to ensure adequate monitoring and access including to assess ventricular systolic function and Aim to improve hemodynamic status, achieving a SBP (cid:116)90 mmHg, guided by physical sig ns and LV \201 lling pressures. As a general guide: \200 with view to PCI or CABG, if appropriate PCWP <15 mmHg in 100 \200\223200 mL aliquots. PCWP >15 mmHg edema). \200\224cautious administration of IV \202 uids (colloids) \200\224inotropic support diuretics (if pulmonary Inotropes should be avoided if at all possible in acutely ischemic patients. The aim should be to rapidly restore or maximize coronary \202 ow and off- load LV. Early revasculariza tion is vital and has been shown to decrease mortality. IABP will help to achieve these goa ls. If hemodynamic status does not improve after revascularization and IABP insertion, inotrope s should be used. The choice of agent can be dif \201 cult and should be guided in part by local protocols and expertise. Generally accepted choices depend on the clinical picture: \200 If the patient is hypotensive ( pulmonary edema) start with dopamine (up to 15 g/kg/min ), and if ineffective, one may substitute epinephrine and/or norepinephrine. CARDIOGENIC SHOCK 121 If the patient has adequate blood pressure ( pulmonary edema) give dobutamine to increase cardiac output (starting at 2.5 \200\2235 g/kg/min and increasing to 20 g/kg/min), tit rating to HR and hemodynamics. Phosphodiesterase inhibitors (PDIs) can be used as an altern ative. If hypotension and tachycardia complicate dobutamine/PDI treatment, norepinephrine c an be added as a second agent to achieve the desired hemodynamic effect. Use of diuretics, thrombolysis, gp IIb/IIIa antagonists, and LMWH/UFH should follow normal principles and are based on the clinical picture. CHAPTER 2 Coronary artery disease 122 Non-ST elevation myocardial infarction (NSTEMI)/unstable angina (UA) UA and NSTEMI are clos ely related conditions with similar clinical pres- entation, treatment, and pathogenesis bu t of varying severity. If there is biochemical evidence of myocardial damage, the condition is termed NSTEMI; in the absence of damage it is termed UA. Unlike patients with a STEMI, in whom diagnosis is generally made on presentation in the em ergency department, diagnosis of NSTEMI/UA may not be de \201 nitive on presentation and e volves over the subsequent hours to days. Therefore, management of patients with NSTEMI/UA is a pro- gression through a number of risk strati \201 cation processes dependent on hist ory, clinical features, and investigative results. These in turn determine the choice and t iming of a number of medical and/or invasive treatment strategies. Figure 2.5 is a summary of a recommended integrated care pathway illustrating a management plan for diagnosis and risk-directed treatment of a patient with STEMI/UA. Clinical presentation There are three distinct presentations: \200 \200 New-onset angina Rest angina prior stable, exertional angina) Increasing angina whom angina has become more frequent or longer in duration or requires a lower threshold to elicit) (in a patient without prior angina) (angina when patient is at rest; may occur in a patient with (in a patient with previously diagnosed angina for General examination must be undertaken to rule out pulmonary edema, assess hemodynamic stab ility, and look for cardiac valve abnormalities. Integrated management plan We recommend that all patients follow a local integrated care pa thway on presentation. The various stages are broadly outlined below. See relevant pages fo r further information. Initial stabilization \200 \200 \200 Transfer patient to an area with continuous ECG monitoring. Strict bed rest is required. Gi ve oxygen, aspirin 325 mg po, sublingual nitrates, and mild sedation if required. If pain p ersists, give morphine 2.5 \200\2235 mg IV prn with metoclopramide 10 mg IV for nausea. General investigations are similar to those for STEMI patients, including blood for CBC, bi ochemical pro \201 le, markers of myocardial injury, and lipid. Arrange portable CXR (rule out LVF and mediastinal abnormalities). NSTEMI/UA 123 Symptoms suggestive of ACS Noncardiac diagnosis Chronic stable angina NSTEMI/UA STEMI Admit ASA, Clopidogrel, LMWH (UFH), NTG infusion, B-blocker, statin Admit to CCU Reperfusion therapy Early risk stratification in emergency room see Table, 2.2 Low risk Intermediate risk High risk No Late risk stratification see pXX X Admit monitored bed. On-going symptoms? Admit to CCU IIb/IIIa Early invasive strategy Yes Treat as high risk Inpatient angiography Low risk High risk Outpatient angiography Figure 2.5 NSTEM/VA \200\224integrated care pathway. Reprinted with permission from ACC Pra ctice Guidelines, J Am Coll Cardiol, 2000; 36:970 \200\2231062. Con \201 rm diagnosis Risk strati \201 cation (see Fig. 2.5, above) to determine appropri ate medical and