NIHR Signal Drug coated balloons have some short-term benefits for peripheral arterial disease

Published on 10 January 2017

Widening damaged blood vessels using balloons coated in a drug called paclitaxel improves blood flow and reduces the risk of a further operation within a year compared to cheaper, uncoated balloons. Rates of amputation and death were no different between groups, though there were few of these events.

This review of 11 studies included over 1,800 adults with peripheral arterial disease (PAD) restricting the blood flow in their legs. Though performing the minimally invasive surgical procedure using coated balloons improved some outcomes up to a year, they did not have an effect on risk of amputation or death. Other important outcomes such as quality of life were inconclusive.

Costs were not considered in this review, but the reduced rate of reoperation may offset the increased cost of the coated balloons. It should be noted that most studies were industry-funded and no information was provided on any safety issues concerning the drug coated balloons.

Why was this study needed?

PAD causes narrowing of the blood vessels in the legs. This can result in pain when walking, called intermittent claudication. An estimated 20% of people aged over 60 in the UK have PAD and 6% have intermittent claudication. In 20% this progresses to pain at rest or gangrene needing amputation.

Initial management includes exercise, medication to dilate the blood vessels or to reduce blood clotting and modification of cardiovascular risk factors including smoking, overweight, high blood pressure, lipids and diabetes.

If treatment fails to improve symptoms, angioplasty (inserting a balloon into the blood vessel to widen it) is the least invasive surgical approach. Paclitaxel is a drug which reduces scar tissue, which can progress to narrowing of the blood vessel after angioplasty. The researchers wanted to see if coating the balloon with paclitaxel prevents the complications of arterial disease or the problem recurring compared with cheaper uncoated balloons.

What did this study do?

This Cochrane systematic review and meta-analysis pooled the findings from 11 randomised controlled trials comparing angioplasty using balloons coated with paclitaxel with uncoated balloons. It included 1,838 adults, who were followed up for 12 to 24 months.

There was a lot of variation between studies in terms of which artery was being treated and whether stents were implanted at the same time as the balloon. Whether the clot reducing drugs aspirin, clopidogrel or both were prescribed, and for how long, also differed, as did the dose of the paclitaxel coating.

Most of the included studies (9/11) were sponsored by manufacturers of the coated balloons and their authors all declared competing financial interests. However, the included studies were of moderate to high quality therefore we can feel confident in their findings.

What did it find?

  • There was no difference between the balloon types in the risk of amputation within 12 months of the operation. There were an estimated 22 amputations per 1,000 people with drug coated balloons compared to 14 per 1,000 with uncoated balloons (odds ratio [OR] 1.56, 95% confidence interval [CI] 0.73 to 3.33, 1649 participants in nine studies).
  • The estimated number of deaths up to 12 months was also similar at 43 per 1,000 for drug coated balloons and 46 per 1,000 for uncoated balloons (OR 1.09, 95% CI 0.64 to 1.85).
  • Vessel patency, good blood flow on imaging, was achieved in 64% of people with drug coated balloons compared to 48% with uncoated ones at 12 months (OR 1.92, 95% CI 1.45 to 2.56; 882 participants in three studies). This improvement remained at 24 months (OR 3.51, 95% CI 2.26 to 5.46; 406 participants in two studies). Of note, this analysis excluded one eligible study because of its high risk of bias.
  • Further surgery was required in 13% of those with balloons within 12 months compared to 26% of those with uncoated balloons (OR 0.40, 95% CI 0.31 to 0.51, 1900 participants in 11 studies).
  • Neither intervention had any meaningful impact on quality of life, but this was based on three dissimilar studies. However, ability to walk was substantially improved by both types of balloons. According to the Walking Impairment Questionnaire (WIQ) which scores 0 as inability to walk and 100 no difficulty, the scores improved by around 36 points by six months.

What does current guidance say on this issue?

2012 NICE guidelines recommend angioplasty for people with intermittent claudication or critical limb ischaemia if exercise, lifestyle modifications and vessel-dilating medication have not controlled symptoms. They do not specify whether drug coated or uncoated balloons should be used.

