Table 1.

Brief overview of PAD trials and percentage of women enrolled

	Study design	Follow-up	Salient features	No. of patients	Men (%)	Women (%)	Outcomes
Pharmacotherapy
CASPAR	RCT placebo	2 years	Patients undergoing vascular grafting as a treatment for PAD and 2 to 4 days after bypass surgery	851	66	34	Combination of clopidogrel plus ASA did not improve limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting. Subgroup analysis: clopidogrel plus ASA conferred benefit in patients receiving prosthetic grafts
AAA	Intention-to-treat double-blind RCT	8.2 years	Patients free of clinical cardiovascular disease, recruited from a community health registry, with a positive ABI screening test	3350	28	72	Aspirin did not result in a significant reduction of vascular events among patients without clinical cardiovascular disease and a low ABI
POPADAD	RCT, double-blind, 2 × 2 factorial, placebo-controlled	6.7 years	Adults aged > 40 with type 1 or type 2 diabetes and an ABI of 0.99 or less but no symptomatic cardiovascular disease	1276	44	56	No benefit from either aspirin or antioxidant treatment on the composite hierarchical primary end points of cardiovascular events and cardiovascular mortality
CAPRIE	Double-blind RCT	1.91 years	Patients with atherosclerotic vascular disease	6452	73	27	Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction, or vascular death
CHARISMA (PAD subgroup)	RCT, double-blind, 2 × 2 factorial, placebo-controlled, multicenter	28 months	Patients with PAD identified in CHARISMA study. Current intermittent claudication + an ABI ≤ 0.85, or a history of intermittent claudication + previous related intervention (amputation, surgical or catheter-based peripheral revascularization)	3096	70	30	Among patients with PAD, the primary end point occurred in 7.6% in the clopidogrel plus aspirin group and 8.9% in the placebo plus aspirin group (p = 0.18). The rate of MI and hospitalization for ischemic events were lower in the DAPT arm than aspirin alone
EUCLID	Double-blind, event-driven RCT	30 months	50 years of age with symptomatic peripheral artery disease. One of two inclusion criteria: previous revascularization of the lower limbs for symptomatic disease more than 30 days before randomization or hemodynamic evidence of peripheral artery disease	13,885	72	28	The primary efficacy end point occurred in 10.8% receiving ticagrelor and in 10.6% receiving clopidogrel failing to show ticagrelor to be superior to clopidogrel for the reduction of cardiovascular events (p = 0.65)
COMPASS	Double-blind double-dummy RCT using a 3-by-2 partial factorial design	23 months	Adults who meet criteria for CAD, PAD or both	27,395	78	22	Combination therapy with rivaroxaban (2.5 mg twice daily) plus aspiring among patients with stable atherosclerotic vascular disease had statistically significant better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone
4S	Double-blind RCT	5.4 years	Adults 35–70 years with history of angina pectoris or MI	4444	81.3	18.7	Simvastatin produced significant reduction of cardiovascular mortality in patients with CAD. Probability of a woman > 60 years escaping a major coronary event was 77.7% in placebo and 85.1% in simvastatin arm (p = 0.01). RR of death or coronary event in women < 60 were 0.63 and 0.61, respectively
WOSCOPS	Double-blind RCT	4.9 years	Fasting LDL > 155; no history of MI, arrhythmia or other serious illness, men with stable angina who had not been hospitalized within the previous 12 months	6595	100	0	Pravastatin lowered plasma cholesterol levels by 20% and low-density lipoprotein cholesterol levels by 26%. A 22% reduction in the risk of death from any cause in the pravastatin group was observed
HOPE	Double-blind, 2 × 2 factorial, RCT	3.5 years	Adults > 55 years old with history of CAD, PAD, CVA, or DM + another CV risk factor	9297	73	27	Treatment with ramipril-reduced rates of death from cardiovascular causes, MI, stroke, death from any cause, revascularization procedures, heart failure and complications related to DM
