Antithrombotic therapy and recommended follow-up

Antithrombotic therapy after TAVI

Prosthetic valves have known thromboembolic complications, especially in the short term, with an incidence observed to be <1% to almost 8% in the first year after transcatheter aortic valve implantation (TAVI). However, the prevention of these complications with routine use of antithrombotic therapy is challenging in this patient population.

• Risk factors that have been reported for stroke in the early period after TAVI include history of atrial fibrillation, female sex, renal dysfunction, and vascular complications.

• Multiple risk factors for bleeding may also exist, including advanced age, frailty, and systemic medical comorbidities of noncardiac organ systems. These contribute to the risk of both long-term bleeding and immediate periprocedural and short-term bleeding.

Current guideline recommendations for antithrombotic therapy after TAVI ( Table 15.1 ) are predominantly based on nonrandomized data and expert consensus according to the protocols used in pivotal clinical trials of TAVI ( Table 15.2 ). ^, Randomized controlled data are now becoming available as well.

• It is most common to use dual antiplatelet therapy for a limited number of months and indefinite aspirin in the absence of contraindications.

• If systemic anticoagulation is indicated, additional single antiplatelet therapy can be considered for a limited period of time or not at all if the bleeding risks are likely to outweigh the benefit.

The objective of routine antiplatelet therapy after TAVI is to prevent the formation of thrombus on metallic stent structure before endothelialization, similar to what is done in the setting of stents used for percutaneous coronary intervention. Endothelialization of TAVI valves has been investigated in postmortem studies but the overall amount of data are limited. There is suggestion that although a significant portion of the outer stent structure of TAVI valves becomes endothelialized, areas that are not in direct contact with native tissue may not endothelialize at all in the short to medium term. Complete or near-complete endothelialization is expected in approximately 3 months after implantation.

Single versus dual antiplatelet therapy after TAVI has been evaluated in several observational and randomized controlled studies ( Table 15.3 ). It should be noted that the statistical power to detect differences in clinical outcomes was limited in some of these small studies.

• Overall, these short-term studies suggest that single antiplatelet therapy does not appear to be inferior to dual antiplatelet therapy in preventing thromboembolic events or mortality.

• The risk of bleeding complications was noted to be statistically significantly higher in one study (POPular TAVI EU), which was consistent with a trend noted in the earlier smaller ARTE study. This is not surprising given the body of evidence showing increased bleeding risk with more intensive antiplatelet and anticoagulation therapy observed in the setting of coronary artery disease, acute coronary syndrome, and percutaneous coronary intervention.

• If there is an indication for systemic anticoagulation, usually atrial fibrillation, this should be continued after TAVI in the absence of any contraindication.

• Antiplatelet therapy in addition to anticoagulation was evaluated in the randomized POPular TAVI EU trial, as well as small observational studies. In the POPular TAVI EU study, there was no reduction in a composite outcome including cardiovascular death, stroke, or myocardial infarction, but an increased risk of bleeding (predominantly at the TAVI access site) was seen.

Observational data have noted that subclinical leaflet thrombosis is seen in some patients after TAVI, most notably through the finding of hypoattenuated leaflet thickening on computed tomography (CT). ^, This finding has also been associated with increased transvalvular gradients as assessed by Doppler echocardiography.

• The prevalence of subclinical leaflet thrombosis is highly variable in the literature, ranging from <10% to as high as 40%, depending on the study design and medication use.

• In multiple studies, these abnormalities seen on CT improve or completely resolve after initiation of systemic anticoagulation with an associated drop in transvalvular gradients.

• There is also an observed association between the use of systemic anticoagulation and a lower incidence of leaflet thickening.

TAVI valves may be at higher risk of thrombus formation compared with surgical aortic valves for many reasons. Crimping causes some degree of trauma to the tissue leaflets, flow dynamics related to the native diseased aortic valve adjacent to the prosthesis may cause some degree of blood stasis, and prosthetic leaflet function may be affected by variability in the degree of prosthesis expansion because of the degree and pattern of native aortic valvular and annular calcification. The exact impact of each factor and strategies to reduce mechanical risk factors for prosthetic thrombus are not well studied. Most TAVI prostheses are manufactured using either bovine or porcine pericardial tissue that has been processed for sterility, immunogenicity, and durability. Although the final tissue characteristics may have implications on leaflet thrombogenicity, there are no studies investigating specific materials or processing in detail to fully understand the potential clinical impact.

