The Role for Combined Antithrombotic Therapy with Platelet and Coagulation Inhibition After Lower Extremity Revascularization

Abstract

Tweet/ handles: @ehweissler, @schuyler_jones, @manesh_patelMD, @AboyansV; Never before have surgeons/interventionalists had enough data to drive antithrombotic decisions after lower extremity revascularization: VOYAGER PAD offered some compelling data for rivaroxaban+ASA, but what are next steps towards answering remaining Q’s & implementing findings?

Antithrombotic treatment following percutaneous coronary intervention (PCI) has been studied in numerous randomized controlled trials (1), yielding class I recommendations to guide management in most situations (2,3). In contrast, the evidence for benefit of antithrombotic treatment following lower extremity revascularization (LER) for peripheral artery disease (PAD) is largely extrapolated from PCI datasets, with limited PAD-specific data. Further complicating the issue are the numerous devices and conduits approved for endovascular and surgical LER, each of which may be associated with a different risk of post-revascularization atherothrombosis. A recent meta-analysis of randomized endovascular LER trials showed marked heterogeneity in the extent to which antithrombotic regimens were specified and in what regimens were used, limiting the ability of these trials to supply evidence for any given antithrombotic strategy (4). This meta-analysis distinguished antiplatelet (targeted at platelet function) from anticoagulant (targeted at the clotting cascade) medications, a convention we follow throughout this Viewpoint, with “antithrombotic” referring to the general strategy of thrombosis prevention (potentially consisting of both antiplatelet and anticoagulant components). The lack of high-quality PAD-specific data has led to variable guideline recommendations (Table 1) as well as inconsistent device labeling (5–8). For instance, the package inserts for the Eluvia (Boston Scientific, Marlborough, MA) and Zilver PTX (Cook Medical, Bloomington, IN) drug-eluting stents (both approved in both the US and Europe) recommend 60 days of dual antiplatelet therapy (DAPT) following implantation, while Angiolite BTK (iVascular, Barcelona, Spain) (available only in Europe) recommends 180 days; the vast majority simply recommend post-procedural antithrombotic treatment per clinician judgement or available guidelines.

Table 1.

Recent guideline recommendations for post-revascularization antithrombotic treatment

	Post-revascularization (General)	Following Endovascular LER	Following Surgical LER
2017 ESC/ESVS PAD Guidelines(5)	Long-term SAPT is recommended in all patients who have undergone revascularization (I C)	DAPT for ≥1 month should be considered after infra-inguinal stent implantation (IIa C)	SAPT is recommended after infra-inguinal bypass surgery (I A)
			VKA may be considered after autologous vein infra-inguinal bypass (IIb B)
			DAPT may be considered in below-the-knee bypass with a prosthetic graft (IIb B)
2019 GVG CLTI Guidelines(7)		Consider DAPT in patients who have undergone infrainguinal PVI for CLTI for a period of at least 1 month (2C)	Consider DAPT in patients who have undergone infrainguinal prosthetic bypass for CLTI for 6 to 24 months to maintain graft patency (2B)
		Consider DAPT for 1 to 6 months in patients undergoing repeated PVI if they are at low risk for bleeding (2C)
2016 ACC/AHA PAD Guidelines(6)	DAPT may be reasonable to reduce the risk of limb-related events in patients with symptomatic PAD after lower extremity revascularization (IIb C-LD)
2019 ESVM PAD Guidelines8	DAPT may be considered in patients at high risk of restenosis or reocclusion. (IIb B)	Following PVI with stent implantations, temporary DAPT should be considered to improve patency. (IIa B)	Long term SAPT is recommended after infra-inguinal bypass surgery (I C)
	Long term SAPT is recommended in patients after revascularization (I C)	DAPT at least 1 month after infrainguinal stent implantation (IIa C)	DAPT may be considered in below the knee prosthetic bypass graft (IIb B)
	The combined therapy of ASA 100 mg/d and rivaroxaban 2 - 2.5 mg/d should be considered in patients without a high risk of bleeding.(IIa B)	DAPT at least 1 month after drug coated balloon angioplasty, drug eluting stent implantation, or covered stent implantation (I C)	VKA may be considered after autologous infrainguinal bypass (IIb B)

Guidelines are paraphrased for concision; refer to the published guidelines for full text.

