Peripheral arterial disease: diagnosis and management

What the guideline recommends

Recommendation 1.5.6 of CG147 states:

"Use bare metal stents when stenting is used for treating people with intermittent claudication."

Drug eluting angioplasty was not considered in CG147.

Methods

A network meta-analysis of randomised controlled trials (RCTs) performed comparing bare nitinol stents (BNS), covered nitinol stents (CNS), paclitaxel- or sirolimus-eluting stents (PES or SES), and paclitaxel-coated balloons (PCB) with plain balloon angioplasty (BA) or with each other in the femoropopliteal artery. Sixteen RCTs comprising 2,532 patients with 4,227 person years (py) of follow up included.

Trials with low risk of bias from 1950 to present with no restrictions on publication language were included. Study population in all 16 trials had similar baseline demographics among the treatment and control arms. However, there was significant variation between trials in both the rate of initial chronic total occlusions and the lesion length and length of antiplatelet therapy (1 to 6 months). To account for this variation meta-regression analyses were incorporated in the Bayesian modelling.

The majority of included patients were treated for intermittent claudication, and only a small percentage of patients had critical limb ischaemia.

Outcomes measures included technical success, vascular restenosis, target lesion revascularisation (TLR), and major amputations. Technical success was defined as successful recanalisation of the target vessel with no significant residual stenosis on completion angiogram (30% to 50% threshold). Vascular restenosis was evaluated on the 50% threshold by quantitative vascular angiography or colour doppler ultrasonography. TLR included any repeat procedures. Major amputations defined as any limb loss that extended above the ankle.

Results

The mean duration of follow up was 22 months (range 9 to 48 months). Data on immediate procedural technical success were reported in 14 RCTs. Compared with BA (success rate 73.9%) both covered (success rate 98%) and uncovered stents (success rate 95%) achieved higher median technical success rate. Covered stents had the highest probability (82.1%) of being best and uncovered stents with an 18% probability of being best, ranked second. There were significantly higher odds of success in both uncovered (odds ratio [OR] 7.0; 95% credible interval [CrI] 2.6 to 129) and covered stents (OR 13.6; 95% CrI 3.3 to 31.1) when compared with BA. There was no significant difference in technical success when comparing uncovered with covered stents.

Vascular restenosis was reported by all 16 RCTs. There were 45 median restenosis events per 100 py in the BA group. PES and PCB both showed 19 events per 100 py and CNS showed 27events per 100 py. Compared with BA, PCB (risk ratio [RR] 0.43; 95% CrI 0.26 to 0.67) and CNS (RR 0.60; 95% CrI 0.36 to 0.94) had significantly fewer events. However there were marginally non-significant difference in the rate of events in BNS (RR 0.78; 95% CrI 0.57 to 1.06) and PES (RR 0.43; 95% CrI 0.16 to 1.18) when compared to BA. PES had the highest probability (45%) of being the best treatment (lowest rate of events), followed by PCB, with a 42% probability.

TLR events were reported by 15 RCTs. The median TLR rates of for BA were 22 events per 100 py. PCB was associated with the highest probability (56%) of being the best treatment (lowest rate of events), followed by PES, with a 33% probability. Compared with BA, there were marginally non-significant difference in the risk of TLR in BNS (RR 0.77; 95% CrI 0.57 to 1.07), CNS (RR 0.74; 95% CrI 0.45 to 1.18), and PES (RR 0.42; 95% CrI 0.16 to 1.06). Compared to BA, PCB was the only treatment that showed consistent lower risk of TLR (RR 0.36; 95% CrI 0.23 to 0.55), BNS (RR 0.47; 95% CrI 0.27 to 0.80), and CNS (RR 0.49; 95% CrI 0.25 to 0.94). No significant difference was observed between PCB and different drug-eluting stents in the risk of TLR. Major amputations were rare in all treatment and control groups.

The study concluded that immediate technical success is better with the use of covered stents, whereas PES and PCB offer the best long-term results in the femoropopliteal artery.

Strengths and limitations

Impact on guideline

The study provides evidence of benefits for drug-eluting technology included drug-eluting balloons in patients with PAD which was not reviewed in CG147.

Topic experts highlighted the ongoing National Institute for Health Research (NIHR) Health Technology Assessment (HTA)-funded BASIL-3 study, which is an RCT of clinical and cost effectiveness of drug-coated balloons, drug-eluting stents and balloon angioplasty with bail-out bare metal stent revascularisation strategies. Based on the feedback from topic experts, this review should be considered for a future update after completion of the BASIL-3 trial. The study is in the recruiting stage and updating the question now could potentially impact on the recruitment process. The surveillance team will track the findings of the BASIL-3 trial.

