Medical therapy for lower extremity peripheral arterial disease: Difference between revisions
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| colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]] | | colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]] | ||
|- | |- | ||
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.'''Antiplatelet therapy with aspirin alone (range 75–325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce MI, stroke, and vascular death in patients with symptomatic PAD.''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]]) | | bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.'''Antiplatelet therapy with aspirin alone (range 75–325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce [[MI]], [[stroke]], and vascular death in patients with symptomatic [[Peripheral arterial disease|PAD]].''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]])''<nowiki>"</nowiki> | ||
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| colspan="1" style="text-align:center; background:LemonChiffon"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIa]] | | colspan="1" style="text-align:center; background:LemonChiffon"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIa]] | ||
|- | |- | ||
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.''' In asymptomatic patients with PAD (ABI ≤0.90), antiplatelet therapy is reasonable to reduce the risk of MI, stroke, or vascular death ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: C-EO]]) | | bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.''' In asymptomatic patients with PAD (ABI ≤0.90), antiplatelet therapy is reasonable to reduce the risk of [[MI]], [[stroke]], or vascular death. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: C-EO]])''<nowiki>"</nowiki> | ||
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| colspan="1" style="text-align:center; background:LemonChiffon"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIb]] | | colspan="1" style="text-align:center; background:LemonChiffon"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIb]] | ||
|- | |- | ||
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.''' In asymptomatic patients with borderline ABI (0.91–0.99), the usefulness of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death is uncertain ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-R]]) | | bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.''' In asymptomatic patients with borderline ABI (0.91–0.99), the usefulness of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death is uncertain. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-R]])''<nowiki>"</nowiki> | ||
|- | |- | ||
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''2.''' The effectiveness of dual-antiplatelet therapy (DAPT) (aspirin and clopidogrel) to reduce the risk of cardiovascular ischemic events in patients with symptomatic PAD is not well established''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-R]]) | | bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''2.''' The effectiveness of dual-antiplatelet therapy ([[Dual antiplatelet therapy|DAPT]]) ([[aspirin]] and [[clopidogrel]]) to reduce the risk of cardiovascular ischemic events in patients with symptomatic PAD is not well established. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-R]])''<nowiki>"</nowiki> | ||
|- | |- | ||
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''3.''' DAPT(aspirin and clopidogrel) may be reasonable to reduce the risk of limb related events in patients with symptomatic PAD after lower extremity revascularization''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: C-LD]]) | | bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''3.''' [[Dual antiplatelet therapy|DAPT]]([[aspirin]] and [[clopidogrel]]) may be reasonable to reduce the risk of limb related events in patients with symptomatic PAD after lower extremity [[revascularization]]. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: C-LD]])''<nowiki>"</nowiki> | ||
|- | |- | ||
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''4.''' The overall clinical benefit of vorapaxar added to existing antiplatelet therapy in patients with symptomatic PAD is uncertain ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-R]]) | | bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''4.''' The overall clinical benefit of vorapaxar added to existing antiplatelet therapy in patients with symptomatic PAD is uncertain. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-R]])''<nowiki>"</nowiki> | ||
|- | |- | ||
|} | |} | ||
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| colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]] | | colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]] | ||
|- | |- | ||
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.'''Treatment with a statin medication is indicated for all patients with PAD''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]]) | | bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.'''Treatment with a [[statin]] medication is indicated for all patients with PAD. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]])''<nowiki>"</nowiki> | ||