ACC=American College of Cardiology; AHA=American Heart Association; ASA=acetylsalicylic acid; CLTI=chronic limb-threatening ischemia; DAPT=dual antiplatelet therapy (specified as aspirin and clopidogrel in all guidelines); ESC=European Society of Cardiology; ESVM=European Society of Vascular Medicine; ESVS=European Society for Vascular Surgery; GVG=Global Vascular Guidelines; LER=lower extremity revascularization; PAD=peripheral artery disease; PVI=peripheral vascular intervention/endovascular therapy; SAPT=single antiplatelet therapy; VKA=vitamin K antagonist.

Without strong professional society guidelines or recommendations from device manufacturers, there is evidence of marked heterogeneity in real-world management strategies. This presumably accounts for some of the wide variation in clinical outcomes between patients receiving an ‘ideal’ strategy and those receiving other treatment regimens. In a Canadian survey of vascular surgeons’ approaches to antithrombotic treatment following urgent or emergent LER, 60% reported consideration of aspirin with anticoagulation, 58% DAPT, 42% full anticoagulation alone, and 29% aspirin with 2.5 mg of rivaroxaban twice daily (9). This diversity of opinion is also reflected in actual practice. In a Vascular Quality Initiative (VQI) analysis of patients undergoing elective LE bypass, 3.4% were discharged on DAPT with anticoagulation, 14.5% on aspirin with anticoagulation, 27.9% on DAPT alone, 37.3% on aspirin alone, 6.9% on non-aspirin single antiplatelet therapy (SAPT), and 10% without any antithrombotic treatment (9). Among endovascular LER patients in the same study, 3.6% were discharged on DAPT with anticoagulation, 5.3% on aspirin with anticoagulation, 51.2% on DAPT alone, 12.3% on non-aspirin SAPT, 18.3% on aspirin alone, and 8.4% without any antithrombotic treatment (10,11). Clearly, clinicians are uncertain about the best approach. In the Canadian and European surveys, 66% and 82% of respondents, respectively, felt that there was insufficient evidence to guide antithrombotic decisions following LER (9,12).

Given that much of the evidence on anti-thrombotic therapy in PAD is derived from sub-analyses of PCI literature, most of the data concerns patients with stable/symptomatic PAD. The PAD subgroup analysis from CAPRIE demonstrated the effectiveness of clopidogrel monotherapy, and from TRA 2°P - TIMI 50 the effectiveness of vorapaxar with aspirin, leading both agents to receive FDA approval for cardiovascular prevention in stable/symptomatic PAD.(13,14) Evidence also exists to support the use of DAPT in patients with stable/symptomatic PAD for mortality-, cardiovascular-, and limb-related benefits.(15,16) Ticagrelor-treated PAD patients in PEGASUS-TIMI 54 had lower cardiovascular or all-cause mortality as well as lower rates of acute limb ischemia (ALI) and revascularization.(17) Ticagrelor also lowered the composite of cardiovascular death, myocardial infarction, or stroke as well as ALI or amputation for vascular cause among patients with stable CAD (of whom 8.6% had PAD) in THEMIS.(18) However, guidelines have cautioned against the routine use of DAPT in patients with stable/symptomatic PAD because of a higher hazard of major bleeding.(5,6,8)

Post-LER patients are at higher risk for ALI, recurrent ischemia, and further intervention,(19,20) reflecting both a more aggressive atherosclerotic process and the consequences of arterial modification/instrumentation. Because the risk-benefit analysis differs in patients in the post-LER period, extrapolation from studies of patients with stable disease is inadequate. Therefore, although guidelines do not recommend routine DAPT for stable/symptomatic PAD, it is preferred over SAPT in the immediate post-LER period based off trial and observational data,(21,22) at least among patients undergoing endovascular LER (as the data for DAPT benefit following surgical LER is mixed).(10,23) Indeed, it appears that DAPT has mortality-, cardiovascular-, and limb-related benefits when used in the post-LER setting.(16,22) However, even though patients treated with DAPT in the post-LER period suffer significant rates of ischemic events,(24) increasing the intensity of antiplatelet therapy beyond aspirin with clopidogrel does not necessarily confer additional benefit to counterbalance the increased bleeding risk. There is no data about increased-intensity DAPT in specifically the post-LER period but evidence in other PAD cohorts has been mixed. For instance, among the 1144 patients with PAD in PLATO, the use of aspirin with ticagrelor rather than clopidogrel decreased death from vascular causes or MI without contributing to increased bleeding risk.(25) In TRA 2°P – TIMI 50, 88% of the 3787-patient PAD subgroup were on aspirin, 9% on thiendopyridine, and 28% on aspirin and thienopyridine in addition to vorapaxar or placebo: vorapaxar decreased the frequency of a hospitalization for ALI, peripheral revascularization, and vascular hospitalization at the cost of a significant increase in GUSTO moderate/severe bleeding.(26) However, in the 936-patient PAD sub-analysis of TRACER, in which almost all patients took aspirin and many more (85%) took a thienopyridine in addition to vorapaxar or placebo, vorapaxar did not reduce any ischemic endpoints besides stroke while leading to a significant increase in TIMI major or minor bleeding.(27)

