Emergency Medicine

A 58-year-old-man with a history of intravenous drug abuse, chronic hepatitis C, and anxiety presented to our emergency department twice in 4 weeks with progressive dyspnea and night sweats. He was a nonsmoker and had been an electrician for 15 years.

The first time he came in, chest radiography revealed bilateral reticulonodular infiltrates in the lung bases. He was treated with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax) for presumed community-acquired pneumonia and was then sent home on a 10-day course of oral amoxicillin-clavulanate (Augmentin). The antibiotics did not improve his symptoms, and 3 weeks later he presented again to the emergency department.

On his second presentation, he was in respiratory distress (oxygen saturation 78% on room air) and was afebrile and tachypneic. Physical examination revealed numerous injection marks or “tracks” on the skin of both arms, and auscultation revealed diminished intensity of breath sounds in both lung bases.

Repeat chest radiography demonstrated that the infiltrates were still there. Computed tomography was ordered and showed mild centrilobular emphysematous changes in both lungs, bibasilar opacifications, and a mass-like lesion (3.3 × 1.9 cm) in the right lower lobe (Figure 1).

He subsequently underwent bronchoscopy, which showed no endobronchial abnormalities. Transbronchial lung biopsy was performed, and histopathologic analysis of the specimen (Figure 2) revealed rodlike, birefringent crystals under polarized light, with an extensive foreign-body giant-cell reaction outside pulmonary capillaries, suggestive of intravascular pulmonary talcosis. Blood and sputum cultures were negative for pathologic organisms. Bronchoalveolar lavage samples were negative for pathologic organisms and malignant cells.

On further questioning, the patient revealed that he intravenously injected various drugs intended for oral use, such as crushed meperidine (Demerol), methylphenidate (Ritalin), and methadone tablets.

Pulmonary function tests indicated a severe obstructive pattern. The predicted forced expiratory volume in the first second of expiration (FEV₁) was 25%, and the ratio of FEV₁ to forced vital capacity was 27%.

Transthoracic echocardiography revealed mild pulmonary hypertension with a right ventricular systolic pressure of 28 mm Hg at rest.

Based on the results of the histologic examination, a diagnosis of intravascular pulmonary talcosis was made. Antibiotics were discontinued, and treatment with albuterol and ipratropium bromide (Combivent) inhalers was started. The patient remained oxygen-dependent at the time of hospital discharge.

INTRAVASCULAR PULMONARY TALCOSIS

Intravascular pulmonary talcosis is seen predominantly in those who chronically inject intravenous drugs intended for oral use.^1,2

Many oral medications contain talc as a filler and lubricant to prevent the tablet from sticking to equipment during the manufacturing process. When oral medications containing talc are crushed, dissolved in water, and injected intravenously, the talc crystals and other particles lodge in the pulmonary vascular bed, resulting in microscopic pulmonary embolizations.

Over time, these particles migrate to the pulmonary interstitium and incite a foreign-body granulomatous reaction, which may be associated with progressive pulmonary fibrosis. The severity of this immune reaction and fibrosis may vary; hence, some patients remain asymptomatic, whereas some present with dyspnea from extensive fibrosis and pulmonary hypertension.

Persistent dyspnea along with persistent infiltrates on chest imaging in an intravenous drug abuser should prompt suspicion for intravascular pulmonary talcosis as well as consideration of other diagnoses, such as pneumonia, malignancy, and septic pulmonary emboli.

There is no established treatment for intravascular pulmonary talcosis; treatment is often supportive. A few studies and case reports have indicated varied success with systemic and inhaled corticosteroids.^3–5 In extreme cases, lung transplantation may be necessary; however, this would require a comprehensive psychiatric assessment to minimize the risk of addiction relapse after transplantation.

A 58-year-old-man with a history of intravenous drug abuse, chronic hepatitis C, and anxiety presented to our emergency department twice in 4 weeks with progressive dyspnea and night sweats. He was a nonsmoker and had been an electrician for 15 years.

The first time he came in, chest radiography revealed bilateral reticulonodular infiltrates in the lung bases. He was treated with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax) for presumed community-acquired pneumonia and was then sent home on a 10-day course of oral amoxicillin-clavulanate (Augmentin). The antibiotics did not improve his symptoms, and 3 weeks later he presented again to the emergency department.

On his second presentation, he was in respiratory distress (oxygen saturation 78% on room air) and was afebrile and tachypneic. Physical examination revealed numerous injection marks or “tracks” on the skin of both arms, and auscultation revealed diminished intensity of breath sounds in both lung bases.

Repeat chest radiography demonstrated that the infiltrates were still there. Computed tomography was ordered and showed mild centrilobular emphysematous changes in both lungs, bibasilar opacifications, and a mass-like lesion (3.3 × 1.9 cm) in the right lower lobe (Figure 1).

He subsequently underwent bronchoscopy, which showed no endobronchial abnormalities. Transbronchial lung biopsy was performed, and histopathologic analysis of the specimen (Figure 2) revealed rodlike, birefringent crystals under polarized light, with an extensive foreign-body giant-cell reaction outside pulmonary capillaries, suggestive of intravascular pulmonary talcosis. Blood and sputum cultures were negative for pathologic organisms. Bronchoalveolar lavage samples were negative for pathologic organisms and malignant cells.

On further questioning, the patient revealed that he intravenously injected various drugs intended for oral use, such as crushed meperidine (Demerol), methylphenidate (Ritalin), and methadone tablets.

Pulmonary function tests indicated a severe obstructive pattern. The predicted forced expiratory volume in the first second of expiration (FEV₁) was 25%, and the ratio of FEV₁ to forced vital capacity was 27%.

Transthoracic echocardiography revealed mild pulmonary hypertension with a right ventricular systolic pressure of 28 mm Hg at rest.

Based on the results of the histologic examination, a diagnosis of intravascular pulmonary talcosis was made. Antibiotics were discontinued, and treatment with albuterol and ipratropium bromide (Combivent) inhalers was started. The patient remained oxygen-dependent at the time of hospital discharge.

INTRAVASCULAR PULMONARY TALCOSIS

Intravascular pulmonary talcosis is seen predominantly in those who chronically inject intravenous drugs intended for oral use.^1,2

Many oral medications contain talc as a filler and lubricant to prevent the tablet from sticking to equipment during the manufacturing process. When oral medications containing talc are crushed, dissolved in water, and injected intravenously, the talc crystals and other particles lodge in the pulmonary vascular bed, resulting in microscopic pulmonary embolizations.

Over time, these particles migrate to the pulmonary interstitium and incite a foreign-body granulomatous reaction, which may be associated with progressive pulmonary fibrosis. The severity of this immune reaction and fibrosis may vary; hence, some patients remain asymptomatic, whereas some present with dyspnea from extensive fibrosis and pulmonary hypertension.

Persistent dyspnea along with persistent infiltrates on chest imaging in an intravenous drug abuser should prompt suspicion for intravascular pulmonary talcosis as well as consideration of other diagnoses, such as pneumonia, malignancy, and septic pulmonary emboli.

There is no established treatment for intravascular pulmonary talcosis; treatment is often supportive. A few studies and case reports have indicated varied success with systemic and inhaled corticosteroids.^3–5 In extreme cases, lung transplantation may be necessary; however, this would require a comprehensive psychiatric assessment to minimize the risk of addiction relapse after transplantation.

A 58-year-old-man with a history of intravenous drug abuse, chronic hepatitis C, and anxiety presented to our emergency department twice in 4 weeks with progressive dyspnea and night sweats. He was a nonsmoker and had been an electrician for 15 years.

The first time he came in, chest radiography revealed bilateral reticulonodular infiltrates in the lung bases. He was treated with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax) for presumed community-acquired pneumonia and was then sent home on a 10-day course of oral amoxicillin-clavulanate (Augmentin). The antibiotics did not improve his symptoms, and 3 weeks later he presented again to the emergency department.

On his second presentation, he was in respiratory distress (oxygen saturation 78% on room air) and was afebrile and tachypneic. Physical examination revealed numerous injection marks or “tracks” on the skin of both arms, and auscultation revealed diminished intensity of breath sounds in both lung bases.

Repeat chest radiography demonstrated that the infiltrates were still there. Computed tomography was ordered and showed mild centrilobular emphysematous changes in both lungs, bibasilar opacifications, and a mass-like lesion (3.3 × 1.9 cm) in the right lower lobe (Figure 1).

He subsequently underwent bronchoscopy, which showed no endobronchial abnormalities. Transbronchial lung biopsy was performed, and histopathologic analysis of the specimen (Figure 2) revealed rodlike, birefringent crystals under polarized light, with an extensive foreign-body giant-cell reaction outside pulmonary capillaries, suggestive of intravascular pulmonary talcosis. Blood and sputum cultures were negative for pathologic organisms. Bronchoalveolar lavage samples were negative for pathologic organisms and malignant cells.

On further questioning, the patient revealed that he intravenously injected various drugs intended for oral use, such as crushed meperidine (Demerol), methylphenidate (Ritalin), and methadone tablets.

Pulmonary function tests indicated a severe obstructive pattern. The predicted forced expiratory volume in the first second of expiration (FEV₁) was 25%, and the ratio of FEV₁ to forced vital capacity was 27%.

Transthoracic echocardiography revealed mild pulmonary hypertension with a right ventricular systolic pressure of 28 mm Hg at rest.

Based on the results of the histologic examination, a diagnosis of intravascular pulmonary talcosis was made. Antibiotics were discontinued, and treatment with albuterol and ipratropium bromide (Combivent) inhalers was started. The patient remained oxygen-dependent at the time of hospital discharge.

INTRAVASCULAR PULMONARY TALCOSIS

Intravascular pulmonary talcosis is seen predominantly in those who chronically inject intravenous drugs intended for oral use.^1,2

Many oral medications contain talc as a filler and lubricant to prevent the tablet from sticking to equipment during the manufacturing process. When oral medications containing talc are crushed, dissolved in water, and injected intravenously, the talc crystals and other particles lodge in the pulmonary vascular bed, resulting in microscopic pulmonary embolizations.

Over time, these particles migrate to the pulmonary interstitium and incite a foreign-body granulomatous reaction, which may be associated with progressive pulmonary fibrosis. The severity of this immune reaction and fibrosis may vary; hence, some patients remain asymptomatic, whereas some present with dyspnea from extensive fibrosis and pulmonary hypertension.

Persistent dyspnea along with persistent infiltrates on chest imaging in an intravenous drug abuser should prompt suspicion for intravascular pulmonary talcosis as well as consideration of other diagnoses, such as pneumonia, malignancy, and septic pulmonary emboli.

There is no established treatment for intravascular pulmonary talcosis; treatment is often supportive. A few studies and case reports have indicated varied success with systemic and inhaled corticosteroids.^3–5 In extreme cases, lung transplantation may be necessary; however, this would require a comprehensive psychiatric assessment to minimize the risk of addiction relapse after transplantation.

In many ways, vascular disease in the leg is similar to that in the heart. The risk factors, underlying conditions, and pathogenetic processes are the same, and in many cases, patients have both conditions. And just as cardiologists and emergency physicians have learned that in acute myocardial infarction “time is muscle,” we are coming to appreciate that in many cases of limb ischemia, “time is limb.”

Most physicians well understand the clinical spectrum of coronary artery disease, which ranges from stable angina to ST-elevation myocardial infarction. In the leg, the same situation exists: at the more benign end of the spectrum, patients experience no symptoms, but often that is because they lead a sedentary lifestyle, modifying their activity level to avoid pain. As the disease worsens, they can develop claudication and critical leg ischemia, comparable to non-ST-elevation myocardial infarction. The most severe condition is acute limb ischemia, analagous to ST-elevation myocardial infarction.

Distinguishing acute from critical limb ischemia is essential in patients who present with leg problems, whether it be leg pain or ulcers. The farther along the clinical spectrum the patient’s condition is, the more important it is to be aggressive in diagnosis and treatment. The history and physical examination are the most important first steps, focusing on the onset of symptoms, history, risk factors, and past interventions.

Peripheral artery disease is increasingly becoming a worldwide problem that is now being emphasized by the World Health Organization. Unfortunately, not enough attention is paid to the problem, not only in less-developed countries but also in the United States. Patients with peripheral artery disease tend to be elderly, in the lowest economic classes, and uninsured, and they often do not understand the impact of the disease on their health.

LEG ULCERS: CAUSES AND COSTS

Finding the underlying cause of leg ulcers is important, and the differential diagnosis is large (Table 1). However, knowing the cause does not necessarily lead to healing; it is still essential to assess perfusion, infection, and wound care, and to arrest edema.

Causes of leg and foot ulcers include venous insufficiency (with an estimated 2.5 million cases annually),^1,2 diabetes (nearly 1 million cases),³ and pressure (ie, bedsores, occurring in up to 28% of patients in extended care),⁴ all at a cost in the billions of dollars.^5–7

In general, peripheral artery disease itself does not cause ulcers; it is an inciting factor. It is important to find what started the process. Ill-fitting shoes, poor sensation because of diabetes, or a cut when trimming toenails can all contribute to a wound, and peripheral artery disease makes it unable to heal. The healing process requires more nutrients and oxygen than poor circulation can provide.

ACUTE LIMB ISCHEMIA

Acute limb ischemia is defined as any sudden decrease in limb perfusion causing a potential threat to limb viability.⁸ Although it comes on suddenly, it does not imply that the patient has not had long-standing peripheral artery disease. It is important to determine what suddenly changed to cause the onset of symptoms.

History and physical examination: The six Ps

A good history includes a thorough evaluation of the present illness, including the pain’s time of onset, abruptness, location, intensity, and change over time, and whether it is present at rest. The medical history should focus on claudication, diabetes, smoking, heart disease, palpitations, atrial fibrillation, and previous ischemic symptoms.⁸

The physical examination should focus on the “six Ps”:

• Pain
• Pulselessness
• Paresthesia (numbness occurs in about half of patients)
• Pallor (obstruction is typically one joint above the level of demarcation of pallor)
• Paralysis (a bad sign, particularly if the calf is tight)
• Poikilothermia (inability to regulate temperature).

A good pulse examination includes measuring the ankle-brachial index and a Doppler examination of both legs. A neurologic examination focusing on sensory and motor function is critical for determining the level of ischemia and the urgency of intervention.

Classification of acute limb ischemia

If it is determined that a patient has acute leg ischemia, it is important to categorize the condition using the classification system devised by the Society of Vascular Surgery and International Society of Cardiovascular Surgery (Table 2).⁹ The category establishes the type and urgency of treatment. This classification system is simple and depends on factors that can be assessed easily by nonspecialists:

• Pulses—arterial and venous pulses assessed by Doppler ultrasonography
• Sensation—the patient closes the eyes and answers if he or she can feel the examiner’s touch
• Motor function—can the patient move his or her toes?

Venous pulses can be difficult to assess. However, if the arterial pulse is present, the venous pulse should be next to it. Knowing the other criteria can determine the category, so not being certain of the venous pulse should not deter a clinician from assessing the other factors.

Category I is “viable.” Patients have intact sensory and motor functions and audible pulses. Patients in this category should be admitted and possibly started on anticoagulation therapy and referred to a vascular specialist within hours.

Category IIa is “threatened.” Sensation is starting to be lost but motor function is still present. These patients are considered to have reversible ischemia, analogous to myocardial infarction of the leg, and they require immediate attention.

Category IIb is similar and it also requires immediate attention.

Category III is usually irreversible, with loss of motor function and sensation.

CAUSES OF ACUTE LIMB ISCHEMIA

Thrombosis accounts for about 50% of cases. Underlying causes of the thrombosis are artherosclerosis (native or bypass), aneurysm, trauma, vasculitis (eg, in a rheumatologic disease such as lupus), and hypercoagulable states (particularly in patients with cancer).

Embolism accounts for about 30% of cases. Emboli usually arise from plaque rupture in atherosclerotic arteries or a clot breaking off from an aneurysm or from within the heart in patients with atrial fibrillation or another underlying heart disease. Paradoxical embolism, caused by an embolism crossing the heart through an opening such as a patent foramen ovale, is rare.

Uncommon causes include arterial dissection following trauma, adventitial cystic disease, popliteal artery entrapment, ergotism (from consuming fungus-contaminated grains), and human immunodeficiency virus arteriopathy.

The physical examination provides clues to the origin: livedo reticularis (purple discoloration in a mottled pattern) and blue nail beds indicate that an embolus is likely. Tests, including electrocardiography, echocardiography, and computed tomography of the chest and abdomen to look for an aneurysm, can help identify the cause. Ultrasonography of the popliteal arteries should also be considered to search for an aneurysm.

CRITICAL LIMB ISCHEMIA

Critical limb ischemia is more likely than acute limb ischemia to be seen in a general practice. Many aspects need to be addressed simultaneously, by different specialists: vascular and endocrine systems, infection, and wound care. The most successful management strategy is a dynamic approach using every piece of information.¹⁰

The Rutherford classification of peripheral artery disease has six categories based on the clinical presentation, with categories I through III being mild to severe claudication. We discuss here only the more severe categories: IV (pain at rest), V (tissue loss), and VI (gangrene).

Strong indicators of pain at rest are that the patient has to get up at night to dangle the leg over the bed or walk a few steps, or sleeps in a chair, or refuses to elevate the leg because of pain. The affected leg tends to appear red when the patient is standing (dependent rubor), but pale when the foot is elevated (elevation pallor).

Confirming that a patient has dependent rubor can be challenging, especially in people with dark skin. Classically, redness is seen when the leg is down and disappears with elevation, but in cellulitis, redness can also be reduced by elevating the leg. A foot that is hot to the touch is an indication of infection and not lack of perfusion alone.

The hemodynamic definition of critical limb ischemia is¹¹:

• Ankle-brachial pressure index less than 0.4
• Reduced toebrachial pressure index, ie, less than 0.7
• Reduced transcutaneous pressure of oxygen (Tcpo₂), ie, less than 40 mm Hg.

From 15% to 20% of patients with claudication will progress to critical ischemia over their lifetime, and in patients with claudication who also have diabetes, the risk is nearly 10 times higher. Without revascularization, the risk of amputation within 1 year is 73% for patients in Rutherford class IV and 95% for patients in class V or VI.

Revascularization and limb preservation

Preserving the limb is a prime goal. For patients who have an amputation, the mortality rate is 40% within 2 years.⁸ These patients tend to be elderly, and after an amputation, most will not learn to use a prosthesis and resume their previous level of activity. Other treatment objectives are to relieve pain, reduce cardiovascular risk, and minimize procedural complications.

Although limb preservation is not a controversial goal, best practices to preserve limbs are not universally available. Goodney et al¹² studied variation in the United States in the use of lower-extremity vascular procedures for critical limb ischemia. They defined “low-intensity” to “high-intensity” regions of the country depending on the proportion of patients who underwent a vascular procedure in the year before amputation. They found considerable variation, but even in the region of highest intensity, more than 40% of patients did not have a vascular procedure in the year before amputation.