Depending on the location and extent of the narrowing, patient preference and suitability for surgery, further options include inserting a stent or bypass surgery. There is however wide variation in practice in type of angioplasty, use of stents and bypass procedures.

What are the implications?

Overall, drug coated balloons were as good as or slightly better than uncoated balloons. Risk of amputation or death was similar across groups, but these events were rare. Similar results were seen in another recent systematic review on this topic, which included many of the same studies, but did not include procedures below the knee.

There was anatomical evidence that both types of balloons improved blood flow through the vessels and ability to walk but impacts on quality of life were not adequately assessed. In addition, any potential side effects from the paclitaxel coating were not reported.

A formal economic evaluation was not performed, but drug coated balloons reduced the rate of reoperation and this should be taken into account when considering the increased cost of drug coated balloons.

Citation and Funding

Kayssi A, Al-Atassi T, Oreopoulos G, et al. Drug-eluting balloon angioplasty versus uncoated balloon angioplasty for peripheral arterial disease of the lower limbs. Cochrane Database Syst Rev. 2016;(8):CD011319.

The Cochrane Vascular editorial base is supported by the Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.

Bibliography

NICE. Lutonix drug-coated balloon for peripheral arterial disease. MIB72. London: National Institute for Health and Care Excellence; 2016.

NICE. Peripheral arterial disease: diagnosis and management. CG147. London: National Institute for Health and Care Excellence; 2012.

Jongsma H, Bekken JA, de Vries JP, et al. Drug-eluting balloon angioplasty versus uncoated balloon angioplasty in patients with femoropopliteal arterial occlusive disease. J Vasc Surg. 2016;64(5):1503-14.

Why was this study needed?

PAD causes narrowing of the blood vessels in the legs. This can result in pain when walking, called intermittent claudication. An estimated 20% of people aged over 60 in the UK have PAD and 6% have intermittent claudication. In 20% this progresses to pain at rest or gangrene needing amputation.

Initial management includes exercise, medication to dilate the blood vessels or to reduce blood clotting and modification of cardiovascular risk factors including smoking, overweight, high blood pressure, lipids and diabetes.

If treatment fails to improve symptoms, angioplasty (inserting a balloon into the blood vessel to widen it) is the least invasive surgical approach. Paclitaxel is a drug which reduces scar tissue, which can progress to narrowing of the blood vessel after angioplasty. The researchers wanted to see if coating the balloon with paclitaxel prevents the complications of arterial disease or the problem recurring compared with cheaper uncoated balloons.

What did this study do?

This Cochrane systematic review and meta-analysis pooled the findings from 11 randomised controlled trials comparing angioplasty using balloons coated with paclitaxel with uncoated balloons. It included 1,838 adults, who were followed up for 12 to 24 months.

There was a lot of variation between studies in terms of which artery was being treated and whether stents were implanted at the same time as the balloon. Whether the clot reducing drugs aspirin, clopidogrel or both were prescribed, and for how long, also differed, as did the dose of the paclitaxel coating.

Most of the included studies (9/11) were sponsored by manufacturers of the coated balloons and their authors all declared competing financial interests. However, the included studies were of moderate to high quality therefore we can feel confident in their findings.

What did it find?

  • There was no difference between the balloon types in the risk of amputation within 12 months of the operation. There were an estimated 22 amputations per 1,000 people with drug coated balloons compared to 14 per 1,000 with uncoated balloons (odds ratio [OR] 1.56, 95% confidence interval [CI] 0.73 to 3.33, 1649 participants in nine studies).
  • The estimated number of deaths up to 12 months was also similar at 43 per 1,000 for drug coated balloons and 46 per 1,000 for uncoated balloons (OR 1.09, 95% CI 0.64 to 1.85).
  • Vessel patency, good blood flow on imaging, was achieved in 64% of people with drug coated balloons compared to 48% with uncoated ones at 12 months (OR 1.92, 95% CI 1.45 to 2.56; 882 participants in three studies). This improvement remained at 24 months (OR 3.51, 95% CI 2.26 to 5.46; 406 participants in two studies). Of note, this analysis excluded one eligible study because of its high risk of bias.
  • Further surgery was required in 13% of those with balloons within 12 months compared to 26% of those with uncoated balloons (OR 0.40, 95% CI 0.31 to 0.51, 1900 participants in 11 studies).
  • Neither intervention had any meaningful impact on quality of life, but this was based on three dissimilar studies. However, ability to walk was substantially improved by both types of balloons. According to the Walking Impairment Questionnaire (WIQ) which scores 0 as inability to walk and 100 no difficulty, the scores improved by around 36 points by six months.

