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Deep Dive into a Topic
At face value, a case study is a deep dive into a topic. Case studies can be found in many fields, particularly across the social sciences and medicine. When you conduct a case study, you create a body of research based on an inquiry and related data from analysis of a group, individual or controlled research environment.
As a researcher, you can benefit from the analysis of case studies similar to inquiries you’re currently studying. Researchers often rely on case studies to answer questions that basic information and standard diagnostics cannot address.
Study a Pattern
One of the main objectives of a case study is to find a pattern that answers whatever the initial inquiry seeks to find. This might be a question about why college students are prone to certain eating habits or what mental health problems afflict house fire survivors. The researcher then collects data, either through observation or data research, and starts connecting the dots to find underlying behaviors or impacts of the sample group’s behavior.
During the study period, the researcher gathers evidence to back the observed patterns and future claims that’ll be derived from the data. Since case studies are usually presented in the professional environment, it’s not enough to simply have a theory and observational notes to back up a claim. Instead, the researcher must provide evidence to support the body of study and the resulting conclusions.
As the study progresses, the researcher develops a solid case to present to peers or a governing body. Case study presentation is important because it legitimizes the body of research and opens the findings to a broader analysis that may end up drawing a conclusion that’s more true to the data than what one or two researchers might establish. The presentation might be formal or casual, depending on the case study itself.
Once the body of research is established, it’s time to draw conclusions from the case study. As with all social sciences studies, conclusions from one researcher shouldn’t necessarily be taken as gospel, but they’re helpful for advancing the body of knowledge in a given field. For that purpose, they’re an invaluable way of gathering new material and presenting ideas that others in the field can learn from and expand upon.
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Shel D. Levine; Peripheral Arterial Disease: A Case Report From the Henry Ford Hospital. Journal of Clinical Exercise Physiology 1 March 2018; 7 (1): 15–21. doi: https://doi.org/10.31189/2165-6193-7.1.15
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A.T. is a 65-year-old black female with claudication secondary to peripheral arterial disease (PAD). She has a history of coronary artery disease, myocardial infarction, heart failure, endarterectomy, hypertension, hyperlipidemia, type 1 diabetes mellitus, and asthma.
She was referred to the Division of Vascular Surgery at Henry Ford Hospital complaining of fatigue and heaviness in her lower thighs and calves during walking. Resting ankle-brachial index (ABI) was 0.50 and 0.70 at the right and left dorsalis pedis, respectively. She was prescribed cilostazol and encouraged to “…walk through the pain as much as possible.”
Due to worsening claudication, A.T. underwent an abdominal aortogram with arteriogram of the lower extremities. Results showed aortoiliac disease with multiple stenoses of varying degrees. Areas of calcification were noted from the lower aorta and iliac artery to the anterior tibial artery affecting both the left and right limbs.
Results from a stress echocardiogram showed cardiac wall motion abnormalities consistent with exercise-induced ischemia. She exercised for 5.8 minutes on the Bruce protocol, limited by general fatigue. The electrocardiogram displayed left bundle branch block, resting ejection fraction was 40%, peak blood pressure was 160/80 mmHg, and peak heart rate was 120 b·min −1 . No symptoms were reported. Her medications are cilostazol, carvedilol, amlodipine, isosorbide dinitrate, clopidogrel, simvastatin, potassium, triamcinolone, ipratropium, and pirbuterol.
She began supervised exercise training in cardiac rehabilitation following a hospitalization for angina. At rest her blood pressure was 120/50 mmHg, heart rate was 79 b·min −1 , blood glucose was 6.89 mmol·L −1 (266 mg·dL −1 ) and her HbA1c was 8.0%. Her initial exercise sessions were limited by bilateral claudication of her thighs and calves. Moderate pain occurred after 9 minutes of walking on day 1. A pain-rest walking program was initiated and followed for 12 weeks. She then joined the Henry Ford PREVENT program, which provides patients with a low-cost, long-term supervised exercise environment.
She now exercises at least 3 d·wk −1 for 60 minutes each session. She splits her exercise time between a seated stepper and a treadmill. On most days she is now able to walk 30 continuous minutes without limiting claudication pain.
The natural history of arteriosclerosis involves an intimal plaque that progressively develops until it eventually causes a significant flow limiting occlusion of the vessel and reduction of blood supply relative to demand. Arteriosclerosis is a systemic disorder affecting the major circulations, with the intimal plaque occurring segmentally in multiple locations. When the plaque occurs in the distal aorta or in the arteries of the lower extremities, it is referred to as PAD.
More than 8 million individuals in the United States above the age of 40 are estimated to have PAD ( 1 ). The prevalence of PAD per ABI is 4.3% in persons older than 40 years and up ( 2 ) and 29% in those 70 years and older ( 3 ). Thus PAD afflicts more than 4 million Americans and more than 200 million people worldwide. The age-adjusted prevalence of PAD increases to approximately 12% when more sensitive vascular imaging studies are used. Unlike coronary artery disease, the incidence of PAD is similar in men and women. Coronary artery disease occurs in 60% to 90% of patients with PAD. The incidence of cerebral vascular disease is increased in patients with PAD as well.
Peripheral arterial disease is part of the spectrum of atherosclerosis. It is associated with coronary and carotid artery disease. PAD increases mortality by 6-fold, due mostly to myocardial infarction and stroke. The 5-year mortality rate in patients with PAD is ≈ 30%, with a major lower extremity amputation rate near 1% to 2%. If the patient continues to smoke, the mortality rate doubles and the risk for amputation increases 10-fold. Aortoiliac disease has a higher mortality than femoral artery disease due to a greater prevalence of coronary artery disease in patients with the former.
Ten percent of patients with intermittent claudication will go on to have ischemic pain at rest (aka, critical limb ischemia), often leading to ulceration or amputation. The presence of diabetes mellitus also affects morbidity and mortality in patients with PAD. Sixty percent of leg amputations are the result of diabetic peripheral vascular disease. In fact, among patients with diabetes for 25 years or more, the risk of below the knee amputation is increased 12-fold.
The risk factors for coronary artery disease are also risk factors for the development of PAD (i.e., age greater than 65 years, cigarette smoking, and diabetes mellitus). Patients with type 2 diabetes mellitus have a 4-fold increased risk for PAD, while their risk for myocardial infarction or stroke is increased only 2-fold. The severity of PAD is not related to glycemic control but rather to the number of coexisting risk factors. Therefore, hypertension, hyperlipidemia and hyperhomocysteinemia are also important risk factors for PAD. For each 0.03 mmol·L −1 (1 mg·dL −1 ) increase in total cholesterol, there is a 1% increased incidence of PAD. A reduced high-density lipoprotein cholesterol and increased triglyceride are also closely associated with PAD. In the presence of these risk factors and given the systemic nature of atherosclerosis and its poor prognosis, patients with PAD should be thought of as already having coronary and carotid artery disease.
Unless there is acute occlusion by thrombosis, the symptoms of PAD occur gradually and progressively. Intermittent claudication is the major symptom of PAD. Claudication is derived from the Latin word claudicato , meaning to limp , which describes the gait of a patient with intermittent claudication. Intermittent claudication is most often described as an aching, cramping, or tightness in the muscles of the leg (usually the calf) that occurs with exercise and is relieved with rest. The pain usually disappears within several minutes after stopping exercise. The discomfort reoccurs at a constant distance. The distance is shorter if the patient is walking uphill or climbing stairs, and this pain does not occur at rest.
Despite claudication being the hallmark symptom of PAD, it is estimated that approximately 60% to 70% of individuals with disease do not have this symptom ( 4 ). The reason for this disparity is not entirely clear, but often patients with PAD may have diabetic neuropathy, which could mask symptoms, or they may simply not report discomfort because of the false assumption that it is simply pain associated with the aging process (e.g., arthritis). Another possibility could be because of avoidance of activities that may cause leg pain (e.g. exercise, yard work, walking long distances).
Some areas of the vascular tree are more likely to develop atherosclerotic plaque than others. In the abdomen, the stenosis usually occurs in the distal aorta or common iliac arteries. Distal to the inguinal ligament, the most common occlusions occur in the adductor canal, the posterior tibial artery at the ankle, and the anterior tibial artery at its origin. Stenosis of the external iliac and popliteal arteries occurs less frequently.
The location of the claudication is useful in predicting the most proximal level of occlusion. Intermittent claudication of the calf muscles does not occur with occlusions in the anterior tibial, posterior tibial, or peroneal arteries. It requires a more proximal lesion. Calf and thigh claudication suggests that the area of stenosis is proximal to the origin of the vascular supply to the thigh muscles (i.e. the profunda femoris artery). Thigh and buttock claudication with impotence in a middle-aged male is called Leriche Syndrome and signifies terminal aortic disease.
Pseudoclaudication must be differentiated from true claudication. Pseudoclaudication occurs from nonvascular causes of leg pain such as spinal stenosis, herniated nucleus pulposus, spinal cord tumors, and degenerative joint disease. It is usually described as a paresthetic discomfort (i.e., numbness, tingling, and/or weakness). The exercise-pain-rest cycle is not consistent in that standing does not relieve the pain. Sitting down may relieve it, and the time required for the pain to disappear is usually several minutes or more.
Patients with isolated nonobstructive lesions frequently have normal-appearing extremities. Paresthesia, numbness, ulceration, and gangrene are also symptoms of PAD but represent an advanced stage with multiple lesions. Loss of hair, trophic nail changes, and dependent rubor (redness caused by swelling) can also be seen. Loss of the peripheral pulse distal to the occlusion occurs in chronic disease. The pulses that should be checked include the femoral, popliteal, dorsalis pedis, and posterior tibial. Pulses should be described as: 0, absent; 1, diminished; 2, normal; or 3, bounding. Auscultation for bruits should also be performed over the abdomen and femoral arteries.
The resting ABI is considered the first-line test for PAD with a sensitivity ranging from 68% to 84% and a specificity of 84% to 99% compared to the gold standard of vascular imaging ( 1 ). ABI is measured by taking systolic blood pressure in the arm (i.e., brachial artery) and dividing it by pressure in the ipsilateral ankle (greater value between the dorsalis pedis or posterior tibial arteries). A normal value is 1.0 or greater ( Table 1 ). Values less than 0.5 are usually seen in patients with diffuse disease. A study of over 2,000 patients with PAD showed an abnormal ABI (< 0.91) to be an independent predictor of cardiovascular events and total mortality, with an annual mortality of 25% for the lowest ABI values ( 5 ). Values over 1.4 are likely due to noncompressible vessels from extensive disease and calcification.
Interpretation of ABI values.
The ABI can also be measured immediately after exercise. It should be the same or higher than the resting value. A drop in the ABI after exercise in someone who was normal or borderline at rest also suggests significant disease. As the arterioles within the exercising muscles dilate, the stenosis in the artery proximal to the muscle limits augmentation of blood flow and pressure drops. The postexercise ABI is often used to follow disease progression, as well as adequacy of medical and surgical therapy.
Ultrasonic duplex scanning, computed tomography angiography, or magnetic resonance angiography can be used to evaluate the severity of the disease and determining a treatment plan. Ultimately, angiography is necessary to localize the lesion and determine the extent of disease prior to surgery or percutaneous transluminal angioplasty.
The goals of treatment include reducing the symptom of intermittent claudication, improving mobility and quality of life, and halting the progression of atherosclerosis. Aggressive risk factor modification should be the cornerstone of any treatment plan. Due to the poor appreciation that PAD represents systemic atherosclerosis and is associated with a poor prognosis, many patients with PAD are undertreated. Smoking cessation through educational programs, nicotine-replacement therapy, and antidepressant drugs should be strongly considered. In those patients with hyperlipidemia, low density lipoprotein cholesterol should be at least less than 2.59 mmol·L −1 (100 mg·dL −1 ) and triglyceride should be less than 3.89 mmol·L −1 (150 mg·dL −1 ). Statin agents, in addition to lowering cholesterol, also may improve endothelial function. The treatment of hypertension and diabetes mellitus does not alter the natural history of PAD. Similarly, hyperhomocysteinemia is easily measured and treated, but there are no clinical trials assessing efficacy, and thus the current guidelines state that homocysteine lowering is of no benefit. At present there is no role for the use of hormone replacement therapy. Antiplatelet agents (i.e., aspirin and clopidogrel) reduce the risk of fatal and nonfatal cardiovascular events and are approved by the Food & Drug Administration for secondary prevention in patients with atherosclerosis. Probably due to a long history of use and few side effects, aspirin remains the drug of choice ( 1 ). Aspirin may also be administered with clopidogrel, which may reduce the risk of myocardial infarction, stroke, and vascular death in those with symptoms ( 1 ).
Meticulous foot care is extremely important, with special attention to properly fitting shoes and immediate attention to cuts and blisters. This is especially true for patients with diabetes mellitus, because with a peripheral neuropathy they might not experience pain as a warning sign of developing foot problems.