Similarly, Jones et al¹³ mapped amputation rates by US state and found significant variation even after adjusting for risk factors such as tobacco use and obesity.

Controversy surrounds the specifics of revascularization treatment, as in many fields in vascular medicine. However, most experts agree that improved perfusion is the goal.

The Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Artery Disease recommends revascularization as the best treatment for patients with critical limb ischemia.⁸ In addition, the American College of Cardiology and American Heart Association Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic) state that the tibial or pedal artery that is capable of providing continuous and uncompromised outflow to the foot should be used as the site of distal anastomosis.¹⁴ These guidelines do not yet mention endovascular therapy.

Angiosomes guide revascularization

In the past few years, the ability to facilitate healing of foot ulcers has improved. Angiosomes—regions of vascularization supplied by specific arteries—can be mapped on the skin, similar to the way dermatomes are mapped for neural innervation (Figure 1). The foot and lower leg region has six angiosomes perfused by three arteries that branch off the popliteal artery after it passes behind the knee:

• The anterior tibial artery supplies the dorsum of the foot and the front of the lower limb.
• The posterior tibial artery supplies the plantar surface of the foot via three branches—the medial plantar, lateral plantar, and calcaneal branches.
• The peroneal artery supplies the lateral part of the foot with collaterals to the anterior and posterior tibial arteries if they are compromised.

Studies have compared angiosome-based treatment vs revascularizing the best available artery (thus depending on collateral flow to compensate to surrounding areas). They have found that regardless of whether an endovascular or bypass method of revascularization was used, an angiosome-based approach led to significantly higher amputation-free survival rates.^15–17

Patients typically do not have blockage of only a single tibial artery. Graziani et al¹⁸ assessed the vascular lesions in 417 patients with critical limb ischemia and found that multiple below-knee arteries were frequently involved. This makes it difficult to decide where to target revascularization efforts, and the angiosome concept helps with that.

ASSESSING WOUND PERFUSION

Ankle- and toe-brachial indices assess perfusion

The ankle-brachial index¹⁹ is a good superficial assessment of perfusion. Multiple epidemiologic studies have shown the prognostic value of the ankle brachial index beyond the traditional risk factors and even the Framingham risk score.¹⁹ Values:

• Normal 1.1–1.30 (> 1.31 is abnormal and consistent with calcified vessels, and is an unreliable measure)
• Low normal 0.91–1.00
• Mild disease 0.71–0.90
• Moderate disease 0.41–0.70
• Severe disease ≤ 0.40.

However, the ankle-brachial index assesses perfusion only to the ankle, and many patients have ulcers in the toes and distal foot. The toe-brachial index must be specifically ordered in most institutions (if the first toe has an ulcer, the second toe should be assessed). The toe-brachial index is also important if the ankle-brachial index cannot be obtained because of calcified, noncompressible arteries in the ankle. A normal toe-brachial index is greater than 0.7.

The segmental blood pressure examination compares blood pressure measurements at multiple sites in the lower extremity. A drop of more than 20 mm Hg between segments indicates obstruction at that location. The test is simple and noninvasive and often can replace computed tomography.²⁰

Transcutaneous oximetry

Transcutaneous oximetry measures the Tcpo₂ from 1 to 2 mm deep in the skin from local capillaries. Measured adjacent to an ulcer, it is useful to predict wound healing and to assess the response to hyperbaric oxygen therapy.²¹ The values are:

• Normal > 70 mm Hg
• Impaired wound healing < 40 mm Hg
• Critical limb ischemia < 30 mm Hg.

Although most agree that a Tcpo₂ below 40 mm Hg requires revascularization, low values can arise from many causes other than peripheral artery disease, including high altitude, pulmonary disease, heart failure, edema, inflammation, callus, and skin diseases such as scleroderma.

Skin perfusion pressure better predicts healing

Skin perfusion pressure is a measure of the capillary opening pressure after occlusion and is another way to assess perfusion. This test is not routinely done and must be specially requested.

The test is performed by inflating a blood pressure cuff on the leg until blood flow is occluded, then using laser Doppler to determine reactive hyperemia, ie, the gradual return of blood flow during controlled pressure release. The pressure at which movement is detected is the skin perfusion pressure.²²

The laser Doppler probe emits and detects light scattered in the tissue. Light hitting moving blood cells undergoes a change in frequency, ie, a Doppler shift. An algorithm converts the optical information in the skin perfusion pressure by capturing the onset of capillary flow return and determining the pressure at which flow returns. Categories of results:

• > 50 mm Hg—normal
• 40–50 mm Hg—mild ischemia (wound healing probable)
• 30–40 mm Hg—moderate ischemia (wound healing uncertain)
• < 30 mm Hg—critical limb ischemia (wound healing unlikely).

Skin perfusion pressure testing has the advantages of not being affected by vessel calcification, thickened skin, or edema. It can be used on the plantar aspect of the foot and on digits. Recent small studies indicate that it is more sensitive for predicting wound healing than Tcpo₂ measures.

On the other hand, skin perfusion pressure testing is not useful for predicting response to hyperbaric oxygen therapy. Also, blood flow occlusion by the cuff may be painful.

Intraoperative fluorescence angiography

Intraoperative fluorescence angiography is used to assess flap viability during reconstructive surgery and is being studied to determine its usefulness for assessing tissue viability in limb ischemia.

The test provides real-time assessment of capillary perfusion, determining surface tissue viability. The imaging head contains a digital camera, a laser light source, and a distance sensor. The test requires intravenous administration of indocyanine green, which binds to plasma proteins and is cleared through the liver, making it safe for patients with renal dysfunction. It cannot be used in patients with allergies to iodine contrast, penicillin, or sulfa.²³

PREVENTION TARGETS CARDIOVASCULAR RISK FACTORS

Preventive measures are the same as for cardiovascular disease, ie, aggressive risk-factor modification: quitting smoking, lowering low-density lipoprotein cholesterol, reducing blood pressure, controlling diabetes, and managing heart failure.

Dual antiplatelet therapy should be instituted with aspirin and clopidogrel (Plavix) in patients undergoing revascularization. One can also consider cilostazol (Pletal); however, the role of this agent in patients with critical limb ischemia is less defined.

BYPASS OR ANGIOPLASTY?

The Bypass Versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial²⁴ randomly assigned 452 patients with severe limb ischemia due to infrainguinal atherosclerosis to receive either surgery-first or angioplasty-first care and followed them for 5.5 years.

No significant differences between the two groups were found in amputation-free survival, deaths, or health-related quality of life. However, hospital costs associated with the surgery-first strategy were about one-third higher. As expected, more patients in the surgery group developed a wound infection, and more patients in the angioplasty group required bypass surgery at some point.

The conclusion that can be reached from this study is that patients presenting with severe limb ischemia due to infrainguinal atherosclerotic occlusive disease who are suitable for both surgical and interventional procedures can be treated with either method. However, most experts consider endovascular therapy as the first option in many patients. The National Institutes of Health recently funded a study to compare contemporary endovascular therapy vs surgery in patients with critical limb ischemia.

TAKE-HOME POINTS

In the last decade, significant endovascular advances have been made. New devices and techniques have enhanced our ability to treat high-risk patients who have critical limb ischemia. The combination of risk factor modification, accurate diagnosis, and aggressive revascularization should prevent limb loss in many of these patients. For the primary care physician, a low threshold for assessing perfusion in patients with critical limb ischemia is important using a screening ankle-brachial index and toe-brachial index. These patients should promptly be referred to a vascular specialist for further evaluation and treatment.

In many ways, vascular disease in the leg is similar to that in the heart. The risk factors, underlying conditions, and pathogenetic processes are the same, and in many cases, patients have both conditions. And just as cardiologists and emergency physicians have learned that in acute myocardial infarction “time is muscle,” we are coming to appreciate that in many cases of limb ischemia, “time is limb.”

Most physicians well understand the clinical spectrum of coronary artery disease, which ranges from stable angina to ST-elevation myocardial infarction. In the leg, the same situation exists: at the more benign end of the spectrum, patients experience no symptoms, but often that is because they lead a sedentary lifestyle, modifying their activity level to avoid pain. As the disease worsens, they can develop claudication and critical leg ischemia, comparable to non-ST-elevation myocardial infarction. The most severe condition is acute limb ischemia, analagous to ST-elevation myocardial infarction.

Distinguishing acute from critical limb ischemia is essential in patients who present with leg problems, whether it be leg pain or ulcers. The farther along the clinical spectrum the patient’s condition is, the more important it is to be aggressive in diagnosis and treatment. The history and physical examination are the most important first steps, focusing on the onset of symptoms, history, risk factors, and past interventions.

Peripheral artery disease is increasingly becoming a worldwide problem that is now being emphasized by the World Health Organization. Unfortunately, not enough attention is paid to the problem, not only in less-developed countries but also in the United States. Patients with peripheral artery disease tend to be elderly, in the lowest economic classes, and uninsured, and they often do not understand the impact of the disease on their health.

LEG ULCERS: CAUSES AND COSTS

Finding the underlying cause of leg ulcers is important, and the differential diagnosis is large (Table 1). However, knowing the cause does not necessarily lead to healing; it is still essential to assess perfusion, infection, and wound care, and to arrest edema.

Causes of leg and foot ulcers include venous insufficiency (with an estimated 2.5 million cases annually),^1,2 diabetes (nearly 1 million cases),³ and pressure (ie, bedsores, occurring in up to 28% of patients in extended care),⁴ all at a cost in the billions of dollars.^5–7

In general, peripheral artery disease itself does not cause ulcers; it is an inciting factor. It is important to find what started the process. Ill-fitting shoes, poor sensation because of diabetes, or a cut when trimming toenails can all contribute to a wound, and peripheral artery disease makes it unable to heal. The healing process requires more nutrients and oxygen than poor circulation can provide.

ACUTE LIMB ISCHEMIA

Acute limb ischemia is defined as any sudden decrease in limb perfusion causing a potential threat to limb viability.⁸ Although it comes on suddenly, it does not imply that the patient has not had long-standing peripheral artery disease. It is important to determine what suddenly changed to cause the onset of symptoms.

History and physical examination: The six Ps

A good history includes a thorough evaluation of the present illness, including the pain’s time of onset, abruptness, location, intensity, and change over time, and whether it is present at rest. The medical history should focus on claudication, diabetes, smoking, heart disease, palpitations, atrial fibrillation, and previous ischemic symptoms.⁸

The physical examination should focus on the “six Ps”:

• Pain
• Pulselessness
• Paresthesia (numbness occurs in about half of patients)
• Pallor (obstruction is typically one joint above the level of demarcation of pallor)
• Paralysis (a bad sign, particularly if the calf is tight)
• Poikilothermia (inability to regulate temperature).

A good pulse examination includes measuring the ankle-brachial index and a Doppler examination of both legs. A neurologic examination focusing on sensory and motor function is critical for determining the level of ischemia and the urgency of intervention.

Classification of acute limb ischemia

If it is determined that a patient has acute leg ischemia, it is important to categorize the condition using the classification system devised by the Society of Vascular Surgery and International Society of Cardiovascular Surgery (Table 2).⁹ The category establishes the type and urgency of treatment. This classification system is simple and depends on factors that can be assessed easily by nonspecialists:

• Pulses—arterial and venous pulses assessed by Doppler ultrasonography
• Sensation—the patient closes the eyes and answers if he or she can feel the examiner’s touch
• Motor function—can the patient move his or her toes?

Venous pulses can be difficult to assess. However, if the arterial pulse is present, the venous pulse should be next to it. Knowing the other criteria can determine the category, so not being certain of the venous pulse should not deter a clinician from assessing the other factors.

Category I is “viable.” Patients have intact sensory and motor functions and audible pulses. Patients in this category should be admitted and possibly started on anticoagulation therapy and referred to a vascular specialist within hours.

Category IIa is “threatened.” Sensation is starting to be lost but motor function is still present. These patients are considered to have reversible ischemia, analogous to myocardial infarction of the leg, and they require immediate attention.

Category IIb is similar and it also requires immediate attention.

Category III is usually irreversible, with loss of motor function and sensation.

CAUSES OF ACUTE LIMB ISCHEMIA

Thrombosis accounts for about 50% of cases. Underlying causes of the thrombosis are artherosclerosis (native or bypass), aneurysm, trauma, vasculitis (eg, in a rheumatologic disease such as lupus), and hypercoagulable states (particularly in patients with cancer).

Embolism accounts for about 30% of cases. Emboli usually arise from plaque rupture in atherosclerotic arteries or a clot breaking off from an aneurysm or from within the heart in patients with atrial fibrillation or another underlying heart disease. Paradoxical embolism, caused by an embolism crossing the heart through an opening such as a patent foramen ovale, is rare.

Uncommon causes include arterial dissection following trauma, adventitial cystic disease, popliteal artery entrapment, ergotism (from consuming fungus-contaminated grains), and human immunodeficiency virus arteriopathy.

The physical examination provides clues to the origin: livedo reticularis (purple discoloration in a mottled pattern) and blue nail beds indicate that an embolus is likely. Tests, including electrocardiography, echocardiography, and computed tomography of the chest and abdomen to look for an aneurysm, can help identify the cause. Ultrasonography of the popliteal arteries should also be considered to search for an aneurysm.

CRITICAL LIMB ISCHEMIA

Critical limb ischemia is more likely than acute limb ischemia to be seen in a general practice. Many aspects need to be addressed simultaneously, by different specialists: vascular and endocrine systems, infection, and wound care. The most successful management strategy is a dynamic approach using every piece of information.¹⁰

The Rutherford classification of peripheral artery disease has six categories based on the clinical presentation, with categories I through III being mild to severe claudication. We discuss here only the more severe categories: IV (pain at rest), V (tissue loss), and VI (gangrene).

Strong indicators of pain at rest are that the patient has to get up at night to dangle the leg over the bed or walk a few steps, or sleeps in a chair, or refuses to elevate the leg because of pain. The affected leg tends to appear red when the patient is standing (dependent rubor), but pale when the foot is elevated (elevation pallor).

Confirming that a patient has dependent rubor can be challenging, especially in people with dark skin. Classically, redness is seen when the leg is down and disappears with elevation, but in cellulitis, redness can also be reduced by elevating the leg. A foot that is hot to the touch is an indication of infection and not lack of perfusion alone.

The hemodynamic definition of critical limb ischemia is¹¹:

• Ankle-brachial pressure index less than 0.4
• Reduced toebrachial pressure index, ie, less than 0.7
• Reduced transcutaneous pressure of oxygen (Tcpo₂), ie, less than 40 mm Hg.

From 15% to 20% of patients with claudication will progress to critical ischemia over their lifetime, and in patients with claudication who also have diabetes, the risk is nearly 10 times higher. Without revascularization, the risk of amputation within 1 year is 73% for patients in Rutherford class IV and 95% for patients in class V or VI.

Revascularization and limb preservation

Preserving the limb is a prime goal. For patients who have an amputation, the mortality rate is 40% within 2 years.⁸ These patients tend to be elderly, and after an amputation, most will not learn to use a prosthesis and resume their previous level of activity. Other treatment objectives are to relieve pain, reduce cardiovascular risk, and minimize procedural complications.

Although limb preservation is not a controversial goal, best practices to preserve limbs are not universally available. Goodney et al¹² studied variation in the United States in the use of lower-extremity vascular procedures for critical limb ischemia. They defined “low-intensity” to “high-intensity” regions of the country depending on the proportion of patients who underwent a vascular procedure in the year before amputation. They found considerable variation, but even in the region of highest intensity, more than 40% of patients did not have a vascular procedure in the year before amputation.

Similarly, Jones et al¹³ mapped amputation rates by US state and found significant variation even after adjusting for risk factors such as tobacco use and obesity.

Controversy surrounds the specifics of revascularization treatment, as in many fields in vascular medicine. However, most experts agree that improved perfusion is the goal.

The Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Artery Disease recommends revascularization as the best treatment for patients with critical limb ischemia.⁸ In addition, the American College of Cardiology and American Heart Association Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic) state that the tibial or pedal artery that is capable of providing continuous and uncompromised outflow to the foot should be used as the site of distal anastomosis.¹⁴ These guidelines do not yet mention endovascular therapy.

Angiosomes guide revascularization

In the past few years, the ability to facilitate healing of foot ulcers has improved. Angiosomes—regions of vascularization supplied by specific arteries—can be mapped on the skin, similar to the way dermatomes are mapped for neural innervation (Figure 1). The foot and lower leg region has six angiosomes perfused by three arteries that branch off the popliteal artery after it passes behind the knee:

• The anterior tibial artery supplies the dorsum of the foot and the front of the lower limb.
• The posterior tibial artery supplies the plantar surface of the foot via three branches—the medial plantar, lateral plantar, and calcaneal branches.
• The peroneal artery supplies the lateral part of the foot with collaterals to the anterior and posterior tibial arteries if they are compromised.

Studies have compared angiosome-based treatment vs revascularizing the best available artery (thus depending on collateral flow to compensate to surrounding areas). They have found that regardless of whether an endovascular or bypass method of revascularization was used, an angiosome-based approach led to significantly higher amputation-free survival rates.^15–17

Patients typically do not have blockage of only a single tibial artery. Graziani et al¹⁸ assessed the vascular lesions in 417 patients with critical limb ischemia and found that multiple below-knee arteries were frequently involved. This makes it difficult to decide where to target revascularization efforts, and the angiosome concept helps with that.

ASSESSING WOUND PERFUSION

Ankle- and toe-brachial indices assess perfusion

The ankle-brachial index¹⁹ is a good superficial assessment of perfusion. Multiple epidemiologic studies have shown the prognostic value of the ankle brachial index beyond the traditional risk factors and even the Framingham risk score.¹⁹ Values:

• Normal 1.1–1.30 (> 1.31 is abnormal and consistent with calcified vessels, and is an unreliable measure)
• Low normal 0.91–1.00
• Mild disease 0.71–0.90
• Moderate disease 0.41–0.70
• Severe disease ≤ 0.40.

However, the ankle-brachial index assesses perfusion only to the ankle, and many patients have ulcers in the toes and distal foot. The toe-brachial index must be specifically ordered in most institutions (if the first toe has an ulcer, the second toe should be assessed). The toe-brachial index is also important if the ankle-brachial index cannot be obtained because of calcified, noncompressible arteries in the ankle. A normal toe-brachial index is greater than 0.7.

The segmental blood pressure examination compares blood pressure measurements at multiple sites in the lower extremity. A drop of more than 20 mm Hg between segments indicates obstruction at that location. The test is simple and noninvasive and often can replace computed tomography.²⁰

Transcutaneous oximetry

Transcutaneous oximetry measures the Tcpo₂ from 1 to 2 mm deep in the skin from local capillaries. Measured adjacent to an ulcer, it is useful to predict wound healing and to assess the response to hyperbaric oxygen therapy.²¹ The values are:

• Normal > 70 mm Hg
• Impaired wound healing < 40 mm Hg
• Critical limb ischemia < 30 mm Hg.

