Veterans with claudication who undergo revascularization ‘significantly more likely to have major amputation than those who do not’

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Elizabeth L. George presenting at VAM in San Diego

Patients within the Veterans Affairs Administration healthcare system who underwent an intervention for intermittent claudication (IC) were consistently at three-to-four times greater risk of undergoing subsequent amputation compared to those who did not, researchers at Stanford University report.

Furthermore, Intervention was associated with a 40% greater hazard of disease progression to chronic limb-threatening ischemia, they found.

The findings were revealed during a Plenary Session 6 presentation at the 2021 Vascular Annual Meeting (VAM) in San Diego on Saturday by Elizabeth L. George, MD, a vascular surgery integrated chief resident at Stanford in California.

George and colleagues looked into the association between intervention for IC, and progression to CLTI and amputation in light of data demonstrating “significant center-level variability” in adherence to guideline-recommended therapy. Both the Society for Vascular Surgery (SVS) and the American Heart Association (AHA) recommend intervention for IC only after a failed trial of medical and exercise therapy, she said.

With recent evidence suggesting intervention for claudication hastens progression of disease in as little as one-and-a-half years, “we sought to answer the question of whether intervention actually carries a risk for limb loss that is worse than the natural history of medically-managed claudication,” George told VAM attendees.

George and colleagues carried out an observational national cohort study of veterans diagnosed with IC between 2003–2012, identifying patients with incident peripheral arterial disease (PAD) and focusing on a diagnosis of claudication. The primary and secondary outcomes of the study were, respectively, major amputation progression to CLTI.

A total 25,737 veterans were diagnosed with IC at 130 Veterans Affairs medical centers during the study period, with a third undergoing vascular intervention during follow-up. A further 755, or 2.9%, had a major amputation—493 of them within five years of diagnosis.

“Veterans who underwent revascularization were overall significantly more likely to have major amputation than patients who did not [5.6% vs. 1.5%; p<0.001], and this was true at the five-year mark as well,” George revealed. “In adjusted Cox proportional hazard modeling, intervention was associated with three times higher hazard of amputation [adjusted hazard ratio (aHR) 3.60, 95% confidence interval (CI) 2.97–4.39; p<0.001].”

Prescription of an antiplatelet agent (aHR 0.77, 95% CI 0.60–0.99; p<0.001] but not statin medication was associated with significantly lower hazard of amputation, George continued.

On multivariable logistic regression, she said, intervention was “significantly associated” with three times greater odds of amputation at five years (adjusted odds ratio [aOR] 3.84, 95% CI 3.14–4.69; p<0.001). “But prescription of statins and antiplatelets were not associated with amputation,” she added. “A number of comorbidities were significantly associated but in both models current smoking status was not.”

George et al also found on Kaplan-Meier analysis that veterans who underwent intervention experienced significantly worse amputation-free survival at five years (p<0.001).

The researchers delved deeper.

“When we used a three-level independent variable—time to diagnosis to intervention less than or greater than six months compared to no intervention—our model revealed that intervention when performed more than six months out from diagnosis was associated with a greater hazard of major amputation compared to earlier intervention,” George explained. “This unexpected finding was also confirmed on Kaplan-Meier analysis and prompted us to perform a post-hoc analysis to incorporate the secondary outcome of progression to CLTI to address the possibility that these later interventions were actually due to rapid progression of disease.”

Using a composite endpoint of CLTI and major amputation, the investigators found that intervention was associated with a 40% greater hazard of disease progression in adjusted Cox proportional hazard modeling.

“Intervention for IC is associated with significantly less freedom from disease progression during five-year follow-up on Kaplan-Meier analysis,” George said “Overall the rates of disease progression in the veteran population included in this study were quite high, with progression of disease from IC to CLTI noted in 60% of veterans who did not undergo a revascularization and 75% who did undergo a revascularization.

“Our post-hoc hypothesis that earlier interventions are associated with more rapid progression of disease appears to be confirmed. And we again see that the progression to amputation and CLTI is much slower in veterans who do not undergo an intervention for claudication.”

George conceded that her research team’s analysis suffers from a number of limitations, including a lack of granular data on symptomatology either at presentation or during follow up; the homogenous patient population served by the Veterans Affairs system; the absence of data on supervised exercise therapy (SET); and the fact the covariates in their models do not vary by time. George further pointed out that the study does not account for different practice patterns.

Citing the SVS Presidential Address given by Kim Hodgson, MD, at VAM earlier in the week, George touched on the controversial use of invasive vascular interventions as a first-line therapy for claudication. “As one of the only risk-based studies that looks at the natural history of claudication, we found that within the VA system 33% of claudicants underwent invasive vascular interventions and, overall, 2.9% of veterans received a major amputation. Amputation risk for those who did not undergo an intervention was 1% at five years,” she said.

Concluding, Geerge added: “Using three different statistical methods as points of comparison, veterans who underwent revascularization for IC were consistently at three-to-four times greater hazard, odds, risk of undergoing subsequent amputation compared to veterans who did not receive revascularization for IC. And intervention was associated with a 40% greater hazard of disease progression to CLTI. Earlier use of medical and exercise therapy along with appropriate preoperative patient counseling regarding increased amputation risk with revascularization for IC is warranted. Future research is needed to identify mechanisms and risk factors for accelerated disease progression following intervention as well as to figure out how procedural approach factors into the equation.”

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