Medical treatment has met with mixed results. Vasodilators are not effective and are not used in the treatment of PAD. Pentoxifylline is no longer recommended as treatment for claudication pain. Cilostazol inhibits platelet aggregation and smooth-muscle proliferation and causes vasodilatation. In 4 randomized placebo-controlled trials, cilostazol improved both pain-free walking and maximal treadmill walking distance, but it did not improve the incidence of cardiovascular death ( 6 , 7 ).
For patients with lifestyle-limiting symptoms and hemodynamically significant aortoiliac disease, percutaneous transluminal angioplasty is an excellent alternative to surgery, giving results comparable to surgery without the morbidity. The ideal lesion for percutaneous transluminal angioplasty is an iliac stenosis less than 5 cm in length or a femoropopliteal stenosis less than 10 cm in length. Long-term results are best when the lesion is above the groin area. The majority of patients with PAD will not require surgical therapy, and a class I recommendation is to offer all patients exercise training therapy initially versus revascularization ( 1 ). Patients who do develop ischemic pain at rest, ulcers, or gangrene may be helped by surgery.
Since atherosclerosis represents the most common cause of death in patients with PAD, screening for coronary artery disease is important. Exercise testing guidelines outlined by the American College of Sports Medicine are appropriate for patients with PAD ( 8 ). A common treadmill protocol used in this patient population is the Gardner protocol ( 9 ) (Box 1). In patients with PAD, a symptom-limited exercise test can help identify exercise-induced myocardial ischemia, quantify aerobic capacity, evaluate postexercise ABI, identify time to initial claudication pain, and develop an exercise prescription.
Constant speed of 2.0 mph (3.2 kph)
Increments of elevation every 2 min
○ Start at 0%
○ Increase by 2%
Record pain-free and maximal walking time
Patients with PAD have 6 times the mortality as their age- and gender-matched peers.
Intermittent claudication is the defining symptom of PAD, traditionally affecting the calves but possibly including the thighs or buttocks.
Patients with diabetes mellitus and peripheral neuropathy may not experience claudication in spite of severe PAD.
In addition to detecting PAD, the ankle-brachial index test is an important non-invasive predictor of cardiovascular events and total mortality.
Smoking cessation, exercise, and modification of other risk factors are the foundation for treating PAD.
Reported peak oxygen consumption values in patients with PAD is 13 to 14 mL·kg −1 ·min −1 ( 10 , 11 ). Tests utilizing treadmill exercise will likely be limited by claudication. Although the time to onset of pain and maximal walking time during treadmill exercise are important markers of the severity of PAD and used for outcome comparisons, tests limited by claudication may not provide sufficient myocardial stress for proper assessment of cardiovascular disease risk. Submaximal stress may be avoided by using leg or arm ergometry while still providing information useful for developing an exercise prescription.
Submaximal functional evaluations, such as the 6-minute walk test, may better reflect the impact of claudication on daily physical activities. Among patients with PAD, Montgomery et al. ( 12 ) found the 6-minute walk test to be reliable and correlated with the time to claudication pain during treadmill testing and ABI.
Exercise training has been recommended to patients with intermittent claudication for many years, with several randomized controlled trials of exercise training reported. And importantly in May 2017 the Centers for Medicare and Medicaid Services (CMS) approved supervised exercise training as a reimbursable intervention for patients with symptomatic PAD who are referred by their physician. The impetus for this approval is an ever-growing amount of research demonstrating functional and quality of life improvements in those with symptomatic PAD who undergo an exercise training program. Virtually all trials that have evaluated the importance of exercise training in patients with PAD have exhibited an increase in exercise tolerance. And the evidence for exercise training benefits has resulted in the higher recommendation by the American Heart Association and American College of Cardiology for supervised exercise training ( 1 ).
Patients with PAD are at increased risk of cardiovascular disease and should be appropriately evaluated for exercise-induced myocardial ischemia.
PAD results in reduced exercise tolerance due to metabolic dysfunction, skeletal muscle abnormalities, diminished cardiorespiratory reserve, and exercise-induced inflammation. Exercise training improves pain-free and peak walking ability. Compared to stenting, improvement with walking is similar for pain-free walking and superior for peak walking time. Both are better than optimal medical therapy.
Optimal exercise training benefits are derived from programs that include walking to moderate pain with intermittent rest, accumulating 30 to 45 minutes, 3 d·wk −1 (or more), for at least 6 months.
The Claudication: Exercise Vs. Endoluminal Revascularization (CLEVER) study was the defining study to convince the CMS to cover supervised exercise training for PAD ( 13 ). CLEVER randomized revascularization-eligible patients to either medical care alone (i.e., advice and cilostazol), medical care plus revascularization, or medical care plus exercise training. The exercise training group had equivalent pain-free walking time as compared to the revascularization group (with both better than medical care alone) at 6 and 18 months. And the exercise group improved more than both other groups in peak walking time, which improved by 4.6 minutes (95% CI, P = 0.001) versus only 2.1 (95% CI, P = 0.04) minutes, respectively for the supervised exercise and control groups. The authors stated that supervised exercise is a reasonable strategy, as compared to stenting, and programs should be developed that are available and affordable to patients ( 13 ).
A meta-analysis from the Cochrane database ( 14 ) involving 32 critically evaluated randomized controlled trials of exercise therapy that randomized a total of 1,835 patients reported an overall improvement in peak walking distance of 120 meters (95% CI 50.79 to 189.92, P < 0.0007, high-quality evidence). Pain-free walking distance was also improved, as compared to a control group, by an average of 82 meters (95% CI 71.73 to 92.48, P < 0.00001, high-quality evidence). These findings are consistent with an earlier meta-analysis that reported improvements of 179% and 122% for walking distance to the onset of pain and to maximal pain, respectively ( 15 ). It is noted that exercise training has not been shown to affect the ABI ( 14 ).
In addition to the reduction in blood flow due to PAD, several factors have been associated with the reduced exercise capacity observed among these patients ( Figure 1 ). These include metabolic dysfunction, skeletal muscle abnormalities, reduced cardiorespiratory reserve, and exercise-induced inflammation. With exercise training there is increased skeletal muscle fiber area and improved oxidative capacity, blood flow, gait biomechanics, and blood rheology (e.g., viscosity, filterability and aggregation) ( 16 ). Due to chronic ischemia and reperfusion, multiple episodes of local and systemic inflammation occur in patients with PAD and is exacerbated by acute exercise, yet its contribution to disease progression is unknown. Also unknown is the role exercise training may have on modifying this inflammatory response.
Factors associated with reduced exercise capacity in patients with PAD.
The majority of exercise training trials in patients with claudication have used walking as the exercise training mode, as well as the primary outcome measured. As a result, walking predominates in the exercise prescription even though the mechanisms by which these patients improve remain unclear. Other exercise modes have also shown benefit. Sanderson et al. ( 17 ) evaluated the training response of 42 patients with symptomatic claudication randomized to 6 weeks of leg cycling, treadmill walking, or non-exercise control. The leg cycling group improved both pain-free and peak walking time versus control. However, this improvement was not as great as the treadmill walking group. Treat-Jacobson et al. ( 18 ) assessed 12 weeks of upper-body ergometry training versus treadmill walking and reported significant improvements in both groups for pain-free and peak walking time. These data suggest a systemic effect with exercise training.
The effects of progressive resistance exercise in patients with claudication are not well investigated. Hiatt et al. ( 19 ) found lesser improvements in walking time following 12 weeks of strength training (36%), compared to treadmill exercise (74%). In addition, strength training combined with treadmill exercise did not provide additional benefits. Similarly, McDermott et al. ( 20 ) compared treadmill walking with progressive resistance training in a group of 156 patients with PAD. They noted improvements in both groups in peak walking time versus control, but the treadmill group improved more than the resistance training group (3.4 vs. 1.9 minutes).
Exercise prescription guidelines outlined by the American College of Sports Medicine are appropriate for patients with PAD ( 8 ). The exercise prescription for maximal walking improvements in patients with claudication secondary to PAD should be walking-focused. Ideally a patient should perform intermittent walking to the point of moderately tolerable claudication pain, alternated with rest ( Figure 2 ). Rest periods should last until pain is completely (or nearly) relieved enough to continue walking. Patients should accumulate at least 30 minutes, but preferably 45 to 60 minutes, of this type of training at least 3 d·wk −1 . Exercise intensity should be slowly increased when a patient can walk more than 8 minutes without at least moderate pain. As exercise tolerance improves, some PAD patients may increase their total continuous walking time, or potentially introduce intermittent bouts throughout the day. Maximal benefits have been reported after 6 months of training, thus it is important to encourage patients to continue exercising beyond a typical 12-week supervised exercise training program. In addition to this standard recommendation, some patients may further improve cardiorespiratory function by performing additional aerobic exercise via exercise modes that are not limited by claudication (e.g., leg cycling, seated stepping, elliptical). This might be useful for select patients who either have a low functional capacity or who are not able to tolerate more than 30 minutes of the walking to moderate claudication pain protocol. Additionally, there are long-term health benefits of performing continuous exercise at an intensity that provides a cardiorespiratory stimulus (i.e., > 50% peak). And it is interesting to note that PAD patients who performed any amount of physical activity beyond light intensity showed a lower mortality rate than similar patients who were effectively sedentary ( 14 ). This reduced risk of mortality remained evident even when the findings were adjusted for age, ABI, and body mass index ( 21 ).
Claudication Training Pain Scale.
“Stop smoking and keep walking” has long been the recommendation for people with claudication. Although significant improvements in pain-free and peak walking distance are well documented by those who perform regular exercise, the mechanisms and their relative contribution remain unclear. In addition, their impact, if any, on disease progression and mortality requires further investigation. In spite of various medical therapies (e.g,, medications, revascularization), exercise training continues to produce the most favorable outcomes and should be routinely incorporated into the treatment plan for patients with PAD.
1 School of Health Promotion & Human Performance, Department of Exercise Science, Eastern Michigan University, Ypsilanti, Michigan
Conflicts of Interest and Source of Funding: None.
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Peripheral vascular disease.
Fahad Gul ; Sean F. Janzer .
Last Update: May 1, 2022 .
- Continuing Education Activity
Peripheral vascular diseases are a significant cause of morbidity and limb loss in the United States. Early identification and risk factor modification are essential to improve the outcomes in patients with peripheral vascular disease. This activity outlines the principles of evaluation and management of peripheral vascular disease and explores the surgical and non-surgical treatment alternatives and highlights the importance of the interprofessional team in the evaluation of this pathology. Peripheral vascular disease has been associated with multiple risk factors, including smoking, diabetes, prior coronary artery disease, and a sedentary lifestyle. This activity highlights the risk factors for peripheral vascular disease and the role of risk factor modification in the treatment of peripheral vascular disease. The cornerstone for the diagnosis of peripheral vascular disease is a thorough history and physical exam, including the ankle-brachial index. This activity describes the role of the interprofessional team in the evaluation and diagnostic workup of the patient with suspected peripheral vascular disease. It provides a guideline for the interpretation of ankle-brachial-index readings. The treatment of peripheral vascular disease includes risk factor modification, antiplatelet therapy, and exercise as the cornerstone of care in these patients. Appropriate patients with severe disease or lifestyle limiting symptoms are frequently managed with endovascular, surgical, or combined interventional approaches. This activity highlights the importance of the interprofessional team in the management of patients suffering from peripheral arterial disease and the selection of the appropriate intervention.
- Identify the etiology for the development of peripheral vascular disease.
- Summarize the appropriate evaluation for the diagnosis of peripheral vascular disease.
- Describe the management options available for peripheral vascular disease.
- Outline interprofessional team strategies for improving care coordination and improve outcomes in patients with peripheral vascular disease.
Peripheral vascular disease (PAD) is a chronic progressive atherosclerotic disease leading to partial or total peripheral vascular occlusion. PAD typically affects the abdominal aorta, iliac arteries, lower limbs, and occasionally the upper extremities.  PAD affects nearly 200 million people worldwide with increasing global importance due to longer life expectancy and prolonged risk factor exposure.   Patients with PAD have a variable disease presentation and course with some patients remaining asymptomatic and with others progressing to arterial ulceration, claudication, resting limb ischemia, and limb loss.  PAD is a cardiovascular disease equivalent, with associated high risk fatal and non-fatal cardiovascular events frequently occurring, such as myocardial infarction and stroke.  PAD is a progressive, debilitating systemic disease that requires interprofessional involvement for improved patient outcomes.
Peripheral vascular disease is primarily driven by progressive atherosclerotic disease resulting in the reduction of major organ blood flow and end-organ ischemia. The process of atherosclerosis is complex, with the involvement of numerous cells, proteins, and pathways. Important non-modifiable and modifiable risk factors have been identified in the advancement of atherosclerosis.
Risk factors include:    
- Tobacco use
- Diabetes mellitus
- High cholesterol
- Age more than 50 years
- Elevated homocysteine levels
- BMI greater than 30
- Family history of cardiovascular disease
Of the above risk factors, smoking is associated with the highest risk of PAD development with an odds ratio of 2.7 (95% CI 2.4–3.1). History of cardiovascular disease and diabetes are also significant risk factors with odds ratios of 2.6 (95% CI 2.2-3) and 1.9 (1.7-2.1), respectively. 
