A 26‐year‐old woman was brought to the emergency department following several episodes of seizures. The patient's friend witnessed several 15‐minute episodes of sudden jerks and tremors of her right arm during which the patient bit her tongue, had word‐finding difficulty, had horizontal eye deviation, and was incontinent of urine. She became unresponsive during the episodes, with incomplete recovery of consciousness between attacks. She was afebrile. Her neurologic exam 4 hours after several seizures revealed word‐finding difficulty and right arm weakness. A complete blood count, chemistry panel including renal and liver function tests, urine toxicology screen, and computed tomography (CT) of the head were normal. After a loading dose of fosphenytoin, the patient did not experience further seizures and was discharged on a maintenance dose of phenytoin.

Over the next week, the patient continued to note a sensation of heaviness in her right arm and felt fatigued. The patient's mother brought her back to the emergency department after witnessing a similar seizure episode that persisted for an hour. On arrival, the patient was no longer seizing.

Although it can sometimes be difficult to differentiate between seizure, stroke, syncope, and other causes of transient loss of consciousness, this constellation of symptoms strongly points to a seizure. I would classify the patient's focal arm movements associated with impaired consciousness as partial complex seizures. One of the first considerations is determining whether the seizure is caused by a systemic process or by an intrinsic central nervous system disorder. Common systemic illnesses include infections, metabolic disturbances, toxins, and malignancies, none of which are evident on the preliminary evaluation. The absence of fever is important as is the time frame (now extending over 1 week) in excluding acute bacterial meningitis. A negative urine toxicology is very helpful but does not exclude the possibility that the seizure is from unmeasured drug intoxication, for example, tricyclic antidepressants, or from drug withdrawal, for example, benzodiazepines, barbiturates, ethanol, and antiepileptic drugs. The persistent right arm heaviness and right arm jerking during the seizures suggest a left cortical focus that the CT scan did not detect. Without a clear diagnosis and with recurrent seizures despite antiepileptic drugs, hospitalization is warranted.

The patient experienced migraine headaches each month during menses. There was no family history of seizures. Her only medication was phenytoin. The mother was unaware of any use of tobacco, alcohol, or recreational drugs. The patient was raised in New Jersey and moved to the San Francisco Bay area 9 months ago. She had no pets and had traveled to Florida and Montreal in the past 6 months. She was a graduate student in performing arts. During the preceding 2 weeks she had been under significant stress and had not slept much in preparation for an upcoming production. The patient's mother was not aware of any head trauma, recent illness, fevers, chills, weight loss, photosensitivity, arthralgias, nausea, vomiting, or diarrhea.

Recent sleep deprivation could provoke seizures in a patient with a latent anatomic focus or metabolic predisposition. Nonadherence to antiepileptic drug therapy is the most common reason for patients to present to the ED with seizures; therefore, I would check a phenytoin level to assess whether she is at a therapeutic level and would consider administering another loading dose. In the absence of immunocompromise or unusual activities or exposures, North American travel does not bring to mind additional etiologies at this time.

On exam, temperature was 37.3C, blood pressure was 148/84 mm Hg, heart rate was 120 per minute, and respiratory rate was 16 per minute. The patient was stuporous and withdrew from painful stimuli. She was unable to speak. Pupils were 4 mm in diameter and reacted to light. No gaze preference or nystagmus was present. There was no meningismus. Deep tendon reflexes were 1+ and symmetrical in both upper and lower extremities. Plantar reflexes were extensor bilaterally. The tone in the right upper extremity was mildly increased compared to the left. The patient demonstrated semipurposeful movement of the limbs, such as reaching for the bed rails with her arms. Examination of the heart, lungs, abdomen, skin, and oropharynx was normal.

The white blood cell count was 22,300/mm³ with 50% neutrophils, 40% lymphocytes, 7% monocytes, and 3% eosinophils. Results of the chemistry panel including electrolytes, glucose, creatinine, and liver enzymes, urinalysis, and thyroid‐stimulating hormone were normal. Serum phenytoin level was 8.1 g/mL. Urine toxicology screen, obtained after the patient had received lorazepam, was positive only for benzodiazepines. A chest radiograph was normal.