CAMELOT	Multicenter, double-blind, placebo-controlled RCT	24 months	Adults 30–79 years old requiring coronary angiography for evaluation for chest pain or percutaneous coronary intervention + DBP < 100 with or without treatment	1991	73.7	26.3	Administration of amlodipine to patients with CAD and normal blood pressure resulted in reduced adverse cardiovascular events particularly in women (RRR 42.8%) + IVUS showed evidence of slowing of atherosclerosis progression
FOURIER (PAD subgroup)	Double-blind RCT	2.2 years	Clinically evident atherosclerotic cardiovascular disease including prior MI, prior ischemic stroke, or symptomatic PAD (intermittent lower extremity claudication and an ankle-brachial index < 0.85, a history of a peripheral artery revascularization procedure, or a history of amputation attributable to atherosclerotic disease)	3642	71.8	28.2	ARR for CV death, MI, or stroke 3.5% in patients with PAD, and 1.4% in patients without PAD
STOP-IC	Prospective RCT, open-label, multicenter	12 months	Patients with symptomatic PAD attributable to de novo femoropopliteal lesions	191	68.5	31.5	The angiographic restenosis rate at 12 months was 20% in the cilostazol group in comparison with 49% in the noncilostazol group (p = 0.001; odds ratio, 0.26; 95% confidence interval, 0.13–0.53)
Exercise therapy
CLEVER	Multicenter RCT across 29 centers in US and Canada	18 months	Adults > 40 years of age with moderate to severe claudication due to aortoiliac PAD. Moderate to severe claudication was defined as the ability to walk at least 2 min on a treadmill at 2 miles per hour at no grade, but <11 min on a graded treadmill test using the Gardner-Skinner protocol	111	62	38	Supervised exercise provides a superior improvement in treadmill walking performance compared to both primary aortoiliac revascularization and optimal medical care (home walking and cilostazol) over 6 months (p < 0.001 for the comparison of SE versus OMC, p = 0.02 for ST versus OMC, and p = 0.04 for SE versus ST). This benefit was also associated with an improvement in self-reported walking distance, an increase in high-density lipoprotein, and a decrease of fibrinogen. Secondary measures of treatment efficacy favored primary stenting, with greater improvements in self-reported physical function
ERASE	Parallel-design RCT conducted in the Netherlands at 10 sites	12 months	PAD and stable claudication (≥ 3 months) with a resting ABI of < 0.90 or if their ABI decreased by more than 0.15 after treadmill testing regardless of their ABI at rest. All participants also had 1 or more vascular stenoses at the aortoiliac level, the femoropopliteal level, or both. Maximum walking distance had to be between 100 m and 500 m	666	62	38	Combination therapy of endovascular revascularization followed by supervised exercise resulted in significantly greater improvement in walking distances and health-related quality of life scores compared with supervised exercise only
Interventional
IN.PACT SFA	prospective, multicenter, single-blinded, RCT	12 months	Patients with intermittent claudication or ischemic rest pain due to superficial femoral and/or popliteal PAD	331	66	34	Drug-coated balloon was superior to PTA and had a favorable safety profile for the treatment of patients with symptomatic femoropopliteal peripheral artery disease
LEVANT-2	Single-blind, RCT	12 months	Rutherford stage 2–4 with ≥ 70% angiographically significant atherosclerotic lesion in the superficial femoral or popliteal artery, or both. The total treated lesion length had to be 15 cm or less, and the reference diameter of the target vessel had to be 4–6 mm	476	63	37	PTA with a paclitaxel-coated balloon resulted in a rate of primary patency at 12 months that was higher than the rate with angioplasty with a standard balloon