Peripheral vascular disease affects nearly 200 million people worldwide, including approximately 40 to 45 million Americans.  The disease is uncommon in younger populations; however, incidence increases sharply, with over 20% of people over 80 years old having PAD.  Data on gender differences is conflicting. In the Framingham study, intermittent claudication (IC) was more prevalent in men compared to women (1.9% to 0.8%; ratio 2.38).  This finding was consistent with the Rotterdam study that found men were 1.83 times more likely to have IC with a prevalence of 2.2% in men and 1.2% in women.  However, a gender shift in prevalence occurs when the diagnosis of PAD is based on the ankle-brachial pressure index (ABI). For example, the Rotterdam study found the prevalence of ABI-based diagnosis of PAD to be 20.5% in women and 16.9% in adults with a ratio of 0.82. Other studies, such as the Cardiovascular Health Study (CHS) and a population-based study, found no significant difference in ABI-based diagnosis of PAD between men and women. Proposed explanations for differences between ABI versus IC-defined PAD gender differences are that women are more likely to have atypical and late presentations and have intrinsically lower ABI values. 
Racial and socioeconomic disparities also exist. In regards to race, the CHS found African Americans to have an odds ratio of 2.12 for PAD compared to Non-Hispanic whites when adjusting for known risk factors.  The compilation of three studies addressing the impact of race on the risk of PAD found odds ratios of 2.3 to 3.1 African Americans compared to Non-Hispanic whites when adjusting for confounders.  A socioeconomic survey study found patients with lower poverty-income ratios (PIR) to have a nearly 2 fold increase in the risk of PAD compared to higher PIR. Furthermore, the study found a lower educational level to be significantly associated with PAD (OR 2.8, 95% CI 1.96–4.0, p<0.0001). 
Peripheral vascular disease is primarily driven by the progression of atherosclerotic disease leading to macro and microvascular dysfunction. PAD typically affects the lower extremity vascular beds, but larger arteries such as the abdominal aorta and iliac arteries are frequently involved. More severe disease can involve multilevel and/or diffuse disease. The pathophysiology of atherosclerosis is a complex inflammatory response with the involvement of various vascular cells, thrombotic factors, and cholesterol and inflammatory molecules.
Atherosclerosis begins with lipoprotein accumulation within the intimal layer of large arteries. The lipoprotein presence within the endothelium leads to lipid oxidation and cytokine response with the infiltration of lymphocytes and macrophages.  Macrophages consume these oxidized lipids and form foam cells leading to the development of "fatty streaks."  Although not clinically significant, these fatty streaks can eventually develop into more advanced plaques consisting of necrotic lipid cores and smooth muscle cells (SMC). SMC and endothelial cells secrete cytokines and growth factors, leading to migration of SMC to the luminal side of the plaque and extracellular matrix synthesis and eventual formation of a fibrous plaque. Fibrous plaque stability is principally dependent on its composition with more vulnerable plaques consisting of a thinner fibrous cap and more numerous inflammatory cells.
Atherosclerotic plaque builds up slowly over decades within the wall of the vessel. Plaque accumulation results in vascular stenosis and frequent vascular dilation to maximize end-organ perfusion. Once the vessel dilation capacity is maximized, the plaque continues to accumulate, which further compromises the lumen occasionally, leading to critical narrowing of the artery. As narrowing progresses and obstructs the artery, collateral circulatory beds frequently develop to preserve distal perfusion and tissue viability. These collateral circulatory pathways are unable to match the blood supply provided by a healthy vessel completely. IC results when blood flow distal to the occlusion is sufficiently compromised, resulting in fixed oxygen delivery that is unable to match oxygen demand.  The most severe form of PAD is critical limb ischemia, which is defined as limb pain at rest or impending limb loss. 
Acute ischemia may ensue if in-situ vascular thrombosis occurs or a cardioembolic source suddenly occludes the narrowed vessel.  Arterial thrombosis secondary to progressive atherosclerotic disease and thrombosis represents 40% of acute limb ischemia (ALI) cases.  Atherosclerotic fibrous plaque rupture leads to exposure of subendothelial collagen and inflammatory cells, causing platelet adhesion and aggregation with rapid in-situ thrombosis of the vessel. Patients with in-situ vascular thrombosis tend to have improved outcomes compared to embolic causes due to the presence of extensive collateral circulation. Embolic ALI causes represent 30% of ALI cases, with the femoral artery being the most common site.  ALI is a vascular emergency with an immediate physician consultation required for the preservation of limb viability.
- History and Physical
Diagnosis of peripheral vascular disease can be difficult due to the increasing prevalence of similarly presenting comorbid conditions and large numbers of patients having an asymptomatic or atypical presentation.  The clinical presentation of PAD is often dependent on the severity of arterial insufficiency and the presence of comorbid conditions, which may alter or mask the symptoms of underlying vascular disease.
Atypical presentation of PAD occurs when patients have existing comorbidities such as lumbosacral disease, spinal stenosis, or advanced diabetes mellitus - all of which may alter the perception of pain. Atypical pain is characterized by pain unrelated to physical activity, pain that occurs both at rest and exertion, and pain lasting longer than 10 minutes after exercise cessation.  Pseudo claudication refers to neuropathic pain observed in patients with spinal stenosis and can be differentiated from PAD with a thorough history and physical examination. Patients with pseudo claudication tend to have pain characterized by weakness and paresthesias that is irrespective of the degree of physical activity and usually is relieved by sitting down or changing body positioning rather than rest. 
Patients with hemodynamically significant PAD based on ABI testing are more likely to have asymptomatic rather than symptomatic disease. This illustrates the importance of maintaining a high clinical suspicion of underlying PAD for effective secondary prevention. Over 50% of patients with PAD are asymptomatic.  The prevalence of asymptomatic PAD may partly be explained by older individuals misinterpreting their symptoms as normal aging processes. Additionally, patients with mild to moderate PAD may be unable to exercise to a capacity where significant oxygen demand is required. Thus a mismatch between supply and demand does not occur, and patients remain asymptomatic.
Intermittent claudication is the most classic symptom of PAD characterized by an exercise-induced cramping sensation with associated fatigue, weakness, and or pressure. It is not uncommon for patients to deny pain, and therefore asking about discomfort while ambulating is a more useful screening question. Symptoms are exacerbated by leg elevation and relieved by placing the limb in a dependent position. Paresthesias, lower extremity weakness, stiffness, and cool extremities may also be present. Anatomically the level of obstruction is usually seen one level above the area of discomfort; for example, patients with aortoiliac disease will have buttock and thigh symptoms. 70% to 80% of patients have stable intermittent claudication over 10 years; however, a portion of patients may progress through debilitating ischemic rest pain, critical limb ischemia, and eventual amputation.  Critical limb ischemia is manifested by pain at rest, nonhealing wounds or ulcers, and gangrene in one or both legs.
The physical exam begins with a general inspection with attention to fingernail tar indicative of cigarette smoking, scars from previous vascular surgeries, and the presence of amputations. A focused cardiovascular examination begins with a pulse examination to determine rate, rhythm, and strength. Chest auscultation should be performed to evaluate for pulmonary diseases such as chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis and heart sounds or murmurs. Neurological examination is essential to evaluate for pseudo claudication. Examination of the limbs should involve assessment for pulselessness, pallor, muscular atrophy, cool or cyanotic skin, or pain with palpation.  Lower extremity ulcers may be arterial, venous, neuropathic, or a combination of two or more. Ulcers secondary to arterial insufficiency are tender and typically have ragged borders with a dry base and pale or necrotic centers.
The diagnosis of peripheral vascular disease can be sufficiently made based on patient risk factors, clinical presentation, and physical exam findings. Occasionally patients can present with atypical symptoms, and objective data can establish the diagnosis. Assessment begins with accounting for known PAD risk factors, including smoking, diabetes, hypertension, hypercholesterolemia, and obesity. Intermittent claudication must be distinguished from neurological, musculoskeletal, or vascular disorders, which may present similarly to PAD. Physical exam findings of the lower extremities may demonstrate shiny skin with coolness to palpation, reduced or absent pulses, abnormal capillary refill time, pallor with leg elevation, dependent rubor, and auscultation of bruits in major vessels including the femoral and popliteal arteries.  Advanced disease may manifest as nonhealing ulcers or gangrene.
Measurement of the ankle-brachial index (ABI) is a cost-effective noninvasive objective measure for PAD diagnosis. The ABI is obtained by measuring the systolic ankle pressure ratio to the systolic brachial pressure. The test is performed by placing a blood pressure cuff above the level of the ankle and placing a Doppler ultrasonography probe on the dorsalis pedis or posterior tibialis and then inflating the cuff until the signal from the probe ceases. The cuff is then slowly deflated, and the return of the Doppler probe signal marks the systolic ankle pressure. The process is then repeated for the opposite leg. The ankle pressure of each leg is then divided by the highest systolic pressure of either brachial artery. A normal ABI ratio ranges from 0.9 to 1.2, and values less than 0.9 are diagnostic of PAD. Noncompressible vessels, as seen in people with diabetes and those with advanced kidney disease and may have falsely elevated ratios.  Individuals with abnormally high ABI ratios have higher all-cause mortality compared to normal ABI ratios. Further diagnostic evaluation for these patients often warrants a toe-brachial index (TBI), which is the comparison of the toe systolic pressure to the higher systolic brachial pressure.  These particular patients illustrate the vital importance of the clinical history and physical examination in the initial evaluation of patients with suspected PAD.
Duplex ultrasonography is a safe and cost-effective method of determining PAD location, stenosis severity, and length of stenosis or occlusion. 2-dimensional imaging, along with color Doppler, provides an accurate assessment of lesion stenosis, hemodynamic severity, and plaque characteristics. Doppler ultrasonography can be used in routine follow-up post-procedure for surveillance of patency. This diagnostic modality can assist in decision-making when further intervention is contemplated. 
Magnetic resonance angiography (MRA) or computed tomography angiography (CTA) both provide excellent high-quality vascular imaging. The advantages of MRA include the ability to identify small runoff vessels that sometimes may not be seen with digital subtraction angiography (DSA). Compared with DSA, MRA has 90% sensitivity and 97% specificity in identifying hemodynamically significant lesions.  CTA has similar diagnostic accuracy to MRA with both imaging techniques useful for determining candidacy for bypass surgery versus angioplasty.
- Treatment / Management
Patients diagnosed with the peripheral vascular disease require a reasoned approach to account for age, risk factors, disease severity, and functional status. Management is divided into two broad categories aimed at decreasing cardiovascular events and improving symptoms. Persons with PAD are at increased risk of coronary artery disease mortality (relative risk = 6.6), cardiovascular mortality (relative risk = 5.9), and all-cause mortality (relative risk = 3.1).  Therefore PAD management begins with lifestyle modification to prevent disease progression with the addition of medical and interventional therapy required for improved symptomatic control and cardiovascular event risk reduction.
Cardiovascular Risk Factor Modification
Aggressive risk factors modification is essential to lowering cardiovascular risk. Smoking cessation reduces the risk of PAD progression, cardiovascular events including myocardial infarction and stroke, and critical limb ischemia.  Patient education, along with the use of behavioral therapy, nicotine replacement therapy, or pharmacological therapy, can be used to reduce smoking and improve cardiovascular outcomes. Statin therapy has been effectively shown to reduce cardiovascular events, all-cause mortality, and reduce the need for revascularization and should be routinely used in patients with PAD. Hypertension management with blood pressure reduction to less than 140/90 in nondiabetic and 130/80 in diabetic patients has been shown to improve outcomes.  Diabetes is a risk factor for symptomatic and asymptomatic PAD by 1.5 to 4 fold, respectively, and a hemoglobin A1c target of less than 7% should be achieved with less stringent goals for individuals with extensive comorbidities. 
Randomized trials have shown supervised exercise therapy programs to have significant improvement in claudication symptoms. A meta-analysis of 27 studies found exercise significantly improved pain-free walking distance by 269 feet and total walking distance by nearly 400 feet.  Exercise programs typically consist of 30- to 45-minute length sessions conducted 4 to 5 times a week over the course of 12 weeks. A meta-analysis of five trials found no improvement in mortality with exercise therapy programs. 
Pharmacological therapy for intermittent claudication (IC) management can be offered to patients who have not benefited from exercise therapy and risk factor modification.  Two medications approved for IC treatment include cilostazol and naftidrofuryl. Cilostazol inhibits phosphodiesterase type 3 and has demonstrated antiplatelet effect, vasodilatory properties, and inhibition of smooth muscle cell proliferation.  A meta-analysis of over 2000 patients found individuals on cilostazol had significantly longer pain-free and total walking distances.  Naftidrofuryl is a 5-hydroxytryptamine-2-receptor antagonist that inhibits glucose uptake and increases adenosine triphosphate levels. It has fewer side effects than cilostazol and should be considered where available. 
Daily aspirin is recommended for overall cardiovascular care. No consensus has been reached on the most effective dose.
