Evidence from Cochrane systematic reviews for effects of antithrombotic drugs for lower-limb revascularization. A narrative review

Dias, Silfayner Victor Mathias; Flumignan, Ronald Luiz Gomes; Iared, Wagner

doi:10.1590/1516-3180.2020.0640.110321

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Sao Paulo Medical Journal

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Narrative Review • Sao Paulo Med. J. 139 (6) • 2021 • https://doi.org/10.1590/1516-3180.2020.0640.110321 copy

Evidence from Cochrane systematic reviews for effects of antithrombotic drugs for lower-limb revascularization. A narrative review

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

BACKGROUND:

Peripheral arterial disease (PAD) is characterized by progressive narrowing of the arterial lumen, resulting from atherosclerotic plaques. Treatment for PAD aims to control atherosclerosis and improve blood flow. Use of antiplatelet agents and anticoagulants has played important roles in helping to prevent occlusions and stenosis.

OBJECTIVE:

To evaluate the evidence from Cochrane systematic reviews regarding the accuracy, effectiveness and safety of use of anticoagulants and antiplatelets in lower-limb revascularization, in patients with peripheral arterial disease.

METHODS:

Systematic reviews found through searches in the Cochrane Library were included. Two authors evaluated whether the reviews found were in line with the inclusion criteria for this investigation. A qualitative synthesis of their findings was presented.

RESULTS:

Three systematic Cochrane reviews were included. Patients who underwent prosthetic bypass surgery probably presented greater benefit from use of antiplatelets, and patients who underwent vein revascularization probably presented greater benefit from use of anticoagulants. Patients who received endovascular treatment benefited from both antiplatelet and anticoagulant treatment. However, the reliability of the results found was impaired because at the time when these reviews were published, there was no mandatory assessment using the GRADE criteria.

CONCLUSION:

Despite the evidence found, it is necessary for these reviews to be updated in order to evaluate the degree of certainty of the results found.

KEYWORDS (MeSH terms):
Peripheral arterial disease; Anticoagulants; Platelet aggregation inhibitors; Systematic review [publication type]; Vascular grafting

AUTHORS’ KEYWORDS:
Antiplatelet; Thromboses; Endovascular; Bypass

Lines	Search terms	Numbers of records
#1	MeSH descriptor: [Peripheral Arterial Disease] explode all trees	1,039
#2	MeSH descriptor: [Arterial Occlusive Diseases] explode all trees	12,019
#3	MeSH descriptor: [Peripheral Vascular Diseases] explode all trees	3,211
#4	#1 OR #2 OR #3	13,967
#5	(Peripheral Arterial Disease) OR (Arterial Occlusive Disease) OR (Arterial Obstructive Disease) OR (Vascular Disease) OR (Peripheral Vascular Disease) OR (Peripheral Angiopath)	29,451
#6	MeSH descriptor: [Anticoagulants] explode all trees	4,596
#7	(Anticoagulant Agent) OR (Anticoagulant Drug) OR (Anticoagulant) OR (Indirect Thrombin Inhibitor*)	6,517
#8	MeSH descriptor: [Platelet Aggregation Inhibitors] explode all trees	3,870
#9	(Blood Platelet Antiaggregant) OR (Platelet Antiaggregant) OR (Platelet Aggregation Inhibitor) OR (Blood Platelet Aggregation Inhibitor) OR (Platelet Inhibitor) OR (Antiplatelet Agent) OR (Antiplatelet Drug) OR (Platelet Antagonist) OR (Blood Platelet Antagonist*)	11,027
#10	#4 OR #5	38,968
#11	#6 OR #7	9,747
#12	#8 OR #9	11,027
#13	#10 AND (#11 OR #12)	3,231
#14	in Cochrane Reviews	370