Although most agree that a Tcpo₂ below 40 mm Hg requires revascularization, low values can arise from many causes other than peripheral artery disease, including high altitude, pulmonary disease, heart failure, edema, inflammation, callus, and skin diseases such as scleroderma.

Skin perfusion pressure better predicts healing

Skin perfusion pressure is a measure of the capillary opening pressure after occlusion and is another way to assess perfusion. This test is not routinely done and must be specially requested.

The test is performed by inflating a blood pressure cuff on the leg until blood flow is occluded, then using laser Doppler to determine reactive hyperemia, ie, the gradual return of blood flow during controlled pressure release. The pressure at which movement is detected is the skin perfusion pressure.²²

The laser Doppler probe emits and detects light scattered in the tissue. Light hitting moving blood cells undergoes a change in frequency, ie, a Doppler shift. An algorithm converts the optical information in the skin perfusion pressure by capturing the onset of capillary flow return and determining the pressure at which flow returns. Categories of results:

• > 50 mm Hg—normal
• 40–50 mm Hg—mild ischemia (wound healing probable)
• 30–40 mm Hg—moderate ischemia (wound healing uncertain)
• < 30 mm Hg—critical limb ischemia (wound healing unlikely).

Skin perfusion pressure testing has the advantages of not being affected by vessel calcification, thickened skin, or edema. It can be used on the plantar aspect of the foot and on digits. Recent small studies indicate that it is more sensitive for predicting wound healing than Tcpo₂ measures.

On the other hand, skin perfusion pressure testing is not useful for predicting response to hyperbaric oxygen therapy. Also, blood flow occlusion by the cuff may be painful.

Intraoperative fluorescence angiography

Intraoperative fluorescence angiography is used to assess flap viability during reconstructive surgery and is being studied to determine its usefulness for assessing tissue viability in limb ischemia.

The test provides real-time assessment of capillary perfusion, determining surface tissue viability. The imaging head contains a digital camera, a laser light source, and a distance sensor. The test requires intravenous administration of indocyanine green, which binds to plasma proteins and is cleared through the liver, making it safe for patients with renal dysfunction. It cannot be used in patients with allergies to iodine contrast, penicillin, or sulfa.²³

PREVENTION TARGETS CARDIOVASCULAR RISK FACTORS

Preventive measures are the same as for cardiovascular disease, ie, aggressive risk-factor modification: quitting smoking, lowering low-density lipoprotein cholesterol, reducing blood pressure, controlling diabetes, and managing heart failure.

Dual antiplatelet therapy should be instituted with aspirin and clopidogrel (Plavix) in patients undergoing revascularization. One can also consider cilostazol (Pletal); however, the role of this agent in patients with critical limb ischemia is less defined.

BYPASS OR ANGIOPLASTY?

The Bypass Versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial²⁴ randomly assigned 452 patients with severe limb ischemia due to infrainguinal atherosclerosis to receive either surgery-first or angioplasty-first care and followed them for 5.5 years.

No significant differences between the two groups were found in amputation-free survival, deaths, or health-related quality of life. However, hospital costs associated with the surgery-first strategy were about one-third higher. As expected, more patients in the surgery group developed a wound infection, and more patients in the angioplasty group required bypass surgery at some point.

The conclusion that can be reached from this study is that patients presenting with severe limb ischemia due to infrainguinal atherosclerotic occlusive disease who are suitable for both surgical and interventional procedures can be treated with either method. However, most experts consider endovascular therapy as the first option in many patients. The National Institutes of Health recently funded a study to compare contemporary endovascular therapy vs surgery in patients with critical limb ischemia.

TAKE-HOME POINTS

In the last decade, significant endovascular advances have been made. New devices and techniques have enhanced our ability to treat high-risk patients who have critical limb ischemia. The combination of risk factor modification, accurate diagnosis, and aggressive revascularization should prevent limb loss in many of these patients. For the primary care physician, a low threshold for assessing perfusion in patients with critical limb ischemia is important using a screening ankle-brachial index and toe-brachial index. These patients should promptly be referred to a vascular specialist for further evaluation and treatment.

In many ways, vascular disease in the leg is similar to that in the heart. The risk factors, underlying conditions, and pathogenetic processes are the same, and in many cases, patients have both conditions. And just as cardiologists and emergency physicians have learned that in acute myocardial infarction “time is muscle,” we are coming to appreciate that in many cases of limb ischemia, “time is limb.”

Most physicians well understand the clinical spectrum of coronary artery disease, which ranges from stable angina to ST-elevation myocardial infarction. In the leg, the same situation exists: at the more benign end of the spectrum, patients experience no symptoms, but often that is because they lead a sedentary lifestyle, modifying their activity level to avoid pain. As the disease worsens, they can develop claudication and critical leg ischemia, comparable to non-ST-elevation myocardial infarction. The most severe condition is acute limb ischemia, analagous to ST-elevation myocardial infarction.

Distinguishing acute from critical limb ischemia is essential in patients who present with leg problems, whether it be leg pain or ulcers. The farther along the clinical spectrum the patient’s condition is, the more important it is to be aggressive in diagnosis and treatment. The history and physical examination are the most important first steps, focusing on the onset of symptoms, history, risk factors, and past interventions.

Peripheral artery disease is increasingly becoming a worldwide problem that is now being emphasized by the World Health Organization. Unfortunately, not enough attention is paid to the problem, not only in less-developed countries but also in the United States. Patients with peripheral artery disease tend to be elderly, in the lowest economic classes, and uninsured, and they often do not understand the impact of the disease on their health.

LEG ULCERS: CAUSES AND COSTS

Finding the underlying cause of leg ulcers is important, and the differential diagnosis is large (Table 1). However, knowing the cause does not necessarily lead to healing; it is still essential to assess perfusion, infection, and wound care, and to arrest edema.

Causes of leg and foot ulcers include venous insufficiency (with an estimated 2.5 million cases annually),^1,2 diabetes (nearly 1 million cases),³ and pressure (ie, bedsores, occurring in up to 28% of patients in extended care),⁴ all at a cost in the billions of dollars.^5–7

In general, peripheral artery disease itself does not cause ulcers; it is an inciting factor. It is important to find what started the process. Ill-fitting shoes, poor sensation because of diabetes, or a cut when trimming toenails can all contribute to a wound, and peripheral artery disease makes it unable to heal. The healing process requires more nutrients and oxygen than poor circulation can provide.

ACUTE LIMB ISCHEMIA

Acute limb ischemia is defined as any sudden decrease in limb perfusion causing a potential threat to limb viability.⁸ Although it comes on suddenly, it does not imply that the patient has not had long-standing peripheral artery disease. It is important to determine what suddenly changed to cause the onset of symptoms.

History and physical examination: The six Ps

A good history includes a thorough evaluation of the present illness, including the pain’s time of onset, abruptness, location, intensity, and change over time, and whether it is present at rest. The medical history should focus on claudication, diabetes, smoking, heart disease, palpitations, atrial fibrillation, and previous ischemic symptoms.⁸

The physical examination should focus on the “six Ps”:

• Pain
• Pulselessness
• Paresthesia (numbness occurs in about half of patients)
• Pallor (obstruction is typically one joint above the level of demarcation of pallor)
• Paralysis (a bad sign, particularly if the calf is tight)
• Poikilothermia (inability to regulate temperature).

A good pulse examination includes measuring the ankle-brachial index and a Doppler examination of both legs. A neurologic examination focusing on sensory and motor function is critical for determining the level of ischemia and the urgency of intervention.

Classification of acute limb ischemia

If it is determined that a patient has acute leg ischemia, it is important to categorize the condition using the classification system devised by the Society of Vascular Surgery and International Society of Cardiovascular Surgery (Table 2).⁹ The category establishes the type and urgency of treatment. This classification system is simple and depends on factors that can be assessed easily by nonspecialists:

• Pulses—arterial and venous pulses assessed by Doppler ultrasonography
• Sensation—the patient closes the eyes and answers if he or she can feel the examiner’s touch
• Motor function—can the patient move his or her toes?

Venous pulses can be difficult to assess. However, if the arterial pulse is present, the venous pulse should be next to it. Knowing the other criteria can determine the category, so not being certain of the venous pulse should not deter a clinician from assessing the other factors.

Category I is “viable.” Patients have intact sensory and motor functions and audible pulses. Patients in this category should be admitted and possibly started on anticoagulation therapy and referred to a vascular specialist within hours.

Category IIa is “threatened.” Sensation is starting to be lost but motor function is still present. These patients are considered to have reversible ischemia, analogous to myocardial infarction of the leg, and they require immediate attention.

Category IIb is similar and it also requires immediate attention.

Category III is usually irreversible, with loss of motor function and sensation.

CAUSES OF ACUTE LIMB ISCHEMIA

Thrombosis accounts for about 50% of cases. Underlying causes of the thrombosis are artherosclerosis (native or bypass), aneurysm, trauma, vasculitis (eg, in a rheumatologic disease such as lupus), and hypercoagulable states (particularly in patients with cancer).

Embolism accounts for about 30% of cases. Emboli usually arise from plaque rupture in atherosclerotic arteries or a clot breaking off from an aneurysm or from within the heart in patients with atrial fibrillation or another underlying heart disease. Paradoxical embolism, caused by an embolism crossing the heart through an opening such as a patent foramen ovale, is rare.

Uncommon causes include arterial dissection following trauma, adventitial cystic disease, popliteal artery entrapment, ergotism (from consuming fungus-contaminated grains), and human immunodeficiency virus arteriopathy.

The physical examination provides clues to the origin: livedo reticularis (purple discoloration in a mottled pattern) and blue nail beds indicate that an embolus is likely. Tests, including electrocardiography, echocardiography, and computed tomography of the chest and abdomen to look for an aneurysm, can help identify the cause. Ultrasonography of the popliteal arteries should also be considered to search for an aneurysm.

CRITICAL LIMB ISCHEMIA

Critical limb ischemia is more likely than acute limb ischemia to be seen in a general practice. Many aspects need to be addressed simultaneously, by different specialists: vascular and endocrine systems, infection, and wound care. The most successful management strategy is a dynamic approach using every piece of information.¹⁰

The Rutherford classification of peripheral artery disease has six categories based on the clinical presentation, with categories I through III being mild to severe claudication. We discuss here only the more severe categories: IV (pain at rest), V (tissue loss), and VI (gangrene).

Strong indicators of pain at rest are that the patient has to get up at night to dangle the leg over the bed or walk a few steps, or sleeps in a chair, or refuses to elevate the leg because of pain. The affected leg tends to appear red when the patient is standing (dependent rubor), but pale when the foot is elevated (elevation pallor).

Confirming that a patient has dependent rubor can be challenging, especially in people with dark skin. Classically, redness is seen when the leg is down and disappears with elevation, but in cellulitis, redness can also be reduced by elevating the leg. A foot that is hot to the touch is an indication of infection and not lack of perfusion alone.

The hemodynamic definition of critical limb ischemia is¹¹:

• Ankle-brachial pressure index less than 0.4
• Reduced toebrachial pressure index, ie, less than 0.7
• Reduced transcutaneous pressure of oxygen (Tcpo₂), ie, less than 40 mm Hg.

From 15% to 20% of patients with claudication will progress to critical ischemia over their lifetime, and in patients with claudication who also have diabetes, the risk is nearly 10 times higher. Without revascularization, the risk of amputation within 1 year is 73% for patients in Rutherford class IV and 95% for patients in class V or VI.

Revascularization and limb preservation

Preserving the limb is a prime goal. For patients who have an amputation, the mortality rate is 40% within 2 years.⁸ These patients tend to be elderly, and after an amputation, most will not learn to use a prosthesis and resume their previous level of activity. Other treatment objectives are to relieve pain, reduce cardiovascular risk, and minimize procedural complications.

Although limb preservation is not a controversial goal, best practices to preserve limbs are not universally available. Goodney et al¹² studied variation in the United States in the use of lower-extremity vascular procedures for critical limb ischemia. They defined “low-intensity” to “high-intensity” regions of the country depending on the proportion of patients who underwent a vascular procedure in the year before amputation. They found considerable variation, but even in the region of highest intensity, more than 40% of patients did not have a vascular procedure in the year before amputation.

Similarly, Jones et al¹³ mapped amputation rates by US state and found significant variation even after adjusting for risk factors such as tobacco use and obesity.

Controversy surrounds the specifics of revascularization treatment, as in many fields in vascular medicine. However, most experts agree that improved perfusion is the goal.

The Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Artery Disease recommends revascularization as the best treatment for patients with critical limb ischemia.⁸ In addition, the American College of Cardiology and American Heart Association Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic) state that the tibial or pedal artery that is capable of providing continuous and uncompromised outflow to the foot should be used as the site of distal anastomosis.¹⁴ These guidelines do not yet mention endovascular therapy.

Angiosomes guide revascularization

In the past few years, the ability to facilitate healing of foot ulcers has improved. Angiosomes—regions of vascularization supplied by specific arteries—can be mapped on the skin, similar to the way dermatomes are mapped for neural innervation (Figure 1). The foot and lower leg region has six angiosomes perfused by three arteries that branch off the popliteal artery after it passes behind the knee:

• The anterior tibial artery supplies the dorsum of the foot and the front of the lower limb.
• The posterior tibial artery supplies the plantar surface of the foot via three branches—the medial plantar, lateral plantar, and calcaneal branches.
• The peroneal artery supplies the lateral part of the foot with collaterals to the anterior and posterior tibial arteries if they are compromised.

Studies have compared angiosome-based treatment vs revascularizing the best available artery (thus depending on collateral flow to compensate to surrounding areas). They have found that regardless of whether an endovascular or bypass method of revascularization was used, an angiosome-based approach led to significantly higher amputation-free survival rates.^15–17

Patients typically do not have blockage of only a single tibial artery. Graziani et al¹⁸ assessed the vascular lesions in 417 patients with critical limb ischemia and found that multiple below-knee arteries were frequently involved. This makes it difficult to decide where to target revascularization efforts, and the angiosome concept helps with that.

ASSESSING WOUND PERFUSION

Ankle- and toe-brachial indices assess perfusion

The ankle-brachial index¹⁹ is a good superficial assessment of perfusion. Multiple epidemiologic studies have shown the prognostic value of the ankle brachial index beyond the traditional risk factors and even the Framingham risk score.¹⁹ Values:

• Normal 1.1–1.30 (> 1.31 is abnormal and consistent with calcified vessels, and is an unreliable measure)
• Low normal 0.91–1.00
• Mild disease 0.71–0.90
• Moderate disease 0.41–0.70
• Severe disease ≤ 0.40.

However, the ankle-brachial index assesses perfusion only to the ankle, and many patients have ulcers in the toes and distal foot. The toe-brachial index must be specifically ordered in most institutions (if the first toe has an ulcer, the second toe should be assessed). The toe-brachial index is also important if the ankle-brachial index cannot be obtained because of calcified, noncompressible arteries in the ankle. A normal toe-brachial index is greater than 0.7.

The segmental blood pressure examination compares blood pressure measurements at multiple sites in the lower extremity. A drop of more than 20 mm Hg between segments indicates obstruction at that location. The test is simple and noninvasive and often can replace computed tomography.²⁰

Transcutaneous oximetry

Transcutaneous oximetry measures the Tcpo₂ from 1 to 2 mm deep in the skin from local capillaries. Measured adjacent to an ulcer, it is useful to predict wound healing and to assess the response to hyperbaric oxygen therapy.²¹ The values are:

• Normal > 70 mm Hg
• Impaired wound healing < 40 mm Hg
• Critical limb ischemia < 30 mm Hg.

Although most agree that a Tcpo₂ below 40 mm Hg requires revascularization, low values can arise from many causes other than peripheral artery disease, including high altitude, pulmonary disease, heart failure, edema, inflammation, callus, and skin diseases such as scleroderma.

Skin perfusion pressure better predicts healing

Skin perfusion pressure is a measure of the capillary opening pressure after occlusion and is another way to assess perfusion. This test is not routinely done and must be specially requested.

The test is performed by inflating a blood pressure cuff on the leg until blood flow is occluded, then using laser Doppler to determine reactive hyperemia, ie, the gradual return of blood flow during controlled pressure release. The pressure at which movement is detected is the skin perfusion pressure.²²

The laser Doppler probe emits and detects light scattered in the tissue. Light hitting moving blood cells undergoes a change in frequency, ie, a Doppler shift. An algorithm converts the optical information in the skin perfusion pressure by capturing the onset of capillary flow return and determining the pressure at which flow returns. Categories of results:

• > 50 mm Hg—normal
• 40–50 mm Hg—mild ischemia (wound healing probable)
• 30–40 mm Hg—moderate ischemia (wound healing uncertain)
• < 30 mm Hg—critical limb ischemia (wound healing unlikely).

Skin perfusion pressure testing has the advantages of not being affected by vessel calcification, thickened skin, or edema. It can be used on the plantar aspect of the foot and on digits. Recent small studies indicate that it is more sensitive for predicting wound healing than Tcpo₂ measures.

On the other hand, skin perfusion pressure testing is not useful for predicting response to hyperbaric oxygen therapy. Also, blood flow occlusion by the cuff may be painful.

Intraoperative fluorescence angiography

Intraoperative fluorescence angiography is used to assess flap viability during reconstructive surgery and is being studied to determine its usefulness for assessing tissue viability in limb ischemia.

The test provides real-time assessment of capillary perfusion, determining surface tissue viability. The imaging head contains a digital camera, a laser light source, and a distance sensor. The test requires intravenous administration of indocyanine green, which binds to plasma proteins and is cleared through the liver, making it safe for patients with renal dysfunction. It cannot be used in patients with allergies to iodine contrast, penicillin, or sulfa.²³

PREVENTION TARGETS CARDIOVASCULAR RISK FACTORS

Preventive measures are the same as for cardiovascular disease, ie, aggressive risk-factor modification: quitting smoking, lowering low-density lipoprotein cholesterol, reducing blood pressure, controlling diabetes, and managing heart failure.

Dual antiplatelet therapy should be instituted with aspirin and clopidogrel (Plavix) in patients undergoing revascularization. One can also consider cilostazol (Pletal); however, the role of this agent in patients with critical limb ischemia is less defined.

BYPASS OR ANGIOPLASTY?

The Bypass Versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial²⁴ randomly assigned 452 patients with severe limb ischemia due to infrainguinal atherosclerosis to receive either surgery-first or angioplasty-first care and followed them for 5.5 years.

No significant differences between the two groups were found in amputation-free survival, deaths, or health-related quality of life. However, hospital costs associated with the surgery-first strategy were about one-third higher. As expected, more patients in the surgery group developed a wound infection, and more patients in the angioplasty group required bypass surgery at some point.

