Improved amputation-free survival in unreconstructable critical limb ischemia

From the Society for Vascular Surgery

Improved amputation-free survival in unreconstructable critical limb ischemia and its implications for clinical trial design and quality measurement Eric Benoit, MD,a Thomas F. O’Donnell Jr, MD,a Georgios D. Kitsios, MD, PhD,b,c and Mark D. Iafrati, MD,a Boston and Burlington, Mass Objective: Amputation-free survival (AFS), a composite endpoint of mortality and amputation, is the preferred outcome measure in critical limb ischemia (CLI). Given the improvements in systemic management of atherosclerosis and interventional management of limb ischemia over the past 2 decades, we examined whether these outcomes have changed in patients with CLI without revascularization options (no option-critical limb ischemia [NO-CLI]).

Methods: We reviewed the literature for published 1-year AFS, mortality, and amputation rates from control groups in NO-CLI trials. Summary proportions of events were estimated by conducting a random effects meta-analysis of proportions. To determine whether there had been any change in event rates over time, we performed a random effects meta-regression and a mixed effects logistic regression, both regressed against the variable “final year of recruitment.”

Results: Eleven trials consisting of 886 patients satisfied search criteria, 7 of which presented AFS data. Summary proportion of events (95% confidence interval [CI]) were 0.551 (0.399 to 0.693) for AFS; 0.198 (0.116 to 0.317) for death; and 0.341 (0.209 to 0.487) for amputation. Regression analyses demonstrated that AFS has risen over time as mortality rates have fallen, and these improvements are statistically significant. The decrease in amputation rates failed to reach statistical significance. The lack of published data precluded a quantitative evaluation of any change in the clinical severity or comorbidities in the NO-CLI population.

Conclusion: AFS and mortality rates in NO-CLI have improved over the past 2 decades. Due to declining event rates, clinical trials may underestimate treatment effects and thus fail to reach statistical significance unless sample sizes are increased or unless a subgroup with a higher event rate can be identified. Alternatively, comparing outcomes to historical values for quality measurement may overestimate treatment effects. Benchmark values of AFS and morality require periodic review and updating. ( J Vasc Surg 2011;䡲䡲:䡲䡲䡲.)

Progress in the management of peripheral arterial disease (PAD) over the past 2 decades has resulted in a decline in mortality rates largely due to systemic treatment of atherosclerotic disease and improved cardiac survival. Numerous population studies have demonstrated a reduction in the number of major amputations over this same time period.1-3 Interventional management of PAD has seen a dramatic increase in the use of endovascular procedures which has outpaced a modest decrease in open surgical bypass. These changes have resulted in an overall increase in the number of revascularizations.4-10 From The Cardio Vascular Center, Tufts Medical Center, Bostona; the Division of General Internal Medicine, Lahey Clinic Medical Center, Burlingtonb; and the Center for Clinical Evidence Synthesis, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston.c Competition of interest: none.

Presented at the 2011 Vascular Annual Meeting of the Society for Vascular Surgery, Chicago, Ill, June 17, 2011.

Reprint requests: Eric Benoit, MD, Tufts Medical Center, The Cardio Vascular Center, 800 Washington Street, Boston, MA 02111 (e-mail: ericbenoit95@gmail.com).

The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a competition of interest.

0741-5214/$36.00 Copyright © 2011 by the Society for Vascular Surgery. doi:10.1016/j.jvs.2011.10.089

Despite the increase in revascularizations, of the roughly 500 to 1000 new cases of critical limb ischemia (CLI) per million population per year in industrialized countries, an estimated 20% to 40% are not suitable for arterial reconstruction or have failed revascularization.11-13 This subgroup of patients without revascularization options (“no option” CLI or NO-CLI) is a particularly challenging population with a high rate of limb loss and death related to their large systemic atherosclerotic burden.14 In the absence of arterial reconstruction options, novel approaches, such as pharmacologic, gene, or stem cell therapy are areas of active investigation.

