There is a need for more clinical trial data to facilitate medical decision making when caring for patients with critical limb ischemia (CLI). Traditionally, outcome assessment in clinical trials for this patient population has focused on amputation-free survival and patency. Choosing the optimal outcome that is important to patients with CLI and their providers will be crucial in designing a valid and generalizable trial that adds meaningfully to the evidence base.
Amputation-free survival is an unavoidably, important ‘hard’ outcome for trials of CLI. In fact, major trials (such as BEST) are likely to be powered for this or a similar endpoint. However, limb therapies probably only affect the amputation component of this composite outcome, as mortality in CLI patients is often due to cardiac causes (1). In addition, amputation-free survival does not always correspond to a patient being ambulatory and living independently. Revascularization is a cornerstone in the management of patients with CLI. However, patency – another traditional outcome — does not preclude limb salvage. In a meta-analysis of 30 studies (2557) patients with CLI undergoing below-knee revascularization, 1-year patency following endovascular therapy was only 58.1 +/- 4.6%, but limb salvage was 86 +/- 2.7% (2). As a corollary, patency does not ensure the optimal clinical outcome. In a series of 1012 patients undergoing infra-inguinal bypass for CLI, 20% of those with patent grafts at 1 year remained symptomatic or had undergone amputation (3). Though important for the clinical care of patients with critical limb ischemia, lower extremity hemodynamics (eg., ankle-brachial indices) is a surrogate for patency in many respects.
Treadmill testing protocols (graded and constant load) and 6-minute walk tests have been well studied in patients with claudication and also have good test characteristics (4). However, is it reasonable to expect a patient with a painful wound that is appropriately dressed and offloaded to walk on a treadmill? Is loss of distance walked post intervention a treatment failure for a CLI patient if that patient is still able to walk at all and live independently? Other functional tests are also being studied in patients with CLI such as the summary performance score (composite of 4-meter walk test, balance test, sit-stand test), vertical accelerometry, and isometric muscle strength measurements (5).
Multiple patient-reported outcomes have been studied in peripheral arterial disease. Some of these instruments are disease-specific; that is, they were derived and validated in populations with peripheral artery disease. Examples include the Walking Impairment Questionnaire, the Nottingham Health Profile, PADQOL, and VASCUQOL. However, no questionnaire has been designed specifically for CLI patients, excluding claudicants.
Wound healing is an important limb outcome for CLI trials. The definition of wound healing is typically a wound that remains healed for 2 weeks. Core labs exist for the assessment of wound healing. The time to wound healing and the resources required to achieve wound healing (revascularization procedures, surgical debridements, totality of wound care) should be considered.
In conclusion, there are challenges in choosing the optimal outcome assessment tools when designing a trial of CLI therapies. Amputation-free survival is likely to always be of interest. Refining the functional assessment of patients with CLI with non-walking functional tests, such as those listed above, may be of use. Developing a CLI-specific questionnaire that assesses quality of life and function would improve outcome assessment in this disease. Constructing an endpoint of ‘limb health’ — comprised of wound healing, function, and lack of pain – would be of value when comparing therapies in CLI patients. Eventually, cost-effectiveness analyses will be important after optimal management strategies and outcome assessments have been better elucidated.