The cerebrospinal fluid (CSF) was colorless, containing 35 white blood cells/mm³ (48% lymphocytes, 30% neutrophils, 22% monocytes), 3 red blood cells/mm³, 62 mg/dL protein, and 50 mg/dL glucose. There was no xanthochromia. The CSF was negative for cryptococcal antigen, antibodies to West Nile virus, PCR for herpes simplex viruses‐1 and ‐2, and PCR for Borrelia burgdorferi. CSF bacterial culture, cryptococcal antigen, and AFB stain were negative. The serum antinuclear antibody, rheumatoid factor, and rapid plasma reagin were negative. Serum antibodies to human immunodeficiency virus, hepatitis B and C viruses, Borrelia burgdorferi, and herpes simplex viruses were negative. The erythrocyte sedimentation rate was 25 mm/hr. There was no growth in her blood cultures.

These CSF findings have to be interpreted in light of her clinical picture, as they are congruent with both an aseptic meningitis and encephalitis. In practice, these can be hard to distinguish, but the early and dominant cortical findings (focal neurologic deficits, prominent altered mental status, bilateral extensor plantar reflexes) and absence of meningeal signs favor encephalitis. This CSF profile can be seen in a variety of disease processes causing a meningoencephalitis, including partially treated bacterial meningitis; meningitis due to viruses, fungi, mycobacteria, or atypical bacteria (eg, Listeria); neurosarcoidosis; carcinomatous meningitis; and infection or inflammation from a parameningeal focus in the sinuses, epidural space, or brain parenchyma. Seizure itself can lead to a postictal pleocytosis in the CSF, although this degree of inflammation would be unusual. Many tests can be sent, and the clinicians appropriately focused on some of the most treatable and serious etiologies first. The negative HIV test limits the list of opportunistic pathogens. The negative ANA substantially lowers the likelihood of systemic lupus, an important consideration in a young woman with an inflammatory disorder involving the central nervous system.

Magnetic resonance imaging (MRI) of the brain showed cortical T2 prolongation with significant enhancement with gadolinium in the cortex and leptomeninges of the left parietal and posterotemporal lobes and right cingulate gyrus region (Fig. 1). The patient was admitted to the intensive care unit, and phenytoin and levetiracetam were administered. Over the next several days, she remained afebrile, and her leukocytosis resolved. She continued to have seizures every day despite receiving phenytoin, levetiracetam, and lamotrigine. She was alert and complained about persistent right arm weakness and word‐finding difficulties. Posterior cervical lymphadenopathy at the base of her left occiput was detected on subsequent exam.

Figure 1

An excisional lymph node biopsy demonstrated extensive necrosis without evidence of granulomata, malignancy, or lymphoproliferative disease. Stains and cultures for bacteria, fungi, and mycobacteria were negative. The patient's electroencephalogram captured epileptiform activity over the left hemisphere 2 hours after a cluster of seizures. MR angiography and cerebral angiography demonstrated no abnormalities.

Despite this additional information, there is no distinguishing clue that points to a single diagnosis. This is a 26‐year‐old healthy, seemingly immunocompetent woman who has had a 2‐week progressive and refractory seizure disorder secondary to a multifocal neuroinvasive process with a CSF pleocytosis. She does not have evidence of a systemic underlying disorder, save for nonspecific localized lymphadenopathy and a transient episode of leukocytosis on admission, and has no distinguishing epidemiological factors or exposures.

Despite my initial concerns for infectious meningoencephalitis, the negative stains, serologies, and cultures of the blood, CSF, and lymph nodes in the setting of a normal immune system and no suspect exposure substantially lower this probability. Arthropod‐borne viruses are still possible, especially West Nile virus, because the serological tests are less sensitive early in the illness, acknowledging that the absence of fever, weakness, and known mosquito bites detracts from this diagnosis. Pathogens that cause regional lymphadenopathy and encephalitis such as Bartonella remain possibilities, as the history of exposure to a kitten can be easily overlooked.

