Medical Grand Rounds

Obstructive sleep apnea (OSA) is common and poorly recognized and, if untreated, leads to serious health consequences. This article discusses the epidemiology of OSA, describes common presenting signs and symptoms, and reviews diagnostic testing and treatment options. Adverse health effects related to untreated sleep apnea are also discussed.

COMMON, POORLY RECOGNIZED, AND COSTLY IF UNTREATED

OSA is very common in the general population and is associated with substantial morbidity and mortality. An estimated 17% of the general adult population has OSA, and the numbers are increasing with the obesity epidemic. Nearly 1 in 15 adults has at least moderate sleep apnea,^1,2 and approximately 85% of cases are estimated to be undiagnosed.³ A 1999 study estimated that untreated OSA resulted in approximately $3.4 billion in additional medical costs per year in the United States,⁴ a figure that is likely to be higher now, given the rising prevalence of OSA. The prevalence of OSA in primary care and subspecialty clinics is even higher than in the community, as more than half of patients who have diabetes or hypertension and 30% to 40% of patients with coronary artery disease are estimated to have OSA.^5–7

REPETITIVE UPPER-AIRWAY COLLAPSE

During sleep, parasympathetic activity is enhanced and the muscle tone of the upper airway is decreased, particularly in the pharyngeal dilator muscles. Still, even in the supine position, a healthy person maintains patency of the airway and adequate airflow during sleep.

OSA is characterized by repetitive complete or partial collapse of the upper airway during sleep, resulting in an apneic or hypopneic event, respectively, and often causing snoring from upper-airway tissue vibration.

People who are susceptible to OSA typically have a smaller, more collapsible airway that is often less distensible and has a higher critical closing pressure. Radiographic and physiologic data have shown that the airway dimensions of patients with OSA are smaller than in those without OSA. The shape of the airway of a patient with OSA is often elliptical, given the extrinsic compression of the lateral aspects of the airway by increased size of the parapharyngeal fat pads. OSA episodes are characterized by closure of the upper airway and by progressively increasing respiratory efforts driven by chemoreceptor and mechanoreceptor stimuli, culminating in an arousal from sleep and a reopening of the airway.

The disease-defining metric used for assessing OSA severity is the apnea-hypopnea index, ie, the number of apneas and hypopneas that occur per hour of sleep.⁸ An apneic or hypopneic event is identified during polysomnography by the complete cessation of airflow or by a reduction in airflow for 10 seconds or longer (Figure 1).

HEALTH CONSEQUENCES IF UNTREATED

Untreated sleep apnea causes numerous pathophysiologic perturbations, including chronic intermittent hypoxia, ventilatory overshoot hyperoxia, increased sympathetic nervous system activity, intrathoracic pressure swings, hypercapnea, sleep fragmentation, increased arousals, reduced sleep duration, and fragmentation of rapid-eye-movement sleep.

Intermittent hypoxia activates the sympathetic nervous system and causes pulmonary vasoconstriction, with increases in pulmonary arterial pressures and myocardial workload. Sympathetic activation, ascertained by peroneal microneurography, has been shown to be increased not only during sleep but also persisting during wakefulness in patients with untreated OSA vs those without OSA.⁹ Autonomic nervous system fluctuations accompany apneic episodes, resulting in enhanced parasympathetic tone and sympathetic activation associated with a rise in blood pressure and heart rate that occur after the respiratory event.

Intermediate pathways that link the negative pathophysiologic effects of OSA with adverse health outcomes include increased systemic inflammation, increased oxidative stress, metabolic dysfunction, insulin resistance, hypercoagulability, endothelial dysfunction, and autonomic dysfunction.

As a result, a variety of adverse clinical outcomes are associated with untreated OSA, including systemic hypertension, ischemic heart disease and atherosclerosis, diastolic dysfunction, congestive heart failure, cardiac arrhythmias, stroke, increased risk of death, and sudden death, as well as noncardiovascular outcomes such as gout, neurocognitive deficits, and mood disorders.¹⁰

Inflammatory and atherogenic effects

Increased levels of markers of systemic inflammation, prothrombosis, and oxidative stress have been observed in OSA and may be key pathophysiologic links between OSA and cardiovascular sequelae. OSA has been associated with up-regulation of a number of inflammatory mediators: interleukin (IL) 6, soluble IL-6 receptor, IL-8, tumor necrosis factor alpha, and C-reactive protein. Soluble IL-6 levels in particular are higher in people who have sleep-disordered breathing, as reflected by the apnea-hypopnea index independent of obesity, with relationships stronger in the morning than in the evening. This likely reflects the overnight OSA-related physiologic stress.¹¹

Thrombotic potential is also enhanced, with higher levels of plasminogen activator inhibitor 1, fibrinogen, P-selectin, and vascular endothelial growth factor. Some of these factors normally have a diurnal cycle, with higher levels in the morning, but in OSA, increasing OSA severity is associated with increased prothrombotic potential in the morning hours. Of interest, levels of these substances showed a plateau effect, rising in people who had only mildly elevated apnea-hypopnea indices and then leveling off.¹² Intermittent hypoxia followed by ventilatory overshoot hyperoxia, characteristic of sleep apnea, provides the ideal environment for augmentation of oxidative stress, with evidence of increased oxidation of serum proteins and lipids. Hypoxia and oxygen-derived free radicals may result in cardiac myocyte injury. Experimental data demonstrate that intermittent hypoxia combined with a high-fat diet results in synergistic acceleration of evidence of atherogenic lesions.

Patients with OSA also have evidence of endothelial dysfunction, insulin resistance, and dyslipidemia, all pathways that can facilitate the progression of atherosclerosis in OSA.^13–15

Cardiac arrhythmias

In the Sleep Heart Health Study, a multicenter epidemiologic study designed to examine the relationships of OSA and cardiovascular outcomes, those who had moderate to severe OSA had a risk of ventricular and atrial arrhythmias two to four times higher than those without OSA, even after correction for the confounding influences of obesity and underlying cardiovascular risk.¹⁴ These findings were corroborated in subsequent work highlighting monotonic dose-response relationships with increasing OSA severity and increased odds of atrial and ventricular arrhythmia in a cohort of about 3,000 older men.¹¹ Additional compelling evidence of a causal relationship is that the risk of discrete arrhythmic events is markedly increased after a respiratory disturbance in sleep.¹⁶

In patients who successfully underwent cardioversion for atrial fibrillation, those who had sleep apnea but were not treated with continuous positive airway pressure (CPAP) had a much higher rate of recurrence of atrial fibrillation during the subsequent year than those with CPAP-treated sleep apnea and than controls never diagnosed with sleep apnea. In the untreated patients with sleep apnea, the mean nocturnal fall in oxygen saturation was significantly greater in those who had recurrence of atrial fibrillation than in those who did not, suggesting hypoxia as an important mechanism contributing to atrial fibrillation.¹⁷

Since then, several other retrospective studies have shown similar findings after pulmonary vein antrum isolation and ablation in terms of reduction of atrial fibrillation recurrence with CPAP treatment in OSA.¹⁸

Walia et al¹⁹ described a patient with moderate sleep apnea who underwent a split-night study. During the baseline part of the study, the patient had about 18 ectopic beats per minute. During the second portion of the study while CPAP was applied, progressively fewer ectopic beats occurred as airway pressure was increased until a normal rhythm without ectopic beats was achieved at the goal treatment CPAP pressure setting.

Cardiovascular disease, stroke, and death

Marin et al²⁰ followed about 1,500 men for 10 years, including some who had severe OSA, some with sleep apnea who were treated with CPAP, and controls. The risk of nonfatal and fatal cardiovascular disease events was nearly three times higher in those with severe disease than in healthy participants. Those treated with CPAP had a risk approximately the same as in the control group.

The Sleep Heart Study followed approximately 6,000 people with untreated sleep apnea for a median of nearly 9 years. It found a significant association between the apnea-hypopnea index and ischemic stroke, especially in men.²¹ Survival in patients with heart failure is also associated with the degree of OSA; patients with more severe disease (an apnea-hypopnea index ≥ 15) have a nearly three times greater risk of death than those with no disease or only mild disease (apnea-hypopnea index < 15).²²

From the standpoint of health care utilization, findings that central sleep apnea predicts an increased risk of hospital readmission in heart failure are of particular interest.²³

People with OSA are at increased risk of nocturnal sudden cardiac death.²⁴ Sleep apnea is also associated with an increased overall death rate, and the higher the apnea-hypopnea index, the higher the death rate,²⁵ even after adjusting for age, sex, body mass index, and underlying cardiovascular risk, with findings most pronounced in men under age 70.

Motor vehicle accidents

The need for caution during driving should be discussed with every patient, as motor vehicle accidents are an immediate danger to the patient and others. The association with motor vehicle accidents is independent of sleepiness, and drivers with sleep apnea often do not perceive performance impairment. Young et al²⁶ found that men who snored were 3.4 times as likely to have an accident over a 5-year period, and that men and women with an apnea-hypopnea index greater than 15 were more than 7 times as likely to have multiple accidents over a 5-year period, highlighting the importance of discussing, documenting, and expeditiously diagnosing and treating OSA, particularly in those who report drowsiness while driving.

CLINICAL RISK FACTORS

Risk factors can be divided into nonmodifiable and modifiable ones.

Nonmodifiable factors

Age. Bimodal distributions in OSA prevalence have been observed; ie, that the pediatric population and people who are middle-aged have the highest prevalence of OSA. A linear relationship between sleep apnea prevalence and age until about age 65 was identified in data from the Sleep Heart Health Study.²⁷ After that, the prevalence rates plateau; it is unclear if this is secondary to natural remission of the disease after a certain age or because patients with more severe disease have died by that age (ie, survivorship bias), blunting an increase in prevalence.

Sex. Men develop sleep apnea at a rate three to five times that of women. Several explanations have been proposed to account for this.^28,29 Sex hormones are one factor; women with sleep apnea on hormone replacement therapy have a significantly less-severe sleep apnea burden than other postmenopausal women,³⁰ suggesting a positive effect from estrogen. Sex-based differences in fat distribution, length and collapsibility of the upper airway, genioglossal activity, neurochemical control mechanisms, and arousal response may also contribute to prevalence differences between men and women.

As with coronary artery disease, the presentation of sleep apnea may be atypical in women, particularly around menopause. Sleep apnea should be considered in women who have snoring and daytime sleepiness.

Race. Whites, African Americans, and Asians have a similar prevalence of sleep apnea, but groups differ in obesity rates and craniofacial anatomy.^31–34 Asians tend to have craniofacial skeletal restriction. African Americans are more likely to have upper-airway soft-tissue risk and to develop more severe OSA. Whites tend to have both craniofacial and soft-tissue risk. For those with craniofacial anatomy predisposing to OSA, even mild obesity can make it manifest.

Syndromes that predispose to OSA can include craniofacial structural abnormalities, connective tissue problems, or alterations in ventilatory control (eg, Marfan, Down, and Pierre Robin syndromes).

Modifiable risk factors

Obesity (body mass index ≥ 30 kg/m²) is a firmly established risk factor, but not all obese patients develop obstructive sleep apnea, and not all people with sleep apnea are obese.

Obesity increases risk by altering the geometry and function of the upper airway, increasing collapsibility. The changes are particularly pronounced in the lateral aspects of the pharynx.³⁵

Obesity also affects respiratory drive, likely in part from leptin resistance. Load compensation is another contributing factor: the increased mass in the thorax and abdomen increases the work of breathing and reduces functional residual capacity, increasing oxygen demands and leading to atelectasis and ventilation-perfusion mismatch.

Although obesity is an important risk factor, it is important to recognize that obesity is not the only one to consider: most people with an apnea-hypopnea index of 5 or greater are not obese. The relationship between body mass index and sleep apnea is weaker in children and in the elderly, probably because other risk factors are more pronounced.³⁶

Craniofacial structural abnormalities such as retrognathia (abnormal posterior position of the mandible) and micrognathia (undersized mandible) can increase the risk of OSA because of a resulting posteriorly displaced genioglossus muscle. Other conditions can alter chemosensitivity, affecting the pH and carbon dioxide level of the blood and therefore affecting ventilatory control mechanisms, making the person more prone to developing sleep apnea. Children and young adults may have tonsillar tissue that obstructs the airway.

The site of obstruction can be behind the palate (retropalatal), behind the tongue (retroglossal), or below the pharynx (hypopharyngeal). This helps explain why positive air way pressure—unlike surgery, which addresses a specific area—is often successful, as it serves to splint or treat all aspects of the airway.

FATIGUE, SLEEPINESS, SNORING, RESTLESS SLEEP

Sleep apnea can result in presentation of multiple signs and symptoms (Table 1).

Daytime sleepiness and fatigue are the most common symptoms. Although nonspecific, they are often quite pronounced. Two short questionnaires—the Epworth Sleepiness Scale³⁷ and the Fatigue Severity Scale—can help distinguish between these two symptoms and assess their impact on a patient’s daily life. In the Epworth Sleepiness Scale, the patient rates his or her chance of dozing on a 4-point scale (0 = would never doze, to 3 = high chance of dozing) in eight situations:

• Sitting and reading
• Watching television
• Sitting inactive in a public place
• As a passenger in a car for an hour without a break
• Lying down to rest in the afternoon
• Sitting and talking to someone
• Sitting quietly after a lunch without alcohol
• In a car while stopped for a few minutes in traffic.

A score of 10 or more is consistent with significant subjective sleepiness.

The Fatigue Severity Scale assesses the impact of fatigue on daily living.

Snoring is a common and specific symptom of sleep apnea; however, not all patients who snore have OSA.

Restlessness during sleep is very common—patients may disturb their bed partner by moving around a lot during sleep or report that the sheets are “all over the place” by morning.

Nocturia can also be a sign of sleep apnea and can contribute to sleep fragmentation. A proposed mechanism of this symptom includes alterations of intrathoracic pressure resulting in atrial stretch, which release atrial natriuretic peptide, leading to nocturia. Treating with CPAP has been found to reduce levels of atrial natriuretic peptide, contributing to better sleep.³⁸

Morning headache may occur and is likely related to increased CO₂ levels, which appear to culminate in the morning hours. End-tidal or transcutaneous CO₂ monitoring during polysomnography can help elucidate the presence of sleep-related hypoventilation.

Libido is often diminished and can actually be improved with CPAP. This is therefore an important point to discuss with patients, as improved libido can often serve as an incentive for adherence to OSA treatment.

Insomnia exists in about 15% of patients, primarily as a result of sleep apnea-related with treatment.

Sweating, particularly forehead sweating associated with sleep apnea, more commonly occurs in children.

The STOP-BANG questionnaire (Table 2)³⁹ was primarily validated in preoperative anesthesia testing. However, because of its ease of use and favorable performance characteristics, it is increasingly used to predict the likelihood of finding OSA before polysomnography. A score of 3 or more has a sensitivity of 93%.

PHYSICAL EXAMINATION PROVIDES CLUES

Although the physical examination may be normal, certain findings indicate risk (Table 3). Obesity alone is not an accepted indication for polysomnography unless there are concomitant worrisome signs or symptoms. Of note, those who are morbidly obese (BMI > 40 kg/m²) have a prevalence of sleep apnea greater than 70%.

The classification by Friedman et al⁴⁰ provides an indicator of risk. The patient is examined with the mouth opened wide and the tongue in a neutral natural position. Grades:

• I—Entire uvula and tonsils are visible
• II—Entire uvula is visible, but tonsils are not
• III—Soft palate is visible, but uvula is not
• IV—Only the hard palate is visible.

Especially in children and young adults, enlarged tonsils (or “kissing tonsils”) and a boggy edematous uvula set the stage for obstructive sleep apnea.

DIAGNOSIS REQUIRES SLEEP TESTING

A sleep study is the primary means of diagnosing OSA. Polysomnography includes electrooculography to determine when rapid-eye-movement sleep occurs; electromyography to measure muscle activity in the chin to help determine onset of sleep, with peripheral leads in the leg to measure leg movements; electroencephalography (EEG) to measure neural activity; electrocardiography; pulse oximetry to measure oxygen saturation; measurement of oronasal flow; and measurements of chest wall effort and body position using thoracic and abdominal belts that expand and contract with breathing; and audio recording to detect snoring.

Attended polysomnography requires the constant presence of a trained sleep technologist to monitor for technical issues and patient adherence.

End-tidal CO₂ monitoring is a reasonable method to detect sleep-related hypoventilation but is not routinely performed in the United States. Transcutaneous CO₂ monitoring is a different way to monitor CO₂ used in the setting of positive airway pressure.

Polysomnography in a normal patient shows a regular pattern of increasing and decreasing airflow with inspiration and expiration while stable oxygen saturation is maintained.

In contrast, polysomnography of a patient with sleep apnea shows repetitive periods of no airflow, oxygen desaturation, and often evidence of thoracoabdominal paradox, punctuated by arousals on EEG associated with sympathetic activation (Figure 1). When the patient falls asleep, upper-airway muscle tone is reduced, causing an apneic event with hypoxia and pleural pressure swings. These prompt arousals with sympathetic activation that reestablish upper-airway muscle tone, allowing ventilation and reoxygenation to resume with a return to sleep.

Apnea-hypopnea index indicates severity

Sleep apnea severity is graded using the apnea-hypopnea index, ie, the number of apneic and hypopneic events per hour of sleep (Table 4).⁴¹ Events must last at least 10 seconds to be considered, ie, two consecutive missed breaths based on an average normal respiratory rate of about 12 breaths per minute for the typical adult.

The apnea-hypopnea index usually correlates with the severity of oxygen desaturation and with electrocardiographic abnormalities, including tachybradycardia and arrhythmias.

Although history, physical examination, and prediction tools are helpful in determining the likelihood that a patient has OSA, only polysomnography testing can establish the diagnosis. To diagnose OSA, 15 or more obstructive events per hour must be observed by polysomnography, or at least 5 events per hour with one of the following:

• Daytime sleepiness, sleep attacks, unrefreshing sleep, fatigue, or insomnia
• Waking with breath-holding, gasping, or choking
• Observer-reported loud snoring or breathing interruptions.⁴¹

Split-night study determines diagnosis and optimum treatment

The split-night study has two parts: the first is diagnostic polysomnography, followed by identification of the positive airway pressure that optimally treats the sleep apnea. The apnea-hypopnea index guides the need for the split-night study, with 40 being the established threshold according to the American Academy of Sleep Medicine.

A home sleep study is appropriate for some patients

Home sleep testing is typically more limited than standard polysomnography; it monitors airflow, effort, and oxygenation. The test is intended for adults with a high pretest probability of moderate to severe obstructive sleep apnea (STOP-BANG score ≥ 3). It is not intended for screening of asymptomatic patients or for those with coexisting sleep disorders (eg, central sleep apnea, sleep hypoventilation, periodic limb movements, insomnia, circadian rhythm disorders, parasomnias, narcolepsy) or medical disorders (eg, moderate to severe heart failure or other cardiac disease, symptomatic neurologic disease, moderate to severe pulmonary disease).⁴² Since March 2008, the Centers for Medicare and Medicaid Services has covered CPAP for obstructive sleep apnea based on diagnosis by home sleep study testing.⁴³

TREATMENT OF SLEEP APNEA

Basic steps for reducing OSA are:

Weight loss. Even small weight changes can significantly affect the severity of sleep apnea, perhaps even leading to a reassessment of the degree of OSA and CPAP requirements. Longitudinal epidemiologic data demonstrate that a 10% weight loss correlates with a 26% reduction in the apnea-hypopnea index, and conversely, a 10% weight gain is associated with a 32% increase.⁴⁴

Some studies have found that bariatric surgery cures OSA in 75% to 88% of cases, independent of approach.^45,46 However, a trial in 60 obese patients with OSA who were randomized to either a low-calorie diet or bariatric surgery found no statistical difference in the apnea-hypopnea index between the two groups despite greater weight loss in the surgery group.⁴⁷

Avoiding certain medications. Benzodiazepines, narcotics, and alcohol reduce upper airway muscle tone and should be avoided. No medications are associated with improvement of OSA, although acetazolamide may be used to treat central sleep apnea.

Positional therapy. Sleeping on the back exacerbates the problem. Supine-related OSA occurs as a result of several factors, including gravity, airway anatomy, airway critical closing pressures, and effects on upper-airway dilator muscle function.

Sleep hygiene. General recommendations to engage in behaviors to promote sleep are recommended, including keeping consistent sleep-wake times, not watching television in bed, and avoidance of caffeine intake, particularly within 4 to 6 hours of bedtime.

POSITIVE AIRWAY PRESSURE THERAPY

Nasal CPAP is the treatment of choice and is successful in 95% of patients when used consistently. It is not as costly as surgery, and results in improved long-term survival compared with uvulopalatopharyngoplasty. Another advantage is that the pressure can be retitrated as the patient’s condition changes, for example after a weight change or during pregnancy.

More than 15 randomized controlled trials have examined the effect of sleep apnea treatment with CPAP compared with either sham CPAP or another control. In a meta-analysis, CPAP was found to lead to an average systolic blood pressure reduction of about 2.5 mm Hg and a diastolic blood pressure reduction of 1.8 mm Hg. Although these reductions may seem negligible, benefits may be significant for cardiovascular outcomes.^48,49

Challenges to treatment adherence

Adherence is the most commonly discussed problem with CPAP, but long-term adherence rates are comparable to medication compliance—about 60% to 70%. To optimize adherence, communication is important to ensure that problems are identified and addressed as they arise. Showing patients examples of apneic events and oxygen desaturation from their sleep study can enhance their understanding of OSA and its importance. Patients need to understand the serious nature of the disease and that CPAP therapy can significantly improve their quality of life and overall health, particularly from a cardiovascular perspective.

CPAP masks can be uncomfortable, posing a major barrier to compliance. But a number of mask designs are available, such as the nasal mask, the nasal pillow mask, and the oronasal mask. For patients with claustrophobia, the nasal pillow mask is an option, as it does not cover the face.

Some patients note symptoms of nasal congestion, although in many patients CPAP improves it. If congestion is a problem, the use of heated humidification with the machine, intranasal saline or gel, or nasal corticosteroids can help relieve it.

Pressure intolerance is a common problem. For those who feel that the pressure is too high, settings can be adjusted so that the pressure is gradually reduced between inspiration and expiration, ie, the use of expiratory pressure relief or consideration of the use of bilevel positive airway pressure.

Aerophagia (swallowing air) is a less common problem. It can also potentially be relieved with use of bilevel positive airway pressure.

Many patients develop skin irritation, which can be helped with moleskin, available at any pharmacy.

Social stigma can be a problem. Education regarding the importance of the treatment to health is essential.

Machine noise is less of a problem with the new machine models, but if it is a problem, a white-noise device or earplugs may help.

Other measures to improve compliance are keeping the regimen simple and ensuring that family support is adequate.

Medicare requires evidence of use and benefit

Medicare requires that clinical benefit be documented between the 31st and 91st day after initiating CPAP therapy. This requires face-to-face clinical reevaluation by the treating physician to document improved symptoms and objective evidence of adherence to use of the device. The devices can store usage patterns, and Medicare requires at least 4 hours per night on 70% of nights during a consecutive 30-day period in the first 3 months of use.

ALTERNATIVE THERAPIES

Alternative therapies may be options for some patients, in particular those who cannot use CPAP or who get no benefit from it. These include oral appliances for those with mild to moderate OSA^50–53 and various surgical procedures, eg, uvulopalatopharyngoplasty,^54,55 maxillomanibular advancement,⁵⁶ tracheostomy (standard treatment before CPAP was identified as an effective treatment),^57,58 and adenotonsillectomy (in children).⁵⁹

Supplemental oxygen is not a first-line treatment for OSA and in general has not been found to be very effective, particularly in terms of intermediate cardiovascular outcomes,^60–62 although a subset of patients with high loop gain may benefit from it.⁶³ Loop gain is a measure of the tendency of the ventilatory control system to amplify respiration in response to a change, conferring less stable control of breathing.

Several novel alternative therapies are starting to be used. Although all of them have been shown to improve measures of OSA, none is as effective as CPAP in improving OSA severity. New therapies include the nasal expiratory positive airway pressure device,⁶⁴ oral pressure therapy,⁶⁵ and hypoglossal nerve stimulation.⁶⁶

Obstructive sleep apnea (OSA) is common and poorly recognized and, if untreated, leads to serious health consequences. This article discusses the epidemiology of OSA, describes common presenting signs and symptoms, and reviews diagnostic testing and treatment options. Adverse health effects related to untreated sleep apnea are also discussed.

COMMON, POORLY RECOGNIZED, AND COSTLY IF UNTREATED

OSA is very common in the general population and is associated with substantial morbidity and mortality. An estimated 17% of the general adult population has OSA, and the numbers are increasing with the obesity epidemic. Nearly 1 in 15 adults has at least moderate sleep apnea,^1,2 and approximately 85% of cases are estimated to be undiagnosed.³ A 1999 study estimated that untreated OSA resulted in approximately $3.4 billion in additional medical costs per year in the United States,⁴ a figure that is likely to be higher now, given the rising prevalence of OSA. The prevalence of OSA in primary care and subspecialty clinics is even higher than in the community, as more than half of patients who have diabetes or hypertension and 30% to 40% of patients with coronary artery disease are estimated to have OSA.^5–7

REPETITIVE UPPER-AIRWAY COLLAPSE

During sleep, parasympathetic activity is enhanced and the muscle tone of the upper airway is decreased, particularly in the pharyngeal dilator muscles. Still, even in the supine position, a healthy person maintains patency of the airway and adequate airflow during sleep.