Patients who have debilitating symptoms unresponsive to risk factor modification and exercise and pharmacological therapy may be candidates for endovascular, surgical, or combined endovascular and surgical intervention. Indications for intervention include individuals with incapacitating claudication interfering with daily activity and limb salvage in patients with critical limb ischemia manifested by ischemic pain at rest, ulceration, and gangrene. The decision on surgical versus percutaneous intervention is dependent on many factors, including the patient's functional status and surgical risk, skills of the operator, anatomic location and extent of disease, presence of multifocal vascular lesions, and patient preference.  An interprofessional team approach involving an internist, interventionalist, and vascular surgeon should be undertaken for personalized patient care to improve outcomes and patient satisfaction.
- Differential Diagnosis
A provider has to take into account various differential diagnoses when a patient presents with the above-mentioned signs and symptoms. Following are some of the most important ones:
- Nerve root compression
- Spinal stenosis
- Peripheral neuropathy
- Nerve entrapment
- Medial tibial stress syndrome
- Muscle strain
- Chronic venous insufficiency
- Deep venous thrombosis
- Raynaud phenomenon
- Thromboangiitis obliterans
The overall prognosis of patients with the peripheral vascular disease must take into account patient risk factors, cardiovascular health, and disease severity. In terms of limb health at 5 years, nearly 80% of patients will have stable claudication symptoms. Only 1% to 2% of patients will progress to critical limb ischemia in 5 years. 20% to 30% of patients with PAD will die within 5 years, with 75% of those deaths attributed to cardiovascular causes. 
Peripheral vascular disease can affect several systems in the body leading to a number of complications as listed below:
- Acute coronary syndrome
- Nonhealing ulcer
- Deep vein thrombosis
- Erectile dysfunction
- Vascular surgery
- Interventional cardiology
- Internal medicine
- Deterrence and Patient Education
Patient management for the desired outcomes is based on a holistic approach that includes non-pharmacological lifestyle modification and pharmacological management, such as:
- Smoking cessation
- Ambulatory blood pressure monitoring
- Medication and exercise therapy compliance
- Cholesterol management through diet and statin therapy
- Weight reduction
- HbA1c goal of less than 7% (or more for significant comorbid conditions or hypoglycemia)
- Regular follow up with an interprofessional team
- Enhancing Healthcare Team Outcomes
Peripheral arterial disease is a progressive systemic disease with poor long-term outcomes. Although symptoms of claudication remain stable for many years, these patients are at high risk of fatal and nonfatal cardiovascular events. Interprofessional coordination is necessary for identifying patients at risk of disease, preventing secondary progression, and presenting patients with various options for their disease. Primary care providers are essential for patient education regarding risk factors for cardiovascular disease and management of tobacco abuse, hypercholesterolemia, hypertension, and diabetes mellitus. Cardiologists should be involved, given nearly 75% of patients with PAD die from cardiovascular events. Vascular surgeons and endovascular specialists' input provides patients with various options for refractory disease. Vascular medicine specialists and podiatrists are very frequently vital members of the interprofessional team. Nurses are valuable for their familiarity with the patient and updates on how the patient's condition has progressed. Pharmacists are needed for patient and physician education on potential medication side effects and drug-to-drug interactions.
Current guidelines by the American College of Cardiology recommend patients with symptoms of IC undergo ABI testing (Level II). Patients diagnosed with PAD and unresponsive to exercise therapy should receive cilostazol for symptomatic improvement and increased walking distance. [Level I] Endovascular procedures are recommended in patients who have not responded to exercise and pharmacological therapy and who have debilitating symptoms.  [Level 1]
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Peripheral Arterial Disease (PAD)
Peripheral arterial disease (PAD) in the legs or lower extremities is the narrowing or blockage of the vessels that carry blood from the heart to the legs. It is primarily caused by the buildup of fatty plaque in the arteries, which is called atherosclerosis. PAD can happen in any blood vessel, but it is more common in the legs than the arms.
How can I prevent PAD?
- Get plenty of physical activity to help prevent PAD or improve symptoms of PAD. 2
- Do not use tobacco. Smoking increases the risk of PAD and makes PAD symptoms worse. 4
- Control high blood pressure and manage high blood cholesterol and diabetes.
If you have PAD, participating in supervised exercise training programs can improve and prolong your ability to walk longer distances.
How is PAD diagnosed?
If you have symptoms of PAD, your doctor may do an ankle brachial index (ABI), which is a noninvasive test that measures the blood pressure in the ankles and compares it with the blood pressure in the arms at rest and after exercise. Your doctor may also do imaging tests such as ultrasound, magnetic resonance angiography (MRA), and computed tomographic (CT) angiography. 1–3
How is PAD treated?
- Your doctor may recommend that you take aspirin or other similar antiplatelet medicines to prevent serious complications from PAD and associated atherosclerosis. You may also need to take medicine to reduce your blood cholesterol. 2,4
- If you smoke, quit. Talk with your doctor about ways to help you quit smoking.
- You may need surgery to bypass blocked arteries.
- A supervised exercise program is recommended for people with pain caused by too little blood flow to muscles to improve functional status, quality of life, and reduce leg symptoms. 5
- Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, et al. Heart disease and stroke statistics—2021 update: a report from the American Heart Association . Circulation. 2021;143:e254–e743.
- Creager MA, Loscalzo J. Chapter 275: Arterial Diseases of the Extremities. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 20e . McGraw-Hill; Accessed August 28, 2020.
- Cohoon KP, Wennberg PW, Rooke TW. CHAPTER 96: DIAGNOSIS AND MANAGEMENT OF DISEASES OF THE PERIPHERAL ARTERIES. In: Fuster V, Harrington RA, Narula J, Eapen ZJ. eds. Hurst’s The Heart. 14e . McGraw-Hill; Accessed August 28, 2020.
- Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in 2017 Mar 21;135(12 ):e790]. Circulation. 2017;135(12):e686-e725.
- Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines . J Am Coll Cardiol . 2016 Nov 8. pii: S0735-1097(16)36902-9.
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- Open Access
- Published: 10 January 2023
Inadequate response to antiplatelet therapy in patients with peripheral artery disease: a prospective cohort study
- B. M. M. Kremers 1 ,
- J. H. C. Daemen 2 ,
- H. ten Cate 1 , 3 , 4 , 5 ,
- H. M. H. Spronk 1 ,
- B. M. E. Mees 2 &
- A. J. ten Cate-Hoek 1 , 3
Thrombosis Journal volume 21 , Article number: 5 ( 2023 ) Cite this article
Patients with peripheral artery disease (PAD) are treated with preventive strategies to improve the cardiovascular risk. The incidence of cardiovascular events and mortality however remains high in PAD populations. We therefore aimed to better characterize PAD patients suffering from cardiovascular events and mortality in order to tailor preventive treatment.
Between 2018 and 2020, 246 PAD outpatients (17 newly diagnosed, 229 with known PAD) were prospectively enrolled in this observational cohort study. Patient data and blood samples were collected after inclusion, and the primary composite endpoint (myocardial infarction, elective coronary revascularization, ischemic stroke, acute limb ischemia, mortality) was evaluated after one year. Secondary outcomes included platelet reactivity, measured using the VerifyNow assay, and medication adherence, assessed using the Morisky Medication Adherence Scale-8 (MMAS-8). Logistic regression models were used to identify associations between characteristics and the occurrence of events.
The cohort comprised 207 patients with claudication and 39 with chronic limb threatening ischemia. Twenty-six (10.6%) patients suffered from an event during follow-up. Prior myocardial infarction (OR 3.3 [1.4–7.7]), prior ischemic stroke (OR 4.5 [1.8–10.9]), higher levels of creatinine (OR 5.2 [2.2–12.6]), lower levels of high-density lipoprotein (OR 4.2 [1.5–10.6]) and lower haemoglobin levels (OR 3.1 [1.3–7.1]) were associated with events. Patients with events had more often high on-treatment platelet reactivity (HTPR) on aspirin (OR 5.9 [1.4–25.1]) or clopidogrel (OR 4.3 [1–19.3]). High adherence to medication was associated with the occurrence of events (OR 4.1 [1–18]).
Patients suffering from cardiovascular events and mortality were characterized by prior cardiovascular events as compared to patients who did not experience any events. Antiplatelet therapy was not optimally protective despite high medication adherence, and HTPR was independently associated with the occurrence of events. More research is needed on alternative treatment strategies such as dual antiplatelet therapy or combinations with anticoagulant drugs.
The Medical Ethics Committee (METC) of the MUMC+ approved the study (NL63235.068.17) and the study was registered in the Netherlands Trial Register ( NTR7250 ).
Peripheral artery disease (PAD) is a vascular disease characterized by atherosclerosis-driven narrowing of peripheral arteries. The prevalence of PAD worldwide in individuals aged twenty-five years and older was estimated at 236 million in 2015 [ 1 ]. Despite its high prevalence, PAD remains underdiagnosed as many patients are asymptomatic and thus not aware of the disease [ 2 ]. However, both asymptomatic and symptomatic PAD patients are at risk of atherothrombotic events such as myocardial infarction and ischemic stroke with incidences of 15% over a period of three years [ 3 , 4 ]. Within the symptomatic patient population, intermittent claudication, a mild manifestation of PAD, can be distinguished from the more severe chronic limb threatening ischemia. Intermittent claudication is classified as Fontaine II with typical symptoms of muscle pain during walking. Chronic limb threatening ischemia is classified as Fontaine III with rest pain and Fontaine IV with ischemic ulcer formation [ 5 , 6 ]. PAD patients with chronic limb threatening ischemia are at a higher risk of adverse cardiovascular events with high mortality rates as compared to patients with intermittent claudication [ 4 ]. Current preventive strategies for cardiovascular events and mortality in PAD patients are based on risk management in which lipid-lowering drugs, antihypertensive drugs and antiplatelet drugs are the main treatment modalities. Statins are most widely used to improve the lipid profile targeted at a low-density lipoprotein (LDL) value of 1.8 mmol/L for PAD patients of 70 years or younger and a value of 2.5 mmol/L for PAD patients above 70 years [ 7 ]. By effectively lowering LDL levels, the incidence of cardiovascular events can be reduced significantly [ 8 ]. Addition of antihypertensive drugs to overcome hypertension as well as the use of antiplatelet drugs to effectively inhibit platelet activation reduces the incidence of cardiovascular events even further. Aspirin and clopidogrel are the antiplatelet drugs most often used as first-line treatment depending on national guidelines [ 5 ]. Although the CAPRIE-study demonstrated that clopidogrel was more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction, and cardiovascular death, this is no preferential treatment strategy [ 9 ]. Despite the established efficacy of antiplatelet regimes with regard to the reduction of cardiovascular events, high on-treatment platelet reactivity (HTPR) for both aspirin and clopidogrel may still occur and interfere with atheroprotective effects. HTPR is referred to as the failure of the antiplatelet agent to inhibit the target of its action [ 10 , 11 ]. Aspirin HTPR prevalence is estimated at 17–26% in PAD populations [ 12 , 13 , 14 ] while clopidogrel HTPR appears to be more common with a prevalence up to 54% [ 12 , 14 , 15 , 16 ]. The incidence of cardiovascular events in PAD populations remains high despite current treatment strategies [ 3 ]. Therefore, the aim of this observational cohort study was to better characterize PAD patients at risk of cardiovascular events and mortality in order to find targets for improved management.
Between May 2018 and May 2020, patients visiting the outpatient clinic of the department of Vascular Surgery of the Maastricht University Medical Center (MUMC+) were screened for PAD. Patients were eligible to participate in the study when the PAD was objectively diagnosed with an ankle-brachial index (ABI) of 0.9 or below. Fontaine II (intermittent claudication) and Fontaine III (chronic limb threatening ischemia) patients were selected and patients with Fontaine IV were excluded because of expected increased inflammatory parameters associated with ulcer formation. Further exclusion criteria were active malignancy, chronic inflammatory disease, coagulation disorders, pregnancy, age below 18, and the use of anticoagulant therapy. All eligible patients that were willing to participate were included after written informed consent was obtained. The Medical Ethics Committee (METC) of the MUMC+ approved the study (NL63235.068.17) and the study was registered in the Netherlands Trial Register (NTR7250; https://www.trialregister.nl/trial/7045 ).
Blood collection and sample storage
Venous blood was drawn from the patients immediately after informed consent was signed. Blood drawing took place in a resting state and blood was collected by antecubital venipuncture with 21-gauge needles and 3.2% (w/v) citrated Vacutainer glass tubes, EDTA Vacutainer glass tubes and VACUETTE 9NC Coagulation 3.2% (w/v) Sodium Nitrate glass tubes. After blood drawing, the EDTA tubes and the citrate tubes were directly processed using the standard platelet-poor plasma centrifugation protocol used at our laboratory (4000 x g for 5 minutes followed by 11,000 x g for 10 minutes). Thereafter samples were, within two hours after blood drawing, frozen and stored at − 80° Celsius for further analysis. The VACUETTE 9NC tubes were immediately used to perform the VerifyNow assays for aspirin and clopidogrel.
