{'fraction_non_alphanumeric': 0.023299599905860204, 'fraction_numerical': 0.009178630265944928, 'mean_word_length': 5.735340729001585, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Safety and tolerability of hirudins in percutaneous coronary intervention and the risk of Kounis syndrome

In the interesting review by Brodie published in this Journal [1], the author wondered how should we as clinicians decide which anticoagulant and which antiplatelet agents to use with primary PCI, because there are still current controversies concerning bleeding with bivalirudin. A recent study showed [2] that for patients undergoing elective PCI, there are no significant differences in bleeding and 6-month major adverse cardiac events between combined low dose of unfractionated heparin and glycoprotein IIb/IIIa inhibitors and bivalirudin. On the contrary, another recent study showed that bivalirudin resulted in 50% reduction in major bleeding compared with consistent unfractionated heparin and a GP IIb/IIIa inhibitor. Patients naive to antithrombin therapy administered bivalirudin monotherapy had a significant reduction in bleeding and similar rates of ischemia compared with naive patients initiated with unfractionated heparin and a GP IIb/IIIa inhibitor. Although bleeding is the major adverse effect of bivalirudin, there are also additional issues concerning safety and tolerability of hirudins that have not been emphasized. In particular, the most frequent adverse effects of bivalirudin include pain (abdominal, pelvic, back pain, pain in the injection site), nausea, hypotension, headache, insomnia, vomiting, anxiety, dyspepsia, bradycardia, fever, and nervousness. Immunogenicity of bivalirudin and especially the potential crossreactivity with the recombinant hirudins such as lepirudin is another issue associated with risk of acute thrombotic coronary events despite the fact that bivalirudin is an active site-directed thrombin inhibitor, which is the most potent stimulus activating platelets in subnanomolar concentrations. It has been shown that patients treated with recombinant hirudins can develop antihirudin antibodies [4]. In particular, lepirudin has been associated with nine cases of severe anaphylactic reactions [5] with four of them having fatal outcome attributed to Kounis syndrome [6]. Kounis syndrome is defined as the association of acute coronary syndromes with allergic or anaphylactic reactions [7]. Chemically, lepirudin and bivalirudin share an identical 11 aminoacid sequence. Bivalirudin has some advantages over other hirudins, as far as immunology is concerned, because it is administered over a short period, e.g., for less than the 2–3 days necessary to a B-cell response, has only 20 amino acids instead of 65 of lepirudin, and lacks disulfide bonds. Among 494 patients who received bivalirudin in clinical trials and who were tested for antibodies, two patients developed antibivalirudin antibodies without overt allergic or anaphylactic reaction [8]. In another study concerning 52 patients with heparin-induced thrombocytopenia undergoing angioplasty with bivalirudin on two or more occasions, no allergic reactions or thrombocytopenia developed [9]. In a study of 222 patients who received bivalirudin by subcutaneous administration 2–3 times daily for 14 days, no antibody formation occurred up to 6 weeks [10]. However, because the C-terminal of bivalirudin is common to lepirudin this can make crossreactivity possible. It also remains possible that longer duration therapy with bivalirudin might be associated with risk of anaphylaxis with drug reexposure. Bivalirudin, therefore, can be the target of polyspecific antilepirudin antibodies in patients previously treated with lepirudin [4]. This could increase antibody titers and trigger immune response. During primary PCI with DES insertion, bivalirudin could constitute the fifth potential antigenic substance together with metal strut, polymer, eluted drug, and clopidogrel [11]. Antibodies with different specificities can have an additive effect and even small amounts of corresponding antigens can trigger intracoronary mediator release when the patient is simultaneously exposed to them [12]. This data suggest that a possible sensitization to any DES component should not be clinically evaluated as a consequence of exposure to a single component but rather viewed as potential sensitization to multiple compounds.