Rheumatologic disorders merit close attention in a young woman, but the negative ANA makes lupus cerebritis unlikely, and the 2 angiograms did not detect evidence of vasculitis. Finally, there is the question of malignancy and other miscellaneous infiltrative disorders (such as sarcoid), which are of importance here because of the multifocal cortical involvement on imaging.

At this point, I would resample the CSF for viral etiologies (eg, West Nile virus) and cytology and would send serum Bartonella serologies. If these studies were negative, a brain biopsy, primarily to exclude malignancy but also to uncover an unsuspected process, would be indicated. I cannot make a definitive diagnosis or find a perfect fit here, but in the absence of strong evidence of an infection, I am concerned about a malignancy, perhaps a low‐grade primary brain tumor.

Brain biopsy of the leptomeninges and cortex of the left parietal lobe showed multiple blood vessels infiltrated by lymphocytes, neutrophils, and eosinophils (Fig. 2). The pattern of inflammation was consistent with primary angiitis of the central nervous system (PACNS). The patient received 1 g of intravenous methylprednisolone on 3 consecutive days, followed by oral prednisone and cyclophosphamide. The seizures ceased, and she made steady progress with rehabilitation therapy. Four months after discharge a cerebral angiogram (done to ensure there was no interval evidence of vasculitis prior to tapering therapy) demonstrated patency of all major intracranial arteries and venous sinuses.

Figure 2

COMMENTARY

When a patient presents with symptoms or signs referable to the central nervous system (CNS), hospitalists must simultaneously consider primary neurologic disorders and systemic diseases that involve the CNS. Initial evaluation includes a thorough history and physical examination, basic lab studies, routine CSF analysis, and neuroimaging (often a CT scan of the head). Complicated neurologic cases may warrant more elaborate testing including EEG, brain MRI, cerebral angiography, and specialized blood and CSF studies. Clinicians may still find themselves faced with a patient who has clear CNS dysfunction but no obvious diagnosis despite an exhaustive and expensive evaluation. Several disorders match this profile including intravascular lymphoma, prion diseases, paraneoplastic syndromes, and cerebritis. Primary angiitis of the central nervous system (PACNS), a rare disorder characterized by inflammation of the medium‐sized and small arteries of the CNS, is among these disorders. Although the aforementioned diseases may sometimes have suggestive or even pathognomonic features (eg, the string of beads angiographic appearance in vasculitides), they are challenging to diagnose when such findings are absent.

Like any vasculitis of the CNS, PACNS may present with a wide spectrum of clinical features.12 Although headache and altered mental status are the most common complaints, paresis, seizures, ataxia, visual changes, and aphasia have all been described. The onset of symptoms ranges from acute to chronic, and neurologic deficits can be focal or diffuse. Systemic manifestations such as fever and weight loss are rare. The average age of onset is 42 years, with no significant sex preponderance. The histopathology of PACNS is granulomatous inflammation of arteries in the parenchyma and leptomeninges of the brain and less commonly in the spinal cord. The narrowing of the affected vessels causes cerebral ischemia and the associated neurologic deficits. The trigger for this focal inflammation is unknown.

After common disorders have been excluded in cases of CNS dysfunction, compatible CSF findings and imaging results may prompt consideration of PACNS. CSF analysis in patients with PACNS typically demonstrates a lymphocytic pleocytosis. MRI abnormalities in PACNS include multiple infarcts in the cortex, deep white matter, or leptomeninges.34 Less specific findings are contrast enhancement in the leptomeninges and white matter disease, both of which may direct the site for meningeal and brain biopsy.