invasive treatment strategies. High-risk patients should be admitted to a c oronary care unit (CCU) and low- to intermediate-risk patients to monitored beds in a step- down unit. Treatment is based on the patient \200\231s risk and includes the following: \200 Medical treatment \200 Anti-ischemic \200 Antiplatelet \200 Antithrombic Invasive str ategies (p. 131) Secondary prevention and discharge CHAPTER 2 Coronary artery disease 124 NSTEMI/UA: diagnosis Diagnosis in NSTEMI/UA is an evolving process and may not be clear on presentation. A combination of history, serial changes in ECG, and biochemical markers of m yocardial injury (usually over a 24- to 48-hour period) determine the diagnosis. Once a pat ient has been designated as having a diagnosis of ACS with probable or possible NSTEMI/UA t hey will require treatment outlined below. 1. Serial ECGs Changes can be transient and/or \201 xed, especially if a diagnosis of NST EMI is made. \200 ST-segment depression of ischemia (unless isolated in V1 \200\223V3, suggesting a posterior STEMI). T-wave inversion is sensitive but nonspeci \201 c for acute ischemia unless very deep ((cid:116)0.3 mV). Rarely, Q waves may evolve or there may be transient or new LBBB. (cid:116)0.05 mV is highly speci \201 c of myocardial 2. Serial biochemical markers of cardiac injury These are used to differentiate between NST EMI and UA, as well as to determine prognosis. We recommend levels at 0, 6, and 12 hours af ter the last episode of pain. A positive biochemical marker (CK, CK-MB, or troponin) in the context of one or more of the ECG changes listed above is diagnostic of NSTEMI. If serial markers over a 24-hour period from the last episode of chest pain remain negative, UA is di agnosed. Cardiac troponin T and I Both of these are highly cardiac speci \201 c and sensitive, can detect \200\234micro- infarction \200\235 in the presence of normal CK-MB, are not affecte d by skeletal muscle injury, and convey prognostic information (worse prognosis if posi- ti ve). Troponins can be raised in nonatherosclerotic myocardial damage (cardiomyopathy, myoca rditis, pericarditis) and should thus be interpreted in the context of the clinical picture . Both TnT and TnI rise within 3 hours of infarction. TnT may persist up to 10 \200\22314 day s and TnI up to 7 \200\22310 days. Results must be interpreted with caution in patients wit h chronic renal failure (see Fig. 2.5). \200 CK levels do not always reach the diagnostic twice upper-limit of normal and generally have little value in diagnosis of NSTEMI. CK-MB has low sensitivity and speci \201 city. CK-MB isoforms improve sensitivity (CK-MB2>1 U/L or CK-MB2/CK-MB1 ratio >1.5), but isoform assay s are not widely available clinically. Myoglobin is non \200\223cardiac speci \201 c, but levels can be detected as early as 2 hours after onset of symptoms. A negative test is usef ul in ruling out myocardial necrosis. 3. Continuous ECG monitoring can detect episodes of silent ischemia and arrhythmia, both of which have been shown to be more prolonged in NSTEMI than in UA. NSTEMI/UA: RISK STRATIFICATION 125 NSTEMI/UA: risk strati \201 cation NSTEMI/UA comprises a heterogeneous group of conditions with variable outcome. An assessment of risk for adverse outcome is vital to ensure format ion of an adequate management plan. Risk strati \201 cation should begin on initial evaluation and continue throughout the hos pital stay. At each stage, patients with a high chance of a poor outcome should be identi \201 ed and managed appropriately. We recommend at least two formal risk strati \201 cation processes. 1. Early risk strati \201 cation (Table 2.2) This should take place on presentation and fo rms part of the initial assess- ment used to make a diagnosis. It involves a combination of clinical fea- tures, ECG changes, and biochemical markers of cardiac injury. Patients are divided into high risk and intermediate/low risk. \200 High-risk patients invasive strategy, and be managed with a combination of \200 \200 \200 should be admitted to the CCU, follow an early ASA, clopidogrel, LMWH (or UFH), and/or gpIIb/IIIa antagonists Anti-ischemic therapy ( \201 rst-line Early invasive strategy (inpatient catheterization and PCI within 48 hours of admission) Intermediate- to low-risk bed on a step-down unit and undergo a second inpatien t risk strati \201 cation once their symptoms have settled, to determine timing of invasiv e investigations. Initial management should include \200 \200 \200 B-blocker, nitroglycerin) patients should be admitted to a monitored ASA, clopidogrel, LMWH (or UFH) Anti-ischemic therapy ( \201 rst-line Undergo a B-blocker, nitroglycerin) late risk strati \201 cation in 48 \200\22372 hours from admission 2. Late risk strati \201 cation This involves a number of noninvasive tests to determine t he optimal tim- ing for invasive investigations