Review	Interventions	Main results
Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery ⁶6. Flumignan CDQ, Amaral FCF, Flumignan RLG, et al. Angioplasty and stenting for below the knee ulcers in diabetic patients: protocol for a systematic review. Syst Rev. 2018;7(1):228. PMID: 30537989; https://doi.org/10.1186/s13643-018-0897-0. https://doi.org/10.1186/s13643-018-0897-...	ASA 400-990 mg/d or ASA 400-900 mg/d plus DIP 150-450 mg/d versus placebo or nothing	Benefits with ASA or ASA plus DIP Primary patency in venous bypass at 12 months Primary patency in prosthetic bypass at 1, 3, 6, 9 and 12 months
		No difference among intervention groups Gastrointestinal side effects; major bleeding; minor bleeding; wound or graft infection; limb amputation; cardiovascular events; mortality; primary patency in venous bypass at 1, 3, 6 and 24 months
		Higher risk with ASA or ASA plus DIP General side effects
	ASA or ASA 1050 mg/d plus DIP 150 mg/d versus pentoxifylline 1200 mg/d; venous or prosthetic bypasses	Benefit with pentoxifylline Less gastric intolerance
		No difference among intervention groups Primary patency at 1, 3, 6 and 12 months; gastric bleeding; dizziness; limb amputation; mortality
	ASA 900 mg/d plus DIP 250 mg/d versus indobufen 400 mg/d; venous or prosthetic bypasses	No difference among intervention groups Primary patency at 1, 3, 6, 9 and 12 months
	ASA 1000 mg or ASA 1000 mg plus DIP 225 mg/d versus VKA; venous or prosthetic bypasses	No difference among intervention groups Graft primary patency at 3, 6, 12 and 24 months; limb amputation; cardiovascular events; mortality
	ASA 900 mg/d plus DIP 300 mg/d versus LMWH 2500 IU/d; venous or prosthetic bypasses	Benefits with ASA plus DIP mortality
		No difference among intervention groups Graft primary patency at 6 and 12 months
	Ticlopidine 500 mg/d versus placebo; venous bypass	Benefits with ticlopidine Graft primary patency at 6, 12 and 24 months
	Ticlopidine 500 mg/d versus placebo; venous bypass	No difference among intervention groups Graft primary patency at 1 month
	ASA 1500 mg/d versus prostaglandins (PGE1) 0.2 ng/kg/min; vein bypass	No difference among intervention groups Early occlusion
	Clopidogrel 75 mg/d plus ASA 75-100 mg/d versus ASA 75-100 mg/d	Benefits with clopidogrel plus ASA Primary patency in prosthetic bypasses at 24 months; amputation in prosthetic bypasses
		No difference among intervention groups Amputation of venous bypasses; mortality for venous or prosthetic bypasses; primary patency in venous bypasses at 24 months; minor, mild or major bleeding for prosthetic bypasses; major bleeding for venous bypasses
		Higher risk with clopidogrel plus ASA Minor or mild bleeding for venous bypasses
Antithrombotic agents for preventing thrombosis after infrainguinal arterial bypass surgery ⁷7. Varga-Szabo D, Pleines I, Nieswandt B. Cell adhesion mechanisms in platelets. Arterioscler Thromb Vasc Biol. 2008;28(3):403-12. PMID: 18174460; https://doi.org/10.1161/ATVBAHA.107.150474. https://doi.org/10.1161/ATVBAHA.107.1504...	VKA versus placebo	Benefits with VKA Occlusion in venous bypasses at 6 months; occlusion in prosthetic bypasses at 5 years; limb loss in venous bypasses at 5 years; limb salvage for venous bypasses at 6 months; limb loss for venous or prosthetic bypasses at 3, 6 and 24 months and 5 years; mortality for venous or prosthetic bypasses at 12 months
	VKA versus placebo	No difference among intervention groups Occlusion in venous bypasses at 3, 12 and 24 months and 5 years; occlusion in prosthetic bypasses at 3, 6, 12 and 24 months; limb loss in venous or prosthetic bypasses at 3, 6, 12, 24 months and 5 years for prosthetic; mortality in venous or prosthetic bypasses at 3, 6, 12 and 24 months and 5 years
