Abstract

Atherothrombotic disease is one of the leading causes of mortality across the globe. A significant percentage of patients have a combined involvement of more than one vascular bed at the same time, which has a substantial effect on cardiovascular outcomes. Peripheral arterial disease is often underdiagnosed, especially in patients with coronary artery disease. This article reviews the approach to patients with combined peripheral and coronary artery disease and highlights the importance of identifying the presence of combined disease, their risk factors, diagnosis and management.

VASCULAR DISEASE MANAGEMENT 2010;7:E135–E141

Key words: atherothrombotic disease, coronary artery disease, peripheral artery disease, cardiovascular risk factors

Introduction

Coronary artery disease (CAD) and peripheral arterial disease (PAD) are important manifestations of atherothrombotic disease. A large proportion of patients with atherothrombotic disease have polyvascular disease.^1–7 The presence of these two concurrently has a huge negative impact on cardiovascular morbidity and mortality.^1,3,5,6,8,9 PAD is often overlooked during the diagnosis and management of CAD, even among a specialist’s care.^10–12 With cardiovascular disease being one of the leading causes of mortality in the United States and across the globe, strategies targeting patients with both CAD and PAD need to be reevaluated.^13,14

Prevalence and Risk of Combined PAD and CAD

The prevalence of CAD and PAD. Both CAD and PAD are manifestations of atherothrombotic disease. Recent data suggest that more than 13 million suffer from CAD, while more than 8 million adults have PAD in the United States.^13,14 Many patients are found to have involvement of both these vascular beds, with the prevalence of both conditions increasing with age.^{1,2,4,7,12,15–17} In the Reduction of Atherothrombosis for Continued Health (REACH) Registry, an international observational registry of 67,888 patients aged > 45 years with an established history of CAD, PAD, cerebrovascular disease (CVD)or ≥ 3 atherosclerotic risk factors who were followed prospectively for 24 months, 4.7% had both CAD and PAD1 (Figure 1). Several studies have also noted a higher prevalence of PAD in patients with CAD, especially in patients with acute coronary syndromes or those undergoing coronary artery revascularization.^{2,4,7,12,15–17} Yet, PAD is still an underdiagnosed and undertreated condition both under primary and specialty care.10–12,18 Results from The PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program showed that in primary-care practice, physician awareness of PAD is relatively low.10 This study was conducted at 27 sites (350 primary-care practices) in United States recruiting 6,979 patients aged > 70 years or 50–69 years of age with a history of smoking or diabetes mellitus who were evaluated by history and ankle brachial index (ABI) measurements. This study was conducted to assess the ability of PAD diagnosis in the primary-care setting and also assess the awareness of both patients and physicians.¹⁰ Intermittent claudication, the classic manifestation of PAD, is infrequently seen in patients, especially those with CAD.^10,19 A large percentage of high-risk patients with coexistent disease may not be diagnosed with underlying PAD, as they may be largely asymptomatic. Thus, standard screening questionnaires have poor sensitivity.¹⁹ With the use of the ABI, studies have shown that there is a significant increase in diagnosis of patients with PAD who have coexistent CAD.^10,20–22 This suggests an important role for ABI in screening of high-risk individuals, especially those with a coexistent diagnosis of CAD.

CAD in patients with PAD.

PAD is considered a strong marker for systemic atherosclerotic disease, and a large number of patients have coexistent CAD. A systematic review with nearly 45,000 patients from 11 different studies conducted in 6 different countries showed that a low ABI (< 0.9) was associated with an increased presence of clinical cardiovascular disease.²³ A high percentage of patients with PAD have underlying CAD, especially in the elderly population. In a study done involving geriatric patients, CAD was present in more than two-thirds of the patients who had a diagnosis of PAD.² Also, it has been demonstrated that patients with PAD have a higher incidence of asymptomatic CAD.^4,17,24