in intermediate/low-risk patients. It is ge ner- ally performed if there have been no further episodes of pain or ischemia at 24 \200 \22348 hours after admission. \200 Intermediate/low-risk patients who develop recurrent pain and/or ischemic ECG changes, hear t failure, or hemodynamic instability (in the absence of a noncardiac cause) should be mana ged as a high-risk patient (see above). Table 2.2 is a summary of a recommended integrated care pathway combining diagnosis, risk strati \201 cation, and treatment. There are other risk strati \201 cation assessment scores, including Braunwald and TIMI. As recommended ab ove, high-risk patients from these assessments should also follow an early invasive strateg y and intermediate/low-risk patients, a more conservative strategy. 1 2 6 Table 2.2 Short-term risk of death nonfatal MI in patients with UA C H A P T E R Intermediate risk (no high-risk feature but must have 1 of the following) High risk (at least 1 of the following features must be present) Feature Low risk (no high- or intermediate-risk feature) but may have any of the following features ) 2 C o r o n a r y Prior MI, peripheral or cerebrovascular disease or CABG, prior aspirin use Accelerating tempo of ischemic symptoms in preceding 48 hours History Prolonged (>20 minutes) rest angina now resolved, with moderate or high likelihood of CAD R est angina (<20 minutes) or relieved with rest or sublingual NTG Prolonged ongoing (>20 minutes) rest pain New-onset or progressive CCS Class III or IV angina the past 2 weeks without prolonged (>20 minutes) rest pain but with moderate or high likelihood of CAD Character of pain a r t e r y d i s e a s e Age >70 years Pulmonary edema, most likely due to ischemia New or worsening MR murmur, S3, or new/ worsen ing rales Hypotension, bradycardia, tachycardia Age >75 years Clinical \201 ndings Normal or unchanged ECG during an episode of chest discomfort T-wave inversions >0.2 mV Pathological Q waves Angina at rest with transient ST-segment changes >0.05 mV Bundle-branch block, new or presu med new sustained ventricular tachycardia Elevated (e.g., TnT or Tnl >0.1 ng/mL) ECG Normal Slightly elevated (e.g., TnT >0.01 but <0.1 ng/mL) Cardiac markers Reprinted with permission from ACC Practice Guidelines, J Am Coll Cardiol, 2000; 36:970 \200\2231062. NSTEMI/UA: LATE RISK STRATIFICATION 127 NSTEMI/UA: late risk strati \201 cation The highest risk of adverse outcome in patients wh o are designated inter- mediate/low risk on presentation is during the early phase of admis sion. Therefore, it is important that the second risk strati \201 cation process occurs wi thin 24 \200\22348 hours of admission if the patient is stable. Late risk strati \201 cation is based on one of the following noninvasive investigations. A patient is regarded as being at high risk of adverse outcome if they ful- \201 ll one o f the features listed below. These patients should have inpatient cardiac catheterization. 1. Exercise ECG test \200 Horizontal/down-sloping ST depression with \200 Onset at HR <120 bpm or <6.5 METS \200 Magnitude of >2.0 mm \200 Post-exercise duration of changes >6 minutes Depression in mult iple leads re \202 ecting multiple coronary \200 distributions Abnormal systolic BP response \200 Sustained decrease of >10 mmHg or \202 at BP response with abnormal ECG Other \200 \200 \200 Exercise-induced ST-segment elevation VT Prolonged elevation of HR 2. Stress radionuclide myocardial perfusion imaging \200 \200 Abnormal tracer distribution in more than one territory Cardiac enlargement 3. LV imaging \200 Stress echocardiography \200 Rest EF <40% \200 Wall motion score index of >1 Stress rad ionuclide ventriculography \200 \200 Rest EF <40% Fall in EF >10% CHAPTER 2 Coronary artery disease 128 NSTEMI/UA: medical management Anti-ischemic therapy All patients should be treated with ade quate analgesia, IV nitrates, B-blockers, and statins (if no contraindications) to ensure a dequate symp- tom control and a favorable hemodynamic status (SBP 100 \200\223110 mmHg, HR approximately 60 bpm). Other agents can also be added depending on the clinical picture. 1. Analgesia \200 Morphine 2.5 \200\2235 mg IV. Acts as anxiolytic, reduces pain and systolic blood pressure through venodilatation and reduction in sympathetic arteriolar constriction. It can result in hypotension (responsive to volume therapy) and respiratory depression (reversal with nal oxone 400 g to 2 mg IV). 2. Nitrates \200 Nitroglycerin infusion (50 mg in 50 mL normal saline at 1 \200\22310 mL/hr) titrated to pai n and keeping SBP >100 mmHg. Tolerance to continuous infusion develops within 24 hours and the lowest ef \201 cacious dose should be used. Common side effects are headache and hypotension both of which are reversible on withdrawal of medication. Absolute contraindication is use of sildena \201 l (Viagra) in the previou s 24 hours. This can result in exaggerated and prolonged hypotension. 