Both brain MRA and cerebral angiography have a limited role in the diagnosis of vasculitis within the CNS. In 18 patients with CNS vasculitis due to autoimmune disease, all had parenchymal abnormalities on MRA but only 65% had evidence of vasculitis on angiography. In 2 retrospective studies of patients with suspected PACNS, abnormal angiograms had a specificity less than 30% for PACNS, whereas brain biopsies had a negative predictive value of 70%.57 Although in practice patients with compatible clinical features are sometimes diagnosed with CNS vasculitis on the basis of angiographic findings, brain biopsy is necessary to differentiate vasculitis from other vasculopathies and to establish a definitive diagnosis.

Before a diagnosis of PACNS is made, care must be taken to exclude infections, neoplasms, and autoimmune processes that cause angiitis of the CNS (Table 1). The presence of any extracranial abnormalities (which were not present in this case) should prompt consideration of an underlying systemic disorder causing a secondary CNS vasculitis and should cast doubt on the diagnosis of PACNS. Meningovascular syphilis and tuberculosis are among the long list of infections that may cause inflammation of the CNS vasculature. Autoimmune disorders that may cause vasculitis inside the brain include polyarteritis nodosa and Wegener's granulomatosis. Reversible cerebral vasoconstrictive disease, which is most commonly seen in women ages 20 to 50, and sympathomimetic toxins such as cocaine and amphetamine may exhibit clinical and angiographic abnormalities indistinguishable from PACNS.89

There are no prospective trials investigating PACNS treatment. Aggressive immunosuppression with cyclophosphamide and glucocorticoids is the mainstay of treatment. The duration of treatment varies with the severity of the disease and response to therapy. One study suggests that treatment should be continued for 6 to 12 months.10 Neurologic deficits may remain irreversible because of scarring of the affected vessels. Serial brain MRI examinations are often used to follow radiographic resolution during and after the therapy, although radiographic changes do not predict clinical response.11 New abnormalities on MRI, however, delay any tapering of treatment. The availability of neuroimaging studies and immunosuppressive therapy has improved the prognosis of PACNS. One study reported a favorable outcome with a 29% relapse rate and a 10% mortality rate in 54 patients over a mean follow‐up period of 35 months.12

PACNS remains a challenging diagnosis because of its rarity, the wide range of neurologic manifestations, and the difficulty in establishing a diagnosis noninvasively. It is an extremely uncommon disease but should be considered in patients with unexplained neurologic deficits referable to the CNS alone after an exhaustive workup. Ultimately, the diagnosis is made by a thorough history and physical examination, exclusion of underlying conditions (particularly systemic vasculitides and infections), and histological confirmation.

A 26‐year‐old woman was brought to the emergency department following several episodes of seizures. The patient's friend witnessed several 15‐minute episodes of sudden jerks and tremors of her right arm during which the patient bit her tongue, had word‐finding difficulty, had horizontal eye deviation, and was incontinent of urine. She became unresponsive during the episodes, with incomplete recovery of consciousness between attacks. She was afebrile. Her neurologic exam 4 hours after several seizures revealed word‐finding difficulty and right arm weakness. A complete blood count, chemistry panel including renal and liver function tests, urine toxicology screen, and computed tomography (CT) of the head were normal. After a loading dose of fosphenytoin, the patient did not experience further seizures and was discharged on a maintenance dose of phenytoin.

Over the next week, the patient continued to note a sensation of heaviness in her right arm and felt fatigued. The patient's mother brought her back to the emergency department after witnessing a similar seizure episode that persisted for an hour. On arrival, the patient was no longer seizing.