Studies have consistently shown that patients with PAD have more severe CAD, often with severe and multivessel involvement, than CAD patients without PAD.^12,15,25,26 Sukhija et al showed that patients with PAD had a higher incidence of left main and triple-vessel disease compared to the cohort without PAD.²⁵ Similar results of a higher prevalence of multivessel disease and left main disease were seen in the Peripheral Arterial Disease in Interventional Patients Study (PIPS), a prospective study assessing PAD by history, medical questionnaires and ABI measurements in 800 patients aged > 70 years or 50–69 years with a history of smoking and/or diabetes referred for coronary angiography without a prior diagnosis of PAD.¹²

PAD in patients with CAD. Similarly, CAD is found to be a strong predictor of the presence of premature PAD. In a population-based observational study using the National Health and Nutritional Survey (NHANES), the presence of CAD was an independent predictor of premature PAD, defined as PAD occurring in patients < 60 years of age.²⁷ This study was conducted to determine the differences in risk factors for developing PAD in patients < 60 years old against patients > 60 years old.²⁷ The use of ABI in screening patients with CAD has significantly increased the diagnosis of PAD, as seen in this study. The results from the PIPS also concluded that patients with multivessel CAD had a two-fold higher risk of being diagnosed with PAD.¹² The presence of combined CAD and PAD, therefore, represents a very high-risk group with an increased incidence of future cardiovascular events and poor outcomes.

Morbidity and Mortality

Cardiovascular disease is the leading cause of mortality in the United States and today, atherothrombotic disease is the leading cause of mortality in the world.^1,13,14 The presence of PAD increases the risk of all-cause mortality by many-fold, even in asymptomatic patients.^23,28,29 This increase in mortality is due to an increase in the incidence of cardiovascular events, mainly from CAD.^8,23,28–31

The literature suggests that the presence of PAD is a strong independent predictor of adverse short- and long-term outcomes in patients with cardiovascular disease. This poor prognosis has been consistently seen in those patients with PAD who present with acute coronary syndromes and in those undergoing coronary revascularization.^3,9,16,32,33 While the risk of periprocedural complications, including in-hospital death, is high in patients admitted for ACS or undergoing coronary revascularization who have underlying PAD, the mortality rate also remains high in this subgroup of patients during long-term follow-up.^5,6,31–34

Critical limb ischemia (CLI) is an important subset of PAD, and these patients tend to have poor prognosis. Patients with CLI have 25% mortality at 12-month follow-up after initial presentation.35 The leading cause of mortality in patients with CLI was found to be due to CAD in a study evaluating the long-term prognosis in diabetic patients with CLI.³⁶ These patients also have higher rates of limb loss.³⁵

Risk Factors for CAD and PAD

PAD and CAD are well-established arterial diseases. The REACH registry showed that approximately 1 in 6 of the 55,499 patients with symptomatic atherothrombosis suffered the disease in multiple arterial territories, and these results would be even higher if asymptomatic disease had been sought more routinely.1 Atherothrombosis as a systemic disease is well-supported by these findings, which suggest the involvement of various vascular beds synchronously. The observations made in this international registry found that risk factors were consistent predictors of both PAD and CAD.

Traditional cardiovascular risk factors. Traditional cardiovascular risk factors, namely hypertension, diabetes mellitus, smoking, hyperlipidemia, advanced age and obesity, contribute to most of the risk for the development of atherothrombosis.¹ The results of the REACH registry showed that these risk factors were more often present in patients with both PAD and CAD.¹ Recent data from the Framingham Heart Study have established that traditional risk factors, which were measured at baseline, were able to significantly predict the 30-year cardiovascular disease risk.³⁷

Studies have repeatedly shown that patients with combined PAD and CAD are older and have more comorbid cardiovascular risk factor profiles than do patients with a single vascular bed involvement. A study based on the NHANES data of 2,174 patients ≥ 40 years of age by Selvin et al demonstrated the presence of at least one or more risk factors in patients with PAD.³⁸ Angiographically, this high-risk group has much more severe and widespread coronary involvement, with increased frequency of left main or multivessel disease.^25,39 As described, the presence of PAD is a significant predictor of a severe CAD, while a diagnosis of CAD increases the risk for developing PAD prematurely, both in turn contributing to the other’s risk.^12,25,27 Even in patients with only premature PAD, hypertension and smoking have been found to be significant predictors, demonstrating the importance of traditional cardiovascular risk factors.²⁷