THUNDER	RCT, multicenter	5 years	Symptomatic peripheral artery disease with one or more obstructive lesions, either new lesions or restenoses, at least 70% of vessel diameter and at least 2 cm in length, in the superficial femoral artery, the popliteal artery, or both	154	65.5	34.5	Use of paclitaxel-coated angioplasty balloons (PCB) during percutaneous treatment of femoropopliteal disease is associated with significant reductions in late lumen loss and target lesion revascularization. Reduced rate of revascularization following PCB treatment was maintained over a 5 year period, although noted to be higher in women
ABSOLUTE	Single-institution RCT	12 months	Symptomatic PAD with Rutherford stage 3–5; > 50% or occlusion of the ipsilateral superficial femoral artery, a target lesion length of more than 30 mm, and at least one patent (< 50% stenosis) tibioperoneal runoff vessel	104	53	47	At 6–12 months, treatment of superficial femoral artery disease by primary implantation of a self-expanding nitinol stent yielded results that were superior to those with the currently recommended approach of balloon angioplasty with optional secondary stenting
ASTRON	Multicenter RCT	12 months	Symptomatic PAD Rutherford class 3–5; > 50% stenosis or occlusion of the SFA with a target lesion length between 30 mm and 200 mm, and at least one patent (< 50% stenosis) tibioperoneal runoff vessel	73	68	32	Primary stenting with a self-expanding nitinol stent for treatment of intermediate length SFA disease resulted morphologically and clinically superior midterm results compared with balloon angioplasty with optional secondary stenting
FAST	Multicenter RCT in 11 European centers	12 months	De novo SFA lesion located at least 1 cm from the SFA origin with a length between 1 and 10 cm. Target lesion diameter stenosis had to be at least 70% by visual estimate. The popliteal artery as well as 1 of the infrapopliteal (below-the-knee) vessels had to be continuously patent for sustained distal runoff. Clinically, patients to have at least Rutherford category 2	244	69	31	No statistically significant difference between treatment groups was observed at 12 months in the improvement by at least 1 Rutherford category of peripheral arterial disease
PACIFIER	Investigator-initiated multicenter RCT conducted in three German institutions	12 months	Claudication or critical limb ischemia (Rutherford 2–5); disease of SFA or popliteal artery; lesion length 3–30 cm; an occlusion or a grade of stenosis ≥ 70%, and absence of contraindications to dual antiplatelet therapy	85	59	41	DEB was associated with significant reductions in late lumen loss and restenosis at 6 months, and re-interventions after femoropopliteal percutaneous transluminal angioplasty up to 1 year of follow-up
VIASTAR	Prospective, single-blind, multicenter, RCT	24 months	Symptomatic PAD in the Rutherford stage 2–5, de novo arteriosclerotic stenosis or occlusion of the SFA and proximal popliteal artery 10–35 cm in length (TASC II classes B-D), patent or successfully treated iliac artery inflow, and outflow of at least 1 tibial artery	141	71	29	In lesions ≥ 20 cm, (TASC class D), the 12-month patency rate was significantly longer in VIA patients. Freedom from target lesion revascularization was 84.6% for Viabahn versus 77.0% for BMS. The ankle-brachial index in the Viabahn group significantly increased compared with the BMS at 12 months
DEBATE-BTK	Single-center, parallel-group, open blinded end point RCT	12 months	presence of diabetes mellitus, CLI (Rutherford class 4 or greater), stenosis or occlusion ≥ 40 mm of at least 1 tibial vessel with distal runoff to the foot, and agreement to 12-month angiographic evaluation	132	80	20	Drug-eluting balloons compared with PTA strikingly reduce 1-year restenosis, target lesion revascularization, and target vessel occlusion in the treatment of below-the-knee lesions in diabetic patients with critical limb ischemia
ZILVER	Prospective, multinational RCT with a complementary single-arm study	24 months	Rutherford category ≥ 2, ≥ 50% diameter stenosis, reference vessel diameter 4–9 mm, lesion length up to 14 cm, and at least 1 patent runoff vessel with < 50% stenosis throughout its course	474	65	35	Primary DES group demonstrated significantly superior 2-year event-free survival and primary patency
