A 56 year old man reports to the OPD with pain in his left fore foot and says that his toes are turning black. His left foot is swollen, with patches of red and blue skin, a non-healing ulcer on the dorsum and left side of the ankle with blue/black discoloration of the big toe which is beginning to shrivel, as well as discoloration of the second and third toes. A quick look at the other foot shows that small patches of blue discoloration are starting on the toes of the right foot too. This started about 6 weeks ago and has been progressive. You are in the short case section of a post graduate exam. What three questions will you ask to clarify a diagnosis?
- Do you smoke and are you a current smoker?
- Have you had pain on walking and is this pain starting at shorter distances now?
- Do you suffer from diabetes?
What is likely to be causing this disease? The patient seems to have gangrene and non-healing ulcers caused by ischaemia of the foot. So why is the blood supply to the foot reducing to the point that it can no longer maintain the viability of the tissue? Peripheral arterial disease (PAD) is most often caused by arteriosclerosis.
How do you assess the risk in the population for PAD? The risk is higher in:
- Male gender more than female gender.
- Black ethnicity.
- Age above 70 years.
- With diabetes onset will be earlier.
- Smokers, specially current smokers , the risk is higher and occurs in younger people.
- Presence of coronary artery disease.
- Hypertension is strongly associated with the development of atherosclerosis in men and women.
- CKD makes the risk higher
- A family history especially if associated with familial hyperlipidemia.
- A history of intermittent claudication.
- Abnormal pulses in the lower extremity.
The risk of PAD is increased in families identified with early-onset atherosclerosis, but no single genetic marker has been identified for PAD in this population.
Smoking . Cigarette smoking correlates significantly with cardiovascular disease. The mechanism by which cigarette smoke promotes the development and progression of atherosclerosis is not clearly understood, but its effects include endothelial damage, arterial smooth muscle proliferation, thrombophilia, inflammation, increased sympathetic tone, and other metabolic abnormalities. The NHANES study: the risk for PAD was increased in active cigarette smokers, but no association was found for other forms of tobacco exposure like gutka. paan, naswar but these were probably not studied in detail. In the Edinburgh Artery Study, smoking appears to be a more powerful risk factor for PAD than for CAD. Passive exposure to smoke appears to increase vascular endothelial inflammation and may increase the risk for atherosclerotic plaque development in children and adults.
Hypertension: Among those with an abnormal ankle-brachial index, the prevalence of hypertension in the Rotterdam Study was 60 percent. The NHANES study found that hypertensive patients also have an even higher prevalence of asymptomatic PAD. Hypertension together with smoking is a major factor for progression of PAD in patients with diabetes mellitus, but there is no evidence that adequate control of hypertension impacts disease progression.
Diabetes also increased the risk for developing symptomatic PAD (OR 2.6) in the Framingham Heart Study, which followed subjects for 38 years. The effect of diabetes on graft patency has varied between studies, with the majority finding no difference in patency rates but retrospective studies showed that the amputation rates are higher in diabetes.
Chronic kidney disease. Many guidelines do not specifically identify chronic kidney disease (CKD) as a risk factor for PAD. However, an association between PAD and CKD is being recognized and reported with increasing frequency.
Metabolic syndrome (a constellation of obesity, hypercholesterolemia, hypertension, and insulin resistance) is associated with increased risk for cardiovascular disease.
Hyperlipidemia. Patients with certain lipid and lipoprotein abnormalities [eg, total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein (a)] have an increased risk for cardiovascular disease, and adverse long-term. cardiovascular outcomes.
Homocysteine was one of the earliest biomarkers to be studied in association with the development of atherosclerosis. Elevated homocysteine is associated with earlier-onset atherosclerosis and is present in up to 40 percent of patients with PAD.
Heavy metals: arsenic, lead, cadmium have been linked to coronary artery disease and PAD. Arsenic is found in sparklingly clear drinking water (ask for symptoms of abdominal pain, vomiting diarrhoea and hair loss) and is associated with high homocysteine levels in blood. In a review using data from the NHANES, after adjusting for known risk factors, comparing the highest with lowest quartiles, the risk for PAD trended higher for cadmium and for lead.
What is the area of distribution or pattern of arterial disease?
- Type I: The coronary arterial bed. Because of the prevalence of CAD many risk factors such as diabetes and hyperlipidemia are considered CAD equivalents. PAD is regarded as a coronary heart disease risk equivalent.
- Type II: The major branches of the aortic arch (eg, carotid, subclavian).
- Type III: The visceral arterial branches of the abdominal aorta.
- Type IV: The abdominal aorta and lower extremity arteries.
- Type V: A combination of two or more of these categories occurring simultaneously.
