Diagnostic Accuracy of the maximum systolic acceleration for detecting the severity of peripheral arterial disease

Epidemiology
Peripheral arterial disease (PAD) is a common vascular disease with a
preference for the lower extremities, and is estimated to affect 200 million
people worldwide, with the burden of disease presenting in the elderly
population.(1) PAD is caused by atherosclerosis, and progresses due to
increased arterial plaque formation and thus reduction in blood flow and oxygen
supply to the extremities. Reduced oxygen supply in the extremities leads to
symptoms such as ischemic pain, and the development and impaired healing of
ulcers. Risk factors for PAD include age, gender, ethnicity, smoking and
Diabetes Mellitus (DM).(2)

It is estimated that the population of persons 65 years old and over will
increase 44% in the coming 20 years. The prevalence of PAD in the general
population in the Netherlands is an estimated 7% to 56% in patients over 55 and
85 years old, respectively. For the larger The Hague area, this PAD prevalence
may be an underestimation as the population is of lower socio-economic status
(SES) and of larger multinational background including a large
Surinam-Hindustan community with a high-risk cardiovascular profile including
high rates of DM.

PAD can be divided into four stages according to the Fontaine classification
system, see Table 1.(3) Fontaine II includes patients with intermittent
claudication, and has a 5-year overall and vascular mortality rate of 9% and
3%, respectively.(4, 5) One-fifth of Fontaine II patients experience worsening
symptoms, and in some eventual amputation. Furthermore, Fontaine II is often
the index presenting symptom in patients with underlying cardiovascular
disease, with 21% of Fontaine II patients developing other cardiovascular
events in the course of five years.(5) While these numbers warrant extensive
secondary prevention and surveillance in PAD patients, current guidelines are
based on either recent small studies or dated larger American studies that may
no longer be relevant due to changing diagnostic and treatment strategies.(6)
There is thus a need for large contemporary studies on the epidemiology and
natural progression of Fontaine II patients.


Table 1: Fontaine Classification

FONTAINE CLASSIFICATION
STAGE Symptoms
I Asymptomatic
II IIa Non-disabling intermittent claudication
IIb Disabling intermittent claudication
III Ischaemic rest pain
IV Ulceration or gangrene



Diagnostics of Fontaine II PAD
A broadly accepted diagnostic modality is the ankle-brachial index (ABI). This
is a measurement of systolic blood pressure differences between the arm and
ankle, where an ABI of less than 0.9 is interpreted as a sign of significant
arterial stenosis.(3) Other non-invasive techniques include exercise testing, a
means of precipitating ischemic symptoms, toe pressure (TP), and the
toe-brachial index (TBI). The TP and TBI measurement are taken distally in the
hallux of the foot, and are said to be less influenced by the presence of
medial sclerosis. However, both TBI and TP can provide falsely elevated values
as a result of incompressible digital arteries. The literature, however, is not
unanimous on the accuracy of this method.(7) Methods focusing principally on
microcirculation include tissue oximetry (TcPO2). This method shows varied
potential in the research setting due to limited repeatability.(8) More
invasive techniques include computed tomography angiography (CT-A)and magnetic
resonance angiography (MR-A). While these methods are effective in assisting
the decision-making process regarding targets for revascularization, they are
of limited value in assessing tissue perfusion in instances of collateral
formation or microvascular occlusion.(9) Digital subtraction angiography (DSA)
was previously considered as a standard vascular imaging technique. However,
due to the invasive nature of this technique it is infrequently applied in the
preclinical setting, with the exception of instances of discrepancy between
non-invasive techniques.(10)

Of the above-mentioned diagnostic modalities, the ABI is the most frequently
adopted technique for initial PAD diagnosis in a primary care setting. However,
ABI measurements can be unreliable through incompressible arteries as a result
of medial calcific sclerosis that occur primarily in patients with DM, advanced
age, or end-stage renal disease. It is expected that one in every three Dutch
persons over 45-years of age will develop DM, and the current prevalence of PAD
in people with diabetes is 20-30%.(11) With an increasing burden of disease
timely diagnosis of PAD in this patient group is paramount, however two recent
reviews have shown poor results and insufficient evidence for the standard test
for diagnosing PAD among patients with DM.(12, 13)