Chronic kidney disease (CKD) is also an independent predictor of PAD.40,41 Patients with CKD have a higher prevalence of obstructive coronary disease.42 Population-based studies have found that cardiovascular mortality is increased in patients with a decreased glomerular filtration rate.^42–44

Racial differences have also been identified in PAD, with African-American race a significant predictor of PAD compared to the Caucasian race.^38,45,46 This increased risk in African-Americans appears to be independent of traditional cardiovascular risk factors and is not yet fully understood.⁴⁶

Novel cardiovascular risk factors. Coronary risk assessment using novel cardiovascular risk factors has gained importance over the past decade, with studies showing an increased pro-inflammatory state in atherosclerotic patients. These markers include C-reactive protein (CRP), fibrinogen, interleukin-6, soluble forms of intercellular adhesion molecule-1 (sICAM-1), serum amyloid A (SAA), myeloperoxidase, the macrophage activation marker neopterin and the infection marker procalcitonin.^39,47,48

Inflammatory markers have been studied in PAD as well, and results conclude that inflammation exhibits an independent association with PAD.^45,48 The results from studies examining the relation between inflammation and atherosclerosis have demonstrated that patients with combined CAD and PAD exhibit a higher inflammatory state than do patients with CAD alone.⁴⁹ Inflammatory markers have also correlated with the extent of disease involvement and mortality risk.^39,50

However, the importance of these novel markers as targets for therapy is not yet clear. For example, an elevated homocysteine level is identified as a risk factor for PAD and CAD, but thus far, studies designed to show outcome benefit from lowering homocysteine levels with folic acid have been disappointing, with no benefit seen.^51–53

Management of Patients with CAD and PAD

The risk factors for atherothrombotic diseases are consistent across the vascular beds.¹ The traditional cardiovascular risk factors as detailed earlier play a very significant role in the occurrence and progression of both PAD and CAD. Although multiple studies have demonstrated the benefit of appropriate guideline-driven management of these risk factors, considerable disparities still exist in care rendered to patients with PAD compared to patients with CAD.¹¹ Multiple studies have shown that PAD patients receive less aggressive therapy and risk-factor modification than CAD patients.^{5,9,16,18,54,55} Disparities have been found both in physicians’ diagnoses and approaches to the disease.^10,12,18 Also, patients with PAD themselves appear to underestimate the benefits of aggressively controlling their own risk factors.⁵⁶

Controlling risk factors has shown to reduce the cardiovascular event rates, but achieving the target goal has been more difficult in patients with PAD than CAD.^57,58 Studies consistently show an increased risk of mortality in patients with synchronous PAD and CAD, thus strategies to diagnose and treat this high-risk group of patients need to be reinforced.

Diagnosis of Combined Disease

The prevalence of the involvement of a second vascular bed in the presence of either CAD or PAD is high. There is, however, a significant pool of patients who have asymptomatic involvement of a second vascular bed and in whom this aspect of their disease is not appreciated. Physician strategies should involve an active search for the presence of combined disease. Current guidelines recommend a comprehensive review of vascular symptoms and examination of patients with risk factors for PAD.⁵² The diagnosis of PAD is done easily with the use of the ABI in most patients⁵⁹ (Table 1). Although a few studies have suggested that obtaining a routine ABI has increased the percentage of asymptomatic PAD being diagnosed in CAD patients, its use in all patients with CAD has not been recommended.^4,21,60 A diagnosis of CLI should be suspected in patients with chronic rest pain or skin ulcerations or gangrenous changes due to the high rates of mortality and morbidity from CAD in this subgroup.^35,36 The clinical diagnosis of CLI is confirmed routinely by ABI or transcutaneous oxygen tension or toe pressure measurements.³⁵

Atherothrombotic disease should be approached as a systemic disease rather than as individual vascular bed involvement. The literature has suggested the involvement of two vascular beds in a high percentage in patients with atherothrombotic disease. The approach to managing patients with combined disease should involve aggressive risk-factor assessment and should strive to achieve target goals based on the existing guidelines.

