Authors: Adam A. Behroozian, Joshua A. Beckman
Categories: Article, Asymptomatic peripheral artery disease, Claudication
Source: Progress in cardiovascular diseases
Authors: Adam A. Behroozian, Joshua A. Beckman
Peripheral Artery Disease (PAD) is a manifestation of atherosclerosis characterized by diminished perfusion of the limb and a state of dysmetabolism. The asymptomatic PAD phenotype is a relatively recent classification. It is unknown how many people currently live with asymptomatic PAD because there are no universal screening recommendations for patients at risk for PAD. Patients with asymptomatic PAD suffer from a similar risk profile of morbidity and mortality as their counterparts with claudication. Despite this increased risk, there is a dearth of clinical investigations into therapies that specifically benefit the asymptomatic PAD population. At present, current pharmacotherapies that have been studied in PAD patient populations do not stratify by symptom status. We believe that further investigation of the impact of existing therapies in this unique population presents an opportunity to reduce morbidity and mortality due to PAD. This can only be achieved in combination with wide-spread adoption of screening for asymptomatic PAD.
Peripheral artery disease (PAD) is a manifestation of atherosclerosis in the lower extremities. In 2000, it was estimated that 8 million people in the United States were living with PAD among the over 200 million people afflicted with the condition globally.^1,2^ This number has likely increased in the United States as the aged population has increased. PAD can be characterized as a state of diminished limb perfusion and dysmetabolism. The PAD phenotype can manifest across a broad spectrum that ranges asymptomatic, functionally impaired, intermittent claudication, to critical limb ischemia (CLI).^3^ It is conservatively estimated that 6 million patients in the United States have asymptomatic or atypically symptomatic PAD while the remainder experience intermittent claudication and limb ischemia at rest. Approaching intermittent claudication from a historic perspective provides the context for asymptomatic and atypically symptomatic peripheral artery disease as a more recently identified phenomenon.
In 1854, French Neurologist Jean-Martin Charcot characterized dysbasia intermittens angiosclerotica or what we have come to understand as intermittent claudication of the lower extremities. His description of the constellation of symptoms defining intermittent claudication holds to this ‘persons past middle life are seized after walking a short distance, occupying perhaps five to ten minutes of time with a helpless, cramp-like feeling in the legs so severe as to render further progress impossible though after a few moments rest they can do their short stint again. It is not the severity of the pain so much as an actual incapacity for motion, an inhibition, accompanied sometimes with abnormal sensations in the feet that hampers them.’^4,5^ Since its initial description, numerous attempts have been made to standardize and distinguish intermittent claudication from other causes of leg pain for both clinical and epidemiologic applications.
It was not until the early 1960s, when English Epidemiologist Geoffrey Rose published a Claudication Questionnaire that created a broadly accepted definition of intermittent claudication.^6^ Originally, the leg pain associated with Rose’s definition of intermittent claudication had 6
These criteria had excellent sensitivity (92%) on the initially studied cohort of 37 hospitalized patients with PAD and 100% specificity. Rose’s Claudication Questionnaire failed to maintain this high sensitivity when applied to general populations and largely fell out of favor due to its dependence on a high proportion of persons with claudication in the sample.
It was widely recognized that the strength of the WHO/Rose Questionnaire was predicated on its specificity but was limited by its inapplicability to a general population. F. Gerry R. Fowkes, an Epidemiologist from the University of Edinburgh, developed a modified questionnaire that maintained that the specificity of the WHO/Rose Questionnaire in high risk groups while increasing its specificity in a general population from 60%. The loss of sensitivity to detect PAD was attributed to a single question in the WHO/Rose Claudication Questionnaire: does the pain ever disappear while you are still walking? Fowkes found that specificity could be maintained at greater than 90% with only three questions from the WHO/Rose Questionnaire: 1) pain with standing or sitting (leg in the dependent position), 2) pain in the calf, 3) pain relieved within 10 min of resting. The Edinburgh Claudication Questionnaire was superior to the Rose Questionnaire in consistency and sensitivity across examinations while rivaling its specificity in a general population. A limitation of the WHO/Rose Claudication Questionnaire that persisted in the Edinburgh Claudication Questionnaire, despite its new applicability to a general population, was its omission of asymptomatic patients with PAD.
