Any Microvascular Disease a Risk Factor for Limb Amputation

Batya Swift Yasgur, MA, LSW

July 11, 2019

The presence of microvascular disease, even in the kidneys or eyes, sharply raises the risk of lower-extremity amputation, and more so in patients who also have peripheral artery disease (PAD), suggests a new analysis of more than 125,600 mostly male participants in the Veterans Aging Cohort Study (VACS). The findings were independent of demographics and other cardiovascular risk factors.

Over an average of 9 years in the cohort, in which no one had had an amputation, there was an incident total of 1185 amputations. The presence of microvascular disease itself, compared with an absence of both microvascular disease or PAD, was associated with a nearly fourfold increased risk of amputation; a presence of PAD by itself, a nearly 14-fold risk.

But the combination of PAD and microvascular disease was associated with a more than 20-fold increased risk of amputation, according to a report published online July 8 in Circulation by lead author Joshua Beckman, MD, Vanderbilt University Medical Center, Nashville, Tennessee.

"Microvascular disease is an important source of amputation risk and requires examination and attentiveness to foot problems in a patient with any form of microvascular disease — even if it is remote from the legs, such as in the case of retinopathy," Beckman told | Medscape Cardiology.

"A patient who has either microvascular disease or PAD deserves to receive a clinical examination to make sure they don't have the other one because that combination is particularly dangerous," he said.

The current study "adds new information on how disorders of both large and small vessels of the leg can lead to amputations," William R. Hiatt, MD, University of Colorado School of Medicine, Aurora, told | Medscape Cardiology.

In people with PAD who have "evidence of kidney, eye, and nerve problems, practitioners should be concerned about foot ulcers that don't heal and can lead to potentially losing a leg," said Hiatt, who was not involved in the analysis.

"If a patient has intact skin on the foot and evidence of vascular disease in the leg, the risk of amputation is not super high. But if they have microvascular disease and large-vessel disease, the risk goes up, which can become a critical situation in terms of limb loss," he cautioned.

The researchers used data from 125,674 participants in VACS, a prospective longitudinal cohort of US veterans who were followed for a median of 9.3 years. Participants with previous amputations or amputations occurring within 180 days of baseline were not included.

Participants were categorized as having neither microvascular disease nor PAD (index group, n = 109,447); microvascular disease alone (n = 9125); PAD alone (n = 5313); or both microvascular disease and PAD (n = 1789).

The study defined microvascular disease according to administrative codes for related peripheral neuropathy or retinopathy prior to baseline or within 180 days after baseline, or a urine protein test result of "+1" or greater indicating proteinuria within 180 days before or after baseline, the report states. PAD was defined according to diagnostic and procedure codes.

Compared to participants with no microvascular disease or PAD, those with PAD, microvascular disease, or both were more likely to have hypertension, diabetes, anemia, and chronic obstructive pulmonary disease.

The rate of incident lower-extremity amputation, the primary endpoint, over a median of 9.3 years of follow-up was 1.16/1000 person-years, with retinopathy, nephropathy, and neuropathy present in 69%, 67%, and 78% of participants, respectively, at the time of amputation.

Adjusted* Hazard Ratio (HR) for Amputation by PAD and Microvascular Disease Status vs Neither Form of Vascular Disease

Vascular Disease Status Incidence per
1000 Patient-Years
HR (95% CI) P
Microvascular Disease Alone 1.59 3.74 (3.03 - 4.62) < .0001
PAD alone 4.54 13.86 (11.25 - 17.07) < .0001
Microvascular Disease and PAD 13.22 22.71 (18.34 - 28.12) < .0001
*Covariates included age, sex, race or ethnicity, substance abuse, and a variety of comorbidities including HIV infection, cardiovascular disease, hypertension, and diabetes.

Multivessel disease and PAD together "represent a particularly high-risk group that requires really aggressive management if any small problem occurs, and certainly very active surveillance," Beckman said.

The location of amputation varied by type of vascular involvement.

A presence of microvascular disease alone accounted for 18% of all amputations, 21% of those below the ankle, 15% of those below the knee, and 6% of all above-knee amputations.

Having PAD by itself was associated with 22% of all amputations, 17% of those below the ankle, and 25% of below-knee and 39% of above-knee amputations.

Combined microvascular disease and PAD was related to 45% of all amputations, including the most amputations at all limb levels.

Microvascular disease was more likely to be associated with below-ankle amputation and PAD more likely to cause below- and above-knee amputations (P < .001).

Members of the cohort with diabetes, which is closely associated with microvascular disease, comprised 41% of those with microvascular disease alone, 32% of those with PAD alone, and 61% of those with microvascular disease and PAD combined, and only 13% of those with neither form of vascular disease.

In an adjusted analysis compared with patients with diabetes but neither microvascular disease nor PAD, those with diabetes and microvascular disease without PAD showed a 3.1-fold increased risk of amputation and those with PAD without microvascular disease showed a 7.9-fold increased risk.

"Even more impressively," the group writes, a combination of PAD and microvascular disease in people with diabetes was associated with a 15.9-fold increased risk of amputation.

There were 24 incident major adverse cardiovascular events (MACE) per 1000 person-years over a median follow-up of 9.2 years. All forms of vascular disease were associated with significantly increased MACE risk in adjusted analyses.

"Although it is true that patients with diabetes are more likely than other people to get microvascular disease, that is far from the only way to get it," Beckman commented.

Other associated conditions include hypertension-related nephropathy, and even prediabetes, Beckman said. "So you can't just not pay attention to this issue because the patient doesn't have diabetes."

Beckman has reported consulting for AstraZeneca, Bristol-Myers Squibb, Amgen, Merck, Sanofi, Antidote Pharmaceutical, and Boehringer Ingelheim, and serving on a data safety monitoring board for Bayer and Novartis. The other authors and Hiatt have reported no relevant financial relationships.

Circulation. Published online July 8, 2019. Full text

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