Evaluation of therapy requires measuring its effectiveness in achieving a given endpoint. There are multiple outcome measures for CLI. Amputation-free survival (AFS) is a composite metric which incorporates the hard endpoints of mortality and amputation, analyzed either as a time-to-event (incidence rates) or as binary endpoints (cumulative incidences). AFS is based on the concept that a successful clinical outcome results in a living patient with an intact limb. The TransAtlantic Inter-Society Consensus II (TASC II) guidelines state that AFS is the primary outcome of successful CLI treatment.11 It is one of the principle endpoints proposed by the Society for Vascular Surgery (SVS) CLI Working Group and has been used in major 1

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randomized controlled trials (RCTs) in CLI such as the PRoject or Ex-Vivo vein graft ENgineering via Transfection III (PREVENT III)15 and Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL).16,17 Furthermore, the Food and Drug Administration considers AFS a preferred primary endpoint for studies of novel CLI therapies.18 Given the declining mortality and amputation rates and expansion of revascularization options in patients with PAD, we questioned whether outcomes in NO-CLI have changed over time. We sought to determine any change in AFS, mortality, or amputation in the NO-CLI population over the past 2 decades by studying the control groups of patients with CLI in nonrevascularization trials.

While this group of patients with NO-CLI may be considered a surrogate natural history population, it is more appropriate to refer to it as a medically managed CLI population that receives the most current standard of care.

The distinction is important because best medical management has changed over time with the wide adoption of statin medications, beta blockade, tighter glucose control, and improvements in antibiotics. We also evaluated whether the NO-CLI population has changed over time in terms of clinical disease severity and presence of comorbidities.

METHODS Systematic review of the literature. To define a medical management population of NO-CLI, we reviewed the literature for clinical trials of alternate therapies in NO-CLI and identified patients in the control groups. We queried the PubMed, Ovid, and Cochrane databases using terms such as “critical limb ischemia,” “amputation,” “randomized controlled trial,” and nonsurgical or nonendovascular treatments such as “cell therapy,” “spinal cord stimulation,” “gene therapy,” and “prostaglandin therapy.” We included only clinical trials published in English within the last 20 years and excluded case series of fewer than five patients. We examined the references in eligible studies and review articles to identify additional trials. We excluded articles which addressed acute limb ischemia, surgical or endovascular revascularization, ischemia due to diseases other than atherosclerosis (such as thromboangiitis obliterans), and trials where the CLI portion of the patient population could not be separately evaluated. In an attempt to minimize heterogeneity, we reviewed the inclusion criteria of studies to determine that enrolled patients were not suitable for revascularization for reasons of comorbidity, anatomy, or previous failed revascularization attempts, rather than reasons such as patient refusal of an invasive procedure. We included only patients in the control groups (ie, those who received best medical management and not an investigational therapy).

Using these studies, we investigated the endpoints of AFS, mortality, and amputation at 1 year. To evaluate changes in disease severity in the NO-CLI population over time, we reviewed baseline characteristics such as age, Rutherford class, and comorbidities.

Statistical analysis. We defined the relevant endpoints as the proportions of patients with the events AFS, mortality, and amputation at 1 year (cumulative incidence of events at 1 year). In each study, we estimated the proportion of each endpoint of interest and estimated summary proportions of these endpoints at 1 year across studies by conducting a random effects meta-analysis of proportions with the Freeman-Tukey arcsine transformation method.19 Between-study heterogeneity was tested with Cochran Q (significant if PQ ⬍ 0.10) and quantified with the I2 statistic (an estimate of how much heterogeneity is unlikely to be due to chance).

