Systematic reviews and meta-analyses for more profitable strategies in peripheral artery disease

Figures & data

Table I. ACC/AHA 2013 recommendations for the diagnosis of PAD by non-invasive tools.

Diagnostic modality	Class of recommendation	Indications
Pulse volume recording	Class 2a; level B	To establish the initial PAD diagnosis, assess localization and severity, follow the status of lower-extremity revascularization procedures
Continuous-wave Doppler ultrasound	Class 1; level B	To provide an accurate assessment of PAD location and severity, to follow PAD progression, to provide quantitative follow-up after revascularization procedures
Treadmill exercise testing with and without ABI assessments and 6-min walk test^a	Class 1; level B	To provide objective evidence of the magnitude of the functional limitation of claudication and to measure the response to therapy
		To differentiate arterial claudication from non-arterial claudication (‘pseudoclaudication’)^b
		To determine functional capacity, assess non-vascular exercise limitations, and demonstrate the safety of exercise^c

^aStandardized exercise protocol (either fixed or graded) with a motorized treadmill should be used to ensure reproducibility of measurements of pain-free walking distance and maximal walking distance (level of evidence: B).

^bExercise treadmill tests with measurement of pre-exercise and post-exercise ABI values are recommended to this end.

^cExercise treadmill tests to be performed in individuals with claudication who are to undergo exercise training (lower extremity PAD rehabilitation). A 6-min walk test may be reasonable to provide an objective assessment of the functional limitation of claudication and response to therapy in elderly individuals or others not amenable to treadmill testing (Class IIb, level of evidence: B).

Table II. TASC II guidelines for ABI interpretation.

ABI value	Interpretation
> 0.9	Normal
< 0.9	Atherosclerotic disease
0.4–0.9	PAD (IC)
< 0.4	PAD (CLI)

Data from: J Vasc Surg. 2007;45(Suppl S):S5–67; modified.

ABI = ankle-brachial index; CLI = critical limb ischemia; IC = intermittent claudication; PAD = peripheral artery disease.

Table III. Recommendations for different imaging techniques to be employed in the diagnosis of PAD and of CLI.

Imaging technique	Indications	PADClass of recommendation	CLIClass of recommendation
DUS	Diagnosis of anatomic location and degree of stenosis	Class 1; level A	Class 1, level A
	Routine surveillance after femoral-popliteal or femoral-tibial-pedal bypass with a venous conduit^a	Class 1; level A	Class 1; level A
	Selection of patients as candidates for endovascular intervention	Class 2a; level B	Class 2a; level B
	Selection of patients as candidates for surgical bypass and selection of the sites of surgical anastomosis	Class 2a; level B	Class 2a; level B
	Assessment of long-term patency of PTA	Class 2b; level B	Class 2b; level B
	Routine surveillance after femoral-popliteal bypass with a synthetic conduit	Class 2b; level B	Class 2b; level B
CV-DUS	Assessment of PAD location and severity, to follow-up PAD progression, and to provide quantitative follow-up after revascularization procedures	Class 1; level B
CTA^e	Anatomic location and presence of significant stenosis	Class 2b; level B	Class 2b; level B
	Substitute for MRA for patients with contraindications to MRA	Class 2b; level B	Class 2b; level B
MRA	Anatomic location and degree of stenosis of PAD	Class 1; level A	Class 1; level A
	Anatomical location with use of gadolinium enhancement	Class 1; level B	Class 1; level B
	Selection of patients as candidates for endovascular intervention	Class 1; level A	Class 1 ; level A
	Selection of patients as candidates for surgical bypass and selection of the sites of surgical anastomosis	Class 2b; level B	Class 2b; level B
	Post-revascularization (endovascular and surgical bypass) surveillance	Class 2b; level B	Class 2b; level B
CA, DSA^f	Arterial anatomy^b	Class 1; level B	Class 1; level B
	Complete anatomic assessment of the affected arterial territory, including imaging of the occlusive lesion, as well as arterial inflow and outflow in patients who may be treated with invasive therapeutic interventions (percutaneous or surgical)	Class 1; level B	Class 1; level B
	Digital subtraction angiography recommended for contrast angiographic studies (enhanced imaging capabilities compared with conventional un-subtracted contrast angiography)	Class 1; level A	Class 1 ; level B
	Complete vascular examination before performing CA^c	Class 1; level C	Class 1; level A
	Selective/super-selective catheter placement during lower-extremity angiography to enhance imaging, reduce contrast dose, and improve sensitivity and specificity of the procedure	Class 1; level C	Class 1; level C
	To image the iliac, femoral, and tibial bifurcations in profile without vessel overlap	Class 1; level B	Class 1; level B
	To develop individualized diagnostic strategic plan, including assistance in selection of access sites, identification of significant lesions, and determination of the need for invasive evaluation^d	Class 2a; level B	Class 2a; level B