|- | |- | ||
|} | |} | ||
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| colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]] | | colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]] | ||
|- | |- | ||
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.''' Antihypertensive therapy should be administered to patients with hypertension and PAD to reduce the risk of MI, stroke, heart failure, and cardiovascular death''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]]) | | bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.''' [[Antihypertensive therapy]] should be administered to patients with [[hypertension]] and [[Peripheral arterial disease|PAD]] to reduce the risk of [[MI]], [[stroke]], [[heart failure]], and cardiovascular death. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]])''<nowiki>"</nowiki> | ||
|- | |- | ||
|} | |} | ||
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| colspan="1" style="text-align:center; background:LemonChiffon"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIa]] | | colspan="1" style="text-align:center; background:LemonChiffon"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIa]] | ||
|- | |- | ||
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.'''The use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers can be effective to reduce the risk of cardiovascular ischemic events in patients with PAD''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]]) | | bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.'''The use of [[angiotensin-converting enzyme inhibitors]] or [[ARBs|angiotensin-receptor blockers]] can be effective to reduce the risk of cardiovascular ischemic events in patients with PAD. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]])''<nowiki>"</nowiki> | ||
|- | |- | ||
|} | |} | ||
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| colspan="1" style="text-align:center; background:LightCoral"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class III]] (Harm) | | colspan="1" style="text-align:center; background:LightCoral"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class III]] (Harm) | ||
|- | |- | ||
| bgcolor="LightCoral"|<nowiki>"</nowiki>'''1.''' Anticoagulation should not be used to reduce the risk of cardiovascular ischemic events in patients with PAD ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]]) | | bgcolor="LightCoral"|<nowiki>"</nowiki>'''1.''' Anticoagulation should not be used to reduce the risk of cardiovascular ischemic events in patients with PAD. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]])''<nowiki>"</nowiki> | ||
|- | |- | ||
|} | |} | ||
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| colspan="1" style="text-align:center; background:LemonChiffon"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIb]] | | colspan="1" style="text-align:center; background:LemonChiffon"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIb]] | ||
|- | |- | ||
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.''' The usefulness of anticoagulation to improve patency after lower extremity autogenous vein or prosthetic bypass is uncertain''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-R]]) | | bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.''' The usefulness of anticoagulation to improve patency after lower extremity autogenous vein or prosthetic bypass is uncertain. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-R]])''<nowiki>"</nowiki> | ||
|- | |- | ||
|} | |} | ||
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| colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]] | | colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]] | ||
|- | |- | ||
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.''' Patients with PAD who smoke cigarettes or use other forms of tobacco should be advised at every visit to quit''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]]) | | bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.''' Patients with [[Peripheral arterial disease|PAD]] who smoke cigarettes or use other forms of tobacco should be advised at every visit to quit. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]])''<nowiki>"</nowiki> | ||
|- | |- | ||
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''2.''' Patients with PAD who smoke cigarettes should be assisted in developing a plan for quitting that includes pharmacotherapy (i.e., varenicline, bupropion, and/or nicotine replacement therapy) and/or referral to a smoking cessation program''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]]) | | bgcolor="LightGreen"|<nowiki>"</nowiki>'''2.''' Patients with [[Peripheral arterial disease|PAD]] who smoke cigarettes should be assisted in developing a plan for quitting that includes pharmacotherapy (i.e., [[varenicline]], [[bupropion]], and/or [[nicotine replacement therapy]]) and/or referral to a [[smoking cessation]] program. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]])''<nowiki>"</nowiki> | ||
|- | |- | ||