The conclusion that can be reached from this study is that patients presenting with severe limb ischemia due to infrainguinal atherosclerotic occlusive disease who are suitable for both surgical and interventional procedures can be treated with either method. However, most experts consider endovascular therapy as the first option in many patients. The National Institutes of Health recently funded a study to compare contemporary endovascular therapy vs surgery in patients with critical limb ischemia.

TAKE-HOME POINTS

In the last decade, significant endovascular advances have been made. New devices and techniques have enhanced our ability to treat high-risk patients who have critical limb ischemia. The combination of risk factor modification, accurate diagnosis, and aggressive revascularization should prevent limb loss in many of these patients. For the primary care physician, a low threshold for assessing perfusion in patients with critical limb ischemia is important using a screening ankle-brachial index and toe-brachial index. These patients should promptly be referred to a vascular specialist for further evaluation and treatment.

ANSWER

The radiograph shows the lungs overall to be clear. There are some slight increased markings, perhaps suggestive of mild congestion, but no infiltrate or consolidation.

Of note is a small nodule within the middle portion of the left upper lobe that requires monitoring and further workup. Also, although it is incompletely imaged, there appears to be a fracture of the right humeral neck.

Additional imaging confirmed the fracture. Orthopedic consultation was obtained.

ANSWER

The radiograph shows the lungs overall to be clear. There are some slight increased markings, perhaps suggestive of mild congestion, but no infiltrate or consolidation.

Of note is a small nodule within the middle portion of the left upper lobe that requires monitoring and further workup. Also, although it is incompletely imaged, there appears to be a fracture of the right humeral neck.

Additional imaging confirmed the fracture. Orthopedic consultation was obtained.

ANSWER

The radiograph shows the lungs overall to be clear. There are some slight increased markings, perhaps suggestive of mild congestion, but no infiltrate or consolidation.

Of note is a small nodule within the middle portion of the left upper lobe that requires monitoring and further workup. Also, although it is incompletely imaged, there appears to be a fracture of the right humeral neck.

Additional imaging confirmed the fracture. Orthopedic consultation was obtained.

To the Editor: In the December 2013 Cleveland Clinic Journal of Medicine, Tehrani and Seto provide a review of the updated definitions of myocardial infarction (MI).¹ A key concept incorporated into the structured definitions is that cardiac biomarkers must be interpreted in a clinical context.² This in turn helps better align the laboratory and clinical findings with the pathophysiologic processes.

However, there is another dimension to the definitions that is sometimes overlooked and requires careful attention: translation of the definitions into codes and comparable databases. Accurate and consistent coding according to the International Statistical Classification of Diseases, ninth edition (ICD-9), and the ICD-10 is critically vital to the appropriate analysis of data, research, quality measurement, and reimbursement of services related to MI. Unfortunately, there is no straightforward translation of the definitions into ICD-9 codes, and the challenge is further confounded when it comes to ICD-10, which will be implemented in October 2014.

The ICD-10-CM Index to Diseases does not yet recognize this nomenclature. ST-elevation MI is the default for the unspecified term “acute MI.” Non-ST-elevation MI requires more explicit documentation and is classified based on whether it occurs during or after a variety of procedures. Type 2 MI is particularly challenging because of the several possible ways to code the condition—for example, as acute subendocardial MI (I21.4), demand ischemia (I24.8), or acute MI, unspecified (I21.9). Coding guidelines are assumed to standardize the approach to coding these conditions, but there is no guarantee that comparability of the data will endure biases of code assignment. Although extreme precision in disease capture by coding may not exist, other clinical conditions have better correlations with coding classifications, such as stages of chronic kidney disease ranging from stage 1 through end-stage renal disease (N18.1 through N18.6). Furthermore, ICD-10 codes are insufficient to clearly distinguish the type of acute MI.³

While the concept of acute MI applies when the stated date of onset is less than 8 weeks in ICD-9,⁴ it changes to 4 weeks in ICD-10. “Acute” can reference an initial or a subsequent MI in ICD-10, but it does not define the time frame of the MI.⁵ This is different than in ICD-9, where the concept of “subsequent” refers to a “subsequent episode of care.”

On the surface, these variations may not seem significant. However, the discriminatory efforts to better define a patient’s clinical condition using the new definitions may get diluted by the challenges of the coding process. The implications on comparability of quality metrics and reporting are not to be underestimated and need to be assessed on a national level.

To the Editor: In the December 2013 Cleveland Clinic Journal of Medicine, Tehrani and Seto provide a review of the updated definitions of myocardial infarction (MI).¹ A key concept incorporated into the structured definitions is that cardiac biomarkers must be interpreted in a clinical context.² This in turn helps better align the laboratory and clinical findings with the pathophysiologic processes.

However, there is another dimension to the definitions that is sometimes overlooked and requires careful attention: translation of the definitions into codes and comparable databases. Accurate and consistent coding according to the International Statistical Classification of Diseases, ninth edition (ICD-9), and the ICD-10 is critically vital to the appropriate analysis of data, research, quality measurement, and reimbursement of services related to MI. Unfortunately, there is no straightforward translation of the definitions into ICD-9 codes, and the challenge is further confounded when it comes to ICD-10, which will be implemented in October 2014.

The ICD-10-CM Index to Diseases does not yet recognize this nomenclature. ST-elevation MI is the default for the unspecified term “acute MI.” Non-ST-elevation MI requires more explicit documentation and is classified based on whether it occurs during or after a variety of procedures. Type 2 MI is particularly challenging because of the several possible ways to code the condition—for example, as acute subendocardial MI (I21.4), demand ischemia (I24.8), or acute MI, unspecified (I21.9). Coding guidelines are assumed to standardize the approach to coding these conditions, but there is no guarantee that comparability of the data will endure biases of code assignment. Although extreme precision in disease capture by coding may not exist, other clinical conditions have better correlations with coding classifications, such as stages of chronic kidney disease ranging from stage 1 through end-stage renal disease (N18.1 through N18.6). Furthermore, ICD-10 codes are insufficient to clearly distinguish the type of acute MI.³

While the concept of acute MI applies when the stated date of onset is less than 8 weeks in ICD-9,⁴ it changes to 4 weeks in ICD-10. “Acute” can reference an initial or a subsequent MI in ICD-10, but it does not define the time frame of the MI.⁵ This is different than in ICD-9, where the concept of “subsequent” refers to a “subsequent episode of care.”

On the surface, these variations may not seem significant. However, the discriminatory efforts to better define a patient’s clinical condition using the new definitions may get diluted by the challenges of the coding process. The implications on comparability of quality metrics and reporting are not to be underestimated and need to be assessed on a national level.

To the Editor: In the December 2013 Cleveland Clinic Journal of Medicine, Tehrani and Seto provide a review of the updated definitions of myocardial infarction (MI).¹ A key concept incorporated into the structured definitions is that cardiac biomarkers must be interpreted in a clinical context.² This in turn helps better align the laboratory and clinical findings with the pathophysiologic processes.

However, there is another dimension to the definitions that is sometimes overlooked and requires careful attention: translation of the definitions into codes and comparable databases. Accurate and consistent coding according to the International Statistical Classification of Diseases, ninth edition (ICD-9), and the ICD-10 is critically vital to the appropriate analysis of data, research, quality measurement, and reimbursement of services related to MI. Unfortunately, there is no straightforward translation of the definitions into ICD-9 codes, and the challenge is further confounded when it comes to ICD-10, which will be implemented in October 2014.

The ICD-10-CM Index to Diseases does not yet recognize this nomenclature. ST-elevation MI is the default for the unspecified term “acute MI.” Non-ST-elevation MI requires more explicit documentation and is classified based on whether it occurs during or after a variety of procedures. Type 2 MI is particularly challenging because of the several possible ways to code the condition—for example, as acute subendocardial MI (I21.4), demand ischemia (I24.8), or acute MI, unspecified (I21.9). Coding guidelines are assumed to standardize the approach to coding these conditions, but there is no guarantee that comparability of the data will endure biases of code assignment. Although extreme precision in disease capture by coding may not exist, other clinical conditions have better correlations with coding classifications, such as stages of chronic kidney disease ranging from stage 1 through end-stage renal disease (N18.1 through N18.6). Furthermore, ICD-10 codes are insufficient to clearly distinguish the type of acute MI.³

While the concept of acute MI applies when the stated date of onset is less than 8 weeks in ICD-9,⁴ it changes to 4 weeks in ICD-10. “Acute” can reference an initial or a subsequent MI in ICD-10, but it does not define the time frame of the MI.⁵ This is different than in ICD-9, where the concept of “subsequent” refers to a “subsequent episode of care.”

On the surface, these variations may not seem significant. However, the discriminatory efforts to better define a patient’s clinical condition using the new definitions may get diluted by the challenges of the coding process. The implications on comparability of quality metrics and reporting are not to be underestimated and need to be assessed on a national level.

In Reply: We thank Dr. Antonios for his comments regarding the current shortcomings of the ICD-9 and ICD-10 coding systems in describing the acute MI types as defined in the universal definition. We share his concern that accurate and consistent coding of MIs may be difficult when the definition of MI changes over a short period of time. Such changes create a disconnect not only between our clinical terminology and coding systems, but also potentially between our conventional sense of a “heart attack” as an acute coronary syndrome or a clinically significant infarction rather than a small troponin elevation from demand ischemia. This has consequences not only for quality measures and reporting, but also for clinical research trials and clinical care. This is exemplified by reports of recent trials that were possibly prematurely discontinued, as the use of troponin thresholds may conflate large MIs with clinically insignificant ones.¹

Recently, the Society for Cardiovascular Angiography and Interventions published a new definition of “clinically relevant” MI after revascularization.² Rather than relying on troponins, which are elevated in as many as 24.3% of uncomplicated percutaneous coronary interventions and in 42% to 82% of uncomplicated coronary artery bypass grafting procedures (based on the 2007 universal definition), they point to extensive literature documenting that only patients with elevated creatine kinase MB more than 10 times the upper limit of normal after revascularization have a worsened prognosis. We favor this clinically relevant MI definition for post-revascularization MI. We also favor the use of creatine kinase MB as a less sensitive but more specific confirmatory marker for acute coronary syndromes (type 1) or clinically significant supply-demand (type 2) MI, when the symptoms or electrocardiographic signs are nondiagnostic, as they often are.³ However, until there is a consensus around a single definition, clinicians are effectively walking around a Tower of Babel and must take care to be specific when documenting an MI.

In Reply: We thank Dr. Antonios for his comments regarding the current shortcomings of the ICD-9 and ICD-10 coding systems in describing the acute MI types as defined in the universal definition. We share his concern that accurate and consistent coding of MIs may be difficult when the definition of MI changes over a short period of time. Such changes create a disconnect not only between our clinical terminology and coding systems, but also potentially between our conventional sense of a “heart attack” as an acute coronary syndrome or a clinically significant infarction rather than a small troponin elevation from demand ischemia. This has consequences not only for quality measures and reporting, but also for clinical research trials and clinical care. This is exemplified by reports of recent trials that were possibly prematurely discontinued, as the use of troponin thresholds may conflate large MIs with clinically insignificant ones.¹

Recently, the Society for Cardiovascular Angiography and Interventions published a new definition of “clinically relevant” MI after revascularization.² Rather than relying on troponins, which are elevated in as many as 24.3% of uncomplicated percutaneous coronary interventions and in 42% to 82% of uncomplicated coronary artery bypass grafting procedures (based on the 2007 universal definition), they point to extensive literature documenting that only patients with elevated creatine kinase MB more than 10 times the upper limit of normal after revascularization have a worsened prognosis. We favor this clinically relevant MI definition for post-revascularization MI. We also favor the use of creatine kinase MB as a less sensitive but more specific confirmatory marker for acute coronary syndromes (type 1) or clinically significant supply-demand (type 2) MI, when the symptoms or electrocardiographic signs are nondiagnostic, as they often are.³ However, until there is a consensus around a single definition, clinicians are effectively walking around a Tower of Babel and must take care to be specific when documenting an MI.

In Reply: We thank Dr. Antonios for his comments regarding the current shortcomings of the ICD-9 and ICD-10 coding systems in describing the acute MI types as defined in the universal definition. We share his concern that accurate and consistent coding of MIs may be difficult when the definition of MI changes over a short period of time. Such changes create a disconnect not only between our clinical terminology and coding systems, but also potentially between our conventional sense of a “heart attack” as an acute coronary syndrome or a clinically significant infarction rather than a small troponin elevation from demand ischemia. This has consequences not only for quality measures and reporting, but also for clinical research trials and clinical care. This is exemplified by reports of recent trials that were possibly prematurely discontinued, as the use of troponin thresholds may conflate large MIs with clinically insignificant ones.¹

Recently, the Society for Cardiovascular Angiography and Interventions published a new definition of “clinically relevant” MI after revascularization.² Rather than relying on troponins, which are elevated in as many as 24.3% of uncomplicated percutaneous coronary interventions and in 42% to 82% of uncomplicated coronary artery bypass grafting procedures (based on the 2007 universal definition), they point to extensive literature documenting that only patients with elevated creatine kinase MB more than 10 times the upper limit of normal after revascularization have a worsened prognosis. We favor this clinically relevant MI definition for post-revascularization MI. We also favor the use of creatine kinase MB as a less sensitive but more specific confirmatory marker for acute coronary syndromes (type 1) or clinically significant supply-demand (type 2) MI, when the symptoms or electrocardiographic signs are nondiagnostic, as they often are.³ However, until there is a consensus around a single definition, clinicians are effectively walking around a Tower of Babel and must take care to be specific when documenting an MI.

ANSWER

The radiograph shows moderate soft-tissue swelling with dislocation of the proximal interphalangeal joint. No definite fracture is seen. In addition, there are some metallic-appearing foreign bodies.

The patient was treated with closed ­reduction and splinting. He also received a referral to outpatient orthopedics for ­follow-up.

ANSWER

The radiograph shows moderate soft-tissue swelling with dislocation of the proximal interphalangeal joint. No definite fracture is seen. In addition, there are some metallic-appearing foreign bodies.

The patient was treated with closed ­reduction and splinting. He also received a referral to outpatient orthopedics for ­follow-up.

ANSWER

The radiograph shows moderate soft-tissue swelling with dislocation of the proximal interphalangeal joint. No definite fracture is seen. In addition, there are some metallic-appearing foreign bodies.

The patient was treated with closed ­reduction and splinting. He also received a referral to outpatient orthopedics for ­follow-up.

Antiplatelet and anticoagulant drugs are a cornerstone of the medical treatment of acute coronary syndrome (ACS), reducing the rates of both morbidity and death.^1–4 However, reductions in ischemic events with these drugs have uniformly been accompanied by increases in bleeding complications, which reduce the net benefit.⁵ Thus, clinical research has been exploring ways to maximize the benefit while minimizing the risk.

Here, we review the guidelines and evidence supporting the use of antiplatelet and anticoagulant drugs in ACS.

ACUTE CORONARY SYNDROMES WITH OR WITHOUT ST ELEVATION

A key distinction when treating ACS is whether the electrocardiogram shows ST-segment elevation. In cases of non-ST-elevation ACS (ie, unstable angina or non-ST-elevation myocardial infarction), a second key question is whether the initial strategy will be invasive (with angiography performed urgently) or conservative (with angiography performed later). In ST-elevation myocardial infarction, another distinction is how perfusion is to be restored, ie, with primary percutaneous coronary intervention or with thrombolysis. All these questions affect the choice of antiplatelet and anticoagulant therapy.

Figure 1 and Figure 2 summarize the guidelines of the American College of Cardiology Foundation and American Heart Association.^1,2,6,7

ANTIPLATELET THERAPY

Aspirin for all

Aspirin irreversibly acetylates the enzyme cyclooxygenase-1, blocking intraplatelet formation of thromboxane A2 (Figure 3), a potent platelet aggregator and endothelial vasoconstrictor. Large clinical trials have confirmed that aspirin reduces morbidity and mortality rates by as much as 50% in patients with ACS.⁸

The ISIS-2 trial⁹ found that giving aspirin early in the emergency department significantly reduced the mortality rate.

The Antithrombotic Trialists’ Collaboration,¹⁰ in a meta-analysis of randomized controlled trials comparing different doses of aspirin in high-risk ACS patients, found no greater benefit for doses of aspirin higher than 162 mg per day when used long-term.

How to use. During an ACS, the patient should receive one dose of aspirin 325 mg (the standard high-dose pill in the United States). This dose should be chewed, as buccal absorption results in more rapid systemic effects.¹¹

Adapted from Storey RF. New developments in antiplatelet therapy. Eur Heart J Suppl 2008; 10(suppl D):D30-D37.

Thereafter, the patient should take 81 mg per day, continued indefinitely. The 81-mg dose also applies to patients who undergo a percutaneous coronary intervention with a drug-eluting stent.⁷ Previous recommendations called for higher doses, but studies have shown that higher doses pose a higher risk of bleeding without additional clinical benefit. The use of enteric-coated aspirin does not reduce this risk,¹² and its delayed release may in fact cause aspirin “pseudoresistance.”¹³

The concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided, as NSAIDs reversibly bind to platelets, thus preventing aspirin from binding.¹⁴ As aspirin washes out of the body, NSAIDs may then become unbound from platelets, leaving platelets activated.

P2Y12 receptor inhibitors: Clopidogrel, prasugrel, ticagrelor

These agents bind to P2Y12 receptors on platelets to inhibit adenosine diphosphate-mediated platelet activation (Figure 3). Clopidogrel and prasugrel are irreversible prodrugs, whereas ticagrelor binds reversibly.

Clopidogrel, a prodrug

Clopidogrel has a half-life of 8 hours and a time to peak concentration of 4 hours. Eighty-five percent of a dose is inactivated by gut esterases. The remainder is metabolized primarily by the cytochrome P4502C19 enzyme system into its active metabolite.

How to use. The recommended dosage is a 600-mg bolus early in the course of ACS. This is associated with a lower rate of cardiovascular events than a 300-mg dose,2,15 although no trial has rigorously compared 300-mg vs 600-mg doses using major clinical end points. In patients presenting with ACS who cannot tolerate aspirin because of hypersensitivity or major gastrointestinal contraindication, clopidogrel is an alternative.1

The CURE trial¹⁶ randomized 12,526 patients with non-ST-elevation ACS to receive clopidogrel or placebo in addition to standard therapy. Clopidogrel was associated with a 20% lower rate of cardiovascular death, myocardial infarction, or stroke in both low- and high-risk patients regardless of whether an invasive or conservative strategy was pursued.