Risk-Factor Modification and Treatment

Smoking cessation. Guidelines for the management of atherosclerotic disease have recommended a complete cessation of smoking as the target goal for these patients.^52,61 Smoking is regarded as the most important modifiable risk factor, especially in PAD patients, particularly those with CLI.^35,62 The recommendations are to ask every patient about smoking during each visit and to advise them in a clear, strong and personalized manner to quit smoking. The patient’s willingness to quit needs to be assessed and assisted by developing a plan for cessation. A combination of physician advice, regular follow-up with appropriate pharmacologic interventions and referral programs have achieved the highest rates of smoking cessation among these patients.^52,63 Various pharmacologic agents are currently available63 (Table 2).

Hypertension. Antihypertensive therapy is known to reduce cardiovascular events. The subgroup of patients who have combined CAD and PAD are at extremely high risk of cardiovascular events. This group of patients should be aggressively treated in order to reach a target blood pressure goal of ≤ 140/90 mmHg or ≤ 130/80 mmHg in the presence of diabetes or CKD, as recommended by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure.52 The approach toward managing high blood pressure should include aggressive lifestyle modification by weight control, healthy diet, low sodium intake, regular exercise and limiting alcohol consumption.^52,61

Appropriate medication to achieve the target blood pressure, depending on risk-factor profile, should be selected for this high-risk group of patients. These medications primarily include beta-blockers, angiotensin-converting enzyme (ACE)-inhibitors and other drugs.⁵² Beta-blockers are indicated in patients with CAD, as their use has shown to reduce future cardiovascular events, and current recommendations have found no contraindications to the use of beta-blockers in patients with coexistent PAD. Contrary to widespread belief, beta-blockers have not been found to adversely affect walking capacity.^52,61

For patients with CAD, especially those with decreased left ventricular function (ejection fraction < 40%), diabetes and CKD, the use of ACE-inhibitors is recommended. ACE-inhibitors in patients with combined disease is beneficial, as a significant reduction in the risk of adverse cardiovascular events is seen. This risk reduction is seen in both symptomatic and asymptomatic PAD patients.^52,61

Lipid management. Low-density lipoprotein (LDL) cholesterol is the primary target for lipid-lowering therapy.64 Patients with a combined diagnosis of PAD and CAD constitute a very high-risk group of patients with an increased rate of adverse cardiovascular events. Current Adult Treatment Panel (ATP) III guidelines recommend a target LDL-C of < 100 mg/dl. Patients with a value > 100 mg/dl should be started on LDL-lowering therapy. This is coupled with aggressive lifestyle modification. Achieving the target goal has been shown to lead to a significant risk reduction. Hence, achieving the goal may involve a combination of drugs.^52,61 Recent data have suggested an optional goal of < 70 mg/dl for LDL-C in very high-risk patients, especially if the baseline LDL-C was between 70–100 mg/dl.⁶⁴ “Very high risk” is conferred by the presence of PAD and CAD with multiple major risk factors or poorly controlled risk factors, or with acute coronary syndromes.⁶⁴ Most of the patients with a combined disease have multiple risk factors and a goal of < 70 mg/dl for LDL-C should be sought.

Apart from LDL-C, treating other lipid fractions have also been shown to reduce the residual risk that remains after reaching target LDL-C goals. Current recommendations target non-high-density lipoprotein (HDL)-C, especially in patients with triglyceride levels > 200 mg/dl. The target goal is a reduction of non-HDL-C level to < 130 mg/dl by a more intensive reduction of LDL-C or medical therapy using niacin or fibric acid derivatives.⁶⁴ A combination of a statin and niacin has shown to decrease LDL-C and increase HDL-C levels.⁶⁴