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''3.''' Patients with PAD should avoid exposure to environmental tobacco smoke at work, at home, and in public places''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-NR]]) | | bgcolor="LightGreen"|<nowiki>"</nowiki>'''3.''' Patients with [[Peripheral arterial disease|PAD]] should avoid exposure to environmental [[tobacco smoke]] at work, at home, and in public places. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-NR]])''<nowiki>"</nowiki> | ||
|- | |- | ||
|} | |} | ||
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| colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]] | | colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]] | ||
|- | |- | ||
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.'''Management of diabetes mellitus in the patient with PAD should be coordinated between members of the healthcare team''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: C-EO]]) | | bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.'''Management of [[diabetes mellitus]] in the patient with [[Peripheral arterial disease|PAD]] should be coordinated between members of the healthcare team. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: C-EO]])''<nowiki>"</nowiki> | ||
|- | |- | ||
|} | |} | ||
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| colspan="1" style="text-align:center; background:LemonChiffon"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIa]] | | colspan="1" style="text-align:center; background:LemonChiffon"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class IIa]] | ||
|- | |- | ||
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.'''Glycemic control can be beneficial for patients with CLI to reduce limb-related outcomes ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-NR]]) | | bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.'''[[Glycemic control]] can be beneficial for patients with CLI to reduce limb-related outcomes. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-NR]])''<nowiki>"</nowiki> | ||
|- | |- | ||
|} | |} | ||
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| colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]] | | colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]] | ||
|- | |- | ||
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.'''Cilostazol is an effective therapy to improve symptoms and increase walking distance in patients with claudication''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]]) | | bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.'''[[Cilostazol]] is an effective therapy to improve symptoms and increase walking distance in patients with [[claudication]]. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: A]])''<nowiki>"</nowiki> | ||
|- | |- | ||
|} | |} | ||
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| colspan="1" style="text-align:center; background:LightCoral"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class III]] (No beneft) | | colspan="1" style="text-align:center; background:LightCoral"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class III]] (No beneft) | ||
|- | |- | ||
| bgcolor="LightCoral"|<nowiki>"</nowiki>'''1.''' Pentoxifylline is not effective for treatment of claudication''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-R]]) | | bgcolor="LightCoral"|<nowiki>"</nowiki>'''1.''' [[Pentoxifylline]] is not effective for treatment of [[claudication]]. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-R]])''<nowiki>"</nowiki> | ||
|- | |- | ||
|} | |} | ||
Line 137: | Line 137: | ||
| colspan="1" style="text-align:center; background:LightCoral"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class III]] (No beneft) | | colspan="1" style="text-align:center; background:LightCoral"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class III]] (No beneft) | ||
|- | |- | ||
| bgcolor="LightCoral"|<nowiki>"</nowiki>'''1.''' Chelation therapy (e.g., ethylenediaminetetraacetic acid) is not beneficial for treatment of claudication''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-R]]) | | bgcolor="LightCoral"|<nowiki>"</nowiki>'''1.''' [[Chelation therapy]] (e.g., ethylenediaminetetraacetic acid) is not beneficial for treatment of [[claudication]]. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-R]])''<nowiki>"</nowiki> | ||
|- | |- | ||
|} | |} | ||
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| colspan="1" style="text-align:center; background:LightCoral"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class III]] (No beneft) | | colspan="1" style="text-align:center; background:LightCoral"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class III]] (No beneft) | ||
|- | |- | ||
| bgcolor="LightCoral"|<nowiki>"</nowiki>'''1.'''B-complex vitamin supplementation to lower homocysteine levels for prevention of cardiovascular events in patients with PAD is not recommended''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-R]]) | | bgcolor="LightCoral"|<nowiki>"</nowiki>'''1.'''B-complex vitamin supplementation to lower [[homocysteine]] levels for prevention of cardiovascular events in patients with [[Peripheral arterial disease|PAD]] is not recommended. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: B-R]])''<nowiki>"</nowiki> | ||
|- | |- | ||
|} | |} | ||
