Current Pharmaceutical Design - Volume 22, Issue 13, 2016

In the 18th century clinical cardiology was based on pulse examination and auscultation by placing the ear directly on the patient’s chest, while diagnosis of heart diseases was done in postmortem examination. In 1749, Jean-Baptiste de Sénac, physician of King Louis XV, published his work on the heart Traité de la structure du coeur, de son action et de ses maladies. It was the result of years of anatomical and physiological study, in an attempt to illuminate heart and its functions. Sénac recognized among several heart disorders, aortic regurgitation, mitral calcification, and mitral regurgitation. His work remained a landmark in valvular pathology and cardiology until the early 19th century.

Thrombosis is a well known phenomenon among physicians since antiquity. A variety of peculiar agents, such as leeches and bark, were used to prevent it. Hirudin was used during the 19th century. The next eon, heparin, strepokinase, urokinase, TPA, dicumarol, warfarin, aspirin, ticlopidine, Clopidogrel, SSHA and SP54 provoked huge advances in anticoagulation. During 21st century with the use of fondaparinux, dabigatran, rivaroxaban and Ticagrelor antithrombotic prevention and therapeutic interaction entered an era of medical challenges. Although the risk after a thrombotic episode is now highly reduced, blood clots still present damaging or even lethal consequences in human organisms and further research is strongly recommended.

The advent of transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of aortic stenosis and established a life-prolonging therapy in patients that are not operative candidates. It is also approved for high-risk surgical candidates and shows effectiveness comparable to surgical aortic valve replacement (SAVR). The inoperable and high-risk groups represent two parallel but partly divergent populations. In those deemed inoperable, decisions revolve around offering TAVR, palliation, or rehabilitation. These are based primarily on the likelihood of procedural success and clinical benefit, with a careful assessment of the source of their debility and features that underlie extreme surgical risk. In patients that are at high-risk for SAVR, determination of the most favorable route of valve replacement is guided by comparative procedural characteristics, the need for coincident interventions, and presumed ability for rehabilitation. These decisions are inherently difficult and currently rely on imperfect but developing risk assessment systems. Given the complexity of these decisions and patient population, the TAVR experience has underscored the value of a multi-disciplinary approach to advanced cardiovascular disease.

Background: Transcatheter aortic valve implantation (TAVI) is becoming a valuable alternative to surgical aortic valve replacement in patients with severe aortic stenosis that are at high surgical risk or deemed inoperable. The optimal anesthesia technique for TAVI is still undecided. We performed a systematic review and metaanalysis to compare the safety of locoregional anesthesia (LRA) with or without conscious sedation and general anesthesia (GA) for the TAVI-procedure. Methods: We searched PUBMED, MEDLINE, EMBASE and the Cochrane central register of controlled trials from January 1st 2002 to February 15th 2015. The primary outcome parameters searched were 30-days mortality, hospital length of stay, procedure time, use of adrenergic support, stroke rate, incidence of myocardial infarction, incidence of acute kidney injury, rate of procedural succes. Results: Ten studies, including 5919 patients, fulfilled the inclusion criteria. None of these studies was randomized resulting in a considerable risk of bias. The choice for a specific anesthesia technique did neither affect the average 30-day mortality rate [RR 0.91 (95% CI: 0.53 to 1.56), p=0.72] nor a wide variety of safety endpoints. LRA for TAVI was associated with a significantly shorter procedure time when compared to GA, and a reduction in hospital length of stay. However, LRA significantly increased the risk for implantation of a permanent pacemaker (RR 1.23, p=0.02) and for paravalvular leakage (RR 1.31, p=0.006.). Conclusion: Neither mortality nor the incidence of major adverse cardiac and cerebrovascular events after TAVI is affected by the choice for either LRA or GA.

Introduction of transcatheter aortic valve implantation (TAVI) has resulted in a paradigm shift in the treatment of patients with high risk or inoperable severe aortic stenosis. This article aims to comprehensively review the mechanisms of neurological injury per se, the read-outs of cerebrovascular events, and strategies currently used to predict and prevent stroke in transcatheter aortic valve implantation.

Transcatheter aortic valve implantation (TAVI) is all the more used therapeutic option for patients suffering from symptomatic severe aortic valvular stenosis declined by surgeons because of high surgical risk. Given the high bleeding and ischemic risk of this vulnerable population, their antithrombotic treatment becomes a crucial issue. There is no consensus on antithrombotic treatment after TAVI and dual antiplatelet therapy (DAPT) with aspirin (indefinitely) and clopidogrel (1-6 months) is, in general, recommended. With regards to patients with an indication for oral anticoagulation (OAC), a combination of OAC plus aspirin or clopidogrel is commonly suggested. This review underscores that it is extremely difficult to compare different antithrombotic regimens in patients undergoing TAVI because of their variable demographic characteristics. Nevertheless, available data suggest that DAPT results to more bleeding events. Still, whether it positively affects ischemic episodes is doubtful. Ongoing trials are expected to draw a clearer picture on the field.