OSA is characterized by repetitive complete or partial collapse of the upper airway during sleep, resulting in an apneic or hypopneic event, respectively, and often causing snoring from upper-airway tissue vibration.

People who are susceptible to OSA typically have a smaller, more collapsible airway that is often less distensible and has a higher critical closing pressure. Radiographic and physiologic data have shown that the airway dimensions of patients with OSA are smaller than in those without OSA. The shape of the airway of a patient with OSA is often elliptical, given the extrinsic compression of the lateral aspects of the airway by increased size of the parapharyngeal fat pads. OSA episodes are characterized by closure of the upper airway and by progressively increasing respiratory efforts driven by chemoreceptor and mechanoreceptor stimuli, culminating in an arousal from sleep and a reopening of the airway.

The disease-defining metric used for assessing OSA severity is the apnea-hypopnea index, ie, the number of apneas and hypopneas that occur per hour of sleep.⁸ An apneic or hypopneic event is identified during polysomnography by the complete cessation of airflow or by a reduction in airflow for 10 seconds or longer (Figure 1).

HEALTH CONSEQUENCES IF UNTREATED

Untreated sleep apnea causes numerous pathophysiologic perturbations, including chronic intermittent hypoxia, ventilatory overshoot hyperoxia, increased sympathetic nervous system activity, intrathoracic pressure swings, hypercapnea, sleep fragmentation, increased arousals, reduced sleep duration, and fragmentation of rapid-eye-movement sleep.

Intermittent hypoxia activates the sympathetic nervous system and causes pulmonary vasoconstriction, with increases in pulmonary arterial pressures and myocardial workload. Sympathetic activation, ascertained by peroneal microneurography, has been shown to be increased not only during sleep but also persisting during wakefulness in patients with untreated OSA vs those without OSA.⁹ Autonomic nervous system fluctuations accompany apneic episodes, resulting in enhanced parasympathetic tone and sympathetic activation associated with a rise in blood pressure and heart rate that occur after the respiratory event.

Intermediate pathways that link the negative pathophysiologic effects of OSA with adverse health outcomes include increased systemic inflammation, increased oxidative stress, metabolic dysfunction, insulin resistance, hypercoagulability, endothelial dysfunction, and autonomic dysfunction.

As a result, a variety of adverse clinical outcomes are associated with untreated OSA, including systemic hypertension, ischemic heart disease and atherosclerosis, diastolic dysfunction, congestive heart failure, cardiac arrhythmias, stroke, increased risk of death, and sudden death, as well as noncardiovascular outcomes such as gout, neurocognitive deficits, and mood disorders.¹⁰

Inflammatory and atherogenic effects

Increased levels of markers of systemic inflammation, prothrombosis, and oxidative stress have been observed in OSA and may be key pathophysiologic links between OSA and cardiovascular sequelae. OSA has been associated with up-regulation of a number of inflammatory mediators: interleukin (IL) 6, soluble IL-6 receptor, IL-8, tumor necrosis factor alpha, and C-reactive protein. Soluble IL-6 levels in particular are higher in people who have sleep-disordered breathing, as reflected by the apnea-hypopnea index independent of obesity, with relationships stronger in the morning than in the evening. This likely reflects the overnight OSA-related physiologic stress.¹¹

Thrombotic potential is also enhanced, with higher levels of plasminogen activator inhibitor 1, fibrinogen, P-selectin, and vascular endothelial growth factor. Some of these factors normally have a diurnal cycle, with higher levels in the morning, but in OSA, increasing OSA severity is associated with increased prothrombotic potential in the morning hours. Of interest, levels of these substances showed a plateau effect, rising in people who had only mildly elevated apnea-hypopnea indices and then leveling off.¹² Intermittent hypoxia followed by ventilatory overshoot hyperoxia, characteristic of sleep apnea, provides the ideal environment for augmentation of oxidative stress, with evidence of increased oxidation of serum proteins and lipids. Hypoxia and oxygen-derived free radicals may result in cardiac myocyte injury. Experimental data demonstrate that intermittent hypoxia combined with a high-fat diet results in synergistic acceleration of evidence of atherogenic lesions.

Patients with OSA also have evidence of endothelial dysfunction, insulin resistance, and dyslipidemia, all pathways that can facilitate the progression of atherosclerosis in OSA.^13–15

Cardiac arrhythmias

In the Sleep Heart Health Study, a multicenter epidemiologic study designed to examine the relationships of OSA and cardiovascular outcomes, those who had moderate to severe OSA had a risk of ventricular and atrial arrhythmias two to four times higher than those without OSA, even after correction for the confounding influences of obesity and underlying cardiovascular risk.¹⁴ These findings were corroborated in subsequent work highlighting monotonic dose-response relationships with increasing OSA severity and increased odds of atrial and ventricular arrhythmia in a cohort of about 3,000 older men.¹¹ Additional compelling evidence of a causal relationship is that the risk of discrete arrhythmic events is markedly increased after a respiratory disturbance in sleep.¹⁶

In patients who successfully underwent cardioversion for atrial fibrillation, those who had sleep apnea but were not treated with continuous positive airway pressure (CPAP) had a much higher rate of recurrence of atrial fibrillation during the subsequent year than those with CPAP-treated sleep apnea and than controls never diagnosed with sleep apnea. In the untreated patients with sleep apnea, the mean nocturnal fall in oxygen saturation was significantly greater in those who had recurrence of atrial fibrillation than in those who did not, suggesting hypoxia as an important mechanism contributing to atrial fibrillation.¹⁷

Since then, several other retrospective studies have shown similar findings after pulmonary vein antrum isolation and ablation in terms of reduction of atrial fibrillation recurrence with CPAP treatment in OSA.¹⁸

Walia et al¹⁹ described a patient with moderate sleep apnea who underwent a split-night study. During the baseline part of the study, the patient had about 18 ectopic beats per minute. During the second portion of the study while CPAP was applied, progressively fewer ectopic beats occurred as airway pressure was increased until a normal rhythm without ectopic beats was achieved at the goal treatment CPAP pressure setting.

Cardiovascular disease, stroke, and death

Marin et al²⁰ followed about 1,500 men for 10 years, including some who had severe OSA, some with sleep apnea who were treated with CPAP, and controls. The risk of nonfatal and fatal cardiovascular disease events was nearly three times higher in those with severe disease than in healthy participants. Those treated with CPAP had a risk approximately the same as in the control group.

The Sleep Heart Study followed approximately 6,000 people with untreated sleep apnea for a median of nearly 9 years. It found a significant association between the apnea-hypopnea index and ischemic stroke, especially in men.²¹ Survival in patients with heart failure is also associated with the degree of OSA; patients with more severe disease (an apnea-hypopnea index ≥ 15) have a nearly three times greater risk of death than those with no disease or only mild disease (apnea-hypopnea index < 15).²²

From the standpoint of health care utilization, findings that central sleep apnea predicts an increased risk of hospital readmission in heart failure are of particular interest.²³

People with OSA are at increased risk of nocturnal sudden cardiac death.²⁴ Sleep apnea is also associated with an increased overall death rate, and the higher the apnea-hypopnea index, the higher the death rate,²⁵ even after adjusting for age, sex, body mass index, and underlying cardiovascular risk, with findings most pronounced in men under age 70.

Motor vehicle accidents

The need for caution during driving should be discussed with every patient, as motor vehicle accidents are an immediate danger to the patient and others. The association with motor vehicle accidents is independent of sleepiness, and drivers with sleep apnea often do not perceive performance impairment. Young et al²⁶ found that men who snored were 3.4 times as likely to have an accident over a 5-year period, and that men and women with an apnea-hypopnea index greater than 15 were more than 7 times as likely to have multiple accidents over a 5-year period, highlighting the importance of discussing, documenting, and expeditiously diagnosing and treating OSA, particularly in those who report drowsiness while driving.

CLINICAL RISK FACTORS

Risk factors can be divided into nonmodifiable and modifiable ones.

Nonmodifiable factors

Age. Bimodal distributions in OSA prevalence have been observed; ie, that the pediatric population and people who are middle-aged have the highest prevalence of OSA. A linear relationship between sleep apnea prevalence and age until about age 65 was identified in data from the Sleep Heart Health Study.²⁷ After that, the prevalence rates plateau; it is unclear if this is secondary to natural remission of the disease after a certain age or because patients with more severe disease have died by that age (ie, survivorship bias), blunting an increase in prevalence.

Sex. Men develop sleep apnea at a rate three to five times that of women. Several explanations have been proposed to account for this.^28,29 Sex hormones are one factor; women with sleep apnea on hormone replacement therapy have a significantly less-severe sleep apnea burden than other postmenopausal women,³⁰ suggesting a positive effect from estrogen. Sex-based differences in fat distribution, length and collapsibility of the upper airway, genioglossal activity, neurochemical control mechanisms, and arousal response may also contribute to prevalence differences between men and women.

As with coronary artery disease, the presentation of sleep apnea may be atypical in women, particularly around menopause. Sleep apnea should be considered in women who have snoring and daytime sleepiness.

Race. Whites, African Americans, and Asians have a similar prevalence of sleep apnea, but groups differ in obesity rates and craniofacial anatomy.^31–34 Asians tend to have craniofacial skeletal restriction. African Americans are more likely to have upper-airway soft-tissue risk and to develop more severe OSA. Whites tend to have both craniofacial and soft-tissue risk. For those with craniofacial anatomy predisposing to OSA, even mild obesity can make it manifest.

Syndromes that predispose to OSA can include craniofacial structural abnormalities, connective tissue problems, or alterations in ventilatory control (eg, Marfan, Down, and Pierre Robin syndromes).

Modifiable risk factors

Obesity (body mass index ≥ 30 kg/m²) is a firmly established risk factor, but not all obese patients develop obstructive sleep apnea, and not all people with sleep apnea are obese.

Obesity increases risk by altering the geometry and function of the upper airway, increasing collapsibility. The changes are particularly pronounced in the lateral aspects of the pharynx.³⁵

Obesity also affects respiratory drive, likely in part from leptin resistance. Load compensation is another contributing factor: the increased mass in the thorax and abdomen increases the work of breathing and reduces functional residual capacity, increasing oxygen demands and leading to atelectasis and ventilation-perfusion mismatch.

Although obesity is an important risk factor, it is important to recognize that obesity is not the only one to consider: most people with an apnea-hypopnea index of 5 or greater are not obese. The relationship between body mass index and sleep apnea is weaker in children and in the elderly, probably because other risk factors are more pronounced.³⁶

Craniofacial structural abnormalities such as retrognathia (abnormal posterior position of the mandible) and micrognathia (undersized mandible) can increase the risk of OSA because of a resulting posteriorly displaced genioglossus muscle. Other conditions can alter chemosensitivity, affecting the pH and carbon dioxide level of the blood and therefore affecting ventilatory control mechanisms, making the person more prone to developing sleep apnea. Children and young adults may have tonsillar tissue that obstructs the airway.

The site of obstruction can be behind the palate (retropalatal), behind the tongue (retroglossal), or below the pharynx (hypopharyngeal). This helps explain why positive air way pressure—unlike surgery, which addresses a specific area—is often successful, as it serves to splint or treat all aspects of the airway.

FATIGUE, SLEEPINESS, SNORING, RESTLESS SLEEP

Sleep apnea can result in presentation of multiple signs and symptoms (Table 1).

Daytime sleepiness and fatigue are the most common symptoms. Although nonspecific, they are often quite pronounced. Two short questionnaires—the Epworth Sleepiness Scale³⁷ and the Fatigue Severity Scale—can help distinguish between these two symptoms and assess their impact on a patient’s daily life. In the Epworth Sleepiness Scale, the patient rates his or her chance of dozing on a 4-point scale (0 = would never doze, to 3 = high chance of dozing) in eight situations:

• Sitting and reading
• Watching television
• Sitting inactive in a public place
• As a passenger in a car for an hour without a break
• Lying down to rest in the afternoon
• Sitting and talking to someone
• Sitting quietly after a lunch without alcohol
• In a car while stopped for a few minutes in traffic.

A score of 10 or more is consistent with significant subjective sleepiness.

The Fatigue Severity Scale assesses the impact of fatigue on daily living.

Snoring is a common and specific symptom of sleep apnea; however, not all patients who snore have OSA.

Restlessness during sleep is very common—patients may disturb their bed partner by moving around a lot during sleep or report that the sheets are “all over the place” by morning.

Nocturia can also be a sign of sleep apnea and can contribute to sleep fragmentation. A proposed mechanism of this symptom includes alterations of intrathoracic pressure resulting in atrial stretch, which release atrial natriuretic peptide, leading to nocturia. Treating with CPAP has been found to reduce levels of atrial natriuretic peptide, contributing to better sleep.³⁸

Morning headache may occur and is likely related to increased CO₂ levels, which appear to culminate in the morning hours. End-tidal or transcutaneous CO₂ monitoring during polysomnography can help elucidate the presence of sleep-related hypoventilation.

Libido is often diminished and can actually be improved with CPAP. This is therefore an important point to discuss with patients, as improved libido can often serve as an incentive for adherence to OSA treatment.

Insomnia exists in about 15% of patients, primarily as a result of sleep apnea-related with treatment.

Sweating, particularly forehead sweating associated with sleep apnea, more commonly occurs in children.

The STOP-BANG questionnaire (Table 2)³⁹ was primarily validated in preoperative anesthesia testing. However, because of its ease of use and favorable performance characteristics, it is increasingly used to predict the likelihood of finding OSA before polysomnography. A score of 3 or more has a sensitivity of 93%.

PHYSICAL EXAMINATION PROVIDES CLUES

Although the physical examination may be normal, certain findings indicate risk (Table 3). Obesity alone is not an accepted indication for polysomnography unless there are concomitant worrisome signs or symptoms. Of note, those who are morbidly obese (BMI > 40 kg/m²) have a prevalence of sleep apnea greater than 70%.

The classification by Friedman et al⁴⁰ provides an indicator of risk. The patient is examined with the mouth opened wide and the tongue in a neutral natural position. Grades:

• I—Entire uvula and tonsils are visible
• II—Entire uvula is visible, but tonsils are not
• III—Soft palate is visible, but uvula is not
• IV—Only the hard palate is visible.

Especially in children and young adults, enlarged tonsils (or “kissing tonsils”) and a boggy edematous uvula set the stage for obstructive sleep apnea.

DIAGNOSIS REQUIRES SLEEP TESTING

A sleep study is the primary means of diagnosing OSA. Polysomnography includes electrooculography to determine when rapid-eye-movement sleep occurs; electromyography to measure muscle activity in the chin to help determine onset of sleep, with peripheral leads in the leg to measure leg movements; electroencephalography (EEG) to measure neural activity; electrocardiography; pulse oximetry to measure oxygen saturation; measurement of oronasal flow; and measurements of chest wall effort and body position using thoracic and abdominal belts that expand and contract with breathing; and audio recording to detect snoring.

Attended polysomnography requires the constant presence of a trained sleep technologist to monitor for technical issues and patient adherence.

End-tidal CO₂ monitoring is a reasonable method to detect sleep-related hypoventilation but is not routinely performed in the United States. Transcutaneous CO₂ monitoring is a different way to monitor CO₂ used in the setting of positive airway pressure.

Polysomnography in a normal patient shows a regular pattern of increasing and decreasing airflow with inspiration and expiration while stable oxygen saturation is maintained.

In contrast, polysomnography of a patient with sleep apnea shows repetitive periods of no airflow, oxygen desaturation, and often evidence of thoracoabdominal paradox, punctuated by arousals on EEG associated with sympathetic activation (Figure 1). When the patient falls asleep, upper-airway muscle tone is reduced, causing an apneic event with hypoxia and pleural pressure swings. These prompt arousals with sympathetic activation that reestablish upper-airway muscle tone, allowing ventilation and reoxygenation to resume with a return to sleep.

Apnea-hypopnea index indicates severity

Sleep apnea severity is graded using the apnea-hypopnea index, ie, the number of apneic and hypopneic events per hour of sleep (Table 4).⁴¹ Events must last at least 10 seconds to be considered, ie, two consecutive missed breaths based on an average normal respiratory rate of about 12 breaths per minute for the typical adult.

The apnea-hypopnea index usually correlates with the severity of oxygen desaturation and with electrocardiographic abnormalities, including tachybradycardia and arrhythmias.

Although history, physical examination, and prediction tools are helpful in determining the likelihood that a patient has OSA, only polysomnography testing can establish the diagnosis. To diagnose OSA, 15 or more obstructive events per hour must be observed by polysomnography, or at least 5 events per hour with one of the following:

• Daytime sleepiness, sleep attacks, unrefreshing sleep, fatigue, or insomnia
• Waking with breath-holding, gasping, or choking
• Observer-reported loud snoring or breathing interruptions.⁴¹

Split-night study determines diagnosis and optimum treatment

The split-night study has two parts: the first is diagnostic polysomnography, followed by identification of the positive airway pressure that optimally treats the sleep apnea. The apnea-hypopnea index guides the need for the split-night study, with 40 being the established threshold according to the American Academy of Sleep Medicine.

A home sleep study is appropriate for some patients

Home sleep testing is typically more limited than standard polysomnography; it monitors airflow, effort, and oxygenation. The test is intended for adults with a high pretest probability of moderate to severe obstructive sleep apnea (STOP-BANG score ≥ 3). It is not intended for screening of asymptomatic patients or for those with coexisting sleep disorders (eg, central sleep apnea, sleep hypoventilation, periodic limb movements, insomnia, circadian rhythm disorders, parasomnias, narcolepsy) or medical disorders (eg, moderate to severe heart failure or other cardiac disease, symptomatic neurologic disease, moderate to severe pulmonary disease).⁴² Since March 2008, the Centers for Medicare and Medicaid Services has covered CPAP for obstructive sleep apnea based on diagnosis by home sleep study testing.⁴³

TREATMENT OF SLEEP APNEA

Basic steps for reducing OSA are:

Weight loss. Even small weight changes can significantly affect the severity of sleep apnea, perhaps even leading to a reassessment of the degree of OSA and CPAP requirements. Longitudinal epidemiologic data demonstrate that a 10% weight loss correlates with a 26% reduction in the apnea-hypopnea index, and conversely, a 10% weight gain is associated with a 32% increase.⁴⁴

Some studies have found that bariatric surgery cures OSA in 75% to 88% of cases, independent of approach.^45,46 However, a trial in 60 obese patients with OSA who were randomized to either a low-calorie diet or bariatric surgery found no statistical difference in the apnea-hypopnea index between the two groups despite greater weight loss in the surgery group.⁴⁷

Avoiding certain medications. Benzodiazepines, narcotics, and alcohol reduce upper airway muscle tone and should be avoided. No medications are associated with improvement of OSA, although acetazolamide may be used to treat central sleep apnea.

Positional therapy. Sleeping on the back exacerbates the problem. Supine-related OSA occurs as a result of several factors, including gravity, airway anatomy, airway critical closing pressures, and effects on upper-airway dilator muscle function.

Sleep hygiene. General recommendations to engage in behaviors to promote sleep are recommended, including keeping consistent sleep-wake times, not watching television in bed, and avoidance of caffeine intake, particularly within 4 to 6 hours of bedtime.

POSITIVE AIRWAY PRESSURE THERAPY

Nasal CPAP is the treatment of choice and is successful in 95% of patients when used consistently. It is not as costly as surgery, and results in improved long-term survival compared with uvulopalatopharyngoplasty. Another advantage is that the pressure can be retitrated as the patient’s condition changes, for example after a weight change or during pregnancy.

More than 15 randomized controlled trials have examined the effect of sleep apnea treatment with CPAP compared with either sham CPAP or another control. In a meta-analysis, CPAP was found to lead to an average systolic blood pressure reduction of about 2.5 mm Hg and a diastolic blood pressure reduction of 1.8 mm Hg. Although these reductions may seem negligible, benefits may be significant for cardiovascular outcomes.^48,49

Challenges to treatment adherence

Adherence is the most commonly discussed problem with CPAP, but long-term adherence rates are comparable to medication compliance—about 60% to 70%. To optimize adherence, communication is important to ensure that problems are identified and addressed as they arise. Showing patients examples of apneic events and oxygen desaturation from their sleep study can enhance their understanding of OSA and its importance. Patients need to understand the serious nature of the disease and that CPAP therapy can significantly improve their quality of life and overall health, particularly from a cardiovascular perspective.

CPAP masks can be uncomfortable, posing a major barrier to compliance. But a number of mask designs are available, such as the nasal mask, the nasal pillow mask, and the oronasal mask. For patients with claustrophobia, the nasal pillow mask is an option, as it does not cover the face.

Some patients note symptoms of nasal congestion, although in many patients CPAP improves it. If congestion is a problem, the use of heated humidification with the machine, intranasal saline or gel, or nasal corticosteroids can help relieve it.

Pressure intolerance is a common problem. For those who feel that the pressure is too high, settings can be adjusted so that the pressure is gradually reduced between inspiration and expiration, ie, the use of expiratory pressure relief or consideration of the use of bilevel positive airway pressure.

Aerophagia (swallowing air) is a less common problem. It can also potentially be relieved with use of bilevel positive airway pressure.

Many patients develop skin irritation, which can be helped with moleskin, available at any pharmacy.

Social stigma can be a problem. Education regarding the importance of the treatment to health is essential.

Machine noise is less of a problem with the new machine models, but if it is a problem, a white-noise device or earplugs may help.

Other measures to improve compliance are keeping the regimen simple and ensuring that family support is adequate.

Medicare requires evidence of use and benefit

Medicare requires that clinical benefit be documented between the 31st and 91st day after initiating CPAP therapy. This requires face-to-face clinical reevaluation by the treating physician to document improved symptoms and objective evidence of adherence to use of the device. The devices can store usage patterns, and Medicare requires at least 4 hours per night on 70% of nights during a consecutive 30-day period in the first 3 months of use.

ALTERNATIVE THERAPIES

Alternative therapies may be options for some patients, in particular those who cannot use CPAP or who get no benefit from it. These include oral appliances for those with mild to moderate OSA^50–53 and various surgical procedures, eg, uvulopalatopharyngoplasty,^54,55 maxillomanibular advancement,⁵⁶ tracheostomy (standard treatment before CPAP was identified as an effective treatment),^57,58 and adenotonsillectomy (in children).⁵⁹

Supplemental oxygen is not a first-line treatment for OSA and in general has not been found to be very effective, particularly in terms of intermediate cardiovascular outcomes,^60–62 although a subset of patients with high loop gain may benefit from it.⁶³ Loop gain is a measure of the tendency of the ventilatory control system to amplify respiration in response to a change, conferring less stable control of breathing.

Several novel alternative therapies are starting to be used. Although all of them have been shown to improve measures of OSA, none is as effective as CPAP in improving OSA severity. New therapies include the nasal expiratory positive airway pressure device,⁶⁴ oral pressure therapy,⁶⁵ and hypoglossal nerve stimulation.⁶⁶

Obstructive sleep apnea (OSA) is common and poorly recognized and, if untreated, leads to serious health consequences. This article discusses the epidemiology of OSA, describes common presenting signs and symptoms, and reviews diagnostic testing and treatment options. Adverse health effects related to untreated sleep apnea are also discussed.

COMMON, POORLY RECOGNIZED, AND COSTLY IF UNTREATED

OSA is very common in the general population and is associated with substantial morbidity and mortality. An estimated 17% of the general adult population has OSA, and the numbers are increasing with the obesity epidemic. Nearly 1 in 15 adults has at least moderate sleep apnea,^1,2 and approximately 85% of cases are estimated to be undiagnosed.³ A 1999 study estimated that untreated OSA resulted in approximately $3.4 billion in additional medical costs per year in the United States,⁴ a figure that is likely to be higher now, given the rising prevalence of OSA. The prevalence of OSA in primary care and subspecialty clinics is even higher than in the community, as more than half of patients who have diabetes or hypertension and 30% to 40% of patients with coronary artery disease are estimated to have OSA.^5–7

REPETITIVE UPPER-AIRWAY COLLAPSE

During sleep, parasympathetic activity is enhanced and the muscle tone of the upper airway is decreased, particularly in the pharyngeal dilator muscles. Still, even in the supine position, a healthy person maintains patency of the airway and adequate airflow during sleep.

OSA is characterized by repetitive complete or partial collapse of the upper airway during sleep, resulting in an apneic or hypopneic event, respectively, and often causing snoring from upper-airway tissue vibration.

People who are susceptible to OSA typically have a smaller, more collapsible airway that is often less distensible and has a higher critical closing pressure. Radiographic and physiologic data have shown that the airway dimensions of patients with OSA are smaller than in those without OSA. The shape of the airway of a patient with OSA is often elliptical, given the extrinsic compression of the lateral aspects of the airway by increased size of the parapharyngeal fat pads. OSA episodes are characterized by closure of the upper airway and by progressively increasing respiratory efforts driven by chemoreceptor and mechanoreceptor stimuli, culminating in an arousal from sleep and a reopening of the airway.

The disease-defining metric used for assessing OSA severity is the apnea-hypopnea index, ie, the number of apneas and hypopneas that occur per hour of sleep.⁸ An apneic or hypopneic event is identified during polysomnography by the complete cessation of airflow or by a reduction in airflow for 10 seconds or longer (Figure 1).