Although it can sometimes be difficult to differentiate between seizure, stroke, syncope, and other causes of transient loss of consciousness, this constellation of symptoms strongly points to a seizure. I would classify the patient's focal arm movements associated with impaired consciousness as partial complex seizures. One of the first considerations is determining whether the seizure is caused by a systemic process or by an intrinsic central nervous system disorder. Common systemic illnesses include infections, metabolic disturbances, toxins, and malignancies, none of which are evident on the preliminary evaluation. The absence of fever is important as is the time frame (now extending over 1 week) in excluding acute bacterial meningitis. A negative urine toxicology is very helpful but does not exclude the possibility that the seizure is from unmeasured drug intoxication, for example, tricyclic antidepressants, or from drug withdrawal, for example, benzodiazepines, barbiturates, ethanol, and antiepileptic drugs. The persistent right arm heaviness and right arm jerking during the seizures suggest a left cortical focus that the CT scan did not detect. Without a clear diagnosis and with recurrent seizures despite antiepileptic drugs, hospitalization is warranted.

The patient experienced migraine headaches each month during menses. There was no family history of seizures. Her only medication was phenytoin. The mother was unaware of any use of tobacco, alcohol, or recreational drugs. The patient was raised in New Jersey and moved to the San Francisco Bay area 9 months ago. She had no pets and had traveled to Florida and Montreal in the past 6 months. She was a graduate student in performing arts. During the preceding 2 weeks she had been under significant stress and had not slept much in preparation for an upcoming production. The patient's mother was not aware of any head trauma, recent illness, fevers, chills, weight loss, photosensitivity, arthralgias, nausea, vomiting, or diarrhea.

Recent sleep deprivation could provoke seizures in a patient with a latent anatomic focus or metabolic predisposition. Nonadherence to antiepileptic drug therapy is the most common reason for patients to present to the ED with seizures; therefore, I would check a phenytoin level to assess whether she is at a therapeutic level and would consider administering another loading dose. In the absence of immunocompromise or unusual activities or exposures, North American travel does not bring to mind additional etiologies at this time.

On exam, temperature was 37.3C, blood pressure was 148/84 mm Hg, heart rate was 120 per minute, and respiratory rate was 16 per minute. The patient was stuporous and withdrew from painful stimuli. She was unable to speak. Pupils were 4 mm in diameter and reacted to light. No gaze preference or nystagmus was present. There was no meningismus. Deep tendon reflexes were 1+ and symmetrical in both upper and lower extremities. Plantar reflexes were extensor bilaterally. The tone in the right upper extremity was mildly increased compared to the left. The patient demonstrated semipurposeful movement of the limbs, such as reaching for the bed rails with her arms. Examination of the heart, lungs, abdomen, skin, and oropharynx was normal.

The white blood cell count was 22,300/mm³ with 50% neutrophils, 40% lymphocytes, 7% monocytes, and 3% eosinophils. Results of the chemistry panel including electrolytes, glucose, creatinine, and liver enzymes, urinalysis, and thyroid‐stimulating hormone were normal. Serum phenytoin level was 8.1 g/mL. Urine toxicology screen, obtained after the patient had received lorazepam, was positive only for benzodiazepines. A chest radiograph was normal.

The cerebrospinal fluid (CSF) was colorless, containing 35 white blood cells/mm³ (48% lymphocytes, 30% neutrophils, 22% monocytes), 3 red blood cells/mm³, 62 mg/dL protein, and 50 mg/dL glucose. There was no xanthochromia. The CSF was negative for cryptococcal antigen, antibodies to West Nile virus, PCR for herpes simplex viruses‐1 and ‐2, and PCR for Borrelia burgdorferi. CSF bacterial culture, cryptococcal antigen, and AFB stain were negative. The serum antinuclear antibody, rheumatoid factor, and rapid plasma reagin were negative. Serum antibodies to human immunodeficiency virus, hepatitis B and C viruses, Borrelia burgdorferi, and herpes simplex viruses were negative. The erythrocyte sedimentation rate was 25 mm/hr. There was no growth in her blood cultures.

