Essay on Transcatheter Aortic Valve Replacement

Transcatheter aortic valve replacement (TAVR) has revolutionized interventional cardiology by providing a valuable option for non-operable patients with severe aortic stenosis or high-risk populations. However, TAVR is associated with the risk of cerebral embolization, ischemic vascular events, and possible neurological impairment. The estimate of these complications varies, but they have been reported early and late after the procedure. Moreover, the reported incidence of bleeding associated with TAVI is relatively high. Therefore, adequate antithrombotic therapy during and following the procedure is required. However, despite current guideline recommendations, the optimal antithrombotic therapy is not well-established.

Introduction:

Severe Aortic Stenosis (AS) is a major cause of mortality and morbidity in the elderly due to a bimodal age distribution. Degenerative calcification of the tricuspid valve is the major cause of AS in the population, unlike the younger patient etiology, which is bicuspid valve calcification or rheumatic heart disease. The burden of the disease is high with a prevalence of 3.4%. With the progressive nature of the disease and the increased severity of the symptoms, surgery is the gold standard for symptomatic AS patients. However, up to 30% of cases are considered too high-risk for classical valve replacement surgery and remain untreated, experiencing poor prognosis. Fortunately, with the introduction of TAVR, it offers a valuable option for inoperable or high-risk surgery patients. The annual eligible candidate for this procedure is expected to be 27,000 in 19 European countries and North America, according to recent meta-analysis and modeling study.

TAVI is associated with a high risk of stroke, transient ischemic stroke, atrial fibrillation, and myocardial infarction. The long-term outcome associated with bleeding complications is mainly due to the use of Dual antiplatelet therapy (DAPT), which raises the need to find the optimal regimen of antithrombotic therapy to avoid early cerebrovascular complications, provide optimum stroke prevention, and avoid bleeding as a long-term outcome. This article will review the current recommendation of antithrombotic therapy during and following TAVI and the recent evidence and advancements in this unique procedure.

TAVI Versus SAVR:

Although there is cumulative data suggesting superior survival and symptomatic outcomes for inoperable patients who undergo TAVI versus medical palliation, the available data on TAVI versus AVR showed that major adverse outcomes, such as mortality and stroke, appeared to be similar between the two treatment modalities. Evidence on the outcomes of TAVI compared with AVR in the current literature is limited by inconsistent patient selection criteria, heterogeneous definitions of clinical endpoints, and relatively short follow-up periods. Two meta-analyses have been conducted that include TAVR and SAVR studies in their evaluation. One meta-analysis compared TAVR to AVR, combining the results from two randomized controlled trials and 11 observational reports comparing TAVI with AVR in patients with severe aortic stenosis. Interestingly, selected studies identified no significant differences in mortality and stroke between the two treatment groups. However, vascular complications, permanent pacemaker insertion, and significant aortic regurgitation were relatively common after TAVI and significantly more frequent than after conventional AVR.

Conversely, major bleeding was more likely to occur after surgical AVR than TAVI. The second meta-analysis of seventeen studies (n=4,659) comparing TAVR (n=2,267) and SAVR (n=2,392) was conducted to determine the differences in postprocedural mortality and major adverse cardiovascular and cerebrovascular events between the two interventions, including major bleeding. Seven endpoints were assessed: baseline logistic European System for Cardiac Operative Risk Evaluation score, all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, and transient ischemic events. There was no significant difference in cardiovascular mortality (p=0.54), as well as the incidence of myocardial infarction (p=0.59), stroke (p=0.36), and transient ischemic attack (p=0.85) at averages of 86, 72, 66, and 89 weeks, respectively.

Similar to the previous meta-analysis, TAVI was noninferior to SAVR for postprocedural myocardial infarctions and cerebrovascular events, but it was superior to SAVR for major bleeding complications. Therefore, TAVR should be considered in selected high-risk elderly patients, and the use of TAVR for eligible surgical candidates should be considered within the boundaries of clinical trials due to the important cerebrovascular and cardiovascular debilitating adverse events, which are significant predictors of mortality. The suggested predisposing factors for the occurrence of stroke are newly onset atrial fibrillation and higher-grade mitral valve insufficiency.

Additionally, the antithrombotic regimen appears to play a major role in the prevention of those fatal complications. However, it is unclear what the optimal antithrombotic regimen is to provide protection for early and late thrombotic events in patients undergoing TAVR. In the absence of randomized control trials and lack of evidence-based recommendations from international societies, which base their recommendations on observational studies, there is no specific recommendation for antithrombotic prior to TAVR. However, a few recent studies have suggested bridging with unfractionated heparin for those who require anticoagulation therapy before TAVR (e.g., mechanical mitral valve).

