Bleeding Events After Transcatheter Aortic Valve Replacement

JACC State-of-the-Art Review

Marisa Avvedimento, MD; Jorge Nuche, MD, PHD; Julio I. Farjat-Pasos, MD, MSC; Josep Rodés-Cabau, MD, PHD

J Am Coll Cardiol. 2023;81(5):684-702.

Abstract and Introduction

Abstract

Transcatheter aortic valve replacement (TAVR) has gained over time a major reduction in procedural complications. Despite this, clinically relevant bleeding still occurs in a non-negligible proportion of patients and adversely affects prognosis. Patients with severe aortic stenosis are at heightened risk for spontaneous bleeding due to advanced age and a high comorbidity burden. Also, procedural factors and antithrombotic management contribute to define individual bleeding susceptibility. Bleeding prevention represents an emerging area for improving patient care. Because of the tight hemorrhagic/ischemic balance, a tailored approach based on individual bleeding-risk profile, such as a less invasive antithrombotic regimen or appropriate diagnostic preprocedural evaluation, should be pursued to avoid bleeding events. This review aims to provide an in-depth overview of bleeding events in the TAVR field, including definitions, timing and the extent of risk, and clinical impact, as well as updates on antithrombotic management and its potential influence on bleeding complications.

Introduction

Transcatheter aortic valve replacement (TAVR) has led to a paradigm shift in the treatment of severe aortic stenosis, being a breakthrough treatment across the entire spectrum of surgical risk.^[1,2] Advances in patient selection, device features, and procedural refinements have driven improvement in safety and reduction of procedural complications, explaining the TAVR-related survival benefit proved over time.^[3–10] However, procedural complications with a detrimental impact on short- and long-term outcomes are still observed in a non-negligible proportion of patients.

Despite TAVR having been historically associated with lower rates of hemorrhagic events than conventional surgery, bleeding events in the context of TAVR have also been associated with poorer outcomes.^[11] The complex balance between bleeding and thrombotic risks is strengthened in the TAVR setting as compared with other percutaneous interventions.^[12] In fact, the 30-day rate of major and life-threatening bleeding ranged broadly between 2.4% and 41.7% in pivotal clinical trials, whereas the 30-day rate of major or disabling stroke ranged between 0% and 5%.^[3–10]

Interestingly, the inclusion of major bleeding as part of the primary outcome in the recent largescale randomized clinical trials emphasizes the need to appropriately capture and report these complications. This review aims to provide an in-depth overview of bleeding events in the TAVR field, including definitions, timing and the extent of risk, and clinical impact, as well as updates on antithrombotic management and its potential influence on bleeding complications.

1 2 3 4 5 6 7 8

Next Section

Table 1. Changes in the VARC-3 Bleeding Definition as Compared With Previous Criteria (VARC-2)
VARC-3	Type 1	Overt bleeding that does not require surgical or percutaneous intervention, but does require medical intervention, leading to hospitalization, an increased level of care, or medical evaluation	BARC 2	BARC 2 BARC 3a	Any bleeding worthy of clinical mention	Minor	VARC-2
		Overt bleeding that requires a transfusion of 1 U of whole blood/red blood cells	BARC 3a
	Type 2	Overt bleeding that requires a transfusion of 2–4 U of whole blood/red blood cells	BARC 3a	BARC 3a	Overt bleeding either associated with a drop in the hemoglobin level of at least 3.0 g/dL or requiring transfusion of 2 or 3 U of whole blood/RBC, or causing hospitalization or permanent injury, or requiring surgery	Major
		Overt bleeding associated with a hemoglobin drop 3–5 g/dL	BARC 3a
	Type 3	Overt bleeding requiring a transfusion of ≥5 U of whole blood/red blood cells	BARC 3a	BARC 3b	Overt source of bleeding with drop in hemoglobin ≥5 g/dL or whole blood or packed red blood cells transfusion ≥4 U	Life-threatening or disabling
		Overt bleeding associated with a hemoglobin drop ≥5 g/dL	BARC 3b
		Overt bleeding causing hypovolemic shock or severe hypotension or requiring vasopressors or surgery	BARC 3b	BARC 3b	Bleeding causing hypovolemic shock or severe hypotension requiring vasopressors or surgery
		Overt bleeding in a critical organ, such as intracranial, intraspinal, intraocular, pericardial, or intramuscular with compartment syndrome	BARC 3b BARC 3c	BARC 3b BARC 3c	Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or pericardial necessitating pericardiocentesis, or intramuscular with compartment syndrome
		Overt bleeding requiring reoperation, surgical exploration, or reintervention for the purpose of controlling bleeding	BARC 3b BARC 4
		Post-thoracotomy chest tube output ≥2 L within 24 h	BARC 4
	Type 4	Overt bleeding leading to death Probable: clinical suspicion BARC 5a Definite: confirmed by autopsy or imaging BARC 5b	BARC 5	BARC 5	Fatal bleeding