New imaging techniques are therefore required to improve early detection and
assist in appropriate and timely management of symptomatic disease and its*
complications. A novel Doppler ultrasonography (DUS) parameter, the maximum
systolic acceleration (ACCmax), is being investigated as an alternative
modality to diagnose PAD. The ACCmax measures the acceleration of blood flow by
quantifying the maximal steepness of the systolic doppler curve. This technique
is believed to provide more accurate measurements across all patients,
including those with incompressible arteries such as diabetes mellitus
patients, and can provide more insight into the anatomical location of a
possible atherosclerotic stenosis.(14, 15) This technique offers a promising
alternative to the ABI, TP or TBI and has recently gained popularity among our
affiliated and other hospitals.(14, 16) However, while promising and easily
applicable, the use of ACCmax still needs large-scale validation in the general
PAD II population, with specific research focussed on the application of this
technique in a pre-clinical setting.

Hypothesis and Rationale
It is hypothesized that validation of the ACCmax will result in the
implementation of a non-invasive PAD diagnostic tool with improved sensitivity
and specificity in comparison to current methods, namely duplex ultrasonography
and the ankle-brachial index.

REFERENCES

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2. Khawaja FJ, Kullo IJ. Novel markers of peripheral arterial disease. Vasc
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4. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FGR.
Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC
II). Eur J Vasc Endovasc Surg. 2006;33(1):S1-S75.
5. Rantner B, Kollerits B, Pohlhammer J, Stadler M, Lamina C, Peric S, et al.
The fate of patients with intermittent claudication in the 21st century
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patients with peripheral arterial disease. Expert review of medical devices.
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jgt-naar-ruim-1-4-miljoen-in-2040.
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al. Lower extremity arterial disease in patients with diabetes: a contemporary
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Primary Objective:
The Primary outcome is to evaluate the sensitivity of the ACCmax compared to
the currently advised diagnostic method the ABI.

Secondary Objectives
To evaluate the sensitivity, specificity, positive and negative likelihood
ratios of the ACCmax compared to duplex ultrasonography.
Additionally, we will also evaluate the association between the diagnosis of
PAD made in the primary objective and the following secondary endpoints: all
clinical and haemodynamic outcomes are assessed within 1- and 5-year postindex
measurement.
a. Walking performance
b. Mortality
c. MACE
d. Progression of disease as defined by the Fontaine Classification
e. Revascularisation: number of procedures and time to revascularisation
f. In-stent thrombosis


Other study objectives
1. Investigate the interobserver variability (reproducibility) of ACCmax and
ABI measurements
2. Investigate the correlation between the ABI and ACCmax
3. Investigate the correlation between the ABI and ACCmax in a resting state
and after treadmill testing
4. Investigate the correlation between the TP and ACCmax
5. Investigate the correlation between the ACCmax and duplex ultrasound in
patients with and without DM, and compare the results to ABI and TP.

This is a prospective observational diagnostic study.
This study will be performed in The Hague, the Netherlands and include patients
receiving care in MijnKliniek and the Haaglanden Medical Centre Hospital (HMC)
in this region.

The diagnostic value of the ACCmax will be analysed in an observational
setting.
Vascular laboratory assistant A. The laboratory assistant will begin with the
ACCmax measurement. The ACCmax value will be recorded after which the index
tests will be performed. In this way the ACCmax result will be blinded.
Thereafter the following diagnostic tests will be performed: duplex ultrasound
of all arteries from the aorta to the lower limb, ABI, TP, TBI, treadmill
exercise testing.
Vascular laboratory assistant B. The ACCmax will be measured at the distal
tibialis posterior artery, dorsalis pedis artery in the context of the
interobserver variability measurement.


The prognostic value of the ACCmax will be evaluated in terms of secondary
endpoints, clinical outcomes. A standard follow-up period of 1- and 5 years
with a physical consultation at 4 months and telephone consultation at 1- and 5
years will be set. Should a treatment intervention fail, or a patient return at
an earlier interval due to progression of disease this will be noted.

There are no risks for patients associated with participation in this study.
Participation in this study will require an extra 45 minutes consultation time
during the primary consultation in order to perform an extra ACCmax
measurement. Furthermore, at a regular follow-up visit at 4 months a second
ACCmax measurement will be performed. The patient will be required to fill out
a questionnaire three times during the study period.