However, patients who underwent coronary artery bypass grafting (CABG) had a 53% higher risk of bleeding (an absolute risk of 3.3%) if they received clopidogrel within 5 days of the surgery. This has led to the practice in some centers of delaying giving clopidogrel until after the coronary anatomy has been defined. This deprives the patient of the anti-ischemic benefits conferred by giving clopidogrel early and remains a contentious issue, with most suggesting that the risk-benefit ratio still favors giving clopidogrel early, before angiography, unless there is a high likelihood that surgery will ultimately be required.17 Alternatively, one could consider using a shorter-acting intravenous glycoprotein IIb/IIIa inhibitor such as eptifibatide as a “bridge” until a definitive reperfusion strategy is chosen.

Effect of CYP2C19 variants. The CLOVIS-2 study¹⁸ assessed the effects of genetic variants on the clopidogrel concentration in 106 patients who had had a myocardial infarction. The study confirmed that patients who carry certain variants of the CYP2C19 gene attain lower plasma concentrations of clopidogrel after receiving this drug.¹⁹ This accounts for its delayed onset of action as well as its variability in response in patients who have reduced expression or inhibition of this enzyme system. Doubling the standard dose in patients who carry these variants does not appear to provide clinical benefit.²⁰

Thus, the thought is emerging that one should consider using prasugrel or ticagrelor instead of clopidogrel in patients who have these polymorphisms, though this is yet to be backed by robust clinical evidence.

Possible interaction with proton pump inhibitors. Controversy exists about whether proton pump inhibitors inhibit clopidogrel’s action. Although the US Food and Drug Administration continues to warn against the concurrent use of omeprazole and clopidogrel,²¹ an analysis of the PLATO trial²² concluded that patients with ACS who were taking proton pump inhibitors were at higher risk of ischemic events regardless of whether they had been randomized to clopidogrel or ticagrelor (a drug that acts independently of the cytochrome P450 system). This observation suggests that patients on proton pump inhibitors are generally sicker and at higher risk of ischemic events regardless of the choice of antiplatelet therapy. The use of other gastroprotective agents did not appear to mitigate these risks.

Prasugrel: Faster metabolism to active drug

Prasugrel is an irreversible P2Y12 receptor antagonist (Figure 3) that is metabolized into its active metabolite faster and in a more predictable fashion than clopidogrel.²³

The TRITON-TIMI 38 study²⁴ included 13,608 ACS patients in whom an early invasive strategy was planned and who were pretreated with prasugrel or clopidogrel in addition to standard treatment. The rate of the primary efficacy end point of death, myocardial infarction, or stroke was 19% lower in the prasugrel group. In those who underwent percutaneous coronary intervention, the incidence of in-stent thrombosis was more than 50% lower in the prasugrel group regardless of whether bare metal stents or drug-eluting stents were used.

Greater platelet inhibition came at the price of a higher incidence of serious bleeding, particularly in the subgroups of patients who were over age 75, had a history of stroke or transient ischemic attack, or weighed less than 60 kg. Prasugrel is therefore contraindicated in patients with a history of transient ischemic attack or stroke. Some suggest that a 5-mg dose can be used with caution (rather than the usual 10-mg dose) in patients over age 75 years or those who have low body weight.

The TRILOGY-ACS trial²⁵ compared prasugrel and clopidogrel in medically managed patients with high-risk non-ST-elevation ACS. It found no difference in the rates of the primary end points of cardiovascular death, myocardial infarction, or stroke at 1 year. In the prespecified subset of patients over age 75 years, the rate of bleeding end points was no higher with prasugrel 5 mg once daily than with clopidogrel.

Prasugrel’s half-life is 7 hours, and its peak antiplatelet effect is within 30 minutes after an oral dose, compared with 4 hours with clopidogrel. Therefore, if a patient with non-ST-elevation ACS is going to go to the catheterization laboratory soon, he or she should not receive prasugrel beforehand, and should receive it later only if the results of angiography indicate that CABG will not be needed urgently. This is an important consideration when using prasugrel, as the rate of surgery-related bleeding was four times higher than with clopidogrel. If possible, this drug should be withheld for at least 7 days before CABG.

Ticagrelor, a direct P2Y12 receptor inhibitor

Ticagrelor, a reversible direct inhibitor of the P2Y12 receptor, inhibits adenosine diphosphate-mediated activation and aggregation (Figure 3). It has a median time to peak concentration of 1.3 to 2 hours and a half-life of 9 hours.

The PLATO trial²⁶ enrolled 18,624 patients with ACS who were given either ticagrelor or clopidogrel in addition to standard therapy. At 12 months, the composite primary end point of myocardial infarction, death, or stroke had occurred in 16% fewer patients receiving ticagrelor than in the clopidogrel group. Analyzed separately, there were 16% fewer myocardial infarctions, 21% fewer cardiovascular deaths, and 22% fewer deaths from any cause, regardless of whether an invasive or conservative strategy was used, and with or without prior clopidogrel use. Fewer cases of stent thrombosis occurred in the ticagrelor group, and the rate of major bleeding was the same.

In a prospectively defined subgroup analysis,²⁷ ticagrelor was beneficial only in patients who received lower doses of aspirin (< 100 mg daily): the hazard ratio for the primary end point was 0.79 (95% confidence interval [CI] 0.71–0.88) in ticagrelor recipients who received low-dose aspirin and 1.45 (95% CI 1.01–2.09) in those who received high-dose aspirin.

Although this analysis is underpowered and controversial, the current evidence suggests that when used in combination with ticagrelor, the aspirin dose should be 81 mg.

Ticagrelor was also associated with a 19% higher incidence of non-CABG- or procedure-related major bleeding, more nonfatal and fatal intracranial bleeding, a higher incidence of dyspnea, and significantly more ventricular pauses.

Although ticagrelor carries no black-box warning about its use in patients with prior stroke or transient ischemic attack, the number of such patients in PLATO was small. Thus, caution should still be used in these patients.²⁸

Ticagrelor should preferably be discontinued 5 days before CABG.

Glycoprotein IIb/IIIa inhibitors: Eptifibatide, tirofiban, abciximab

Glycoprotein IIb/IIIa inhibitors are intravenous agents that act by inhibiting fibrinogen-and von Willebrand factor-mediated platelet-to-platelet cross-linkage, the final pathway of platelet aggregation (Figure 3).

Use of these agents in ACS has been decreasing, as evidence supporting their use was largely established before the era of dual antiplatelet therapy.

A meta-analysis29 of 46,374 patients with non-ST-elevation ACS found that routinely adding a glycoprotein IIb/IIIa inhibitor “upstream” as a third agent in patients receiving dual antiplatelet therapy bought only a modest (11%) reduction in death or myocardial infarction at 30 days, at the price of a 23% increase in major bleeding and no decrease in the overall rate of death. Roughly 70% of the patients were receiving dual antiplatelet therapy before cardiac catheterization.

These agents can be considered in high-risk ACS patients, such as those with ST-segment changes or elevated troponin concentrations, and in diabetic patients, on the assumption that these patients likely have a high intracoronary thrombus burden and are at higher risk of microvascular embolization.^6,30 They can also be considered at the time of primary percutaneous coronary intervention in selected patients receiving heparin.⁷

Eptifibatide

Eptifibatide is a small-molecule, short-acting glycoprotein IIb/IIIa inhibitor with a half-life of 2.5 hours. Its inhibition of platelet aggregation is reversible by stopping the drug infusion and is thought to be a result of dissociation of the drug from platelets.

The PURSUIT trial³¹ studied 10,948 patients presenting with non-ST-elevation ACS randomized to placebo, eptifibatide in a 180-μg/kg bolus followed by a 2.0-μg/kg/min infusion, or eptifibatide in a 180-μg/kg bolus followed by a 1.3-μg/kg/min infusion. Both eptifibatide groups had a 1.5% absolute reduction in the incidence of the primary end point of death or myocardial infarction, a benefit that was apparent at 96 hours and that persisted through 30 days. Bleeding was more common in the eptifibatide groups, but there was no increase in the rate of hemorrhagic stroke.

The ACUITY trial³² found that early use of eptifibatide or tirofiban had no effect on the primary outcome. (See the section below on bivalirudin for more information about the ACUITY trial.)

PARENTERAL ANTICOAGULANTS

Unfractionated heparin: A declining role

Heparin binds to antithrombin and induces a conformational change, causing rapid inhibition of factor IIa (thrombin), factor IXa, and factor Xa, thus preventing further thrombus propagation (Figure 4). An intravenous bolus of 60 units/kg produces a time to peak of 5 to 10 minutes and a half-life of 30 to 60 minutes.

Heparin can be reversed by giving protamine sulfate (1 mg per 100 units of heparin). For ACS, it is given in a bolus of 60 units/kg not exceeding 4,000 units, followed by an infusion of 12 units/kg/hour, with monitoring of the activated partial thromboplastin time every 6 hours with a goal value of 50 to 70 seconds or 1.5 to 2.5 times control.

Side effects include thrombocytopenia, heparin-induced thrombocytopenia (a distinct condition), and bleeding.

The use of unfractionated heparin was tested in ACS in the early 1990s. Oler et al³³ performed a meta-analysis of six randomized trials and found a 33% lower rate of death in patients treated with heparin in addition to aspirin in ACS, as well less reported ischemic pain.

Advantages of unfractionated heparin are that it has stood the test of time, is inexpensive, and can be rapidly reversed. The disadvantages are that it can have serious side effects, including heparin-induced thrombocytopenia, and is more likely to cause bleeding than the newer intravenous anticoagulants discussed below. Thus, its position as the main anticoagulant in ACS is being challenged.

Bivalirudin is a synthetic direct thrombin inhibitor of fluid-phase and clot-bound thrombin (Figure 4). It also inhibits platelets directly.

The ACUITY trial³² randomized 13,819 patients with moderate to high-risk ACS scheduled for invasive treatment into three treatment groups:

• Heparin (either unfractionated heparin or enoxaparin) plus a glycoprotein IIb/IIIa inhibitor (either eptifibatide, tirofiban, or abciximab)
• Bivalirudin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin alone.

The bivalirudin-alone treatment was as sociated with noninferior rates of composite ischemia end points and significantly lower rates of major bleeding, adding up to a significant reduction in the net clinical outcome end point. An important caveat is that bivalirudin’s noninferiority was mostly in the group of patients already receiving a thienopyridine before angiography and percutaneous coronary intervention (RR 0.97 vs 1.27, P = .054). There was less major, nonmajor, minor, CABG-related, and non-CABG-related bleeding as well as need for transfusion in the bivalirudin-alone group, making bivalirudin monotherapy an attractive option in ACS patients with or without ST-segment elevation undergoing a percutaneous coronary intervention.^1,31

The ISAR-REACT trial³⁴ later compared bivalirudin alone vs unfractionated heparin and abciximab in patients with non-ST-elevation myocardial infarction undergoing percutaneous coronary intervention pretreated with aspirin and clopidogrel. The composite rate of ischemia was similar in the two treatment groups, with significantly lower rates of bleeding in the bivalirudin group.

HORIZONS-AMI³⁵ randomized 3,602 patients with ST-elevation myocardial infarction receiving aspirin and clopidogrel either to unfractionated heparin and a glycoprotein IIb/IIIa inhibitor or to bivalirudin. As in the ACUITY trial, there was no difference in ischemic end points and a 40% to 45% lower rate of major bleeding end points in the bivalirudin group, translating into an overall lower rate of death.

Enoxaparin, a low-molecular weight heparin

Enoxaparin is a low-molecular-weight heparin that inhibits factor IIa and factor Xa via antithrombin, roughly in a ratio of 1:3 (Figure 4). It has a time to peak effect of 10 minutes when given intravenously³⁶ and 3 to 5 hours when given subcutaneously.³⁷ Its half-life is 4.5 hours, but it is longer in patients with renal dysfunction, requiring dose adjustments in this population.

Its anticoagulant effect is partially reversible. If it is to be reversed between 0 and 8 hours after dosing, the recommended reversal regimen is 1 mg of protamine sulfate for every 1 mg of enoxaparin used. At 8 to 12 hours, it is 0.5 mg of protamine for every 1 mg of enoxaparin. After 12 hours, no protamine is required.

Compared with unfractionated heparin, enoxaparin has less plasma protein binding and a more consistent anticoagulant effect. Its high bioavailability also allows for subcutaneous dosing. Its greater anti-Xa activity inhibits thrombin generation more effectively, and it causes lower rates of thrombocytopenia and heparin-induced thrombocytopenia.

de Lemos et al³⁸ found that, in ACS patients in whom an early conservative approach of medical management was planned, enoxaparin was more efficacious than unfractionated heparin and caused a similar rate of bleeding.

Murphy et al,³⁹ in a meta-analysis of 12 trials in 49,088 ACS patients, also found that enoxaparin had a net clinical benefit compared with unfractionated heparin in reducing rates of myocardial infarction and death despite more bleeding.

The ESSENCE trial⁴⁰ compared enoxaparin vs unfractionated heparin in 3,171 patients with ACS. It found fewer ischemic events with enoxaparin in the early phase, more minor bleeding, but no increase in major bleeding.

The SYNERGY trial,⁴¹ in 10,027 patients with high-risk non-ST-elevation ACS undergoing percutaneous coronary intervention, compared subcutaneous enoxaparin with intravenous heparin. Enoxaparin was found to be noninferior to heparin but caused more bleeding, including major bleeding, drops in hemoglobin, and intracranial hemorrhage.

The EXTRACT-TIMI 25 trial.⁴² In patients with ST-elevation myocardial infarction, enoxaparin has been shown to be beneficial both in patients treated with fibrinolysis and in those who underwent primary percutaneous coronary intervention. The EXTRACT-TIMI 25 trial randomized 20,749 patients to receive either enoxaparin (an intravenous bolus and maintenance subcutaneous dosing based on renal function) or intravenous heparin in addition to thrombolysis within 6 hours of the diagnosis of ST-elevation myocardial infarction. Although the enoxaparin group had more bleeding end points, they had fewer primary and secondary efficacy end points, translating into an overall net clinical benefit in favor of enoxaparin.

The ATOLL trial⁴³ examined the use of enoxaparin (0.5 mg/kg intravenously) or unfractionated heparin in 910 patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention (via the radial artery in 66% to 69%). Although there was a trend towards benefit in terms of the primary end point of death, myocardial infarction complications, procedure failure, and major bleeding favoring enoxaparin, it was not statistically significant (95% CI 0.68–1.01, P = .06).

However, there was a 37% to 42% lower rate of the secondary end point of death, recurrent myocardial infarction or ACS, or urgent target-vessel revascularization in the enoxaparin group, with a 40% reduction in death from any cause, death from a cardiac cause, or shock. The safety profiles of the two drugs were similar, and the net clinical benefit significantly favored enoxaparin.

Fondaparinux, a factor Xa inhibitor

Fondaparinux is a synthetic pentasaccharide that indirectly inhibits factor Xa through the action of antithrombin (Figure 4). After a 2.5-mg subcutaneous dose, it has a time to peak concentration of 2 hours and a half-life of 17 to 21 hours.

The OASIS-5 trial⁴⁴ compared fondaparinux and enoxaparin in 20,078 patients treated for non-ST-elevation ACS. Although the rates of death, myocardial infarction, and refractory ischemia at 9 days were similar for both drugs, the fondaparinux group had a significantly (almost 50%) lower rate of bleeding at 30 days, translating into significantly fewer deaths at 30 days. However, patients receiving fondaparinux who underwent percutaneous coronary intervention had a threefold higher rate of catheter-related thrombosis.

The OASIS-6 trial⁴⁵ compared fondaparinux vs usual care (placebo in those in whom unfractionated heparin was not indicated or unfractionated heparin for up to 48 hours followed by placebo for up to 8 days) in 12,092 patients with ST-elevation myocardial infarction. There was a 1.5% absolute risk reduction in death and reinfarction without an increase in bleeding at 30 days, with trends persisting 6 months into the study. However, fondaparinux was not superior to heparin in the 3% of patients who underwent primary percutaneous coronary intervention. As in OASIS-5, there was more catheter-related thrombosis in the fondaparinux group.

Although the use of supplemental unfractionated heparin appears to have mitigated this risk, fondaparinux remains a less-than-ideal option in the era of primary percutaneous coronary intervention for ST-elevation myocardial infarction and has therefore found limited use in this group of patients. It should, however, be considered in patients for whom a conservative strategy is planned, especially if bleeding risk is deemed to be high.

ORAL ANTICOAGULANTS

Oral anticoagulants provide ischemic benefit in selected patients with ACS—at the price of a higher risk of significant bleeding.

Warfarin

Warfarin was investigated after myocardial infarction in the WARIS II,⁴⁶ CARS,⁴⁷ and CHAMP⁴⁸ trials.

WARIS II⁴⁶ looked at the use of aspirin alone, warfarin alone, and aspirin and warfarin in combination. The rates of the primary end points of stroke, nonfatal infarction, and death were lower in the warfarin group.

CARS⁴⁷ found no difference in the rate of the primary end point of fatal infarction, nonfatal ischemic stroke, or cardiovascular death with aspirin vs warfarin plus aspirin.

CHAMP⁴⁸ saw similar trends, ie, no difference in the rate of death, recurrent myocardial infarction, or stroke with warfarin plus aspirin vs aspirin alone.

All three studies showed increases in major bleeding with warfarin use.

Putting these trials into context, the significant net clinical benefit of dual antiplatelet therapy in the current era compared with the significant bleeding and questionable conflicting evidence supporting benefit with warfarin has limited its use in ACS patients.

Rivaroxaban, an oral factor Xa inhibitor

Rivaroxaban is a novel oral direct reversible factor Xa inhibitor.

The ATLAS ACS 2-TIMI 51 trial⁴⁹ found rivaroxaban 2.5 mg or 5 mg to yield a significantly lower rate of the primary outcome of cardiovascular death, myocardial infarction, ischemic stroke, and in-stent thrombosis compared with placebo, but significantly more major non-CABG bleeding and intracranial hemorrhage.

The dose used in this trial was much lower than the dose used in trials investigating the role of this drug in stroke prophylaxis in atrial fibrillation.

Apixaban, an oral factor Xa inhibitor

Apixaban is another direct factor Xa inhibitor.

The APPRAISE-2 trial⁵⁰ compared apixaban 5 mg twice daily vs placebo in ACS. There was no difference in the rate of cardiovascular death, myocardial infarction, or stroke, but there was significantly more bleeding in the apixaban group, prompting early termination of this study.

Dabigatran, an oral thrombin inhibitor

Dabigatran is an oral direct thrombin inhibitor.

The RE-DEEM trial⁵¹ compared four doses of dabigatran (50, 75, 110, and 150 mg twice daily) and placebo in ACS patients. The dabigatran groups had more major and minor bleeding, and the higher the dose, the higher the incidence of bleeding. In addition, the rates of ischemic end points were no lower with dabigatran, although this trial was not powered to show differences in clinical events.