The inability to capture asymptomatic individuals in epidemiologic studies was a limiting factor of previous questionnaires. It is estimated that there are 2–5 cases of asymptomatic PAD for every case of typical intermittent claudication in the general population.^1^ Michael Criqui, at the University of California in San Diego, developed a revised questionnaire that incorporated both leg symptom laterality and the asymptomatic state of PAD. Symptoms were categorized into 5 no pain, pain at rest, non-calf claudication, non-Rose calf claudication (e.g. walk through pain) and Rose claudication. PAD patients were stratified based on non-invasive testing (i.e. ankle brachial index and peak velocity in the posterior tibial artery) and further stratified by receipt of invasive revascularization. In this cohort, claudication correlated well with severity of PAD in a graded fashion.^7,8^ The inclusion of patients with asymptomatic disease, based on ankle-brachial index (ABI) alone, was an important advance in the characterization of PAD.
While the San Diego Claudication Questionnaire was the first of its kind to capture asymptomatic patients, a more recent iteration of that questionnaire now subdivides the clinical phenotypes of asymptomatic PAD in a more nuanced active or inactive asymptomatic PAD. Mary McDermott postulated that many ‘asymptomatic’ PAD patients lacked classic Rose claudication because of limited exertional effort related to limb dysfunction. This created a subdivision of clinical asymptomatic PAD phenotypes into ‘active’ or ‘inactive’. Common features included absence of exertional leg/buttock pain with walking but diverged with the ability of subjects to walk >6 blocks (active) or inability to walk 6 blocks (inactive), the latter termed masked PAD.^3^ While limb dysfunction is one proposed mechanism masking ischemic symptom development, it should be noted that other systemic illnesses (i.e. heart failure), local complications (joint disease), and altered pain sensitivity (neuropathy) may provide an explanation for the delayed presentation of severe forms of PAD without prior complaint.
The application of the ankle-brachial index (ABI), which is both non-invasive and widely accessible, has been valuable in identifying patients with asymptomatic PAD.^9^ Clinically and epidemiologically, an ABI of ≤0.90 defines PAD although it is estimated that up to 25% of patients with PAD have an ABI between 0.90 and 1.0. In a 5080-person population-based point-prevalence study of peripheral artery disease conducted in a general Swedish population where individuals were screened by ABI, 914 subjects were determined to have PAD by ABI ≤0.9. Of those diagnosed with PAD, 566 or 62% of patients with ABI ≤0.9 were asymptomatic. The prevalence of asymptomatic atherosclerotic PAD in this study represented 11% of the general population, however, the investigators did not stratify this data by groups with different burdens of atherogenic risk factors.^10^
The PAD Awareness, Risk and Treatment: New Resources for Survival (PARTNERS) program was a multicenter, cross-sectional study of nearly 7000 patients selected for specific risk factors for atherosclerosis including age >50 years and a tobacco history and/or diabetes or age >70 years. ABI and standardized questionnaires were used to screen and subdivide subjects into clinical those without clinically recognized atherosclerosis of any vascular bed (referent group), PAD only, non-PAD cardiovascular disease (atherosclerotic coronary, cerebrovascular and abdominal aortic artery disease) only, and those with both. New, asymptomatic PAD was identified in ~45% of patients independent of atherosclerosis in other arterial beds. Classic Rose claudication occurred in less than 15% of the study cohort.^11^ This work demonstrated that the clinical phenotype of asymptomatic PAD represents the largest proportion of patients with PAD. Once the variations in PAD symptomatic status had been clarified, the question became are there differences in clinical outcomes between symptomatic and asymptomatic subgroups?