To determine any changes in the published proportions of events over time, we conducted cumulative metaanalyses of the proportions, and we examined the plots for trends over time.20 To formally test for changes in published proportions of events over time, we performed a random effects meta-regression analysis in which we regressed the proportion of events in each study against the indicator variable “final year of recruitment” in each study.21 This variable was used as a proxy for the time period during which each study was conducted and was considered indicative of the standard of care during each time period. We examined the coefficient of this indicator variable for the direction of effect. In a secondary analysis, we constructed a mixed-effects logistic regression model for the estimated proportions of events in each study; in these models, the effects of the variable “final year of recruitment” were considered as fixed, studies varied additionally by normally distributed random effects, and proportion of events were weighted inversely to their estimated variances according to the binomial distribution.22 The coefficients of the indicator variable “final year of recruitment” were again examined for direction and statistical significance. Statistical analyses were conducted using Stata version 11.1/SE (Stata Corp, College Station, Tex) and Meta-analyst (version 3.0␤, Tufts Medical Center, Boston, Mass).

RESULTS No option-critical limb ischemia studies in the literature. We identified 11 studies in the literature that met criteria. All of them provided data on amputation and mortality at 1 year. Seven provided data on AFS at 1 year (Table I).

One trial was a retrospective review of 5 years of nonreconstructible patients with CLI with 1 year follow-up.23 One was a prospective study of wound care in patients with arterial disease from which we included only the patients that met CLI criteria.24 The remaining articles were RCTs of CLI therapy: five spinal cord stimulation studies25-29; one pharmacologic trial of a prostaglandin E1 analog (CIRCULASE)30; two gene therapy trials of NV1FGF (TALISMAN31 and TAMARIS32); and one gene therapy trial of hepatocyte growth factor.33 We included 86 patients that met CLI criteria from the wound care study and all the patients from the control groups of the other 10 trials for a total NO-CLI study population of 886 patients.

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Table I. Published 1-year event rates from NO-CLI trials Author Jivegård Lepäntalo Claeys Klomp Spincemaille Amann Marston Brass Nikol Hiatt Powell

Trial

Year

No.

Amp

Death

AFS

Spinal cord stimulation Retrospective clinical review Spinal cord stimulation Spinal cord stimulation Spinal cord stimulation Spinal cord stimulation Wound care only CIRCULASE (PGE1 analog) TALISMAN (NV1FGF) TAMARIS (NV1FGF) Intramuscular hepatocyte GF

1995 1996 1996 1999 2000 2003 2006 2006 2008 2010 2010

26 105 41 60 18 39 86 190 56 259 6

50.0% 46.3% 19.5% 48.3% 50.0% 46.2% 38.4% 10.5% 33.9% 21.2% 33.3%

30.8% 54.3% 29.3% 23.3% 27.8% 0.0% 0.0% 10.0% 23.2% 15.1% 16.7%

X 28.0% X 40.0% X 54.0% 61.6% 81.0% 48.2% 66.8% X

AFS, Amputation-free survival; Amp, amputation; GF, growth factor; NO-CLI, no option-critical limb ischemia; NV1FGF, nonviral 1 fibroblast growth factor; PGE, prostaglandin E; X, not documented.

The summary proportions at 1 year (95% confidence interval [CI]) were as follows: AFS, 0.55 (0.40 to 0.69); death, 0.20 (0.12 to 0.32); and amputation, 0.34 (0.25 to 0.45). All meta-analyses were characterized by statistically significant heterogeneity (PQ ⬍ 0.10).

Change in amputation-free survival, mortality, and amputation. Inspecting the plots of the cumulative metaanalyses for each endpoint, we discerned a pattern of declining proportions of events for death and a pattern of increasing proportions of events for AFS (Fig 1).

We formally tested for change in event rates over time using both a meta-regression analysis and a mixed-effects logistic regression, and the results are presented in Table II. In both analyses for AFS, the coefficients for the variable “final year of recruitment” were positive and statistically significant (P ⬍ .05), indicating that AFS has increased over time (Fig 2).