REDUCING THE RISK OF BLEEDING

In the treatment of ACS, the benefits of restoring perfusion by preventing further propagation of thrombus and platelet aggregation come at a significant price of higher bleeding risk. This in turn increases the risk of death through various mechanisms, including shock, worsening ischemia, discontinuation of antiplatelet and anticoagulation therapy causing stent thrombosis, and anemia leading to transfusion, which propagates the underlying inflammatory milieu.⁵²

Giugliano and Braunwald⁵³ provide practical suggestions to reduce this risk, advising physicians to:

• Avoid inappropriately high dosing, particularly in patients with renal insufficiency
• Preferentially use agents that cause less bleeding (eg, bivalirudin, fondaparinux) without compromising anti-ischemic efficacy
• Minimize the concomitant use of other drugs that cause bleeding (eg, NSAIDs)
• Use drugs that protect against bleeding (eg, proton pump inhibitors) in patients at high risk
• Prevent access-site bleeding by using the radial artery, smaller sheaths, and appropriate sheath and closure device management. Indeed, the use of radial interventions in ACS has been shown to reduce access-site-related bleeding, even in patients at high risk.⁵⁴

The reduction in bleeding risk may provide future trials the opportunity to increase antithrombotic efficacy of different agents with goals of reducing ischemic end points.

Antiplatelet and anticoagulant drugs are a cornerstone of the medical treatment of acute coronary syndrome (ACS), reducing the rates of both morbidity and death.^1–4 However, reductions in ischemic events with these drugs have uniformly been accompanied by increases in bleeding complications, which reduce the net benefit.⁵ Thus, clinical research has been exploring ways to maximize the benefit while minimizing the risk.

Here, we review the guidelines and evidence supporting the use of antiplatelet and anticoagulant drugs in ACS.

ACUTE CORONARY SYNDROMES WITH OR WITHOUT ST ELEVATION

A key distinction when treating ACS is whether the electrocardiogram shows ST-segment elevation. In cases of non-ST-elevation ACS (ie, unstable angina or non-ST-elevation myocardial infarction), a second key question is whether the initial strategy will be invasive (with angiography performed urgently) or conservative (with angiography performed later). In ST-elevation myocardial infarction, another distinction is how perfusion is to be restored, ie, with primary percutaneous coronary intervention or with thrombolysis. All these questions affect the choice of antiplatelet and anticoagulant therapy.

Figure 1 and Figure 2 summarize the guidelines of the American College of Cardiology Foundation and American Heart Association.^1,2,6,7

ANTIPLATELET THERAPY

Aspirin for all

Aspirin irreversibly acetylates the enzyme cyclooxygenase-1, blocking intraplatelet formation of thromboxane A2 (Figure 3), a potent platelet aggregator and endothelial vasoconstrictor. Large clinical trials have confirmed that aspirin reduces morbidity and mortality rates by as much as 50% in patients with ACS.⁸

The ISIS-2 trial⁹ found that giving aspirin early in the emergency department significantly reduced the mortality rate.

The Antithrombotic Trialists’ Collaboration,¹⁰ in a meta-analysis of randomized controlled trials comparing different doses of aspirin in high-risk ACS patients, found no greater benefit for doses of aspirin higher than 162 mg per day when used long-term.

How to use. During an ACS, the patient should receive one dose of aspirin 325 mg (the standard high-dose pill in the United States). This dose should be chewed, as buccal absorption results in more rapid systemic effects.¹¹

Adapted from Storey RF. New developments in antiplatelet therapy. Eur Heart J Suppl 2008; 10(suppl D):D30-D37.

Thereafter, the patient should take 81 mg per day, continued indefinitely. The 81-mg dose also applies to patients who undergo a percutaneous coronary intervention with a drug-eluting stent.⁷ Previous recommendations called for higher doses, but studies have shown that higher doses pose a higher risk of bleeding without additional clinical benefit. The use of enteric-coated aspirin does not reduce this risk,¹² and its delayed release may in fact cause aspirin “pseudoresistance.”¹³

The concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided, as NSAIDs reversibly bind to platelets, thus preventing aspirin from binding.¹⁴ As aspirin washes out of the body, NSAIDs may then become unbound from platelets, leaving platelets activated.

P2Y12 receptor inhibitors: Clopidogrel, prasugrel, ticagrelor

These agents bind to P2Y12 receptors on platelets to inhibit adenosine diphosphate-mediated platelet activation (Figure 3). Clopidogrel and prasugrel are irreversible prodrugs, whereas ticagrelor binds reversibly.

Clopidogrel, a prodrug

Clopidogrel has a half-life of 8 hours and a time to peak concentration of 4 hours. Eighty-five percent of a dose is inactivated by gut esterases. The remainder is metabolized primarily by the cytochrome P4502C19 enzyme system into its active metabolite.

How to use. The recommended dosage is a 600-mg bolus early in the course of ACS. This is associated with a lower rate of cardiovascular events than a 300-mg dose,2,15 although no trial has rigorously compared 300-mg vs 600-mg doses using major clinical end points. In patients presenting with ACS who cannot tolerate aspirin because of hypersensitivity or major gastrointestinal contraindication, clopidogrel is an alternative.1

The CURE trial¹⁶ randomized 12,526 patients with non-ST-elevation ACS to receive clopidogrel or placebo in addition to standard therapy. Clopidogrel was associated with a 20% lower rate of cardiovascular death, myocardial infarction, or stroke in both low- and high-risk patients regardless of whether an invasive or conservative strategy was pursued.

However, patients who underwent coronary artery bypass grafting (CABG) had a 53% higher risk of bleeding (an absolute risk of 3.3%) if they received clopidogrel within 5 days of the surgery. This has led to the practice in some centers of delaying giving clopidogrel until after the coronary anatomy has been defined. This deprives the patient of the anti-ischemic benefits conferred by giving clopidogrel early and remains a contentious issue, with most suggesting that the risk-benefit ratio still favors giving clopidogrel early, before angiography, unless there is a high likelihood that surgery will ultimately be required.17 Alternatively, one could consider using a shorter-acting intravenous glycoprotein IIb/IIIa inhibitor such as eptifibatide as a “bridge” until a definitive reperfusion strategy is chosen.

Effect of CYP2C19 variants. The CLOVIS-2 study¹⁸ assessed the effects of genetic variants on the clopidogrel concentration in 106 patients who had had a myocardial infarction. The study confirmed that patients who carry certain variants of the CYP2C19 gene attain lower plasma concentrations of clopidogrel after receiving this drug.¹⁹ This accounts for its delayed onset of action as well as its variability in response in patients who have reduced expression or inhibition of this enzyme system. Doubling the standard dose in patients who carry these variants does not appear to provide clinical benefit.²⁰

Thus, the thought is emerging that one should consider using prasugrel or ticagrelor instead of clopidogrel in patients who have these polymorphisms, though this is yet to be backed by robust clinical evidence.

Possible interaction with proton pump inhibitors. Controversy exists about whether proton pump inhibitors inhibit clopidogrel’s action. Although the US Food and Drug Administration continues to warn against the concurrent use of omeprazole and clopidogrel,²¹ an analysis of the PLATO trial²² concluded that patients with ACS who were taking proton pump inhibitors were at higher risk of ischemic events regardless of whether they had been randomized to clopidogrel or ticagrelor (a drug that acts independently of the cytochrome P450 system). This observation suggests that patients on proton pump inhibitors are generally sicker and at higher risk of ischemic events regardless of the choice of antiplatelet therapy. The use of other gastroprotective agents did not appear to mitigate these risks.

Prasugrel: Faster metabolism to active drug

Prasugrel is an irreversible P2Y12 receptor antagonist (Figure 3) that is metabolized into its active metabolite faster and in a more predictable fashion than clopidogrel.²³

The TRITON-TIMI 38 study²⁴ included 13,608 ACS patients in whom an early invasive strategy was planned and who were pretreated with prasugrel or clopidogrel in addition to standard treatment. The rate of the primary efficacy end point of death, myocardial infarction, or stroke was 19% lower in the prasugrel group. In those who underwent percutaneous coronary intervention, the incidence of in-stent thrombosis was more than 50% lower in the prasugrel group regardless of whether bare metal stents or drug-eluting stents were used.

Greater platelet inhibition came at the price of a higher incidence of serious bleeding, particularly in the subgroups of patients who were over age 75, had a history of stroke or transient ischemic attack, or weighed less than 60 kg. Prasugrel is therefore contraindicated in patients with a history of transient ischemic attack or stroke. Some suggest that a 5-mg dose can be used with caution (rather than the usual 10-mg dose) in patients over age 75 years or those who have low body weight.

The TRILOGY-ACS trial²⁵ compared prasugrel and clopidogrel in medically managed patients with high-risk non-ST-elevation ACS. It found no difference in the rates of the primary end points of cardiovascular death, myocardial infarction, or stroke at 1 year. In the prespecified subset of patients over age 75 years, the rate of bleeding end points was no higher with prasugrel 5 mg once daily than with clopidogrel.

Prasugrel’s half-life is 7 hours, and its peak antiplatelet effect is within 30 minutes after an oral dose, compared with 4 hours with clopidogrel. Therefore, if a patient with non-ST-elevation ACS is going to go to the catheterization laboratory soon, he or she should not receive prasugrel beforehand, and should receive it later only if the results of angiography indicate that CABG will not be needed urgently. This is an important consideration when using prasugrel, as the rate of surgery-related bleeding was four times higher than with clopidogrel. If possible, this drug should be withheld for at least 7 days before CABG.

Ticagrelor, a direct P2Y12 receptor inhibitor

Ticagrelor, a reversible direct inhibitor of the P2Y12 receptor, inhibits adenosine diphosphate-mediated activation and aggregation (Figure 3). It has a median time to peak concentration of 1.3 to 2 hours and a half-life of 9 hours.

The PLATO trial²⁶ enrolled 18,624 patients with ACS who were given either ticagrelor or clopidogrel in addition to standard therapy. At 12 months, the composite primary end point of myocardial infarction, death, or stroke had occurred in 16% fewer patients receiving ticagrelor than in the clopidogrel group. Analyzed separately, there were 16% fewer myocardial infarctions, 21% fewer cardiovascular deaths, and 22% fewer deaths from any cause, regardless of whether an invasive or conservative strategy was used, and with or without prior clopidogrel use. Fewer cases of stent thrombosis occurred in the ticagrelor group, and the rate of major bleeding was the same.

In a prospectively defined subgroup analysis,²⁷ ticagrelor was beneficial only in patients who received lower doses of aspirin (< 100 mg daily): the hazard ratio for the primary end point was 0.79 (95% confidence interval [CI] 0.71–0.88) in ticagrelor recipients who received low-dose aspirin and 1.45 (95% CI 1.01–2.09) in those who received high-dose aspirin.

Although this analysis is underpowered and controversial, the current evidence suggests that when used in combination with ticagrelor, the aspirin dose should be 81 mg.

Ticagrelor was also associated with a 19% higher incidence of non-CABG- or procedure-related major bleeding, more nonfatal and fatal intracranial bleeding, a higher incidence of dyspnea, and significantly more ventricular pauses.

Although ticagrelor carries no black-box warning about its use in patients with prior stroke or transient ischemic attack, the number of such patients in PLATO was small. Thus, caution should still be used in these patients.²⁸

Ticagrelor should preferably be discontinued 5 days before CABG.

Glycoprotein IIb/IIIa inhibitors: Eptifibatide, tirofiban, abciximab

Glycoprotein IIb/IIIa inhibitors are intravenous agents that act by inhibiting fibrinogen-and von Willebrand factor-mediated platelet-to-platelet cross-linkage, the final pathway of platelet aggregation (Figure 3).

Use of these agents in ACS has been decreasing, as evidence supporting their use was largely established before the era of dual antiplatelet therapy.

A meta-analysis29 of 46,374 patients with non-ST-elevation ACS found that routinely adding a glycoprotein IIb/IIIa inhibitor “upstream” as a third agent in patients receiving dual antiplatelet therapy bought only a modest (11%) reduction in death or myocardial infarction at 30 days, at the price of a 23% increase in major bleeding and no decrease in the overall rate of death. Roughly 70% of the patients were receiving dual antiplatelet therapy before cardiac catheterization.

These agents can be considered in high-risk ACS patients, such as those with ST-segment changes or elevated troponin concentrations, and in diabetic patients, on the assumption that these patients likely have a high intracoronary thrombus burden and are at higher risk of microvascular embolization.^6,30 They can also be considered at the time of primary percutaneous coronary intervention in selected patients receiving heparin.⁷

Eptifibatide

Eptifibatide is a small-molecule, short-acting glycoprotein IIb/IIIa inhibitor with a half-life of 2.5 hours. Its inhibition of platelet aggregation is reversible by stopping the drug infusion and is thought to be a result of dissociation of the drug from platelets.

The PURSUIT trial³¹ studied 10,948 patients presenting with non-ST-elevation ACS randomized to placebo, eptifibatide in a 180-μg/kg bolus followed by a 2.0-μg/kg/min infusion, or eptifibatide in a 180-μg/kg bolus followed by a 1.3-μg/kg/min infusion. Both eptifibatide groups had a 1.5% absolute reduction in the incidence of the primary end point of death or myocardial infarction, a benefit that was apparent at 96 hours and that persisted through 30 days. Bleeding was more common in the eptifibatide groups, but there was no increase in the rate of hemorrhagic stroke.

The ACUITY trial³² found that early use of eptifibatide or tirofiban had no effect on the primary outcome. (See the section below on bivalirudin for more information about the ACUITY trial.)

PARENTERAL ANTICOAGULANTS

Unfractionated heparin: A declining role

Heparin binds to antithrombin and induces a conformational change, causing rapid inhibition of factor IIa (thrombin), factor IXa, and factor Xa, thus preventing further thrombus propagation (Figure 4). An intravenous bolus of 60 units/kg produces a time to peak of 5 to 10 minutes and a half-life of 30 to 60 minutes.

Heparin can be reversed by giving protamine sulfate (1 mg per 100 units of heparin). For ACS, it is given in a bolus of 60 units/kg not exceeding 4,000 units, followed by an infusion of 12 units/kg/hour, with monitoring of the activated partial thromboplastin time every 6 hours with a goal value of 50 to 70 seconds or 1.5 to 2.5 times control.

Side effects include thrombocytopenia, heparin-induced thrombocytopenia (a distinct condition), and bleeding.

The use of unfractionated heparin was tested in ACS in the early 1990s. Oler et al³³ performed a meta-analysis of six randomized trials and found a 33% lower rate of death in patients treated with heparin in addition to aspirin in ACS, as well less reported ischemic pain.

Advantages of unfractionated heparin are that it has stood the test of time, is inexpensive, and can be rapidly reversed. The disadvantages are that it can have serious side effects, including heparin-induced thrombocytopenia, and is more likely to cause bleeding than the newer intravenous anticoagulants discussed below. Thus, its position as the main anticoagulant in ACS is being challenged.

Bivalirudin is a synthetic direct thrombin inhibitor of fluid-phase and clot-bound thrombin (Figure 4). It also inhibits platelets directly.

The ACUITY trial³² randomized 13,819 patients with moderate to high-risk ACS scheduled for invasive treatment into three treatment groups:

• Heparin (either unfractionated heparin or enoxaparin) plus a glycoprotein IIb/IIIa inhibitor (either eptifibatide, tirofiban, or abciximab)
• Bivalirudin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin alone.

The bivalirudin-alone treatment was as sociated with noninferior rates of composite ischemia end points and significantly lower rates of major bleeding, adding up to a significant reduction in the net clinical outcome end point. An important caveat is that bivalirudin’s noninferiority was mostly in the group of patients already receiving a thienopyridine before angiography and percutaneous coronary intervention (RR 0.97 vs 1.27, P = .054). There was less major, nonmajor, minor, CABG-related, and non-CABG-related bleeding as well as need for transfusion in the bivalirudin-alone group, making bivalirudin monotherapy an attractive option in ACS patients with or without ST-segment elevation undergoing a percutaneous coronary intervention.^1,31

The ISAR-REACT trial³⁴ later compared bivalirudin alone vs unfractionated heparin and abciximab in patients with non-ST-elevation myocardial infarction undergoing percutaneous coronary intervention pretreated with aspirin and clopidogrel. The composite rate of ischemia was similar in the two treatment groups, with significantly lower rates of bleeding in the bivalirudin group.

HORIZONS-AMI³⁵ randomized 3,602 patients with ST-elevation myocardial infarction receiving aspirin and clopidogrel either to unfractionated heparin and a glycoprotein IIb/IIIa inhibitor or to bivalirudin. As in the ACUITY trial, there was no difference in ischemic end points and a 40% to 45% lower rate of major bleeding end points in the bivalirudin group, translating into an overall lower rate of death.

Enoxaparin, a low-molecular weight heparin

Enoxaparin is a low-molecular-weight heparin that inhibits factor IIa and factor Xa via antithrombin, roughly in a ratio of 1:3 (Figure 4). It has a time to peak effect of 10 minutes when given intravenously³⁶ and 3 to 5 hours when given subcutaneously.³⁷ Its half-life is 4.5 hours, but it is longer in patients with renal dysfunction, requiring dose adjustments in this population.

Its anticoagulant effect is partially reversible. If it is to be reversed between 0 and 8 hours after dosing, the recommended reversal regimen is 1 mg of protamine sulfate for every 1 mg of enoxaparin used. At 8 to 12 hours, it is 0.5 mg of protamine for every 1 mg of enoxaparin. After 12 hours, no protamine is required.

Compared with unfractionated heparin, enoxaparin has less plasma protein binding and a more consistent anticoagulant effect. Its high bioavailability also allows for subcutaneous dosing. Its greater anti-Xa activity inhibits thrombin generation more effectively, and it causes lower rates of thrombocytopenia and heparin-induced thrombocytopenia.

de Lemos et al³⁸ found that, in ACS patients in whom an early conservative approach of medical management was planned, enoxaparin was more efficacious than unfractionated heparin and caused a similar rate of bleeding.

Murphy et al,³⁹ in a meta-analysis of 12 trials in 49,088 ACS patients, also found that enoxaparin had a net clinical benefit compared with unfractionated heparin in reducing rates of myocardial infarction and death despite more bleeding.

The ESSENCE trial⁴⁰ compared enoxaparin vs unfractionated heparin in 3,171 patients with ACS. It found fewer ischemic events with enoxaparin in the early phase, more minor bleeding, but no increase in major bleeding.

The SYNERGY trial,⁴¹ in 10,027 patients with high-risk non-ST-elevation ACS undergoing percutaneous coronary intervention, compared subcutaneous enoxaparin with intravenous heparin. Enoxaparin was found to be noninferior to heparin but caused more bleeding, including major bleeding, drops in hemoglobin, and intracranial hemorrhage.

