Current Vascular Pharmacology - Volume 17, Issue 2, 2019

This paper provides an overview of the pathogenesis, presentation and diagnosis of clopidogrel hypersensitivity. The majority of clopidogrel hypersensitivity cases are due to a T cell mediated Gell and Coombs Type IV reaction. History, histology, and patch testing have shown consistency with a T cell mediated mechanism. Clopidogrel reactions most commonly present as a mild delayed maculopapular erythematous rash 5 to 10 days after introduction of the drug, and do not always require discontinuation of the drug. Severe cutaneous, systemic, and immediate adverse reactions to clopidogrel are rare. For the diagnosis of clopidogrel hypersensitivity, drug causality can be determined using patch testing, or for mild reactions, recurrence of symptoms after drug reintroduction, although neither are required for diagnosis.

The purpose of this section is to educate the reader on how to successfully manage patients with a hypersensitivity reaction to clopidogrel using desensitization protocol based on various published protocols. Additionally, we will define drug desensitization, and describe the possible mechanism of how desensitization may function as alternative medication. The indications/contraindications for desensitization will be reviewed. The different published clopidogrel desensitization protocols will be discussed. Based on those protocols, we recommend a protocol we feel is safe and efficacious. Clopidogrel is a thienopyridine antiplatelet drug widely used for treatment and also employed for secondary prevention regarding a range of cardiovascular diseases. However, it has been reported to cause hypersensitivity reactions. Ticlopidine is an alternative medication that can be considered when patients have an allergic reaction to clopidogrel. Additionally, ticlopidine is associated with increased risk causing potentially life-threatening adverse reactions to include: Aplastic anemia, reversible neutropenia, and thrombotic thrombocytopenia purpura vs. clopidogrel. Thus, clopidogrel desensitization offers an attractive alternative. Drug desensitization is defined as causing a temporary state of tolerance to a specific medication responsible for a hypersensitivity reaction. Furthermore, drug desensitization can only be maintained by continuous administration of this drug. Discussion: The exact immunologically mediated mechanism of how rapid oral desensitization works is not fully understood and yet to be defined. Ultimately desensitization results in causing antigen-specific mast cell tolerance. Various protocols have been published. The length of desensitization ranged from 2 h using 9 doses to 7 h using 15 doses. Recommendations: Taking the above into account, we recommend using a modification to the protocol that has the largest number of patients to undergo a standardized clopidogrel desensitization. This approach is shorter, as time has immense importance for these patients. Dosing starts at 10 mg dose and with 60 min intervals between doses, this now becomes a 4 h desensitization protocol.

Clopidogrel remains a widely used antiplatelet agent for patients with established or high risk of atherothrombotic disease, particularly those treated with coronary, carotid or peripheral endovascular stenting. Clopidogrel hypersensitivity is an uncommon but well established adverse drug reaction presenting a challenge for patient management. The clinical presentation ranges from focal or diffuse cutaneous manifestations in most patients to angioedema in some and a systemic immune response in rare cases. The treatment options include drug discontinuation with or without desensitization therapy, switching to alternate ADP receptor antagonists or administration of oral steroids while continuing clopidogrel in patients at high risk of adverse events with clopidogrel discontinuation. In this review the author describes the phenomenon of clopidogrel hypersensitivity, various treatment strategies.

Despite the advent of newer antiplatelet therapies, clopidogrel remains the mainstay of treatment for patients with cardiovascular disease, especially those who undergo coronary stent implantation. Hypersensitivity reactions to clopidogrel that develop soon after stenting present a significant clinical challenge. The widespread use of clopidogrel in the management of patients with coronary artery disease necessitates awareness of treatment options in the setting of an allergic reaction. It has been demonstrated that clopidogrel hypersensitivity can be successfully managed without interrupting clopidogrel therapy. We review available treatment options and highlight the treating-through approach developed at our institution.

Clopidogrel is a widely used agent for secondary prevention of vascular events and is a cornerstone of dual antiplatelet therapy in patients with acute coronary syndrome (ACS) post coronary stent implantation. Hypersensitivity reactions to clopidogrel are well documented and may range from localized to systemic in presentation. This can lead to discontinuation of therapy, thus increasing the risk of vascular events. The authors have developed recommendations for potential alternative agents for the management of clopidogrel hypersensitivity reactions. Proposed strategies include treatment with an alternative P2Y12 inhibitor, cilostazol or warfarin.