What the guideline recommends

Recommendation 1.5.6 of CG147 states:

"Use bare metal stents when stenting is used for treating people with intermittent claudication."

Recommendation 1.6.5 of CG147 states:

"Use bare metal stents when stenting is used for treating people with critical limb ischaemia."

Methods

A multicentre RCT including 55 cities in the US, Germany and Japan evaluated clinical durability of Zilver PTX, a paclitaxel-coated drug-eluting stent (DES) for femoropopliteal artery lesions. This study is 5-year follow up of the RCT. The original RCT with the 12-month result is included in CG147. The original study included patients with Rutherford category ≥2, ≥50% diameter stenosis, reference vessel diameter 4 to 9 mm, lesion length up to 14 cm, and at least 1 patent runoff vessel with <50% stenosis. Exclusion criteria were patients with untreated >50% stenosis of the inflow tract and previous target vessel stenting. The detailed description of the study design and methods, endpoint at 1-year and 2-year follow up were previously reported and published separately.

Patients were randomised to DES (n=236) or percutaneous transluminal angioplasty (PTA; n=238). The patients with acute PTA failure (n=120) were then randomised to provisional DES (n=61) or provisional bare metal stent (BMS) placement (n=59). At 5-year follow up the primary DES group was compared to the PTA group and the provisional DES group to the provisional BMS group. In addition, the overall DES group (comprised of both primary and provisional DES) was compared to the standard care group (including patients with provisional BMS placement plus patients with optimal PTA). This overall comparison was non-randomised.

For patients randomised to DES, stents placed at least 1 cm below the SFA origin and above the medial femoral epicondyle to fully cover the target lesion(s). For patients in the PTA group, PTA was performed according to the institutional standard practice. Patients experiencing acute PTA failure underwent secondary randomisation to provisional BMS or provisional DES placement. Acute PTA failure was defined as ≥30% residual stenosis or a ≥5 mm Hg mean trans-stenotic pressure gradient.

Patients underwent in-clinic assessment at 6 months, 1 year, and annually thereafter through 5 years. The assessment included Rutherford classification, ankle brachial index (ABI), and Walking Impairment Questionnaire (WIQ).

Duplex ultrasound evaluation of patency was performed for all patients at 6 months, and at 1-year and 2-year follow up. To assess stent integrity, high-resolution stent radiographs were obtained at 1, 3, and 5 years.

Results

The 1-year primary endpoints of event-free survival (EFS) and primary patency showed superiority of primary DES compared to PTA; these results were constant through 5 years.

The EFS rate was greater through 5 years in the primary DES group compared to the PTA group (Kaplan–Meier estimates 81.4% versus 70.1% p<0.01 respectively).

The primary patency rate was also significantly greater in the DES group through 5 years compared to the PTA group (Kaplan–Meier estimates 64.9% versus 19.0% p<0.01 respectively).

All-cause mortality rate at 5 years was 13.6% (10.2% in the primary DES group and 16.6% in the PTA group, p=0.03). There were no differences observed between the 2 groups in the rate of freedom from thrombosis/occlusion through 5 years (p=0.68).

Five-year freedom from TLR and primary patency rate were significantly higher at the overall DES group compared to the standard care group (p<0.01).

Significantly higher number of patients in the overall DES group maintained clinical benefit compared with patients in the standard care group (Kaplan–Meier estimates 79.8 % versus 59.3% p<0.01). Clinical benefit was defined as freedom from persistent or worsening claudication, rest pain, ulcer or tissue loss after the initial study treatment.

Significantly more patients in the provisional DES group (81.8%) maintained clinical benefit compared to the provisional BMS group (63.8%; p=0.02). Clinical benefit was defined as freedom from persistent or worsening claudication, rest pain, ulcer or tissue loss after the initial study treatment.

These results for restenosis and TLR represent >40% RR reduction through 5 years for the overall DES group compared to the standard care group and provisional the DES group compared to the provisional BMS group.

Strengths and limitations

Impact on guideline

The 5-year follow up results from this large study provided evidence for safety and clinical durability for drug-eluting stents compared to standard endovascular treatments. The original study with 12-month results is included in the CG147.

Topic experts highlighted the ongoing NIHR HTA-funded BASIL-3 study, which is an RCT of clinical and cost effectiveness of drug-coated balloons, drug-eluting stents and balloon angioplasty with bail-out bare metal stent revascularisation strategies. Based on the feedback from topic experts, this review should be considered for a future update after completion of BASIL-3 trial. The study is in the recruiting stage and updating the question now could potentially impact on the recruitment process. The surveillance team will track the findings of the BASIL-3 trial.