Diabetes mellitus. A high percentage of patients with atherothrombotic disease have diabetes mellitus.¹ Diabetes has been closely linked to the development and progression of atherosclerosis, especially CAD.^65,66 The American Diabetic Association has recommended that patients with diabetes achieve the goal of a hemoglobin A1C level < 7%^52,61,67 through initiation of aggressive lifestyle modification, appropriate pharmacology therapy and control of other cardiovascular risk factors. This may potentially reduce overall cardiovascular mortality, especially in this high-risk group of patients with both PAD and CAD.⁶¹

Antiplatelet therapy. Large clinical trials have shown that the use of antiplatelet therapy including either aspirin or clopidogrel results in a significant reduction in cardiovascular events.68,69 Patients with PAD have increased platelet activation and a prothrombotic state and benefit from the use of antiplatelet therapy.⁷⁰ Current recommendations emphasize the use of antiplatelet therapy in every patient diagnosed with PAD and CAD; this therapy consists of aspirin (75–325 mg daily), or in cases of aspirin allergy, clopidogrel 75 mg daily.^52,61 However, the use of dual-antiplatelet therapy needs further study in patients with PAD alone. Dual-antiplatelet therapy is routinely used in patients with CAD who have undergone percutaneous revascularization or a recent ACS episode. The duration of dual-antiplatelet therapy is continued according to the recommended guidelines.^52,61

Weight management and physical exercise. Patients with combined disease should be encouraged to lose weight and maintain a healthy body mass index.⁶¹ Obesity predisposes to increased cardiovascular risk factors. An active search for metabolic syndrome should be done and appropriate life-style modifications and therapies considered.⁶¹ The current recommendation for patients with atherosclerotic disease is 30–60 minutes of moderate aerobic activity on most or all days of the week.⁶¹ However, in patients with PAD, claudication may be an important limiting factor. These patients benefit from a formal rehabilitation program that can lead to a demonstrable increase in walking time and reduced symptoms of claudication.^71,72 The exercise program may also benefit the patient’s cardiovascular risk profile.⁷¹

Anticlaudication therapy. Cilastozol, at a dose of 100 mg twice daily, has been effectively used in patients with claudication, with a significant improvement in symptoms and walking distance.⁵² A small improvement in the ABI has also been demonstrated. However, the use of cilastozol is not recommended in patients with heart failure. Appropriate risk-factor control such as smoking cessation and exercise should always be emphasized.⁵² Benefit from therapies for claudication like pentoxifylline, L-arginine, oral prostaglandins, vitamin E and others is not well-established.⁵²

Revascularization. Revascularization is routinely used in the management of patients with CAD as well as PAD. The optimal management strategy in patients with CLI includes early referral to vascular specialist and prompt revascularization so as to eliminate the physiologic features of CLI.^35,52 However, current recommendations do not favor coronary revascularization procedures in preparation for peripheral revascularization.³⁵ A secondary analysis from the Coronary Artery Revascularization Prophylaxis (CARP) trial with a cohort consisting of 510 patients with significant CAD randomized to coronary intervention versus no intervention found no significant differences in rates of myocardial infarction or death in either group, both perioperatively or at long-term follow-up.⁷³

Conclusion

Patients with a combined CAD and PAD represent a very high-risk group with a high rate of cardiovascular morbidity and mortality. Although the management of risk factors is similar in both conditions, the urgency to achieve the target goals for individual risk factors must be greater. The absolute benefits of secondary prevention are enormous in this subgroup, as these patients are at an increased risk for future events. Physicians must be aware that a significant percentage of patients have more than one vascular bed involved.

The approach to a patient with combined PAD and CAD involves a targeted approach with involvement of specialist care. Strategies to actively assess and manage the risk factors based on the current guidelines should be incorporated.

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From the Department of Internal Medicine, Detroit Medical Center (DMC), Detroit, Michigan, and the *University of Michigan, Ann Arbor, Michigan.

Disclosure: Dr. Froehlich discloses the following: Sanofi-Avenis – consultancy, speakers bureau, grants; Pfizer – consultancy, speakers bureau; Merck/Shering-Plough – speakers bureau, honoraria.

Address for correspondence: Vikas Veeranna, MD, 6071 West Outer Drive, Detroit, MI 48235. E-mail: vveerann@dmc.org