The Impact of Peripheral Arterial Disease on Patients w i t h C o n g e s t i v e H e a r t F a i l u re Amit N. Keswani, MD, Christopher J. White, MD* KEYWORDS Congestive heart failure Peripheral arterial disease Peripheral angioplasty
KEY POINTS
INTRODUCTION AND BACKGROUND Peripheral arterial disease (PAD) includes a large group of arterial disorders in which atherosclerosis is the predominant etiology. Atherosclerotic PAD leads to progressive stenosis/occlusion, or aneurysmal dilation of noncoronary arteries that supply the brain, visceral organs, and limbs. Lower extremity PAD is the preferred clinical term that should be used to denote stenotic, occlusive, and/or aneurysmal diseases of the abdominal aorta and lower extremities.1 Atherosclerosis remains the most common cause of PAD, although many other additional pathologic processes can contribute to stenosis or aneurysms of the noncoronary arterial circulation. Congestive heart failure (CHF) also has been implicated in increased patient morbidity and mortality, and has been shown that, along with other comorbid illnesses commonly occurring within this disease, often comprise synergistic negative
outcomes. As an independent risk factor, PAD has been shown to cause worse patient outcomes.2–6 CHF and PAD share risk factors, pathophysiology, treatment strategies, and prognostic features, with a worse overall prognosis in patients who have concurrent CHF and PAD.7–11 The presence of PAD is associated with a twofold increase in the prevalence of CHF.12 Shared risk factors for CHF and PAD include increased age, diabetes, tobacco use, atherosclerosis, and poor renal function.2,13 The self-reported prevalence of cardiovascular disease (CVD) in the United States (coronary heart disease, CHF, or stroke) was 12.9%.14 The prevalence of PAD in patients with CHF across 3 racial/ethnic groups was 17.1%.14 PAD is most commonly asymptomatic, so it is underdiagnosed in the general population.6 In matched patients with PAD and CHF, all-cause mortality occurred in 43% of the patients with CHF with PAD and 33% of the patients with CHF without PAD, and the patients with CHF without
Department of Cardiology, Ochsner Clinic Foundation, Ochsner Clinical School, University of Queensland, New Orleans, LA, USA * Corresponding author. Department of Cardiology, Ochsner Clinic Foundation, Ochsner Clinical School, University of Queensland, 1514 Jefferson Highway, Jefferson, LA 70121. E-mail address: [email protected] Heart Failure Clin 10 (2014) 327–338 http://dx.doi.org/10.1016/j.hfc.2013.10.006 1551-7136/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
heartfailure.theclinics.com
Peripheral arterial disease (PAD) is quite prevalent in patients with congestive heart failure (CHF). PAD and CHF share several similar risk factors. Patients with PAD and concomitant CHF have increased hospitalizations as well as worse overall prognosis. Risk factor modification and supervised exercise training are effective treatments of patients with PAD. A comprehensive, multidisciplinary approach to patients with PAD and CHF is needed to potentially improve patient outcomes.
328
Keswani & White PAD had significantly greater survival than patients with PAD.8 The health care utilization of patients with concomitant PAD and CHF is significantly increased when compared with utilization of patients with CHF without PAD.8 The Controlled Rosuvastatin Multinational Trial in Heart Failure Trial (CORONA) found that 12.7% of patients with CHF had PAD (Figs. 1 and 2, Table 1).7 Patients with PAD were more likely to be hospitalized for cardiovascular reasons and were at greater risk of cardiovascular death as well as allcause mortality. In the Upon further analysis of the Heart Failure–A Controlled Trial Investigating Outcomes in Exercise Training (HF-ACTION) trial, patients with PAD and CHF had decreased baseline functional capacity compared with patients with CHF without PAD, and those with PAD had substantially worse clinical outcomes (Fig. 3, Table 2).11
More recent studies show that more than 50% of patients with clinically evident CHF have normal left ventricular ejection fraction15,16 and are now referred to as “heart failure with preserved ejection fraction” (HFpEF) as compared with “heart failure with reduced ejection fraction” (HFrEF). The overall prognosis of patients with HFpEF is similar to the prognosis of patients with HFrEF.15,16 PAD had a more deleterious effect in patients with HFpEF compared with those with HFrEF, which points to a role for ventriculo-vascular coupling in the development of HFpEF.10 In this article, we review lower extremity PAD, those without symptoms but an abnormal ankle brachial index, intermittent claudication, and critical limb ischemia, and their impact for patients with CHF.