Data from: J Am Coll Cardiol. 2013;6:1555–70, modified.

^aMinimum surveillance intervals are approximately 3, 6, and 12 months, and then yearly after graft placement for PAD and for CLI.

^bRecommended for evaluation of patients when revascularization is contemplated.

^cTo optimize decisions on the access site, and to minimize contrast dose and catheter manipulation.

^dAs other non-invasive imaging modalities including MRA, CTA, and color flow duplex imaging, to be used in advance of invasive imaging procedures.

^ePatients with baseline renal insufficiency should receive hydration before undergoing CTA (Grade A, level 2b).

^fA documented history of contrast reaction before the performance of contrast angiography implies that an appropriate pre-treatment should be administered before contrast is given (Class 1; level B). When conducting a diagnostic lower-extremity arteriogram in which the significance of an obstructive lesion is ambiguous, trans-stenotic pressure gradients and supplementary angulated views should be obtained (Class 1; level B); hydration is needed before undergoing contrast angiography in patients with baseline renal insufficiency (Class 1; level B); treatment with n-acetylcysteine in advance of contrast angiography is suggested for patients with baseline renal insufficiency (creatinine > 2.0 mg per dL) (Class 2a; level B); follow-up clinical evaluation, including a physical examination and measurement of renal function is recommended within 2 weeks after contrast angiography to detect potential delayed adverse effects, such as atheroembolism, deterioration in renal function, or access site injury (e.g. pseudoaneurysm or arteriovenous fistula) (Class 1; level C).

CV-DUS = continuous wave Doppler ultrasound; PTA = percutaneous trans-luminal angioplasty.

Table IV. Comparison of different imaging techniques for patients with PAD: additional data.^a

Parameters	Comparisons (over)	Comments
General:
Time employed	CTA> MRA or DSA> DUS	15 min for CTA, 30 min for MRA and DSA, > 40 min for DUS (both legs)
Operator expertise	DUS> MRA or DSA> CTA	Expert operators needed especially for DUS
Arteriographic map^b	MRA = DSA = CTA = DUS	Immediately available with MRA or DSA; post-processing needed for CTA, expert operators for DUS
Availability	DUS or DSA> CTA or MRA
Equipment cost	MRA or DSA> CTA> DUS
Diagnostic accuracy:
Plaque composition^c	CTA> MRA> DSA> DUS	Plaques: lipid-enriched necrotic core, hemorrhages, calcifications, surrounding fibrous tissue, neo-angiogenesis best seen with CTA
Stent assessment	DUS> DSA> CTA> MRA	MRA: poor assessment in those with steel stents, fair in those with nitinol stents
Aortoiliac	CTA, MRA or DSA> DUS
Femoropopliteal	MRA = DSA = CTA = DUS
Tibial	DSA> MRA> DUS or CTA
Limitations by vascular calcification	MRA> DSA> DUS or CTA
Complications and risks:
Contraindications^c	DUS> MRA> CTA or DSA	DUS: none; MRA: claustrophobia, cerebrovascular clips, electronic implants (infusion or monitoring devices, pace-makers, neurostimulatory devices, cardioverters, defibrillators); DSA: severe renal impairment
Radiation exposure	DUS or MRA> CTA> DSA	CTA: 7.5–13.7 mSv
Contrast-enhanced nephropathy	DUS> MRA> CTA or DSA
Nephrogenic systemic fibrosis avoidance	DUS, CTA, or DSA> MRA
Allergic reaction	DUS> MRA> CTA or DSA
Access site	DUS, CTA, or MRA> DSA

