Download Footnotes on Critical Limb Ischemia

Journal of the American College of Cardiology
© 2008 by the American College of Cardiology Foundation
Published by Elsevier Inc.
EDITORIAL COMMENT
Footnotes on
Critical Limb Ischemia*
Andrew J. Feiring, MD, FACC
Milwaukee, Wisconsin
In this issue of the Journal, Guzman et al. (1) investigate a
novel approach for identifying patients at risk for amputation secondary to peripheral arterial disease. This study is
the first to use multidetector computed tomography to
quantify tibial artery calcification (TAC). The authors
advance the hypothesis that TAC is a measure of the
severity of below the knee atherosclerotic disease much in
the same way as coronary artery calcification (CAC) reflects
the severity of coronary arteriopathy (2). In the lower
extremities, amputations most commonly result from critical limb ischemia (CLI) brought about by multilevel arterial
involvement. However, the common anatomic denominator
that unites many of these patients is the severity of concomitant
tibial arterial disease. Consequently, using TAC as a measure
of the index of the severity of tibial disease is reasonable.
See page 1967
Critical limb ischemia is a manifestation of peripheral
arterial disease that severely restricts limb perfusion resulting in a mismatch between metabolic tissue demands and
oxygen delivery. By definition, CLI is associated with the
clinical constellation of chronic ischemic rest pain or ulceration in conjunction with hemodynamic evidence of reduced tissue perfusion (abnormal ankle pressure or great toe
pressures or transcutaneous oxygen pressure) (3,4). It is noteworthy, although not surprising, that many physicians are
unfamiliar with the concept of CLI, since medical training
programs place little emphasis on the diagnosis and treatment
of vascular disease. For example, neither Harrison’s, nor Cecil’s
textbooks of medicine have a single index entry for CLI (5,6).
A title search for CLI in articles published in the Journal reveals
a single citation (7). Based on CLI’s literary representation,
one might assume that CLI is of little importance in the
day-to-day practice of cardiologists or primary care physicians.
Critical limb ischemia is a silent plague whose enormity is
underappreciated even by those who routinely treat it. Few
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From Cardiac and Vascular Intervention, Columbia St-Mary’s Hospital, Milwaukee, Wisconsin.
Vol. 51, No. 20, 2008
ISSN 0735-1097/08/$34.00
doi:10.1016/j.jacc.2008.02.041
realize that the number of CLI cases exceeds the number of
new colorectal or breast cancer cases in the U.S. (3,8). The
estimated incidence of new CLI cases in Western countries
is between 500 to 1,000/million population/year, which
translates into 150,000 to 300,000 cases annually in the U.S.
The first year mortality and morbidity of CLI exceeds most
malignancies with a death rate of 25% and amputation rate
of 30% (3). Within 3 years, 60% of CLI patients will have
died (3). It is surprising that despite modern medical
management (or the absence thereof), amputations for
vascular disease continue to increase (9).
So why should cardiologists worry about CLI? The reason is
that most of these patients die from unrecognized and
undertreated cardiovascular causes (3). This is not unexpected since CLI and coronary artery disease, carotid, and
renal vascular diseases share similar risk factors and pathophysiology. Yet for some inexplicable reason, most physicians are indifferent when it comes to aggressively treating
risk factors in patients with vascular disease. For instance, in
the contemporary BASIL (Bypass versus Angioplasty in
Severe Ischemia of the Leg) trial (a randomized trial of
percutaneous transluminal angioplasty vs. bypass surgery for
CLI), only one-third of the patients received lipid-lowering
agents and barely 50% were on any antiplatelets (10).
With these issues in mind, I read the study of Guzman
et al. (1) with anticipation. The authors measured TAC
from knee to ankle using the well-established Agatston
CAC scoring algorithm. The TAC scores were calculated
for normal control subjects, patients with claudication, and
CLI. The latter 2 groups were culled from their vascular
surgery clinic. Receiver-operating characteristic analysis
yielded a TAC cutoff value ⱖ400 that resulted in a
sensitivity of 94%, specificity of 47%, and negative predictive value of 98% for amputations. Multivariate analysis
demonstrated that TAC ⬎400 was the strongest predictor
of amputation when compared with either ankle-brachial
index or traditional coronary risk factors. Furthermore, no
patients with TAC ⬍400 underwent amputation, whereas 1
of 5 with TAC ⬎400 were amputated. The authors conclude
that TAC by multidetector computed tomography “may be a
useful measure to stratify patients into risk categories and guide
therapy aimed at limb preservation” (1).