3. B-Blockers \200 These should be started on presentation. Initially use a short-acting agent (e.g., metoprol ol 12.5 \200\223100 mg po bid), which if tolerated, may be converted to a longer acting age nt (e.g., atenolol 25 \200\2231000 mg qd). Rapid B-blockade may be achieved using short-act ing IV agents such as metoprolol. Aim for HR of 50 \200\22360 beats/min. Mild LVF is not an absolute contraindication to B-blocker therapy. Pulmonary congestion may be secondary to ischemic LV systolic dysfunc- tion and/or reduced compliance. If there is overt heart failure B-blockade is contraindicated. By reducing heart rate and blood pressure, B-blockers reduce myocar- dial oxygen demand and thus angina. When used alone or in combination with nitrates and/or calcium antagonists, B -blockers are effective in reduc- ing the frequency and duration of both symptomatic and si lent ischemic episodes. 4. Calcium antagonists \200 Diltiazem 60 \200\223360 mg po, verapamil 40 \200\223120 mg po tid. These aim to reduce HR and BP and are a useful adjunct to treatments 1 \200\2233 above. Amlodipine/felodipine 5 \200\22310 mg po qd can be used with pulmonary edema and in poor LV function. NSTEMI/UA: MEDICAL MANAGEMENT 129 Calcium antagonists alone do not appear to reduce mortality or risk of MI in patients with UA. However, when combined with nitrates and/or B-blockers they are effective in reducing s ymptomatic and silent ischemic episodes, nonfatal MI, and need for revascularization. 5. Statins (HMG-CoA reductase inhibitors) High-dose statins (e.g., atorvastatin 80 mg qd) h ave been shown to reduce mortality and recurrent MI in the acute setting. The role of stat- ins in primary and secondary prevention of cardiovascular events is well documented. 6. ACE inhibitors Unlike patients with STEMI, in whom early introduction of an ACE inhibi- tor has signi \201 cant prognostic bene \201 ts, speci \201 c trials in the NSTEMI/UA se tting are lacking. However, there is good evidence that patients with low or high risk of c ardiovascular disease will bene \201 t from long-term ACE inhibition (HOPE and EUROPA Tria ls). Antiplatelet therapy All patients should be given aspirin and clopidogrel (unless contraind ications) \200\224gp IIb/IIIa antagonists to high-risk patients only. 1. Aspirin \200 (325 mg po) should be administered immediately in the emergency department and continued in de \201 nitely (unless there are contraindications). In many trials, aspirin has been shown to consistently reduce mortality and recurrent ische mic events. In patients with aspirin hypersensitivity or major gastrointestinal intolerance , clopidogrel 75 mg qd should be used. 2. Thienopyidines \200 Clopidogrel (75 mg qd) should be given on admission to all patients with proven NSTEMI/UA, regardless of risk, and continued for at least 1 month and ideally for 12 months. Clopidogrel should be withheld in patients requiring CABG for 5 \200\2237 days to reduce he morrhagic complications. Clopidogrel is preferred over ticlo- pidine because of its rapid o nset of action and better safety pro \201 le. 3. Glycoprotein IIb/IIIa antagonists There are multiple short- and long-acting commercially available mole- cules. These agents should be used in conjunction with aspirin, clopidog- rel, and LMWH (or UFH). \200 Epti \201 batide and tiro \201 ban should be used in high-risk patients with ongoing isch emia and elevated troponin in whom an early invasive management strategy is not planned or available (<24 hours). In patients with an early invasive strategy all gpIIb/IIIa antagonis ts can be used. Infusion is generally continued for 12 hours post-PCI. Taken as a group, these agents protect NSTEMI/UA patients from death and nonfatal MI during the acute phase of their presentation and 24 hours post-intervention. See Box 2.7 for dose s and administration regime. CHAPTER 2 Coronary artery disease 130 Antithrombotic therapy All patients should be given LMWH (UFH). 1. Low-molecular-weight heparins (LMWH) These have been shown to be as good as, or superior to, UFH in short- term reduction of death, MI, and revascularization in patients with NSTE MI/ UA. They should be used in conjunction with aspirin and clopidogrel in all patients on presentation and continued for 2 \200\2235 days after the last episode of pain and ischemic ECG changes. Other advantages over UFH include subcutaneous administration, lack of monitoring, and redu ced resistance and thrombocytopenia. Box 2.7 lists the doses of various agents in use for N STEMI/UA. 2. Unfractionated heparin (UFH) Multiple trials have demonstrated reduction of risk of deat h and MI in patients with UA/NSTEMI. UFH should be started on presentation as an alternativ e to LMWH in conjunction with aspirin and clopidogrel. Infusion should be continued for 2 \200\2235 