Routine use of direct oral anticoagulants in the absence of other indications for anticoagulation is not well studied but has become an area of great clinical interest.

• A single randomized trial (GALILEO) evaluated the use of the direct factor Xa inhibitor rivaroxaban after TAVI in patients without a specific indication for anticoagulation. In this study and the GALILEO-4D imaging substudy, whereas presence of subclinical leaflet thickening on CT was lower with rivaroxaban, the clinical outcomes of death combined with first thromboembolic event and overall bleeding were higher.

• These findings highlight that the risks of anticoagulation in this patient population are very important to consider and are consistent with findings from other observational studies ( Table 15.4 ).

  TABLE 15.4

  Select Studies Investigating Oral Anticoagulation Therapy After TAVI

  	STUDY
  	POPular TAVI EU [CR]	GALILEO [CR]	FRANCE TAVI [CR]	RESOLVE/SAVORY 4	ATLANTIS [CR]
  Year	2020	2020	2019	2017	2022
  N	326	1644	11,469	890	Estimated 1510
  Design	Randomized open label	Randomized open label	Observational registry	Observational registry	Randomized open label
  Key exclusion criteria	Intolerant to clopidogrel, drug-eluting stent within 3 months, bare-metal stent within 1 month	Indication for long-term anticoagulation or dual antiplatelet therapy		Lack of interpretable CT scans or CT imaging	Contraindication to oral anticoagulants
  Intervention	Oral anticoagulation alone	Rivaroxaban 10 mg daily (+ ASA 75–100 mg daily for 3 months)	Oral anticoagulation	Oral anticoagulation	Apixaban 5 mg twice daily
  Comparison	Oral anticoagulation plus clopidogrel 75 mg daily for 3 months	ASA 75–100 mg daily (+ clopidogrel 75 mg daily for 3 months)	Antiplatelet therapy	Dual antiplatelet therapy	Antiplatelet therapy or vitamin K antagonist (stratified based on baseline indication for anticoagulation)
  Outcome	All bleeding, nonprocedure-related bleeding, composite bleeding plus MACE, MACE	Death or first thromboembolic event	All-cause mortality, bioprosthetic valve dysfunction	Subclinical leaflet thrombosis, leaflet thrombosis resolution, stroke, TIA	Composite including death, MI, stroke, embolism, prosthesis thrombus, DVT, PE, major/disabling/life-threatening bleed
  Follow-up	At least 1 year	Median 17 months	Mean 495 ± 3.5 days	83 days (IQR 33–281 days)	Up to 13 months
  Key finding	Less bleeding (all bleeding RR 0.63 [95% CI 0.43–0.9] p = 0.01) and composite bleeding plus MACE with anticoagulation alone; anticoagulation alone noninferior for MACE	Composite outcome worse with rivaroxaban (HR 1.35 [95% CI 1.01–1.81] p = 0.04)	Increased risk of mortality with oral anticoagulation (HR 1.25 [95% CI 1.08–1.44] p = 0.002)	Subclinical leaflet thrombosis less likely with anticoagulation (4% vs. 15%, p <0.0001)	No difference in primary outcome (HR 0.92 [95% CI 0.73–1.16]) and no interaction by stratum ( p = 0.57)
  Other findings		Trend to higher bleed risk with rivaroxaban (HR 1.5, p = 0.08)	Reduced risk of bioprosthetic valve dysfunction with rivaroxaban (HR 0.51 [95% CI 0.33–0.79] p = 0.003)	Subclinical leaflet thrombosis was associated with increased rates of TIA (4.18 vs. 0.6 per 100 PY, p = 0.0005) but not with stroke ( p = 0.1)	In apixaban vs. antiplatelet stratum, obstructive valve thrombosis lower with apixaban (HR 0.19 [95% CI 0.08–0.46]) but signal for possible increased noncardiac death

  Table References:

  • 1.

