June 5, 2019
UK MHRA Issues Recommendations on Use of Paclitaxel Devices in PAD
June 6, 2019—The United Kingdom Medicines & Healthcare Products Regulatory Agency (UK MHRA) announced that it has issued the agency's recommendations for ongoing use of paclitaxel drug-coated balloons (DCBs) and implantable drug-eluting stents (DESs) in the treatment of patients with peripheral artery disease (PAD). The recommendations allow for the continued use of these devices in patients with critical limb ischemia (CLI, or chronic limb-threatening ischemia) but advise that they should not be used in the routine treatment of patients with intermittent claudication until further notice.
The document is a response to the study published online in December 2018 by Konstantinos Katsanos, MD, et al in Journal of the American Heart Association. The study's findings raised significant concerns on their use in routine clinical practice and clinical trials, stated MHRA.
As outlined by UK MHRA, the recommendations are the following:
- Do not use paclitaxel DCBs or DESs in the routine treatment of patients with intermittent claudication until further notice, as the potential mortality risk generally outweighs the benefits.
- Use of paclitaxel DCBs and DESs in patients with CLI remains an appropriate option in accordance with the National Institute for Health and Care Excellence's NICE guidance document, as the benefits may outweigh the risks. This is because these patients generally have a higher risk of irreversible ischemic damage resulting from restenosis, and a lower life expectancy.
- Assess the relative risks on an individual patient basis, and if this supports use of a paclitaxel DCB or DES, ensure that (a) the process of informed consent includes a risk-benefit discussion regarding the uncertainty in long-term outcomes with these devices, and the current evidence that indicates an increased mortality rate; and (b) the patient receives enhanced life-long follow-up.
- Ensure local procedures accounting for duty of candor are in place for the continued management of patients who have already been treated with paclitaxel DCBs and DESs. Consider the need for enhanced patient follow-up and the provision of information and advice to address patient concerns arising from the current uncertainty in long-term outcomes with these devices.
- Where enhanced patient follow-up is appropriate this may include telephone consultations or review in the community, and any serious adverse events and cause of death should be reported.
- Interventionalists should report adverse events involving these devices through their local incident reporting system and/or their national incident reporting authority as appropriate. Also, they should report directly to manufacturers if the local or national systems do not.
Additionally, as part of MHRA’s investigation of this potential concern, the agency formed an independent Paclitaxel Expert Advisory Group (EAG), composed of practicing vascular surgeons and interventional radiologists, supported by MHRA toxicologic and statistic experts.
The EAG's findings and recommendations were also posted online by MHRA. The review concluded that the statistical analysis in the Katsanos et al paper is robust, noting the following:
- There is a possible dose-dependent effect of the use of paclitaxel DCBs/DESs on mortality although no scientific or clinical explanation is currently available.
- There are some established causal links between multiple factors and mortality, but the association of increased mortality and the use of paclitaxel DCBs/DESs is established by randomized controlled trials (RCTs), which control for confounding in known factors.
- There is no evidence to suggest that confounding persisted within these studies.
The EAG stated that current knowledge gaps include dose-time relationship, outcomes of paclitaxel DCBs versus paclitaxel DESs, patient factors, effect on patients with claudication compared with those with CLI, peer-reviewed publication of commercial evidence, mechanistic explanation, and biologic evidence.
The EAG's recommendation relating to routine clinical use were adopted in the MHRA's recommendations outlined above. The group advised that the situation should be reviewed again following completion of the meta-analysis using patient level data from currently available RCTs.
Additionally, they recommended that the BASIL 3 and other suspended RCTs involving patients with CLI should consider resumption in recruitment and that ongoing and completed trials that have reported results from 1- or 2-year follow-up should continue or reopen patient follow-up to establish the longer-term mortality status of all patients, up to at least 5 years.
Among a list of six general recommendations, the EAG calls for all approved trials (both premarket and postmarket) to be submitted for publication in peer-review journals regardless of outcome, and if not accepted for publication, the data should be made available in the public domain.