Data collection and measurements
Age, sex and date of PAD diagnosis of each patient were registered upon inclusion. The medical history of each patient including prior cardiovascular events such as myocardial infarction, ischemic stroke and PAD revascularization was collected from patient records. Each patient provided an updated medication list from which the use of lipid-lowering drugs, antihypertensive drugs and antiplatelet drugs were collected. The intensity of lipid-lowering strategies was categorized as high, medium and low intensity according to the ACC/AHA guideline [ 17 ]. Current smoking status, diabetes mellitus type 2 (DM2) and body mass index (BMI) were recorded. Patients were classified based on their symptoms upon inclusion using the Fontaine classification, and were then grouped as having intermittent claudication (Fontaine II) or chronic limb threatening ischemia (Fontaine III). The ABI at the time of diagnosis was measured and grouped by ratio as greater than 1.3 (incompressible), between 0.91 and 1.3, between 0.7 and 0.9, between 0.4 and 0.69 and below 0.4.
A complete blood cell count was performed at baseline and included levels of haemoglobin, haematocrit, thrombocytes and leukocytes with respective subpopulations. Platelet reactivity was assessed using the VerifyNow Aspi assay for Aspirin and VerifyNow P2Y12 assay for Clopidogrel (Accumetrics, San Diego, CA, USA). Blood collected in the VACUETTE 9NC tube was used in the optical detection system using a specific cartridge. The cut-off value for aspirin and clopidogrel HTPR was based on the most recent consensus document on the definition of on-treatment platelet reactivity, and was set at Aspirin Reaction Units (ARU) > 550 for aspirin [ 18 ] and P2Y12 Reaction Units (PRU) > 208 for clopidogrel [ 11 ]. Laboratory results that were collected from recent blood drawing included kidney function (creatinine, estimated glomerular filtration rate-Chronic Kidney Disease Epidemiology Collaboration (eGFR (CKD-EPI))), lipid profile (cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides) and haemoglobin A1c levels (HbA1c). The KDIGO guideline was used to classify the kidney function, and the stage of chronic kidney disease in each patient when appropriate [ 19 ].
Medication adherence was assessed by the licensed Morisky Medication Adherence Scale-8 (MMAS-8), which was developed by Morisky et al. The MMAS-8 is a validated assessment tool verified by numerous studies, consisting of eight questions to assess medication adherence [ 20 , 21 , 22 ]. Patients that were completely adherent scored a maximum score of 8, whereas the lowest possible adherence was scored 0. Each point decrease marked lower adherence to the medical treatment. According to MMAS-8 user guidelines the adherence was categorized as high (8 points), medium (7 or 6 points) and low (5 points or below).
The primary outcome consisted of a composite endpoint comprising myocardial infarction, ischemic stroke, acute limb ischemia, elective percutaneous intervention (PCI) or coronary artery bypass grafting (CABG) and all-cause mortality during the one-year follow-up. The outcome was assessed at 3, 6 and 12 months and was verified by telephone calls to the patient combined with hospital records. Patients who reached the composite endpoint were grouped as the “PAD event group” while patients who did not reach the composite endpoint were grouped as the “PAD no event group”. The secondary outcomes were platelet reactivity, HTPR and medication adherence.
Baseline characteristics were collected for all patients and presented for patients with and without events during follow-up. Differences between both groups were analyzed using the chi-square test for dichotomous and categorical variables. For continuous variables, differences were analyzed using the parametric two-samples t-test or the non-parametric Mann-Whitney U test, as appropriate. Youden’s index was used, when appropriate, to determine optimal cut-off values for continuous variables. Univariable logistic regression models were used to test the associations of characteristics with the occurrence of events, reported as odds ratios with respective 95% confidence intervals (OR [95% CI]). Characteristics with an association with the occurrence of events ( p < 0.05) in the univariable analysis were then used in multivariable models with backward stepwise logistic regression analysis for the occurrence of events, reported as odds ratios with respective 95% confidence intervals. Statistical significance was reached when p < 0.05. All analyses were performed using SPSS (IBM SPSS Statistics for Macintosh, Version 27.0. Armonk, NY: IBM Corp). All figures were created using GraphPad Prism (GraphPad Prism version 9 for Mac OS X, GraphPad Software, San Diego, California USA, www.graphpad.com ).
The cohort comprised 246 patients and baseline characteristics of the entire cohort as well as the distribution of patients with and without events are shown in Table 1 . All patients had been diagnosed with PAD at a median of 33 (8–101) months prior to inclusion, while in 17 (6.9%) patients the diagnosis was established at the time of inclusion. Upon inclusion, most patients had intermittent claudication (207 (84.1%)) and 39 (15.9%) had chronic limb threatening ischemia. The cohort consisted of 141 (57.3%) male patients and the mean age was 68.7 ± 9.2 years. Most patients (109 (44.3%)) had an ABI between 0.7 and 0.9, while 99 (40.2%) and 21 (8.5%) patients had an ABI between 0.4 and 0.69 or below 0.4, respectively. The remaining 17 (6.9%) patients had incompressible arteries. Patient history revealed that 151 (61.4%) patients had previously undergone a peripheral revascularization procedure. Moreover, 72 (29.3%) patients had a prior myocardial infarction and 37 (15%) had a prior ischemic stroke. DM2 was present in 67 (27.2%) patients and the mean BMI was 26.4 ± 4.41 kg/m 2 . Of all patients, 229 (93.1%) had a history of smoking and 94 (38.2%) were current smokers with a median of 29 (15–40) pack years upon inclusion. A normal kidney function (G1) was observed in 41 (16.7%) patients, a mildly decreased kidney function (G2) in 138 (56.1%) patients, a mildly to moderately decreased kidney function (G3a) in 41 (16.7%) patients, a moderately to severe decreased kidney function (G3b) in 19 (7.7%) patients, a severely decreased kidney function (G4) in 6 (2.3%) patients and kidney failure (G5) in 1 (0.4%) patient.
All patients were followed for one year in which 26 (10.6%) patients reached the composite endpoint. Ten (38.5%) myocardial infarctions, four (15.4%) elective coronary revascularizations, five (19.2%) ischemic strokes and seven (26.9%) deaths were recorded. No differences were observed between patients with and without events regarding smoking status, DM2 and BMI. Both prior myocardial infarction (OR 3.3 [1.4–7.7]) and prior ischemic stroke (OR 4.5 [1.8–10.9]) were associated with the occurrence of events (Fig. 1 ). Also, decreased kidney function (plasma creatinine level > 111 μmol/L, OR 5.2 [2.2–12.6]) and plasma haemoglobin levels < 8.1 mmol/L (OR 3.1 [1.3–7.1]) were associated with the occurrence of events. Leukocyte and thrombocyte count were not associated .
Univariable logistic regression analysis of characteristics associated with the occurrence of cardiovascular events and mortality, with corresponding odds ratios and 95% confidence intervals. HTPR = high on-treatment platelet reactivity, HDL = high-density lipoprotein, SD = standard deviation, IQR = interquartile range
Evaluation of medication strategies
All patients were treated according to current guidelines [ 5 ] which included the use of antihypertensive drugs, lipid-lowering drugs and antiplatelet drugs. The prescription of antihypertensive drugs (73.1% vs 72.7%, p = 0.834), lipid-lowering drugs (88.5% vs 90%, p = 0.396) and antiplatelet drugs (100% vs 100%, p = 1.000) did not differ between patients with and without events. Lipid-lowering strategies were prescribed in different intensities. A total of 71 (32.6%) patients were on high intensity lipid-lowering therapy without differences between patients with and without events (31.8% vs 32.7%, p = 0.937). Moderate and low intensity therapy had been applied in 138 (63.3%) and 9 (4.1%) patients, but also in these groups no differences were observed between patients with and without events (63.6% vs 63.3%, p = 0.973 and 4.5% vs 4.1%, p = 0.917 respectively). The effectiveness of the lipid-lowering therapies was assessed using the cholesterol profile, showing similar mean LDL levels of 2.44 ± 1.07 mmol/L between patients with events and those without (2.31 ± 1.14 mmol/L vs 2.45 ± 1.06 mmol/L, p = 0.542). In 58.5% of patients above 70 years old the LDL target level of 2.5 mmol/L was reached (2.49 ± 1.18 mmol/L), while the target level of 1.8 mmol/L was not reached in 95 (72%) patients 70 years or younger (2.39 ± 0.97 mmol/L). HDL levels were significantly lower in patients who experienced an event during follow-up (OR 4.2 [1.5–10.6]). The use of antiplatelet agents was evenly distributed in the cohort with 130 (52.8%) patients on aspirin, 127 (51.6%) on clopidogrel. Additionally, 11 (4.5%) patients were on dual antiplatelet therapy. During the conduct of this study, there was a transitioning of aspirin to clopidogrel as first choice antiplatelet agent in the hospital where patients were recruited. Therefore, some patients were using aspirin upon inclusion, while others were using clopidogrel. The median ARU on aspirin was 435 (402–482) and 12 (8.5%) patients had HTPR. The ARU in patients with events during follow-up was significantly higher compared to those without events (521 (452–554) vs 428 (401–478), p = 0.011) and HTPR was associated with the occurrence of events (OR 5.9 [1.4–25.1]). PRU in patients on clopidogrel were 100 (46–155) for the whole cohort and significantly higher in patients with events (144 (102–190) vs 96 (43–144), p = 0.019) (Fig. 2 ). HTPR on clopidogrel was observed in 8 (5.8%) patients and was associated with events (OR 4.3 [1–19.3]) . In the multivariable analysis the adjusted OR for antiplatelet therapy was 5.2 [1.5–18.5] (Fig. 3 ).
Platelet reactivity measured by the use of the VerifyNow assay in Aspirin Reactions Units (ARU) for aspirin users and P2Y12 Reaction Units (PRU) for clopidogrel users. Dotted lines represent HTPR which is an ARU > 550 for aspirin and a PRU > 208 for clopidogrel
Multivariable logistic regression of characteristics associated with the occurrence of cardiovascular events and mortality, with corresponding odds ratios and 95% confidence intervals. HTPR = high on-treatment platelet reactivity, HDL = high-density lipoprotein, SD = standard deviation, IQR = interquartile range
High medication adherence was observed in 188 (76.4%) patients and was positively associated with the occurrence of events (OR 4.1 [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]). Medium adherence was observed in 46 (18.7%) patients and low adherence in 12 (4.9%) patients, both were not associated with the occurrence of events.
In this prospective observational cohort study, we characterized PAD patients with enhanced risk for cardiovascular events and mortality with the aim to find targets for improved management. Most patients in our cohort had prevalent PAD with a chronic state of atherosclerosis with years of plaque build-up and involvement of multiple vascular beds with associated decrease in renal function in conjunction with lower haemoglobin levels. Patients with such polyvascular disease are at increased risk for cardiovascular events with worsening prognosis when more vascular beds are affected [ 23 ]. In almost half of the patients in the cohort this polyvascular diseased state was present.
All patients in our cohort were treated with lipid-lowering agents, antiplatelet therapy and antihypertensive drugs. Interestingly, the medication prescribed did not appear to be sufficiently protective for PAD patients experiencing cardiovascular events and mortality, despite adequate adherence to the medication. Suboptimal target LDL levels were observed. The intensity of the lipid-lowering strategies prescribed was medium to high according to the ACC/AHA guidelines [ 7 ]. The LDL target level of 2.5 mmol/L was indeed reached in more than half of all patients older than 70 years. On the other hand, average LDL levels in patients of 70 years or younger were similar to the older patient group, while in these patients LDL levels of 1.8 mmol/L or lower are recommended. Especially in these younger patients the lipid-lowering regimen should ideally be intensified, which will likely result in a reduced incidence of cardiovascular events as the association between increased LDL levels and cardiovascular risk is well established [ 24 ]. Potentially, LDL target values of 1.8 and 2.5 mmol/L could even be lowered further as a recent study showed that lower concentrations of LDL may even better prevent cardiovascular events [ 25 ]. Also lower HDL levels were seen in patients that suffered from an event during follow-up, which indirectly supports the known atheroprotective effects of HDL including counteracting inflammation [ 26 ] and oxidative stress [ 27 ]. Several studies have found an association between lower HDL levels and cardiovascular risk in patients with coronary artery disease [ 28 , 29 ] and low concentrations of HDL as one of the strongest lipoprotein risk factors for PAD [ 30 , 31 ].