For death and amputation, the meta-regression analyses demonstrated that all coefficients for the variable “final year of recruitment” were negative, indicating that for each ascending year of recruitment there has been a reduction in the published proportion of events (ie, death and amputation rates have decreased over time). These results were not statistically significant for amputation but reached borderline significance for death (P ⫽ .056). In the mixed-effects logistic regression model, the coefficient of the “final year of recruitment” was statistically significant for death. The pattern of decreasing proportions of events for death and amputation provides complementary evidence for the improvement in AFS over the same time period.

Because the number of studies that contributed to the analyses for each endpoint were different (11 studies reporting death or amputation and seven studies reporting AFS), we performed a sensitivity analysis by considering the seven studies that contributed data to all three endpoints of interest. The results were similar to the ones obtained in the main analyses, and we found no changes in statistical significance of the coefficient of the indicator variable.

Definition of no option-critical limb ischemia and inclusion/exclusion criteria. We examined the definitions of CLI used in each study as well as the inclusion and

exclusion criteria to determine if the enrolled populations were similar. The earliest trial simply defined CLI as “severe chronic (duration more than 2 weeks) lower limb ischemia in atherosclerotic and diabetic patients with rest pain and/or ischemic ulcerations.” They used no hemodynamic criteria, although the mean ankle-brachial index in the control group was 0.39 ⫾ 10.06. Later trials defined CLI according to consensus documents which have changed over time (eg, the Second European Consensus Document on Chronic Critical Leg Ischemia from 1992; the original TASC statement from 2000; and TASC II from 2007).

With regard to hemodynamic criteria, eight of the 11 trials used ankle pressure as an inclusion criteria. Two earlier trials required values under 50 mm Hg while the five most recent trials used 70 mm Hg, although one of these trials differentiated between patients with rest pain (50 mm Hg) and tissue loss (70 mm Hg). Six of 11 trials used toe pressures less than 30 to 50 mm Hg for inclusion. Four trials used transcutaneous oxygen tension of ⬍30 mm Hg. Exclusion criterion were variably delineated with most trials excluding patients with extensive infection or ischemic lesions leading to imminent amputation. Two trials explicitly excluded patients with endstage renal disease. No other trial reported on the percentage of enrolled patients on dialysis.

“No option” status was defined by the participating vascular surgeons and based on anatomy (eg, poor outflow vessels), lack of conduit, extensive comorbidities resulting in unacceptable risk of a revascularization procedure, as well as patients who had previously failed revascularization attempts. Of note, one author commented on the fact that technical advances over time allowed surgical bypass of more distal vessels that would have rendered patients “no option” in earlier years of their study.

Change in the no option-critical limb ischemia population. We attempted to analyze change in severity of disease and prevalence of comorbidities by analyzing baseline characteristics of patients in NO-CLI trials. However, the lack of published data precluded a quantitative analysis.

For example, one trial did not present data on their control patients while another trial did not differentiate the

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Fig 1. Cumulative meta-analysis plots for amputation-free survival (AFS) (A), death (B), and amputation (C) demonstrate decreasing summary proportions of events. Studies are added one at a time according to their “final year of recruitment” and the results are summarized as each new study is added. Each horizontal line represents the updated results with summary proportion of events (95% confidence interval [CI] in parentheses) listed to the right. The size of the squares demonstrates the size of each study.

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Fig 1. Continued

Table II. Change in AFS, death, and amputation over time regression analyses for variable “final year of recruitment” Meta-regression analysis on arcsine transformed proportions

Mixed-effects logistic regression on proportions of events

Endpoint

No.

Coefficient of “final year of recruitment”

P value

Coefficient of “final year of recruitment”

P value

Amputation Death AFS

11 11 7

⫺0.025 (⫺0.062-0.012) ⫺0.047 (⫺0.948-0.001) 0.052 (0.001-0.104)

.157 .056 .047

⫺0.058 (⫺0.124-0.009) ⫺0.128 (⫺0.243-0.014) 0.109 (0.036-0.183)

.088 .028 .004

AFS, Amputation-free survival.

baseline characteristics of patients with CLI from those with less severe PAD. None of the trials presented the same set of patient characteristics (eg, none of the trials before 2003 presented data on hyperlipidemia). Furthermore, the definition of comorbidities varied among trials which confounds comparison (eg, some trials use “coronary artery disease” while others use “previous myocardial infarction”).