EPIDEMIOLOGIC INSIGHTS BETWEEN PAD AND CHF The documented worldwide prevalence of lower extremity PAD ranges from 3% to 12%.1,17–21 The PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program included 6979 subjects, and found the prevalence of PAD almost 30% in individuals at high risk for PAD (50–69 years of age and diabetes mellitus or >10 pack-year history of smoking, or >70 years of age). This study also demonstrated a significant overlap of disease and showed 16% of patients had concomitant PAD and CVD, which included patients with CHF.22 PAD disproportionately affects individuals who are older, African American, and current smokers, and those who have diabetes or abnormal renal function. PAD in those who are Caucasian has a prevalence of 13.2%, 22.8% in African American individuals, and 13.7% among Hispanic individuals.23 The prevalence of concomitant CHF and PAD in those who are Caucasian is 25.9%, African American is 13.7%, and Hispanic is 13.4%.14 Additional studies demonstrate an increased prevalence of CHF in patients with PAD ranging from 5.3% to 13.9%.12,22,24
PATHOPHYSIOLOGY AND RISK FACTORS
Fig. 1. Kaplan Meier plots for all-cause mortality (A) and all-cause hospitalization (B) by a history of PAD. (From Ahmed MI, Aronow WS, Criqui MH, et al. Effects of peripheral arterial disease on outcomes in advanced chronic systolic heart failure: a propensitymatched study. Circ Heart Fail 2010;3(1):121; with permission.)
Although no single targeted study addresses actual treatment of concomitant PAD and CHF, current guidelines recommend treatment to reduce several similarly associated risk factors in CHF and PAD.25,26 Atherosclerosis is the most common cause of lower extremity PAD and risk factors for development of atherosclerosis include hypertension, diabetes, and cigarette smoking.20 Patients with known atherosclerotic disease are
Peripheral Arterial Disease
Fig. 2. Association between PAD and all-cause mortality in subgroups of propensity score-matched patients in the BEST trial. (From Ahmed MI, Aronow WS, Criqui MH, et al. Effects of peripheral arterial disease on outcomes in advanced chronic systolic heart failure: a propensity-matched study. Circ Heart Fail 2010;3(1):121; with permission.)
also more likely to develop CHF as well as PAD, and current guidelines recommend modifying these risk factors associated with the development of atherosclerosis.19,27,28 Hypertension (HTN) is a known risk factor for atherosclerosis and development of both PAD and CHF.29–34 Additionally, hypertension is identified as a recognized risk of development of both HFpEF and HFrEF.25,35,36 Long-term treatment of both systolic and diastolic hypertension has been shown to reduce the risk of incident CHF by 50%.37–40 Cigarette smoking and diabetes are additional risk factors for development of lower extremity PAD and CHF. Cigarette smoking is 2 to 3 times more likely to cause lower extremity PAD than coronary artery disease.41 Tobacco use is also strongly associated as an independent risk factor for CHF.36,42 The presence of diabetes mellitus increases the risk of lower extremity PAD by twofold to fourfold.43–45 Additionally, insulin resistance has been shown to be an important risk factor in development of CHF.42,46–48 The prevalence of smoking and diabetes in patients with concomitant PAD and CVD when compared with the reference group in the PARTNERS study is increased. In patients with concomitant PAD and CVD, the prevalence of
smokers was 64% and significantly higher when compared with the study reference group, which was 50%. The prevalence of diabetes mellitus in patients with concomitant PAD and CVD was significantly higher (44%) when compared with the reference group (34%) in the PARTNERS study.22
DIAGNOSTIC ISSUES A careful and detailed history and physical examination is essential in the assessment of patients with CHF as well as distinguishing PAD from nonvascular causes of lower extremity pain. When assessing patients for PAD, fewer than 20% report typical symptoms of intermittent claudication (leg-muscle discomfort on exertion that is relieved with rest), making this assessment a clinical challenge.49 In the assessment of PAD, it is important to delineate chronic stable PAD (intermittent claudication) from chronic critical PAD (critical limb ischemia [CLI]), as this will help drive treatment and therapy. Chronic stable PAD classically presents as intermittent claudication, and physical examination findings include changes in skin color, decreased pulses, cool extremities, and decreased hair distribution. However many patients with PAD are