BARC = Bleeding Academic Research Consortium; RBC = red blood cells; VARC = Valve Academic Research Consortium.

Table 2. Predictors of Vascular Complications in Transfemoral TAVR Cohorts
First Author (Ref. #)	Predictors	OR/HR for Vascular Complications (95% CI)	P Value	HR for Mortality in Patients Who Experienced Vascular Complications (95% CI)	P Value
Sherwood⁴⁶ N = 34,893	Sex, female	1.97 (1.82–2.13)	<0.001	2.23 (1.80–2.77) 30 d 1.17 (1.05–1.30) 1 y	NR
	Sheath size, >17 F	1.28 (1.16–1.42)	<0.001
	Peripheral artery disease	1.33 (1.22–1.46)	<0.001
	BMI	1.11 (1.03–1.20)	0.009
	Femoral cutdown vs femoral percutaneous access	1.24 (1.09–1.41)	0.001
Piccolo¹⁵ N = 926	Sex, female	2.59 (1.10–6.13)	0.030	1.33 (0.99–1.79)	0.056
van Wiechen⁹³ N = 512	Femoral artery diameter, per mm increase	0.81 (0.54–0.99)	0.015	—	—
	Femoral artery puncture height <0 cm, 0–2 cm as reference	3.47 (1.21–10.0)	0.002	—	—
	Femoral artery puncture height >2 cm, 0–2 cm as reference	2.43 (1.16–5.10)	0.002	—	—
Langouet⁹⁴ N = 479	Moderate-severe iliofemoral calcification	2.0 (1.29–3.10)	0.002	18.69 (5.7–61.1) 1 y (major vascular complications)	<0.001
	Moderate-severe iliofemoral tortuosity	2.36 (1.48–3.76)	<0.001
	Sheath-to-iliofemoral artery ratio	6.52 (1.19–21.34)	0.002
	Iliac morphology score	1.25 (1.08–1.46)	0.003
van Kesteren⁹⁵ N = 400	Sheath-to-iliofemoral artery ratio	7.51 (1.61–34.95)	0.010	—	—
Batchelor⁹⁶ N = 303	Vessel tortuosity	3.1 (1.1–9.2)	0.04	—	—
Batchelor⁹⁶ N = 303	CAD	8.2 (1.8–37)	0.00	—	—

BMI = body mass index; CAD = coronary artery disease; TAVR = transcatheter aortic replacement.

Table 3. Current Recommendations for Antithrombotic Strategies in TAVR
		ESC/EAPCI 2021⁶⁰	ACC/AHA 2020²	CCS Statement 2019⁹⁷
Preprocedural	No indication for OAC	Aspirin (or clopidogrel)	—	—
Preprocedural	Indication for OAC	OAC	—	—
Procedural		Unfractionated heparin Goal ACT: 250–300 s Reversal with protamine recommended Bivalirudin in patients with contraindication to unfractionated heparin	—	—
Postprocedural	No indication for OAC	Recent PCI (<3 mo) 1–6 mo: aspirin + clopidogrel Lifelong: aspirin or clopidogrel No recent PCI Aspirin (or Clopidogrel)	Aspirin or 3–6 mo: aspirin + clopidogrel (Low bleeding risk) or 3 mo: VKA (Low bleeding risk)	Recent PCI Aspirin + clopidogrel As per treating physician No recent PCI Aspirin
Postprocedural	Indication for OAC	Recent PCI (<3 mo) 1–6 mo: OAC + aspirin (Or clopidogrel) Lifelong: OAC No recent PCI OAC	No specific recommendation	DOAC^a + aspirin or OAC Avoid triple therapy in patients at increased bleeding risk

