Outcomes of revascularization in patients with lower extremity critical limb ischemia should be defined according to patient goals and functional criteria rather than more traditional, physician-oriented variables such as limb salvage and graft patency.
By Ginger L. Manos, MD, John W. York, MD, FACS, and Brent L. Johnson, MS
An estimated 8 million Americans suffer from peripheral arterial disease (PAD), and the prevalence increases with age, reaching as high as 25% in elderly adults older than 80 years.1-3 Patients with symptomatic PAD may present with intermittent claudication or critical limb ischemia (CLI). CLI is defined as tissue loss (gangrene or nonhealing wound) or pain at rest secondary to inadequate tissue oxygenation to meet baseline metabolic demands.
The natural history of patients who suffer from claudication differs significantly from that of patients with CLI, which leads to different management strategies. The risk of major limb amputation is <1% per year in patients with claudication, however, patients with CLI have a 14% to 45% risk of major amputation resulting from unreconstructed ischemic vascular disease.4
As the natural history of these disease states differs, so do the goals of therapy. For patients with vasculogenic claudication, practitioners’ primary goals are to decrease or eliminate pain with ambulation and to initiate lifestyle modifications that decrease the risk of death related to cardiovascular disease. Lifestyle modifications such as smoking cessation, statin therapy, exercise programs, and hypertension control comprise an integral component of the treatment of patients with claudication. The focus is quite different in patients with CLI, in which physician-oriented goals are limb salvage and reconstruction patency and patient-oriented goals are maintenance of ambulation and independent living.
The management of lower extremity ischemia is the most challenging and sometimes frustrating component of vascular surgery. Over the past decade, the management of claudication has dictated exercise and medical management until symptoms became severe, followed by bypass or amputation if the patient is deemed unreconstructable. The advent of catheter-based interventions in the hands of vascular specialists has changed that paradigm. Peripheral intervention for claudication and CLI has become commonplace, in many cases, without much level-one evidence to support its use. This has left interventionalists and payers wondering which patients are most appropriate for this type of intervention, who, ideally, should be performing these interventions, how patients should be followed, and about the true outcomes of such procedures. The real question is: Have we improved our patients’ lives in a manner that provides a reasonably long-term benefit at an affordable price?
For patients with CLI, the stakes are much higher than for those with claudication, and expectations following intervention or reconstruction are far different. Historically, as with claudication, the treatment of CLI, particularly tissue loss, has been relatively straightforward and included surgical debridement of necrotic tissue, often with primary amputation, and wound care. The development of lower extremity arterial reconstruction in the 1970s provided new tools and techniques to achieve limb salvage in patients with severe ischemia and gangrene; this change required a more thoughtful approach. With the popularization of peripheral intervention in the 1990s, the vascular specialists’ armamentarium had become replete with procedures that could potentially target revascularization and limb salvage.
Currently, multiple trials are underway to determine the best method of revascularization in patients facing potential limb loss. It is our opinion that it makes no difference what technique is utilized to achieve tissue perfusion (i.e., surgical reconstruction versus catheter-based intervention) and that studies comparing open surgical bypass with angioplasty/stenting are missing the proverbial boat.
We have come to support the idea that patients’ outcomes are generally predicted by their presenting physiologic state and that treatment goals should be made accordingly. For example, patients who present with CLI but who are minimal ambulators due to advanced comorbidities are unlikely to benefit from a peripheral intervention or arterial reconstruction. In this situation, the most appropriate management may be pain medication, wound “hospice,” (i.e., managing wounds that are not actively infected with local wound care), or primary amputation.
Although this is an abrupt shift from the standard philosophy in vascular surgery, we feel this approach is most beneficial for our patients. Our philosophy has led to development of patient-oriented goals, such as maintenance of independent living and ambulation (with or without a prosthesis), as opposed to physician-oriented goals, such as graft patency and limb salvage, which have been the primary criteria for success in vascular surgery for decades. Over time, we have focused our research efforts on optimizing surgical decision-making through the identification of preoperative factors predictive of clinical success and patient-oriented outcomes, as well as standardization of care delivery to maximize our ability to achieve these desired outcomes.