days subsequent to the last episode of pain and/ or ischemic ECG changes. Initial bolus of 60 \200\22370 U/kg (maximum 5000 U) should be followed by an infusion of 12 \200 \22315 U/kg/h (1000 U/h). The infu- sion rate should be altered to achieve an aPTT value of 1.5 \200\2232.0 times control. Coagulation should be checked initially every 6 hours followed by once every 24 hours after two consistent values have been obtained. Thrombolysis There is no evidence to suggest that combining thrombolytic agents with aspiri n, LMWH, and conventional anti-ischemic therapy is of bene \201 t in patients with NSTEMI. In the TIMI IIIB trial, the rtPA group had a worse outcome at 6 weeks, and risk of bleedin g was also greater with the throm- bolyis group. Box 2.7 Doses of LMWH IIb/IIIa antagonists licensed for NSTEMI/UA LMWH \200 \200 Dalteparin Enoxaparin 120 U/kg bid (max 10,000 U twice daily) 1 mg/kg bid (100 U/kg twice daily) IIb/IIIa antagonists \200 (Reopro ) Bolus 250 g/kg over 1 minute followed by IV Abciximab infusion 125 ng/kg/min Tiro \201 ban infusion 100 ng/kg/min Epti \201 batide 2 g/kg/min (Aggrastat ) 400 ng/kg/min for 30 minutes followed by IV (Integrilin ) Bolus 180 g/kg followed by IV infusion NSTEMI: INVASIVE VS. NONINVASIVE STRATEGIES 131 NSTEMI: invasive vs. noninvasive strategies The current evidence supports early angiography and revascularization in patients who present with either high-risk features or intermedia te/ low-risk features with ongoing symptoms. Furthermore, low- and interme- diate-risk pati ents who settle on medical therapy should undergo symp- tom-limited noninvasive stress test ing to identify a cohort of patients with an increased risk of adverse outcome. This second group will also bene \201 t from an early invasive management. Patients managed with an early conservative strategy tend to have an increased need for ant ianginal therapy and rehospitalization for angina, and many undergo coronary angiography wi thin the year. The following groups are recommended to bene \201 t from an early inva- sive strategy (inpatient cardiac catheterization and PCI): \200 Patients with high-risk f eatures of NSTEMI/UA \200 Recurrent angina/ischemic ECG changes despite optimal medical therapy Elevated troponin New /presumed new ST-segment depression Chest pain with clinical features of heart failure (pul monary edema, new/worsening MR, S3 gallop) \200 Hemodynamic instability \200 Sustained ventricular tachycardia Poor LV systolic function (EF <40%) Patients allocated to low/mediu m risk in whom, subsequent noninvasive testing demonstrates high-risk features PCI in previ ous 6 months Previous CABG Patients with other comorbidities disease) in whom risks of reva scularization are not likely to outweigh bene \201 ts. \200 \200 \200 \200 \200 (e.g., malignancy, liver failure, renal CHAPTER 2 Coronary artery disease 132 Discharge and secondary prevention \200 Length of hospital stay of progression through the NSTEMI/UA pathway. Generally patients ar e hospitalized for 3 \200\2237 days. Secondary prevention in principle to that for STEMI pa tients. will be determined by symptoms and the rate remains of paramount importance and is similar 133 Chapter 3 Peripheral vascular disease Introduction 134 Epidemiology 135 Risk factors 136 Natural history 137 Pathophysiology 139 Clinical presentation 140 Testing for peripheral artery disease 141 Prognosis in peripheral artery disease 147 Acute limb ischemia 152 Cerebrovascular disease 155 Renovascular diseas e 157 Aortic disease 161 Noninvasive and invasive vascular diagnostic tools 166 Further rea ding 170 CHAPTER 3 Peripheral vascular disease 134 Introduction In peripheral arterial disease (PAD), there is an obstruction to the blood sup ply of the upper or lower extremities. While this is most commonly caused by atherosclerosi s, thrombosis, embolism, vasculitis, \201 bromuscular dysplasia, or entrapment can result in blood \202 ow obstruction. Peripheral vascular disease more broadly encompasses diseases that include renovascular and carotid disease, vasospasm, and venous disor- ders. PAD strongly correlates with risk of m ajor adverse cardiovascular events. Unlike cardiovascular disease, PAD is frequently underd iagnosed and undertreated. This chapter will focus on the diagnosis and management of peripheral vascular disease. EPIDEMIOLOGY 135 Epidemiology The prevalence of PAD varies according to the study population. In large popul ation-based studies conducted in the United States, Europe, and Middle East, the prevalence of PAD varied from 3.6% to 29%, based on abnormal ankle \200\223brachial index (ABI). PAD is more common in the elderly, present in 15% \200\22320% of those older than 65 years. It is more prevalent in men than in women. PAD is more common in blacks than in non-Hispan ic whites. The incidence of critical limb ischemia is estimated