Dual antiplatelet therapy (DAPT) is standard treatment for endoluminal stent insertion, and complete resistance to DAPT is rare. A case of in-stent thrombosis occurring 3 hours after stent-assisted coiling of internal carotid artery aneurysm is presented despite compliance with DAPT. Platelet function tests (PFTs) revealed complete clopidogrel and prasugrel resistance.

While developments in oncology have lengthened survival in patients with cancer, such patients often develop cardiovascular diseases. Thus, percutaneous coronary intervention (PCI) is frequently undertaken in them. Although stent thrombosis remains a fatal complication in stent-based PCI, worldwide consensus panels tend to recommend shorter duration of dual-antiplatelet therapy. This is based on its clinical efficacy that has resulted from technological innovation. However, there is insufficient discussion on the risk of stent thrombosis in cancer patients with coronary artery disease, especially in those undergoing chemotherapeutic regimens that have a risk for thrombosis, such as regimens with the anti-vascular endothelial growth factor. Presented here is a case of early stent thrombosis that occurred in a cancer patient on regorafenib, despite the administration of triple antithrombotic therapy. Case presentation A 66-year-old Japanese male patient received regorafenib for metastatic colorectal carcinoma and apixaban for deep vein thrombosis. Coronary angiography revealed severe stenosis in the proximal left anterior descending artery. A sirolimus-eluting stent was implanted, without malapposition and under-expansion, under intravascular ultrasound guidance while administering a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day). However, he was admitted to the hospital for exacerbation of heart failure 1 month after PCI. Coronary angiography revealed contrastive defects in the previous stent. Optical frequency domain imaging confirmed stent thrombosis. PCI was successfully performed with perfusion balloon long-inflation. Antithrombotic therapy was enhanced (aspirin: 100 mg/day, ticagrelor: 120 mg/day, and apixaban: 10 mg/day) and regorafenib was discontinued permanently. While ischemic events did not occur thereafter, the patient died due to metastatic carcinoma progression.
This case suggests that anti-vascular endothelial growth factor might contribute to early stent thrombosis, despite triple antithrombotic therapy. Further discussion is needed on the surveillance and management of cancer patients with coronary artery disease receiving chemotherapy, which carries a risk of thrombosis.

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The aim of the current research was to develop an in silico oral absorption model coupled with an in vitro dissolution/precipitation testing to predict gastric pH-dependent drug-drug interactions for weakly basic drugs. The effects of elevated gastric pH on the plasma profiles of dipyridamole, prasugrel, and nelfinavir were simulated and compared with pharmacokinetic data reported in humans with or without use of proton pump inhibitors or histamine H2 receptor antagonists. The in vitro dissolution and precipitation data for the weakly basic drugs in biorelevant media were obtained using paddle apparatus. An in silico prediction model based on the STELLA software was designed and simulations were conducted to predict the oral pharmacokinetic profiles of the 3 drugs under both usual (low) and elevated gastric pH conditions. The changes in oral absorption of dipyridamole and prasugrel in subjects with elevated gastric pH compared with those with low stomach pH were predicted well using the in vitro-in silico-in vivo approach. The proposed approach could become a powerful tool in the formulation development of poorly soluble weak base drugs.

Striking an adequate balance between bleeding risks and prevention of stent thrombosis can be challenging in the setting of percutaneous coronary intervention (PCI) with drug eluting stents (DES) in acute myocardial infarction (MI). This is more pronounced in patients treated with both low molecular weight heparin (LMWH) and dual antiplatelet therapy (DAPT). Prasugrel, a second generation thienopyridine with more potent platelet inhibition capability, is associated with significant bleeding risks. This risk of bleeding is often underestimated when prescribing pharmacological agents such as DAPT and LMWH, designed to reduce ischaemic events following PCI in acute MI. Life-threatening haemorrhagic pericardial and pleural effusions not associated with access site bleeding are a rare example of such bleeding complications.
We report a case of a Bangladeshi male who developed cardiac tamponade resulting from haemorrhagic pericardial effusion as well as bilateral pleural effusions, 9 days after PCI with a DES, while on prasugrel and aspirin. He had presented late with inferior ST elevation myocardial infarction (STEMI), and was therefore also given enoxaparin initially. Haemorrhagic pericardial and pleural fluid were drained, and the patient was discharged on DAPT comprising of aspirin and clopidogrel. Following PCI to obtuse marginal, which was done as a staged procedure 6 months later, he was commenced on ticagrelor instead of clopidogrel. He developed no further bleeding complications over 1 year of follow up.
Non-access site bleeding such as this, leading to haemorrhagic pericardial and pleural effusions can be rare and life-threatening. Furthermore, patients with acute coronary syndromes (ACS) have marked variation in their risk of major bleeding. Since haemorrhagic complications are associated with mortality, maintaining a balance between the risk of recurrent ischemia and that of bleeding is of paramount importance. The use of validated bleeding risk scores, careful monitoring of patients on DAPT with LMWH, or a switch over to agents with lesser risk of bleeding may reduce such complications.