HEALTH CONSEQUENCES IF UNTREATED

Untreated sleep apnea causes numerous pathophysiologic perturbations, including chronic intermittent hypoxia, ventilatory overshoot hyperoxia, increased sympathetic nervous system activity, intrathoracic pressure swings, hypercapnea, sleep fragmentation, increased arousals, reduced sleep duration, and fragmentation of rapid-eye-movement sleep.

Intermittent hypoxia activates the sympathetic nervous system and causes pulmonary vasoconstriction, with increases in pulmonary arterial pressures and myocardial workload. Sympathetic activation, ascertained by peroneal microneurography, has been shown to be increased not only during sleep but also persisting during wakefulness in patients with untreated OSA vs those without OSA.⁹ Autonomic nervous system fluctuations accompany apneic episodes, resulting in enhanced parasympathetic tone and sympathetic activation associated with a rise in blood pressure and heart rate that occur after the respiratory event.

Intermediate pathways that link the negative pathophysiologic effects of OSA with adverse health outcomes include increased systemic inflammation, increased oxidative stress, metabolic dysfunction, insulin resistance, hypercoagulability, endothelial dysfunction, and autonomic dysfunction.

As a result, a variety of adverse clinical outcomes are associated with untreated OSA, including systemic hypertension, ischemic heart disease and atherosclerosis, diastolic dysfunction, congestive heart failure, cardiac arrhythmias, stroke, increased risk of death, and sudden death, as well as noncardiovascular outcomes such as gout, neurocognitive deficits, and mood disorders.¹⁰

Inflammatory and atherogenic effects

Increased levels of markers of systemic inflammation, prothrombosis, and oxidative stress have been observed in OSA and may be key pathophysiologic links between OSA and cardiovascular sequelae. OSA has been associated with up-regulation of a number of inflammatory mediators: interleukin (IL) 6, soluble IL-6 receptor, IL-8, tumor necrosis factor alpha, and C-reactive protein. Soluble IL-6 levels in particular are higher in people who have sleep-disordered breathing, as reflected by the apnea-hypopnea index independent of obesity, with relationships stronger in the morning than in the evening. This likely reflects the overnight OSA-related physiologic stress.¹¹

Thrombotic potential is also enhanced, with higher levels of plasminogen activator inhibitor 1, fibrinogen, P-selectin, and vascular endothelial growth factor. Some of these factors normally have a diurnal cycle, with higher levels in the morning, but in OSA, increasing OSA severity is associated with increased prothrombotic potential in the morning hours. Of interest, levels of these substances showed a plateau effect, rising in people who had only mildly elevated apnea-hypopnea indices and then leveling off.¹² Intermittent hypoxia followed by ventilatory overshoot hyperoxia, characteristic of sleep apnea, provides the ideal environment for augmentation of oxidative stress, with evidence of increased oxidation of serum proteins and lipids. Hypoxia and oxygen-derived free radicals may result in cardiac myocyte injury. Experimental data demonstrate that intermittent hypoxia combined with a high-fat diet results in synergistic acceleration of evidence of atherogenic lesions.

Patients with OSA also have evidence of endothelial dysfunction, insulin resistance, and dyslipidemia, all pathways that can facilitate the progression of atherosclerosis in OSA.^13–15

Cardiac arrhythmias

In the Sleep Heart Health Study, a multicenter epidemiologic study designed to examine the relationships of OSA and cardiovascular outcomes, those who had moderate to severe OSA had a risk of ventricular and atrial arrhythmias two to four times higher than those without OSA, even after correction for the confounding influences of obesity and underlying cardiovascular risk.¹⁴ These findings were corroborated in subsequent work highlighting monotonic dose-response relationships with increasing OSA severity and increased odds of atrial and ventricular arrhythmia in a cohort of about 3,000 older men.¹¹ Additional compelling evidence of a causal relationship is that the risk of discrete arrhythmic events is markedly increased after a respiratory disturbance in sleep.¹⁶

In patients who successfully underwent cardioversion for atrial fibrillation, those who had sleep apnea but were not treated with continuous positive airway pressure (CPAP) had a much higher rate of recurrence of atrial fibrillation during the subsequent year than those with CPAP-treated sleep apnea and than controls never diagnosed with sleep apnea. In the untreated patients with sleep apnea, the mean nocturnal fall in oxygen saturation was significantly greater in those who had recurrence of atrial fibrillation than in those who did not, suggesting hypoxia as an important mechanism contributing to atrial fibrillation.¹⁷

Since then, several other retrospective studies have shown similar findings after pulmonary vein antrum isolation and ablation in terms of reduction of atrial fibrillation recurrence with CPAP treatment in OSA.¹⁸

Walia et al¹⁹ described a patient with moderate sleep apnea who underwent a split-night study. During the baseline part of the study, the patient had about 18 ectopic beats per minute. During the second portion of the study while CPAP was applied, progressively fewer ectopic beats occurred as airway pressure was increased until a normal rhythm without ectopic beats was achieved at the goal treatment CPAP pressure setting.

Cardiovascular disease, stroke, and death

Marin et al²⁰ followed about 1,500 men for 10 years, including some who had severe OSA, some with sleep apnea who were treated with CPAP, and controls. The risk of nonfatal and fatal cardiovascular disease events was nearly three times higher in those with severe disease than in healthy participants. Those treated with CPAP had a risk approximately the same as in the control group.

The Sleep Heart Study followed approximately 6,000 people with untreated sleep apnea for a median of nearly 9 years. It found a significant association between the apnea-hypopnea index and ischemic stroke, especially in men.²¹ Survival in patients with heart failure is also associated with the degree of OSA; patients with more severe disease (an apnea-hypopnea index ≥ 15) have a nearly three times greater risk of death than those with no disease or only mild disease (apnea-hypopnea index < 15).²²

From the standpoint of health care utilization, findings that central sleep apnea predicts an increased risk of hospital readmission in heart failure are of particular interest.²³

People with OSA are at increased risk of nocturnal sudden cardiac death.²⁴ Sleep apnea is also associated with an increased overall death rate, and the higher the apnea-hypopnea index, the higher the death rate,²⁵ even after adjusting for age, sex, body mass index, and underlying cardiovascular risk, with findings most pronounced in men under age 70.

Motor vehicle accidents

The need for caution during driving should be discussed with every patient, as motor vehicle accidents are an immediate danger to the patient and others. The association with motor vehicle accidents is independent of sleepiness, and drivers with sleep apnea often do not perceive performance impairment. Young et al²⁶ found that men who snored were 3.4 times as likely to have an accident over a 5-year period, and that men and women with an apnea-hypopnea index greater than 15 were more than 7 times as likely to have multiple accidents over a 5-year period, highlighting the importance of discussing, documenting, and expeditiously diagnosing and treating OSA, particularly in those who report drowsiness while driving.

CLINICAL RISK FACTORS

Risk factors can be divided into nonmodifiable and modifiable ones.

Nonmodifiable factors

Age. Bimodal distributions in OSA prevalence have been observed; ie, that the pediatric population and people who are middle-aged have the highest prevalence of OSA. A linear relationship between sleep apnea prevalence and age until about age 65 was identified in data from the Sleep Heart Health Study.²⁷ After that, the prevalence rates plateau; it is unclear if this is secondary to natural remission of the disease after a certain age or because patients with more severe disease have died by that age (ie, survivorship bias), blunting an increase in prevalence.

Sex. Men develop sleep apnea at a rate three to five times that of women. Several explanations have been proposed to account for this.^28,29 Sex hormones are one factor; women with sleep apnea on hormone replacement therapy have a significantly less-severe sleep apnea burden than other postmenopausal women,³⁰ suggesting a positive effect from estrogen. Sex-based differences in fat distribution, length and collapsibility of the upper airway, genioglossal activity, neurochemical control mechanisms, and arousal response may also contribute to prevalence differences between men and women.

As with coronary artery disease, the presentation of sleep apnea may be atypical in women, particularly around menopause. Sleep apnea should be considered in women who have snoring and daytime sleepiness.

Race. Whites, African Americans, and Asians have a similar prevalence of sleep apnea, but groups differ in obesity rates and craniofacial anatomy.^31–34 Asians tend to have craniofacial skeletal restriction. African Americans are more likely to have upper-airway soft-tissue risk and to develop more severe OSA. Whites tend to have both craniofacial and soft-tissue risk. For those with craniofacial anatomy predisposing to OSA, even mild obesity can make it manifest.

Syndromes that predispose to OSA can include craniofacial structural abnormalities, connective tissue problems, or alterations in ventilatory control (eg, Marfan, Down, and Pierre Robin syndromes).

Modifiable risk factors

Obesity (body mass index ≥ 30 kg/m²) is a firmly established risk factor, but not all obese patients develop obstructive sleep apnea, and not all people with sleep apnea are obese.

Obesity increases risk by altering the geometry and function of the upper airway, increasing collapsibility. The changes are particularly pronounced in the lateral aspects of the pharynx.³⁵

Obesity also affects respiratory drive, likely in part from leptin resistance. Load compensation is another contributing factor: the increased mass in the thorax and abdomen increases the work of breathing and reduces functional residual capacity, increasing oxygen demands and leading to atelectasis and ventilation-perfusion mismatch.

Although obesity is an important risk factor, it is important to recognize that obesity is not the only one to consider: most people with an apnea-hypopnea index of 5 or greater are not obese. The relationship between body mass index and sleep apnea is weaker in children and in the elderly, probably because other risk factors are more pronounced.³⁶

Craniofacial structural abnormalities such as retrognathia (abnormal posterior position of the mandible) and micrognathia (undersized mandible) can increase the risk of OSA because of a resulting posteriorly displaced genioglossus muscle. Other conditions can alter chemosensitivity, affecting the pH and carbon dioxide level of the blood and therefore affecting ventilatory control mechanisms, making the person more prone to developing sleep apnea. Children and young adults may have tonsillar tissue that obstructs the airway.

The site of obstruction can be behind the palate (retropalatal), behind the tongue (retroglossal), or below the pharynx (hypopharyngeal). This helps explain why positive air way pressure—unlike surgery, which addresses a specific area—is often successful, as it serves to splint or treat all aspects of the airway.

FATIGUE, SLEEPINESS, SNORING, RESTLESS SLEEP

Sleep apnea can result in presentation of multiple signs and symptoms (Table 1).

Daytime sleepiness and fatigue are the most common symptoms. Although nonspecific, they are often quite pronounced. Two short questionnaires—the Epworth Sleepiness Scale³⁷ and the Fatigue Severity Scale—can help distinguish between these two symptoms and assess their impact on a patient’s daily life. In the Epworth Sleepiness Scale, the patient rates his or her chance of dozing on a 4-point scale (0 = would never doze, to 3 = high chance of dozing) in eight situations:

• Sitting and reading
• Watching television
• Sitting inactive in a public place
• As a passenger in a car for an hour without a break
• Lying down to rest in the afternoon
• Sitting and talking to someone
• Sitting quietly after a lunch without alcohol
• In a car while stopped for a few minutes in traffic.

A score of 10 or more is consistent with significant subjective sleepiness.

The Fatigue Severity Scale assesses the impact of fatigue on daily living.

Snoring is a common and specific symptom of sleep apnea; however, not all patients who snore have OSA.

Restlessness during sleep is very common—patients may disturb their bed partner by moving around a lot during sleep or report that the sheets are “all over the place” by morning.

Nocturia can also be a sign of sleep apnea and can contribute to sleep fragmentation. A proposed mechanism of this symptom includes alterations of intrathoracic pressure resulting in atrial stretch, which release atrial natriuretic peptide, leading to nocturia. Treating with CPAP has been found to reduce levels of atrial natriuretic peptide, contributing to better sleep.³⁸

Morning headache may occur and is likely related to increased CO₂ levels, which appear to culminate in the morning hours. End-tidal or transcutaneous CO₂ monitoring during polysomnography can help elucidate the presence of sleep-related hypoventilation.

Libido is often diminished and can actually be improved with CPAP. This is therefore an important point to discuss with patients, as improved libido can often serve as an incentive for adherence to OSA treatment.

Insomnia exists in about 15% of patients, primarily as a result of sleep apnea-related with treatment.

Sweating, particularly forehead sweating associated with sleep apnea, more commonly occurs in children.

The STOP-BANG questionnaire (Table 2)³⁹ was primarily validated in preoperative anesthesia testing. However, because of its ease of use and favorable performance characteristics, it is increasingly used to predict the likelihood of finding OSA before polysomnography. A score of 3 or more has a sensitivity of 93%.

PHYSICAL EXAMINATION PROVIDES CLUES

Although the physical examination may be normal, certain findings indicate risk (Table 3). Obesity alone is not an accepted indication for polysomnography unless there are concomitant worrisome signs or symptoms. Of note, those who are morbidly obese (BMI > 40 kg/m²) have a prevalence of sleep apnea greater than 70%.

The classification by Friedman et al⁴⁰ provides an indicator of risk. The patient is examined with the mouth opened wide and the tongue in a neutral natural position. Grades:

• I—Entire uvula and tonsils are visible
• II—Entire uvula is visible, but tonsils are not
• III—Soft palate is visible, but uvula is not
• IV—Only the hard palate is visible.

Especially in children and young adults, enlarged tonsils (or “kissing tonsils”) and a boggy edematous uvula set the stage for obstructive sleep apnea.

DIAGNOSIS REQUIRES SLEEP TESTING

A sleep study is the primary means of diagnosing OSA. Polysomnography includes electrooculography to determine when rapid-eye-movement sleep occurs; electromyography to measure muscle activity in the chin to help determine onset of sleep, with peripheral leads in the leg to measure leg movements; electroencephalography (EEG) to measure neural activity; electrocardiography; pulse oximetry to measure oxygen saturation; measurement of oronasal flow; and measurements of chest wall effort and body position using thoracic and abdominal belts that expand and contract with breathing; and audio recording to detect snoring.

Attended polysomnography requires the constant presence of a trained sleep technologist to monitor for technical issues and patient adherence.

End-tidal CO₂ monitoring is a reasonable method to detect sleep-related hypoventilation but is not routinely performed in the United States. Transcutaneous CO₂ monitoring is a different way to monitor CO₂ used in the setting of positive airway pressure.

Polysomnography in a normal patient shows a regular pattern of increasing and decreasing airflow with inspiration and expiration while stable oxygen saturation is maintained.

In contrast, polysomnography of a patient with sleep apnea shows repetitive periods of no airflow, oxygen desaturation, and often evidence of thoracoabdominal paradox, punctuated by arousals on EEG associated with sympathetic activation (Figure 1). When the patient falls asleep, upper-airway muscle tone is reduced, causing an apneic event with hypoxia and pleural pressure swings. These prompt arousals with sympathetic activation that reestablish upper-airway muscle tone, allowing ventilation and reoxygenation to resume with a return to sleep.

Apnea-hypopnea index indicates severity

Sleep apnea severity is graded using the apnea-hypopnea index, ie, the number of apneic and hypopneic events per hour of sleep (Table 4).⁴¹ Events must last at least 10 seconds to be considered, ie, two consecutive missed breaths based on an average normal respiratory rate of about 12 breaths per minute for the typical adult.

The apnea-hypopnea index usually correlates with the severity of oxygen desaturation and with electrocardiographic abnormalities, including tachybradycardia and arrhythmias.

Although history, physical examination, and prediction tools are helpful in determining the likelihood that a patient has OSA, only polysomnography testing can establish the diagnosis. To diagnose OSA, 15 or more obstructive events per hour must be observed by polysomnography, or at least 5 events per hour with one of the following:

• Daytime sleepiness, sleep attacks, unrefreshing sleep, fatigue, or insomnia
• Waking with breath-holding, gasping, or choking
• Observer-reported loud snoring or breathing interruptions.⁴¹

Split-night study determines diagnosis and optimum treatment

The split-night study has two parts: the first is diagnostic polysomnography, followed by identification of the positive airway pressure that optimally treats the sleep apnea. The apnea-hypopnea index guides the need for the split-night study, with 40 being the established threshold according to the American Academy of Sleep Medicine.

A home sleep study is appropriate for some patients

Home sleep testing is typically more limited than standard polysomnography; it monitors airflow, effort, and oxygenation. The test is intended for adults with a high pretest probability of moderate to severe obstructive sleep apnea (STOP-BANG score ≥ 3). It is not intended for screening of asymptomatic patients or for those with coexisting sleep disorders (eg, central sleep apnea, sleep hypoventilation, periodic limb movements, insomnia, circadian rhythm disorders, parasomnias, narcolepsy) or medical disorders (eg, moderate to severe heart failure or other cardiac disease, symptomatic neurologic disease, moderate to severe pulmonary disease).⁴² Since March 2008, the Centers for Medicare and Medicaid Services has covered CPAP for obstructive sleep apnea based on diagnosis by home sleep study testing.⁴³

TREATMENT OF SLEEP APNEA

Basic steps for reducing OSA are:

Weight loss. Even small weight changes can significantly affect the severity of sleep apnea, perhaps even leading to a reassessment of the degree of OSA and CPAP requirements. Longitudinal epidemiologic data demonstrate that a 10% weight loss correlates with a 26% reduction in the apnea-hypopnea index, and conversely, a 10% weight gain is associated with a 32% increase.⁴⁴

Some studies have found that bariatric surgery cures OSA in 75% to 88% of cases, independent of approach.^45,46 However, a trial in 60 obese patients with OSA who were randomized to either a low-calorie diet or bariatric surgery found no statistical difference in the apnea-hypopnea index between the two groups despite greater weight loss in the surgery group.⁴⁷

Avoiding certain medications. Benzodiazepines, narcotics, and alcohol reduce upper airway muscle tone and should be avoided. No medications are associated with improvement of OSA, although acetazolamide may be used to treat central sleep apnea.

Positional therapy. Sleeping on the back exacerbates the problem. Supine-related OSA occurs as a result of several factors, including gravity, airway anatomy, airway critical closing pressures, and effects on upper-airway dilator muscle function.

Sleep hygiene. General recommendations to engage in behaviors to promote sleep are recommended, including keeping consistent sleep-wake times, not watching television in bed, and avoidance of caffeine intake, particularly within 4 to 6 hours of bedtime.

POSITIVE AIRWAY PRESSURE THERAPY

Nasal CPAP is the treatment of choice and is successful in 95% of patients when used consistently. It is not as costly as surgery, and results in improved long-term survival compared with uvulopalatopharyngoplasty. Another advantage is that the pressure can be retitrated as the patient’s condition changes, for example after a weight change or during pregnancy.

More than 15 randomized controlled trials have examined the effect of sleep apnea treatment with CPAP compared with either sham CPAP or another control. In a meta-analysis, CPAP was found to lead to an average systolic blood pressure reduction of about 2.5 mm Hg and a diastolic blood pressure reduction of 1.8 mm Hg. Although these reductions may seem negligible, benefits may be significant for cardiovascular outcomes.^48,49

Challenges to treatment adherence

Adherence is the most commonly discussed problem with CPAP, but long-term adherence rates are comparable to medication compliance—about 60% to 70%. To optimize adherence, communication is important to ensure that problems are identified and addressed as they arise. Showing patients examples of apneic events and oxygen desaturation from their sleep study can enhance their understanding of OSA and its importance. Patients need to understand the serious nature of the disease and that CPAP therapy can significantly improve their quality of life and overall health, particularly from a cardiovascular perspective.

CPAP masks can be uncomfortable, posing a major barrier to compliance. But a number of mask designs are available, such as the nasal mask, the nasal pillow mask, and the oronasal mask. For patients with claustrophobia, the nasal pillow mask is an option, as it does not cover the face.

Some patients note symptoms of nasal congestion, although in many patients CPAP improves it. If congestion is a problem, the use of heated humidification with the machine, intranasal saline or gel, or nasal corticosteroids can help relieve it.

Pressure intolerance is a common problem. For those who feel that the pressure is too high, settings can be adjusted so that the pressure is gradually reduced between inspiration and expiration, ie, the use of expiratory pressure relief or consideration of the use of bilevel positive airway pressure.

Aerophagia (swallowing air) is a less common problem. It can also potentially be relieved with use of bilevel positive airway pressure.

Many patients develop skin irritation, which can be helped with moleskin, available at any pharmacy.

Social stigma can be a problem. Education regarding the importance of the treatment to health is essential.

Machine noise is less of a problem with the new machine models, but if it is a problem, a white-noise device or earplugs may help.

Other measures to improve compliance are keeping the regimen simple and ensuring that family support is adequate.

Medicare requires evidence of use and benefit

Medicare requires that clinical benefit be documented between the 31st and 91st day after initiating CPAP therapy. This requires face-to-face clinical reevaluation by the treating physician to document improved symptoms and objective evidence of adherence to use of the device. The devices can store usage patterns, and Medicare requires at least 4 hours per night on 70% of nights during a consecutive 30-day period in the first 3 months of use.

ALTERNATIVE THERAPIES

Alternative therapies may be options for some patients, in particular those who cannot use CPAP or who get no benefit from it. These include oral appliances for those with mild to moderate OSA^50–53 and various surgical procedures, eg, uvulopalatopharyngoplasty,^54,55 maxillomanibular advancement,⁵⁶ tracheostomy (standard treatment before CPAP was identified as an effective treatment),^57,58 and adenotonsillectomy (in children).⁵⁹

Supplemental oxygen is not a first-line treatment for OSA and in general has not been found to be very effective, particularly in terms of intermediate cardiovascular outcomes,^60–62 although a subset of patients with high loop gain may benefit from it.⁶³ Loop gain is a measure of the tendency of the ventilatory control system to amplify respiration in response to a change, conferring less stable control of breathing.

Several novel alternative therapies are starting to be used. Although all of them have been shown to improve measures of OSA, none is as effective as CPAP in improving OSA severity. New therapies include the nasal expiratory positive airway pressure device,⁶⁴ oral pressure therapy,⁶⁵ and hypoglossal nerve stimulation.⁶⁶

Most decisions for managing acute coronary syndromes can be based on ample data from large randomized trials with hard clinical end points, so there is little reason to provide care that is not evidence-based.

This article reviews some of the trials that provide guidance on diagnosing and managing acute coronary syndromes, including the timing of reperfusion and adjunctive therapies in different situations.

MOST ACUTE CORONARY SYNDROMES ARE NON-ST-ELEVATION CONDITIONS

Acute coronary syndromes range from unstable angina and non-ST-elevation myocardial infarction (NSTEMI) to ST-elevation MI (STEMI), reflecting a continuum of severity of coronary stenosis. The degree of coronary occlusion may ultimately determine whether a patient has unstable angina or MI with or without ST elevation.¹

The substrate for all of these is vulnerable plaque. Angiographic studies have indicated that in many cases medium-size plaques (30%–40% stenosis) are more likely to rupture than larger, more obstructive ones. Moderate plaques may be vulnerable because they are less mature, with a large lipid core and a thin cap prone to rupture or erode, exposing the thrombogenic subendothelial components.²

Because the vulnerability of a coronary plaque may not correlate with the severity of stenosis before the plaque ruptures, stress tests and symptoms may not predict the risk of MI. The key role of thrombosis in the pathogenesis also highlights the importance of antithrombotic therapy in the acute phases of acute coronary syndromes, which can significantly reduce mortality and morbidity rates.

Perhaps because of the widespread use of aspirin and statins, most patients who currently present with an acute coronary syndrome have either unstable angina or NSTEMI: of about 1.57 million hospital admissions in 2004 for acute coronary syndromes, for example, only 330,000 (21%) were for STEMI.³

DIAGNOSING ACUTE CORONARY SYNDROME

Symptoms may not be classic

The classic symptoms of acute coronary syndromes are intense, oppressive chest pressure radiating to the left arm, but nearly any discomfort “between the nose and navel” (eg, including the jaw, arm, and epigastric and abdominal areas) may be an acute coronary syndrome. Associated symptoms may include chest heaviness or burning, radiation to the jaw, neck, shoulder, back, or arms, and dyspnea.

Particularly in older, female, postoperative, or diabetic patients, the presentation may be atypical or “silent,” including nausea or vomiting; breathlessness; sweating; arrhythmias; or light-headedness. Especially in these groups, symptoms may be mild or subtle, and acute coronary syndrome may manifest only as “not feeling well.”

The differential diagnosis of acute coronary syndromes is broad. Most important to immediately consider are pulmonary embolism and aortic dissection, as they are life-threatening and are treated differently from acute coronary syndromes. Otherwise, it is best to err on the side of caution and treat for an acute coronary syndrome until it is proven otherwise.

Electrocardiography is critical

Electrocardiography (ECG) gives valuable information about the location, extent, and prognosis of infarction, and it is critically important for distinguishing STEMI from NSTEMI, with ST elevation classically diagnostic of complete coronary occlusion. Q waves can occur early and do not necessarily signify completed infarction, as traditionally thought. ST depression or T inversion indicates that total coronary occlusion is unlikely unless they are in a pattern of circumflex infarct associated with an enlarging R wave in lead V₁. An ST elevation in RV₄ indicates right ventricular infarction.

The appearance on ECG may evolve over time, so a patient with atypical symptoms and a nonspecific electrocardiogram should be observed for 24 hours or until more specific criteria develop.

Biomarkers in NSTEMI

In MI, cardiac troponin levels begin to rise about 3 hours after the onset of chest pain, and elevations can last for up to 14 days. Levels can also be mildly elevated chronically in patients with renal dysfunction, so positive biomarker tests in that population should be interpreted cautiously.