^aWarfarin would be preferable for patients with contraindications to direct oral anticoagulants (DOACs) in the setting of mitral valve stenosis or mechanical valve replacement.
ACC = American College of Cardiology; ACT = activated clotting time; AHA = American Heart Association; CCS = Canadian Cardiovascular Society; EAPCI = European Association of Percutaneous Cardiovascular Interventions; ESC = European Society of Cardiology; OAC = oral anticoagulation; PCI = percutaneous coronary intervention; TAVR = transcatheter aortic replacement; VKA = vitamin K antagonist.

Table 4. Ongoing Randomized Studies on Antithrombotic Therapy After TAVR
Study ClinicalTrials.gov Identifier	Experimental Arm	Comparison Arm	Primary Endpoint	Population	Sample Size	Follow-Up
Recruiting
AVATAR NCT02735902	OAC (VKA or DOAC)	Aspirin + OAC	Composite of death from any cause, myocardial infarction, stroke, valve thrombosis and hemorrhage ≥2 as defined by the VARC 2	Indication for OAC	170	12 mo
REAC-TAVI2 NCT05283356	Ticagrelor 60 mg	Aspirin	Composite of all-cause mortality, transient ischemic attack or stroke, myocardial infarction, angina, rehospitalization or new coronary angiography, valve thrombosis, claudication, acute limb ischemia, any bleeding	All TAVR patients	1,206	12 mo
ACASA-TAVI NCT05035277	DOAC	Aspirin	Hypoattenuated leaflet thickening, composite of VARC-3 bleeding events, thromboembolic events (myocardial infarction or stroke), and all-cause mortality	All TAVR patients	360	12 mo
REDOX-TAVI NCT04171726	Edoxaban	VKA	Incidence of aortic valve leaflet thickening after TAVI as assessed by cardiac 4D CT	All TAVR patients	100	3 mo
PTOLEMAIOS NCT02989558	Ticagrelor + Aspirin	Clopidogrel + Aspirin	The number of HITS as assessed with transcranial Doppler on middle cerebral arteries	All TAVR patients	90	3 mo
Not yet recruiting
Antithrombotic Strategy Based on Clinical Events and 4D-CT for Patients After TAVR NCT05375474	OAC (VKA)	Clopidogrel + Aspirin	Composite of all-cause mortality, myocardial infarction, stroke, TIA, peripheral artery thrombosis, disabling, life-threatening and major bleeding Rates of prosthetic valve thrombosis detected by 4D-CT	All TAVR patients	420	12 mo
ACLO-TAVR NCT05493657	Aspirin	Clopidogrel	Leaflet thrombosis on cardiac CT	No indication for OAC	230	3 mo

4D = 4-dimensional; ACASA-TAVI = Anticoagulation Versus Acetylsalicylic Acid After Transcatheter Aortic Valve Implantation; ACLO-TAVR = Aspirin vs Clopidogrel After TAVR; AVATAR = Anticoagulation Alone Versus Anticoagulation and Aspirin Following Transcatheter Aortic Valve Interventions (1:1); CT = computed tomography; DOAC = direct oral anticoagulant; HITS = high intensity transient signals; PTOLEMAIOS = A Trial to Assess the Safety and Efficacy of Prophylactic Ticagrelor With Acetylsalicylic Acid Versus Clopidogrel With Acetylsalicylic Acid in the Development of Cerebrovascular Embolic Events During TAVI; REAC-TAVI2 = Single Antiplatelet Treatment With Ticagrelor or Aspirin After Transcatheter Aortic Valve Implantation; REDOX-TAVI = Rotterdam Edoxaban Leaflet Evaluation in Patients After Transcatheter Aortic Valve Implantation; TIA = transient ischemic attack; other abbreviations as in Tables 1 and 3.