Introduction: Aortic stenosis is one of the most frequent valvulopathy of modern time necessitating interventional therapy when symptoms arise and stenosis becomes severe. First line treatment has traditionally been surgical aortic valve replacement (SAVR). However in the last decade transcatheter aortic valve implantation (TAVI) with bioprosthetic valves has proved to be a sound solution for high-risk for SAVR or inoperable patients. As expected implantation of the bioprosthetic device requires administration of antiplatelet regimen to the patients for a certain period. Atrial fibrillation (AF) may occur frequently during the peri-procedural period. In this background, the occurrence of AF after device implantation may be a challenging issue. Methods: We performed a literature search of PubMed and Embase database. Published articles reporting the incidence, clinical implications and description of antithrombotic regimen of New-onset atrial fibrillation (NOAF) in individuals undergoing TAVI were considered eligible. Incidence, Implications and Antithrombotic Regimen: The overall occurrence of NOAF is reported to be 1%-32% after TAVI. Left atrial enlargement and transapical approach constitute independent predictors for NOAF. Additionally it has been shown that patients with AF face an increased risk of death irrespective of the type of AF. Patients, with a history of AF, present greater rate of death than individuals with NOAF. NOAF is responsible for cerebrovascular events (CVE) occurring in the subacute phase (days 1–30) after the procedure. The risk of stroke/transient ischemic attack after TAVI is increased at least two fold by the presence of atrial fibrillation. Empirically, a dual antiplatelet strategy has been used for patients undergoing TAVR, including aspirin and a thienopyridine. In cases where patients are in need of oral anticoagulation after TAVI a combination of aspirin or thienopyridine with acenocoumarol has been the preferred regimen. Discussion: Despite the continuously crescent use of TAVI for patients with symptomatic severe aortic stenosis, there are still many aspects of this procedure to be clarified. A lack of data exists from the available clinical trials regarding the appropriate anticoagulation therapy for patients with greater risk for thromboembolic events. As a result, patient’s treatment remains at the discretion of the physician. Conclusion: Limited data are available regarding the optimal therapeutic regimen in patients undergoing TAVI who need therapy for AF. Carefully designed clinical studies might further clarify the incidence and interrelation between atrial fibrillation and TAVI. The balance between the efficacy and risk of anticoagulation needs to be further clarified in patients undergoing TAVI.

While transcatheter aortic valve implantation (TAVI) has rapidly evolved as an acceptable alternative to conventional surgical aortic valve replacement in elderly, high-risk surgical candidates with critical aortic stenosis, thrombotic and bleeding complications remain relatively frequent and potentially life-threatening. Thrombotic events during and following TAVI relate to the dynamic interplay between the systemic burden of atherosclerotic disease, atrial arrhythmias, device and native aortic valve interactions, as well as platelet and coagulation cascade activation. Bleeding in the acute setting relates primarily to access site vascular complications, but also appears related to pre-existing renal impairment and anemia. Current pre-, peri- and post-procedural anti-thrombotic regimens are empirical, based on expert consensus following extrapolation from the wealth of experience gleaned following percutaneous coronary intervention. However the complexities of the TAVI procedure, the high-risk clinical substrate and competing effects of anti-thrombotic regimens and bleeding risk are yet to be prospectively assessed in randomized clinical trials for defining evidence-based anti-thrombotic strategies.

While the main gist of research pertaining to TAVR procedure involves improvement of existing valve technologies, lower size delivery systems and post-procedure antithrombotic therapy, the optimal intra-procedure anticoagulation has not been sufficiently defined. Peri-procedural complications such as cerebrovascular events and bleeding are largely associated with the safety and efficacy of anticoagulation regimen. Current guidelines advocate the use of heparin for anticoagulation with a target activated clotting time ≥300 seconds and careful protamine infusion in patients with high estimated bleeding risk. In this setting bivalirudin, devoid of all undesirable properties of unfractionated heparin such as highly variable elimination time and heparin-induced thrombocytopenia, may represent an alternative option in the interventionist’s armamentarium. Initial experience with bivalirudin has been encouraging as shown in two observational studies in the context of TAVR and balloon aortic valvuloplasty. The need for bleeding events reduction is particularly pronounced in this population that exhibits an inherent high bleeding risk due to platelet and von Willebrand factor dysfunction. Nevertheless, data from randomized studies are needed to establish bivalirudin role during TAVR procedure.