For STEMI, the opportunity to reperfuse is lost if one waits for cardiac biomarkers to become elevated. But for NSTEMI, they are highly sensitive and specific for identifying patients at high risk and determining who should be treated aggressively. Patients who are biomarker-negative have a better prognosis than patients with identical symptoms and electrocardiograms who are biomarker-positive.

MI is currently defined as a rise in any biomarker (usually troponin) above the 99th percentile for a reference population, with at least one of the following:

• Ischemic symptoms
• New ST/T changes or left bundle branch block
• Pathologic Q waves
• Loss of myocardium or abnormal wall motion seen by imaging
• Intracoronary thrombus.

REPERFUSION FOR ACUTE STEMI

Because acute coronary syndromes have a common pathophysiology, for the most part, lessons from clinical trials in one syndrome are relevant to the others. However, important differences exist regarding the need for immediate reperfusion in STEMI, since in most cases these patients have total rather than partial occlusion.

Fibrinolysis has limitations

The standard of management for STEMI is immediate reperfusion. The goal is to interrupt the wave front of myocardial necrosis, salvage threatened myocardium, and ultimately improve survival.

Five placebo-controlled trials showed a 30% reduction in the death rate in patients who received fibrinolytic therapy within 6 to 12 hours of presentation.⁴

Patients with ST elevation or with new bundle branch block benefit most from fibrinolytic therapy. Those with ST depression, T inversion, or nonspecific changes on ECG do not benefit; they probably do not have complete coronary occlusion, so the prothrombotic or platelet-activating effects of fibrinolytic therapy may make them worse.⁵ Further, fibrinolytic therapy poses the risk of intracranial hemorrhage, which, although rare (occurring in up to 1% of cases depending on the drug regimen), is a devastating complication.

In general, absolute contraindications to fibrinolysis include intracranial abnormalities, hemorrhage, and head trauma. An important relative contraindication is uncontrolled blood pressure (> 180/110 mm Hg at any point during hospitalization, including during the immediate presentation). Studies show that even if blood pressure can be controlled, the risk of intracranial hemorrhage is substantially higher, although the risk may not outweigh the benefit of reperfusion, particularly for large infarctions when percutaneous coronary intervention (PCI) is not available as an alternative to fibrinolysis.

Prompt PCI is preferable to fibrinolysis

If PCI is available on site, there is nearly no role for fibrinolytic therapy. PCI is better than fibrinolytic therapy in terms of the degree of reperfusion, reocclusion, MI recurrence, and mortality rate, and it poses little or no risk of intracranial hemorrhage.⁶

For either fibrinolytic therapy or percutaneous therapy, “time is muscle”: the longer the ischemic time, the higher the mortality rate (relative risk = 1.075 for every 30 minutes of delay, P = .041).⁷

At centers that do not have PCI on site, studies (mainly from Europe) have shown that it is better to transport the patient for PCI than to give immediate fibrinolytic therapy.^7,8 But because the centers studied tended to have short transport times (usually 40 minutes or less), it is uncertain whether the results are applicable throughout the United States.

The delay between symptom onset and presentation is also relevant. Reperfusion within the first 1 to 2 hours after the onset of symptoms provides the greatest degree of myocardial salvage and of reduction in the risk of death; the extent of benefit thereafter is substantially less. As a result, patients who present very early after symptom onset have the most to lose if their reperfusion is delayed by even a few more hours, whereas patients who have already experienced several hours of pain are affected less by additional delay.⁹ Thus, patients presenting within the “golden” 1 or 2 hours after symptoms begin should be considered for fibrinolytic therapy if transfer for PCI cannot be done expeditiously. It is important for hospitals without PCI available on site to have a system in place for rapid transport of patients when needed.

Guidelines advise that patients with STEMI should undergo PCI rather than receive fibrinolytic therapy as long as PCI is available within 90 minutes of first medical contact. Otherwise, fibrinolysis should be started within 30 minutes.¹⁰ For patients who present several hours after symptom onset, PCI may still be preferable even if the transport time is somewhat longer.

PCI after fibrinolytic therapy

In prior decades, PCI immediately after fibrinolytic therapy was associated with an increased risk of bleeding complications and reinfarction. That has changed with improvements in equipment and antithrombotic therapy.

Two large trials conclusively found that routinely transferring high-risk patients for PCI immediately after receiving fibrinolytic therapy (combined half-dose reteplase [Retavase] and abciximab [ReoPro]¹¹ or full-dose tenecteplase [TNKase]¹²) resulted in much lower rates of ischemic end points without an increase in bleeding complications compared with transferring patients only for rescue PCI after fibrinolytic therapy.

Routine transfer is now the standard of care for high-risk patients after fibrinolytic therapy and probably is best for all patients after an MI.

MANAGING NSTEMI AND UNSTABLE ANGINA

For patients with NSTEMI, immediate reperfusion is usually not required, although initial triage for “early invasive” vs “initial conservative” management must be done early in the hospital course. Randomized trials have evaluated these two approaches, with most studies in the contemporary era reporting improved outcomes with an early invasive approach.

The TACTICS trial,¹³ the most important of these, enrolled more than 2,200 patients with unstable angina or NSTEMI and randomized them to an early invasive strategy or a conservative strategy. Overall, results were better with the early invasive strategy.

The ICTUS trial.¹⁴ Although several studies showed that an early invasive approach was better, the most recent study using the most modern practices—the ICTUS trial—did not find that it reduced death rates. Most patients eventually underwent angiography and revascularization, but not early on. However, all studies showed that rates of recurrent unstable angina and hospitalization were reduced by an early invasive approach, so revascularization does have a role in stabilizing the patient. But in situations of aggressive medical management with antithrombotic and other therapies, an early conservative approach may be an appropriate alternative for many patients.¹⁵

The selection of an invasive vs a conservative approach should include a consideration of risk, which can be estimated using a number of criteria, including the Thrombolysis in Myocardial Infarction (TIMI) or the GRACE risk score. When risk was stratified using the TIMI risk score,¹⁶ in the TACTICS trial, the higher the risk score, the more likely patients were to benefit from early revascularization.

When an invasive approach is chosen, it does not appear necessary to take patients to catheterization immediately (within 2–24 hours) compared with later during the hospital course.

The TIMACS trial,¹⁷ with more than 3,000 patients, tested the benefits of very early vs later revascularization for patients with NSTEMI and unstable angina. Early intervention did not significantly improve outcomes for the primary composite end point of death, MI, and stroke in the overall population enrolled in the trial, but when the secondary end point of refractory ischemia was added in, early intervention was found to be beneficial overall. Moreover, when stratified by risk, high-risk patients significantly benefited from early intervention for the primary end point.

Guidelines for NSTEMI and unstable angina continue to prefer an early invasive strategy, particularly for high-risk patients, although a conservative strategy is considered acceptable if patients receive intensive evidence-based medical therapy and remain clinically stable.¹⁸

ANTITHROMBOTIC THERAPIES

Once a revascularization strategy has been chosen, adjunctive therapies should be considered. The most important are the antithrombotic therapies.

Many drugs target platelet activity. Most important are the thromboxane inhibitor aspirin, the adenosine diphosphate (ADP) receptor antagonists clopidogrel (Plavix), prasugrel (Effient), and ticagrelor (Brilinta), and the glycoprotein (GP) IIb/IIIa antagonists abciximab and eptifibatide (Integrilin). Others, such as thrombin receptor antagonists, are under investigation.¹⁹

Aspirin for secondary prevention

Evidence is unequivocal for the benefit of aspirin therapy in patients with established or suspected vascular disease.

The ISIS-2 trial²⁰ compared 35-day mortality rates in 16,000 patients with STEMI who were given aspirin, streptokinase, combined streptokinase and aspirin, or placebo. Mortality rates were reduced by aspirin compared with placebo by an extent similar to that achieved with streptokinase, with a further reduction when aspirin and streptokinase were given together.

Therefore, patients with STEMI should be given aspirin daily indefinitely unless they have true aspirin allergy. The dose is 165 to 325 mg initially and 75 to 162 mg daily thereafter.

For NSTEMI and even for secondary prevention in less-acute situations, a number of smaller trials also provide clear evidence of benefit from aspirin therapy.

The CURRENT-OASIS 7 trial²¹ showed that low maintenance dosages of aspirin (75–100 mg per day) resulted in the same incidence of ischemic end points (cardiovascular death, MI, or stroke) as higher dosages. Although rates of major bleeding events did not differ, a higher rate of gastrointestinal bleeding was evident at just 30 days in patients taking the higher doses. This large trial clearly established that there is no advantage to daily aspirin doses of more than 100 mg.

DUAL ANTIPLATELET THERAPY IS STANDARD

Standard practice now is to use aspirin plus another antiplatelet agent that acts by inhibiting either the ADP receptor (for which there is the most evidence) or the GP IIb/IIIa receptor (which is becoming less used). Dual therapy should begin early in patients with acute coronary syndrome.

Clopidogrel: Well studied with aspirin

The most commonly used ADP antagonist is clopidogrel, a thienopyridine. Much evidence exists for its benefit.

The CURE trial²² randomized more than 12,000 patients with NSTEMI or unstable angina to aspirin plus either clopidogrel or placebo. The incidence of the combined end point of MI, stroke, and cardiovascular death was 20% lower in the clopidogrel group than in the placebo group over 12 months of follow-up. The benefit of clopidogrel began to occur within the first 24 hours after randomization, with a 33% relative risk reduction in the combined end point of cardiovascular death, MI, stroke, and severe ischemia, demonstrating the importance of starting this agent early in the hospital course.

COMMIT²³ found a benefit in adding clopidogrel to aspirin in patients with acute STEMI. Although it was only a 30-day trial, significant risk reduction was found in the dual-therapy group for combined death, stroke, or reinfarction. The results of this brief trial were less definitive, but the pathophysiology was similar to non-ST-elevation acute coronary syndromes, so it is reasonable to extrapolate the long-term findings to this setting.

The CURRENT-OASIS 7 trial²¹ randomized more than 25,000 patients to either clopidogrel in a double dosage (600 mg load, 150 mg/day for 6 days, then 75 mg/day) or standard dosage (300 mg load, 75 mg/day thereafter). Although no overall benefit was found for the higher dosage, a subgroup of more than 17,000 patients who underwent PCI after randomization had a lower risk of developing stent thrombosis. On the other hand, higher doses of clopidogrel caused more major bleeding events.

Ticagrelor and prasugrel: New alternatives to clopidogrel

The principal limitation of clopidogrel is its metabolism. It is a prodrug, ie, it is not active as taken and must be converted to its active state by cytochrome P450 enzymes in the liver. Patients who bear certain polymorphisms in the genes for these enzymes or who are taking other medications that affect this enzymatic pathway may derive less platelet inhibition from the drug, leading to considerable patient-to-patient variability in the degree of antiplatelet effect.

Alternatives to clopidogrel have been developed that inhibit platelets more intensely, are activated more rapidly, and have less interpatient variability. Available now are ticagrelor and prasugrel.²⁴ Like clopidogrel, prasugrel is absorbed as an inactive prodrug, but it is efficiently metabolized by esterases to an active form, and then by a simpler step within the liver to its fully active metabolite.²⁵ Ticagrelor is active as absorbed.²⁶

Pharmacodynamically, the two drugs perform almost identically and much faster than clopidogrel, with equilibrium platelet inhibition reached in less than 1 hour. The degree of platelet inhibition is also more—sometimes twice as much—with the new drugs compared with clopidogrel, and the effect is much more consistent between patients.

Both clopidogrel and prasugrel permanently inhibit the platelet ADP receptor, and 3 to 7 days are therefore required for their antiplatelet effects to completely wear off. In contrast, ticagrelor is a reversible inhibitor and its effects wear off more rapidly. Despite achieving a much higher level of platelet inhibition than clopidogrel, ticagrelor’s activity falls below that of clopidogrel’s by 48 hours of discontinuing the drugs.

The TRITON-TIMI 38 trial²⁷ enrolled more than 13,000 patients with acute coronary syndromes, randomized to receive, either prasugrel or clopidogrel, in addition to aspirin. The patients were all undergoing PCI, so the findings do not apply to patients treated medically with an early conservative approach. The study drug was given only after the decision was made to perform PCI in patients with non-ST-elevation acute coronary syndrome (but given immediately for patients with STEMI, because nearly all those patients undergo PCI).

Prasugrel was clearly beneficial, with a significant 20% lower rate of the combined end point of cardiovascular death, MI, and stroke at 15 months. However, bleeding risk was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% confidence interval 1.02–1.68, P = .03). Looking at individual end points, the advantages of prasugrel were primarily in reducing rates of stent thrombosis and nonfatal MI. Death rates with the two drugs were equivalent, possibly because of the higher risk of bleeding with prasugrel. Bleeding in the prasugrel group was particularly increased in patients who underwent bypass surgery; more patients also needed transfusion.

Subgroup analysis showed that patients with a history of stroke or transient ischemic attack had higher rates of ischemic and bleeding events with prasugrel than with clopidogrel, leading to these being labeled as absolute contraindications to prasugrel. Patients over age 75 or who weighed less than 60 kg experienced excess bleeding risk that closely matched the reduction in ischemic event rates and thus did not have a net benefit with prasugrel.

Trial of ticagrelor vs clopidogrel

The PLATO trial²⁸ included 18,000 patients, of whom 65% underwent revascularization and 35% were treated medically. The drug—clopidogrel or ticagrelor—was given in addition to aspirin at randomization (within 24 hours of symptom onset); this more closely follows clinical practice, in which dual antiplatelet therapy is started as soon as possible. This difference makes the PLATO study more relevant to practice for patients with non-ST-elevation acute coronary syndrome. Also, because they gave the drugs to all patients regardless of whether they were to undergo PCI, this study likely had a higher-risk population, which may be refected in the higher mortality rate at 30 days (5.9% in the clopidogrel group in the PLATO study vs 3.2% in the clopidogrel group in the TRITON study).

Another important difference between the trials testing prasugrel and ticagrelor is that patients who had already received a thienopyridine were excluded from the prasugrel trial but not from the ticagrelor trial. Nearly half the patients in the ticagrelor group were already taking clopidogrel. The clinical implication is that for patients who arrive from another facility and already have been given clopidogrel, it is safe to give ticagrelor. There is limited information about whether that is also true for prasugrel, although there is no known reason why the safety of adding prasugrel to clopidogrel should be different from that of ticagrelor.

The rate of ischemic events was 20% lower in the ticagrelor group than in the clopidogrel group, importantly including reductions in the incidence of death, MI, and stent thrombosis. There was no increase with ticagrelor compared with clopidogrel in bleeding associated with coronary artery bypass graft surgery, likely because of the more rapid washout of the ticagrelor effect, or in the need for blood transfusions. However, the rate of bleeding unrelated to coronary artery bypass was about 20% higher with ticagrelor.

In summary, more intense platelet inhibition reduces the risk of ischemic events, but, particularly for the irreversible inhibitor prasugrel, at the cost of a higher risk of bleeding. In general, the net benefit of these agents in preventing the irreversible complications of MI and (in the case of ticagrelor) death favor the use of the more intense ADP inhibitors in appropriate patients. Ticagrelor is indicated in patients with acute coronary syndromes undergoing invasive or conservative management; prasugrel is indicated in patients undergoing PCI, but contraindicated in patients with a previous stroke or transient ischemic event. Neither drug is indicated in patients undergoing elective PCI outside the setting of acute coronary syndromes, although these agents may be appropriate in patients with intolerance or allergy to clopidogrel.

Glycoprotein IIb/IIIa antagonists for select cases only

GP IIb/IIIa antagonists such as abciximab were previously used more commonly than they are today. Now, with routine pretreatment using thienopyridines, their role in acute coronary syndromes is less clear. They still play a role when routine dual antiplatelet therapy is not used, when prasugrel or ticagrelor is not used, and when heparin rather than an alternative antithrombin agent is used.

A meta-analysis²⁹ of 3,755 patients showed a clear reduction in ischemic complications with abciximab as an adjunct to primary PCI for STEMI in patients treated with heparin.

Kastrati et al³⁰ found that patients with non-ST-elevation acute coronary syndromes benefited from abciximab at the time of PCI with heparin, even though they had been routinely pretreated with clopidogrel. However, benefits were seen only in high-risk patients who had presented with elevated troponins.

On the other hand, the role of GP IIb/IIIa blockade for “upstream” medical management in patients with acute coronary syndromes has been eroded by several studies.

The ACUITY trial³¹ randomized more than 9,000 patients to receive either routine treatment with a GP IIb/IIIa inhibitor before angiography or deferred selective use in the catheterization laboratory only for patients undergoing PCI. No significant differences were found in rates of MI and death.

The Early ACS trial³² compared early routine eptifibatide vs delayed, provisional eptifibatide in 9,492 patients with acute coronary syndromes without ST elevation and who were assigned to an invasive strategy. The early-eptifibatide group received two boluses and an infusion of eptifibatide before angiography; the others received a placebo infusion, with provisional eptifibatide after angiography if the patient underwent PCI and was deemed at high risk. No significant difference in rates of death or MI were noted, and the early-eptifibatide group had significantly higher rates of bleeding and need for transfusion.

The FINESSE trial³³ also discredited “facilitating” PCI by giving GP IIb/IIIa antagonists in patients with STEMI before arrival in the catheterization laboratory, with no benefit to giving abciximab ahead of time vs in the catheterization laboratory, and with an increased risk of bleeding complications.

These studies have helped narrow the use of GP IIb/IIIa inhibitors to the catheterization laboratory in conjunction with heparin anticoagulation (as compared with bivalirudin [Angiomax]; see below) and only in select or high-risk cases. These drugs are indicated in the medical phase of management only if patients cannot be stabilized by aspirin or ADP inhibition.

NEWER ANTITHROMBOTICS: ADVANTAGES UNCLEAR

The complex coagulation cascade has a number of components, but only a few are targeted by drugs that are approved and recommended: fondaparinux (Arixtra) and oral factor Xa inhibitors affect the prothrombinase complex (including factor X); bivalirudin and oral factor IIa inhibitors affect thrombin; and heparin and the low-molecular-weight heparins inhibit both targets.

The SYNERGY trial³⁴ randomized nearly 10,000 patients with non-ST-elevation acute coronary syndromes at high risk for ischemic cardiac complications managed with an invasive approach to either the low-molecular-weight heparin enoxaparin (Lovenox) or intravenous unfractionated heparin immediately after enrollment. Most patients underwent catheterization and revascularization. No clinical advantage was found for enoxaparin, and bleeding complications were increased.

The EXTRACT-TIMI 25 trial³⁵ randomized more than 20,000 patients with STEMI who were about to undergo fibrinolysis to receive either enoxaparin throughout hospitalization (average of 8 days) or unfractionated heparin for at least 48 hours. The enoxaparin group had a lower rate of recurrent MI, but it was unclear if the difference was in part attributable to the longer therapy time. The enoxaparin group also had more bleeding.

Fondaparinux

The OASIS-5 trial^36,37 compared enoxaparin and fondaparinux, an exclusive factor Xa inhibitor, in more than 20,000 patients with unstable angina or NSTEMI. Fondaparinux was associated with a lower risk of death and reinfarction as well as fewer bleeding events. However, the benefits were almost exclusively in patients treated medically. In those undergoing PCI within the first 8 days, no benefit was found, although there was still a significant reduction in major bleeding events. Catheter thrombosis was also increased in patients taking fondaparinux, but only in those who did not receive adequate unfractionated heparin treatment before PCI.

Bivalirudin superior at time of catheterization

The most significant advance in antithrombotic therapy for patients with acute coronary syndromes is bivalirudin. This drug has a clear role only in the catheterization laboratory, where patients can be switched to it from heparin, low-molecular-weight heparin, or fondaparinux.

Three trials^38–40 evaluated the drug in a total of more than 20,000 patients receiving invasive management of coronary artery disease undergoing PCI for elective indications, NSTEMI, or STEMI.

Results were remarkably similar across the three trials. Patients who were treated with bivalirudin alone had the same rate of ischemic end points at 30 days as those receiving heparin plus a GP IIb/IIIa inhibitor, but bivalirudin was associated with a consistent and significant 40% to 50% lower bleeding risk. For the highest-risk patients, those with STEMI, the bivalirudin group also had a significantly lower risk of death at 1 year.⁴¹

OTHER DRUGS: EARLY TREATMENT NO LONGER ROUTINE

Most data for the use of therapies aside from antithrombotics are from studies of patients with STEMI, but findings can logically be extrapolated to those with non-ST-elevation acute coronary syndromes.

Beta-blockers: Cardiogenic shock a risk

For beta-blockers, many historical trials were done in stable coronary disease, but there are no large trials in the setting of NSTEMI or unstable angina, and only recently have there been large trials for STEMI. Before the availability of recent evidence, standard practice was to treat STEMI routinely with intravenous metoprolol (Lopressor) and then oral metoprolol.

When large studies were finally conducted, the results were sobering.

COMMIT.⁴² Nearly 46,000 patients with suspected acute MI were randomized to receive either metoprolol (up to 15 mg intravenously, then 200 mg by mouth daily until discharge or for up to 4 weeks in the hospital) or placebo. Surprisingly, although rates of reinfarction and ventricular fibrillation were lower with metoprolol, a higher risk of cardiogenic shock with early beta-blockade offset these benefits and the net mortality rate was not reduced. This study led to a reduction in the early use of beta-blockers in patients with STEMI.

The standard of care has now shifted from beta-blockers in everyone as early as possible after MI to being more cautious in patients with contraindications, including signs of heart failure or a low-output state, or even in those of advanced age or with borderline low blood pressure or a high heart rate. Patients who present late and therefore may have a larger infarct are also at higher risk.

Although the goal should be to ultimately discharge patients on beta-blocker therapy after an MI, there should be no rush to start one early.

Carvedilol now preferred after STEMI

The CAPRICORN trial⁴³ randomized nearly 2,000 patients following MI with left ventricular dysfunction (an ejection fraction of 40% or below) to either placebo or the beta-blocker carvedilol (Coreg). Patients taking the drug had a clear reduction in rates of death and reinfarction, leading to this drug becoming the beta-blocker of choice in patients with ventricular dysfunction after STEMI.

Angiotensin-converting enzyme inhibitors: Early risk of cardiogenic shock

The use of angiotensin-converting enzyme (ACE) inhibitors after MI is also supported by several studies.⁴⁴ Two very large studies, one of nearly 60,000 patients and one of nearly 20,000, showed a clear reduction in the mortality rate in those who received an ACE inhibitor. Most of the benefit was in patients with an ejection fraction of less than 40%. On the basis of these trials, ACE inhibitors are indicated for all patients for the first 30 days after MI and then indefinitely for those with left ventricular dysfunction. However, the trial in which an ACE inhibitor was given intravenously early on had to be stopped prematurely because of worse outcomes owing to cardiogenic shock.

These studies highlight again that for patients who are unstable in the first few days of an acute coronary syndrome, it is best to wait until their condition stabilizes and to start these therapies before hospital discharge.

Intensive statin therapy

In the last 20 years, unequivocal evidence has emerged to support the beneficial role of statins for secondary prevention in patients with established coronary artery disease. More-recent trials have also shown that intensive statin therapy (a high dose of a potent statin) improves outcomes better than lower doses.

The PROVE-IT TIMI 22 trial⁴⁵ randomized patients after an acute coronary syndrome to receive either standard therapy (pravastatin [Pravachol] 40 mg) or intensive therapy (atorvastatin [Lipitor] 80 mg). The intensive-therapy group had a significantly lower rate of major cardiovascular events, and the difference persisted and grew over 30 months of follow-up.

A number of studies confirmed this and broadened the patient population to those with unstable or stable coronary disease. Regardless of the risk profile, the effects were consistent and showed that high-dose statins were better in preventing coronary death and MI.⁴⁶

Guidelines are evolving toward recommendation of highest doses of statins independently of the target level of low-density lipoprotein cholesterol.

Most decisions for managing acute coronary syndromes can be based on ample data from large randomized trials with hard clinical end points, so there is little reason to provide care that is not evidence-based.

This article reviews some of the trials that provide guidance on diagnosing and managing acute coronary syndromes, including the timing of reperfusion and adjunctive therapies in different situations.

MOST ACUTE CORONARY SYNDROMES ARE NON-ST-ELEVATION CONDITIONS

Acute coronary syndromes range from unstable angina and non-ST-elevation myocardial infarction (NSTEMI) to ST-elevation MI (STEMI), reflecting a continuum of severity of coronary stenosis. The degree of coronary occlusion may ultimately determine whether a patient has unstable angina or MI with or without ST elevation.¹

The substrate for all of these is vulnerable plaque. Angiographic studies have indicated that in many cases medium-size plaques (30%–40% stenosis) are more likely to rupture than larger, more obstructive ones. Moderate plaques may be vulnerable because they are less mature, with a large lipid core and a thin cap prone to rupture or erode, exposing the thrombogenic subendothelial components.²

Because the vulnerability of a coronary plaque may not correlate with the severity of stenosis before the plaque ruptures, stress tests and symptoms may not predict the risk of MI. The key role of thrombosis in the pathogenesis also highlights the importance of antithrombotic therapy in the acute phases of acute coronary syndromes, which can significantly reduce mortality and morbidity rates.