What does current guidance say on this issue?

2012 NICE guidelines recommend angioplasty for people with intermittent claudication or critical limb ischaemia if exercise, lifestyle modifications and vessel-dilating medication have not controlled symptoms. They do not specify whether drug coated or uncoated balloons should be used.

Depending on the location and extent of the narrowing, patient preference and suitability for surgery, further options include inserting a stent or bypass surgery. There is however wide variation in practice in type of angioplasty, use of stents and bypass procedures.

What are the implications?

Overall, drug coated balloons were as good as or slightly better than uncoated balloons. Risk of amputation or death was similar across groups, but these events were rare. Similar results were seen in another recent systematic review on this topic, which included many of the same studies, but did not include procedures below the knee.

There was anatomical evidence that both types of balloons improved blood flow through the vessels and ability to walk but impacts on quality of life were not adequately assessed. In addition, any potential side effects from the paclitaxel coating were not reported.

A formal economic evaluation was not performed, but drug coated balloons reduced the rate of reoperation and this should be taken into account when considering the increased cost of drug coated balloons.

Citation and Funding

Kayssi A, Al-Atassi T, Oreopoulos G, et al. Drug-eluting balloon angioplasty versus uncoated balloon angioplasty for peripheral arterial disease of the lower limbs. Cochrane Database Syst Rev. 2016;(8):CD011319.

The Cochrane Vascular editorial base is supported by the Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.

Bibliography

NICE. Lutonix drug-coated balloon for peripheral arterial disease. MIB72. London: National Institute for Health and Care Excellence; 2016.

NICE. Peripheral arterial disease: diagnosis and management. CG147. London: National Institute for Health and Care Excellence; 2012.

Jongsma H, Bekken JA, de Vries JP, et al. Drug-eluting balloon angioplasty versus uncoated balloon angioplasty in patients with femoropopliteal arterial occlusive disease. J Vasc Surg. 2016;64(5):1503-14.

Drug-eluting balloon angioplasty versus uncoated balloon angioplasty for peripheral arterial disease of the lower limbs

Published on 5 August 2016

Kayssi, A.,Al-Atassi, T.,Oreopoulos, G.,Roche-Nagle, G.,Tan, K. T.,Rajan, D. K.