These CSF findings have to be interpreted in light of her clinical picture, as they are congruent with both an aseptic meningitis and encephalitis. In practice, these can be hard to distinguish, but the early and dominant cortical findings (focal neurologic deficits, prominent altered mental status, bilateral extensor plantar reflexes) and absence of meningeal signs favor encephalitis. This CSF profile can be seen in a variety of disease processes causing a meningoencephalitis, including partially treated bacterial meningitis; meningitis due to viruses, fungi, mycobacteria, or atypical bacteria (eg, Listeria); neurosarcoidosis; carcinomatous meningitis; and infection or inflammation from a parameningeal focus in the sinuses, epidural space, or brain parenchyma. Seizure itself can lead to a postictal pleocytosis in the CSF, although this degree of inflammation would be unusual. Many tests can be sent, and the clinicians appropriately focused on some of the most treatable and serious etiologies first. The negative HIV test limits the list of opportunistic pathogens. The negative ANA substantially lowers the likelihood of systemic lupus, an important consideration in a young woman with an inflammatory disorder involving the central nervous system.

Magnetic resonance imaging (MRI) of the brain showed cortical T2 prolongation with significant enhancement with gadolinium in the cortex and leptomeninges of the left parietal and posterotemporal lobes and right cingulate gyrus region (Fig. 1). The patient was admitted to the intensive care unit, and phenytoin and levetiracetam were administered. Over the next several days, she remained afebrile, and her leukocytosis resolved. She continued to have seizures every day despite receiving phenytoin, levetiracetam, and lamotrigine. She was alert and complained about persistent right arm weakness and word‐finding difficulties. Posterior cervical lymphadenopathy at the base of her left occiput was detected on subsequent exam.

Figure 1

An excisional lymph node biopsy demonstrated extensive necrosis without evidence of granulomata, malignancy, or lymphoproliferative disease. Stains and cultures for bacteria, fungi, and mycobacteria were negative. The patient's electroencephalogram captured epileptiform activity over the left hemisphere 2 hours after a cluster of seizures. MR angiography and cerebral angiography demonstrated no abnormalities.

Despite this additional information, there is no distinguishing clue that points to a single diagnosis. This is a 26‐year‐old healthy, seemingly immunocompetent woman who has had a 2‐week progressive and refractory seizure disorder secondary to a multifocal neuroinvasive process with a CSF pleocytosis. She does not have evidence of a systemic underlying disorder, save for nonspecific localized lymphadenopathy and a transient episode of leukocytosis on admission, and has no distinguishing epidemiological factors or exposures.

Despite my initial concerns for infectious meningoencephalitis, the negative stains, serologies, and cultures of the blood, CSF, and lymph nodes in the setting of a normal immune system and no suspect exposure substantially lower this probability. Arthropod‐borne viruses are still possible, especially West Nile virus, because the serological tests are less sensitive early in the illness, acknowledging that the absence of fever, weakness, and known mosquito bites detracts from this diagnosis. Pathogens that cause regional lymphadenopathy and encephalitis such as Bartonella remain possibilities, as the history of exposure to a kitten can be easily overlooked.

Rheumatologic disorders merit close attention in a young woman, but the negative ANA makes lupus cerebritis unlikely, and the 2 angiograms did not detect evidence of vasculitis. Finally, there is the question of malignancy and other miscellaneous infiltrative disorders (such as sarcoid), which are of importance here because of the multifocal cortical involvement on imaging.

At this point, I would resample the CSF for viral etiologies (eg, West Nile virus) and cytology and would send serum Bartonella serologies. If these studies were negative, a brain biopsy, primarily to exclude malignancy but also to uncover an unsuspected process, would be indicated. I cannot make a definitive diagnosis or find a perfect fit here, but in the absence of strong evidence of an infection, I am concerned about a malignancy, perhaps a low‐grade primary brain tumor.

Brain biopsy of the leptomeninges and cortex of the left parietal lobe showed multiple blood vessels infiltrated by lymphocytes, neutrophils, and eosinophils (Fig. 2). The pattern of inflammation was consistent with primary angiitis of the central nervous system (PACNS). The patient received 1 g of intravenous methylprednisolone on 3 consecutive days, followed by oral prednisone and cyclophosphamide. The seizures ceased, and she made steady progress with rehabilitation therapy. Four months after discharge a cerebral angiogram (done to ensure there was no interval evidence of vasculitis prior to tapering therapy) demonstrated patency of all major intracranial arteries and venous sinuses.