Antiplatelet drugs are the cornerstone of therapy in many cardiovascular conditions. With the current success and increased use of transcatheter aortic valve implantation (TAVI), the use of antiplatelet therapy is considered part of the medical therapy for these patients. Clinicians caring for these patients need to have a thorough understanding of the pharmacology, pharmacokinetics, pharmacodynamic, and clinical efficacy and safety of commonly used antiplatelet therapy. While aspirin therapy is widely used, dual antiplatelet therapy with clopidogrel has become part of standard of care. Despite the extensive experience with clopidogrel, there are limitations such as drug interactions, metabolism genetic polymorphisms, and variability in the antiplatelet response. More predictable and more potent antiplatelet agents, prasugrel and ticagrelor, have demonstrated superior reductions in ischemic endpoints as part of dual antiplatelet therapy compared to clopidogrel, but at the cost of more major bleeding in patients with an acute coronary syndrome. Significant research needs to be conducted in the setting of TAVI to help define the optimal antiplatelet regimen.

Pharmacogenomics is a relatively recent yet rapidly expanding field of study examining how genetic variations influence responses to drugs. Antithrombotic drugs include the anticoagulant and antiplatelet compounds widely prescribed for the treatment and prevention of cardiovascular diseases. However, there is a large variability in response to antithrombotics, and this can modify the benefit/risk ratio of taking such medications. This variability can be explained by clinical factors such as age, sex, and drug-drug interactions, but also by genetic variants. In recent years, several genetic polymorphisms have been associated with variable biological responses to antithrombotics. Relevant polymorphisms related to antithrombotics have included target genes and genes that participate in the drugs’ pharmacokinetics. This article provides a comprehensive review of the published literature about the pharmacogenomics of antithrombotic drugs, including well-studied compounds such as vitamin K antagonists (e.g., warfarin, acenocoumarol, and phenprocoumon), aspirin, and clopidogrel, as well as more recently approved compounds such as prasugrel, ticagrelor, and direct oral anticoagulants.

Acute kidney injury (AKI) is relatively common in patients undergoing transcatheter aortic valve implantation (TAVI) and has been associated with increased mortality and worse outcomes. The administration of iodinated contrast media in an elderly population with increased rates of chronic kidney injury and heart failure, the risk of hemodynamic compromise and the use of large catheters intra-procedurally make patients undergoing TAVI particularly vulnerable to renal insults and AKI. Furthermore, these patients are commonly exposed to iodinated contrast media during diagnostic and possible interventional procedures pre-TAVI. While risk factors such as baseline comorbidities are non-modifiable, others such as administration of nephrotoxic medications, the type and amount of contrast medium and the catheters size can be avoided, modified and improved. In addition, numerous other interventions such as volume expansion and possibly medications can prevent contrast related kidney injury. In this review, we sought to focus on strategies aiming at reducing the incidence of TAVI-related AKI.

During the last decade, transcatheter aortic valve implantation (TAVI) has become a widespread procedure for the treatment of symptomatic severe aortic stenosis in patients with high surgical risk. In conjunction with the growing experience, the adverse outcomes of TAVI have arisen, including transcatheter aortic valve infective endocarditis (TAVIE). Although rare, TAVIE has been shown as a major etiology of transcatheter aortic valve failure and its magnitude is expected to increase as TAVI will become more frequent, and long term follow-ups will accumulate. To date, large scale TAVI cohorts have restrictively addressed TAVIE-related data and details regarding TAVIE course and management are available only in sporadic case reports, which have been recently collected and published. In this review, we present a case of TAVIE from our institution and analyze the available data regarding prevalence, clinical presentation and microbiology of TAVIE, as depicted from the current literature. We discuss TAVIE treatment and prophylaxis strategies, which are expected to gain growing attention in the years to come, as TAVI will be established as a key procedure in aortic stenosis management.

Objective: Transcatheter aortic valve implantation (TAVI) has emerged as a feasible alternative treatment to conventional surgical aortic valve replacement (AVR) for high-risk patients with aortic stenosis. The present systematic review aimed to assess the comparative clinical and cost-effectiveness outcomes of TAVI versus AVR, and meta-analyse standardized clinical endpoints. Methods: An electronic search was conducted on 9 online databases to identify all relevant studies. Eligible studies had to report on either periprocedural mortality or incremental cost-effectiveness ratio (ICER) to be included for analysis. Results: The systematic review identified 24 studies that reported on comparative clinical outcomes, including three randomized controlled trials and ten matched observational studies involving 7906 patients. Meta-analysis demonstrated no significant differences in regards to mortality, stroke, myocardial infarction or acute renal failure. Patients who underwent TAVI were more likely to experience major vascular complications or arrhythmias requiring permanent pacemaker insertion. Patients who underwent AVR were more likely to experience major bleeding. Eleven analyses from 7 economic studies reported on ICER. Six analyses defined TAVI to be low value, 2 analyses defined TAVI to be intermediate value, and three analyses defined TAVI to be high value. Conclusion: The present study demonstrated no significant differences in regards to mortality or stroke between the two therapeutic procedures. However, the cost-effectiveness and long-term efficacy of TAVI may require further investigation. Technological improvement and increased experience may broaden the clinical indication for TAVI for low-intermediate risk patients in the future.