Abdominal aortic aneurysm (AAA) is a degenerative disease of the aortic wall with potentially fatal complications. Open repair (OR) was considered the gold standard, until the emergence of endovascular aneurysm repair (EVAR), which is less invasive and equally (if not more) effective. As the popularity of endovascular procedures grows, related complications become more evident, with kidney damage being one of them. Although acute kidney injury (AKI) following EVAR is relatively common, its true incidence is still uncertain. Also, there is insufficient data concerning long-term renal outcomes after EVAR, especially with repeated contrast agent exposure. Despite the lack of firm evidence on the effectiveness of individual strategies, it is evident that prevention of AKI following EVAR requires a multifactorial approach. This review focuses on recent findings based on human studies regarding the current evidence of renal impairment after EVAR, its quantification and strategies for its prevention.

Paraoxonase-1 (PON-1) is a calcium-dependent enzyme that is synthesized in the liver and then secreted in blood where it is bound to high density lipoprotein (HDL). PON-1 is a hydrolase with a wide range of substrates, including lipid peroxides. It is considered responsible for many of the antiatherogenic properties of HDL. PON-1 prevents low density lipoprotein (LDL) oxidation, a process that is considered to contribute to the initiation and development of atherosclerosis. PON-1 activity and levels are influenced by gene polymorphisms; of the 2 common variants, one is in position 192 (Q192R) and one in position 55 (M55L). Also, many drugs affect PON-1 activity. The role of PON-1 in carotid atherosclerosis is inconsistent. Some studies show an association of PON-1 polymorphisms with carotid plaque formation, whereas others do not. The aim of this review is to summarize the characteristics of PON-1, its interactions with drugs and its role in atherosclerosis and especially its relationship with carotid artery disease.

Background: Epidemiological studies and experimental studies have demonstrated that intrauterine adverse environment increases the risk of Cardiovascular Disease (CVD) in adulthood. However, whether an individual develops a cardiovascular dysfunctional phenotype may depend on genetic background, age, and sex. Methods: In this review, we summarize some of the recent experimental animal studies in the developmental programming of adult CVD with an emphasis on sex differences and the potential role of estrogen in mediating sexual dimorphism. Results: Few epidemiological studies report the effect of sex on the developmental programming of CVD. However, numerous experimental animal studies have shown a sex difference in fetal programming of adult cardiovascular dysfunction. Most of the animal studies indicate that male offspring develop cardiovascular dysfunction and CVD in adulthood, whereas adult females appear to be protected. Estrogen is one of the key factors that contributes to the sex difference of adult CVD. Estrogen/its Receptor (ER) may interact with the RAS system by changes of DNA methylation patterns at the target gene promoter, serve as an antioxidant to counteract the prenatal insults-induced heightened ROS, and function as an eNOS activator to increase vasodilation, resulting in the protection of female offspring from the development of hypertension and other CVDs. Conclusion: These studies suggest that estrogen/ER may contribute to sex differences in cardiovascular response to an adverse intrauterine environment and play a significant role in modulating the cardiovascular response in adulthood.

Insulin resistance (IR) is a cardinal feature of type 2 diabetes mellitus (T2DM). It also is associated with multiple metabolic abnormalities which are known cardiovascular disease (CVD) risk factors. Thus, IR not only contributes to the development of hyperglycemia in T2DM patients, but also to the elevated CVD risk. Improving insulin sensitivity is anticipated to both lower the plasma glucose concentration and decrease CVD risk in T2DM patients, independent of glucose control. We review the molecular mechanisms and metabolic consequences of IR in T2DM patients and discuss the importance of addressing IR in the management of T2DM.

Background: Intracoronary thrombus in acute Myocardial Infarction (MI) confers higher rates of no-reflow with attendant adverse consequences. Earlier Randomized-Controlled-Trials (RCTs) of routine thromboaspiration during Percutaneous Coronary Intervention (PCI) indicated a clinical benefit, but more recent RCTs were negative. However, data of selective use of this adjunctive approach remain scarce. Objective: The aim of this single-centre prospective study was to report the results of selective thromboaspiration during PCI in patients with intracoronary thrombi, and also to provide an extensive literature review on current status of thromboaspiration. Methods: The study included 90 patients (77 men; aged 59.3±12.7 years) presenting with acute MI (STElevation MI (STEMI) in 74, non-STEMI in 16) who had intracoronary thrombi and were submitted to thromboaspiration. Results: Total (n=67) or subtotal (n=18) vessel occlusions were present in 85 (94%) patients. Thromboaspiration and subsequent PCI were successful in 89/90 (98.9%) patients, with coronary stenting in 86 (96.6%). In 4 patients with residual thrombus, a mesh-covered stent was implanted. IIb/IIIa-inhibitors were administered in 57 (63.3%) patients. No-reflow occurred in only 1 (1.1%) patient. The postprocedural course was uneventful. Review of the literature revealed several early observational and RCTs and meta-analyses favouring manual, not mechanical, thrombectomy. However, newer RCTs and meta-analyses significantly curtailed the initial enthusiasm for the clinical benefits of routine use of thromboaspiration. Conclusion: Selective thromboaspiration for angiographically visible thrombi in MI patients undergoing PCI, as an adjunct to mechanical reperfusion and to IIb/IIIa-inhibitors, may be an option since this manoeuvre may improve procedural and clinical outcome.