Risk factors for amputation and death in the NO-CLI trials are presented in Table III. The presence of renal disease was either not reported or used various definitions and was therefore not included in the table. The mean patient age ranged from 69 to 75 years with no trend over time. The percentage of patients with diabetes ranged from 38.3% to 54.44% with no trend over time. With regard to clinical severity of disease, early studies do not differentiate between patients with rest pain and tissue loss, whereas several of the more recent trials are composed only of

patients with tissue loss. We therefore cannot speak to any trends in the severity of disease in the NO-CLI population.

DISCUSSION We examined AFS, mortality, and amputation rates in the NO-CLI population from 1995 to 2010 and found that mortality rates decreased significantly over time whereas the corresponding AFS rates have increased. Results were robust to secondary analyses with different statistical models and to sensitivity analyses that excluded specific studies.

We were unable to determine if there has been any change in disease severity or comorbidities in patients with NOCLI largely due to lack of consensus in the reporting of such factors.

Trends in the treatment of peripheral arterial disease. Mortality and amputation rates have decreased in patients with PAD over the past 20 years as demonstrated by numerous population studies.1,4,6,7,9,10 Over the same

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Fig 2. Change in amputation-free survival (AFS) in patients with no option-critical limb ischemia (NO-CLI) over time. Reference line is derived from meta-regression analysis. Size of circles demonstrates weighting of each study.

Table III. Risk factors in NO-CLI trials Author

Year

Mean age

% Tissue loss

% Diabetes

Jivegård Lepäntalo Claeys Klomp Spincemaille Amann Marston Brass Nikol Hiatt Powell

1995 1996 1996 1999 2000 2003 2006 2006 2008 2010 2010

73.0 75.0 NA 72.1 NA NA NA 69.7 73.3 69.0 78.0

50.0% NA NA 68.3% NA 33.3% 100.0% 52.1% 100.0% 100.0% 100.0%

19.2% 50.5% NA 38.3% NA NA NA 53.7% 50.0% 54.0% 50.0%

NA, Data not available; NO-CLI, no option-critical limb ischemia.

time, the increase in the number of endovascular procedures has outpaced a decrease in open surgical bypasses, resulting in an overall increase in the number of patients receiving revascularization.

Many studies have demonstrated an increase in age and comorbidities among patients receiving interventions for CLI. In a study of surgical revascularization for CLI from 1978 to 1997, Conte et al34 demonstrated that, despite significantly increased severity of CLI, prevalence of comorbidities, surgical complexity, patient age, limb salvage, and survival rates were maintained. Egorova et al6 evaluated national and state discharge databases for lower extremity revascularizations from 1998 to 2007 and found increased

numbers of revascularization procedures and that, despite increased patient age and comorbidities, the rates of amputation and mortality declined.

Although improved and expanded access to revascularization has likely contributed to the improved outcomes seen in these older and sicker patients during the last 2 decades, these improved outcomes are due to more than just expanded revascularization. Better diabetes control, antiplatelet therapy, infection control, and smoking cessation may result in improved limb salvage.1 Goodney et al7 found an increase in podiatric visits and HgbA1c measurements in patients with diabetes as evidence for improved diabetic management, as well as increased testing for hyperlipidemia.

The use of amputation-free survival. There are multiple measures of successful CLI therapy. Surrogate measures, such as ankle-brachial index or transcutaneous oxygen tension, may elucidate mechanisms of therapy, but are not necessarily related to clinical outcomes. Functional outcomes, such as quality of life, are valuable but may be influenced by factors other than disease state or therapy.