^aData from: Eur J Vascular Endovasc Surg. 2011;42(S2):S13–S32; modified.

^bWith CTA, scanning of the entire vascular tree is achieved in a limited time, and the amount of contrast medium and radiation burden is low.

^cKnown allergy to contrast media for both MRA and DSA.

Table V. Antithrombotic drugs for PAD: different strategies for different objectives.

Patients with	Drug	Over	Grade of recommendation	Objectives, comments
Asymptomatic PAD^a	Aspirin^d	No therapy	2B	In 60-year-old men, aspirin use would result in six fewer deaths (12 fewer to 0 fewer) per 1000 patients treated (16 and 22 major extracranial bleeding events per 1000 moderate- and high-risk patients treated) if taken over 10 years and an increase in major bleeding events
Symptomatic PAD^b	Aspirin^dClopidogrel^eAspirin^d + clopidogrel^eAspirin^d + warfarin	No therapyAspirinAspirin or clopidogrelAspirin	1A1A2B1B	In a high-risk (8.2%/year) population for serious events, aspirin significantly reduces total mortality, and the recurrence of non-fatal MI and non-fatal stroke. The number of vascular events and total deaths prevented is greater than the number of resulting bleeding events (mostly, non-fatal extracranial bleeding events) The primary efficacy analysis of CAPRIE was conducted in 19,185 patients on an intent-to-treat basis. After a mean follow-up of 1.9 years, a total of 939 patients in the clopidogrel group and 1021 patients in the aspirin group experienced one of the following events: ischemic stroke, AMI, or vascular death. The relative risk reduction (RRR) with clopidogrel versus aspirin was 8.7% (clopidogrel only marginally superior to aspirin: RRR 8.7; P < 0.043). As to the pre-specified RRR by qualifying entry criteria, the following was found: Stroke: Clopidogrel better vs Aspirin better, 7.3%; AMI: Aspirin better vs Clopidogrel better, –3.7%; PAD: Aspirin better vs Clopidogrel better, 23.8 In the CHARISMA trial, the long-term (28-mo follow-up, mean) efficacy of clopidogrel+ aspirin was evaluated versus aspirin alone in 15,603 patients with established vascular disease, PAD, or multiple risk factors. Dual therapy was associated with a reduction in non-fatal stroke and an increase in non-fatal extracranial bleeding with no effect on total mortality or non-fatal AMI Warfarin (PT-INR 2-3)+ aspirin versus aspirin in patients with asymptomatic coronary artery disease has been tested in the setting of a recent ACS. Together with a significant increase in major extracranial non-fatal bleeding events (from 20 more to 112 more), there was no detectable effect on mortality (from 25 fewer to 66 more), and non-fatal AMI/non-fatal stroke (from 28 fewer to 32 more), in those receiving warfarin+ aspirin
Claudication unresponsive to physical exercise and smoking cessation^c	Cilostazol (100 mg b.i.d.)^h	Pentoxifylline or placebo	2C	In 1374 participants randomized to 100 mg b.i.d. cilostazol (475 patient-years exposure) and 973 randomized to placebo (357 patient-years exposure), no difference in rates of AMI (1.0% vs 0.8%), stroke (0.5% vs 0.5%), or death (0.6% vs 0.5%) was found. Nor was a significant effect of cilostazol detected on major or minor bleeding rates (in a systematic review in 2809 patients undergoing percutaneous coronary intervention in which aspirin+ clopidogrel was compared with aspirin+ clopidogrel+ cilostazol)
Chronic CLI/rest pain in patients who are not candidates for vascular interventions	E.v. Prostanoids^hS.c. Heparin (therapeutic doses)Surgery	PlaceboNo therapyIntra-arterial thrombolysis^g	2C2C1B2C	Prostanoids improve rest pain and ulcer healing (77 and 136 patients per 1000 treated, respectively) but do not significantly prevent amputations (from 75 fewer to 12 more) or mortality (from 42 fewer to 90 more)There are no formal studies demonstrating improved outcomes with short-term anticoagulation treatment (therapeutic doses of heparin) in acute limb ischemia
Acute CLI due to arterial emboli or thrombosis	Intra-arterial thrombolysis^g	E.v. Streptokinase		In 1180 patients. Intra-arterial thrombolysis has been compared with surgery for ALI. While there was no effect on amputation, limb salvage, or death, compared to surgery, thrombolysis was associated with a high risk of stroke (10 per 1000 treated) and major bleeding (16 per 1000 treated) at 30 days