A recent study evaluated early and long-term bleeding complications after TAVR and suggests avoiding pretreatment with clopidogrel in patients with advanced age, BMI, and a history of anemia who have an increased risk for early bleeding. They suggested that vitamin K antagonists with clopidogrel seem to be the safest therapy in the early post-TAVI period. Antithrombotic during TAVR: The current expert consensus document of ACCF/AATS/SCAI/STS on transcatheter aortic valve replacement guidelines recommended unfractionated heparin to be started prior to insertion of the arterial sheath with a target activated clotting time (ACT) greater than 250-300 seconds. This ACT target was extrapolated from other cardiovascular invasive procedure targets to provide ischemic cerebrovascular protection following the perioperative period, which required higher doses of heparin administered during the procedure compared to the dose given during.

Percutaneous interventions (PCI) aim for a target of 220-250 seconds to prevent coronary thrombosis and myocardial infarction, with an acceptable risk of bleeding (19, 20). This is one of the reasons why intravenous Protamine is given at the end of the procedure (1 mg can neutralize nearly 100 units of UFH) (16, 21). Additionally, it helps to avoid bleeding related to mechanical factors such as a larger size of the delivery catheter and minimizes access site bleeding events. However, the short half-life of protamine can lead to rebound anticoagulation and prolonged bleeding (22). Other side effects of Protamine include hypotension and bradycardia, which are related to the infusion rate and can increase the hospital mortality rate after invasive cardiovascular procedures. The influence of these drug-induced adverse events on TAVR has not yet been addressed (20, 23).

Another major side effect of heparin is thrombocytopenia (HIT). The guidelines do not recommend any other anticoagulants to manage patients who have a history or have developed HIT. However, a few reports suggest direct thrombin inhibitors for this patient population, specifically bivalirudin, which has more predictable pharmacokinetics than unfractionated heparin and reduces the need for laboratory monitoring with a lower incidence of bleeding rate (24).

The disadvantage of bivalirudin is that clinicians are less familiar with it, and there is no study comparing it to heparin in TAVR settings. Future procedural anticoagulation trials should compare regimens that have complications (bivalirudin) compared with the current standard of care (heparin).

Antiplatelet therapy: The role of pre-operative antiplatelet therapy in TAVI is not fully understood or studied. Therefore, the current guidelines do not suggest a specific recommendation in this regard. However, in PARTNER trials and several survey studies, a loading dose of aspirin 300 mg and clopidogrel of 300 mg was given (14). The role of early administration of antiplatelet therapy and if the early antithrombotic events are platelet events is not yet established, and no prospective study has evaluated it (16, 25).

Antithrombotic therapy after TAVR: DAPT is the most widely used antithrombotic strategy after TAVR, and the suggested duration is 3-6 months according to international guidelines. Interestingly, these are not evidence-based recommendations and were extrapolated from the ischemic events post PCI to reduce the risk of thrombosis and embolization. However, the pathology of thromboembolic events related to TAVI is unknown to provide information about the optimal duration of DAPT. The similarity between the mechanical pathobiology of the stent after PCI and bioprosthetic valve does exist since they both require neointimal tissue growth and endothelialization, which is associated with a higher stroke risk after 3 months of implementation. Therefore, the future direction of antithrombotic prevention will be as early as 24 hours after the procedure up to 3 months thereafter (21, 26). Although small sample size studies showed no difference in terms of ischemic and bleeding events between aspirin alone or DAPT post TAVR (27).

Which enables clinicians to have a definite conclusion about the combination therapy, showed no differences in ischemic and bleeding events. A definite conclusion about the role of combination therapy is needed. In addition, an ongoing ARTE (Aspirin Versus Aspirin and Clopidogrel Following Transcatheter Aortic Valve Implantation)28 pilot study compared the previous regimen to provide solid evidence to draw a conclusion for DAPT controversy regarding possible premature discontinuation of them in special patient populations, such as the elderly who have a high risk of cardiovascular events and tend to bleed, and patients who are high on clopidogrel platelet activity and the potential alternative to replace clopidogrel, especially in patients with an increased risk of bleeding21,29.

Conclusion: TAVR is a unique procedure, and implementing optimal antithrombotic therapy during and after it is challenging. Several technical limitations limit its widespread use in elderly patients who have a higher atherosclerotic plaque burden, severe calcification, or peripheral vascular disease. The risks of ischemic stroke and major bleeding remain high, and both of these complications continue to occur throughout the first month after the procedure. DAPT duration is not evidence-based, and it needs to be addressed in future clinical trials for clinical decision-making in this fast-growing patient population.

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