AFS captures two hard endpoints, mortality and amputation, that are obviously important to patients and clinicians.

The TASC II guidelines suggest that AFS is a primary measure of success in CLI treatment11 and AFS has become the accepted endpoint for multiple RCTs in CLI.15,17 Recently the SVS-CLI Working Group published objective performance goals (OPGs), benchmark values for various endpoints.35 One of the strengths of the OPGs was

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to define a standardized set of outcome measurements, with major adverse limb event and postoperative death determining early safety and AFS capturing later clinical efficacy. Results were derived from patients undergoing open bypass from several RCTs. Values at 1 year were AFS 76.5%, mortality 14.3%, and amputation 11.1%. The intent of the OPGs was to establish benchmark values against which novel endovascular therapies could be measured, thereby providing an evaluation method less burdensome than RCTs. But benchmark values can also become a powerful tool for quality comparison and improvement, as recently demonstrated by Goodney et al.36 They interrogated their regional vascular registry to evaluate outcomes of over 1000 patients undergoing lower extremity bypass and found that their results were not statistically different from the OPGs (AFS 84.4%, mortality 8.4%, and amputation 9.1%). The OPGs are likely to gain further use in the evaluation of novel therapies and as quality control benchmarks for current therapy.

AFS from our NO-CLI population cannot be directly compared to the OPG AFS because the latter were derived from revascularized patients. Our finding that AFS has increased over time, however, suggests an overall improvement in the level of medical care for patients with CLI and supports the statement by the SVS-CLI Working Group that the OPGs require reassessment and updating.

Some authors have questioned whether limb salvage and AFS are the most appropriate endpoints in patients with CLI given their poor prognosis.14,37 One of the criticisms of AFS is the inclusion of all-cause mortality in the endpoint; this may obscure the impact of a therapy directed at limb salvage. However, if AFS in NO-CLI is rising over time and this change is due to decreasing mortality, the “noise” introduced by the mortality component may lessen, improving the use of AFS as a measure of efficacy. Our demonstration of improving AFS in NO-CLI raises a further point: if outcomes are improving without revascularization, any planned intervention must demonstrate an even greater improvement in efficacy while maintaining a safety profile that limits morbidity and mortality.

Impact of declining event rates on clinical trials and quality measurement. The medically managed NO-CLI population serves as the control group for RCTs of novel treatments such as gene or stem cell therapies. Yet a declining event rate in this group (as evidenced by increasing AFS) makes it more difficult to demonstrate a difference in outcome between experimental therapy and control. This has been seen in other cardiovascular diseases such as stroke38 and coronary disease.39 Kent and Trikalinos39 highlighted the impact of declining control event rates on clinical trial design. As baseline outcomes improve, demonstrating the smaller marginal efficacy of a novel therapeutic becomes increasingly difficult. Studies must become exponentially larger, with associated increases in costs and complexity, or run the risk of being underpowered. Kent and Trikalinos39 offer several solutions to this problem, including “idiopathic control

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rate inflation,” that is, identifying a clinically relevant subpopulation with an increased event rate.

In NO-CLI, we previously demonstrated that patients with tissue loss (Rutherford 5) have a much higher amputation rate than those with rest pain (Rutherford 4).40 A mixed population of patients with CLI will have a diluted event rate, at least with regard to amputation possibly resulting in a baseline event rate too small to allow for detection of a treatment effect as defined by AFS. In this report, we found that many of the more recent studies were comprised only of patients with tissue loss.

This population can be expected to have a higher event rate than a mixed population, yet these studies demonstrated lower AFS than earlier trials which contained both patients with R4 and R5. This suggests that increasing AFS may be even more pronounced in the overall NO-CLI population.

Because AFS is rising over time, the use of historical benchmarks (such as OPGs) for comparison of novel therapy may exaggerate the impact of new therapies. This overestimation of treatment effect also holds true for comparing clinical performance against OPGs for quality measurement.