Allergic reactions to clopidogrel soon after coronary stent implantation pose an important and challenging clinical problem. We describe a 44-year-old man who developed a diffuse maculopapular rash four days after initiation of clopidogrel with drug-eluting coronary stent placement. An initial treat-through strategy was unsuccessful due to patient intolerance to corticosteroids. Because of persistent hypersensitivity, clopidogrel was substituted with prasugrel which was continued successfully for one year without reaction. A systematic review of the literature was performed which identified 10 prior case reports of patients with clopidogrel hypersensitivity who were subsequently treated with prasugrel. Patient characteristics and clinical outcomes of these patients plus the current case were reviewed. There were 9 men and 2 women with ages from 44 to 76 years. All patients had undergone coronary stent procedures. Prasugrel was successfully used without cross-reactivity in 9 of the 11 patients (82%). Cross-reactivity was reported in two patients who developed hypersensitivity reactions to prasugrel similar to those experienced on clopidogrel. In conclusion, prasugrel can be used successfully in most patients with a history of clopidogrel hypersensitivity. However, potential cross-reactivity between these two thienopyridines may occur in some patients.

Cross-trial comparisons are typically inappropriate as there are often numerous differences in study designs, populations, end points, and loading doses of the study drugs. These differences are clearly reflected in the most recent updates to the European Society of Cardiology (ESC) non-ST elevation acute coronary syndrome (NSTE-ACS) and ST elevation myocardial infarction (STEMI) guidelines, which include recommendations for the use of the antiplatelet agents ticagrelor, prasugrel, and clopidogrel, based in part on results from the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel-Thrombolysis In Myocardial Infarction (TRITON-TIMI) 38, TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY-ACS) and PLATelet inhibition and patient Outcomes (PLATO) trials. Here, we describe each of these trials in detail and explain the differences between them that make direct comparisons difficult. In conclusion, this information, along with the current guidelines and recommendations, will assist clinicians in deciding the most appropriate treatment pathway for their patients with NSTE-ACS and STEMI.

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Aggressive dual antiplatelet therapy is associated not only with more bleeding, impaired wound healing, and potentially more solid cancer rates but it also causes higher infection risks including sepsis, and systemic inflammatory response syndrome (SIRS). This may be especially true considering the alarming off-label use of prasugrel. A 65-year-old white male patient with a history of myocardial infarction treated with percutaneous coronary intervention and implantation of 2 bare metal stents, was treated with off-label clopidogrel for 4 years, including a double daily dose (150 mg) for the initial 13 months. Still on clopidogrel, the patient was hospitalized with suspected pneumonia. A diagnostic cardiac catheterization revealed a 60%-70% blockage of the mid left anterior descending, but there was no need for coronary intervention. At discharge, clopidogrel 75 mg/d was switched over to off-label prasugrel 10 mg/d on top of aspirin (81 mg/d). On day 3 after prasugrel was given, a football-sized bruise appeared on the patient\'s lower right abdomen, but computed tomography results were unremarkable. On day 6 after administration of prasugrel, the patient became dizzy, disoriented, confused, experienced difficulty breathing, severe headache, weakness, intensive petechial rash covering the entire body, and breathing difficulty requiring ventilation. Within 24 hours, the patient was unable to correctly identify his age; his eyes were pale in color to almost colorless and when hearing a sound he would turn his entire head toward the sound and he appeared to be blind. His lungs, liver, and kidneys began to show signs of failure over the next 5-9 days. Sixteen days after the administration of the first prasugrel dose, the patient died of sepsis complicated with SIRS. Aggressive off-label use of clopidogrel (double dose for 13 months, and >4 years overall duration), followed by off-label switchover to the highest daily dose (10 mg) prasugrel may trigger sepsis and fatal SIRS. The mechanism responsible for such harmful association is probably indirect, and involves the weakening of platelet-neutrophil-endothelial crosstalk necessary to combat infections, and/or keep inflammation from spreading.