The VerifyNow assay was used to measure platelet reactivity while on aspirin or clopidogrel (or both). The residual platelet reactivity in patients on aspirin or on clopidogrel was significantly higher in patients experiencing events, indicating that platelets are less efficiently inhibited. Lack of medication adherence could have caused residual platelet reactivity. However, this did not seem to be the case as the results of the adherence score revealed that highly adherent patients were in the majority in the event group, which could be the result of increased awareness in this patient group as these patients more often experienced prior myocardial infarctions and ischemic strokes. Therefore, assuming that the adherence assessment is reliable, the current antithrombotic regime appears to be insufficient for adequate cardiovascular protection in these high-risk patients. Published studies show conflicting results regarding the association of HTPR with cardiovascular outcome. Two studies investigating clopidogrel HTPR found a significant association with cardiovascular events while two other studies did not [ 12 , 14 , 15 , 16 ]. These studies used the same cut-off values for HTPR and follow-up duration was also similar. The contradicting results may however be explained by the lack of power. One study found a non-significant trend between clopidogrel HTPR and cardiovascular events [ 12 ], while the other study found a non-significantly increased hazard ratio in patients with HTPR [ 14 ]. In all four studies the prevalence of clopidogrel HTPR was higher as compared to the HTPR prevalence in our study, which could be explained by differences in medication adherence. We were not able to confirm this as other studies did not report on adherence. The strength of the risk association of HTPR that we found for both aspirin and clopidogrel suggests that optimization of antiplatelet therapy is an important management target for improvement. For aspirin, there is no known mechanism for biochemical resistance, but high platelet turnover could be a reason for residual platelet hyperreactivity [ 32 ]. In patients taking clopidogrel the HTPR could be explained by genetic polymorphisms in platelet receptor P2Y12 [ 33 , 34 ] or polymorphisms of the CYP2C9 and CYP2C19 genes [ 35 , 36 ]. Recent studies in patients with coronary artery disease investigated pharmacogenomics based on CYP2C19 gene variations to optimize therapy [ 37 , 38 ]. Moreover, a meta-analysis concluded that the use of ticagrelor or prasugrel appeared more effective than clopidogrel in reducing the cardiovascular risk in patients with CYP2C19 gene variants [ 39 ]. Similar studies have yet to be performed in patients with PAD. The association between P2Y12 polymorphisms and the risk for cerebrovascular events in PAD patients has been established in the past [ 40 ]. Indeed, recent studies suggest that a twice-daily dosing of aspirin could improve its pharmacological efficacy. In patients with essential thrombocythemia a once-daily dose of aspirin as antithrombotic regime appeared inadequate in reducing platelet activation, while a dosing interval of 12 hours increased the antiplatelet response to aspirin [ 41 , 42 ]. For clopidogrel, studies with increased dosing to compensate for the low inhibitory efficacy have been performed in the past [ 43 ], assuming “resistance” to be in part explained by too low concentrations of active clopidogrel at the platelet surface [ 44 , 45 ]. However, apart from the use of loading doses in patients undergoing percutaneous coronary interventions, such regimens were never introduced in clinical practice in patients with PAD [ 46 ]. Dual antiplatelet therapy (DAPT) has been studied in the large CHARISMA trial [ 47 ]. Except for exceptionally thrombogenic conditions DAPT has not been introduced for long-term treatment of patients with PAD because of increased bleeding risk as compared to single antiplatelet therapy. Guidelines only recommend DAPT for a short period of time following percutaneous interventions and stenting in PAD. Several studies demonstrated that fibrinogen [ 48 , 49 ] and d-dimer [ 50 ] levels were increased in high-risk PAD patients indicating an underlying hypercoagulable state. Anticoagulant treatment may counteract this prothrombotic state in PAD patients which is characterized by increased clot formation [ 51 ]. The COMPASS-trial has shown that dual pathway inhibition with aspirin and a low dose rivaroxaban reduced the incidence of cardiovascular events in high-risk PAD patients [ 52 ], suggesting that a reasonably low level of anticoagulation on top of antiplatelet therapy provides additional benefit. In spite of its demonstrated cost-effectiveness in at least a subset of PAD patients [ 53 ], the use of dual pathway inhibition in practice is still hindered by low uptake due to concerns about the number of pills per day in combination with an increased risk of major bleeding, even though fatal or critical organ bleeding events remained limited [ 52 ].
The use of the VerifyNow assay to identify HTPR may be perceived as a possible limitation of this study. Several studies have however shown that this assay correlates well with the “gold standard” of light transmission aggregometry for both aspirin [ 54 ] and clopidogrel [ 55 ]. The recorded rates of HTPR within our study population were lower than rates reported by most other studies [ 12 , 14 , 15 , 16 ], this can however be explained by the overall high medication adherence rate that we recorded. The positive association that was found between high medication adherence and higher risk for cardiovascular events in the multivariable analysis may be confounded as this risk is likely to be primarily attributed to the higher rate of comorbidities and prior cardiovascular events leading to the increased motivation to be adherent to medication in these patients. Finally, due to sample size limitations, there is a lack of precision surrounding the estimates which demonstrates that there is still uncertainty about the actual effect size and that further information is needed.
In our single-center cohort of PAD patients, current treatment strategies appeared to be insufficient for the reduction of cardiovascular risk. Lipid-lowering strategies should be intensified to further reduce LDL levels and improve the lipid profile. Antiplatelet agents were found to be inadequate despite high medication adherence, as platelet reactivity was insufficiently decreased in patients experiencing cardiovascular events. More research is needed on alternative treatment strategies such as dual antiplatelet therapy or combinations with anticoagulant drugs.
Availability of data and materials
Data will be available upon reasonable request by B. Kremers.
Aspirin reaction units
Body mass index
Coronary artery bypass grafting
Diabetes mellitus type 2
Estimated glomerular filtration rate-Chronic Kidney Disease Epidemiology Collaboration
- High on-treatment platelet reactivity
Medical Ethics Committee
Morisky Medication Adherence Scale-8
Maastricht University Medical Center
P2Y12 reaction units
- Peripheral artery disease
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We thank Marieke Pavlicic for blood drawing and inclusion of patients. We also thank Stella Schreurs and the vascular surgery residents of the MUMC+ for the recruitment of patients.
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Department of Biochemistry, Laboratory for Clinical Thrombosis and Hemostasis, Maastricht University, Maastricht, The Netherlands
B. M. M. Kremers, H. ten Cate, H. M. H. Spronk & A. J. ten Cate-Hoek
Department of Vascular Surgery, Maastricht University Medical Center, Maastricht, The Netherlands
J. H. C. Daemen & B. M. E. Mees
Thrombosis Expertise Center, Maastricht University Medical Center, Maastricht, The Netherlands
H. ten Cate & A. J. ten Cate-Hoek
Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
H. ten Cate
Center for Thrombosis and Hemostasis, Gutenberg University Medical Center, Mainz, Germany
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BK, JD, HC, HS, BM, AtC-H contributed to the conception and design of the study. JD and BM included patients. BK acquired data and BK and AtC-H analyzed and interpreted the data. BK drafted the manuscript, JD, HC, HS, BM and AtC-H performed critical revision of the manuscript. All authors read and approved the final manuscript.
Correspondence to B. M. M. Kremers .
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Kremers, B.M.M., Daemen, J.H.C., ten Cate, H. et al. Inadequate response to antiplatelet therapy in patients with peripheral artery disease: a prospective cohort study. Thrombosis J 21 , 5 (2023). https://doi.org/10.1186/s12959-022-00445-4
Received : 07 March 2022
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Published : 10 January 2023
DOI : https://doi.org/10.1186/s12959-022-00445-4
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Peripheral artery disease (PAD) affects 15%-20% of persons older than 70 years of age, 1-3 though its prevalence is probably even greater if we include asymptomatic persons. The diagnostic test most used to check the asymptomatic population is the ankle-brachial index (ABI). In asymptomatic persons, an ABI 95% and a specificity approaching 100% as compared with arteriography. 4 Comparison of patients with PAD versus age-matched controls shows an incidence of cardiovascular death of 0.5% in controls and 2.5% in the patients with PAD. Additionally, in persons with known coronary artery disease, the presence of PAD raises the risk of death by 25% in comparison with controls. It is thus important to examine for PAD, even in asymptomatic patients, in order to control the risk factors as soon as possible and reduce mortality. 4
CARDIOVASCULAR RISK FACTORS AND PERIPHERAL ARTERY DISEASE
The major risk factors for PAD have been determined from large epidemiologic studies and are concordant with the risk factors for cerebrovascular disease and ischemic heart disease. Studies have confirmed that the most important risk factors (diabetes, hypertension, smoking, and hyperlipidemia) are involved in 80%-90% of cardiovascular diseases. 5,6
The prevalence of PAD, both symptomatic and asymptomatic, is greater in men than in women, especially in young persons. At very advanced ages almost no differences exist between the sexes. Moreover, the prevalence in men is greater for the more severe degrees of involvement (critical ischemia).
Age is the main marker of PAD risk. The estimated prevalence of intermittent claudication in persons aged 60-65 years is 35%. However, the prevalence in persons 10 years older (70-75 years) rises to 70%.
Some studies 4 have found a stronger association between tobacco abuse and PAD than between tobacco abuse and ischemic heart disease. Moreover, the heavier smokers not only have a greater risk for PAD, they also have the more severe forms that cause critical ischemia. 7-9 The cessation of smoking is accompanied by a reduction in the risk for PAD 10 and, although the risk for PAD in ex-smokers is 7 times greater than in non-smokers, the risk in active smokers is 16 times greater. 11 Additionally, the permeability of both venous coronary bypass and prosthetic grafts is reduced in patients who smoke. The rates of amputations and mortality are also greater in smokers. 7
Diabetes is not only a qualitative risk factor, it is also a quantitative risk factor as each 1% increase in glycosylated hemoglobin is associated with a 25% increase in the risk for PAD. 12 The involvement of distal vessels in the extremities is typical and, together with microangiopathy and neuropathy, which imply a poor response to infection and a specific healing disorder, diabetes is associated with a risk of amputation 10 fold that of non-diabetic patients. Of importance is the fact that diabetic patients may have abnormally high pressure values in the ankle and, consequently, have a false negative evaluation of the ABI.
The importance of hypertension as a risk factor is less than that of diabetes or smoking. Nevertheless, the risk for PAD is considered to be double in patients with hypertension as compared with controls.
Various epidemiologic studies have shown that raised levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) and reduced levels of high-density lipoprotein cholesterol (HDL-C) are associated with greater cardiovascular mortality. Independent risk factors for the development of PAD are total cholesterol, LDL-C, triglycerides, and lipoprotein(a). The Framingham study found that the ratio of total cholesterol to HDL-C was the best predictor of PAD. Treatment of hyperlipidemia has been shown to reduce the progression of PAD and the development of critical ischemia.
Alterations in the metabolism of homocysteine are an important risk for arteriosclerosis and, especially, for PAD. 13 Up to 30% of young patients with PAD have hyperhomocysteinemia. The mechanism of action could be double: on one hand, it promotes the oxidization of LDL-C and, on the other hand, it inhibits the synthesis of nitric oxide.
In patients with established PAD have proven to be a marker of the risk for future cardiovascular events. The risk of myocardial infarction during the follow-up of patients with advanced PAD susceptible to surgical treatment appears to be conditioned by the high pre-surgical values of CRP, independently of the presence of the factors traditionally considered for cardiovascular risk or a clinical history of ischemic heart disease. 14 The values for fibrinogen and alterations in the hemorrheologic properties of the blood have also been associated with a greater prevalence of PAD. Some studies have shown that high concentrations of fibrinogen cause an alteration of the microcirculation that is associated with more pronounced symptoms of intermittent claudication.
Peripheral arterial disease is considered to be a set of chronic or acute syndromes, generally derived from the presence of occlusive arterial disease, which cause inadequate blood flow to the limbs. On most occasions, the underlying disease process is arteriosclerotic disease, mainly affecting the vascularization to the lower limbs; we will, therefore, refer to this localization.
From the pathophysiologic point of view, ischemia of the lower limbs can be classified as functional or critical. Functional ischemia occurs when the blood flow is normal at rest but insufficient during exercise, presenting clinically as intermittent claudication. Critical ischemia is produced when the reduction in blood flow results in a perfusion deficit at rest and is defined by the presence of pain at rest or trophic lesions in the legs. In this situation, precise diagnosis is fundamental, as there exists a clear risk of loss of the limb if adequate blood flow is not re-established, either by surgery or by endovascular therapy. Differentiating between the 2 concepts is important in order to establish the therapeutic indication and the prognosis in patients with PAD.
The degree of clinical involvement depends on 2 factors: the chronologic evolution of the process (acute or chronic) and the localization, and extension of the disease (involvement of 1 or more sectors).
The pathophysiologic mechanism by which arterial insufficiency develops is based on the presence of arterial stenosis that progresses naturally to cause complete occlusion of the artery. This results in a greater or lesser degree of development of collateral supply vessels. When the imbalance between the needs of the peripheral tissues and the blood supply is produced more or less abruptly (high risk plaque), we are faced with a situation of acute ischemia of thrombotic origin. Differences have been found in the behavior of the atheromatous plaque depending on its anatomic site. High risk plaques in the arteries of the lower limbs are very stenotic and fibrous. 15 This stenosis, accompanied by a state of hypercoagulability, contributes decisively to the development of acute events. This type of plaque contrasts clearly with lesions present in the coronary arteries, which are often composed of a large extracellular lipid nucleus and a large number of foamy cells, covered by a fine fibrous layer susceptible to rupture. 16 In this situation, the vulnerability of the plaque at the most fragile points (greater number of foamy cells and thinner fibrous layer) is the cause of the acute events.
When the plaque ruptures, this results in thrombosis that obliterates the vascular lumen, triggering the acute syndrome. However, because new-formed collateral circulation has often taken place prior to the rupture of the plaque, acute ischemia is tolerated better than when the underlying cause of the acute ischemia is of embolic origin.