Cochrane Database Syst Rev Volume 8 , 2016

BACKGROUND: Atherosclerotic peripheral arterial disease (PAD) can lead to disabling ischemia and limb loss. Treatment modalities have included risk factor optimization through life-style modifications and medications, or operative approaches using both open and minimally invasive techniques, such as balloon angioplasty. Drug-eluting balloon (DEB) angioplasty has emerged as a promising alternative to uncoated balloon angioplasty for the treatment of this difficult disease process. By ballooning and coating the inside of atherosclerotic vessels with cytotoxic agents, such as paclitaxel, cellular mechanisms responsible for atherosclerosis and neointimal hyperplasia are inhibited and its devastating complications are prevented or postponed. DEBs are considerably more expensive than uncoated balloons, and their efficacy in improving patient outcomes is unclear. OBJECTIVES: To assess the efficacy of drug-eluting balloons (DEBs) compared with uncoated, nonstenting balloon angioplasty in people with symptomatic lower-limb peripheral arterial disease (PAD). SEARCH METHODS: The Cochrane Vascular Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched December 2015) and Cochrane Register of Studies (CRS) (2015, Issue 11). The TSC searched trial databases for details of ongoing and unpublished studies. SELECTION CRITERIA: We included all randomized controlled trials that compared DEBs with uncoated, nonstenting balloon angioplasty for intermittent claudication (IC) or critical limb ischemia (CLI). DATA COLLECTION AND ANALYSIS: Two review authors (AK, TA) independently selected the appropriate trials and performed data extraction, assessment of trial quality, and data analysis. The senior review author (DKR) adjudicated any disagreements. MAIN RESULTS: Eleven trials that randomized 1838 participants met the study inclusion criteria. Seven of the trials included femoropopliteal arterial lesions, three included tibial arterial lesions, and one included both. The trials were carried out in Europe and in the USA and all used the taxane drug paclitaxel in the DEB arm. Nine of the 11 trials were industry-sponsored. Four companies manufactured the DEB devices (Bard, Bavaria Medizin, Biotronik, and Medtronic). The trials examined both anatomic and clinical endpoints. There was heterogeneity in the frequency of stent deployment and the type and duration of antiplatelet therapy between trials. Using GRADE assessment criteria, the quality of the evidence presented was moderate for the outcomes of target lesion revascularization and change in Rutherford category, and high for amputation, primary vessel patency, binary restenosis, death, and change in ankle-brachial index (ABI). Most participants were followed up for 12 months, but one trial reported outcomes at five years.There were better outcomes for DEBs for up to two years in primary vessel patency (odds ratio (OR) 1.47, 95% confidence interval (CI) 0.22 to 9.57 at six months; OR 1.92, 95% CI 1.45 to 2.56 at 12 months; OR 3.51, 95% CI 2.26 to 5.46 at two years) and at six months and two years for late lumen loss (mean difference (MD) -0.64 mm, 95% CI -1.00 to -0.28 at six months; MD -0.80 mm, 95% CI -1.44 to -0.16 at two years). DEB were also superior to uncoated balloon angioplasty for up to five years in target lesion revascularization (OR 0.28, 95% CI 0.17 to 0.47 at six months; OR 0.40, 95% CI 0.31 to 0.51 at 12 months; OR 0.28, 95% CI 0.18 to 0.44 at two years; OR 0.21, 95% CI 0.09 to 0.51 at five years) and binary restenosis rate (OR 0.44, 95% CI 0.29 to 0.67 at six months; OR 0.38, 95% CI 0.15 to 0.98 at 12 months; OR 0.26, 95% CI 0.10 to 0.66 at two years; OR 0.12, 95% CI 0.05 to 0.30 at five years). There was no significant difference between DEB and uncoated angioplasty in amputation, death, change in ABI, change in Rutherford category and quality of life (QoL) scores, or functional walking ability, although none of the trials were powered to detect a significant difference in these clinical endpoints. We carried out two subgroup analyses to examine outcomes in femoropopliteal and tibial interventions as well as in people with CLI (4 or greater Rutherford class), and showed no advantage for DEBs in tibial vessels at six and 12 months compared with uncoated balloon angioplasty. There was also no advantage for DEBs in CLI compared with uncoated balloon angioplasty at 12 months. AUTHORS' CONCLUSIONS: Based on a meta-analysis of 11 trials with 1838 participants, there is evidence of an advantage for DEBs compared with uncoated balloon angioplasty in several anatomic endpoints such as primary vessel patency (high-quality evidence), binary restenosis rate (moderate-quality evidence), and target lesion revascularization (low-quality evidence) for up to 12 months. Conversely, there is no evidence of an advantage for DEBs in clinical endpoints such as amputation, death, or change in ABI, or change in Rutherford category during 12 months' follow-up. Well-designed randomized trials with long-term follow-up are needed to compare DEBs with uncoated balloon angioplasties adequately for both anatomic and clinical study endpoints before the widespread use of this expensive technology can be justified.

Expert commentary

Advances in technology continue relentlessly, but not necessarily for patient benefit? This meta-analysis highlights this problem; 11 trials compared drug eluting angioplasty technology compared to simple angioplasty. Radiological results were better in the short to mid-term but there with no effect on any patient outcomes. Therefore, should the NHS use these devices?

On-going NIHR HTA BASIL 2 & BASIL 3 trials are running to compare angioplasty (with or without drug coated balloons to surgical bypass. All clinicians have a responsibility to the patient and the NHS to ensure good (research) practice and should offer entry into clinic trials as NHS standard of care to ensure best treatment for the patient.

Mr Toby Richards, Vascular and Endovascular Surgeon, University College Hospital

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