329
330
Step 1: Adjusted for Demographic/Clinical Variables (n 5 20 Variables) Type of End Point Mortality All-cause (n 5 934) Cardiovascular death (n 5 725) Sudden death (n 5 407) Death due to worsening heart failure (n 5 230) Hospitalizations Cardiovascular cause (n 5 1452) Worsening heart failure (n 5 823) Combined end points Primary (n 5 883) Coronary (n 5 741) Athero-thrombotic (n 5 284) Death or heart failure hospitalization (n 5 1376)
Step 2: Step 1 D Laboratory Values (n 5 27 Variables)
Step 3: Step 2 D NT proBNP and hs-C-Reactive Protein (n 5 29 Variables)
Hazard Ratio (95% CI)
Rank
P Value
Hazard Ratio (95% CI)
Rank
P Value
Hazard Ratio (95% CI)
Rank
P Value
1.40 (1.18–1.67) 1.43 (1.17–1.75) 1.28 (0.97–1.69) 1.61 (1.14–2.27)
7 7 9 8
.0002 .0005 .0835 .0064
1.33 1.35 1.21 1.50
(1.11–1.58) (1.11–1.65) (0.91–1.59) (1.06–2.13)
10 11 12 11
.0017 .0034 .19 .021
1.27 (1.07–1.52) 1.31 (1.07–1.60) 1.17 (0.89–1.55) 1.46 (1.03–2.07)
12 9 13 10
.0076 .0089 .26 .035
1.45 (1.25–1.67) 1.30 (1.07–1.58)
3 8
KEY POINTS
INTRODUCTION AND BACKGROUND Peripheral arterial disease (PAD) includes a large group of arterial disorders in which atherosclerosis is the predominant etiology. Atherosclerotic PAD leads to progressive stenosis/occlusion, or aneurysmal dilation of noncoronary arteries that supply the brain, visceral organs, and limbs. Lower extremity PAD is the preferred clinical term that should be used to denote stenotic, occlusive, and/or aneurysmal diseases of the abdominal aorta and lower extremities.1 Atherosclerosis remains the most common cause of PAD, although many other additional pathologic processes can contribute to stenosis or aneurysms of the noncoronary arterial circulation. Congestive heart failure (CHF) also has been implicated in increased patient morbidity and mortality, and has been shown that, along with other comorbid illnesses commonly occurring within this disease, often comprise synergistic negative
outcomes. As an independent risk factor, PAD has been shown to cause worse patient outcomes.2–6 CHF and PAD share risk factors, pathophysiology, treatment strategies, and prognostic features, with a worse overall prognosis in patients who have concurrent CHF and PAD.7–11 The presence of PAD is associated with a twofold increase in the prevalence of CHF.12 Shared risk factors for CHF and PAD include increased age, diabetes, tobacco use, atherosclerosis, and poor renal function.2,13 The self-reported prevalence of cardiovascular disease (CVD) in the United States (coronary heart disease, CHF, or stroke) was 12.9%.14 The prevalence of PAD in patients with CHF across 3 racial/ethnic groups was 17.1%.14 PAD is most commonly asymptomatic, so it is underdiagnosed in the general population.6 In matched patients with PAD and CHF, all-cause mortality occurred in 43% of the patients with CHF with PAD and 33% of the patients with CHF without PAD, and the patients with CHF without
Department of Cardiology, Ochsner Clinic Foundation, Ochsner Clinical School, University of Queensland, New Orleans, LA, USA * Corresponding author. Department of Cardiology, Ochsner Clinic Foundation, Ochsner Clinical School, University of Queensland, 1514 Jefferson Highway, Jefferson, LA 70121. E-mail address: [email protected] Heart Failure Clin 10 (2014) 327–338 http://dx.doi.org/10.1016/j.hfc.2013.10.006 1551-7136/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
heartfailure.theclinics.com
Peripheral arterial disease (PAD) is quite prevalent in patients with congestive heart failure (CHF). PAD and CHF share several similar risk factors. Patients with PAD and concomitant CHF have increased hospitalizations as well as worse overall prognosis. Risk factor modification and supervised exercise training are effective treatments of patients with PAD. A comprehensive, multidisciplinary approach to patients with PAD and CHF is needed to potentially improve patient outcomes.