Figure 2

COMMENTARY

When a patient presents with symptoms or signs referable to the central nervous system (CNS), hospitalists must simultaneously consider primary neurologic disorders and systemic diseases that involve the CNS. Initial evaluation includes a thorough history and physical examination, basic lab studies, routine CSF analysis, and neuroimaging (often a CT scan of the head). Complicated neurologic cases may warrant more elaborate testing including EEG, brain MRI, cerebral angiography, and specialized blood and CSF studies. Clinicians may still find themselves faced with a patient who has clear CNS dysfunction but no obvious diagnosis despite an exhaustive and expensive evaluation. Several disorders match this profile including intravascular lymphoma, prion diseases, paraneoplastic syndromes, and cerebritis. Primary angiitis of the central nervous system (PACNS), a rare disorder characterized by inflammation of the medium‐sized and small arteries of the CNS, is among these disorders. Although the aforementioned diseases may sometimes have suggestive or even pathognomonic features (eg, the string of beads angiographic appearance in vasculitides), they are challenging to diagnose when such findings are absent.

Like any vasculitis of the CNS, PACNS may present with a wide spectrum of clinical features.12 Although headache and altered mental status are the most common complaints, paresis, seizures, ataxia, visual changes, and aphasia have all been described. The onset of symptoms ranges from acute to chronic, and neurologic deficits can be focal or diffuse. Systemic manifestations such as fever and weight loss are rare. The average age of onset is 42 years, with no significant sex preponderance. The histopathology of PACNS is granulomatous inflammation of arteries in the parenchyma and leptomeninges of the brain and less commonly in the spinal cord. The narrowing of the affected vessels causes cerebral ischemia and the associated neurologic deficits. The trigger for this focal inflammation is unknown.

After common disorders have been excluded in cases of CNS dysfunction, compatible CSF findings and imaging results may prompt consideration of PACNS. CSF analysis in patients with PACNS typically demonstrates a lymphocytic pleocytosis. MRI abnormalities in PACNS include multiple infarcts in the cortex, deep white matter, or leptomeninges.34 Less specific findings are contrast enhancement in the leptomeninges and white matter disease, both of which may direct the site for meningeal and brain biopsy.

Both brain MRA and cerebral angiography have a limited role in the diagnosis of vasculitis within the CNS. In 18 patients with CNS vasculitis due to autoimmune disease, all had parenchymal abnormalities on MRA but only 65% had evidence of vasculitis on angiography. In 2 retrospective studies of patients with suspected PACNS, abnormal angiograms had a specificity less than 30% for PACNS, whereas brain biopsies had a negative predictive value of 70%.57 Although in practice patients with compatible clinical features are sometimes diagnosed with CNS vasculitis on the basis of angiographic findings, brain biopsy is necessary to differentiate vasculitis from other vasculopathies and to establish a definitive diagnosis.

Before a diagnosis of PACNS is made, care must be taken to exclude infections, neoplasms, and autoimmune processes that cause angiitis of the CNS (Table 1). The presence of any extracranial abnormalities (which were not present in this case) should prompt consideration of an underlying systemic disorder causing a secondary CNS vasculitis and should cast doubt on the diagnosis of PACNS. Meningovascular syphilis and tuberculosis are among the long list of infections that may cause inflammation of the CNS vasculature. Autoimmune disorders that may cause vasculitis inside the brain include polyarteritis nodosa and Wegener's granulomatosis. Reversible cerebral vasoconstrictive disease, which is most commonly seen in women ages 20 to 50, and sympathomimetic toxins such as cocaine and amphetamine may exhibit clinical and angiographic abnormalities indistinguishable from PACNS.89