at 400 \200\223450 per mil- lion popul ation per year. The incidence of limb amputation is estimated at 112 \200\223250 per millio n population per year. Classi \201 cation of peripheral artery disease is commonly divided into the Fontaine stag es, introduced by Dr. Rene Fontaine in 1954, and Rutherford categories (see Table 3.1). Table 3.1 Classi \201 cation of peripheral artery disease (PAD) Fontaine Rutherford Stage/clinical Grade Category Clinical I: Asymptomatic 0 0 Asymptomatic IIa: Mild pain on walking I 1 Mild claudication I 2 Moderate claudication IIb: Moderate to severe pain on walking relatively short distances (intermittent claudicati on) I 3 Severe claudication III: Ischemic rest pain II 4 Ischemic rest pain IV: Ulceration or gangrene III 5 Minor tissue loss III 6 Major tissue loss Reprinted from Dormandy JA, Rutherford RB (2000). Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Concensus (TASC). J Vasc Surg 31:S1 . CHAPTER 3 Peripheral vascular disease 136 Risk factors Traditional risk factors for cardiovascular disease contribute to athero- scle rosis of the peripheral circulation. The risk of PAD is increased by cigarette smoking, dia betes mellitus, dyslipidemia, and hypertension (see Table 3.2). Table 3.2 Risk of peripheral artery disease by risk factor Risk factor Odds ratio Cigarette smoking 2.0 \200\2232.7 Diabetes mellitus 1.9 \200\2234.0 Hypertension 1.3 \200\2232.2 Hypercholesterolemia 1.05 \200\2231.1 Fibrinogen 2.2 \200\2232.5 C reactive protein 2.1 \200\2232.8 Hyperhomocysteinemia 1.7 \200\2236.8 NATURAL HISTORY 137 Natural history The 2005 American College of Cardiology/American Heart Association (ACC/AHA ) guidelines on PAD estimated the following rates of limb and cardiovascular outcomes at 5 years in patients with noncritical claudication: \200 For limb morbidity: stable claudication in 70% \200\22380%, worsening claudication in 10% \200\22320%, and critical limb ischemia in 1% \200\2232% (Fig. 3.1). For cardiovascular mor bidity and mortality: nonfatal myocardial infarction (MI) or stroke in 20%, and death in 15 % \200\22330% (three-quarters due to cardiovascular causes). An association between cardiov ascular disease and PAD has been noted in multiple studies and this association cannot be o veremphasized. Among the 1% \200\2232% of patients with critical limb ischemia, the guidelines estimated t he following outcomes at 1 year: \200 \200 \200 Alive with two limbs: 50% Amputation: 25% Cardiovascular mortality: 25% 1 3 8 Natural History of Atherosclerotic Lower Extremity PAD Syndromes C H A P T E R PAD Population (50 Years and Older) Initial clinical presentation 3 P e r i p h e r a l Critical limb ischemia 1% \200\2232% Asymptomatic PAD 20% \200\22350% Claudication 10% \200\22335% Atypical leg pain 40% \200\22350% 1-year outcomes Progressive functional impairment Alive with two limbs 50% Amputation 20% CV Mortality 25% v a s c u l a r 5-year outcomes Limb morbidity CV morbidity & mortality d i s e a s e Worsening claudication 10% \200\22320% Stable claudication 70% \200\22380% Critical limp ischemia 1% \200\2232% Nonfatal cardiovascular event (MI or stroke) 20% Mortality 15% \200\22330% Amputation (see CLI data) CV causes 75% Non-CV causes 25% Figure 3.1 The natural history of atherosclerotic lower extremity peripheral arterial disea se (PAD). Individuals with atherosclerotic lower extremity PAD may a) be asymptomatic (with out identi \201 ed ischemic leg symptoms, albeit with a functional impairment); b) present with leg symptoms (classic claudication or atypical leg symptoms); or c) present with crit ical limb ischemia. All individuals with PAD face a risk of progressive limb ischemic sympt oms, as well as a high short-term cardiovascular ischemic event rate and increased mortalit y. These event rates are most clearly de \201 ned for individuals with claudication or cri tical limb ischemia (CLI), and less well de \201 ned for individuals with asymptomatic PAD . CV, cardiovascular; MI, myocardial infarction. Adapted from 1) ACC/AHA Practice Guideline s. Hirsch et al. (2006). Circulation 113:e463 \200\223 e465 and 2) Weitz JI, Byrne J, Clage tt GP, et al. (1996). Circulation 94(11):3026 \200\2233049. PATHOPHYSIOLOGY 139 Pathophysiology The balance of circulatory supply of nutrients to skeletal muscle and the o xygen and nutrient demand of skeletal muscle are key features in the pathophysiology of PAD . The symptoms of claudication develop when the oxygen and nutrient supply is less than the demand in skeletal muscle as during exercise. Local sensory receptors are activated by the accumula- tion of lactate and other metabolites. Typically, resting blood \202 ow is preserved until critical limb ischemia develops and t he resting blood supply diminishes to the point that the nutritional needs of the limb can no longer be met. Ultimately, there is impaired vasodilation, accentuated