328
Keswani & White PAD had significantly greater survival than patients with PAD.8 The health care utilization of patients with concomitant PAD and CHF is significantly increased when compared with utilization of patients with CHF without PAD.8 The Controlled Rosuvastatin Multinational Trial in Heart Failure Trial (CORONA) found that 12.7% of patients with CHF had PAD (Figs. 1 and 2, Table 1).7 Patients with PAD were more likely to be hospitalized for cardiovascular reasons and were at greater risk of cardiovascular death as well as allcause mortality. In the Upon further analysis of the Heart Failure–A Controlled Trial Investigating Outcomes in Exercise Training (HF-ACTION) trial, patients with PAD and CHF had decreased baseline functional capacity compared with patients with CHF without PAD, and those with PAD had substantially worse clinical outcomes (Fig. 3, Table 2).11
More recent studies show that more than 50% of patients with clinically evident CHF have normal left ventricular ejection fraction15,16 and are now referred to as “heart failure with preserved ejection fraction” (HFpEF) as compared with “heart failure with reduced ejection fraction” (HFrEF). The overall prognosis of patients with HFpEF is similar to the prognosis of patients with HFrEF.15,16 PAD had a more deleterious effect in patients with HFpEF compared with those with HFrEF, which points to a role for ventriculo-vascular coupling in the development of HFpEF.10 In this article, we review lower extremity PAD, those without symptoms but an abnormal ankle brachial index, intermittent claudication, and critical limb ischemia, and their impact for patients with CHF.
EPIDEMIOLOGIC INSIGHTS BETWEEN PAD AND CHF The documented worldwide prevalence of lower extremity PAD ranges from 3% to 12%.1,17–21 The PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program included 6979 subjects, and found the prevalence of PAD almost 30% in individuals at high risk for PAD (50–69 years of age and diabetes mellitus or >10 pack-year history of smoking, or >70 years of age). This study also demonstrated a significant overlap of disease and showed 16% of patients had concomitant PAD and CVD, which included patients with CHF.22 PAD disproportionately affects individuals who are older, African American, and current smokers, and those who have diabetes or abnormal renal function. PAD in those who are Caucasian has a prevalence of 13.2%, 22.8% in African American individuals, and 13.7% among Hispanic individuals.23 The prevalence of concomitant CHF and PAD in those who are Caucasian is 25.9%, African American is 13.7%, and Hispanic is 13.4%.14 Additional studies demonstrate an increased prevalence of CHF in patients with PAD ranging from 5.3% to 13.9%.12,22,24
PATHOPHYSIOLOGY AND RISK FACTORS
Fig. 1. Kaplan Meier plots for all-cause mortality (A) and all-cause hospitalization (B) by a history of PAD. (From Ahmed MI, Aronow WS, Criqui MH, et al. Effects of peripheral arterial disease on outcomes in advanced chronic systolic heart failure: a propensitymatched study. Circ Heart Fail 2010;3(1):121; with permission.)