The observation that increasing antiplatelet therapy intensity seemed to have diminishing marginal benefit with increasing bleeding risk has increased interest in exploring whether dual inhibition of both platelet and thrombin activity may benefit patients with PAD who are undergoing revascularization (Figure 1). Historically, antiplatelet therapy has been favored over anticoagulation following LER, in part because vitamin K antagonists (VKAs) were not shown to have any benefit in 2 randomized controlled trials (WAVE [patients with PAD], Dutch BOA [patients undergoing bypass]), and because VKAs are associated with significant safety concerns.(11) Interest in dual pathway inhibition (DPI) for patients with PAD has increased for several reasons. First, anticoagulant options (specifically factor Xa inhibitors) have better safety and effectiveness profiles than VKAs. Second, clopidogrel, which is currently favored in guidelines and in practice despite minimal supporting clinical trial evidence (23), may not be the ideal drug for PAD patients due to high rates of CYP2C19 polymorphisms and high on-treatment platelet reactivity (18). Third, as discussed above, increasing intensity of antiplatelet therapy has not been shown to provide adequate and consistent benefit to outweigh the increased bleeding risk. Fourth, there is evidence from coronary-specific research (e.g., ATLAS ACS-TIMI 51) and limited PAD-specific research (i.e., COMPASS and the ePAD trial of edoxaban versus DAPT following femoropopliteal endovascular intervention) that DPI safely reduces thrombotic events (28–30).

Figure 1. Dual pathway inhibition in the setting of endothelial disruption.

Dual pathway inhibition targets both platelet function and the extrinsic pathway of hemostasis.

The COMPASS trial showed that rivaroxaban 2.5 mg twice daily in addition to aspirin reduced major adverse cardiovascular events (MACE) compared with aspirin alone in patients with chronic coronary artery disease or stable PAD, as well as ALI in patients with symptomatic PAD, but left the question of rivaroxaban efficacy in post-LER PAD patients unanswered.(19) The recent completion of VOYAGER PAD has supplied much-needed evidence to guide post-revascularization antithrombotic therapy. VOYAGER PAD used a composite of MACE plus ALI and major vascular amputation as its primary endpoint, more fully capturing the spectrum of thrombotic events among this patient population.(31) It randomized 6564 patients within 10 days of infrainguinal revascularization and showed that rivaroxaban 2.5 mg twice daily plus aspirin reduced the primary composite outcome at 3 years (hazard ratio [HR] 0.85, 95% CI 0.76–0.96) while leading to a non-significant increase in Thrombolysis in Myocardial Infarction major bleeding (HR 1.43, 95% CI 0.97–2.10). One-third of patients had undergone open surgical revascularization and two-thirds endovascular revascularization; 23% of patients had critical limb ischemia (CLI) and 76% had claudication. Half of patients were taking clopidogrel at randomization, which was permitted up to 6 months

While there is no doubt that VOYAGER PAD will significantly affect the post-revascularization management of PAD patients, crucial sub-analyses are yet to come, and its impact will vary based on intervention type, modality, and location. For instance, among patients undergoing open surgical revascularization, the implications of VOYAGER PAD will likely depend on whether the conduit is autologous or prosthetic. Neither CASPAR nor Dutch BOA showed any benefit to increased-intensity antithrombotic therapy following open bypasses overall, but both showed a patency benefit in the prosthetic bypass subgroup (16,17). While only one-third of VOYAGER PAD patients underwent open revascularization, this 2271 patient subgroup is nearly as large as the Dutch BOA study (N=2690), which was also published in 1995. Future guideline recommendations for antithrombotic therapy following prosthetic bypass may therefore be updated to include DPI.

