting the use of glycoprotein IIb/IIIa receptor blockers and thienopyridines will then be addressed, with an emphasis on reconciling recent controversies in the literature. Future advances in the treatment of coronary artery disease will likely occur as we further refine the role of these established antiplatelet drugs and develop agents that bind to novel targets in the thrombotic cascade.     

The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme; rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease.

BACKGROUND: Other than aspirin, there are few oral antithrombotic treatments with proven efficacy in patients with acute coronary syndrome. In this report, we present the rationale, design and baseline characteristics of the Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events (CURE) trial, which includes a meta-analysis of the effects of thienopyridines in patients with vascular disease. METHODS AND RESULTS: Combined data from randomized trials of thienopyrindines in patients with atherosclerotic disease demonstrated a 29% reduction in vascular events when compared with placebo/control (n=2392) (OR 0.71, 95% CI 0.58-0.86, P=0.0006) and a 10% reduction in vascular events when compared with aspirin (n=22 254) (OR 0.91, 95% Cl 0.84-0.99, P=0.039). Similarly, randomized trials of aspirin plus thienopyridines in patients undergoing intracoronary stenting, demonstrated a marked benefit of aspirin plus ticlopidine in reducing death or myocardial infarction compared with aspirin alone (OR 0.23, 95% CI 0.11-0.49, P=0.0001) or aspirin plus warfarin (OR 0.51, 95% CI 0.33-0.78, P=0.002). Whether these benefits extend to the much larger population of patients with acute coronary syndrome is unknown. CURE is an international, randomized, double-blind trial, in which patients with acute coronary syndrome will be randomized to receive either a bolus dose of clopidogrel (300 mg) followed by 75 mg per day for 3-12 months, or matching placebo. Both groups will receive aspirin. The co-primary efficacy end-points of CURE are: (1) the composite of cardiovascular death, myocardial infarction or stroke; and (2) the composite of cardiovascular death, myocardial infarction, stroke or refractory ischaemia. CURE will recruit approximately 12 500 patients with acute coronary syndrome (from 28 countries) and its power to detect moderate treatment benefits will be in the region of 80-90%, while maintaining an overall type I error (alpha) of 0.05. The baseline characteristics of the study population are consistent with at least a moderate risk group of patients with acute coronary syndrome. CONCLUSIONS: Randomized trials of thienopyridines in patients with vascular disease demonstrate that thienopyridines are effective in reducing vascular events when compared with placebo/control or aspirin, as well as when used in combination with aspirin in patients undergoing intracoronary stent implantation. The CURE trial is a large international study to determine if acute and long-term treatment with the combination of clopidogrel and aspirin is superior to aspirin alone in patients with acute coronary syndrome.     

The Glomerulus: The Sphere of Influence

The glomerulus, the filtering unit of the kidney, is a unique bundle of capillaries lined by delicate fenestrated endothelia, a complex mesh of proteins that serve as the glomerular basement membrane and specialized visceral epithelial cells that form the slit diaphragms between interdigitating foot processes. Taken together, this arrangement allows continuous filtration of the plasma volume. The dynamic physical forces that determine the single nephron glomerular filtration are considered. In addition, new insights into the cellular and molecular components of the glomerular tuft and their contribution to glomerular disorders are explored.