The EXTRACT-TIMI 25 trial.⁴² In patients with ST-elevation myocardial infarction, enoxaparin has been shown to be beneficial both in patients treated with fibrinolysis and in those who underwent primary percutaneous coronary intervention. The EXTRACT-TIMI 25 trial randomized 20,749 patients to receive either enoxaparin (an intravenous bolus and maintenance subcutaneous dosing based on renal function) or intravenous heparin in addition to thrombolysis within 6 hours of the diagnosis of ST-elevation myocardial infarction. Although the enoxaparin group had more bleeding end points, they had fewer primary and secondary efficacy end points, translating into an overall net clinical benefit in favor of enoxaparin.

The ATOLL trial⁴³ examined the use of enoxaparin (0.5 mg/kg intravenously) or unfractionated heparin in 910 patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention (via the radial artery in 66% to 69%). Although there was a trend towards benefit in terms of the primary end point of death, myocardial infarction complications, procedure failure, and major bleeding favoring enoxaparin, it was not statistically significant (95% CI 0.68–1.01, P = .06).

However, there was a 37% to 42% lower rate of the secondary end point of death, recurrent myocardial infarction or ACS, or urgent target-vessel revascularization in the enoxaparin group, with a 40% reduction in death from any cause, death from a cardiac cause, or shock. The safety profiles of the two drugs were similar, and the net clinical benefit significantly favored enoxaparin.

Fondaparinux, a factor Xa inhibitor

Fondaparinux is a synthetic pentasaccharide that indirectly inhibits factor Xa through the action of antithrombin (Figure 4). After a 2.5-mg subcutaneous dose, it has a time to peak concentration of 2 hours and a half-life of 17 to 21 hours.

The OASIS-5 trial⁴⁴ compared fondaparinux and enoxaparin in 20,078 patients treated for non-ST-elevation ACS. Although the rates of death, myocardial infarction, and refractory ischemia at 9 days were similar for both drugs, the fondaparinux group had a significantly (almost 50%) lower rate of bleeding at 30 days, translating into significantly fewer deaths at 30 days. However, patients receiving fondaparinux who underwent percutaneous coronary intervention had a threefold higher rate of catheter-related thrombosis.

The OASIS-6 trial⁴⁵ compared fondaparinux vs usual care (placebo in those in whom unfractionated heparin was not indicated or unfractionated heparin for up to 48 hours followed by placebo for up to 8 days) in 12,092 patients with ST-elevation myocardial infarction. There was a 1.5% absolute risk reduction in death and reinfarction without an increase in bleeding at 30 days, with trends persisting 6 months into the study. However, fondaparinux was not superior to heparin in the 3% of patients who underwent primary percutaneous coronary intervention. As in OASIS-5, there was more catheter-related thrombosis in the fondaparinux group.

Although the use of supplemental unfractionated heparin appears to have mitigated this risk, fondaparinux remains a less-than-ideal option in the era of primary percutaneous coronary intervention for ST-elevation myocardial infarction and has therefore found limited use in this group of patients. It should, however, be considered in patients for whom a conservative strategy is planned, especially if bleeding risk is deemed to be high.

ORAL ANTICOAGULANTS

Oral anticoagulants provide ischemic benefit in selected patients with ACS—at the price of a higher risk of significant bleeding.

Warfarin

Warfarin was investigated after myocardial infarction in the WARIS II,⁴⁶ CARS,⁴⁷ and CHAMP⁴⁸ trials.

WARIS II⁴⁶ looked at the use of aspirin alone, warfarin alone, and aspirin and warfarin in combination. The rates of the primary end points of stroke, nonfatal infarction, and death were lower in the warfarin group.

CARS⁴⁷ found no difference in the rate of the primary end point of fatal infarction, nonfatal ischemic stroke, or cardiovascular death with aspirin vs warfarin plus aspirin.

CHAMP⁴⁸ saw similar trends, ie, no difference in the rate of death, recurrent myocardial infarction, or stroke with warfarin plus aspirin vs aspirin alone.

All three studies showed increases in major bleeding with warfarin use.

Putting these trials into context, the significant net clinical benefit of dual antiplatelet therapy in the current era compared with the significant bleeding and questionable conflicting evidence supporting benefit with warfarin has limited its use in ACS patients.

Rivaroxaban, an oral factor Xa inhibitor

Rivaroxaban is a novel oral direct reversible factor Xa inhibitor.

The ATLAS ACS 2-TIMI 51 trial⁴⁹ found rivaroxaban 2.5 mg or 5 mg to yield a significantly lower rate of the primary outcome of cardiovascular death, myocardial infarction, ischemic stroke, and in-stent thrombosis compared with placebo, but significantly more major non-CABG bleeding and intracranial hemorrhage.

The dose used in this trial was much lower than the dose used in trials investigating the role of this drug in stroke prophylaxis in atrial fibrillation.

Apixaban, an oral factor Xa inhibitor

Apixaban is another direct factor Xa inhibitor.

The APPRAISE-2 trial⁵⁰ compared apixaban 5 mg twice daily vs placebo in ACS. There was no difference in the rate of cardiovascular death, myocardial infarction, or stroke, but there was significantly more bleeding in the apixaban group, prompting early termination of this study.

Dabigatran, an oral thrombin inhibitor

Dabigatran is an oral direct thrombin inhibitor.

The RE-DEEM trial⁵¹ compared four doses of dabigatran (50, 75, 110, and 150 mg twice daily) and placebo in ACS patients. The dabigatran groups had more major and minor bleeding, and the higher the dose, the higher the incidence of bleeding. In addition, the rates of ischemic end points were no lower with dabigatran, although this trial was not powered to show differences in clinical events.

REDUCING THE RISK OF BLEEDING

In the treatment of ACS, the benefits of restoring perfusion by preventing further propagation of thrombus and platelet aggregation come at a significant price of higher bleeding risk. This in turn increases the risk of death through various mechanisms, including shock, worsening ischemia, discontinuation of antiplatelet and anticoagulation therapy causing stent thrombosis, and anemia leading to transfusion, which propagates the underlying inflammatory milieu.⁵²

Giugliano and Braunwald⁵³ provide practical suggestions to reduce this risk, advising physicians to:

• Avoid inappropriately high dosing, particularly in patients with renal insufficiency
• Preferentially use agents that cause less bleeding (eg, bivalirudin, fondaparinux) without compromising anti-ischemic efficacy
• Minimize the concomitant use of other drugs that cause bleeding (eg, NSAIDs)
• Use drugs that protect against bleeding (eg, proton pump inhibitors) in patients at high risk
• Prevent access-site bleeding by using the radial artery, smaller sheaths, and appropriate sheath and closure device management. Indeed, the use of radial interventions in ACS has been shown to reduce access-site-related bleeding, even in patients at high risk.⁵⁴

The reduction in bleeding risk may provide future trials the opportunity to increase antithrombotic efficacy of different agents with goals of reducing ischemic end points.

Antiplatelet and anticoagulant drugs are a cornerstone of the medical treatment of acute coronary syndrome (ACS), reducing the rates of both morbidity and death.^1–4 However, reductions in ischemic events with these drugs have uniformly been accompanied by increases in bleeding complications, which reduce the net benefit.⁵ Thus, clinical research has been exploring ways to maximize the benefit while minimizing the risk.

Here, we review the guidelines and evidence supporting the use of antiplatelet and anticoagulant drugs in ACS.

ACUTE CORONARY SYNDROMES WITH OR WITHOUT ST ELEVATION

A key distinction when treating ACS is whether the electrocardiogram shows ST-segment elevation. In cases of non-ST-elevation ACS (ie, unstable angina or non-ST-elevation myocardial infarction), a second key question is whether the initial strategy will be invasive (with angiography performed urgently) or conservative (with angiography performed later). In ST-elevation myocardial infarction, another distinction is how perfusion is to be restored, ie, with primary percutaneous coronary intervention or with thrombolysis. All these questions affect the choice of antiplatelet and anticoagulant therapy.

Figure 1 and Figure 2 summarize the guidelines of the American College of Cardiology Foundation and American Heart Association.^1,2,6,7

ANTIPLATELET THERAPY

Aspirin for all

Aspirin irreversibly acetylates the enzyme cyclooxygenase-1, blocking intraplatelet formation of thromboxane A2 (Figure 3), a potent platelet aggregator and endothelial vasoconstrictor. Large clinical trials have confirmed that aspirin reduces morbidity and mortality rates by as much as 50% in patients with ACS.⁸

The ISIS-2 trial⁹ found that giving aspirin early in the emergency department significantly reduced the mortality rate.

The Antithrombotic Trialists’ Collaboration,¹⁰ in a meta-analysis of randomized controlled trials comparing different doses of aspirin in high-risk ACS patients, found no greater benefit for doses of aspirin higher than 162 mg per day when used long-term.

How to use. During an ACS, the patient should receive one dose of aspirin 325 mg (the standard high-dose pill in the United States). This dose should be chewed, as buccal absorption results in more rapid systemic effects.¹¹

Adapted from Storey RF. New developments in antiplatelet therapy. Eur Heart J Suppl 2008; 10(suppl D):D30-D37.

Thereafter, the patient should take 81 mg per day, continued indefinitely. The 81-mg dose also applies to patients who undergo a percutaneous coronary intervention with a drug-eluting stent.⁷ Previous recommendations called for higher doses, but studies have shown that higher doses pose a higher risk of bleeding without additional clinical benefit. The use of enteric-coated aspirin does not reduce this risk,¹² and its delayed release may in fact cause aspirin “pseudoresistance.”¹³

The concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided, as NSAIDs reversibly bind to platelets, thus preventing aspirin from binding.¹⁴ As aspirin washes out of the body, NSAIDs may then become unbound from platelets, leaving platelets activated.

P2Y12 receptor inhibitors: Clopidogrel, prasugrel, ticagrelor

These agents bind to P2Y12 receptors on platelets to inhibit adenosine diphosphate-mediated platelet activation (Figure 3). Clopidogrel and prasugrel are irreversible prodrugs, whereas ticagrelor binds reversibly.

Clopidogrel, a prodrug

Clopidogrel has a half-life of 8 hours and a time to peak concentration of 4 hours. Eighty-five percent of a dose is inactivated by gut esterases. The remainder is metabolized primarily by the cytochrome P4502C19 enzyme system into its active metabolite.

How to use. The recommended dosage is a 600-mg bolus early in the course of ACS. This is associated with a lower rate of cardiovascular events than a 300-mg dose,2,15 although no trial has rigorously compared 300-mg vs 600-mg doses using major clinical end points. In patients presenting with ACS who cannot tolerate aspirin because of hypersensitivity or major gastrointestinal contraindication, clopidogrel is an alternative.1

The CURE trial¹⁶ randomized 12,526 patients with non-ST-elevation ACS to receive clopidogrel or placebo in addition to standard therapy. Clopidogrel was associated with a 20% lower rate of cardiovascular death, myocardial infarction, or stroke in both low- and high-risk patients regardless of whether an invasive or conservative strategy was pursued.

However, patients who underwent coronary artery bypass grafting (CABG) had a 53% higher risk of bleeding (an absolute risk of 3.3%) if they received clopidogrel within 5 days of the surgery. This has led to the practice in some centers of delaying giving clopidogrel until after the coronary anatomy has been defined. This deprives the patient of the anti-ischemic benefits conferred by giving clopidogrel early and remains a contentious issue, with most suggesting that the risk-benefit ratio still favors giving clopidogrel early, before angiography, unless there is a high likelihood that surgery will ultimately be required.17 Alternatively, one could consider using a shorter-acting intravenous glycoprotein IIb/IIIa inhibitor such as eptifibatide as a “bridge” until a definitive reperfusion strategy is chosen.

Effect of CYP2C19 variants. The CLOVIS-2 study¹⁸ assessed the effects of genetic variants on the clopidogrel concentration in 106 patients who had had a myocardial infarction. The study confirmed that patients who carry certain variants of the CYP2C19 gene attain lower plasma concentrations of clopidogrel after receiving this drug.¹⁹ This accounts for its delayed onset of action as well as its variability in response in patients who have reduced expression or inhibition of this enzyme system. Doubling the standard dose in patients who carry these variants does not appear to provide clinical benefit.²⁰

Thus, the thought is emerging that one should consider using prasugrel or ticagrelor instead of clopidogrel in patients who have these polymorphisms, though this is yet to be backed by robust clinical evidence.

Possible interaction with proton pump inhibitors. Controversy exists about whether proton pump inhibitors inhibit clopidogrel’s action. Although the US Food and Drug Administration continues to warn against the concurrent use of omeprazole and clopidogrel,²¹ an analysis of the PLATO trial²² concluded that patients with ACS who were taking proton pump inhibitors were at higher risk of ischemic events regardless of whether they had been randomized to clopidogrel or ticagrelor (a drug that acts independently of the cytochrome P450 system). This observation suggests that patients on proton pump inhibitors are generally sicker and at higher risk of ischemic events regardless of the choice of antiplatelet therapy. The use of other gastroprotective agents did not appear to mitigate these risks.

Prasugrel: Faster metabolism to active drug

Prasugrel is an irreversible P2Y12 receptor antagonist (Figure 3) that is metabolized into its active metabolite faster and in a more predictable fashion than clopidogrel.²³

The TRITON-TIMI 38 study²⁴ included 13,608 ACS patients in whom an early invasive strategy was planned and who were pretreated with prasugrel or clopidogrel in addition to standard treatment. The rate of the primary efficacy end point of death, myocardial infarction, or stroke was 19% lower in the prasugrel group. In those who underwent percutaneous coronary intervention, the incidence of in-stent thrombosis was more than 50% lower in the prasugrel group regardless of whether bare metal stents or drug-eluting stents were used.

Greater platelet inhibition came at the price of a higher incidence of serious bleeding, particularly in the subgroups of patients who were over age 75, had a history of stroke or transient ischemic attack, or weighed less than 60 kg. Prasugrel is therefore contraindicated in patients with a history of transient ischemic attack or stroke. Some suggest that a 5-mg dose can be used with caution (rather than the usual 10-mg dose) in patients over age 75 years or those who have low body weight.

The TRILOGY-ACS trial²⁵ compared prasugrel and clopidogrel in medically managed patients with high-risk non-ST-elevation ACS. It found no difference in the rates of the primary end points of cardiovascular death, myocardial infarction, or stroke at 1 year. In the prespecified subset of patients over age 75 years, the rate of bleeding end points was no higher with prasugrel 5 mg once daily than with clopidogrel.

Prasugrel’s half-life is 7 hours, and its peak antiplatelet effect is within 30 minutes after an oral dose, compared with 4 hours with clopidogrel. Therefore, if a patient with non-ST-elevation ACS is going to go to the catheterization laboratory soon, he or she should not receive prasugrel beforehand, and should receive it later only if the results of angiography indicate that CABG will not be needed urgently. This is an important consideration when using prasugrel, as the rate of surgery-related bleeding was four times higher than with clopidogrel. If possible, this drug should be withheld for at least 7 days before CABG.

Ticagrelor, a direct P2Y12 receptor inhibitor

Ticagrelor, a reversible direct inhibitor of the P2Y12 receptor, inhibits adenosine diphosphate-mediated activation and aggregation (Figure 3). It has a median time to peak concentration of 1.3 to 2 hours and a half-life of 9 hours.

The PLATO trial²⁶ enrolled 18,624 patients with ACS who were given either ticagrelor or clopidogrel in addition to standard therapy. At 12 months, the composite primary end point of myocardial infarction, death, or stroke had occurred in 16% fewer patients receiving ticagrelor than in the clopidogrel group. Analyzed separately, there were 16% fewer myocardial infarctions, 21% fewer cardiovascular deaths, and 22% fewer deaths from any cause, regardless of whether an invasive or conservative strategy was used, and with or without prior clopidogrel use. Fewer cases of stent thrombosis occurred in the ticagrelor group, and the rate of major bleeding was the same.

In a prospectively defined subgroup analysis,²⁷ ticagrelor was beneficial only in patients who received lower doses of aspirin (< 100 mg daily): the hazard ratio for the primary end point was 0.79 (95% confidence interval [CI] 0.71–0.88) in ticagrelor recipients who received low-dose aspirin and 1.45 (95% CI 1.01–2.09) in those who received high-dose aspirin.

Although this analysis is underpowered and controversial, the current evidence suggests that when used in combination with ticagrelor, the aspirin dose should be 81 mg.

Ticagrelor was also associated with a 19% higher incidence of non-CABG- or procedure-related major bleeding, more nonfatal and fatal intracranial bleeding, a higher incidence of dyspnea, and significantly more ventricular pauses.

Although ticagrelor carries no black-box warning about its use in patients with prior stroke or transient ischemic attack, the number of such patients in PLATO was small. Thus, caution should still be used in these patients.²⁸

Ticagrelor should preferably be discontinued 5 days before CABG.

Glycoprotein IIb/IIIa inhibitors: Eptifibatide, tirofiban, abciximab

Glycoprotein IIb/IIIa inhibitors are intravenous agents that act by inhibiting fibrinogen-and von Willebrand factor-mediated platelet-to-platelet cross-linkage, the final pathway of platelet aggregation (Figure 3).

Use of these agents in ACS has been decreasing, as evidence supporting their use was largely established before the era of dual antiplatelet therapy.

A meta-analysis29 of 46,374 patients with non-ST-elevation ACS found that routinely adding a glycoprotein IIb/IIIa inhibitor “upstream” as a third agent in patients receiving dual antiplatelet therapy bought only a modest (11%) reduction in death or myocardial infarction at 30 days, at the price of a 23% increase in major bleeding and no decrease in the overall rate of death. Roughly 70% of the patients were receiving dual antiplatelet therapy before cardiac catheterization.

These agents can be considered in high-risk ACS patients, such as those with ST-segment changes or elevated troponin concentrations, and in diabetic patients, on the assumption that these patients likely have a high intracoronary thrombus burden and are at higher risk of microvascular embolization.^6,30 They can also be considered at the time of primary percutaneous coronary intervention in selected patients receiving heparin.⁷

Eptifibatide

Eptifibatide is a small-molecule, short-acting glycoprotein IIb/IIIa inhibitor with a half-life of 2.5 hours. Its inhibition of platelet aggregation is reversible by stopping the drug infusion and is thought to be a result of dissociation of the drug from platelets.

The PURSUIT trial³¹ studied 10,948 patients presenting with non-ST-elevation ACS randomized to placebo, eptifibatide in a 180-μg/kg bolus followed by a 2.0-μg/kg/min infusion, or eptifibatide in a 180-μg/kg bolus followed by a 1.3-μg/kg/min infusion. Both eptifibatide groups had a 1.5% absolute reduction in the incidence of the primary end point of death or myocardial infarction, a benefit that was apparent at 96 hours and that persisted through 30 days. Bleeding was more common in the eptifibatide groups, but there was no increase in the rate of hemorrhagic stroke.

The ACUITY trial³² found that early use of eptifibatide or tirofiban had no effect on the primary outcome. (See the section below on bivalirudin for more information about the ACUITY trial.)