Treatment decisions in patients with symptomatic lower extremity ischemia are challenging because of the multiple individual factors that must be considered as well as the wealth of procedures and devices currently available to vascular specialists. This has led to broad variability in the types of treatments offered to patients with lower extremity ischemia. The lower extremity grading system (LEGS) score5 was developed at our institution, Greenville Hospital System-University Medical Center in South Carolina, as an objective scoring system to help physicians select the most effective intervention in patients with severe recalcitrant claudication or CLI.
The LEGS score is based on five categories of clinical factors: arteriographic findings, presentation (claudication versus limb-threatening ischemia), the patient’s functional status, comorbidities, and technical factors. Clinicians assign each patient a point value based on his or her individual constellation of factors (Figure 1). Treatment recommendations are made based on patients’ scores: 0-9, open intervention; 10-19, endovascular intervention; and ≥20, primary amputation. Clinical situations in which the LEGS score should not be applied involve patients who have a nonsalvageable leg or foot, acute and/or severe infection, or blue-toe syndrome.
In our practice, the LEGS system has been a useful tool for standardizing treatments and developing treatment algorithms, which are based on validation studies conducted at our institution. The system also allows for outcomes analysis to determine if our protocols are achieving optimal results, and subsequent studies at out institution have validated treatment outcomes based on LEGS recommendations.5-7
Our research has also focused on identification of clinical factors that predict functional outcomes in patients undergoing either revascularization or major amputation.8 Specific clinical factors we have identified include preoperative ambulatory status (ambulatory, ambulatory/homebound, nonambulatory/transfer only, or nonambulatory/bedridden) and living status (independent [residing in an independent dwelling without external assistance] versus nonindependent [assisted living facility or private residence with external assistance for activities of daily living]).
In patients who undergo major limb amputation, preoperative functional status directly influences postoperative functional outcome. Factors associated with diminished ambulatory capacity following major limb amputation include age >70 years, bilateral amputations, ambulatory/homebound states, and end-stage renal disease (ESRD). In fact, increasing age (>70 years) has been associated with a three-fold higher risk of death compared with similar patients aged >50 years. These younger patients are also three times less likely to wear a prosthesis following amputation. Thus, the elderly population is 2.3 times also more likely to be nonambulatory and 4 times more likely to lose their independent living status one year following major limb amputation compared with patients >50 years.8
Functional outcomes have been evaluated in patients >80 years who have undergone either endovascular or open intervention for CLI. We evaluated 122 patients (140 limbs) treated with bypass (n=66) or percutaneous intervention (n=75). The three-year secondary patency was 73%; maintenance of ambulation, 77%; and maintenance of independent living status, 83%. However, amputation-free survival was only 50% at three years. Patients with diabetes were four times as likely as those without diabetes to experience limb loss or a decline in functional status. Amputation-free survival for patients whose preoperative ambulatory status was transfer only at presentation was only 37%.9
A subsequent study performed by our practice evaluated 1000 critically ischemic limbs treated with either open or endovascular intervention. The five-year secondary patency and limb salvage rates were both 72%; however, the five-year survival rate was only 42%, while maintenance of ambulation and living were 70% and 81%, respectively. Significant factors associated with independent living status following intervention were impaired ambulatory status at presentation (i.e., ambulatory/homebound or nonambulatory/ transfer only), dementia, and advanced age (>70 years).10, 11
Endovascular intervention in critically ischemic patients is commonly utilized at our institution as a first-line therapy, especially in patients older than 70 years or who have severe comorbidities. The actual benefit of endovascular therapy in this patient group is uncertain. Our group has demonstrated multiple factors that suggest the degree of chronic functional impairment in patients presenting with CLI may contribute to poor endovascular outcomes. To further explore this, we compared outcomes in patients with CLI deemed unfit for open surgery (i.e., medically, functionally, or mentally impaired) who underwent angioplasty with those who underwent primary amputation. Endovascular patients were significantly more likely to maintain their ambulatory ability (P< 0.001) and independence in activities of daily living (p=0.046) than patients undergoing primary amputation. However, this advantage was only present for an average of 12 months relative to maintenance of ambulation, and only three months in terms of maintaining independent living.11 Our findings suggest that patients with CLI who are physiologically unsuitable for surgery have only modest functional benefits with percutaneous interventions compared with amputation.