Perhaps because of the widespread use of aspirin and statins, most patients who currently present with an acute coronary syndrome have either unstable angina or NSTEMI: of about 1.57 million hospital admissions in 2004 for acute coronary syndromes, for example, only 330,000 (21%) were for STEMI.³

DIAGNOSING ACUTE CORONARY SYNDROME

Symptoms may not be classic

The classic symptoms of acute coronary syndromes are intense, oppressive chest pressure radiating to the left arm, but nearly any discomfort “between the nose and navel” (eg, including the jaw, arm, and epigastric and abdominal areas) may be an acute coronary syndrome. Associated symptoms may include chest heaviness or burning, radiation to the jaw, neck, shoulder, back, or arms, and dyspnea.

Particularly in older, female, postoperative, or diabetic patients, the presentation may be atypical or “silent,” including nausea or vomiting; breathlessness; sweating; arrhythmias; or light-headedness. Especially in these groups, symptoms may be mild or subtle, and acute coronary syndrome may manifest only as “not feeling well.”

The differential diagnosis of acute coronary syndromes is broad. Most important to immediately consider are pulmonary embolism and aortic dissection, as they are life-threatening and are treated differently from acute coronary syndromes. Otherwise, it is best to err on the side of caution and treat for an acute coronary syndrome until it is proven otherwise.

Electrocardiography is critical

Electrocardiography (ECG) gives valuable information about the location, extent, and prognosis of infarction, and it is critically important for distinguishing STEMI from NSTEMI, with ST elevation classically diagnostic of complete coronary occlusion. Q waves can occur early and do not necessarily signify completed infarction, as traditionally thought. ST depression or T inversion indicates that total coronary occlusion is unlikely unless they are in a pattern of circumflex infarct associated with an enlarging R wave in lead V₁. An ST elevation in RV₄ indicates right ventricular infarction.

The appearance on ECG may evolve over time, so a patient with atypical symptoms and a nonspecific electrocardiogram should be observed for 24 hours or until more specific criteria develop.

Biomarkers in NSTEMI

In MI, cardiac troponin levels begin to rise about 3 hours after the onset of chest pain, and elevations can last for up to 14 days. Levels can also be mildly elevated chronically in patients with renal dysfunction, so positive biomarker tests in that population should be interpreted cautiously.

For STEMI, the opportunity to reperfuse is lost if one waits for cardiac biomarkers to become elevated. But for NSTEMI, they are highly sensitive and specific for identifying patients at high risk and determining who should be treated aggressively. Patients who are biomarker-negative have a better prognosis than patients with identical symptoms and electrocardiograms who are biomarker-positive.

MI is currently defined as a rise in any biomarker (usually troponin) above the 99th percentile for a reference population, with at least one of the following:

• Ischemic symptoms
• New ST/T changes or left bundle branch block
• Pathologic Q waves
• Loss of myocardium or abnormal wall motion seen by imaging
• Intracoronary thrombus.

REPERFUSION FOR ACUTE STEMI

Because acute coronary syndromes have a common pathophysiology, for the most part, lessons from clinical trials in one syndrome are relevant to the others. However, important differences exist regarding the need for immediate reperfusion in STEMI, since in most cases these patients have total rather than partial occlusion.

Fibrinolysis has limitations

The standard of management for STEMI is immediate reperfusion. The goal is to interrupt the wave front of myocardial necrosis, salvage threatened myocardium, and ultimately improve survival.

Five placebo-controlled trials showed a 30% reduction in the death rate in patients who received fibrinolytic therapy within 6 to 12 hours of presentation.⁴

Patients with ST elevation or with new bundle branch block benefit most from fibrinolytic therapy. Those with ST depression, T inversion, or nonspecific changes on ECG do not benefit; they probably do not have complete coronary occlusion, so the prothrombotic or platelet-activating effects of fibrinolytic therapy may make them worse.⁵ Further, fibrinolytic therapy poses the risk of intracranial hemorrhage, which, although rare (occurring in up to 1% of cases depending on the drug regimen), is a devastating complication.

In general, absolute contraindications to fibrinolysis include intracranial abnormalities, hemorrhage, and head trauma. An important relative contraindication is uncontrolled blood pressure (> 180/110 mm Hg at any point during hospitalization, including during the immediate presentation). Studies show that even if blood pressure can be controlled, the risk of intracranial hemorrhage is substantially higher, although the risk may not outweigh the benefit of reperfusion, particularly for large infarctions when percutaneous coronary intervention (PCI) is not available as an alternative to fibrinolysis.

Prompt PCI is preferable to fibrinolysis

If PCI is available on site, there is nearly no role for fibrinolytic therapy. PCI is better than fibrinolytic therapy in terms of the degree of reperfusion, reocclusion, MI recurrence, and mortality rate, and it poses little or no risk of intracranial hemorrhage.⁶

For either fibrinolytic therapy or percutaneous therapy, “time is muscle”: the longer the ischemic time, the higher the mortality rate (relative risk = 1.075 for every 30 minutes of delay, P = .041).⁷

At centers that do not have PCI on site, studies (mainly from Europe) have shown that it is better to transport the patient for PCI than to give immediate fibrinolytic therapy.^7,8 But because the centers studied tended to have short transport times (usually 40 minutes or less), it is uncertain whether the results are applicable throughout the United States.

The delay between symptom onset and presentation is also relevant. Reperfusion within the first 1 to 2 hours after the onset of symptoms provides the greatest degree of myocardial salvage and of reduction in the risk of death; the extent of benefit thereafter is substantially less. As a result, patients who present very early after symptom onset have the most to lose if their reperfusion is delayed by even a few more hours, whereas patients who have already experienced several hours of pain are affected less by additional delay.⁹ Thus, patients presenting within the “golden” 1 or 2 hours after symptoms begin should be considered for fibrinolytic therapy if transfer for PCI cannot be done expeditiously. It is important for hospitals without PCI available on site to have a system in place for rapid transport of patients when needed.

Guidelines advise that patients with STEMI should undergo PCI rather than receive fibrinolytic therapy as long as PCI is available within 90 minutes of first medical contact. Otherwise, fibrinolysis should be started within 30 minutes.¹⁰ For patients who present several hours after symptom onset, PCI may still be preferable even if the transport time is somewhat longer.

PCI after fibrinolytic therapy

In prior decades, PCI immediately after fibrinolytic therapy was associated with an increased risk of bleeding complications and reinfarction. That has changed with improvements in equipment and antithrombotic therapy.

Two large trials conclusively found that routinely transferring high-risk patients for PCI immediately after receiving fibrinolytic therapy (combined half-dose reteplase [Retavase] and abciximab [ReoPro]¹¹ or full-dose tenecteplase [TNKase]¹²) resulted in much lower rates of ischemic end points without an increase in bleeding complications compared with transferring patients only for rescue PCI after fibrinolytic therapy.

Routine transfer is now the standard of care for high-risk patients after fibrinolytic therapy and probably is best for all patients after an MI.

MANAGING NSTEMI AND UNSTABLE ANGINA

For patients with NSTEMI, immediate reperfusion is usually not required, although initial triage for “early invasive” vs “initial conservative” management must be done early in the hospital course. Randomized trials have evaluated these two approaches, with most studies in the contemporary era reporting improved outcomes with an early invasive approach.

The TACTICS trial,¹³ the most important of these, enrolled more than 2,200 patients with unstable angina or NSTEMI and randomized them to an early invasive strategy or a conservative strategy. Overall, results were better with the early invasive strategy.

The ICTUS trial.¹⁴ Although several studies showed that an early invasive approach was better, the most recent study using the most modern practices—the ICTUS trial—did not find that it reduced death rates. Most patients eventually underwent angiography and revascularization, but not early on. However, all studies showed that rates of recurrent unstable angina and hospitalization were reduced by an early invasive approach, so revascularization does have a role in stabilizing the patient. But in situations of aggressive medical management with antithrombotic and other therapies, an early conservative approach may be an appropriate alternative for many patients.¹⁵

The selection of an invasive vs a conservative approach should include a consideration of risk, which can be estimated using a number of criteria, including the Thrombolysis in Myocardial Infarction (TIMI) or the GRACE risk score. When risk was stratified using the TIMI risk score,¹⁶ in the TACTICS trial, the higher the risk score, the more likely patients were to benefit from early revascularization.

When an invasive approach is chosen, it does not appear necessary to take patients to catheterization immediately (within 2–24 hours) compared with later during the hospital course.

The TIMACS trial,¹⁷ with more than 3,000 patients, tested the benefits of very early vs later revascularization for patients with NSTEMI and unstable angina. Early intervention did not significantly improve outcomes for the primary composite end point of death, MI, and stroke in the overall population enrolled in the trial, but when the secondary end point of refractory ischemia was added in, early intervention was found to be beneficial overall. Moreover, when stratified by risk, high-risk patients significantly benefited from early intervention for the primary end point.

Guidelines for NSTEMI and unstable angina continue to prefer an early invasive strategy, particularly for high-risk patients, although a conservative strategy is considered acceptable if patients receive intensive evidence-based medical therapy and remain clinically stable.¹⁸

ANTITHROMBOTIC THERAPIES

Once a revascularization strategy has been chosen, adjunctive therapies should be considered. The most important are the antithrombotic therapies.

Many drugs target platelet activity. Most important are the thromboxane inhibitor aspirin, the adenosine diphosphate (ADP) receptor antagonists clopidogrel (Plavix), prasugrel (Effient), and ticagrelor (Brilinta), and the glycoprotein (GP) IIb/IIIa antagonists abciximab and eptifibatide (Integrilin). Others, such as thrombin receptor antagonists, are under investigation.¹⁹

Aspirin for secondary prevention

Evidence is unequivocal for the benefit of aspirin therapy in patients with established or suspected vascular disease.

The ISIS-2 trial²⁰ compared 35-day mortality rates in 16,000 patients with STEMI who were given aspirin, streptokinase, combined streptokinase and aspirin, or placebo. Mortality rates were reduced by aspirin compared with placebo by an extent similar to that achieved with streptokinase, with a further reduction when aspirin and streptokinase were given together.

Therefore, patients with STEMI should be given aspirin daily indefinitely unless they have true aspirin allergy. The dose is 165 to 325 mg initially and 75 to 162 mg daily thereafter.

For NSTEMI and even for secondary prevention in less-acute situations, a number of smaller trials also provide clear evidence of benefit from aspirin therapy.

The CURRENT-OASIS 7 trial²¹ showed that low maintenance dosages of aspirin (75–100 mg per day) resulted in the same incidence of ischemic end points (cardiovascular death, MI, or stroke) as higher dosages. Although rates of major bleeding events did not differ, a higher rate of gastrointestinal bleeding was evident at just 30 days in patients taking the higher doses. This large trial clearly established that there is no advantage to daily aspirin doses of more than 100 mg.

DUAL ANTIPLATELET THERAPY IS STANDARD

Standard practice now is to use aspirin plus another antiplatelet agent that acts by inhibiting either the ADP receptor (for which there is the most evidence) or the GP IIb/IIIa receptor (which is becoming less used). Dual therapy should begin early in patients with acute coronary syndrome.

Clopidogrel: Well studied with aspirin

The most commonly used ADP antagonist is clopidogrel, a thienopyridine. Much evidence exists for its benefit.

The CURE trial²² randomized more than 12,000 patients with NSTEMI or unstable angina to aspirin plus either clopidogrel or placebo. The incidence of the combined end point of MI, stroke, and cardiovascular death was 20% lower in the clopidogrel group than in the placebo group over 12 months of follow-up. The benefit of clopidogrel began to occur within the first 24 hours after randomization, with a 33% relative risk reduction in the combined end point of cardiovascular death, MI, stroke, and severe ischemia, demonstrating the importance of starting this agent early in the hospital course.

COMMIT²³ found a benefit in adding clopidogrel to aspirin in patients with acute STEMI. Although it was only a 30-day trial, significant risk reduction was found in the dual-therapy group for combined death, stroke, or reinfarction. The results of this brief trial were less definitive, but the pathophysiology was similar to non-ST-elevation acute coronary syndromes, so it is reasonable to extrapolate the long-term findings to this setting.

The CURRENT-OASIS 7 trial²¹ randomized more than 25,000 patients to either clopidogrel in a double dosage (600 mg load, 150 mg/day for 6 days, then 75 mg/day) or standard dosage (300 mg load, 75 mg/day thereafter). Although no overall benefit was found for the higher dosage, a subgroup of more than 17,000 patients who underwent PCI after randomization had a lower risk of developing stent thrombosis. On the other hand, higher doses of clopidogrel caused more major bleeding events.

Ticagrelor and prasugrel: New alternatives to clopidogrel

The principal limitation of clopidogrel is its metabolism. It is a prodrug, ie, it is not active as taken and must be converted to its active state by cytochrome P450 enzymes in the liver. Patients who bear certain polymorphisms in the genes for these enzymes or who are taking other medications that affect this enzymatic pathway may derive less platelet inhibition from the drug, leading to considerable patient-to-patient variability in the degree of antiplatelet effect.

Alternatives to clopidogrel have been developed that inhibit platelets more intensely, are activated more rapidly, and have less interpatient variability. Available now are ticagrelor and prasugrel.²⁴ Like clopidogrel, prasugrel is absorbed as an inactive prodrug, but it is efficiently metabolized by esterases to an active form, and then by a simpler step within the liver to its fully active metabolite.²⁵ Ticagrelor is active as absorbed.²⁶

Pharmacodynamically, the two drugs perform almost identically and much faster than clopidogrel, with equilibrium platelet inhibition reached in less than 1 hour. The degree of platelet inhibition is also more—sometimes twice as much—with the new drugs compared with clopidogrel, and the effect is much more consistent between patients.

Both clopidogrel and prasugrel permanently inhibit the platelet ADP receptor, and 3 to 7 days are therefore required for their antiplatelet effects to completely wear off. In contrast, ticagrelor is a reversible inhibitor and its effects wear off more rapidly. Despite achieving a much higher level of platelet inhibition than clopidogrel, ticagrelor’s activity falls below that of clopidogrel’s by 48 hours of discontinuing the drugs.

The TRITON-TIMI 38 trial²⁷ enrolled more than 13,000 patients with acute coronary syndromes, randomized to receive, either prasugrel or clopidogrel, in addition to aspirin. The patients were all undergoing PCI, so the findings do not apply to patients treated medically with an early conservative approach. The study drug was given only after the decision was made to perform PCI in patients with non-ST-elevation acute coronary syndrome (but given immediately for patients with STEMI, because nearly all those patients undergo PCI).

Prasugrel was clearly beneficial, with a significant 20% lower rate of the combined end point of cardiovascular death, MI, and stroke at 15 months. However, bleeding risk was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% confidence interval 1.02–1.68, P = .03). Looking at individual end points, the advantages of prasugrel were primarily in reducing rates of stent thrombosis and nonfatal MI. Death rates with the two drugs were equivalent, possibly because of the higher risk of bleeding with prasugrel. Bleeding in the prasugrel group was particularly increased in patients who underwent bypass surgery; more patients also needed transfusion.

Subgroup analysis showed that patients with a history of stroke or transient ischemic attack had higher rates of ischemic and bleeding events with prasugrel than with clopidogrel, leading to these being labeled as absolute contraindications to prasugrel. Patients over age 75 or who weighed less than 60 kg experienced excess bleeding risk that closely matched the reduction in ischemic event rates and thus did not have a net benefit with prasugrel.

Trial of ticagrelor vs clopidogrel

The PLATO trial²⁸ included 18,000 patients, of whom 65% underwent revascularization and 35% were treated medically. The drug—clopidogrel or ticagrelor—was given in addition to aspirin at randomization (within 24 hours of symptom onset); this more closely follows clinical practice, in which dual antiplatelet therapy is started as soon as possible. This difference makes the PLATO study more relevant to practice for patients with non-ST-elevation acute coronary syndrome. Also, because they gave the drugs to all patients regardless of whether they were to undergo PCI, this study likely had a higher-risk population, which may be refected in the higher mortality rate at 30 days (5.9% in the clopidogrel group in the PLATO study vs 3.2% in the clopidogrel group in the TRITON study).

Another important difference between the trials testing prasugrel and ticagrelor is that patients who had already received a thienopyridine were excluded from the prasugrel trial but not from the ticagrelor trial. Nearly half the patients in the ticagrelor group were already taking clopidogrel. The clinical implication is that for patients who arrive from another facility and already have been given clopidogrel, it is safe to give ticagrelor. There is limited information about whether that is also true for prasugrel, although there is no known reason why the safety of adding prasugrel to clopidogrel should be different from that of ticagrelor.

The rate of ischemic events was 20% lower in the ticagrelor group than in the clopidogrel group, importantly including reductions in the incidence of death, MI, and stent thrombosis. There was no increase with ticagrelor compared with clopidogrel in bleeding associated with coronary artery bypass graft surgery, likely because of the more rapid washout of the ticagrelor effect, or in the need for blood transfusions. However, the rate of bleeding unrelated to coronary artery bypass was about 20% higher with ticagrelor.

In summary, more intense platelet inhibition reduces the risk of ischemic events, but, particularly for the irreversible inhibitor prasugrel, at the cost of a higher risk of bleeding. In general, the net benefit of these agents in preventing the irreversible complications of MI and (in the case of ticagrelor) death favor the use of the more intense ADP inhibitors in appropriate patients. Ticagrelor is indicated in patients with acute coronary syndromes undergoing invasive or conservative management; prasugrel is indicated in patients undergoing PCI, but contraindicated in patients with a previous stroke or transient ischemic event. Neither drug is indicated in patients undergoing elective PCI outside the setting of acute coronary syndromes, although these agents may be appropriate in patients with intolerance or allergy to clopidogrel.

Glycoprotein IIb/IIIa antagonists for select cases only

GP IIb/IIIa antagonists such as abciximab were previously used more commonly than they are today. Now, with routine pretreatment using thienopyridines, their role in acute coronary syndromes is less clear. They still play a role when routine dual antiplatelet therapy is not used, when prasugrel or ticagrelor is not used, and when heparin rather than an alternative antithrombin agent is used.

A meta-analysis²⁹ of 3,755 patients showed a clear reduction in ischemic complications with abciximab as an adjunct to primary PCI for STEMI in patients treated with heparin.

Kastrati et al³⁰ found that patients with non-ST-elevation acute coronary syndromes benefited from abciximab at the time of PCI with heparin, even though they had been routinely pretreated with clopidogrel. However, benefits were seen only in high-risk patients who had presented with elevated troponins.

On the other hand, the role of GP IIb/IIIa blockade for “upstream” medical management in patients with acute coronary syndromes has been eroded by several studies.

The ACUITY trial³¹ randomized more than 9,000 patients to receive either routine treatment with a GP IIb/IIIa inhibitor before angiography or deferred selective use in the catheterization laboratory only for patients undergoing PCI. No significant differences were found in rates of MI and death.

The Early ACS trial³² compared early routine eptifibatide vs delayed, provisional eptifibatide in 9,492 patients with acute coronary syndromes without ST elevation and who were assigned to an invasive strategy. The early-eptifibatide group received two boluses and an infusion of eptifibatide before angiography; the others received a placebo infusion, with provisional eptifibatide after angiography if the patient underwent PCI and was deemed at high risk. No significant difference in rates of death or MI were noted, and the early-eptifibatide group had significantly higher rates of bleeding and need for transfusion.

The FINESSE trial³³ also discredited “facilitating” PCI by giving GP IIb/IIIa antagonists in patients with STEMI before arrival in the catheterization laboratory, with no benefit to giving abciximab ahead of time vs in the catheterization laboratory, and with an increased risk of bleeding complications.

These studies have helped narrow the use of GP IIb/IIIa inhibitors to the catheterization laboratory in conjunction with heparin anticoagulation (as compared with bivalirudin [Angiomax]; see below) and only in select or high-risk cases. These drugs are indicated in the medical phase of management only if patients cannot be stabilized by aspirin or ADP inhibition.

NEWER ANTITHROMBOTICS: ADVANTAGES UNCLEAR

The complex coagulation cascade has a number of components, but only a few are targeted by drugs that are approved and recommended: fondaparinux (Arixtra) and oral factor Xa inhibitors affect the prothrombinase complex (including factor X); bivalirudin and oral factor IIa inhibitors affect thrombin; and heparin and the low-molecular-weight heparins inhibit both targets.

The SYNERGY trial³⁴ randomized nearly 10,000 patients with non-ST-elevation acute coronary syndromes at high risk for ischemic cardiac complications managed with an invasive approach to either the low-molecular-weight heparin enoxaparin (Lovenox) or intravenous unfractionated heparin immediately after enrollment. Most patients underwent catheterization and revascularization. No clinical advantage was found for enoxaparin, and bleeding complications were increased.

The EXTRACT-TIMI 25 trial³⁵ randomized more than 20,000 patients with STEMI who were about to undergo fibrinolysis to receive either enoxaparin throughout hospitalization (average of 8 days) or unfractionated heparin for at least 48 hours. The enoxaparin group had a lower rate of recurrent MI, but it was unclear if the difference was in part attributable to the longer therapy time. The enoxaparin group also had more bleeding.

Fondaparinux

The OASIS-5 trial^36,37 compared enoxaparin and fondaparinux, an exclusive factor Xa inhibitor, in more than 20,000 patients with unstable angina or NSTEMI. Fondaparinux was associated with a lower risk of death and reinfarction as well as fewer bleeding events. However, the benefits were almost exclusively in patients treated medically. In those undergoing PCI within the first 8 days, no benefit was found, although there was still a significant reduction in major bleeding events. Catheter thrombosis was also increased in patients taking fondaparinux, but only in those who did not receive adequate unfractionated heparin treatment before PCI.

Bivalirudin superior at time of catheterization

The most significant advance in antithrombotic therapy for patients with acute coronary syndromes is bivalirudin. This drug has a clear role only in the catheterization laboratory, where patients can be switched to it from heparin, low-molecular-weight heparin, or fondaparinux.

Three trials^38–40 evaluated the drug in a total of more than 20,000 patients receiving invasive management of coronary artery disease undergoing PCI for elective indications, NSTEMI, or STEMI.

Results were remarkably similar across the three trials. Patients who were treated with bivalirudin alone had the same rate of ischemic end points at 30 days as those receiving heparin plus a GP IIb/IIIa inhibitor, but bivalirudin was associated with a consistent and significant 40% to 50% lower bleeding risk. For the highest-risk patients, those with STEMI, the bivalirudin group also had a significantly lower risk of death at 1 year.⁴¹

OTHER DRUGS: EARLY TREATMENT NO LONGER ROUTINE

Most data for the use of therapies aside from antithrombotics are from studies of patients with STEMI, but findings can logically be extrapolated to those with non-ST-elevation acute coronary syndromes.

Beta-blockers: Cardiogenic shock a risk

For beta-blockers, many historical trials were done in stable coronary disease, but there are no large trials in the setting of NSTEMI or unstable angina, and only recently have there been large trials for STEMI. Before the availability of recent evidence, standard practice was to treat STEMI routinely with intravenous metoprolol (Lopressor) and then oral metoprolol.

When large studies were finally conducted, the results were sobering.

COMMIT.⁴² Nearly 46,000 patients with suspected acute MI were randomized to receive either metoprolol (up to 15 mg intravenously, then 200 mg by mouth daily until discharge or for up to 4 weeks in the hospital) or placebo. Surprisingly, although rates of reinfarction and ventricular fibrillation were lower with metoprolol, a higher risk of cardiogenic shock with early beta-blockade offset these benefits and the net mortality rate was not reduced. This study led to a reduction in the early use of beta-blockers in patients with STEMI.

The standard of care has now shifted from beta-blockers in everyone as early as possible after MI to being more cautious in patients with contraindications, including signs of heart failure or a low-output state, or even in those of advanced age or with borderline low blood pressure or a high heart rate. Patients who present late and therefore may have a larger infarct are also at higher risk.

Although the goal should be to ultimately discharge patients on beta-blocker therapy after an MI, there should be no rush to start one early.

Carvedilol now preferred after STEMI

The CAPRICORN trial⁴³ randomized nearly 2,000 patients following MI with left ventricular dysfunction (an ejection fraction of 40% or below) to either placebo or the beta-blocker carvedilol (Coreg). Patients taking the drug had a clear reduction in rates of death and reinfarction, leading to this drug becoming the beta-blocker of choice in patients with ventricular dysfunction after STEMI.

Angiotensin-converting enzyme inhibitors: Early risk of cardiogenic shock

The use of angiotensin-converting enzyme (ACE) inhibitors after MI is also supported by several studies.⁴⁴ Two very large studies, one of nearly 60,000 patients and one of nearly 20,000, showed a clear reduction in the mortality rate in those who received an ACE inhibitor. Most of the benefit was in patients with an ejection fraction of less than 40%. On the basis of these trials, ACE inhibitors are indicated for all patients for the first 30 days after MI and then indefinitely for those with left ventricular dysfunction. However, the trial in which an ACE inhibitor was given intravenously early on had to be stopped prematurely because of worse outcomes owing to cardiogenic shock.

These studies highlight again that for patients who are unstable in the first few days of an acute coronary syndrome, it is best to wait until their condition stabilizes and to start these therapies before hospital discharge.

Intensive statin therapy

In the last 20 years, unequivocal evidence has emerged to support the beneficial role of statins for secondary prevention in patients with established coronary artery disease. More-recent trials have also shown that intensive statin therapy (a high dose of a potent statin) improves outcomes better than lower doses.