	VKA versus ASA 80 mg/d or ASA 1000 mg/d plus DIP 225 mg/d	Benefits with VKA Occlusion in venous bypasses at 3, 6, 12 and 24 months
		Benefits with ASA plus DIP Occlusion in prosthetic bypasses at 6, 12 and 24 months
		No difference among intervention groups Occlusion in prosthetic bypasses at 3 months
	LMWH (enoxaparin) 40 mg versus UFH 5000 IU (intraoperative)	Benefits with LMWH Occlusion in venous or prosthetic bypasses at 10 and 30 days
	LMWH (enoxaparin) 40 mg versus UFH 5000 IU (intraoperative)	No difference among intervention groups Occlusion in venous or prosthetic bypasses at 24 hours
	LMWH (dalteparin) 2500 IU versus ASA 900 mg/d plus DIP 300 mg/d	Benefits with LMWH Occlusion in venous or prosthetic bypasses at 6 and 12 months
	LMWH (dalteparin) 5000 IU versus placebo	No difference among intervention groups Occlusion in venous or prosthetic bypasses at 1, 3 and 12 months
	UFH 5000 IU versus antithrombin 1500 IU	Benefits with UFH Intraoperative occlusion of venous or prosthetic bypasses.
	UFH 5000 IU versus antithrombin 1500 IU	No difference among intervention groups Occlusion in venous or prosthetic bypasses at 1 month
	LMWH (enoxaparin) 40 mg/d versus dextran 2500 ml plus heparin 5000 IU	No difference among intervention groups Early occlusion in venous or prosthetic bypasses
Antiplatelet and anticoagulant drugs for prevention of restenosis/reocclusion after peripheral endovascular treatment ⁸8. Bedenis R, Lethaby A, Maxwell H, Acosta S, Prins MH. Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery. Cochrane Database Syst Rev. 2015;2015(2):CD000535. PMID: 25695213; https://doi.org/10.1002/14651858.CD000535.pub3. https://doi.org/10.1002/14651858.CD00053...	ASA 50-330 mg/d plus DIP 75-400 mg/d versus placebo	Benefits with ASA (330 mg)/DIP Occlusion/restenosis at 6 months
		No difference found among interventions Occlusion/ restenosis at 1, 3 and 6 months (other doses) and 12 months; amputation, mortality and bleeding at the puncture site at 1 month
		Higher risk with ASA (1000 mg/d) plus DIP Gastrointestinal side effects at 12 and 24 months
	ASA 150-990 mg/d plus DIP 225-400 mg/d versus VKA	No difference found Occlusion/restenosis at 1, 3, 6, 12, 24 and 36 months
	Clopidogrel 75 mg/d plus ASA 100 mg/d versus LMWH (dalteparin) 5000 IU followed by warfarin	No difference found Occlusion/restenosis at 24 hours and 1, 6, 12 and 18 months
		Higher risk with LMWH followed by warfarin Major bleeding
	Ticlopidine 1000 mg/d versus VKA	No difference found Occlusion/restenosis at 12 months
	Ticlopidine 1000 mg/d versus VKA	Higher risk with ticlopidine Gastrointestinal side effects
	Cilostazol 200 mg/d plus ASA 100 mg/d versus ticlopidine 200 mg/d plus ASA 100 mg/d	Benefits with cilostazol plus ASA Occlusion/restenosis at 36 months.
		No difference found Occlusion/restenosis at 12 and 24 months; amputation, mortality and side effects at 36 months
	LMWH (therapeutic nadroparin) plus ASA 200 mg/d versus UFH (heparinization followed by ASA)	Benefits with LMWH versus UFH Occlusion/restenosis at 3 weeks and 3 and 6 months (femoropopliteal arteries); occlusion/restenosis at 12 months for patients with critical ischemia
		No difference found among interventions Occlusion/restenosis at 3 weeks and 3 and 6 months (arteries of the pelvis); pseudoaneurysm hematoma and amputation
	LMWH (dalteparin) 2500 IU/d plus ASA 100 mg/d versus ASA 100 mg/d	Benefit with LMWH plus ASA Occlusion/restenosis at 12 months for critical ischemia
		No difference found among interventions Occlusion/restenosis at 12 months for intermittent claudication

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[1] Address for correspondence: Silfayner Victor Mathias Dias, Av. Cascata, 123 Jardim Maria Izabel — Marília (SP) — Brasil CEP 17515-300 Tel. (+55 11) 94440-3464 E-mail: silfayner@gmail.com