FEMPAC	Multicenter RCT	6 months	Occlusion/stenosis ≥ 70% diameter of the SFA and/or popliteal artery with clinical Rutherford stages 1–5; successful guidewire passage of the lesion during angiography	87	60	40	The number of target lesion revascularizations was lower in the paclitaxel-coated balloon group than in control subjects (p = 0.002). Improvement in Rutherford class was greater in the coated balloon group (p = 0.045), whereas the improvement in ankle-brachial index did not achieve statistical significance
BASIL	Multicenter RCT, prospective, across 27 UK hospitals	5.5 years	Severe limb ischemia, for > 2 weeks, and who on diagnostic imaging had a pattern of disease which, in joint investigator opinions, could equally well be treated by either infra-inguinal bypass surgery or balloon angioplasty	452	59.5	40.5	In patients presenting with severe limb ischemia due to infra-inguinal disease and who are suitable for surgery and angioplasty, a bypass surgery-first and a balloon angioplasty-first strategy are associated with broadly similar outcomes in terms of amputation-free survival, and in the short-term, surgery is more expensive than angioplasty
ACHILLES	Prospective multicenter RCT in nine European countries	1 year	Adults with infrapopliteal PAD. Reasons for exclusion were significant stenoses (> 50%) distal to the target lesion that might require revascularization or impede runoff; angiographically evident thrombus or history of thrombolysis within 72 h; untreated lesions (> 75% stenosis), Cr > 2.5 mg/dl	200	71.5	28.5	lower angiographic restenosis rates (22.4 vs 41.9%, p = 0.019), greater vessel patency (75.0% vs 57.1%, p = 0.025), and similar death, repeat revascularization, index-limb amputation rates, and proportions of patients with improved Rutherford class for sirolimus-eluting stents vs PTA
DESTINY	RCT, multicenter European	12 months	Symptomatic PAD due to a maximum of two focal de novo atherosclerotic target lesions in one or more infrapopliteal vessels	140	63.5	36.5	Treatment of the infrapopliteal occlusive lesions of CLI with everolimus stents demonstrated an 85% patency vs 54% with BMS at 12 months, decrease in restenosis, as well as statistically significant independence from revascularization
YUKON-BTX	Double-blind RCT	12 months	Rutherford class 3–5, presence of a single primary target lesion in a native infrapopliteal artery that was 2.5–3.5 mm in diameter and that did not exceed 45 mm in length	161	66.5	33.5	BMS placement was associated with a hazard ratio for restenosis of 3.2 (95% CI 1.5 to 6.7; p = 0.003) compared with sirolimus-eluting stents (SES) after 1 year. No significant differences between the study groups concerning mortality and amputation rates were observed, but mean ABI and Rutherford scores showed significant improvements in sirolimus group
IN.PACT DEEP CLI	Prospective multicenter RCT	12 months	Rutherford class 4–6 symptomatic CLI patients; reference vessel diameters between 2 and 4 mm; single or multiple lesions with ≥ 70% stenosis of different lengths in one or more main afferent crural vessels including tibioperoneal trunk	358	74.3	25.7	IN.PACT Amphirion drug-eluting balloons demonstrated comparable and non-inferior efficacy to PTA in CLI patients. The overall complication rate, a composite of core laboratory-adjudicated incidence of vasospasm, abrupt closure, vessel recoil, thrombus, and perforation, was higher in the IA-DEB arm versus the PTA arm (9.7 vs 3.4%; p = 0.035). Major amputation-free survival had a trend favoring DEB
IDEAS	Prospective RCT	6 months	Rutherford classes 3–6 and angiographically documented infrapopliteal disease with a minimum lesion length of 70 mm	50	76	34	DES are related with significantly lower residual immediate post-procedure stenosis and have shown significantly reduced vessel restenosis at 6 months