Despite 20 years of investigation, the clinical utility of CAC
remains controversial (11,12). Most studies of CAC either
address risk stratification in the asymptomatic patient or triage
of the symptomatic patient (i.e., chest pain) who might benefit
from coronary angiography. A recent study in asymptomatic
subjects has convincingly demonstrated that the higher the
CAC score the more strongly it was an independent predictor
of all-cause mortality (13). Unfortunately, few studies of CAC
are directly analogous to the present one. However, if we
extrapolate and consider claudication to be equivalent to stable
angina, CLI (rest pain or ulceration) to be equivalent to
unstable angina/myocardial infarction, and death comparable to amputation, then this study can reconcile the results
1976
Feiring
Editorial Comment
that show that the rate of amputation may be a function of
the number and extent of diseased tibial vessels.
As the authors note, there is no reliable test for predicting
the risk of amputation in CLI. The question then becomes
whether TAC can be used to fill this void. Although the
data convincingly demonstrate the relationship between a
TAC ⱖ400 and amputation, the interpretation is less
persuasive regarding its clinical utility. In this study, the
mere presence of CLI conferred a 1 in 3 risk of major
amputation, whereas a TAC cutoff of ⱖ400 predicted
amputation in 1 in 2 patients. However, it is not apparent
that this additional knowledge would translate into a clinically meaningful dividend because the converse is also true:
one-half of the patients with TAC ⬎400 did not undergo
amputations. Since the relationship between TAC ⬎400
and amputation was not linear, does this method help us
assess the relative risk for an individual patient? Clearly, until
proven otherwise, all patients with CLI should be considered
to be at risk for amputation regardless of the TAC score.
Despite this limitation, TAC may prove to be a useful tool for
future investigations. The impressive negative predictive value
of TAC, especially among claudicants, may permit identification of those patients at low risk for subsequent amputation,
because virtually no patients were amputated when the TAC
was ⱕ400. Additionally, serial measurement of TAC may
prove to be a robust epidemiologic tool when investigating the
natural history of claudication and CLI.
As demonstrated by this study, a 33% major 1-year
amputation rate in the 21st millennium is distressing. The
delayed medical awareness and subsequent poor clinical
outcomes clearly underscore the need for a reappraisal of our
educational, diagnostic, and therapeutic approach to CLI.
The most effective first step is to have patients at risk
(those with coronary risk factors) remove their shoes and
socks once a year when they come to the office. As Yogi
Berra said, “you can observe a lot by watching” (14).
Additionally, the traditional, surgically driven “conservative” algorithms for treating CLI have been successful in
conserving neither the limb nor the patient. Emerging
evidence suggests that CLI should be approached in the
same manner as patients with unstable coronary syndrome (i.e., early angiographic evaluation and aggressive
endovascular intervention). Recently, a number of smaller
studies have suggested that this approach may yield limb
salvage rates in excess of 90% (15–17). Furthermore,
emerging data suggest that aggressive modification with
lipid lowering and antiplatelet agents yields significant
clinical dividends (18,19).
Albert Einstein noted that “not everything that counts
can be counted, and not everything that can be counted
counts” (20). Is TAC worth counting? It is far too early
to tell. However, as with all compelling studies, this one
raises more questions than it answers and illuminates an
area of clinical confusion and frustration. I am encouraged by the authors’ fresh approach and eagerly look
forward to further application of their methodology.
JACC Vol. 51, No. 20, 2008
May 20, 2008:1975–6
Reprint requests and correspondence: Dr. Andrew J. Feiring,
Cardiac and Vascular Intervention, Columbia St-Mary’s Hospital,
Suite 600, 2015 East Newport Avenue, Milwaukee, Wisconsin
53211. E-mail: [email protected].
REFERENCES
1. Guzman RJ, Brinkley DM, Schumacher PM, Donahue RMJ, Beavers H,
Qin X. Tibial artery calcification as a marker of amputation risk in patients
with peripheral arterial disease. J Am Coll Cardiol 2008;51:1967–74.