Rising AFS means that RCTs risk underestimating treatment effects and thus may fail to reach statistical significance unless sample sizes are increased or unless a subpopulation of patients with a higher event rate is identified.

We found that in order to maintain the same statistical power for AFS, using data in this report from the time period of the earliest study to the most recent one would require nearly a threefold increase in sample size.

In the planning of clinical trials of CLI, estimation of control event rates warrants careful attention. Due to falling event rates, it becomes increasingly important to identify the appropriate patient population and to use the most appropriate endpoint for that group. The right question must be asked of the right patients to give a trial the best chance of succeeding.

We suggest that although AFS is an important outcome measure, due to the declining death rate in all patients with CLI, as well as the low mortality and amputation rates within rest pain patients (R4), AFS is not an ideal endpoint for a mixed population of patients with CLI. However, AFS is an appropriate primary endpoint for trials restricted to patients with tissue loss (R5). Studies that contain a mixed CLI population require different endpoints, and at a minimum require stratified randomization to distribute disease severity evenly between treatment groups. The rising AFS must be taken into account when estimating treatment effect and sample size calculation.

Limitations of current study. Our study is a metaanalysis and is only as good as the methods of the component articles. One of the major confounding factors in this study is the lack of data on clinical classification by the Rutherford criteria, specifically tissue loss in many of the early studies. The contribution of tissue loss to increased amputation rates and mortality has only recently been demonstrated.35,41,42 It is interesting to note that two of the more recent NO-CLI trials treated only patients with

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tissue loss yet demonstrated lower amputation and mortality rates than early trials with mixed populations. Analysis of other major risk factors, such as end-stage renal disease, was hampered by variability in definitions and reporting.

Lacking individual patient data, it is impossible for us to determine how the severity of disease in the NO-CLI population has changed over time. Advances in surgical technique, anesthesia, and endovascular procedures have expanded revascularization options to a greater number of patients with CLI. Has this culled the healthier patients from the NO-CLI population? On the other hand, have more stringent adverse event reporting requirements resulted in RCTs enrolling patients with less severe disease?

Our analysis was unable to answer these questions.

We have relied on the proxy “final year of recruitment” to facilitate our analysis. We wanted to test temporal trends and in order to evaluate change over time we had to assign each trial a given time point, therefore, we used “final year of recruitment” to approximate the time of conduct of each study. Certainly trials are conducted over a variable length of time, not a single year, and changes may occur within a trial, but the “final year of recruitment” was an approximation made to allow our analysis.

CONCLUSIONS Using a population of patients with NO-CLI derived from control groups of clinical trials, we have demonstrated that AFS has risen over the past 2 decades. This is due to a decrease in mortality rates. This increase in AFS has implications for evaluation of CLI therapy. Clinical trials may underestimate treatment effects and thus fail to reach statistical significance unless sample sizes are increased or unless a subgroup of patients with a higher event rate can be identified. If AFS is used as a primary endpoint in CLI, we suggest that the study population should consist of patients with tissue loss so as to maintain a sufficient event rate to demonstrate treatment effect. Comparing outcomes to historical values for quality measurement may overestimate treatment effects. Benchmark values of AFS and mortality in NO-CLI require periodic review and updating.

AUTHOR CONTRIBUTIONS Conception and design: EB, TO, MI Analysis and interpretation: EB, TO, GK Data collection: EB Writing the article: EB, TO, GK Critical revision of the article: EB, TO, GK, MI Final approval of the article: EB, TO, GK, MI Statistical analysis: GK Obtained funding: Not applicable Overall responsibility: EB REFERENCES 1. Eskelinen E, Eskelinen A, Albäck A, Lepäntalo M. Major amputation incidence decreases both in non-diabetic and in diabetic patients in Helsinki. Scand J Surg 2006;95:185-9.

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Submitted Jul 10, 2011; accepted Oct 16, 2011.