Pharmacological treatment for Buerger's disease

Background

Buerger's disease is characterized by recurring progressive inflammation and clotting in small and medium arteries and veins of the hands and feet. Its cause is unknown, but it is most common in men with a history of tobacco use. It is responsible for ulcers and extreme pain in the limbs of young smokers. In many cases, mainly in patients with the most severe form, there is no possibility of improving the condition with surgery, and therefore, drugs (pharmacological agents) are used. These can be pharmacological agents, such as cilostazol, clopidogrel, and pentoxifylline, or medicine derivatives of prostacyclin and prostaglandin, which redirect blood flow and improve the circulation in affected areas, and theoretically, help to heal ulcers and relieve rest pain. This review assessed the effectiveness of pharmacological agents in the treatment of patients with Buerger's disease.

Key results

Our search identified five randomised controlled trials, with a total of 602 participants and a treatment period of around four weeks (evidence current until April 2015). The comparisons included prostacyclin analogue versus placebo, aspirin, and a prostaglandin analogue, and folic acid versus placebo. We did not identify studies that assessed pharmacological agents such as cilostazol, clopidogrel and pentoxifylline, or studies that compared oral prostanoid versus intravenous prostanoid. The included studies assessed derivatives of prostacyclin and prostaglandin, which have the ability to redirect blood flow and improve the circulation in affected areas.

Moderate quality evidence from one study suggested that intravenous iloprost was effective in healing ulcers and relieving rest pain after 28 days of treatment when compared with oral aspirin, but no differences were found in the rates of amputation. Evidence from two studies suggested that prostacyclin was as effective as prostaglandin analogues in healing ulcers (very low quality evidence) and eradicating pain at rest (low quality evidence), but rates of amputation were not assessed. Moderate quality evidence from one study suggested that there was no difference between placebo and the oral prostacyclin analogue iloprost (200 mcg and 400 mcg) in healing ischaemic ulcers or eradicating pain at rest after eight weeks and six months, and rates of amputation after six months. Very-low quality evidence from one study showed no difference between placebo and folic acid, in patients with Buerger's disease and hyperhomocysteinaemia (a medical condition characterized by abnormally high level of homocysteine in the blood), in rates of amputation and pain scores. Ulcer healing was not measured. Treatment side effects, such as headaches or nausea, did not result in treatment interruptions or more serious consequences. Outcomes such as amputation-free survival, walking distance or pain-free walking distance, and ankle brachial index were not assessed by any study.

Quality of the evidence

Overall, the quality of the evidence was very low to moderate, with few studies, small numbers of participants, variation in severity of disease of participants between studies and missing information regarding for example baseline tobacco exposure. High quality trials assessing the effectiveness of pharmacological agents (intravenous or oral) in people with Buerger's disease are needed.

Authors' conclusions: 

Moderate quality evidence suggests that intravenous iloprost (prostacyclin analogue) is more effective than aspirin for eradicating rest pain and healing ischaemic ulcers in Buerger’s disease, but oral iloprost is not more effective than placebo. Verylow and low quality evidence suggests there is no difference between prostacyclin (iloprost and clinprost) and the prostaglandin analogue alprostadil for healing ulcers and relieving pain respectively in severe Buerger’s disease. Very-low quality evidence suggests there is no difference in pain scores and amputation rates between folic acid and placebo, in people with Buerger's disease and hyperhomocysteinaemia. High quality trials assessing the effectiveness of pharmacological agents (intravenous or oral) in people with Buerger's disease are needed.

Read the full abstract...
Background: 

Buerger's disease (thromboangiitis obliterans) is a non-atherosclerotic, segmental inflammatory pathology that most commonly affects the small and medium sized arteries, veins, and nerves in the upper and lower extremities. The etiology is unknown, but involves hereditary susceptibility, tobacco exposure, immune and coagulation responses. In many cases, there is no possibility of revascularization to improve the condition. Pharmacological treatment is an option for patients with severe complications, such as ischaemic ulcers or rest pain.

Objectives: 

To assess the effectiveness of any pharmacological agent (intravenous or oral) compared with placebo or any other pharmacological agent in patients with Buerger's disease.

Search strategy: 

The Cochrane Vascular Trials Search Co-ordinator searched their Specialised Register (last searched in April 2015) and the Cochrane Register of Studies (Issue 3, 2015). The review authors searched trial registers and the European grey literature; screened reference lists of relevant studies, and contacted study authors and major pharmaceutical companies.

Selection criteria: 

Randomised controlled trials (RCTs) involving pharmacological agents used in the treatment of Buerger's disease.

Data collection and analysis: 

Two review authors, independently assessed the studies, extracted data and performed data analysis.

Main results: 

Five randomised controlled trials (total 602 participants) compared prostacyclin analogue with placebo, aspirin, or a prostaglandin analogue, and folic acid with placebo. No studies assessed other pharmacological agents such as cilostazol, clopidogrel and pentoxifylline or compared oral versus intravenous prostanoid.

Compared with aspirin, intravenous prostacyclin analogue iloprost improved ulcer healing (risk ratio (RR) 2.65; 95% confidence interval (CI) 1.15 to 6.11; 98 participants; one study; moderate quality evidence), and helped to eradicate rest pain after 28 days (RR 2.28; 95% CI 1.48 to 3.52; 133 participants; one study; moderate quality evidence), although amputation rates were similar six months after treatment (RR 0.32; 95% CI 0.09 to 1.15; 95 participants; one study; moderate quality evidence). When comparing prostacyclin (iloprost and clinprost) with prostaglandin (alprostadil) analogues, ulcer healing was similar (RR 1.13; 95% CI 0.76 to 1.69; 89 participants; two studies; I² = 0%; very low quality evidence), as was the eradication of rest pain after 28 days (RR 1.57; 95% CI 0.72 to 3.44; 38 participants; one study; low quality evidence), while amputation rates were not measured. Compared with placebo, the effects of oral prostacyclin analogue iloprost were similar for: healing ischaemic ulcers (iloprost 200 mcg: RR 1.11; 95% CI 0.54 to 2.29; 133 participants; one study; moderate quality evidence, and iloprost 400 mcg: RR 0.90; 95% CI 0.42 to 1.93; 135 participants; one study; moderate quality evidence), eradication of rest pain after eight weeks (iloprost 200 mcg: RR 1.14; 95% CI 0.79 to 1.63; 207 participants; one study; moderate quality evidence, and iloprost 400 mcg: RR 1.11; 95% CI 0.77 to 1.59; 201 participants; one study; moderate quality evidence), and amputation rates after six months (iloprost 200 mcg: RR 0.54; 95% CI 0.19 to 1.56; 209 participants; one study, and iloprost 400 mcg: RR 0.42; 95% CI 0.13 to 1.31; 213 participants; one study). When comparing folic acid with placebo in patients with Buerger's disease and hyperhomocysteinaemia, pain scores were similar, there were no new cases of amputation in either group, and ulcer healing was not assessed (very low quality evidence).

Treatment side effects such as headaches, flushing or nausea were not associated with treatment interruptions or more serious consequences. Outcomes such as amputation-free survival, walking distance or pain-free walking distance, and ankle brachial index were not assessed by any study.

Overall, the quality of the evidence was very low to moderate, with few studies, small numbers of participants, variation in severity of disease of participants between studies and missing information regarding for example baseline tobacco exposure.

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