Although the merits of endovascular intervention for treatment of CLI with tissue loss have not been clearly demonstrated, mainstream acceptance of endovascular techniques over the last 20 years has led to a dramatic increase in endovascular intervention in our practice and nationally. In an effort to evaluate the impact of this shifting practice pattern toward an endovascular-first approach for CLI in our state, we studied the overall amputation rate in South Carolina and its relationship to revascularization for CLI at two time points, once in 1996 during the traditional “open surgical era” and again in 2005 during the “endovascular era”, and found no significant reduction in major amputation rates related to revascularizations for CLI. However, the number of peripheral interventions did increase exponentially, and the number of secondary procedures performed in the same calendar year more than doubled.12
:532,545.)”]Our group has also investigated patients with ESRD (n=40) who underwent surgical revascularization. We defined clinical success in these patients as: graft patency to wound healing, limb salvage of one year, postoperative survival to six months, and maintenance of ambulatory status for one year. We chose these criteria based on what we felt were reasonable outcomes of an invasive procedure. Only 40% of patients achieved a successful outcome for the composite measure of these four outcomes after surgical intervention. Secondary graft patency was 54% and limb salvage 53% at 36 months. Median overall survival was 25 months. Thus, this study suggested that surgical success does not necessarily translate to clinical success.13 In fact, when we applied the same definition of clinical success to any patient with CLI with tissue loss, we found that only 44% achieve this goal. The 36-month secondary graft patency and limb salvage rates were 72% and 73%, respectively. Predictors of poor surgical outcomes in these patients were diabetes, ESRD, dementia, impaired preoperative ambulatory status (i.e., ambulatory/homebound or nonambulatory/transfer), and presence of gangrene.14
The same criteria that became our minimum definition of a successful intervention/reconstruction were used to evaluate outcomes in patients who undergo lower extremity bypass versus endovascular intervention for ischemic tissue loss. The 361 patients who underwent an open bypass procedure experienced a greater clinical success rate (44%) than the 316 patients who underwent endovascular intervention (37%). Wound healing was also significantly better for patients undergoing open revascularization (47%) versus endovascular intervention (39%). The mortality in this patient cohort was 6% per year, with a five-year survival rate of 29%.15
In some instances amputation is unavoidable and perhaps preferable to the morbidity associated with prolonged treatment of chronic foot ischemia and infection. Thus, we evaluated specific clinical outcomes to define clinical success in patients who received a below-knee amputation at our institution. Our definition of clinical success included wound healing of the below-knee amputation, maintenance of ambulation for one year, and six-month survival. Only 51% of patients undergoing below-the-knee amputation met all of these parameters. Predictors of poor outcomes included existing coronary artery disease, diabetes, increased age, and chronic obstructive pulmonary disease. However, the strongest predictor of postoperative functional outcome was preoperative functional performance.16
Patients with diabetes
In patients with diabetes, the risk of PAD increases with age, duration and severity of diabetes, and the presence of peripheral neuropathy.17,18 Patients with diabetes aged ≥40 years are two to three times more likely to suffer from PAD than those without diabetes, and as many as one-third of patients with diabetes may have concomitant lower extremity ischemia.19-21 Unfortunately, patients with diabetes are also prone to develop PAD at earlier ages, have more progressive and severe disease, and are more likely to undergo surgery and amputation for CLI.21-23 The lifetime risk of foot ulceration in diabetic patients is 15% to 25%, with an annual incidence between 1% and 4%.19,24
One of the most difficult challenges in peripheral vascular surgery is management of diabetic patients with neuropathic foot ulcers. This patient group represents approximately 60% of the patients treated by our group and has become a major focus of our clinical research. In an effort to improve our outcomes in this difficult group we evaluated the functional outcomes in patients with diabetes and neuropathic foot ulcerations who were managed in our practice utilizing open arterial reconstruction, endovascular intervention, medical management and wound care, or a combination of all modalities.25