Despite the definition of PAD (ABI) requiring decreased perfusion of the distal extremity due to arterial occlusive disease, the presence or absence of symptoms is not a reliable indicator of outcomes. Mohler et al. designed a prospective cohort study of asymptomatic PAD patients over follow up period of one year to evaluate the time course and pathophysiology of converting from asymptomatic to symptomatic PAD. The study included patients with abnormal ABI’s both with and without complaints of typical claudication on the San Diego Claudication Questionnaire (SDCQ). Thirty three patients met both inclusion and exclusion criteria and completed baseline and 1 year follow up assessment which included duplex ultrasound and SDCQ. The authors reported that 11% of previously normal legs developed new PAD and 35% of legs with PAD at baseline developed new or progressive disease. In addition, 21% of asymptomatic patients developed claudication symptoms over the one year follow up. New claudication manifested as a significant impairment in the 6-Minute Walk Test at 1 year follow up. This data supports the hypothesis that asymptomatic patients with PAD and abnormal ABI can progress rapidly.^12^
Beyond progression of limb disease and functional decline, patients with asymptomatic PAD are at heightened risk for cardiovascular morbidity and mortality. Criqui et al. studied prospectively cohorts of age matched control subjects without PAD, patients with asymptomatic large-vessel PAD and patients with symptomatic disease over a ten-year period. Only 3 in 5 patients with asymptomatic large vessel PAD were alive after a ten year period, while their symptomatic counterparts fared worse.^13^ Several studies have corroborated the increased risk for morbidity due to cardiovascular disease (CVD) as well as increased mortality due to CVD and all-causes with the advent of leg symptoms. The Edinburgh cohort demonstrated a higher rate of death from cardiovascular disease in the group with claudication compared with the asymptomatic PAD group, (RR: 2.67, CI: 1.3–5.3) versus (RR: ~2, CI 1.1–3), respectively. An unexpected finding in this cohort was that patients with asymptomatic disease had a higher risk for non-cardiovascular death which resulted in an increase in all-cause mortality surpassing that of the group experiencing intermittent claudication, (RR: 2.44; CI 1.6–3.7) versus (RR: 1.55; CI: 0.9–2.8), respectively.^14^ A 10-year prospective cohort of patients with newly identified asymptomatic PAD and type 2 diabetes in the Spanish region of Catalonia were followed for incident nonfatal cardiovascular events and mortality. The incidence rate of fatal and nonfatal CVD was much greater in the group of patients with asymptomatic PAD compared to those with normal ABI.^15^ In the getABI study, a prospective cohort study of nearly 7000 unselected primary care patients ≥65 years of age all of whom had ABI measurement, 836 were found to have asymptomatic PAD (ABI ≤0.9) and 593 were found to have symptomatic PAD (either by intermittent claudication and ABI ≤0.9 or prior lower extremity revascularization). Over follow-up of five years, patients with PAD, both asymptomatic and symptomatic, were at significantly increased risk of morbid and mortal events. Further, there was no difference between asymptomatic and symptomatic PAD groups in all-cause death alone, all-cause death/myocardial/stroke alone, CVD events or cerebrovascular events alone. Taken together, after adjustment for multiple known CVD risk factors, asymptomatic and symptomatic PAD both had significant associations with the composite outcome of death or vascular events compared to their non-PAD counterparts. These findings have been supported by a large systematic review.^16,17^ Table 1 summarizes several key observational studies that quantified the morbidity and mortality of asymptomatic PAD.