For patients undergoing endovascular intervention, the treatment modality used may affect the relative benefit of increased-intensity antithrombotic treatment. For instance, there may be certain techniques leading to endothelial trauma, like atherectomy or subintimal recanalization, after which DPI may be more beneficial. This is because endothelial damage leads both to platelet activation, adhesion, and aggregation, and to creation and acceleration of extrinsic ten-ase and prothrombinase (Figure). In VOYAGER PAD, 39.5% of patients had treatment with conventional balloon angioplasty, 22.3% with bare metal stents, 20.1% with drug-coated devices, 4.7% with atherectomy, and 1.9% with covered stents. Analysis of DPI benefit by device type may identify subgroups more likely to benefit as well as areas for further investigation.

Lesion location also drives the need for increased-intensity antithrombotic therapy because lesion location is related to wall shear stress and flow velocity (both of which are related to thrombosis). For instance, patients undergoing iliac endovascular intervention are less likely to receive increased-intensity antithrombotic treatment (12). At the same time, though there are no prospective data about the utility of increased-intensity antithrombotic therapy among patients undergoing infrapopliteal intervention, it seems reasonable that increased-intensity therapy may improve outcomes given that the tibial arteries generally have lower flow velocities and volumes. Only 6.2% of patients (n=408) in VOYAGER PAD had primarily infrapopliteal revascularization, which, though a relatively small number, is larger than the upcoming AGRIPPA trial, which will randomize 200 CLI patients following infrapopliteal LER to clopidogrel versus apixaban on a background of aspirin.(20)

VOYAGER PAD is the first large, modern, randomized controlled trial to examine DPI in post-revascularization PAD patients. Further analyses, including subgroup analyses of different revascularization types and locations, will further elucidate VOYAGER PAD’s full implications. Defining optimal approaches for specific revascularization locations and modalities, which can then support guidelines and performance metrics, will reduce post-LER treatment variability and improve outcomes. Preventing ischemic events is of the utmost importance, whether in the immediate post-LER period or among patients with stable disease, as a subanalysis from COMPASS reported that patients who suffered a first limb event experienced a drastic worsening in their subsequent prognosis, with dramatic increases in hospitalization, vascular amputation, and mortality.(32) VOYAGER PAD included in its primary endpoint ALI and major vascular amputation, and other future trials must also include limb events as primary endpoints in order to elucidate whether the studied intervention prevents limb events.

Furthermore, while a VOYAGER PAD sub-analysis has shown that clopidogrel added bleeding risk without antithrombotic benefit to aspirin plus rivaroxaban,(33) future comparisons of the VOYAGER regimen to DAPT with aspirin plus clopidogrel and to newer antithrombotic agents (e.g. factor XI inhibitors) will be needed. DAPT with aspirin plus clopidogrel is currently the most commonly-used antithrombotic regimen following LER, while factor XI inhibitors hold some promise of delivering therapeutic anticoagulation with an improved safety profile due to the relative preservation of hemostasis with factor XI inhibition.(34,35) While factor XI inhibition phase II studies are currently ongoing, comparative effectiveness trials will be needed in order to determine whether these compounds are capable of delivering superior effectiveness and safety results when compared with low-dose rivaroxaban or DAPT. This research will be critical in helping surgeons and interventionalists understand the relationship of aspirin and rivaroxaban to one of the most commonly used post-LER antithrombotic approaches and to newer medications in the pipeline.

Finally, VOYAGER PAD excluded patients with procedural complications, significant ulceration, undergoing treatment for ALI, and poorly controlled diabetes, meaning that any benefit of increased-intensity antithrombotic therapy must be replicated among “real-world” patients. For instance, the XATOA registry of patients with stable CAD and/or PAD treated with rivaroxaban and aspirin will eventually provide long-term information about treatment, event, and bleeding risk patterns among this cohort in clinical practice.(36) A similar examination of DPI among “real-world” post-LER PAD patients will be a critical step towards implementing these findings into practice, as it will better elucidate heterogeneity of the risk-benefit ratio across different patient subgroups. While low-dose anticoagulation in addition to aspirin may be beneficial for patients with PAD throughout the course of their disease and its treatment, further investigations are essential for confirmation of benefits and risks among real-world patients and to speed implementation of this potentially life- and limb-saving advance.

ABBREVIATIONS AND ACRONYMS

ALI

acute limb ischemia

CLI

critical limb ischemia

DAPT

dual antiplatelet therapy

DPI

=dual pathway inhibition

LER

lower extremity revascularization

PAD

peripheral artery disease

PCI

percutaneous coronary intervention

SAPT

single antiplatelet therapy

VKA

vitamin K antagonist