Extension of the Disease
The clinical manifestation of PAD depends decisively on the number of territories affected. Persons with a sedentary lifestyle and arterial involvement in just 1 zone are often asymptomatic or oligosymptomatic. The other end of the spectrum is formed by persons who have the disease at various sites, in whom critical ischemia is frequent.
Correlation Between Pathophysiology and Evolution of the Disease
On most occasions the clinical evolution of PAD is fairly stable, due to the development of collateral circulation, the metabolic adaptation of the muscle masses involved and the use, often unknowingly, of non-ischemic muscle groups. It is estimated that just 25% of patients with claudication will experience worsening and evolve towards critical ischemia, which is more usual 1 year after diagnosis. 17 If we exclude patients with diabetes, PAD leads to loss of a limb even more frequently. The Framingham study 18 found that less than 2% of patients with PAD required major amputation. In patients with claudication, the best predictor of disease progression is the ABI. Patients with an AAI 0.5. The systolic blood pressure (SBP) measured at the ankle is also a predictive factor of greater disease progression for patients with values <50 mm Hg. Nevertheless, it is important to note that patients with diabetes, due to their high prevalence of calcification in distal vessels, may have abnormally high SBP values in the malleolar region, with indices even above 1 in the presence of PAD. These 2 parameters, therefore, have limited validity in non-invasive evaluation.
One of the most important aspects in the evaluation of patients with PAD is probably the identification of cases at greater risk of developing critical ischemia and, therefore, of losing the limb. It is also important to note that the presence of several cardiovascular risk factors acts synergically, multiplying the risk of limb loss. 19 Individual analysis has shown that the presence of diabetes mellitus multiplies by 4 the risk of critical ischemia, smoking multiplies it by 3, and an AAI <0.5 does so by 2.5 times. Accordingly, it is of the utmost importance to make the earliest possible diagnosis of arterial disease in order to initiate treatment and modify the risk factors, thereby reducing the risk of disease progression.
VASCULAR DISEASE COEXISTING WITH PERIPHERAL ARTERY DISEASE
Clinical practice has demonstrated the multisystemic involvement of vascular disease and it is usual to find coronary or cerebrovascular disease in patients with vascular disease. Various epidemiologic studies have shown that up to 50% of patients with PAD also have symptoms of cerebrovascular or heart disease. 4 In the PARTNERS study, 20 of all the patients who were screened for vascular disease, only 13% had isolated PAD with no other manifestation of cardiovascular disease. Thirty-two percent of the patients also had either coronary disease or cerebrovascular disease, and 24% had involvement in all 3 territories. The main cause of late death in patients with PAD is ischemic heart disease (up to 50% of deaths in patients with PAD). Inversely, the prevalence of PAD in patients diagnosed with coronary disease reaches 30%. 4 The mortality in this group of patients is 2.5 times greater than that of the group with no clinical symptoms of PAD.
The association between PAD and cerebrovascular ischemia is not as prevalent as it is with coronary disease. Some studies using Doppler ultrasound to analyze the presence of carotid stenosis in patients with PAD have found a prevalence of lesions at this site of up to 50%. However, only 5% of the patients with PAD have a neurological event.
Finally, from an epidemiologic point of view, the association between the ABI and the presence of vascular disease in other territories is also very interesting. Variations in the ABI have been correlated with the severity and extension of coronary disease, as well as with the carotid intima-media index. Population studies have shown each reduction of 0.1 in the ABI is associated with a 10% increase in the risk of having a major vascular event. 21
SYMPTOMS AND BASIC EXAMINATION
The symptoms in patients with arterial failure in the limbs caused by chronic arterial disease can be stratified according to the classification of Leriche-Fontaine (Table 1). This classification, which groups patients who have progressive arterial failure into 4 stages, has prognostic value and is very useful for treatment indication.
Stage I is characterized by the absence of symptoms. It includes patients with arterial disease but no clinical repercussions. This should not be associated with a benign course of the disease. It is obvious that patients who have an extensive occlusive arterial lesion in the legs, who have a sedentary lifestyle or who are incapacitated due to osteoarticular, or neurologic disease will not present symptoms of arterial failure. In these situations, the patients may present with critical ischemia straight from an asymptomatic stage.
Stage II is characterized by the presence of intermittent claudication. This stage is itself divided into groups. Stage IIa includes patients with non-invalidating claudication or at long distances. Stage IIb refers to patients with short claudications or claudications that impede activities of daily living.
The intermittent claudication that is typical in patients with PAD is defined as the appearance of pain in muscle masses caused by walking and which ceases immediately after stopping exercise. It is important to note that the pain always presents in the same muscle groups and after covering a similar distance, provided the same slope and speed are maintained.
A great number of patients report pain in the legs associated with walking, but not with the presence of arterial disease. Many of them have muscle, osteoarticular, or neurologic diseases, and these may occasionally coexist with obstructive arterial disease. In these cases it is very important to establish a correct differential diagnosis, which initially will be clinical and later will be confirmed with non-invasive studies. The clinical presentation in these patients usually concerns joint pain related with exercise, but also during passive movement of the limb. When the symptoms concern muscle pains, the pains do not usually present systematically at the same place, and are often not localized to muscle groups involved in walking (glutei, quadriceps, and calf muscles). The walking distance with these non-vascular claudications varies considerably, even over the day. However, the pain does not cease simply by stopping walking, but rather the patient has to sit down, lie down, or adopt a special posture, with the symptoms usually disappearing after a much longer period of rest than required with vascular claudication.
The muscle group affected during gait is useful for determining the site of the occlusive lesion. Although most patients report calf muscle claudication, the presence of claudication in the buttocks or thighs may indicate the presence of disease in the iliac region. Claudication due to femoropopliteal disease is typically located in the calf muscles, and infrapopliteal occlusions may only manifest themselves as claudication in the sole of the foot (Table 2).
Stage III constitutes a more advanced phase of ischemia and is characterized by the presence of symptoms at rest. The predominant symptom is usually pain, although the patient often reports paresthesia and hypoesthesia, usually at the front of the foot and the toes. Paresthesia at rest may be indistinguishable from that due to diabetic neuropathy, although in the latter the paresthesia is usually bilateral, symmetrical, and with a "sock distribution." One characteristic of this pain is that it improves at rest when the patient lowers the limb, so that many patients dangle their leg out of the bed or sleep in an armchair. This is the cause of the appearance of distal edema in the limb due to the continued dangling. In stage III the patient usually has a cold limb with a variable degree of paleness. Some patients with more intense ischemia, however, have erythrosis of the dangling foot due to extreme cutaneous vasodilatation, which is called the "lobster foot."
Stage IV is characterized by the presence of trophic lesions. It is due to the critical reduction of distal perfusion pressure, insufficient to maintain tissue trophism. These lesions are situated in the more distal areas of the limb, usually the toes, although on occasions they may present in the malleolus or the heel. They are usually very painful, except in diabetic patients with associated neuropathy, and are very susceptible to infection.
The basic examination of the arterial system is based on the evaluation of the presence of pulses, which in the lower limbs will include the search in the femoral, popliteal, pedal, and posterior tibial arteries. In the event of aortoiliac occlusive disease a reduction in all the pulses in the limb or their complete absence will be evident. In the case of femoropopliteal disease, the femoral pulse will be present, but it will be absent in the popliteal and distal arteries. Auscultation of the abdomen will enable identification of the presence of murmurs, which are indicative of disease in the aorta or the iliac arteries. Auscultation of the inguinal region may reveal the presence of lesions in the external iliac or femoral bifurcation vessels. It is also important to check the temperature, color, and trophism of the foot. Patients with claudication do not usually show a reduction in temperature or capillary filling. The reduction in temperature, however, and paleness, with or without cyanosis or dangling erythrosis, are common in patients with critical ischemia. Finally, clinical examination of the upper limbs should not be forgotten as well as cervical auscultation due to the great prevalence of carotid lesions or supra-aortic trunk lesions, which in most cases are subclinical.
Diagnostic Approach for a Patient With Peripheral Artery Disease
After the initial clinical and physical examination, patients with suspected occlusive arterial disease should be studied in a non-invasive vascular examination laboratory. This evaluation enables the degree of functional involvement to be quantified and the occlusive lesions to be localized. The basic study consists of recording the segmental pressures of the limb (upper thigh, lower thigh, calf, and ankle) by means of Doppler ultrasound to detect flow in the malleolar arteries (anterior tibial, posterior tibial, and fibula). Comparison between the systolic pressure obtained in the brachial artery and that obtained in the different segments of the leg permits the site of the lesion to be determined and provides information about the intensity of the hemodynamic involvement.
Recording the pulse wave volumes along the limb by plethysmography is particularly useful in patients in whom arterial calcification prevents a reliable recording of systolic pressures. Transmetatarsal or digital recording provides important information about the state of the vascularization in this zone, which is difficult to obtain with other techniques (Figure 1).
Figure 1. Study of segmental pressures and wave volume according to the affected sector. A: normal study: pulse wave volumes (PWV) with dicrotic wave. Segmental indices >1 at all sites. B: iliac occlusion: flattening of the PWV and indices <1 from the proximal thigh. C: femoropopliteal occlusion: normal PWV and indices in proximal thigh. Distal flattening of PWV with index <1 in ankle. D: intense calcification: the vessels do not collapse despite the very high sleeve pressures (falsely high ankle-arm index). Very pathologic PWV, transmetatarsal planes.
Finally, recording the velocimetric wave obtained by Doppler can also provide very useful information by means of evaluating the changes in the different components of the arterial velocimetric wave (Figure 2).
Figure 2. Doppler velocimetric wave. A: normal study. Prominent systolic wave with dicrotism in the descending wave. B: mildly pathologic study. Absence or reduction of the dicrotism in the descending wave. C: very pathologic study. Flattening of the systolic wave.
Some patients may have symptoms of typical claudication at mid-long distance, but with a study and ABI within normal ranges. In these cases it is convenient to carry out a claudicometry, which consists of the measurement of the ABI after walking on a treadmill. A normal physiological response consists of a rise in the pressure at the ankle in response to exercise. When an occlusive lesion is present that is not important at rest, this can be shown up by a reduction in the ABI with exercise. This method enables the symptoms of the patients to be reproduced objectively and the claudication distance quantified. In the case of claudication of non-vascular origin, the ABI will not fall and the studies to be undertaken can then be adequately oriented.
Imaging techniques are indicated if surgical or endovascular repair is contemplated after identification of a susceptible lesion. The clinical situation (short or progressive claudication, pain at rest, or trophic lesions) is the main factor to be evaluated regarding the indication for surgery. Angiography remains the reference study, but it involves certain risks, such as intense reactions to iodized contrast material, the possibility of worsening renal function, and other local complications, like dissection, atheroemboly, or problems related with the access site (hemorrhage, pseudoaneurysm, or arteriovenous fistula).
Echo-Doppler is a less costly and safer technique. In expert hands, it can reliably show the main anatomic characteristics in order to undertake revascularization. Its main limitations concern the fact that it is excessively dependent on the operator, that it has a poor reliability in the evaluation of the infrapopliteal vessels and the time required to carry out a complete examination.
Both multislice computerized angiotomography and magnetic resonance angiography are being increasingly used for the diagnosis and surgical planning. Magnetic resonance angiography enables 3-dimensional images to be obtained safely of the whole abdomen, the pelvis, and the lower limbs at 1 single study. Its usefulness is limited by the presence of such devices as defibrillators, cochlear implants, or intracerebral stents, as well as by the fact that certain patients suffer claustrophobia. The study is not affected by the presence of parietal calcium nor by nitinol stents, although stainless steel stents can provoke artifacts.
Multislice computerized tomography can also provide excellent 3-dimensional images and give information about the characteristics of the plaque, and all during a very quick study. However, the important doses of iodized contrast material required may be affected by the presence of calcium and the patient is exposed to radiation.
Medical Treatment of Peripheral Artery Disease
Medical treatment of patients with PAD has 2 objectives. One, to improve the functional situation of the limb, and 2, to prevent events secondary to the multifocal distribution of the disease. Patients with symptomatic PAD are known to have a very poor long-term prognosis, with an increase in 10-year mortality 15 times higher than patients without PAD. 22 The first therapeutic indication is therefore to eliminate risk factors. For patients who smoke, quitting is probably a more effective factor than any pharmacologic therapy to reduce morbidity and late cardiovascular mortality. 23,24 Moreover, intermittent claudication has been shown to improve after starting supervised programs of physical exercise. These programs also affect quality of life indices, risk factors, endothelial function, and hemorrheologic markers. 25
The drugs used in PAD can be directed at specific treatment of the claudication, in an attempt to achieve increased walking distance, or at the secondary prevention of cardiovascular events, thus achieving a better vital prognosis for these patients.