    Nijenhuis VJ, Brouwer J, Delewi R, et al. Anticoagulation with or without clopidogrel after transcatheter aortic-valve implantation. N Engl J Med . 2020;382(18):1696-1707.

  • 2.

    Dangas GD, Tijssen JGP, Wöhrle J, et al. A controlled trial of rivaroxaban after transcatheter aortic-valve replacement. N Engl J Med . 2020;382(2):120-129

  • 3.

    Overtchouk P, Guedeney P, Rouanet S, et al. Long-Term Mortality and Early Valve Dysfunction According to Anticoagulation Use: The FRANCE TAVI Registry [published correction appears in J Am Coll Cardiol . 2019 Jun 4;73(21):2788]. J Am Coll Cardiol . 2019;73(1):13-21.

  • 4.

    Chakravarty T, Søndergaard L, Friedman J, et al. Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study. Lancet . 2017;389(10087):2383-2392.

  • 5.

    Collet JP, Van Belle E, Thiele H, et al. Apixaban vs. standard of care after transcatheter aortic valve implantation: the ATLANTIS trial. Eur Heart J . 2022;ehac242. doi:10.1093/eurheartj/ehac242 . Online ahead of print.

  ASA, Aspirin; CI, confidence interval; CT, computed tomography; DVT, deep vein thrombosis; HR, hazard ratio; IQR, interquartile range; MACE , major adverse cardiac events; MI, myocardial infarction; PE, pulmonary embolism; PY, person-year; TAVI , transcatheter aortic valve implantation; TIA, transient ischemic attack.

Ongoing trials evaluating antithrombotic therapy after TAVI include ATLANTIS (apixaban vs. antiplatelet or vitamin K antagonist), AVATAR (vitamin K antagonist alone vs. vitamin K antagonist plus aspirin), AUREA (acenocumarol vs. dual antiplatelet therapy), ENVISAGE TAVI-AF (edoxaban vs. vitamin K antagonist), and ADAPT-TAVR (edoxaban vs. dual antiplatelet therapy).

Based on the current body of evidence and guideline recommendations (see Table 15.1 ), a proposed scheme for antithrombotic therapy considerations is summarized in Fig. 15.1 . Initiation of anticoagulation to replace antiplatelet therapy is also reasonable if subclinical leaflet thrombosis is detected through imaging studies.

Clinical follow-up after TAVI

Clinical follow-up after TAVI has been addressed in international valve disease guidelines ( Table 15.5 ).

• Although a short-term baseline follow-up visit has not been specifically recommended, it is routine practice in many high-volume heart valve centers to have a first follow-up appointment with the patient at 4 to 8 weeks after the implantation ( Fig. 15.2 ).

  

• The first post-TAVI visit has the goals of ensuring good clinical recovery from the implantation procedure and the absence of symptoms to suggest a complication or early device dysfunction.

• This early postprocedure visit also allows clinicians to review patient medications and ensure dual antiplatelet therapy is not prolonged unintentionally.

• Annual routine follow-up appointments including a clinical history for cardiovascular symptoms and physical examination are then recommended to assess for potential prosthetic valve dysfunction.

• If new symptoms develop between routine appointments, additional clinical follow-up with associated appropriate investigations is indicated. In particular, syncope and significant presyncope should prompt urgent clinical evaluation including potential inpatient hospital monitoring because of the known risk of conduction disease requiring a permanent pacemaker after TAVI.

Whether the follow-up appointments occur with the primary cardiac care provider, heart valve team performing the implantation (if separate from the primary cardiac care provider), or both is variable and depends on local practice culture, patient expectations, and logistic system-related factors. What is crucial is that follow-up should occur with at least one qualified cardiovascular health care professional if practical within the context of the individual health care system.

Imaging follow-up after TAVI

Imaging plays an important role in the follow-up of patients after TAVI because it allows for a noninvasive assessment of valvular function to complement the clinical history and physical examination findings. Most modalities are also readily available and pose little to no risk to the patient.