vasoconstriction, and abnormal rhe- ology, all of which contribute to critical limb ischemia. While most commonly this is due to atherosclerosis and frequently multiple obstructive lesi ons exist, there are other causes of claudication, listed in Table 3.3. Table 3.3 Causes of claudication Major cause Atherosclerosis (arteriosclerosis obliterans) Other causes Acute arterial disease (dissection, embolism, thrombosis, trauma) Adventitial cystic diseas e Aortic coarctation Arterial \201 brodysplasia Arterial tumor Ergot toxicity Iliac endo \201 brosis of athletes Occluded limb aneurysms Popliteal-artery entrapment Pseudoxanthoma elasticum Radiation \201 brosis Retroperitoneal \201 brosis Takayasu \200\231s arterit is Temporal arteritis Thoracic outlet obstruction Thromboangiitis obliterans (Buerger \200 \231s disease) Vasospasm CHAPTER 3 Peripheral vascular disease 140 Clinical presentation Symptoms \200 \200 Intermittent claudication and rest pain with critical limb ischemia Discomfort often with w alking or exertion and resolves at rest The site of pain correlates with the location of stenosis: \200 \200 \200 \200 Buttock and hip: aortoiliac disease Thigh: common femoral artery or aortoiliac Upper two-th irds of the calf: super \201 cial femoral artery Lower one-third of the calf: popliteal ar tery Foot claudication: tibial or peroneal artery Parasthesias \200 Skin sensitivity On examination Features may include the following: \200 \200 \200 \200 \200 \200 \200 \200 \200 Normal \201 ndings Diminished or absent pulses Poor wound healing Bruit Shiny skin Prolon ged venous \201 lling Hair loss, skin atrophy, nail changes Unilateral cool extremity Foo t pallor with elevation of the leg and with leg in the dependent posi- tion, a dusky red \202 ush spreading proximally from the toes (Buerger test) Muscle atrophy Ulceration (arter ial typically have a pale base and involve the toes, heel of the foot, or pressure sites) ( Table 3.4) Gangrene \200 Table 3.4 Differential diagnosis of common foot and leg ulcers Origin Cause Location Pain Appearance Toes, foot Severe Irregular, pink base Main arteries Atherosclerotic lower extremity PAD, Buerger \200\231s disease, acute arterial occlusion Venous Venous disease Malleolar Mild Irregular, pink base Skin infarct Systemic disease, embolism, hypertension Lower third of leg Severe Small after infarction, often multiple Neurotrophic Neuropathy Foot sole None Often deep, infected Adapted from 1) the ACC/AHA Practice Guidelines. Hirsch et al. (2006). Circulation 113:e463 \200\223e465, and 2) Differential Diagnosis of Critical Limb Ischemia. J Vasc Surg 2000; 3 1(1) Supplement 1:S184 \200\223S188. TESTING FOR PERIPHERAL ARTERY DISEASE 141 Testing for peripheral artery disease Ankle \200\223brachial index (ABI) The ABI provides a measure of PAD and is simple and inexpensive to perform (see Fig. 3.2). Calculation is by measuring the systolic blood pres- sure (by Doppler probe) in the brachial, posterior tibia l, and dorsalis pedis arteries. The higher ankle measurement is divided by the higher brach ial measurement. 146 144 142 122 138 100 140 80 1.00 ABI 0.56 Figure 3.2 Ankle \200\223brachial indices (ABI). CHAPTER 3 Peripheral vascular disease 142 ABI 1.0 \200\2231.3 is the normal value. Values >1.3 suggest a noncompressible calci \201 ed vessel. ABI below 0.9 is associated with a >50% stenosis in one or more major vessels an d has a 95% sensitivity for detecting angiogram-positive PAD. ABI 0.4 \200\2230.9 suggests arterial obstruction often associated with claudication. ABI <0.4 represents advanced ische mia. ABIs typically correlate with the clinical measures of lower extremity func- tion such as w alking distances, balance, and overall physical activity. Lower ABIs correlate with a highe r risk of coronary artery disease (CAD), stroke, progressive renal insuf \201 cency, and a ll-cause mortality. Treadmill exercise testing Exercise decreases vascular resistance and enhances blood \202 ow to exer- cising extremities. According to Poiseuille \200\231s law, the pressure gradie nt across the stenosis increases in direct proportion to \202 ow. Exercise in lesions with <70% stenosis may induce a systolic pressure gradient across the s tenosis or increase the systolic pressure gradient. This change can be detected by serial p ost-exercise ABIs at 1-minute intervals for 5 minutes after exercise. This is particularly useful in patients who have normal resting ABIs and typical symptoms of claudication. In addition, treadmill testing allows for an objective measure of the patient \200\231s walking capacity. Duplex ultrasound imaging Ultrasound examination of the lower extremity includes localizati on of stenosis with color Doppler, B-mode imaging, pulse-wave Doppler, and continuous-wave Doppler. Examinations begin with the common femoral artery and proceed dis- tally to the