Secondary Prevention of Cardiovascular Events
Acetylsalicylic acid . A review undertaken by the Antithrombotic Trialists Callaboration 26 of 42 clinical trials found that the use of anti-platelet therapy (mainly acetylsalicylic acid) was associated with a 23% reduction in the combined outcome variable of cardiovascular death, acute myocardial infarction, or ictus. This study, and other similar studies, 27,28 determined that the best therapeutic dose with the lowest digestive risk profile was 75-100 mg per day. Acetylsalicylic acid, therefore, should be used in all patients with PAD in order to reduce cardiovascular death. Importantly, acetylsalicylic acid has not been shown to improve claudication distance or symptoms of PAD (Table 3).
Thienopyridines . Clopidogrel is an anti-platelet agent that has been shown to be more potent than aspirin for the reduction of secondary cardiovascular events. The CAPRIE 29 study found that the group in which clopidogrel was more effective at reducing major secondary events (ictus, acute myocardial infarction, death) was the group of patients with PAD. Whereas the overall reduction of secondary events in the whole series was 8.7%, this reduction was 3 times greater in the patients with PAD (23.8%). The combination of clopidogrel and acetylsalicylic acid might be better than monotherapy alone. Whilst this association has been contrasted in patients with coronary disease, it has not been verified in patients with PAD. As occurs with acetylsalicylic acid, no scientific proof exists that clopidogrel improves the symptoms of intermittent claudication.
Statins . The Heart Protection Study 30 compared placebo with simvastatin and found that, in the group of patients who received placebo, the greater number of major secondary events was seen in the subgroup of patients who had PAD. Likewise, these latter patients also received most benefit from treatment with simvastatin (relative risk reduction of 24%). Moreover, the benefit was found to be the same in the patients who had baseline LDL-C levels <100 mg/dL as in those who had higher concentrations. The best evidence for the beneficial effect of statins in PAD comes from the more potent drugs (simvastatin and atorvastatin). The dose should be sufficient to attain LDL-C values <100 mg/dL or in the patients at greater risk (diabetes, active smokers, acute coronary syndrome) values of <70 mg/dL. Control of statin toxicity should include the measurement of creatine kinase and the transaminases.
Angiotensin-converting enzyme inhibitors . The HOPE clinical trial 31 found that the patients with PAD who were randomly assigned to receive ramipril experienced a 25% reduction in the number of major cardiovascular events. Moreover, the patients with PAD included in this study had mean blood pressure figures of 143/79 mm Hg, suggesting that angiotensin-converting enzyme (ACE) inhibitors could even be beneficial in normotensive patients.
Specific Treatment of the Intermittent Claudication
Pentoxifylline . This was the first drug approved specifically for intermittent claudication. Its mechanism of action is based mainly on increasing the deformity of the red blood cells, although it also reduces blood viscosity, inhibits platelet aggregation, and reduces fibrinogen levels. However, the true benefit of this drug is controversial and it has been questioned in different studies. 32-33 Some authors 34 have reported a benefit during just the initial phase of treatment, with no changes in claudication distance after 12 weeks of treatment. Two meta-analyses have confirmed the discordance of the results and concluded that the benefit of pentoxifylline in intermittent claudication is really small. 35,36
Cilostazol (not available in Spain) . This is a phosphodiesterase inhibitor that increases cAMP concentrations inside platelets, and blood cells, inhibiting platelet aggregation. Increased concentrations of HDL-C and reduced levels of triglycerides have also been reported. Numerous clinical trials have shown the benefit of this drug, 37,38 as it increases claudication distance by up to 100%. In these studies the patients who took cilostazol showed an increased claudication distance of 140 m versus the patients treated with placebo. Pentoxifylline and cilostazol are currently the only 2 drugs authorized by the Food and Drug Administration specifically for intermittent claudication.
Statins . Some randomized trials have shown that the patients who received statins experienced an improvement in claudication distance. 39,40
Specific Treatment for Critical Ischemia
Prostanoids . The prostanoids PGE 1 and PGI 2 are used parenterally. Their mechanism of action is based on inhibition of platelet aggregation and leukocyte activation, with an important vasodilator effect. A recent meta-analysis 4 reported that the patients who received the treatment had a greater survival and a higher rate of limb salvation. Other recent studies, however, have failed to find that these drugs reduce the risk of amputation. 4
Others. Anticoagulants, hyperbaric oxygen, spinal stimulation, etc, are other alternatives that have been used for critical ischemia. However, only marginal benefit has been obtained with these measures. 4
Surgical Treatment of Peripheral Artery Disease
Indications for Surgery
The indication for surgical treatment (conventional or endovascular) of PAD depends above all on the joint evaluation of 2 fundamental aspects, the clinical situation of the patient and the vascular bed that requires reconstruction (Table 4).
The clearest indication for revascularization is the patient with advanced stages of ischemia (III and IV), due to the high risk of loss of limb resulting from these situations. In these cases, independently of the bed affected, some type of surgical repair should be undertaken. It should be recalled that multisegment involvement is usually the norm in patients with trophic lesions. It is not unusual for these patients to have combined occlusive disease of the aortoiliac and femoropopliteal sector, or else simultaneous femoropopliteal and infrapopliteal disease. In this situation, where the aim is to obtain scarring of the lesions, the repair should be directed at achieving the maximum amount of direct flow to the foot, which may on occasions require more than one surgical procedure.
In patients with intermittent claudication, however, the attitude will depend in great part on the bed requiring reconstruction. This is due to the fact that the results of surgery in terms of permeability vary according to the sector reconstructed. For example, in a patient with intermittent claudication due to occlusive aortoiliac disease, open or endovascular reconstruction of this sector can be considered, with high rates of permeability at 5 years. At the opposite end of the scale is the patient with infrapopliteal disease, in whom the late results do not warrant an interventional attitude.
The indication for intervention should also include evaluation of the particular surgical technique required. Femoropopliteal and infrapopliteal bypass surgery is known to afford greater permeability when the patient's saphenous vein is used rather than the implantation of a prosthetic bypass. Implantation of a prosthesis in the femoropopliteal sector for the treatment of intermittent claudication is not therefore recommended.
The development of new endovascular techniques has resulted in debate about their role in occlusive arterial disease. An expert group has drawn up a document dealing with the recommendations for treatment, known as the TASC (Inter-Society Consensus for the Management of Peripheral Arterial Disease), whose first edition was published in 2000 and with a second revision announced in 2007. 4 This document includes multiple recommendations about the treatment of patients with PAD and establishes 4 categories (A, B, C, and D), according to the morphology and extension of the disease (Figures 3 and 4). Although a detailed analysis of the recommendations is outside the scope of this review, we can summarize by saying that endovascular surgery is recommended for simpler lesions (category A) and open surgery for the more advanced lesions (category D). The indication in the other categories depends on the evaluation of the accompanying diseases, patient preferences after being fully informed, and the experience of the surgical team.
Figure 3. Classification of iliac lesions (TASC II). AAA indicates abdominal aorta aneurysm; CFA, common femoral artery; CIA, common iliac artery; EIA, external iliac artery.
Figure 4. Classification of femoropopliteal lesions (TASC II). CFA indicates common femoral artery; SFA, superficial femoral artery.
Aortoiliac Revascularization (Suprainguinal)
Suprainguinal occlusive disease has a very variable distribution, ranging from involvement of a segmental stenosis of an iliac axis to complete obstruction of the abdominal aorta and both iliac arteries. The extension of the lesion and its characteristics determine the best treatment option.
Revascularization surgery. Diffuse, extensive involvement is usually best treated by placement of an aortic-unifemoral or -bifemoral prosthesis (Figures 5 and 6). The effects of this well-systematized technique are known. The results in terms of permeability are above 85% and 80% at 5 and 10 years, with operative mortality below 5%. 4 However, the technique involves major arterial surgery and requires quantifying the surgical risk to select the most suitable candidates. The operation in patients at high risk or who have a hostile abdomen (multiple reoperations, prior radiotherapy, active infection, etc) is carried out by means of what is referred to as "extraanatomic techniques," which enable revascularization of the limbs via non-anatomic pathways, and with less aggression. The most commonly used are axilo-unifemoral or -bifemoral, and femorofemoral bypass surgery. Both types of bypass surgery are performed via a subcutaneous tunnel, the former via the lateral region of the thorax and the abdomen, and the latter via the suprapubic region. They can be done with locoregional anesthesia. The figures for permeability with extraanatomic bypass surgery are lower, ranging between 40% and 70% at 5 years, depending on the clinical indication. 4 They are, therefore, rarely indicated in the absence of critical ischemia.
Figure 5. Arteriography showing extensive aortoiliac occlusion and the result after aortobifemoral bypass surgery.
Figure 6. Image of a Dacron prosthesis with infrarenal anastomosis. Control of left renal artery with elastic tape.
Angioplasty/stenting. Angioplasty provides the best results in short lesions, preferably stenosis and non-calcified lesions in the common iliac artery. Its long-term results in these situations are good, with permeability figures of 70% at 5 years for patients with claudication. 41 However, when it is performed in longer lesions, especially when complete occlusions are recanalized, the permeability is clearly lower. The advantages of implanting a stent in iliac angioplasties have been assessed in clinical trials, with permeability figures just a little better for systematic stenting as compared with simple ballon angioplasty. 42-44 The best approach is probably to implant a stent selectively in those patients in whom ballon angioplasty shows an initially suboptimal result (Figure 7).
Figure 7. Arteriographic image of an occlusion of the primitive iliac artery and stenosis of external iliac artery, resolved by implanting a coated stent.
Analysis of occlusive superficial femoral artery lesions shows 2 determinant characteristics for their reconstruction. One, it is a diffuse disease, with occlusions that are usually longer than 10-15 cm, generally calcified and in which the occluded areas coexist with long segments of artery affected by the disease. And second, the shorter lesions usually cause little clinical involvement, due to the important role of the deep femoral artery as a source of collateral circulation. Accordingly, critical ischemia of the superficial femoral artery caused by a segmental occlusion is unusual if the other proximal or distal vessels remain free of disease. Finally, isolated involvement of any of the infrapopliteal vessels (anterior tibial, posterior tibial, and fibula) only rarely cause symptoms of arterial failure, and multiple occlusions or stenosis must be present to threaten the viability of the limb.
Revascularization surgery. This is the technique of choice in patients with extensive femoropopliteal and distal disease. When the obstruction of the superficial femoral artery is recanalized via the popliteal artery and permeable distal vessels are present, femoropopliteal bypass surgery is performed and the distal anastomosis is done in the supragenicular or infragenicular region. Generalizing and resuming, this operation can be done with postoperative mortality rates below 5% and an early success rate above 90%. The 5-year permeability rates range from 65% to 80%, provided that the bypass is done with the saphenous vein. The results are at least 15%-20% lower when a prosthesis is used. Other factors that influence the rate of permeability are the state of the distal bed, the area of the distal anastomosis (supragenicular or infragenicular) and the indication for surgery (critical ischemia vs claudication).
When the obstruction extends to the infragenicular popliteal artery and the distal vessels, revascularization is carried out with bypass surgery whose distal anastomosis is done in the distal vessel with the best state to ensure direct perfusion to the foot (Figure 8). In this case we refer to femorodistal, popliteodistal, or tibiotibial revascularization surgery, depending on the site of the proximal anastomosis. In general, these bypass operations are associated with similar rates of permeability to those obtained with bypass to the popliteal artery, provided that autologous material is used, but much worse when a prosthesis is used. Nevertheless, the rates of limb salvation surpass 70% at 5 years.
Figure 8. Femoroperoneal venous bypass surgery. Control arteriography.
Endovascular surgery. The techniques for endovascular surgery involve greater difficulty for implants in the femoropopliteal and distal sectors, precisely because of the diffuse involvement of the disease. Different methods have been tried, such as simple angioplasty, subintimal angioplasty, stenting, atherotomy, laser, coated stents, etc, with greatly varying results.
In general, we can say that short lesions, less than 10 cm, preferably with stenosis, are the most suitable for endovascular treatment, 45-48 especially angioplasty, whereas stents have shown a high rate of fractures with important clinical consequences. In longer lesions, the use of expanded polytetrafluoroethylene coated stents seems to afford advantages over the other methods, though randomized studies with a greater follow-up are required 49 (Figure 9).
Figure 9. Diffuse intense disease of the superficial femoral artery resolved by implanting a coated stent.
Surgery Plus Coadjuvant Medical Treatment
Patients who undergo open or endovascular surgery should continue an indefinite program of anti-aggregation, which must be started prior to the surgery. The usefulness of ant-aggregating drugs has proved greater in patients with a venous bypass as compared with a prosthesis, especially in the infrainguinal region. 50 A Cochrane review 51,52 found that patients who were being treated with acetylsalicylic acid after revascularization surgery had a 41% lower risk of graft occlusion after 12 months of follow-up. Although double anti-aggregation is often used in accordance with the results obtained in patients with coronary disease, no conclusive information is available concerning its usefulness in PAD.
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ABBREVIATIONS AAI: ankle-arm index CRP: C-reactive protein HDL: high-density lipoprotein LDL: low-density lipoprotein PAD: peripheral artery disease PWV: pulse wave volume
Correspondence: Dr. F.J. Serrano Hernando. Servicio de Cirugía Vascular. Hospital Clínico San Carlos. Martín Lagos, s/n. 28040 Madrid. España. E-mail: [email protected]
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