Reduced ABI (≤0.9) alone was an independent risk factor for coronary- and CVD-mortality in a group of asymptomatic middle-aged Belgian males. In this prospective cohort of over 2000 asymptomatic patients without known pre-existing coronary or PAD, a PAD diagnosis by ABI was associated with increased risk of CVD events. Specifically, the relative risks for ten-year all cause, cardiovascular and coronary mortalities were 2.77 (p = 0.01), 4.16 (p = 0.01) and 4.97 (p = 0.06), respectively.^18^ Combined with the Framingham risk score, a lower ABI predicts higher rates of MACE and mortality (Fig. 1).^19^ In a different multicenter cohort, from the Limberg Peripheral Arterial Occlusive Disease (PAOD) group, over 3100 patients were screened and 314 subjects were determined to have asymptomatic PAD (ABI ≤0.95). All subjects were followed longitudinally for a mean follow-up period of 7.2 years and incident nonfatal cardiovascular disease was reported. 35% of asymptomatic PAD patients developed nonfatal CVD, while their symptomatic PAD and non-PAD counterparts experienced an incident rate of 40% and 16%, respectively, after adjustment for other covariates. The asymptomatic PAD group also experienced an increased hazard ratio of total fatal events (HR: 1.4;95% CI: 1.1–1.8).^20^ Asymptomatic PAD portends a poor prognosis with respect to CVD morbidity and mortality and has implications in deleterious extremity-specific characteristics. Overt clinical disease in one arterial bed is likely a marker of subclinical or overt disease in distant arterial beds.^21^
Asymptomatic PAD is associated with more adverse lower extremity characteristics than intermittent claudication. McDermott et al. studied a group of 429 men and women with PAD noting that individuals with PAD who are always asymptomatic, despite completing a 6-min walk test, have significantly smaller calf muscle area, higher calf muscle percent fat, lower calf muscle density, poorer lower extremity peripheral nerve function, and poorer lower extremity functional performance compared with PAD participants with classic symptoms of intermittent claudication. These findings were of particular clinical importance because they suggested that a lack of symptoms may be a surrogate for inactivity and challenged the prevailing paradigm of using leg symptoms as an eligibility criterion for therapeutic clinical trials designed to improve walking performance in persons with PAD.^22^
The understanding of the role of inflammation as a core principle of atherogenesis continues to evolve. Traditionally, flow-limiting stenosis to the lower limb and inability to meet oxygen demand has been thought to be the primary driver of claudication in PAD. Several studies suggest the role of oxidative stress, inflammation and endothelial dysfunction evoked by exercise in limb ischemia as an alternative explanation. Increased levels of exercise induced-inflammatory mediators have been demonstrated in the plasma of patients with claudication. Among these, elastase is released by activated neutrophils and causes digestion of basement membranes causing increased permeability on the endothelium in vitro. Levels of elastase increase progressively from healthy individuals to asymptomatic PAD patients to claudicants.^23,24^ Furthermore, elastase levels increase acutely with exercise in claudicants.^25^ The exercise induced inflammatory response results in microcirculatory dysfunction and skeletal muscle metabolism derangements may be an important mechanism of claudication.^26^ Additionally, inflammation severity paralleled the staging of the Fontaine classification in a small study of 40 PAD patients. High-sensitivity CRP and IL-6 levels were highest in the half of patients with claudication (Fontaine stage II) when compared to patients with asymptomatic PAD (Fontaine stage I) and healthy controls.^27^ The Edinburgh Artery Study group published longitudinal data over a 12 year period that demonstrated CRP and IL-6 were implicated in the progression of atherosclerotic disease and their presence was seen in increasing concentration in order of healthy controls to asymptomatic PAD patients to claudicants.^28^ A parallel increase in high-sensitivity CRP has also been in progression of disease manifestation as extreme as ischemic rest pain and trophic lesions in critical limb ischemia (Fontaine III and IV, respectively).^29,30^ The mechanisms of discomfort likely extend beyond just reductions in perfusion pressure and may provide an explanation for the modest predictive capacity of the ABI to determine limb function and the wide range of symptomatology associated with exercise limitation.
PAD is underdiagnosed and undertreated.^11^ PAD has an established increased risk profile for developing incident CVD events. Examples of classes of medications previously investigated to prevent incident CVD events in PAD patients Proprotein Convertase Subtilisin/Kexin type 9 (PSCK-9: Evolocumab) inhibitors,^33^ Protease-activated receptor-1 antagonists (Vorapaxar)^34^ and Factor Xa inhibitors^35,36^ but their study was not focused on asymptomatic PAD. The mainstays of pharmacotherapy for asymptomatic PAD focus on atherogenic risk factor modification and their two aspirin and statins.