Although no single targeted study addresses actual treatment of concomitant PAD and CHF, current guidelines recommend treatment to reduce several similarly associated risk factors in CHF and PAD.25,26 Atherosclerosis is the most common cause of lower extremity PAD and risk factors for development of atherosclerosis include hypertension, diabetes, and cigarette smoking.20 Patients with known atherosclerotic disease are
Peripheral Arterial Disease
Fig. 2. Association between PAD and all-cause mortality in subgroups of propensity score-matched patients in the BEST trial. (From Ahmed MI, Aronow WS, Criqui MH, et al. Effects of peripheral arterial disease on outcomes in advanced chronic systolic heart failure: a propensity-matched study. Circ Heart Fail 2010;3(1):121; with permission.)
also more likely to develop CHF as well as PAD, and current guidelines recommend modifying these risk factors associated with the development of atherosclerosis.19,27,28 Hypertension (HTN) is a known risk factor for atherosclerosis and development of both PAD and CHF.29–34 Additionally, hypertension is identified as a recognized risk of development of both HFpEF and HFrEF.25,35,36 Long-term treatment of both systolic and diastolic hypertension has been shown to reduce the risk of incident CHF by 50%.37–40 Cigarette smoking and diabetes are additional risk factors for development of lower extremity PAD and CHF. Cigarette smoking is 2 to 3 times more likely to cause lower extremity PAD than coronary artery disease.41 Tobacco use is also strongly associated as an independent risk factor for CHF.36,42 The presence of diabetes mellitus increases the risk of lower extremity PAD by twofold to fourfold.43–45 Additionally, insulin resistance has been shown to be an important risk factor in development of CHF.42,46–48 The prevalence of smoking and diabetes in patients with concomitant PAD and CVD when compared with the reference group in the PARTNERS study is increased. In patients with concomitant PAD and CVD, the prevalence of
smokers was 64% and significantly higher when compared with the study reference group, which was 50%. The prevalence of diabetes mellitus in patients with concomitant PAD and CVD was significantly higher (44%) when compared with the reference group (34%) in the PARTNERS study.22
DIAGNOSTIC ISSUES A careful and detailed history and physical examination is essential in the assessment of patients with CHF as well as distinguishing PAD from nonvascular causes of lower extremity pain. When assessing patients for PAD, fewer than 20% report typical symptoms of intermittent claudication (leg-muscle discomfort on exertion that is relieved with rest), making this assessment a clinical challenge.49 In the assessment of PAD, it is important to delineate chronic stable PAD (intermittent claudication) from chronic critical PAD (critical limb ischemia [CLI]), as this will help drive treatment and therapy. Chronic stable PAD classically presents as intermittent claudication, and physical examination findings include changes in skin color, decreased pulses, cool extremities, and decreased hair distribution. However many patients with PAD are
329
330
Step 1: Adjusted for Demographic/Clinical Variables (n 5 20 Variables) Type of End Point Mortality All-cause (n 5 934) Cardiovascular death (n 5 725) Sudden death (n 5 407) Death due to worsening heart failure (n 5 230) Hospitalizations Cardiovascular cause (n 5 1452) Worsening heart failure (n 5 823) Combined end points Primary (n 5 883) Coronary (n 5 741) Athero-thrombotic (n 5 284) Death or heart failure hospitalization (n 5 1376)
Step 2: Step 1 D Laboratory Values (n 5 27 Variables)
Step 3: Step 2 D NT proBNP and hs-C-Reactive Protein (n 5 29 Variables)
Hazard Ratio (95% CI)
Rank
P Value
Hazard Ratio (95% CI)
Rank
P Value
Hazard Ratio (95% CI)
Rank
P Value
1.40 (1.18–1.67) 1.43 (1.17–1.75) 1.28 (0.97–1.69) 1.61 (1.14–2.27)
7 7 9 8
.0002 .0005 .0835 .0064
1.33 1.35 1.21 1.50
(1.11–1.58) (1.11–1.65) (0.91–1.59) (1.06–2.13)
10 11 12 11
.0017 .0034 .19 .021
1.27 (1.07–1.52) 1.31 (1.07–1.60) 1.17 (0.89–1.55) 1.46 (1.03–2.07)
12 9 13 10
.0076 .0089 .26 .035
1.45 (1.25–1.67) 1.30 (1.07–1.58)
3 8