popliteal a rtery. A twofold or greater increase in peak systo- lic velocity at the site of an atherosc lerotic plaque indicates a 50% or greater stenosis. Similarly, a threefold increase in velo city indicates a 75% or greater stenosis. In an occluded artery there is no Doppler signal. When using contrast angiography as a gold standard, duplex ultrasound imaging has a sensitivity of 80% \200\22390% and speci \201 city of 95%. See Figure 3.3. Magnetic resonance angiography Magnetic resonance angiography (MRA) can be used to noninvas ively image the aorta and vascular territories. The resolution of MRA with gado- linium app roaches that of contrast digital subtraction angiography. In patients at risk for complications from conventional angiography, MRA provides an accura te noninvasive tool prior to planning endovascular or surgical intervention. TESTING FOR PERIPHERAL ARTERY DISEASE 143 Normal Progressive disease Early disease Severe disease Figure 3.3 Ultrasonography in peripheral arterial disease. Schematic representation of peri pheral arterial waveforms in duplex Doppler ultrasonography in peripheral vascular disease. The normal peripheral arterial velocity waveform is triphasic and consists of a forward \202 ow systolic peak, reversal of \202 ow in early diastole, and forward \202 ow in la te diastole (top left). With progressive peripheral vascular disease, there is elimination of the reverse \202 ow (top right), a decrease in systolic peak and an increase in \202 ow in diastole (bottom right). Reproduced with permission from Mohler III, ER (2009). Noni nvasive diagnosis of peripheral arterial disease. In Basow DS (Ed.), UpToDate, Waltham, MA. Copyright 2009 UpToDate, Inc. For more information visit www.uptodate.com. Computed tomographic angiography (CTA) Multidetector CT scanners allow for rapid acquisitio n of high-resolution images. The addition of IV contrast allows visualization of the aorta and peripheral arteries. Multidetector technology has improved the spatial resolution of images over a relatively sh ort period of time. In addition, evolving software appli- cations enable three-dimensional display and post-processing techniques that can aid in visualization of stenoses. Contrast angiography This remains the gold standard in evaluation of peripheral vascular di sease. Digital subtraction techniques following contrast administration are typi- cally use d to enhance resolution. While the femoral approach is most common, brachial, axillary, or translumbar approaches can be used to attain aortic access. Summaries of diagnosis of PAD, asymptomatic PAD and leg pain, and clau- dication are given in Figures 3.4, 3.5, and 3.6. CHAPTER 3 Peripheral vascular disease 144 Individuals at Risk for Lower Extremity PAD: Age less than 50 years with diabetes and one other atherosclerosis risk factor (smoking, dy slipidemia, hypertension, or hyperhomocysteinemia) Age 50 to 69 years and history of smokin g or diabetes Age 70 years and older Leg symptoms with exertion (suggestive of claudication ) or ischemic rest pain Abnormal lower extremity pulse examination Know atherosclerotic cor onary, carotid, or renal arterial disease Obtain history of walking impairment and/or limb ischemic symptoms: Obtain a vascular revie w of symptoms: \200 Leg discomfort with exertion \200 Leg pain at rest; nonhealing woun d; gangrene Classic claudication symptoms: Exertional fatigue, discomfort, or frank pain localized to l eg muscle groups that consistently resolves with rest No leg pain \200\234Atypical \200\235 leg pain* Ischemic leg pain at rest \200 Nonhealing wound \200 Gangrene Sudden onset ischemic leg symptoms or signs of acute limb ischemia: The five \200\234Ps \200\235 \200 Perform a resting ankle \200\223brachial index measurement See Figure 3.5, Diagnosis and Treatment of Asymptomatic PAD and Atypical Leg Pain See Figure 3.9 and 3.10, Diagnosis and Treatment of Acute Limp Ischemia See Figures 3.6 and 3.7, Diagnosis and Treatment of Claudication See Figure 3.8, Diagnosis and Treatment of Critical Limp Ischemia See Figure 3.5, Diagnosis and Treatment of Asymptomatic PAD and Atypical Leg Pain Figure 3.4 Steps toward the diagnosis of peripheral arterial disease (PAD). * \200\234Atypi cal \200\235 leg pain is de \201 ned by lower extremity discomfort that is exertional but that does not consistently resolve with rest, consistently limit exercise at a reproducible distance, or meet all \200\234Rose questionnaire \200\235 criteria. \200 The \201 ve \200\234Ps \200\235 are de \201 ned by the clinical symptoms and signs that suggest potent ial limb jeopardy: pain, pulselessness, pallor, parasthesias, and paralysis (with polar bei ng a sixth \200\234P \200\235). Reprinted with permission from the ACC/AHA Practice Guidel ines. Hirsch et al. (2006). Circulation 113:e463 \200\223e465. TESTING FOR PERIPHERAL ARTERY DISEASE 145