We retrospectively reviewed a total of 917 wounds in 706 diabetic patients treated during a five-year period. Mean ulcer healing time was 33 weeks. Primary wound healing occurred in only 27% of patients, while functional wound healing (i.e., wound healing to a point at which routine medical care is no longer required) occurred in 53% of patients. The average time to functional wound healing was 29 weeks, and the ulcer recurrence rate was 31%. Half of the diabetic wounds had concomitant ischemia, which served as a marker for poor outcomes and was incompletely mitigated by revascularization. For every functional outcome measure (limb salvage, survival, amputation-free survival, maintenance of ambulatory status, maintenance of independent living status), nonischemic patients fared significantly better than ischemic patients. Ischemic patients undergoing revascularization did experience significantly superior outcomes (except maintenance of ambulatory status, p=0.08) compared with ischemic patients who were not revascularized.
However, the most pronounced differences in functional outcome were noted between patients who achieved a functionally healed wound compared with patients who did not. Patients with healed wounds experienced significant benefits at five years with regard to limb salvage (83% versus 19%, p<0.01), survival (51% versus 23%, p=0.03), amputation-free survival (48% versus 8%, p=0.02), maintenance of ambulatory status (65% versus 38%, p<0.01) and maintenance of independent living status (75% versus 52%, p<0.01) compared with patients who were unable to heal their wounds (Figure 2).
Moreover, the functional benefits of revascularization appear to have been primarily mediated through its influence on wound healing, suggesting that revascularization in the absence of healing is of little functional benefit to the patient. Although the inability to heal a wound may serve as a marker for poor underlying physiologic condition, these data certainly emphasize the importance of wound healing and appear to contextualize the role of revascularization in the treatment of the diabetic foot.25
Patients with diabetes tend to have a more distal distribution of PAD, most frequently afflicting the infrapopliteal vessels, and are likely to benefit less from revascularization efforts than patients without diabetes.21-23 We have found that patients with isolated tibial disease are more likely to be diabetic and present with more advanced ischemia than patients who have multilevel disease.26 This patient population also exhibits significantly lower rates of survival, limb salvage, maintenance of ambulation, maintenance of independence, and secondary patency. Although the majority of patients with isolated tibial disease tend to be diabetic, outcomes of revascularization do not appear to differ between diabetic and nondiabetic patients in this group. However, of the patients exhibiting multilevel disease, those with diabetes experienced lower limb salvage and amputation-free survival rates than those without diabetes and were more likely to lose ambulatory ability, all of which contributed to diminished clinical success rates.26
In summary, patients who present with CLI present a unique challenge for the vascular specialist. In reviewing our experience over the past 15 years, we have come to believe that a patent revascularization is indeed not the “holy grail” of vascular surgery. It has become apparent that patient-oriented outcomes should be at the top of the list of priorities and take into account reasonable expectations for success to have a real and positive impact on the lives of our patients.
As a result of our investigations, we have developed goals based on specific clinical scenarios to maximize the benefit to our patients. This concept ultimately has led to a focus on patient-oriented goals and functional outcomes rather than more traditional measures of clinical success. This paradigm shift has gained a foothold nationally and hopefully will continue to guide the manner in which vascular specialists choose to treat their patients. Finally, we believe a standardized approach to the management of lower extremity ischemia offers the best opportunity to achieve reproducible successful outcomes while minimizing resource utilization.
Ginger Manos, MD, is a vascular surgery resident; John York, MD, FACS, is assistant professor of vascular surgery; and Brent Johnson, MS, is a biostatistician at Greenville Hospital System-University Medical Center in South Carolina.
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