Peripheral artery PTA with/without stenting^f,hPeripheral arterial bypass with/without stenting^f	Aspirin^dClopidogrel^eAspirin + dipyridamoleAspirin^d + clopidogrel^eAspirin^d Clopidogrel^e	No therapyNo therapyNo therapyNo therapyNo therapyNo therapy	1A1A1B2C1A1A	Compared with placebo, pooled data from 356 PTA patients without stent placement showed a reduction in reocclusion at 6 months in those taking aspirin+ dipyridamole (OR 0.69; 95% CI 0.44–1.10). Following PTA (pelvic or lower extremity), in 179 patients complicated by extensive dissection to i.v. unfractionated heparin vs subcutaneous nadroparin was administered for 1 week post-procedure (followed by 6 months of aspirin in each arm). Nadroparin was associated with a reduction in vessel restenosis/occlusion at 6 months (OR 0.35; 95% CI 0.19–0.65) but not in the amputation rate (OR 1.0; 95% CI 0.20–5.10). However, the overall quality of the evidence is low due to risk of bias, imprecision, and indirectness. Thus, aspirin or clopidogrel should be preferred as in symptomatic PAD. In patients undergoing PTA with stent placement, the practice of a loading dose of clopidogrel in addition to aspirin pre-procedure and then continuing dual antiplatelet therapy for 1–3 months post-PTA, particularly if a stent is placed in a small peripheral vessel, is based on the results from coronary artery stenting trials. However, dual antiplatelet therapy is associated with a high risk of major bleeding compared with single antiplatelet therapy. Thus, aspirin or clopidogrel alone should be preferredIn 966 patients receiving post-infrainguinal (venous or prosthetic) bypass graft surgery (for refractory claudication and limb salvage), aspirin+ dipyridamole resulted in 22 fewer graft occlusions per 1000 patients (32 fewer to 12 fewer) treated for 12 months (placebo as a comparator). The relative effects of aspirin plus dipyridamole vs aspirin alone have not been evaluated (Cochrane Systematic Review) In one study of that Cochrane Systematic Review, compared with placebo, aspirin plus dipyridamole for 12 months was associated with a reduction in amputations rates (34 fewer amputations per 1000 patients treated (51 fewer to one more)) Pooled data from three studies of that review suggested that treatment with aspirin plus dipyridamole was associated with a possible reduction in non-fatal AMI but not in non-fatal stroke. However, aspirin plus dipyridamole was associated with an increase in bleeding (eight more major bleeding events per 1000 treated (one fewer to 30 more)). However, the overall quality of the evidence is low due to risk of bias, imprecision, and indirectness. Thus, aspirin or clopidogrel alone should be preferred
Below-knee bypass graft surgery with prosthetic grafts	Aspirin^d + clopidogrel^e for at least 1 year	Aspirin	2C	The CASPAR study randomized 851 patients undergoing unilateral below-knee bypass graft surgery for PAD to clopidogrel (75 mg/d) plus aspirin (75–100 mg/d) vs placebo plus aspirin. In the (pre-specified) subgroup of patients undergoing venous graft bypass (n = 598), there was no difference in the rates of amputation, major bleeding, or death between the two treatment arms. In the subgroup of patients undergoing prosthetic graft bypass (n = 253), there was a significant decrease in amputations in those on clopidogrel+ aspirin (24 per 1000 treated; 95% CI, 35 fewer to three fewer)). No difference was found in total mortality or major extracranial bleeding
	High-intensity oral anticoagulation (target PT-INR 3-4.5)	Or aspirin	2C	The BOA study randomized 2650 patients who had undergone infrainguinal bypass grafting to either high-intensity oral anticoagulation (target PT-INR 3-4.5) or aspirin. Together with a reduction in non-fatal AMI, there was no effect of oral anticoagulation versus aspirin on all-cause mortality, non-fatal stroke, or limb loss, while there was a significant increase in extracranial major bleeding events (17 more per 1000, from 6 more to 32 more) in the oral anticoagulation group