The PROVE-IT TIMI 22 trial⁴⁵ randomized patients after an acute coronary syndrome to receive either standard therapy (pravastatin [Pravachol] 40 mg) or intensive therapy (atorvastatin [Lipitor] 80 mg). The intensive-therapy group had a significantly lower rate of major cardiovascular events, and the difference persisted and grew over 30 months of follow-up.

A number of studies confirmed this and broadened the patient population to those with unstable or stable coronary disease. Regardless of the risk profile, the effects were consistent and showed that high-dose statins were better in preventing coronary death and MI.⁴⁶

Guidelines are evolving toward recommendation of highest doses of statins independently of the target level of low-density lipoprotein cholesterol.

Most decisions for managing acute coronary syndromes can be based on ample data from large randomized trials with hard clinical end points, so there is little reason to provide care that is not evidence-based.

This article reviews some of the trials that provide guidance on diagnosing and managing acute coronary syndromes, including the timing of reperfusion and adjunctive therapies in different situations.

MOST ACUTE CORONARY SYNDROMES ARE NON-ST-ELEVATION CONDITIONS

Acute coronary syndromes range from unstable angina and non-ST-elevation myocardial infarction (NSTEMI) to ST-elevation MI (STEMI), reflecting a continuum of severity of coronary stenosis. The degree of coronary occlusion may ultimately determine whether a patient has unstable angina or MI with or without ST elevation.¹

The substrate for all of these is vulnerable plaque. Angiographic studies have indicated that in many cases medium-size plaques (30%–40% stenosis) are more likely to rupture than larger, more obstructive ones. Moderate plaques may be vulnerable because they are less mature, with a large lipid core and a thin cap prone to rupture or erode, exposing the thrombogenic subendothelial components.²

Because the vulnerability of a coronary plaque may not correlate with the severity of stenosis before the plaque ruptures, stress tests and symptoms may not predict the risk of MI. The key role of thrombosis in the pathogenesis also highlights the importance of antithrombotic therapy in the acute phases of acute coronary syndromes, which can significantly reduce mortality and morbidity rates.

Perhaps because of the widespread use of aspirin and statins, most patients who currently present with an acute coronary syndrome have either unstable angina or NSTEMI: of about 1.57 million hospital admissions in 2004 for acute coronary syndromes, for example, only 330,000 (21%) were for STEMI.³

DIAGNOSING ACUTE CORONARY SYNDROME

Symptoms may not be classic

The classic symptoms of acute coronary syndromes are intense, oppressive chest pressure radiating to the left arm, but nearly any discomfort “between the nose and navel” (eg, including the jaw, arm, and epigastric and abdominal areas) may be an acute coronary syndrome. Associated symptoms may include chest heaviness or burning, radiation to the jaw, neck, shoulder, back, or arms, and dyspnea.

Particularly in older, female, postoperative, or diabetic patients, the presentation may be atypical or “silent,” including nausea or vomiting; breathlessness; sweating; arrhythmias; or light-headedness. Especially in these groups, symptoms may be mild or subtle, and acute coronary syndrome may manifest only as “not feeling well.”

The differential diagnosis of acute coronary syndromes is broad. Most important to immediately consider are pulmonary embolism and aortic dissection, as they are life-threatening and are treated differently from acute coronary syndromes. Otherwise, it is best to err on the side of caution and treat for an acute coronary syndrome until it is proven otherwise.

Electrocardiography is critical

Electrocardiography (ECG) gives valuable information about the location, extent, and prognosis of infarction, and it is critically important for distinguishing STEMI from NSTEMI, with ST elevation classically diagnostic of complete coronary occlusion. Q waves can occur early and do not necessarily signify completed infarction, as traditionally thought. ST depression or T inversion indicates that total coronary occlusion is unlikely unless they are in a pattern of circumflex infarct associated with an enlarging R wave in lead V₁. An ST elevation in RV₄ indicates right ventricular infarction.

The appearance on ECG may evolve over time, so a patient with atypical symptoms and a nonspecific electrocardiogram should be observed for 24 hours or until more specific criteria develop.

Biomarkers in NSTEMI

In MI, cardiac troponin levels begin to rise about 3 hours after the onset of chest pain, and elevations can last for up to 14 days. Levels can also be mildly elevated chronically in patients with renal dysfunction, so positive biomarker tests in that population should be interpreted cautiously.

For STEMI, the opportunity to reperfuse is lost if one waits for cardiac biomarkers to become elevated. But for NSTEMI, they are highly sensitive and specific for identifying patients at high risk and determining who should be treated aggressively. Patients who are biomarker-negative have a better prognosis than patients with identical symptoms and electrocardiograms who are biomarker-positive.

MI is currently defined as a rise in any biomarker (usually troponin) above the 99th percentile for a reference population, with at least one of the following:

• Ischemic symptoms
• New ST/T changes or left bundle branch block
• Pathologic Q waves
• Loss of myocardium or abnormal wall motion seen by imaging
• Intracoronary thrombus.

REPERFUSION FOR ACUTE STEMI

Because acute coronary syndromes have a common pathophysiology, for the most part, lessons from clinical trials in one syndrome are relevant to the others. However, important differences exist regarding the need for immediate reperfusion in STEMI, since in most cases these patients have total rather than partial occlusion.

Fibrinolysis has limitations

The standard of management for STEMI is immediate reperfusion. The goal is to interrupt the wave front of myocardial necrosis, salvage threatened myocardium, and ultimately improve survival.

Five placebo-controlled trials showed a 30% reduction in the death rate in patients who received fibrinolytic therapy within 6 to 12 hours of presentation.⁴

Patients with ST elevation or with new bundle branch block benefit most from fibrinolytic therapy. Those with ST depression, T inversion, or nonspecific changes on ECG do not benefit; they probably do not have complete coronary occlusion, so the prothrombotic or platelet-activating effects of fibrinolytic therapy may make them worse.⁵ Further, fibrinolytic therapy poses the risk of intracranial hemorrhage, which, although rare (occurring in up to 1% of cases depending on the drug regimen), is a devastating complication.

In general, absolute contraindications to fibrinolysis include intracranial abnormalities, hemorrhage, and head trauma. An important relative contraindication is uncontrolled blood pressure (> 180/110 mm Hg at any point during hospitalization, including during the immediate presentation). Studies show that even if blood pressure can be controlled, the risk of intracranial hemorrhage is substantially higher, although the risk may not outweigh the benefit of reperfusion, particularly for large infarctions when percutaneous coronary intervention (PCI) is not available as an alternative to fibrinolysis.

Prompt PCI is preferable to fibrinolysis

If PCI is available on site, there is nearly no role for fibrinolytic therapy. PCI is better than fibrinolytic therapy in terms of the degree of reperfusion, reocclusion, MI recurrence, and mortality rate, and it poses little or no risk of intracranial hemorrhage.⁶

For either fibrinolytic therapy or percutaneous therapy, “time is muscle”: the longer the ischemic time, the higher the mortality rate (relative risk = 1.075 for every 30 minutes of delay, P = .041).⁷

At centers that do not have PCI on site, studies (mainly from Europe) have shown that it is better to transport the patient for PCI than to give immediate fibrinolytic therapy.^7,8 But because the centers studied tended to have short transport times (usually 40 minutes or less), it is uncertain whether the results are applicable throughout the United States.

The delay between symptom onset and presentation is also relevant. Reperfusion within the first 1 to 2 hours after the onset of symptoms provides the greatest degree of myocardial salvage and of reduction in the risk of death; the extent of benefit thereafter is substantially less. As a result, patients who present very early after symptom onset have the most to lose if their reperfusion is delayed by even a few more hours, whereas patients who have already experienced several hours of pain are affected less by additional delay.⁹ Thus, patients presenting within the “golden” 1 or 2 hours after symptoms begin should be considered for fibrinolytic therapy if transfer for PCI cannot be done expeditiously. It is important for hospitals without PCI available on site to have a system in place for rapid transport of patients when needed.

Guidelines advise that patients with STEMI should undergo PCI rather than receive fibrinolytic therapy as long as PCI is available within 90 minutes of first medical contact. Otherwise, fibrinolysis should be started within 30 minutes.¹⁰ For patients who present several hours after symptom onset, PCI may still be preferable even if the transport time is somewhat longer.

PCI after fibrinolytic therapy

In prior decades, PCI immediately after fibrinolytic therapy was associated with an increased risk of bleeding complications and reinfarction. That has changed with improvements in equipment and antithrombotic therapy.

Two large trials conclusively found that routinely transferring high-risk patients for PCI immediately after receiving fibrinolytic therapy (combined half-dose reteplase [Retavase] and abciximab [ReoPro]¹¹ or full-dose tenecteplase [TNKase]¹²) resulted in much lower rates of ischemic end points without an increase in bleeding complications compared with transferring patients only for rescue PCI after fibrinolytic therapy.

Routine transfer is now the standard of care for high-risk patients after fibrinolytic therapy and probably is best for all patients after an MI.

MANAGING NSTEMI AND UNSTABLE ANGINA

For patients with NSTEMI, immediate reperfusion is usually not required, although initial triage for “early invasive” vs “initial conservative” management must be done early in the hospital course. Randomized trials have evaluated these two approaches, with most studies in the contemporary era reporting improved outcomes with an early invasive approach.

The TACTICS trial,¹³ the most important of these, enrolled more than 2,200 patients with unstable angina or NSTEMI and randomized them to an early invasive strategy or a conservative strategy. Overall, results were better with the early invasive strategy.

The ICTUS trial.¹⁴ Although several studies showed that an early invasive approach was better, the most recent study using the most modern practices—the ICTUS trial—did not find that it reduced death rates. Most patients eventually underwent angiography and revascularization, but not early on. However, all studies showed that rates of recurrent unstable angina and hospitalization were reduced by an early invasive approach, so revascularization does have a role in stabilizing the patient. But in situations of aggressive medical management with antithrombotic and other therapies, an early conservative approach may be an appropriate alternative for many patients.¹⁵

The selection of an invasive vs a conservative approach should include a consideration of risk, which can be estimated using a number of criteria, including the Thrombolysis in Myocardial Infarction (TIMI) or the GRACE risk score. When risk was stratified using the TIMI risk score,¹⁶ in the TACTICS trial, the higher the risk score, the more likely patients were to benefit from early revascularization.

When an invasive approach is chosen, it does not appear necessary to take patients to catheterization immediately (within 2–24 hours) compared with later during the hospital course.

The TIMACS trial,¹⁷ with more than 3,000 patients, tested the benefits of very early vs later revascularization for patients with NSTEMI and unstable angina. Early intervention did not significantly improve outcomes for the primary composite end point of death, MI, and stroke in the overall population enrolled in the trial, but when the secondary end point of refractory ischemia was added in, early intervention was found to be beneficial overall. Moreover, when stratified by risk, high-risk patients significantly benefited from early intervention for the primary end point.

Guidelines for NSTEMI and unstable angina continue to prefer an early invasive strategy, particularly for high-risk patients, although a conservative strategy is considered acceptable if patients receive intensive evidence-based medical therapy and remain clinically stable.¹⁸

ANTITHROMBOTIC THERAPIES

Once a revascularization strategy has been chosen, adjunctive therapies should be considered. The most important are the antithrombotic therapies.

Many drugs target platelet activity. Most important are the thromboxane inhibitor aspirin, the adenosine diphosphate (ADP) receptor antagonists clopidogrel (Plavix), prasugrel (Effient), and ticagrelor (Brilinta), and the glycoprotein (GP) IIb/IIIa antagonists abciximab and eptifibatide (Integrilin). Others, such as thrombin receptor antagonists, are under investigation.¹⁹

Aspirin for secondary prevention

Evidence is unequivocal for the benefit of aspirin therapy in patients with established or suspected vascular disease.

The ISIS-2 trial²⁰ compared 35-day mortality rates in 16,000 patients with STEMI who were given aspirin, streptokinase, combined streptokinase and aspirin, or placebo. Mortality rates were reduced by aspirin compared with placebo by an extent similar to that achieved with streptokinase, with a further reduction when aspirin and streptokinase were given together.

Therefore, patients with STEMI should be given aspirin daily indefinitely unless they have true aspirin allergy. The dose is 165 to 325 mg initially and 75 to 162 mg daily thereafter.

For NSTEMI and even for secondary prevention in less-acute situations, a number of smaller trials also provide clear evidence of benefit from aspirin therapy.

The CURRENT-OASIS 7 trial²¹ showed that low maintenance dosages of aspirin (75–100 mg per day) resulted in the same incidence of ischemic end points (cardiovascular death, MI, or stroke) as higher dosages. Although rates of major bleeding events did not differ, a higher rate of gastrointestinal bleeding was evident at just 30 days in patients taking the higher doses. This large trial clearly established that there is no advantage to daily aspirin doses of more than 100 mg.

DUAL ANTIPLATELET THERAPY IS STANDARD

Standard practice now is to use aspirin plus another antiplatelet agent that acts by inhibiting either the ADP receptor (for which there is the most evidence) or the GP IIb/IIIa receptor (which is becoming less used). Dual therapy should begin early in patients with acute coronary syndrome.

Clopidogrel: Well studied with aspirin

The most commonly used ADP antagonist is clopidogrel, a thienopyridine. Much evidence exists for its benefit.

The CURE trial²² randomized more than 12,000 patients with NSTEMI or unstable angina to aspirin plus either clopidogrel or placebo. The incidence of the combined end point of MI, stroke, and cardiovascular death was 20% lower in the clopidogrel group than in the placebo group over 12 months of follow-up. The benefit of clopidogrel began to occur within the first 24 hours after randomization, with a 33% relative risk reduction in the combined end point of cardiovascular death, MI, stroke, and severe ischemia, demonstrating the importance of starting this agent early in the hospital course.

COMMIT²³ found a benefit in adding clopidogrel to aspirin in patients with acute STEMI. Although it was only a 30-day trial, significant risk reduction was found in the dual-therapy group for combined death, stroke, or reinfarction. The results of this brief trial were less definitive, but the pathophysiology was similar to non-ST-elevation acute coronary syndromes, so it is reasonable to extrapolate the long-term findings to this setting.

The CURRENT-OASIS 7 trial²¹ randomized more than 25,000 patients to either clopidogrel in a double dosage (600 mg load, 150 mg/day for 6 days, then 75 mg/day) or standard dosage (300 mg load, 75 mg/day thereafter). Although no overall benefit was found for the higher dosage, a subgroup of more than 17,000 patients who underwent PCI after randomization had a lower risk of developing stent thrombosis. On the other hand, higher doses of clopidogrel caused more major bleeding events.

Ticagrelor and prasugrel: New alternatives to clopidogrel

The principal limitation of clopidogrel is its metabolism. It is a prodrug, ie, it is not active as taken and must be converted to its active state by cytochrome P450 enzymes in the liver. Patients who bear certain polymorphisms in the genes for these enzymes or who are taking other medications that affect this enzymatic pathway may derive less platelet inhibition from the drug, leading to considerable patient-to-patient variability in the degree of antiplatelet effect.

Alternatives to clopidogrel have been developed that inhibit platelets more intensely, are activated more rapidly, and have less interpatient variability. Available now are ticagrelor and prasugrel.²⁴ Like clopidogrel, prasugrel is absorbed as an inactive prodrug, but it is efficiently metabolized by esterases to an active form, and then by a simpler step within the liver to its fully active metabolite.²⁵ Ticagrelor is active as absorbed.²⁶

Pharmacodynamically, the two drugs perform almost identically and much faster than clopidogrel, with equilibrium platelet inhibition reached in less than 1 hour. The degree of platelet inhibition is also more—sometimes twice as much—with the new drugs compared with clopidogrel, and the effect is much more consistent between patients.

Both clopidogrel and prasugrel permanently inhibit the platelet ADP receptor, and 3 to 7 days are therefore required for their antiplatelet effects to completely wear off. In contrast, ticagrelor is a reversible inhibitor and its effects wear off more rapidly. Despite achieving a much higher level of platelet inhibition than clopidogrel, ticagrelor’s activity falls below that of clopidogrel’s by 48 hours of discontinuing the drugs.

The TRITON-TIMI 38 trial²⁷ enrolled more than 13,000 patients with acute coronary syndromes, randomized to receive, either prasugrel or clopidogrel, in addition to aspirin. The patients were all undergoing PCI, so the findings do not apply to patients treated medically with an early conservative approach. The study drug was given only after the decision was made to perform PCI in patients with non-ST-elevation acute coronary syndrome (but given immediately for patients with STEMI, because nearly all those patients undergo PCI).

Prasugrel was clearly beneficial, with a significant 20% lower rate of the combined end point of cardiovascular death, MI, and stroke at 15 months. However, bleeding risk was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% confidence interval 1.02–1.68, P = .03). Looking at individual end points, the advantages of prasugrel were primarily in reducing rates of stent thrombosis and nonfatal MI. Death rates with the two drugs were equivalent, possibly because of the higher risk of bleeding with prasugrel. Bleeding in the prasugrel group was particularly increased in patients who underwent bypass surgery; more patients also needed transfusion.

Subgroup analysis showed that patients with a history of stroke or transient ischemic attack had higher rates of ischemic and bleeding events with prasugrel than with clopidogrel, leading to these being labeled as absolute contraindications to prasugrel. Patients over age 75 or who weighed less than 60 kg experienced excess bleeding risk that closely matched the reduction in ischemic event rates and thus did not have a net benefit with prasugrel.

Trial of ticagrelor vs clopidogrel

The PLATO trial²⁸ included 18,000 patients, of whom 65% underwent revascularization and 35% were treated medically. The drug—clopidogrel or ticagrelor—was given in addition to aspirin at randomization (within 24 hours of symptom onset); this more closely follows clinical practice, in which dual antiplatelet therapy is started as soon as possible. This difference makes the PLATO study more relevant to practice for patients with non-ST-elevation acute coronary syndrome. Also, because they gave the drugs to all patients regardless of whether they were to undergo PCI, this study likely had a higher-risk population, which may be refected in the higher mortality rate at 30 days (5.9% in the clopidogrel group in the PLATO study vs 3.2% in the clopidogrel group in the TRITON study).

Another important difference between the trials testing prasugrel and ticagrelor is that patients who had already received a thienopyridine were excluded from the prasugrel trial but not from the ticagrelor trial. Nearly half the patients in the ticagrelor group were already taking clopidogrel. The clinical implication is that for patients who arrive from another facility and already have been given clopidogrel, it is safe to give ticagrelor. There is limited information about whether that is also true for prasugrel, although there is no known reason why the safety of adding prasugrel to clopidogrel should be different from that of ticagrelor.

The rate of ischemic events was 20% lower in the ticagrelor group than in the clopidogrel group, importantly including reductions in the incidence of death, MI, and stent thrombosis. There was no increase with ticagrelor compared with clopidogrel in bleeding associated with coronary artery bypass graft surgery, likely because of the more rapid washout of the ticagrelor effect, or in the need for blood transfusions. However, the rate of bleeding unrelated to coronary artery bypass was about 20% higher with ticagrelor.

In summary, more intense platelet inhibition reduces the risk of ischemic events, but, particularly for the irreversible inhibitor prasugrel, at the cost of a higher risk of bleeding. In general, the net benefit of these agents in preventing the irreversible complications of MI and (in the case of ticagrelor) death favor the use of the more intense ADP inhibitors in appropriate patients. Ticagrelor is indicated in patients with acute coronary syndromes undergoing invasive or conservative management; prasugrel is indicated in patients undergoing PCI, but contraindicated in patients with a previous stroke or transient ischemic event. Neither drug is indicated in patients undergoing elective PCI outside the setting of acute coronary syndromes, although these agents may be appropriate in patients with intolerance or allergy to clopidogrel.

Glycoprotein IIb/IIIa antagonists for select cases only

GP IIb/IIIa antagonists such as abciximab were previously used more commonly than they are today. Now, with routine pretreatment using thienopyridines, their role in acute coronary syndromes is less clear. They still play a role when routine dual antiplatelet therapy is not used, when prasugrel or ticagrelor is not used, and when heparin rather than an alternative antithrombin agent is used.

A meta-analysis²⁹ of 3,755 patients showed a clear reduction in ischemic complications with abciximab as an adjunct to primary PCI for STEMI in patients treated with heparin.

Kastrati et al³⁰ found that patients with non-ST-elevation acute coronary syndromes benefited from abciximab at the time of PCI with heparin, even though they had been routinely pretreated with clopidogrel. However, benefits were seen only in high-risk patients who had presented with elevated troponins.

On the other hand, the role of GP IIb/IIIa blockade for “upstream” medical management in patients with acute coronary syndromes has been eroded by several studies.

The ACUITY trial³¹ randomized more than 9,000 patients to receive either routine treatment with a GP IIb/IIIa inhibitor before angiography or deferred selective use in the catheterization laboratory only for patients undergoing PCI. No significant differences were found in rates of MI and death.

The Early ACS trial³² compared early routine eptifibatide vs delayed, provisional eptifibatide in 9,492 patients with acute coronary syndromes without ST elevation and who were assigned to an invasive strategy. The early-eptifibatide group received two boluses and an infusion of eptifibatide before angiography; the others received a placebo infusion, with provisional eptifibatide after angiography if the patient underwent PCI and was deemed at high risk. No significant difference in rates of death or MI were noted, and the early-eptifibatide group had significantly higher rates of bleeding and need for transfusion.

The FINESSE trial³³ also discredited “facilitating” PCI by giving GP IIb/IIIa antagonists in patients with STEMI before arrival in the catheterization laboratory, with no benefit to giving abciximab ahead of time vs in the catheterization laboratory, and with an increased risk of bleeding complications.

These studies have helped narrow the use of GP IIb/IIIa inhibitors to the catheterization laboratory in conjunction with heparin anticoagulation (as compared with bivalirudin [Angiomax]; see below) and only in select or high-risk cases. These drugs are indicated in the medical phase of management only if patients cannot be stabilized by aspirin or ADP inhibition.

NEWER ANTITHROMBOTICS: ADVANTAGES UNCLEAR

The complex coagulation cascade has a number of components, but only a few are targeted by drugs that are approved and recommended: fondaparinux (Arixtra) and oral factor Xa inhibitors affect the prothrombinase complex (including factor X); bivalirudin and oral factor IIa inhibitors affect thrombin; and heparin and the low-molecular-weight heparins inhibit both targets.

The SYNERGY trial³⁴ randomized nearly 10,000 patients with non-ST-elevation acute coronary syndromes at high risk for ischemic cardiac complications managed with an invasive approach to either the low-molecular-weight heparin enoxaparin (Lovenox) or intravenous unfractionated heparin immediately after enrollment. Most patients underwent catheterization and revascularization. No clinical advantage was found for enoxaparin, and bleeding complications were increased.

The EXTRACT-TIMI 25 trial³⁵ randomized more than 20,000 patients with STEMI who were about to undergo fibrinolysis to receive either enoxaparin throughout hospitalization (average of 8 days) or unfractionated heparin for at least 48 hours. The enoxaparin group had a lower rate of recurrent MI, but it was unclear if the difference was in part attributable to the longer therapy time. The enoxaparin group also had more bleeding.

Fondaparinux

The OASIS-5 trial^36,37 compared enoxaparin and fondaparinux, an exclusive factor Xa inhibitor, in more than 20,000 patients with unstable angina or NSTEMI. Fondaparinux was associated with a lower risk of death and reinfarction as well as fewer bleeding events. However, the benefits were almost exclusively in patients treated medically. In those undergoing PCI within the first 8 days, no benefit was found, although there was still a significant reduction in major bleeding events. Catheter thrombosis was also increased in patients taking fondaparinux, but only in those who did not receive adequate unfractionated heparin treatment before PCI.

Bivalirudin superior at time of catheterization

The most significant advance in antithrombotic therapy for patients with acute coronary syndromes is bivalirudin. This drug has a clear role only in the catheterization laboratory, where patients can be switched to it from heparin, low-molecular-weight heparin, or fondaparinux.

Three trials^38–40 evaluated the drug in a total of more than 20,000 patients receiving invasive management of coronary artery disease undergoing PCI for elective indications, NSTEMI, or STEMI.

Results were remarkably similar across the three trials. Patients who were treated with bivalirudin alone had the same rate of ischemic end points at 30 days as those receiving heparin plus a GP IIb/IIIa inhibitor, but bivalirudin was associated with a consistent and significant 40% to 50% lower bleeding risk. For the highest-risk patients, those with STEMI, the bivalirudin group also had a significantly lower risk of death at 1 year.⁴¹

OTHER DRUGS: EARLY TREATMENT NO LONGER ROUTINE

Most data for the use of therapies aside from antithrombotics are from studies of patients with STEMI, but findings can logically be extrapolated to those with non-ST-elevation acute coronary syndromes.

Beta-blockers: Cardiogenic shock a risk

For beta-blockers, many historical trials were done in stable coronary disease, but there are no large trials in the setting of NSTEMI or unstable angina, and only recently have there been large trials for STEMI. Before the availability of recent evidence, standard practice was to treat STEMI routinely with intravenous metoprolol (Lopressor) and then oral metoprolol.

When large studies were finally conducted, the results were sobering.

COMMIT.⁴² Nearly 46,000 patients with suspected acute MI were randomized to receive either metoprolol (up to 15 mg intravenously, then 200 mg by mouth daily until discharge or for up to 4 weeks in the hospital) or placebo. Surprisingly, although rates of reinfarction and ventricular fibrillation were lower with metoprolol, a higher risk of cardiogenic shock with early beta-blockade offset these benefits and the net mortality rate was not reduced. This study led to a reduction in the early use of beta-blockers in patients with STEMI.