2. Rumberger JA, Schwartz RS, Simons DB, Sheedy PF, Edwards WD,
Fitzpatrick LA. Relation of coronary calcium determined by electron
beam computed tomography and lumen narrowing determined by
autopsy. Am J Cardiol 1994;92:2157– 62.
3. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes
FG, on behalf of the TASC II Working Group. Inter-society consensus
for the management of PAD. J Vasc Surg 2007;45 Suppl S:S5– 67.
4. Dormandy J, Verstraete M, Andreani D, et al. Second European
consensus document on chronic critical leg ischemia. Circulation
1991;84 Suppl 4:1–26.
5. Goldman L, Ausiello D, editors. Cecil’s Textbook of Medicine. 22nd
edition. Philadelphia, PA: Saunders, 2004.
6. Kasper DL, Braunwald E, Fauci FS, et al. Harrison’s Principles of
Internal Medicine. 16th edition. New York, NY: McGraw-Hill, 2005.
7. Feiring A, Wesolowski A, Lade S. Primary stent support below knee
angioplasty for critical limb ischemia and severe life style limiting
claudication. J Am Coll Cardiol 2004;44:2307–14.
8. American Cancer Society. Cancer Facts and Figures 2007. Atlanta
American Cancer Society. Available at: www.cancer.org/downloads/
STT/CAFF2007PWSecured.pdf. Accessed April 3, 2008.
9. Allie DE, Hebert CJ, Lirtzman MD, et al. Critical limb ischemia: a
global epidemic a critical analysis of current treatment unmasks the
clinical and economic costs of CLI. EuroIntervention 2005;1:60 – 8.
10. BASIL Trial Participants. Bypass versus Angioplasty in Severe Ischemia of the Leg (BASIL): multicentre, randomized controlled trial.
Lancet 2005;306:1925–34.
11. Greenland P, Bonow RO, Brundage BH, et al. ACCF/AHA 2007
clinical expert consensus document on coronary artery calcium scoring
by computed tomography in global cardiovascular risk assessment and
in evaluation of patients with chest pain: a report of the American
College of Cardiology Foundation Clinical Expert Consensus Task
Force (ACCF/AHA Writing Committee to Update the 2000 Expert
Consensus Document on Electron Beam Computed Tomography).
J Am Coll Cardiol 2007;49:378 – 402.
12. Budoff MJ, Achenbach S, Blumenthal RS, et al. Assessment of
coronary artery disease by cardiac computed tomography: a scientific
statement from the American Heart Association. Circulation 2006;
114:1761–91.
13. Budoff MJ, Shaw LJ, Liu ST, et al. Long-term prognosis associated
with coronary calcification observations from a registry of 25,253
patients. J Am Coll Cardiol 2007;49:1860 –70.
14. Yogi Berra Quotes. Available at: http://thinkexist.com/quotes/
yogi_berra. Accessed April 3, 2008.
15. Dorros G, Jaff MR, Dorros AM, Mathiak LM, He T. Tibioperoneal
(outflow lesion) angioplasty can be used as primary treatment in 235
patients with critical limb ischemia: five-year follow-up. Circulation
2001;104:2057– 62.
16. Laird JR, Zeller T, Gray BH, et al., LACI Investigators. Limb salvage
following laser-assisted angioplasty for critical limb ischemia: results of
the LACI multicenter trial. J Endovasc Ther 2006;13:1–11.
17. Feiring AJ, Krahn M, Thompson L. Treating below-knee critical limb
ischemia with drug eluting stents, early and late clinical outcomes.
Am J Cardiol 2007;100:48L.
18. Ferinag HHH, Karagiannis SE, vanWaning VH, et al. The effect of
intensified lipid-lowering therapy on long-term prognosis in patients
with peripheral arterial disease. J Vasc Surg 2007;45:936 – 43.
19. CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
Lancet 1996;348:1329 –39.
20. Collected Quotes from Albert Einstein. Available at: http://
rescomp.stanford.edu/⬃cheshire/EinsteinQuotes.html. Accessed
April 4, 2008.