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| colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]] | | colspan="1" style="text-align:center; background:LightGreen"|[[ACC AHA guidelines classification scheme#Classification of Recommendations|Class I]] | ||
|- | |- | ||
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.'''Patients with PAD should have an annual influenza vaccination''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: C-EO]]) | | bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.'''Patients with [[Peripheral arterial disease|PAD]] should have an annual [[influenza vaccination]]. ''([[ACC AHA guidelines classification scheme#Level of Evidence|Level of Evidence: C-EO]])''<nowiki>"</nowiki> | ||
|- | |- | ||
|} | |} |
Latest revision as of 20:26, 22 November 2016
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Usama Talib, BSc, MD [2]
2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease[1]
Recommendations for Medical Therapy for the Patient With PAD
Recommendations for Antiplatelet Agents:
Class I |
"1.Antiplatelet therapy with aspirin alone (range 75–325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce MI, stroke, and vascular death in patients with symptomatic PAD.(Level of Evidence: A)" |
Class IIa |
"1. In asymptomatic patients with PAD (ABI ≤0.90), antiplatelet therapy is reasonable to reduce the risk of MI, stroke, or vascular death. (Level of Evidence: C-EO)" |
Class IIb |
"1. In asymptomatic patients with borderline ABI (0.91–0.99), the usefulness of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death is uncertain. (Level of Evidence: B-R)" |
"2. The effectiveness of dual-antiplatelet therapy (DAPT) (aspirin and clopidogrel) to reduce the risk of cardiovascular ischemic events in patients with symptomatic PAD is not well established. (Level of Evidence: B-R)" |
"3. DAPT(aspirin and clopidogrel) may be reasonable to reduce the risk of limb related events in patients with symptomatic PAD after lower extremity revascularization. (Level of Evidence: C-LD)" |
"4. The overall clinical benefit of vorapaxar added to existing antiplatelet therapy in patients with symptomatic PAD is uncertain. (Level of Evidence: B-R)" |
Recommendation for Statin Agents:
Class I |
"1.Treatment with a statin medication is indicated for all patients with PAD. (Level of Evidence: A)" |
Recommendations for Antihypertensive Agents:
Class I |
"1. Antihypertensive therapy should be administered to patients with hypertension and PAD to reduce the risk of MI, stroke, heart failure, and cardiovascular death. (Level of Evidence: A)" |
Class IIa |
"1.The use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers can be effective to reduce the risk of cardiovascular ischemic events in patients with PAD. (Level of Evidence: A)" |
Recommendation for Oral Anticoagulation:
Class III (Harm) |
"1. Anticoagulation should not be used to reduce the risk of cardiovascular ischemic events in patients with PAD. (Level of Evidence: A)" |
Class IIb |
"1. The usefulness of anticoagulation to improve patency after lower extremity autogenous vein or prosthetic bypass is uncertain. (Level of Evidence: B-R)" |
Recommendation for Recommendations for Smoking Cessation:
Class I |
"1. Patients with PAD who smoke cigarettes or use other forms of tobacco should be advised at every visit to quit. (Level of Evidence: A)" |
"2. Patients with PAD who smoke cigarettes should be assisted in developing a plan for quitting that includes pharmacotherapy (i.e., varenicline, bupropion, and/or nicotine replacement therapy) and/or referral to a smoking cessation program. (Level of Evidence: A)" |
"3. Patients with PAD should avoid exposure to environmental tobacco smoke at work, at home, and in public places. (Level of Evidence: B-NR)" |
Recommendations for Glycemic Control:
Class I |
"1.Management of diabetes mellitus in the patient with PAD should be coordinated between members of the healthcare team. (Level of Evidence: C-EO)" |
Class IIa |
"1.Glycemic control can be beneficial for patients with CLI to reduce limb-related outcomes. (Level of Evidence: B-NR)" |
Recommendation for Cilostazol:
Class I |
"1.Cilostazol is an effective therapy to improve symptoms and increase walking distance in patients with claudication. (Level of Evidence: A)" |
Recommendation for Pentoxifylline:
Class III (No beneft) |
"1. Pentoxifylline is not effective for treatment of claudication. (Level of Evidence: B-R)" |
Recommendation for Chelation Therapy:
Class III (No beneft) |
"1. Chelation therapy (e.g., ethylenediaminetetraacetic acid) is not beneficial for treatment of claudication. (Level of Evidence: B-R)" |
Recommendation for Homocysteine Lowering:
Class III (No beneft) |
"1.B-complex vitamin supplementation to lower homocysteine levels for prevention of cardiovascular events in patients with PAD is not recommended. (Level of Evidence: B-R)" |
Recommendation for Influenza Vaccination:
Class I |
"1.Patients with PAD should have an annual influenza vaccination. (Level of Evidence: C-EO)" |
References
- ↑ Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE; et al. (2016). "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines". Circulation. doi:10.1161/CIR.0000000000000471. PMID 27840333.