Background: Hypertension (HT) is an important risk factor for cardiovascular disease and might precipitate pathology of the aortic valve. Objective: To investigate the association of HT with aortic dysfunction (including both aortic regurgitation and stenosis) and the impact of antihypertensive treatment on the natural course of underlying aortic disease. Methods: We performed a systematic review of the literature for all relevant articles assessing the correlation between HT and phenotype of aortic disease. Results: Co-existence of HT with aortic stenosis and aortic regurgitation is highly prevalent in hypertensive patients and predicts a worse prognosis. Certain antihypertensive agents may improve haemodynamic parameters (aortic jet velocity, aortic regurgitation volume) and remodeling of the left ventricle, but there is no strong evidence of benefit regarding clinical outcomes. Renin-angiotensin system inhibitors, among other vasodilators, are well-tolerated in aortic stenosis. Conclusion: Several lines of evidence support a detrimental association between HT and aortic valve disease. Therefore, HT should be promptly treated in aortic valvulopathy. Despite conventional wisdom, specific vasodilators can be used with caution in aortic stenosis.

Background and Objectives: The majority of patients included in trials of anti-platelet therapy are male. This systematic review and meta-analysis aimed to determine whether, in addition to aspirin, P2Y12 blockade is beneficial in both women and men with acute coronary syndromes. Methods: Electronic databases were searched and nine eligible randomised controlled studies were identified that had sex-specific clinical outcomes (n=107,126 patients). Risk Ratios (RR) and 95% Confidence Intervals (CI) were calculated for a composite of cardiovascular death, myocardial infarction or stroke (MACE), and a safety endpoint of major bleeding for each sex. Indirect comparison analysis was performed to statistically compare ticagrelor against prasugrel. Results: Compared to aspirin alone, clopidogrel reduced MACE in men (RR, 0.79; 95% CI, 0.68 to 0.92; p=0.003), but was not statistically significant in women (RR, 0.88; 95% CI, 0.75 to 1.02, p=0.08). Clopidogrel therapy significantly increased bleeding in women but not men. Compared to clopidogrel, prasugrel was beneficial in men (RR, 0.84; 95% CI, 0.73 to 0.97; p=0.02) but not statistically significant in women (RR, 0.94; 95% CI, 0.83 to 1.06; p=0.30); ticagrelor reduced MACE in both men (RR, 0.85; 95% CI, 0.77 to 0.94; p=0.001) and women (RR, 0.84; 95% CI, 0.73 to 0.97; p=0.02). Indirect comparison demonstrated no significant difference between ticagrelor and prasugrel in either sex. Compared to clopidogrel, ticagrelor and prasugrel increased bleeding risk in both women and men. Conclusion: In summary, in comparison to monotherapy with aspirin, P2Y12 inhibitors reduce MACE in women and men. Ticagrelor was shown to be superior to clopidogrel in both sexes. Prasugrel showed a statistically significant benefit only in men; however indirect comparison did not demonstrate superiority of ticagrelor over prasugrel in women.

Background: Adiponectin gene (ADIPOQ) variability may affect the risk for type 2 diabetes mellitus (T2DM) but it remains unclear whether it is involved in microvascular complications. Objective: To explore the impact of ADIPOQ variability on markers of inflammation and angiogenesis in T2DM. Methods: Overall, 220 consecutive T2DM patients from our outpatient diabetic clinic were genotyped for G276T (rs1501299) and T45G (rs2241766) single nucleotide polymorphisms of ADIPOQ gene. Serum levels of interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), vascular endothelial growth factor (VEGF) were measured by enzyme-linked immunosorbent assay and high sensitivity Creactive protein (hsCRP) by immunonephelometry. Results: Homozygosity for the G allele on rs2241766 was associated with significantly lower serum VEGF and ICAM-1 levels compared with other genotype groups, but had no effect on IL-6. Genetic variability on rs1501299 was not associated with either VEGF or ICAM-1 levels, but T homozygotes for rs1501299 had significantly lower IL-6 concentrations compared with G carriers. Furthermore, the presence of the G allele on rs2241766 was associated with significantly lower HbA1c, whereas no associations were observed for both body mass index and hsCRP with either rs2241766 or rs1501299. Conclusion: Genetic variability on adiponectin gene was associated with serum levels of inflammatory and angiogenetic markers. Further research is required to elucidate the role of adiponectin in the development and/or progression of microvascular disease in T2DM patients.