The standard of care has now shifted from beta-blockers in everyone as early as possible after MI to being more cautious in patients with contraindications, including signs of heart failure or a low-output state, or even in those of advanced age or with borderline low blood pressure or a high heart rate. Patients who present late and therefore may have a larger infarct are also at higher risk.

Although the goal should be to ultimately discharge patients on beta-blocker therapy after an MI, there should be no rush to start one early.

Carvedilol now preferred after STEMI

The CAPRICORN trial⁴³ randomized nearly 2,000 patients following MI with left ventricular dysfunction (an ejection fraction of 40% or below) to either placebo or the beta-blocker carvedilol (Coreg). Patients taking the drug had a clear reduction in rates of death and reinfarction, leading to this drug becoming the beta-blocker of choice in patients with ventricular dysfunction after STEMI.

Angiotensin-converting enzyme inhibitors: Early risk of cardiogenic shock

The use of angiotensin-converting enzyme (ACE) inhibitors after MI is also supported by several studies.⁴⁴ Two very large studies, one of nearly 60,000 patients and one of nearly 20,000, showed a clear reduction in the mortality rate in those who received an ACE inhibitor. Most of the benefit was in patients with an ejection fraction of less than 40%. On the basis of these trials, ACE inhibitors are indicated for all patients for the first 30 days after MI and then indefinitely for those with left ventricular dysfunction. However, the trial in which an ACE inhibitor was given intravenously early on had to be stopped prematurely because of worse outcomes owing to cardiogenic shock.

These studies highlight again that for patients who are unstable in the first few days of an acute coronary syndrome, it is best to wait until their condition stabilizes and to start these therapies before hospital discharge.

Intensive statin therapy

In the last 20 years, unequivocal evidence has emerged to support the beneficial role of statins for secondary prevention in patients with established coronary artery disease. More-recent trials have also shown that intensive statin therapy (a high dose of a potent statin) improves outcomes better than lower doses.

The PROVE-IT TIMI 22 trial⁴⁵ randomized patients after an acute coronary syndrome to receive either standard therapy (pravastatin [Pravachol] 40 mg) or intensive therapy (atorvastatin [Lipitor] 80 mg). The intensive-therapy group had a significantly lower rate of major cardiovascular events, and the difference persisted and grew over 30 months of follow-up.

A number of studies confirmed this and broadened the patient population to those with unstable or stable coronary disease. Regardless of the risk profile, the effects were consistent and showed that high-dose statins were better in preventing coronary death and MI.⁴⁶

Guidelines are evolving toward recommendation of highest doses of statins independently of the target level of low-density lipoprotein cholesterol.

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.

Severe acute pancreatitis has been known since the time of Rembrandt, with Nicolaes Tulp—the physician credited as first describing it—immortalized in the famous painting, The Anatomy Lesson. However, progress in managing this disease has been disappointing. Treatment is mainly supportive, and we lack any true disease-modifying therapy. But we are learning to recognize the disease and treat it supportively better than in the past.

The early hours of severe acute pancreatitis are critical for instituting appropriate intervention. Prompt fluid resuscitation is key to preventing immediate and later morbidity and death. This article focuses on identifying and managing the most severe form of acute pancreatitis—necrotizing disease—and its complications.

NECROTIZING DISEASE ACCOUNTS FOR MOST PANCREATITIS DEATHS

The classification and definitions of acute pancreatitis were recently revised from the 1992 Atlanta system and published early in 2013.¹ In addition, the American Pancreatic Association and the International Association of Pancreatology met in 2012 to develop evidence-based guidelines on managing severe pancreatitis.

An estimated 210,000 new cases of acute pancreatitis occur each year in the United States. About 20% of cases of severe acute pancreatitis are necrotizing disease, which accounts for nearly all the morbidity and death associated with acute pancreatitis.

The clinical spectrum of acute pancreatitis ranges from mild to life-threatening, reflecting interstitial (death rate < 1%) to necrotizing histology (the latter associated with a 25% risk of death if the pancreatitis becomes infected and a 10% risk if it is sterile). When death occurs early in the disease course, it tends to be from multiorgan failure; when death occurs later in the course, it tends to be from infection. Appropriate early treatment may prevent death in both categories.

DIAGNOSING ACUTE PANCREATITIS AND PREDICTING ITS SEVERITY

The diagnosis of acute pancreatitis requires two of the following three criteria:

• Clinical presentation—epigastric pain, nausea, vomiting
• Biochemical—amylase level more than three times the upper limit of normal, or lipase more than three times the upper limit of normal
• Evidence from computed tomography (CT), ultrasonography, or magnetic resonance imaging.

Although the biochemical criteria are variably sensitive for detecting acute pancreatitis (55%–100%), the specificity is very high (93% to 99%).

Recently, urinary trypsinogen-2, measured by dipstick, has also been used to aid diagnosis. It has a reasonable sensitivity (53%–96%) and specificity (85%) if positive (> 50 ng/mL).

Speed is critical

Over the years, many clinical prediction rules have been used for predicting the severity of acute pancreatitis. The Ranson criteria,² from 1974, and the Acute Physiology and Chronic Health Evaluation (APACHE) II system³ are cumbersome and require waiting up to 48 hours after the onset of acute pancreatitis to obtain a complete score. The Imrie-Glasgow score is another predictor.

The systemic inflammatory response syndrome (SIRS) is currently the most important indicator of prognosis.⁴ Originally adopted for predicting the development of organ failure with sepsis, it requires at least two of the following criteria:

• Heart rate > 90 beats/min
• Core temperature < 36°C or > 38°C
• White blood cells < 4,000 or > 12,000/mm³
• Respirations > 20/min.

The advantages of this system are that it identifies risk very early in the course of the disease and can be assessed quickly in the emergency department.

The Bedside Index for Severity of Acute Pancreatitis (BISAP) score is another simple, easy-to-perform prognostic index,^5,6 calculated by assigning 1 point for each of the following if present within the first 24 hours of presentation:

• Blood urea nitrogen > 25 mg/dL
• Abnormal mental status (Glasgow coma score < 15)
• Evidence of systemic inflammatory response syndrome
• Age > 60 years
• Pleural effusion seen on imaging study.

A score of 3 points is associated with a 5.3% rate of hospital death, 4 points with 12.7%, and 5 points with 22.5%.

At its most basic, severe acute pancreatitis is defined by organ failure (at least one organ from the respiratory, renal, or cardiovascular system) lasting for more than 48 hours. Failure for each organ is defined by the Marshall scoring system.¹

EARLY MANAGEMENT IS KEY TO OUTCOME

The window of opportunity to make a significant difference in outcome is within the first 12 to 24 hours of presentation. Volume resuscitation is the cornerstone of early management. By the time of presentation for severe acute pancreatitis, the pancreas is already necrotic, so the aim is to minimize the systemic inflammatory response syndrome with the goals of reducing rates of organ failure, morbidity, and death. Necrotizing pancreatitis is essentially an ischemic event, and the goal of volume resuscitation is to maintain pancreatic and intestinal microcirculation to prevent intestinal ischemia and subsequent bacterial translocation.⁷

Early resuscitation with lactated Ringer’s solution recommended

The evidence supporting a specific protocol for fluid resuscitation in severe acute pancreatitis is not strong, but a few studies provide guidance.

Wu et al⁸ randomized 40 patients with acute pancreatitis to one of four arms: “goal-directed fluid resuscitation” with either lactated Ringer’s solution or normal saline, or standard therapy (by physician discretion) with either lactated Ringer’s solution or normal saline. Goal-directed therapy involved a bolus of 20 mL/kg given over 30 to 45 minutes at presentation followed by infusion with rates dependent on an algorithm based on change in blood urea nitrogen level at set times. Patients receiving either goal-directed or standard therapy had significantly lower rates of systemic inflammatory response syndrome at 24 hours than at admission. Most striking was that treatment with lactated Ringer’s solution was associated with dramatically improved rates, whereas normal saline showed no improvement.

In a retrospective study of patients with acute pancreatitis, Warndorf et al⁹ identified 340 patients who received early resuscitation (more than one-third of the total 72-hour fluid volume within 24 hours of presentation) and 90 patients who received late resuscitation (less than one-third of the total 72-hour fluid volume within 24 hours of presentation). Patients who received early resuscitation developed less systemic inflammatory response syndrome and organ failure, and required fewer interventions.

Monitoring for optimum fluid resuscitation

Fluid resuscitation should be carefully managed to avoid administering either inadequate or excessive amounts of fluid. Inadequate fluid resuscitation can result in renal failure, progression of necrosis, and possibly infectious complications. Excessive resuscitation—defined as more than 4 L in the first 24 hours—is associated with respiratory failure, pancreatic fluid collections, and abdominal compartment syndrome.

Optimum resuscitation is controlled fluid expansion averaging 5 to 10 mL/kg per hour, with 2,500 to 4,000 mL given in the first 24 hours.

Adequate volume resuscitation can be evaluated clinically with the following goals:

• Heart rate < 120 beats per minute
• Mean arterial pressure 65–85 mm Hg
• Urinary output > 1 mL/kg per hour
• Hematocrit 35%–44%.

EARLY CT IS JUSTIFIED ONLY IF DIAGNOSIS IS UNCLEAR

The normal pancreas takes up contrast in the same way as do the liver and spleen, so its enhancement on CT is similar. If there is interstitial pancreatitis, CT shows the pancreas with normal contrast uptake, but the organ appears “boggy” with indistinct outlines. With necrotizing pancreatitis, only small areas of tissue with normal contrast may be apparent.

Peripancreatic fat necrosis may also be visible on CT. Obese patients tend to have a worse clinical course of necrotizing pancreatitis, probably because of the associated peripancreatic fat that is incorporated into the pancreatic necrosis.

For clear-cut cases of acute pancreatitis, time is wasted waiting to obtain CT images, and this could delay fluid resuscitation. Results from immediate CT almost never change the clinical management during the first week of acute pancreatitis, and obtaining CT images is usually not recommended if the diagnosis of acute pancreatitis is clear. CT’s sensitivity for detecting necrosis is only 70% in the first 48 hours of presentation, so it is easy to be fooled by a false-negative scan: frequently, a scan does not show necrotizing pancreatitis until after 72 hours. In addition, evidence from animal studies indicates that contrast agents might worsen pancreatic necrosis.

Immediate CT is justified if the diagnosis is in doubt at presentation, such as to evaluate for other intra-abdominal conditions such as intestinal ischemia or a perforated duodenal ulcer.

Contrast-enhanced CT is recommended 72 to 96 hours after presentation, or earlier if the patient is worsening despite treatment. Specific CT protocols will be included in new management guidelines, expected to be published soon.

PREVENTING INFECTIOUS COMPLICATIONS

Risk of infection is associated with the degree of pancreatic necrosis. Patients with less than 30% necrosis have a 22.5% chance of infection, whereas those with more than 50% necrosis have a 46.5% risk of infection.¹⁰

Infection can develop from a variety of sources:

Bacterial translocation from the colon and small bowel is thought to be one of the major sources of infection in necrotic pancreatitis. Volume resuscitation and maintaining gut integrity with early enteral nutrition are believed to minimize the risk of bacterial translocation.

Hematogenous spread of bacteria is another suspected source of infection into the pancreas. Again, enteral nutrition also reduces the risk by minimizing the need for central catheters.

Biliary sources may also play a role. Bile duct stones or gall bladder infection can lead to infected pancreatic necrosis.

ANTIBIOTICS NOT ROUTINELY RECOMMENDED

Treating acute pancreatitis with antibiotics has fallen in and out of favor over the past decades. From being standard practice in the 1970s, it dropped off in the 1980s and 1990s and then became more common again.

Current recommendations from the American Pancreatic Association and the International Association of Pancreatology are not to routinely use intravenous antibiotics to prevent infection in necrotizing pancreatitis because of lack of evidence that it changes overall outcome. Antibiotic usage may be associated with more bacterial resistance and the introduction of fungal infections into the pancreas.

Selective gut decontamination, involving oral and rectal administration of neomycin and other antibiotics, was shown in a single randomized trial to reduce the incidence of infection, but it is very cumbersome and is not recommended for acute pancreatitis.

Treatment with probiotics is also not recommended and was shown in one study to lead to a worse outcome.¹¹

ENTERAL BETTER THAN TOTAL PARENTERAL NUTRITION

Enteral tube feeding with either an elemental diet or a polymeric enteral formulation is the first-line therapy for necrotizing pancreatitis. Compared with total parenteral nutrition, it reduces infection, organ failure, hospital length of stay, the need for surgical intervention, and the risk of death. Total parenteral nutrition should be considered only for patients who do not tolerate enteral feeding because of severe ileus.

Conventional thinking for many years was to provide enteral feeding with a tube passed beyond the ligament of Treitz, thinking that it reduced stimulation to the pancreas. However, recent studies indicate that nasogastric feeding is equivalent to nasojejunal feeding in terms of nutrition, maintaining gut integrity, and outcome.

INTRA-ABDOMINAL HYPERTENSION AND ABDOMINAL COMPARTMENT SYNDROME

Movement of fluid into the intracellular space (“third-spacing”) occurs in acute pancreatitis and is exacerbated by fluid resuscitation. Intra-abdominal hypertension is associated with poor outcomes in patients with severe acute pancreatitis. Especially for patients with severe pancreatitis who are on mechanical ventilation, pressure should be monitored with transvesicular bladder measurements.

Intra-abdominal hypertension is defined as a sustained intra-abdominal pressure of more than 12 mm Hg, with the following grades:

• Grade 1: 12–15 mm Hg
• Grade 2: 16–20 mm Hg
• Grade 3: 21–25 mm Hg
• Grade 4: > 25 mm Hg.

Abdominal compartment syndrome is defined as a sustained intra-abdominal pressure of more than 20 mm Hg. It is associated with new organ dysfunction or failure. It should first be managed with ultrafiltration or diuretics to try to reduce the amount of fluid in the abdomen. Lumenal decompression can be tried with nasogastric or rectal tubes for the stomach and bowels. Ascites or retroperitoneal fluid can be drained percutaneously. In addition, analgesia and sedation to reduce abdominal muscle tone can help the patient become better ventilated. Neuromuscular blockade can also relax the abdomen.

Open abdominal decompression is the treatment of last resort to relieve abdominal compartment syndrome. The abdominal wall is not closed surgically but is allowed to heal by secondary intention (it “granulates in”).¹²

IDENTIFYING INFECTION

Fine-needle aspiration if clinical and imaging signs are not clear

Untreated infected pancreatitis is associated with a much higher risk of death than sterile pancreatic necrosis. Unfortunately, it can be difficult to determine if a patient with necrotizing pancreatitis has an infection because fever, tachycardia, and leukocytosis are usually present regardless. It is important to determine because mechanically intervening for sterile necrosis does not improve outcome.

Fine-needle aspiration, either guided by CT or done at the bedside with ultrasonography, with evaluation with Gram stain and culture, was widely used in the 1990s in cases of necrotizing pancreatitis to determine if infection was present. There has been a shift away from this because, although it can confirm the presence of infection, the false-negative rate is 15%. Clinical and imaging signs can be relied on in most cases to determine the presence of infection, and it is now recognized that fineneedle aspiration should be used only for select cases. Clinical studies have not shown that fine-needle aspiration improves outcomes.

Clinical scenarios typical of infected pancreatic necrosis include patients who have obvious signs of infection with no identifiable source, such as those who stabilize after acute severe acute pancreatitis, and then 10 to 14 days later become worse, with a dramatically higher white blood cell count and tachycardia. Such a patient likely needs an intervention regardless of the results of fine-needle aspiration.

On the other hand, a patient with a continually up-and-down course that never stabilizes over 3 weeks, with no identifiable source of infection, and with no peripancreatic gas apparent on imaging would be a good candidate for fine-needle aspiration.

If peripancreatic gas is seen on imaging, fine-needle aspiration is unnecessary. Peripancreatic gas is traditionally attributed to gasforming bacteria within the pancreas, but in my experience, it is usually from a fistula from the necrosis to the duodenum or the colon, the fistula being caused as the necrosis erodes at the hepatic flexure, the transverse colon, or the splenic flexure.

MECHANICAL INTERVENTIONS FOR INFECTIVE NECROSIS

Late, minimally invasive procedures preferred

Conventional management has shifted away from removing the necrosis with early surgical debridement of the pancreas. Experience with myocardial infarction shows that it is not necessary to remove a sterile necrotic organ, and studies with sterile pancreatic necrosis have found that surgical intervention is associated with a higher risk of death than medical management.

Documented infection has traditionally been considered a definite indication for debridement, but even that is being called into question as more studies are emerging of infected necrosis treated successfully with antibiotics alone.

Sterile necrosis with a fulminant course is a controversial indication for surgery. It was traditionally felt that surgery was worth trying for such patients, but this is no longer common practice.

For cases in which debridement was deemed advisable, surgery was done more frequently in the past. Now, a minimally invasive approach such as with endoscopy or percutaneous catheter is also used. Waiting until at least 4 weeks after the onset of acute pancreatitis is associated with a better outcome than intervening early.

WALLED-OFF NECROSIS

Watchful waiting or minimally invasive intervention

Patients who survive multiorgan failure but are still ill more than 4 weeks after the onset of pancreatitis should be suspected of having walled-off necrosis, formerly referred to as a pancreatic phlegmon. This term was abandoned after the 1992 Atlanta symposium.¹³ In the mid to late 1990s, the process was referred to as organized pancreatic necrosis. It is characterized by a mature, encapsulated collection of pancreatic or peripancreatic necrosis that contains variable amounts of amylase-rich fluid from pancreatic duct disruption.

Walled-off pancreatic necrosis (WOPN) is often confused with pancreatic pseudocyst; these may appear similar on CT, and higherdensity solid debris may be visible in walled-off necrosis within an otherwise homogenous-appearing collection. Magnetic resonance imaging defines liquid and solid much better than CT.

The best way to distinguish WOPN from pseudocyst is by clinical history: a patient with a preceding history of clinically severe acute pancreatitis almost always has necrotizing pancreatitis that evolves to walled-off necrosis, usually over 3 to 4 weeks.

Endoscopic removal and other minimally invasive approaches, such as aggressive percutaneous interventions, have replaced open necrosectomy for treatment, which was associated with high morbidity and mortality rates.^14–16

Intervening for sterile walled-off necrosis is still a controversial topic: although systemically ill, the patient is no longer having life-threatening consequences, and watchful waiting might be just as expedient as intervention. Evidence to support either view is lacking. Most experts believe that intervention should be done if the patient has gastric outlet obstruction and intractable pain and is unable to eat 4 to 6 weeks after the onset of pancreatitis with WOPN. Infected WOPN is considered an indication for drainage.

Severe acute pancreatitis has been known since the time of Rembrandt, with Nicolaes Tulp—the physician credited as first describing it—immortalized in the famous painting, The Anatomy Lesson. However, progress in managing this disease has been disappointing. Treatment is mainly supportive, and we lack any true disease-modifying therapy. But we are learning to recognize the disease and treat it supportively better than in the past.

The early hours of severe acute pancreatitis are critical for instituting appropriate intervention. Prompt fluid resuscitation is key to preventing immediate and later morbidity and death. This article focuses on identifying and managing the most severe form of acute pancreatitis—necrotizing disease—and its complications.

NECROTIZING DISEASE ACCOUNTS FOR MOST PANCREATITIS DEATHS

The classification and definitions of acute pancreatitis were recently revised from the 1992 Atlanta system and published early in 2013.¹ In addition, the American Pancreatic Association and the International Association of Pancreatology met in 2012 to develop evidence-based guidelines on managing severe pancreatitis.

An estimated 210,000 new cases of acute pancreatitis occur each year in the United States. About 20% of cases of severe acute pancreatitis are necrotizing disease, which accounts for nearly all the morbidity and death associated with acute pancreatitis.

The clinical spectrum of acute pancreatitis ranges from mild to life-threatening, reflecting interstitial (death rate < 1%) to necrotizing histology (the latter associated with a 25% risk of death if the pancreatitis becomes infected and a 10% risk if it is sterile). When death occurs early in the disease course, it tends to be from multiorgan failure; when death occurs later in the course, it tends to be from infection. Appropriate early treatment may prevent death in both categories.

DIAGNOSING ACUTE PANCREATITIS AND PREDICTING ITS SEVERITY

The diagnosis of acute pancreatitis requires two of the following three criteria:

• Clinical presentation—epigastric pain, nausea, vomiting
• Biochemical—amylase level more than three times the upper limit of normal, or lipase more than three times the upper limit of normal
• Evidence from computed tomography (CT), ultrasonography, or magnetic resonance imaging.

Although the biochemical criteria are variably sensitive for detecting acute pancreatitis (55%–100%), the specificity is very high (93% to 99%).

Recently, urinary trypsinogen-2, measured by dipstick, has also been used to aid diagnosis. It has a reasonable sensitivity (53%–96%) and specificity (85%) if positive (> 50 ng/mL).

Speed is critical

Over the years, many clinical prediction rules have been used for predicting the severity of acute pancreatitis. The Ranson criteria,² from 1974, and the Acute Physiology and Chronic Health Evaluation (APACHE) II system³ are cumbersome and require waiting up to 48 hours after the onset of acute pancreatitis to obtain a complete score. The Imrie-Glasgow score is another predictor.

The systemic inflammatory response syndrome (SIRS) is currently the most important indicator of prognosis.⁴ Originally adopted for predicting the development of organ failure with sepsis, it requires at least two of the following criteria:

• Heart rate > 90 beats/min
• Core temperature < 36°C or > 38°C
• White blood cells < 4,000 or > 12,000/mm³
• Respirations > 20/min.

The advantages of this system are that it identifies risk very early in the course of the disease and can be assessed quickly in the emergency department.

The Bedside Index for Severity of Acute Pancreatitis (BISAP) score is another simple, easy-to-perform prognostic index,^5,6 calculated by assigning 1 point for each of the following if present within the first 24 hours of presentation:

• Blood urea nitrogen > 25 mg/dL
• Abnormal mental status (Glasgow coma score < 15)
• Evidence of systemic inflammatory response syndrome
• Age > 60 years
• Pleural effusion seen on imaging study.

A score of 3 points is associated with a 5.3% rate of hospital death, 4 points with 12.7%, and 5 points with 22.5%.

At its most basic, severe acute pancreatitis is defined by organ failure (at least one organ from the respiratory, renal, or cardiovascular system) lasting for more than 48 hours. Failure for each organ is defined by the Marshall scoring system.¹

EARLY MANAGEMENT IS KEY TO OUTCOME

The window of opportunity to make a significant difference in outcome is within the first 12 to 24 hours of presentation. Volume resuscitation is the cornerstone of early management. By the time of presentation for severe acute pancreatitis, the pancreas is already necrotic, so the aim is to minimize the systemic inflammatory response syndrome with the goals of reducing rates of organ failure, morbidity, and death. Necrotizing pancreatitis is essentially an ischemic event, and the goal of volume resuscitation is to maintain pancreatic and intestinal microcirculation to prevent intestinal ischemia and subsequent bacterial translocation.⁷

Early resuscitation with lactated Ringer’s solution recommended

The evidence supporting a specific protocol for fluid resuscitation in severe acute pancreatitis is not strong, but a few studies provide guidance.

Wu et al⁸ randomized 40 patients with acute pancreatitis to one of four arms: “goal-directed fluid resuscitation” with either lactated Ringer’s solution or normal saline, or standard therapy (by physician discretion) with either lactated Ringer’s solution or normal saline. Goal-directed therapy involved a bolus of 20 mL/kg given over 30 to 45 minutes at presentation followed by infusion with rates dependent on an algorithm based on change in blood urea nitrogen level at set times. Patients receiving either goal-directed or standard therapy had significantly lower rates of systemic inflammatory response syndrome at 24 hours than at admission. Most striking was that treatment with lactated Ringer’s solution was associated with dramatically improved rates, whereas normal saline showed no improvement.

In a retrospective study of patients with acute pancreatitis, Warndorf et al⁹ identified 340 patients who received early resuscitation (more than one-third of the total 72-hour fluid volume within 24 hours of presentation) and 90 patients who received late resuscitation (less than one-third of the total 72-hour fluid volume within 24 hours of presentation). Patients who received early resuscitation developed less systemic inflammatory response syndrome and organ failure, and required fewer interventions.

Monitoring for optimum fluid resuscitation

Fluid resuscitation should be carefully managed to avoid administering either inadequate or excessive amounts of fluid. Inadequate fluid resuscitation can result in renal failure, progression of necrosis, and possibly infectious complications. Excessive resuscitation—defined as more than 4 L in the first 24 hours—is associated with respiratory failure, pancreatic fluid collections, and abdominal compartment syndrome.

Optimum resuscitation is controlled fluid expansion averaging 5 to 10 mL/kg per hour, with 2,500 to 4,000 mL given in the first 24 hours.

Adequate volume resuscitation can be evaluated clinically with the following goals:

• Heart rate < 120 beats per minute
• Mean arterial pressure 65–85 mm Hg
• Urinary output > 1 mL/kg per hour
• Hematocrit 35%–44%.

EARLY CT IS JUSTIFIED ONLY IF DIAGNOSIS IS UNCLEAR

The normal pancreas takes up contrast in the same way as do the liver and spleen, so its enhancement on CT is similar. If there is interstitial pancreatitis, CT shows the pancreas with normal contrast uptake, but the organ appears “boggy” with indistinct outlines. With necrotizing pancreatitis, only small areas of tissue with normal contrast may be apparent.