Antiplatelet therapy has been studied extensively in PAD patients. Numerous trials and meta-analyses have been carried out to demonstrate the role of aspirin in PAD with varying protective or neutral results.^37–39^ The majority of these trials did not stratify results based on the presence or absence of claudication.
The POPADAD trial (Prevention Of Progression of Arterial Disease And Diabetes) was a multicenter, randomized, double-blinded, 2 × 2 factorial, placebo controlled trial across Scotland and included nearly 1300 patients with diabetes and decreased ABI with no symptomatic CVD. The composite end point was death from coronary heart disease or stroke, non-fatal myocardial infarction or stroke, or amputation above the ankle for critical limb ischemia. The trial authors found no evidence to support the use of aspirin in isolation or combination with antioxidant therapy in the primary prevention of cardiovascular events and mortality in this diabetic popoulation with asymptomatic PAD.^40^ An important limitation in the study of this population is that the authors defined PAD using an ABI of <0.99, which diminishes the specificity of the ABI.^9^ A subsequent study of over 3000 patients with asymptomatic PAD, defined as ABI <0.95, and no other symptomatic CVD were followed over a mean period of 8.2 years. Patients were randomized to receive low dose enteric coated aspirin or placebo for primary prevention of the primary endpoint of composite initial fatal or nonfatal coronary event or stroke or revascularization. Secondary endpoints were all-cause mortality or any initial vascular event including angina, intermittent claudication or transient ischemic attack. Ultimately, the results of this trial did not support the use of aspirin for primary prevention in patients with asymptomatic PAD to significantly reduce the aforementioned endpoints.^41,42^ However, this study also did not use the standard ABI measurement for PAD. Indeed, the diagnosis was made by using the lowest ABI pressure rather than the highest. In both studies, it is unclear if a true PAD population was studied. In both studies, the rates of adverse events were similar to non-PAD subjects, suggesting a dilution of patients with true disease and limiting the understanding of the aspirin intervention.
Antiplatelet therapy remains a staple in secondary prevention of CVD and in primary prevention of patients with symptomatic PAD. The most recently published American Heart Association/American College of Cardiology Guidelines on the Management of Patients with Lower Extremity Peripheral Artery Disease Executive Summary from 2016 reflect the more neutral outcomes with aspirin for primary prevention in patients with asymptomatic PAD and recommend that it is reasonable to start this therapy in patients with asymptomatic PAD with ABI ≤0.9 to reduce the risk of MI, stroke or CVD death (Class of Recommendation: IIa).^43^
We believe, based on the outcomes data and atypical populations studied in clinical trials of asymptomatic patients, that antiplatelet therapy should be considered.
The advent of HMG-CoA reductase inhibitor (statin) therapy has fundamentally changed atherosclerotic CVD medical management. Several studies have explored the anti-inflammatory properties of statin and demonstrated their role in inducing atherosclerotic plaque regression.^44,45^ Statins play an integral role in risk reduction for patients with asymptomatic peripheral artery disease by reducing major adverse CVD events (MACE) and all-cause mortality. In one study of nearly 5500 patients, the number needed to treat to prevent MACE or mortality was 200 and 239, respectively.^46^ Statin’s protective effects on limb outcomes have been investigated and associated with improved outcomes.^47^ Additionally, a large epidemiological study of over 150,000 patients demonstrated a dose-dependent reduction in limb loss and mortality where the highest benefit was seen in high-intensity statin formulations.^48^ There has yet to be a large placebo controlled trial focused on asymptomatic PAD and limb outcomes.