PARENTERAL ANTICOAGULANTS

Unfractionated heparin: A declining role

Heparin binds to antithrombin and induces a conformational change, causing rapid inhibition of factor IIa (thrombin), factor IXa, and factor Xa, thus preventing further thrombus propagation (Figure 4). An intravenous bolus of 60 units/kg produces a time to peak of 5 to 10 minutes and a half-life of 30 to 60 minutes.

Heparin can be reversed by giving protamine sulfate (1 mg per 100 units of heparin). For ACS, it is given in a bolus of 60 units/kg not exceeding 4,000 units, followed by an infusion of 12 units/kg/hour, with monitoring of the activated partial thromboplastin time every 6 hours with a goal value of 50 to 70 seconds or 1.5 to 2.5 times control.

Side effects include thrombocytopenia, heparin-induced thrombocytopenia (a distinct condition), and bleeding.

The use of unfractionated heparin was tested in ACS in the early 1990s. Oler et al³³ performed a meta-analysis of six randomized trials and found a 33% lower rate of death in patients treated with heparin in addition to aspirin in ACS, as well less reported ischemic pain.

Advantages of unfractionated heparin are that it has stood the test of time, is inexpensive, and can be rapidly reversed. The disadvantages are that it can have serious side effects, including heparin-induced thrombocytopenia, and is more likely to cause bleeding than the newer intravenous anticoagulants discussed below. Thus, its position as the main anticoagulant in ACS is being challenged.

Bivalirudin is a synthetic direct thrombin inhibitor of fluid-phase and clot-bound thrombin (Figure 4). It also inhibits platelets directly.

The ACUITY trial³² randomized 13,819 patients with moderate to high-risk ACS scheduled for invasive treatment into three treatment groups:

• Heparin (either unfractionated heparin or enoxaparin) plus a glycoprotein IIb/IIIa inhibitor (either eptifibatide, tirofiban, or abciximab)
• Bivalirudin plus a glycoprotein IIb/IIIa inhibitor
• Bivalirudin alone.

The bivalirudin-alone treatment was as sociated with noninferior rates of composite ischemia end points and significantly lower rates of major bleeding, adding up to a significant reduction in the net clinical outcome end point. An important caveat is that bivalirudin’s noninferiority was mostly in the group of patients already receiving a thienopyridine before angiography and percutaneous coronary intervention (RR 0.97 vs 1.27, P = .054). There was less major, nonmajor, minor, CABG-related, and non-CABG-related bleeding as well as need for transfusion in the bivalirudin-alone group, making bivalirudin monotherapy an attractive option in ACS patients with or without ST-segment elevation undergoing a percutaneous coronary intervention.^1,31

The ISAR-REACT trial³⁴ later compared bivalirudin alone vs unfractionated heparin and abciximab in patients with non-ST-elevation myocardial infarction undergoing percutaneous coronary intervention pretreated with aspirin and clopidogrel. The composite rate of ischemia was similar in the two treatment groups, with significantly lower rates of bleeding in the bivalirudin group.

HORIZONS-AMI³⁵ randomized 3,602 patients with ST-elevation myocardial infarction receiving aspirin and clopidogrel either to unfractionated heparin and a glycoprotein IIb/IIIa inhibitor or to bivalirudin. As in the ACUITY trial, there was no difference in ischemic end points and a 40% to 45% lower rate of major bleeding end points in the bivalirudin group, translating into an overall lower rate of death.

Enoxaparin, a low-molecular weight heparin

Enoxaparin is a low-molecular-weight heparin that inhibits factor IIa and factor Xa via antithrombin, roughly in a ratio of 1:3 (Figure 4). It has a time to peak effect of 10 minutes when given intravenously³⁶ and 3 to 5 hours when given subcutaneously.³⁷ Its half-life is 4.5 hours, but it is longer in patients with renal dysfunction, requiring dose adjustments in this population.

Its anticoagulant effect is partially reversible. If it is to be reversed between 0 and 8 hours after dosing, the recommended reversal regimen is 1 mg of protamine sulfate for every 1 mg of enoxaparin used. At 8 to 12 hours, it is 0.5 mg of protamine for every 1 mg of enoxaparin. After 12 hours, no protamine is required.

Compared with unfractionated heparin, enoxaparin has less plasma protein binding and a more consistent anticoagulant effect. Its high bioavailability also allows for subcutaneous dosing. Its greater anti-Xa activity inhibits thrombin generation more effectively, and it causes lower rates of thrombocytopenia and heparin-induced thrombocytopenia.

de Lemos et al³⁸ found that, in ACS patients in whom an early conservative approach of medical management was planned, enoxaparin was more efficacious than unfractionated heparin and caused a similar rate of bleeding.

Murphy et al,³⁹ in a meta-analysis of 12 trials in 49,088 ACS patients, also found that enoxaparin had a net clinical benefit compared with unfractionated heparin in reducing rates of myocardial infarction and death despite more bleeding.

The ESSENCE trial⁴⁰ compared enoxaparin vs unfractionated heparin in 3,171 patients with ACS. It found fewer ischemic events with enoxaparin in the early phase, more minor bleeding, but no increase in major bleeding.

The SYNERGY trial,⁴¹ in 10,027 patients with high-risk non-ST-elevation ACS undergoing percutaneous coronary intervention, compared subcutaneous enoxaparin with intravenous heparin. Enoxaparin was found to be noninferior to heparin but caused more bleeding, including major bleeding, drops in hemoglobin, and intracranial hemorrhage.

The EXTRACT-TIMI 25 trial.⁴² In patients with ST-elevation myocardial infarction, enoxaparin has been shown to be beneficial both in patients treated with fibrinolysis and in those who underwent primary percutaneous coronary intervention. The EXTRACT-TIMI 25 trial randomized 20,749 patients to receive either enoxaparin (an intravenous bolus and maintenance subcutaneous dosing based on renal function) or intravenous heparin in addition to thrombolysis within 6 hours of the diagnosis of ST-elevation myocardial infarction. Although the enoxaparin group had more bleeding end points, they had fewer primary and secondary efficacy end points, translating into an overall net clinical benefit in favor of enoxaparin.

The ATOLL trial⁴³ examined the use of enoxaparin (0.5 mg/kg intravenously) or unfractionated heparin in 910 patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention (via the radial artery in 66% to 69%). Although there was a trend towards benefit in terms of the primary end point of death, myocardial infarction complications, procedure failure, and major bleeding favoring enoxaparin, it was not statistically significant (95% CI 0.68–1.01, P = .06).

However, there was a 37% to 42% lower rate of the secondary end point of death, recurrent myocardial infarction or ACS, or urgent target-vessel revascularization in the enoxaparin group, with a 40% reduction in death from any cause, death from a cardiac cause, or shock. The safety profiles of the two drugs were similar, and the net clinical benefit significantly favored enoxaparin.

Fondaparinux, a factor Xa inhibitor

Fondaparinux is a synthetic pentasaccharide that indirectly inhibits factor Xa through the action of antithrombin (Figure 4). After a 2.5-mg subcutaneous dose, it has a time to peak concentration of 2 hours and a half-life of 17 to 21 hours.

The OASIS-5 trial⁴⁴ compared fondaparinux and enoxaparin in 20,078 patients treated for non-ST-elevation ACS. Although the rates of death, myocardial infarction, and refractory ischemia at 9 days were similar for both drugs, the fondaparinux group had a significantly (almost 50%) lower rate of bleeding at 30 days, translating into significantly fewer deaths at 30 days. However, patients receiving fondaparinux who underwent percutaneous coronary intervention had a threefold higher rate of catheter-related thrombosis.

The OASIS-6 trial⁴⁵ compared fondaparinux vs usual care (placebo in those in whom unfractionated heparin was not indicated or unfractionated heparin for up to 48 hours followed by placebo for up to 8 days) in 12,092 patients with ST-elevation myocardial infarction. There was a 1.5% absolute risk reduction in death and reinfarction without an increase in bleeding at 30 days, with trends persisting 6 months into the study. However, fondaparinux was not superior to heparin in the 3% of patients who underwent primary percutaneous coronary intervention. As in OASIS-5, there was more catheter-related thrombosis in the fondaparinux group.

Although the use of supplemental unfractionated heparin appears to have mitigated this risk, fondaparinux remains a less-than-ideal option in the era of primary percutaneous coronary intervention for ST-elevation myocardial infarction and has therefore found limited use in this group of patients. It should, however, be considered in patients for whom a conservative strategy is planned, especially if bleeding risk is deemed to be high.

ORAL ANTICOAGULANTS

Oral anticoagulants provide ischemic benefit in selected patients with ACS—at the price of a higher risk of significant bleeding.

Warfarin

Warfarin was investigated after myocardial infarction in the WARIS II,⁴⁶ CARS,⁴⁷ and CHAMP⁴⁸ trials.

WARIS II⁴⁶ looked at the use of aspirin alone, warfarin alone, and aspirin and warfarin in combination. The rates of the primary end points of stroke, nonfatal infarction, and death were lower in the warfarin group.

CARS⁴⁷ found no difference in the rate of the primary end point of fatal infarction, nonfatal ischemic stroke, or cardiovascular death with aspirin vs warfarin plus aspirin.

CHAMP⁴⁸ saw similar trends, ie, no difference in the rate of death, recurrent myocardial infarction, or stroke with warfarin plus aspirin vs aspirin alone.

All three studies showed increases in major bleeding with warfarin use.

Putting these trials into context, the significant net clinical benefit of dual antiplatelet therapy in the current era compared with the significant bleeding and questionable conflicting evidence supporting benefit with warfarin has limited its use in ACS patients.

Rivaroxaban, an oral factor Xa inhibitor

Rivaroxaban is a novel oral direct reversible factor Xa inhibitor.

The ATLAS ACS 2-TIMI 51 trial⁴⁹ found rivaroxaban 2.5 mg or 5 mg to yield a significantly lower rate of the primary outcome of cardiovascular death, myocardial infarction, ischemic stroke, and in-stent thrombosis compared with placebo, but significantly more major non-CABG bleeding and intracranial hemorrhage.

The dose used in this trial was much lower than the dose used in trials investigating the role of this drug in stroke prophylaxis in atrial fibrillation.

Apixaban, an oral factor Xa inhibitor

Apixaban is another direct factor Xa inhibitor.

The APPRAISE-2 trial⁵⁰ compared apixaban 5 mg twice daily vs placebo in ACS. There was no difference in the rate of cardiovascular death, myocardial infarction, or stroke, but there was significantly more bleeding in the apixaban group, prompting early termination of this study.

Dabigatran, an oral thrombin inhibitor

Dabigatran is an oral direct thrombin inhibitor.

The RE-DEEM trial⁵¹ compared four doses of dabigatran (50, 75, 110, and 150 mg twice daily) and placebo in ACS patients. The dabigatran groups had more major and minor bleeding, and the higher the dose, the higher the incidence of bleeding. In addition, the rates of ischemic end points were no lower with dabigatran, although this trial was not powered to show differences in clinical events.

REDUCING THE RISK OF BLEEDING

In the treatment of ACS, the benefits of restoring perfusion by preventing further propagation of thrombus and platelet aggregation come at a significant price of higher bleeding risk. This in turn increases the risk of death through various mechanisms, including shock, worsening ischemia, discontinuation of antiplatelet and anticoagulation therapy causing stent thrombosis, and anemia leading to transfusion, which propagates the underlying inflammatory milieu.⁵²

Giugliano and Braunwald⁵³ provide practical suggestions to reduce this risk, advising physicians to:

• Avoid inappropriately high dosing, particularly in patients with renal insufficiency
• Preferentially use agents that cause less bleeding (eg, bivalirudin, fondaparinux) without compromising anti-ischemic efficacy
• Minimize the concomitant use of other drugs that cause bleeding (eg, NSAIDs)
• Use drugs that protect against bleeding (eg, proton pump inhibitors) in patients at high risk
• Prevent access-site bleeding by using the radial artery, smaller sheaths, and appropriate sheath and closure device management. Indeed, the use of radial interventions in ACS has been shown to reduce access-site-related bleeding, even in patients at high risk.⁵⁴

The reduction in bleeding risk may provide future trials the opportunity to increase antithrombotic efficacy of different agents with goals of reducing ischemic end points.

A 64-year-old man with chronic kidney disease and recent upper gastrointestinal hemorrhage suffered pulseless electrical activity and cardiac arrest. Cardiopulmonary resuscitation was started, with three attempted but failed electrical cardioversions. Return of spontaneous circulation required prolonged resuscitation efforts, including multiple rounds of epinephrine, calcium, and sodium bicarbonate. The standard 12-lead electrocardiogram (Figure 1) showed an irregular wide-QRS-complex rhythm, with right bundle branch block and right-superior-axis deviation.

What was the cause of the pulseless electrical activity and the features on the electrocardiogram?

The presentation of cardiac arrest with pulseless electrical activity usually has a grave prognosis, and in the acute setting, the cause may be difficult to establish. However, several conditions that cause this presentation have treatments that, applied immediately, can lead to quick and sustained recovery.¹

Electrocardiography can be a powerful tool in the urgent evaluation of pulseless electrical activity.^2,3 Narrow-QRS-complex pulseless electrical activity is often caused by mechanical factors such as cardiac tamponade, tension pneumothorax, pulmonary embolism, and major hemorrhage.³ Pulseless electrical activity associated with a wide QRS complex and marked axis deviation, as in this patient, is usually the result of a metabolic abnormality, most often hyperkalemia³; additional indicators of severe hyperkalemia include ST-segment elevation in the anterior chest leads (including the Brugada pattern⁴) and, as in this patient, “double counting” of the heart rate by the interpretation software (Figure 1).^5,6

Based on the suspicion of a metabolic cause, the serum potassium was tested and was 8.9 mmol/L (reference range 3.5–5.0). The patient was given intravenous calcium, sodium bicarbonate, glucose, and insulin, and 2 hours later the serum potassium had decreased to 7.1 mmol/L. At that time, the electrocardiogram (Figure 2) showed a regular rhythm with ectopic P waves, probably an ectopic atrial tachycardia. There were now narrow QRS complexes with J-point depression, upsloping ST segments, and tall, hyperacute T waves in the chest leads—a pattern recently described in proximal left anterior descending coronary artery occlusion.⁷ The electrocardiographic similarities in hyperkalemia and acute myocardial infarction are probably the result of potassium accumulation in the ischemic myocardium associated with acute coronary occlusion.⁷

The patient had a full recovery, both clinically and on electrocardiography.

A 64-year-old man with chronic kidney disease and recent upper gastrointestinal hemorrhage suffered pulseless electrical activity and cardiac arrest. Cardiopulmonary resuscitation was started, with three attempted but failed electrical cardioversions. Return of spontaneous circulation required prolonged resuscitation efforts, including multiple rounds of epinephrine, calcium, and sodium bicarbonate. The standard 12-lead electrocardiogram (Figure 1) showed an irregular wide-QRS-complex rhythm, with right bundle branch block and right-superior-axis deviation.

What was the cause of the pulseless electrical activity and the features on the electrocardiogram?

The presentation of cardiac arrest with pulseless electrical activity usually has a grave prognosis, and in the acute setting, the cause may be difficult to establish. However, several conditions that cause this presentation have treatments that, applied immediately, can lead to quick and sustained recovery.¹

Electrocardiography can be a powerful tool in the urgent evaluation of pulseless electrical activity.^2,3 Narrow-QRS-complex pulseless electrical activity is often caused by mechanical factors such as cardiac tamponade, tension pneumothorax, pulmonary embolism, and major hemorrhage.³ Pulseless electrical activity associated with a wide QRS complex and marked axis deviation, as in this patient, is usually the result of a metabolic abnormality, most often hyperkalemia³; additional indicators of severe hyperkalemia include ST-segment elevation in the anterior chest leads (including the Brugada pattern⁴) and, as in this patient, “double counting” of the heart rate by the interpretation software (Figure 1).^5,6

Based on the suspicion of a metabolic cause, the serum potassium was tested and was 8.9 mmol/L (reference range 3.5–5.0). The patient was given intravenous calcium, sodium bicarbonate, glucose, and insulin, and 2 hours later the serum potassium had decreased to 7.1 mmol/L. At that time, the electrocardiogram (Figure 2) showed a regular rhythm with ectopic P waves, probably an ectopic atrial tachycardia. There were now narrow QRS complexes with J-point depression, upsloping ST segments, and tall, hyperacute T waves in the chest leads—a pattern recently described in proximal left anterior descending coronary artery occlusion.⁷ The electrocardiographic similarities in hyperkalemia and acute myocardial infarction are probably the result of potassium accumulation in the ischemic myocardium associated with acute coronary occlusion.⁷

The patient had a full recovery, both clinically and on electrocardiography.

A 64-year-old man with chronic kidney disease and recent upper gastrointestinal hemorrhage suffered pulseless electrical activity and cardiac arrest. Cardiopulmonary resuscitation was started, with three attempted but failed electrical cardioversions. Return of spontaneous circulation required prolonged resuscitation efforts, including multiple rounds of epinephrine, calcium, and sodium bicarbonate. The standard 12-lead electrocardiogram (Figure 1) showed an irregular wide-QRS-complex rhythm, with right bundle branch block and right-superior-axis deviation.

What was the cause of the pulseless electrical activity and the features on the electrocardiogram?

The presentation of cardiac arrest with pulseless electrical activity usually has a grave prognosis, and in the acute setting, the cause may be difficult to establish. However, several conditions that cause this presentation have treatments that, applied immediately, can lead to quick and sustained recovery.¹

Electrocardiography can be a powerful tool in the urgent evaluation of pulseless electrical activity.^2,3 Narrow-QRS-complex pulseless electrical activity is often caused by mechanical factors such as cardiac tamponade, tension pneumothorax, pulmonary embolism, and major hemorrhage.³ Pulseless electrical activity associated with a wide QRS complex and marked axis deviation, as in this patient, is usually the result of a metabolic abnormality, most often hyperkalemia³; additional indicators of severe hyperkalemia include ST-segment elevation in the anterior chest leads (including the Brugada pattern⁴) and, as in this patient, “double counting” of the heart rate by the interpretation software (Figure 1).^5,6

Based on the suspicion of a metabolic cause, the serum potassium was tested and was 8.9 mmol/L (reference range 3.5–5.0). The patient was given intravenous calcium, sodium bicarbonate, glucose, and insulin, and 2 hours later the serum potassium had decreased to 7.1 mmol/L. At that time, the electrocardiogram (Figure 2) showed a regular rhythm with ectopic P waves, probably an ectopic atrial tachycardia. There were now narrow QRS complexes with J-point depression, upsloping ST segments, and tall, hyperacute T waves in the chest leads—a pattern recently described in proximal left anterior descending coronary artery occlusion.⁷ The electrocardiographic similarities in hyperkalemia and acute myocardial infarction are probably the result of potassium accumulation in the ischemic myocardium associated with acute coronary occlusion.⁷

The patient had a full recovery, both clinically and on electrocardiography.