Peripancreatic fat necrosis may also be visible on CT. Obese patients tend to have a worse clinical course of necrotizing pancreatitis, probably because of the associated peripancreatic fat that is incorporated into the pancreatic necrosis.

For clear-cut cases of acute pancreatitis, time is wasted waiting to obtain CT images, and this could delay fluid resuscitation. Results from immediate CT almost never change the clinical management during the first week of acute pancreatitis, and obtaining CT images is usually not recommended if the diagnosis of acute pancreatitis is clear. CT’s sensitivity for detecting necrosis is only 70% in the first 48 hours of presentation, so it is easy to be fooled by a false-negative scan: frequently, a scan does not show necrotizing pancreatitis until after 72 hours. In addition, evidence from animal studies indicates that contrast agents might worsen pancreatic necrosis.

Immediate CT is justified if the diagnosis is in doubt at presentation, such as to evaluate for other intra-abdominal conditions such as intestinal ischemia or a perforated duodenal ulcer.

Contrast-enhanced CT is recommended 72 to 96 hours after presentation, or earlier if the patient is worsening despite treatment. Specific CT protocols will be included in new management guidelines, expected to be published soon.

PREVENTING INFECTIOUS COMPLICATIONS

Risk of infection is associated with the degree of pancreatic necrosis. Patients with less than 30% necrosis have a 22.5% chance of infection, whereas those with more than 50% necrosis have a 46.5% risk of infection.¹⁰

Infection can develop from a variety of sources:

Bacterial translocation from the colon and small bowel is thought to be one of the major sources of infection in necrotic pancreatitis. Volume resuscitation and maintaining gut integrity with early enteral nutrition are believed to minimize the risk of bacterial translocation.

Hematogenous spread of bacteria is another suspected source of infection into the pancreas. Again, enteral nutrition also reduces the risk by minimizing the need for central catheters.

Biliary sources may also play a role. Bile duct stones or gall bladder infection can lead to infected pancreatic necrosis.

ANTIBIOTICS NOT ROUTINELY RECOMMENDED

Treating acute pancreatitis with antibiotics has fallen in and out of favor over the past decades. From being standard practice in the 1970s, it dropped off in the 1980s and 1990s and then became more common again.

Current recommendations from the American Pancreatic Association and the International Association of Pancreatology are not to routinely use intravenous antibiotics to prevent infection in necrotizing pancreatitis because of lack of evidence that it changes overall outcome. Antibiotic usage may be associated with more bacterial resistance and the introduction of fungal infections into the pancreas.

Selective gut decontamination, involving oral and rectal administration of neomycin and other antibiotics, was shown in a single randomized trial to reduce the incidence of infection, but it is very cumbersome and is not recommended for acute pancreatitis.

Treatment with probiotics is also not recommended and was shown in one study to lead to a worse outcome.¹¹

ENTERAL BETTER THAN TOTAL PARENTERAL NUTRITION

Enteral tube feeding with either an elemental diet or a polymeric enteral formulation is the first-line therapy for necrotizing pancreatitis. Compared with total parenteral nutrition, it reduces infection, organ failure, hospital length of stay, the need for surgical intervention, and the risk of death. Total parenteral nutrition should be considered only for patients who do not tolerate enteral feeding because of severe ileus.

Conventional thinking for many years was to provide enteral feeding with a tube passed beyond the ligament of Treitz, thinking that it reduced stimulation to the pancreas. However, recent studies indicate that nasogastric feeding is equivalent to nasojejunal feeding in terms of nutrition, maintaining gut integrity, and outcome.

INTRA-ABDOMINAL HYPERTENSION AND ABDOMINAL COMPARTMENT SYNDROME

Movement of fluid into the intracellular space (“third-spacing”) occurs in acute pancreatitis and is exacerbated by fluid resuscitation. Intra-abdominal hypertension is associated with poor outcomes in patients with severe acute pancreatitis. Especially for patients with severe pancreatitis who are on mechanical ventilation, pressure should be monitored with transvesicular bladder measurements.

Intra-abdominal hypertension is defined as a sustained intra-abdominal pressure of more than 12 mm Hg, with the following grades:

• Grade 1: 12–15 mm Hg
• Grade 2: 16–20 mm Hg
• Grade 3: 21–25 mm Hg
• Grade 4: > 25 mm Hg.

Abdominal compartment syndrome is defined as a sustained intra-abdominal pressure of more than 20 mm Hg. It is associated with new organ dysfunction or failure. It should first be managed with ultrafiltration or diuretics to try to reduce the amount of fluid in the abdomen. Lumenal decompression can be tried with nasogastric or rectal tubes for the stomach and bowels. Ascites or retroperitoneal fluid can be drained percutaneously. In addition, analgesia and sedation to reduce abdominal muscle tone can help the patient become better ventilated. Neuromuscular blockade can also relax the abdomen.

Open abdominal decompression is the treatment of last resort to relieve abdominal compartment syndrome. The abdominal wall is not closed surgically but is allowed to heal by secondary intention (it “granulates in”).¹²

IDENTIFYING INFECTION

Fine-needle aspiration if clinical and imaging signs are not clear

Untreated infected pancreatitis is associated with a much higher risk of death than sterile pancreatic necrosis. Unfortunately, it can be difficult to determine if a patient with necrotizing pancreatitis has an infection because fever, tachycardia, and leukocytosis are usually present regardless. It is important to determine because mechanically intervening for sterile necrosis does not improve outcome.

Fine-needle aspiration, either guided by CT or done at the bedside with ultrasonography, with evaluation with Gram stain and culture, was widely used in the 1990s in cases of necrotizing pancreatitis to determine if infection was present. There has been a shift away from this because, although it can confirm the presence of infection, the false-negative rate is 15%. Clinical and imaging signs can be relied on in most cases to determine the presence of infection, and it is now recognized that fineneedle aspiration should be used only for select cases. Clinical studies have not shown that fine-needle aspiration improves outcomes.

Clinical scenarios typical of infected pancreatic necrosis include patients who have obvious signs of infection with no identifiable source, such as those who stabilize after acute severe acute pancreatitis, and then 10 to 14 days later become worse, with a dramatically higher white blood cell count and tachycardia. Such a patient likely needs an intervention regardless of the results of fine-needle aspiration.

On the other hand, a patient with a continually up-and-down course that never stabilizes over 3 weeks, with no identifiable source of infection, and with no peripancreatic gas apparent on imaging would be a good candidate for fine-needle aspiration.

If peripancreatic gas is seen on imaging, fine-needle aspiration is unnecessary. Peripancreatic gas is traditionally attributed to gasforming bacteria within the pancreas, but in my experience, it is usually from a fistula from the necrosis to the duodenum or the colon, the fistula being caused as the necrosis erodes at the hepatic flexure, the transverse colon, or the splenic flexure.

MECHANICAL INTERVENTIONS FOR INFECTIVE NECROSIS

Late, minimally invasive procedures preferred

Conventional management has shifted away from removing the necrosis with early surgical debridement of the pancreas. Experience with myocardial infarction shows that it is not necessary to remove a sterile necrotic organ, and studies with sterile pancreatic necrosis have found that surgical intervention is associated with a higher risk of death than medical management.

Documented infection has traditionally been considered a definite indication for debridement, but even that is being called into question as more studies are emerging of infected necrosis treated successfully with antibiotics alone.

Sterile necrosis with a fulminant course is a controversial indication for surgery. It was traditionally felt that surgery was worth trying for such patients, but this is no longer common practice.

For cases in which debridement was deemed advisable, surgery was done more frequently in the past. Now, a minimally invasive approach such as with endoscopy or percutaneous catheter is also used. Waiting until at least 4 weeks after the onset of acute pancreatitis is associated with a better outcome than intervening early.

WALLED-OFF NECROSIS

Watchful waiting or minimally invasive intervention

Patients who survive multiorgan failure but are still ill more than 4 weeks after the onset of pancreatitis should be suspected of having walled-off necrosis, formerly referred to as a pancreatic phlegmon. This term was abandoned after the 1992 Atlanta symposium.¹³ In the mid to late 1990s, the process was referred to as organized pancreatic necrosis. It is characterized by a mature, encapsulated collection of pancreatic or peripancreatic necrosis that contains variable amounts of amylase-rich fluid from pancreatic duct disruption.

Walled-off pancreatic necrosis (WOPN) is often confused with pancreatic pseudocyst; these may appear similar on CT, and higherdensity solid debris may be visible in walled-off necrosis within an otherwise homogenous-appearing collection. Magnetic resonance imaging defines liquid and solid much better than CT.

The best way to distinguish WOPN from pseudocyst is by clinical history: a patient with a preceding history of clinically severe acute pancreatitis almost always has necrotizing pancreatitis that evolves to walled-off necrosis, usually over 3 to 4 weeks.

Endoscopic removal and other minimally invasive approaches, such as aggressive percutaneous interventions, have replaced open necrosectomy for treatment, which was associated with high morbidity and mortality rates.^14–16

Intervening for sterile walled-off necrosis is still a controversial topic: although systemically ill, the patient is no longer having life-threatening consequences, and watchful waiting might be just as expedient as intervention. Evidence to support either view is lacking. Most experts believe that intervention should be done if the patient has gastric outlet obstruction and intractable pain and is unable to eat 4 to 6 weeks after the onset of pancreatitis with WOPN. Infected WOPN is considered an indication for drainage.

Severe acute pancreatitis has been known since the time of Rembrandt, with Nicolaes Tulp—the physician credited as first describing it—immortalized in the famous painting, The Anatomy Lesson. However, progress in managing this disease has been disappointing. Treatment is mainly supportive, and we lack any true disease-modifying therapy. But we are learning to recognize the disease and treat it supportively better than in the past.

The early hours of severe acute pancreatitis are critical for instituting appropriate intervention. Prompt fluid resuscitation is key to preventing immediate and later morbidity and death. This article focuses on identifying and managing the most severe form of acute pancreatitis—necrotizing disease—and its complications.

NECROTIZING DISEASE ACCOUNTS FOR MOST PANCREATITIS DEATHS

The classification and definitions of acute pancreatitis were recently revised from the 1992 Atlanta system and published early in 2013.¹ In addition, the American Pancreatic Association and the International Association of Pancreatology met in 2012 to develop evidence-based guidelines on managing severe pancreatitis.

An estimated 210,000 new cases of acute pancreatitis occur each year in the United States. About 20% of cases of severe acute pancreatitis are necrotizing disease, which accounts for nearly all the morbidity and death associated with acute pancreatitis.

The clinical spectrum of acute pancreatitis ranges from mild to life-threatening, reflecting interstitial (death rate < 1%) to necrotizing histology (the latter associated with a 25% risk of death if the pancreatitis becomes infected and a 10% risk if it is sterile). When death occurs early in the disease course, it tends to be from multiorgan failure; when death occurs later in the course, it tends to be from infection. Appropriate early treatment may prevent death in both categories.

DIAGNOSING ACUTE PANCREATITIS AND PREDICTING ITS SEVERITY

The diagnosis of acute pancreatitis requires two of the following three criteria:

• Clinical presentation—epigastric pain, nausea, vomiting
• Biochemical—amylase level more than three times the upper limit of normal, or lipase more than three times the upper limit of normal
• Evidence from computed tomography (CT), ultrasonography, or magnetic resonance imaging.

Although the biochemical criteria are variably sensitive for detecting acute pancreatitis (55%–100%), the specificity is very high (93% to 99%).

Recently, urinary trypsinogen-2, measured by dipstick, has also been used to aid diagnosis. It has a reasonable sensitivity (53%–96%) and specificity (85%) if positive (> 50 ng/mL).

Speed is critical

Over the years, many clinical prediction rules have been used for predicting the severity of acute pancreatitis. The Ranson criteria,² from 1974, and the Acute Physiology and Chronic Health Evaluation (APACHE) II system³ are cumbersome and require waiting up to 48 hours after the onset of acute pancreatitis to obtain a complete score. The Imrie-Glasgow score is another predictor.

The systemic inflammatory response syndrome (SIRS) is currently the most important indicator of prognosis.⁴ Originally adopted for predicting the development of organ failure with sepsis, it requires at least two of the following criteria:

• Heart rate > 90 beats/min
• Core temperature < 36°C or > 38°C
• White blood cells < 4,000 or > 12,000/mm³
• Respirations > 20/min.

The advantages of this system are that it identifies risk very early in the course of the disease and can be assessed quickly in the emergency department.

The Bedside Index for Severity of Acute Pancreatitis (BISAP) score is another simple, easy-to-perform prognostic index,^5,6 calculated by assigning 1 point for each of the following if present within the first 24 hours of presentation:

• Blood urea nitrogen > 25 mg/dL
• Abnormal mental status (Glasgow coma score < 15)
• Evidence of systemic inflammatory response syndrome
• Age > 60 years
• Pleural effusion seen on imaging study.

A score of 3 points is associated with a 5.3% rate of hospital death, 4 points with 12.7%, and 5 points with 22.5%.

At its most basic, severe acute pancreatitis is defined by organ failure (at least one organ from the respiratory, renal, or cardiovascular system) lasting for more than 48 hours. Failure for each organ is defined by the Marshall scoring system.¹

EARLY MANAGEMENT IS KEY TO OUTCOME

The window of opportunity to make a significant difference in outcome is within the first 12 to 24 hours of presentation. Volume resuscitation is the cornerstone of early management. By the time of presentation for severe acute pancreatitis, the pancreas is already necrotic, so the aim is to minimize the systemic inflammatory response syndrome with the goals of reducing rates of organ failure, morbidity, and death. Necrotizing pancreatitis is essentially an ischemic event, and the goal of volume resuscitation is to maintain pancreatic and intestinal microcirculation to prevent intestinal ischemia and subsequent bacterial translocation.⁷

Early resuscitation with lactated Ringer’s solution recommended

The evidence supporting a specific protocol for fluid resuscitation in severe acute pancreatitis is not strong, but a few studies provide guidance.

Wu et al⁸ randomized 40 patients with acute pancreatitis to one of four arms: “goal-directed fluid resuscitation” with either lactated Ringer’s solution or normal saline, or standard therapy (by physician discretion) with either lactated Ringer’s solution or normal saline. Goal-directed therapy involved a bolus of 20 mL/kg given over 30 to 45 minutes at presentation followed by infusion with rates dependent on an algorithm based on change in blood urea nitrogen level at set times. Patients receiving either goal-directed or standard therapy had significantly lower rates of systemic inflammatory response syndrome at 24 hours than at admission. Most striking was that treatment with lactated Ringer’s solution was associated with dramatically improved rates, whereas normal saline showed no improvement.

In a retrospective study of patients with acute pancreatitis, Warndorf et al⁹ identified 340 patients who received early resuscitation (more than one-third of the total 72-hour fluid volume within 24 hours of presentation) and 90 patients who received late resuscitation (less than one-third of the total 72-hour fluid volume within 24 hours of presentation). Patients who received early resuscitation developed less systemic inflammatory response syndrome and organ failure, and required fewer interventions.

Monitoring for optimum fluid resuscitation

Fluid resuscitation should be carefully managed to avoid administering either inadequate or excessive amounts of fluid. Inadequate fluid resuscitation can result in renal failure, progression of necrosis, and possibly infectious complications. Excessive resuscitation—defined as more than 4 L in the first 24 hours—is associated with respiratory failure, pancreatic fluid collections, and abdominal compartment syndrome.

Optimum resuscitation is controlled fluid expansion averaging 5 to 10 mL/kg per hour, with 2,500 to 4,000 mL given in the first 24 hours.

Adequate volume resuscitation can be evaluated clinically with the following goals:

• Heart rate < 120 beats per minute
• Mean arterial pressure 65–85 mm Hg
• Urinary output > 1 mL/kg per hour
• Hematocrit 35%–44%.

EARLY CT IS JUSTIFIED ONLY IF DIAGNOSIS IS UNCLEAR

The normal pancreas takes up contrast in the same way as do the liver and spleen, so its enhancement on CT is similar. If there is interstitial pancreatitis, CT shows the pancreas with normal contrast uptake, but the organ appears “boggy” with indistinct outlines. With necrotizing pancreatitis, only small areas of tissue with normal contrast may be apparent.

Peripancreatic fat necrosis may also be visible on CT. Obese patients tend to have a worse clinical course of necrotizing pancreatitis, probably because of the associated peripancreatic fat that is incorporated into the pancreatic necrosis.

For clear-cut cases of acute pancreatitis, time is wasted waiting to obtain CT images, and this could delay fluid resuscitation. Results from immediate CT almost never change the clinical management during the first week of acute pancreatitis, and obtaining CT images is usually not recommended if the diagnosis of acute pancreatitis is clear. CT’s sensitivity for detecting necrosis is only 70% in the first 48 hours of presentation, so it is easy to be fooled by a false-negative scan: frequently, a scan does not show necrotizing pancreatitis until after 72 hours. In addition, evidence from animal studies indicates that contrast agents might worsen pancreatic necrosis.

Immediate CT is justified if the diagnosis is in doubt at presentation, such as to evaluate for other intra-abdominal conditions such as intestinal ischemia or a perforated duodenal ulcer.

Contrast-enhanced CT is recommended 72 to 96 hours after presentation, or earlier if the patient is worsening despite treatment. Specific CT protocols will be included in new management guidelines, expected to be published soon.

PREVENTING INFECTIOUS COMPLICATIONS

Risk of infection is associated with the degree of pancreatic necrosis. Patients with less than 30% necrosis have a 22.5% chance of infection, whereas those with more than 50% necrosis have a 46.5% risk of infection.¹⁰

Infection can develop from a variety of sources:

Bacterial translocation from the colon and small bowel is thought to be one of the major sources of infection in necrotic pancreatitis. Volume resuscitation and maintaining gut integrity with early enteral nutrition are believed to minimize the risk of bacterial translocation.

Hematogenous spread of bacteria is another suspected source of infection into the pancreas. Again, enteral nutrition also reduces the risk by minimizing the need for central catheters.

Biliary sources may also play a role. Bile duct stones or gall bladder infection can lead to infected pancreatic necrosis.

ANTIBIOTICS NOT ROUTINELY RECOMMENDED

Treating acute pancreatitis with antibiotics has fallen in and out of favor over the past decades. From being standard practice in the 1970s, it dropped off in the 1980s and 1990s and then became more common again.

Current recommendations from the American Pancreatic Association and the International Association of Pancreatology are not to routinely use intravenous antibiotics to prevent infection in necrotizing pancreatitis because of lack of evidence that it changes overall outcome. Antibiotic usage may be associated with more bacterial resistance and the introduction of fungal infections into the pancreas.

Selective gut decontamination, involving oral and rectal administration of neomycin and other antibiotics, was shown in a single randomized trial to reduce the incidence of infection, but it is very cumbersome and is not recommended for acute pancreatitis.

Treatment with probiotics is also not recommended and was shown in one study to lead to a worse outcome.¹¹

ENTERAL BETTER THAN TOTAL PARENTERAL NUTRITION

Enteral tube feeding with either an elemental diet or a polymeric enteral formulation is the first-line therapy for necrotizing pancreatitis. Compared with total parenteral nutrition, it reduces infection, organ failure, hospital length of stay, the need for surgical intervention, and the risk of death. Total parenteral nutrition should be considered only for patients who do not tolerate enteral feeding because of severe ileus.

Conventional thinking for many years was to provide enteral feeding with a tube passed beyond the ligament of Treitz, thinking that it reduced stimulation to the pancreas. However, recent studies indicate that nasogastric feeding is equivalent to nasojejunal feeding in terms of nutrition, maintaining gut integrity, and outcome.

INTRA-ABDOMINAL HYPERTENSION AND ABDOMINAL COMPARTMENT SYNDROME

Movement of fluid into the intracellular space (“third-spacing”) occurs in acute pancreatitis and is exacerbated by fluid resuscitation. Intra-abdominal hypertension is associated with poor outcomes in patients with severe acute pancreatitis. Especially for patients with severe pancreatitis who are on mechanical ventilation, pressure should be monitored with transvesicular bladder measurements.

Intra-abdominal hypertension is defined as a sustained intra-abdominal pressure of more than 12 mm Hg, with the following grades:

• Grade 1: 12–15 mm Hg
• Grade 2: 16–20 mm Hg
• Grade 3: 21–25 mm Hg
• Grade 4: > 25 mm Hg.

Abdominal compartment syndrome is defined as a sustained intra-abdominal pressure of more than 20 mm Hg. It is associated with new organ dysfunction or failure. It should first be managed with ultrafiltration or diuretics to try to reduce the amount of fluid in the abdomen. Lumenal decompression can be tried with nasogastric or rectal tubes for the stomach and bowels. Ascites or retroperitoneal fluid can be drained percutaneously. In addition, analgesia and sedation to reduce abdominal muscle tone can help the patient become better ventilated. Neuromuscular blockade can also relax the abdomen.

Open abdominal decompression is the treatment of last resort to relieve abdominal compartment syndrome. The abdominal wall is not closed surgically but is allowed to heal by secondary intention (it “granulates in”).¹²

IDENTIFYING INFECTION

Fine-needle aspiration if clinical and imaging signs are not clear

Untreated infected pancreatitis is associated with a much higher risk of death than sterile pancreatic necrosis. Unfortunately, it can be difficult to determine if a patient with necrotizing pancreatitis has an infection because fever, tachycardia, and leukocytosis are usually present regardless. It is important to determine because mechanically intervening for sterile necrosis does not improve outcome.

Fine-needle aspiration, either guided by CT or done at the bedside with ultrasonography, with evaluation with Gram stain and culture, was widely used in the 1990s in cases of necrotizing pancreatitis to determine if infection was present. There has been a shift away from this because, although it can confirm the presence of infection, the false-negative rate is 15%. Clinical and imaging signs can be relied on in most cases to determine the presence of infection, and it is now recognized that fineneedle aspiration should be used only for select cases. Clinical studies have not shown that fine-needle aspiration improves outcomes.

Clinical scenarios typical of infected pancreatic necrosis include patients who have obvious signs of infection with no identifiable source, such as those who stabilize after acute severe acute pancreatitis, and then 10 to 14 days later become worse, with a dramatically higher white blood cell count and tachycardia. Such a patient likely needs an intervention regardless of the results of fine-needle aspiration.

On the other hand, a patient with a continually up-and-down course that never stabilizes over 3 weeks, with no identifiable source of infection, and with no peripancreatic gas apparent on imaging would be a good candidate for fine-needle aspiration.

If peripancreatic gas is seen on imaging, fine-needle aspiration is unnecessary. Peripancreatic gas is traditionally attributed to gasforming bacteria within the pancreas, but in my experience, it is usually from a fistula from the necrosis to the duodenum or the colon, the fistula being caused as the necrosis erodes at the hepatic flexure, the transverse colon, or the splenic flexure.

MECHANICAL INTERVENTIONS FOR INFECTIVE NECROSIS

Late, minimally invasive procedures preferred

Conventional management has shifted away from removing the necrosis with early surgical debridement of the pancreas. Experience with myocardial infarction shows that it is not necessary to remove a sterile necrotic organ, and studies with sterile pancreatic necrosis have found that surgical intervention is associated with a higher risk of death than medical management.

Documented infection has traditionally been considered a definite indication for debridement, but even that is being called into question as more studies are emerging of infected necrosis treated successfully with antibiotics alone.

Sterile necrosis with a fulminant course is a controversial indication for surgery. It was traditionally felt that surgery was worth trying for such patients, but this is no longer common practice.

For cases in which debridement was deemed advisable, surgery was done more frequently in the past. Now, a minimally invasive approach such as with endoscopy or percutaneous catheter is also used. Waiting until at least 4 weeks after the onset of acute pancreatitis is associated with a better outcome than intervening early.

WALLED-OFF NECROSIS

Watchful waiting or minimally invasive intervention

Patients who survive multiorgan failure but are still ill more than 4 weeks after the onset of pancreatitis should be suspected of having walled-off necrosis, formerly referred to as a pancreatic phlegmon. This term was abandoned after the 1992 Atlanta symposium.¹³ In the mid to late 1990s, the process was referred to as organized pancreatic necrosis. It is characterized by a mature, encapsulated collection of pancreatic or peripancreatic necrosis that contains variable amounts of amylase-rich fluid from pancreatic duct disruption.

Walled-off pancreatic necrosis (WOPN) is often confused with pancreatic pseudocyst; these may appear similar on CT, and higherdensity solid debris may be visible in walled-off necrosis within an otherwise homogenous-appearing collection. Magnetic resonance imaging defines liquid and solid much better than CT.

The best way to distinguish WOPN from pseudocyst is by clinical history: a patient with a preceding history of clinically severe acute pancreatitis almost always has necrotizing pancreatitis that evolves to walled-off necrosis, usually over 3 to 4 weeks.

Endoscopic removal and other minimally invasive approaches, such as aggressive percutaneous interventions, have replaced open necrosectomy for treatment, which was associated with high morbidity and mortality rates.^14–16

Intervening for sterile walled-off necrosis is still a controversial topic: although systemically ill, the patient is no longer having life-threatening consequences, and watchful waiting might be just as expedient as intervention. Evidence to support either view is lacking. Most experts believe that intervention should be done if the patient has gastric outlet obstruction and intractable pain and is unable to eat 4 to 6 weeks after the onset of pancreatitis with WOPN. Infected WOPN is considered an indication for drainage.