^aPatients > 50 y of age. The overall quality of evidence is moderate (imprecision in the estimates).

^bSimilar to patients with PTA with/without stenting.

^cAvailable results in this clinical setting exclude benefits/harm as to quality of life related to the use of pentoxifylline, heparins (including low-molecular-weight heparins) or prostanoids.

^dLong-term aspirin: 75–100 mg/d. Limited evidence (Grade 2B) of aspirin+ clopidogrel or aspirin+ warfarin over aspirin alone.

^eLong-term clopidogrel: 75 mg/d. To be avoided in association with aspirin or warfarin (also in patients undergoing stent application).

^fDual antiplatelet treatment to be avoided for the inherent bleeding risk. Other studies failed to demonstrate or exclude an effect of aspirin and dipyridamole vs warfarin in reocclusion at 6 months following PTA or an effect on 12-month reocclusion in patients taking ticlopidine compared with warfarin.

^gUrokinase bolus or t-PA 100 mg bolus. Compared to surgery, thrombolysis has a significantly higher 30-d risk of bleeding and stroke. Initially, streptokinase was the most widely used agent, but because of safety concerns (e.g. allergic reactions), it has largely been replaced by urokinase and rt-PA.

^hLong-term aspirin^d or clopidogrel^e to be added for prevention of vascular events.

Table VI. TASC II classification of aortoiliac lesions.

Type A lesions	• Unilateral or bilateral stenosis of common iliac artery • Unilateral or bilateral single short (< 3 cm) stenosis of external iliac artery
Type B lesions	• Short (< 3 cm) stenosis of infrarenal aorta • Unilateral occlusion of common iliac artery • Single or multiple stenoses totaling 3–10 cm involving the external iliac artery not extending into the common femoral artery • Unilateral occlusion of the external iliac artery not involving the origins of the internal iliac or common femoral arteries
Type C lesions	• Bilateral occlusions of the common iliac arteries • Bilateral stenoses of the external iliac artery 3–10 cm long not extending into the common femoral artery • Unilateral stenosis of the external iliac artery extending into the common femoral artery • Unilateral occlusion of the external iliac artery involving the internal iliac and/or common femoral artery • Heavily calcified unilateral external iliac artery occlusion with or without involvement of the origins of internal iliac or common femoral artery
Type D lesions	• Infrarenal aortic occlusion • Diffuse disease involving the aorta and both iliac arteries requiring treatment • Diffuse multiple stenoses involving the unilateral common iliac artery, external iliac artery, and common femoral artery • Unilateral occlusion of both common iliac and external iliac artery • Bilateral occlusion of external iliac arteries • Iliac stenosis in patients with AAA requiring treatment and not amenable to endograft placement or other lesions requiring open aortic or iliac surgery

Data from: Vasa. 2011;40:359–67; modified.