Is there a difference in the progression of disease in in the different arterial beds? More rapid progression of disease occurred most frequently in those with aortic arch branch disease and visceral artery disease. Gender did not influence the rate of progression; however, the risk for recurrence or progression of disease in the same category and in a new category was significantly greater in younger patients. In most other studies evaluating the natural progression of disease of the aorta and lower extremities, symptoms tend to remain stable . Patients who continue to smoke cigarettes and those with diabetes mellitus are generally at the highest risk for progression of disease.
What are the risks in early onset of PAD?
Early-onset atherosclerosis, or premature atherosclerosis, is defined as PAD presenting prior to 50 years of age. Patients with early-onset atherosclerosis are more frequently male, are active smokers, have diabetes, and more often present with critical limb ischemia. A defect in coagulation or fibrinolysis is identified in up to 75 percent of patients with early-onset atherosclerosis. In one study, 30 percent had hypercoagulable states, and 47 percent had platelet aggregation defects.
This patient was not a diabetic. His blood pressure was 130/75 mmHg and he had never been treated for hypertension. He was lean and thin and had never had angina or a heart attack. He needs to be asked about transient ischaemic attacks. He is 56 so should be investigated for coagulation defects. He had been a smoker in his youth but had not smoked for 10 years.
The clinical manifestations of PAD (claudication, rest pain, ulceration, and gangrene) are predominantly due to progressive luminal narrowing (stenosis/occlusion), although thrombosis or embolism of unstable atherosclerotic plaque or thrombotic material can also occur.
What tissue diagnosis will you make for this patient?
Chronic limb-threatening ischemia (CLTI) is the clinical syndrome, defined by the presence of PAD in combination with rest pain, gangrene, or a lower limb ulceration >2 weeks duration, which fits this patient best. The nature of the clinical manifestations depends upon the time course over which arterial narrowing or occlusion occurs; this in turn affects the extent to which the collateral circulation can develop. Acute-on-chronic reductions in limb perfusion, which may be due to atheroembolism, cholesterol embolism, or thrombotic occlusion of a stenotic vessel, cause diffuse limb pain. Chronic severe reduction in limb perfusion is present as ischemic rest pain, typically localized to the forefoot and toes, and as tissue loss (nonhealing ulcer, gangrene) are also present.
How are you going to assess this patient?
- Check the peripheral pulses.
- Measure the an ankle-brachial index (ABI) ≤0.9. The ABI is a comparison of the resting systolic blood pressure at the ankle to the higher systolic brachial pressure.
- Duplex ultrasonography is commonly used in conjunction with the ABI to identify the location and severity of arterial obstruction.
- Advanced vascular imaging (computed tomographic [CT] angiography,
- Magnetic resonance [MR] angiography,
- Catheter-based arteriography) is usually reserved for patients in whom there remains uncertainty following noninvasive testing, or in whom intervention is anticipated.
Medical management consists of cessation of smoking, reduction in weight in obese patients. Does not apply to this patient. Control of diabetes and hypertension. Measure serum lipids and modify them with dietary measures and statins and antiplatelet therapy. Consider aspirin, clopidogrel, ticagrelor, vorapaxar. Read up the PEGASUS-TIMI, the CAPRI and EUCLID trials.
Claudication is managed with supervised exercising, the addition of the phosphodiesterase inhibitor, cilostazol, may also improve symptoms. Statin therapy may also improve pain-free walking time in patients with claudication, but the evidence for this is conflicting. There is no evidence that beta blocker therapy for treatment of high blood pressure worsens claudication.
Ischemic rest pain or tissue loss. Once a patient develops ischemic rest pain or tissue loss, the natural history often involves a persistent decline and an increased risk of major limb amputation unless there is some form of intervention to improve arterial perfusion. This patient will need forefoot amputation after waiting to see where the ischaemia line develops. For this patient:
- As this patient has wet gangrene/ abscess ulcers, the wound should be debrided or drained immediately regardless of the anticipated need for revascularization.
- Use of antibiotics.
- The wound should be lightly wrapped with a bulky dry gauze bandage, avoiding excess pressure that could aggravate ischemia. Following revascularization, the wound should be monitored closely for signs of healing, or for tissue necrosis/drainage that may indicate a need for further debridement.
- Once the decision has been made to intervene, a three-step integrated approach (PLAN) is suggested that includes Patient risk estimation, Limb staging using WIfI and determining the ANatomic pattern of disease using the Global Anatomic Staging System (GLASS).
Concern over paclitaxel. Following percutaneous intervention, a number of medical therapies aimed at preventing restenosis, but only local delivery of the drug paclitaxel has been shown to improve the longevity of interventions for lower extremity PAD. However, the overall safety of paclitaxel-coated balloons and stents placed into the legs of patients with PAD has come into question.
I have tried to put in all the points where you can be assessed or a point put forward for discussion or your opinion can be sought. Please read up the trials mentioned and many others which clinicians use to improve the management of their patients.