The anti-inflammatory properties of statins may reduce claudication. One randomized, double-blind, parallel-design study that included 354 persons with claudication attributable to PAD were treated with placebo, low dose (10 mg) and high dose (80 mg) atorvastatin. The patients were assessed for functional status at baseline and 12 months for changes in treadmill exercise time, patient-reported measures of physical activity and questionnaire-based quality of life. This study demonstrated that treatment with high dose atorvastatin improved pain-free walking distance in patients with intermittent claudication but did not change absolute walking distance.^49^ This supports the hypothesis that inflammation and dysmetabolism play a role in the underlying pathophysiology of claudication.
The Heart Outcomes Prevention Evaluation (HOPE) study was a randomized placebo-controlled prospective study of patients with PAD to characterize the impact of ACE-inhibitor therapy on clinical outcomes. This study of over 3000 PAD patients demonstrated that Ramipril reduced incident MACE regardless of PAD symptoms status. In addition, the HOPE study demonstrated that low ABI in the absence of clinical symptoms was a strong predictor of morbidity and mortality.^50,51^
Supervised exercise therapy improves walking ability, overall functional status, and health-related quality of life in patients with claudication.^52^ Exercise therapy also appears to help those with asymptomatic PAD. Patients with asymptomatic PAD were enrolled in a 12 week in home self-monitored physical activity program while the control group was six bimonthly online videos involving health recommendations related to PAD but were otherwise asked to continue normal activities and routines. Modest improvements in microvascular reactivity but not arterial stiffness were demonstrated after a 12 week home exercise intervention targeting sedentary behavior reduction and increased lifestyle physical activity in individuals with asymptomatic PAD.^53^ Supervised exercise therapy programs appear to have objective positive impacts on microcirculatory endothelial function in the limbs of patients with asymptomatic PAD.
The Mediterranean Diet, characterized by high intakes of fruits and vegetables with high levels of antioxidants, has been touted as a primary prevention strategy for atherosclerotic CVD.^54,55^ There is a dearth of quality scientific literature reviewing the relationship between diet and asymptomatic PAD. A retrospective analysis of 425 pre-menopausal women with asymptomatic PAD studied patient adherence to the Mediterranean Diet,^56^ and its association with the ABI. Women in the low quartiles of adherence to the Mediterranean Diet had a lower ABI.^57^
Tobacco smokers have a dose-dependent risk of developing asymptomatic PAD.^58^ Smoking promotes oxidative stress,^59^ dyslipidemia^60^ and endothelial dysfunction.^61^ Smoking cessation represents a cost-effective intervention that should be incorporated in the treatment of asymptomatic PAD.
The ABI is a low cost, non-invasive study with far-reaching access to both urban and rural healthcare providers.^62^ Attempts have been made to demonstrate the cost effectiveness of initiating targeted screening and pharmacotherapeutic interventions to prevent subsequent CVD in this patient population.^63,64^ Currently, access to the ABI for diagnostic testing is variable with unsupported criteria to limit its use.^65^ Further, population screening, despite evidence of reductions in mortality and in-hospital time for PAD^64^ remains a non-recommended service. The United States Preventive Services Task Force most recent recommendation published in 2018 reports insufficient evidence to support screening asymptomatic patients for peripheral artery disease using the ABI.^66^
Symptomatic PAD, what we have come to know as intermittent claudication, was initially described in the mid 19th century. In contrast, asymptomatic PAD is a modern construction and less understood phenomenon. The disease is best characterized as decreased perfusion at the level of the ankle, as measured by ABI, and absence of claudication symptoms reported with validated claudication questionnaires. Asymptomatic PAD associates directly with systemic manifestations, limb and CVD morbidity, and mortality. The mainstays of therapy have similarities to other atherosclerotic CVD: lifestyle modification, aspirin and statin therapy. Asymptomatic PAD patients represent a readily identifiable group at-risk of serious CVD morbidity. Attempts have been made to demonstrate the cost-effectiveness of screening for asymptomatic PAD. This disease entity warrants additional attention and future investigation to improve our existing armament of treatment options.