Date of Award

January 2019

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Alexandra J. Lansky

Abstract

Objective: To quantify the 6- and 12-month amputation-free survival (AFS) in patients with “no-option” Rutherford category 5/6 critical limb ischemia (CLI) in current clinical practice and to characterize outcomes and methods for deep vein arterialization as a possible means for revascularization in patients who are not candidates for conventional surgical or endovascular revascularization. We also sought to determine if there was any trend in amputation-free survival before and after 2003 which was the year of publication for the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).

Background:

The natural history of patients with Rutherford category 5/6 CLI who are not candidates for revascularization is not well-known. Deep vein arterialization, or arterial shunting of blood to the deep veins, may offer a potential revascularization option for this select patient population.

Methods:

Data Sources and Study Selection

Natural History of “no-option” Rutherford category 5/6 CLI: 6- and 12-month AFS

A systematic review was performed according to PRISMA guidelines. Two pre-specified literature searches were conducted via Ovid utilizing the following databases: MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews (CDSR). For the first literature search, we identified studies reporting AFS in patients with non-revascularizable Rutherford Category 5 or 6 CLI (or any symptomatic/ischemic equivalent) at a minimum follow-up of 6 months. Studies that included a subset of patients with less severe disease (Rutherford Category ≤4) were included. An exploratory search had determined that nearly all studies also included Ruther category 4 patients. As such, a supplemental search was conducted to identify hazard ratios for amputation-free survival or its components between patients (regardless of revascularization status) with more severe (Rutherford Category 5/6), compared with less severe (Rutherford Category ≤4) disease to inform appropriate risk adjustment due to limited available outcome data in high risk patients. For the supplemental search, we selected studies of Rutherford category 4, 5, or 6 patients that reported hazard ratios (HR) for outcomes (AFS, all-cause mortality, or major amputation) between high-risk (Rutherford 5/6) and lower-risk (Rutherford 4) patients.

Deep Vein Arterialization

A separate (third) systematic review was conducted via Ovid utilizing the following databases: MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews (CDSR). We identified prospective, randomized clinical trials as well as retrospective studies utilizing surgical or percutaneous deep vein arterialization (DVA) for revascularization of lower-extremity peripheral vascular disease.

Data Extraction and Synthesis:

Natural History of “no-option” Rutherford category 5/6 CLI: 6- and 12-month AFS

Data was extracted from relevant articles in duplicate. Extracted information included qualifying CLI criteria, baseline demographics, enrollment dates, and proportion of patients with each Rutherford classification [(3) severe claudication; (4) ischemic rest pain; (5) minor tissue loss; or 6 (major tissue loss)]or Fontaine stage [(IIa) mild claudication; (IIb) moderate severe claudication; (III) ischemic rest pain with or without minor tissue loss; (IV) ulceration or gangrene], and 6- and 12- month endpoints of interest (major amputation, defined as any amputation performed above the level of the ankle, all-cause mortality, and amputation-free survival). Risk of bias of individual studies was assessed with the Cochrane Risk of Bias tool. Objective criteria such as the ability to complete standard treadmill exercise testing, ankle pressures before and after exercise, metatarsal peripheral vascular resistance, and toe pressures were used to impute the Rutherford categories of a study population if they were not directly reported. For studies that included a subset of lower-risk patients (Rutherford class ≤4), an adjustment factor was developed and applied to the observed rates to better reflect outcomes in the population of interest.

An adjustment factor for AFS rates was calculated from the reported HRs by log transforming the HR, calculating the weighted average of the log HR, and inverting back to the arithmetic scale. The adjustment factor was then applied to the observed AFS rates in the applicable studies of no-option CLI patients according to the proportion of high-risk (Rutherford category 5/6) and low-risk (Rutherford category ≤4) patients in each study to arrive at an adjusted AFS rate

Deep Vein Arterialization

Data was extracted from relevant articles in duplicate for studies of deep vein arterialization in patients with CLI (Rutherford class 4 or higher or Fontaine stage III or higher). Extracted information included baseline patient demographics (Rutherford classification or Fontaine stage and comorbidities), peri-procedural outcomes (technical success rate, mortality, and complications within 30 days of procedure), medium-term outcomes (survival, limb salvage rate, cumulative patency, and mean follow-up time).

Main Outcomes and Measures:

Natural History of “no-option” Rutherford category 5/6 CLI: 6- and 12-month AFS

Amputation-free survival (a composite of major amputation, defined as any amputation performed above the level of the ankle, and all-cause mortality) at 6- and 12-months in patients with Rutherford class 5 or 6 CLI and no revascularization options. Due to a scarcity of evidence, we collected HRs for any outcome (n=1 AFS; N=1 death; and N=1 major amputation).

Deep Vein Arterialization

Technical success, peri-procedural (within 30 days of procedure) mortality and complications, and postprocedural (>30 days postprocedure) survival, limb salvage, and cumulative patency.

Results:

Natural History of “no-option” Rutherford category 5/6 CLI: 6- and 12-month AFS

The meta-analytic adjustment factor for AFS rate at 6- and 12-months between Rutherford 4 patients and Rutherford 5/6 patients was 2.18. A total of 36 studies meeting the selection criteria reported AFS at 6 and/or 12 months; the meta-analytic average AFS rates were 56.5% and 49.8%, respectively. An analysis by time of enrollment determined that AFS was significantly higher at 6 and 12 months in studies enrolling patients after 2003 versus before 2003; therefore, analyses were limited to the recent (after 2003) cohort. The unadjusted meta-analytic average AFS rates at 6 and 12 months were 60.0% (n=23 publications; 1238 patients; 67.5% average Rutherford 5/6) and 56.1% (n=19 studies; 1161 patients; 57.7% average Rutherford 5/6), respectively. The risk-adjusted estimated AFS rates were 43.6% (95% CI, 33.7 – 53.5) at 6 months (n=16 publications, 826 patients; 67.5% average Rutherford 5/6) and 36.8 (95% CI, 19.6-54.1) at 12 months (n=12 publications, 659 patients; 57.7% Rutherford 5/6) in no-option Rutherford category 5 or 6 CLI patients.

Deep Vein Arterialization

A total of 16 studies were identified reporting results for surgical DVA while 5 studies were identified reporting results for percutaneous (endovascular) DVA. We collected baseline patient comorbidities, Rutherford classification, Fontaine stage, peri-procedural outcomes (technical success, mortality, and complications) and medium-term outcomes (survival, limb salvage, cumulative patency).

The average proportions of comorbidities in the surgical deep vein arterialization studies were 73% for diabetes, 60% for hypertension, 38% for hyperlipidemia, 54% for coronary artery disease, 28% for chronic renal disease, and 45% for current smokers. The average technical success rate for surgical deep vein arterialization was 81% with an average periprocedural (<30 days) mortality of 2.4% and an average complication (<30 days) rate of 25%. The average technical success rate for percutaneous deep vein arterialization was 93% with an average periprocedural (<30 days) mortality of 0% and an average periprocedural (<30 days) complication rate of 16%.

Conclusions and Relevance: Approximately half of all patients with advanced critical limb ischemia who are not candidates for current revascularization approaches will die or require major amputation within 1 year. These outcomes have not changed significantly in recent years, and alternative treatments that can address this high-risk population are urgently needed. Percutaneous deep vein arterialization is a promising technique for revascularization in patients with no other treatment options.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 07/15/2021

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