There are no prospective trials investigating PACNS treatment. Aggressive immunosuppression with cyclophosphamide and glucocorticoids is the mainstay of treatment. The duration of treatment varies with the severity of the disease and response to therapy. One study suggests that treatment should be continued for 6 to 12 months.10 Neurologic deficits may remain irreversible because of scarring of the affected vessels. Serial brain MRI examinations are often used to follow radiographic resolution during and after the therapy, although radiographic changes do not predict clinical response.11 New abnormalities on MRI, however, delay any tapering of treatment. The availability of neuroimaging studies and immunosuppressive therapy has improved the prognosis of PACNS. One study reported a favorable outcome with a 29% relapse rate and a 10% mortality rate in 54 patients over a mean follow‐up period of 35 months.12

PACNS remains a challenging diagnosis because of its rarity, the wide range of neurologic manifestations, and the difficulty in establishing a diagnosis noninvasively. It is an extremely uncommon disease but should be considered in patients with unexplained neurologic deficits referable to the CNS alone after an exhaustive workup. Ultimately, the diagnosis is made by a thorough history and physical examination, exclusion of underlying conditions (particularly systemic vasculitides and infections), and histological confirmation.

A 26‐year‐old woman was brought to the emergency department following several episodes of seizures. The patient's friend witnessed several 15‐minute episodes of sudden jerks and tremors of her right arm during which the patient bit her tongue, had word‐finding difficulty, had horizontal eye deviation, and was incontinent of urine. She became unresponsive during the episodes, with incomplete recovery of consciousness between attacks. She was afebrile. Her neurologic exam 4 hours after several seizures revealed word‐finding difficulty and right arm weakness. A complete blood count, chemistry panel including renal and liver function tests, urine toxicology screen, and computed tomography (CT) of the head were normal. After a loading dose of fosphenytoin, the patient did not experience further seizures and was discharged on a maintenance dose of phenytoin.

Over the next week, the patient continued to note a sensation of heaviness in her right arm and felt fatigued. The patient's mother brought her back to the emergency department after witnessing a similar seizure episode that persisted for an hour. On arrival, the patient was no longer seizing.

Although it can sometimes be difficult to differentiate between seizure, stroke, syncope, and other causes of transient loss of consciousness, this constellation of symptoms strongly points to a seizure. I would classify the patient's focal arm movements associated with impaired consciousness as partial complex seizures. One of the first considerations is determining whether the seizure is caused by a systemic process or by an intrinsic central nervous system disorder. Common systemic illnesses include infections, metabolic disturbances, toxins, and malignancies, none of which are evident on the preliminary evaluation. The absence of fever is important as is the time frame (now extending over 1 week) in excluding acute bacterial meningitis. A negative urine toxicology is very helpful but does not exclude the possibility that the seizure is from unmeasured drug intoxication, for example, tricyclic antidepressants, or from drug withdrawal, for example, benzodiazepines, barbiturates, ethanol, and antiepileptic drugs. The persistent right arm heaviness and right arm jerking during the seizures suggest a left cortical focus that the CT scan did not detect. Without a clear diagnosis and with recurrent seizures despite antiepileptic drugs, hospitalization is warranted.

The patient experienced migraine headaches each month during menses. There was no family history of seizures. Her only medication was phenytoin. The mother was unaware of any use of tobacco, alcohol, or recreational drugs. The patient was raised in New Jersey and moved to the San Francisco Bay area 9 months ago. She had no pets and had traveled to Florida and Montreal in the past 6 months. She was a graduate student in performing arts. During the preceding 2 weeks she had been under significant stress and had not slept much in preparation for an upcoming production. The patient's mother was not aware of any head trauma, recent illness, fevers, chills, weight loss, photosensitivity, arthralgias, nausea, vomiting, or diarrhea.

Recent sleep deprivation could provoke seizures in a patient with a latent anatomic focus or metabolic predisposition. Nonadherence to antiepileptic drug therapy is the most common reason for patients to present to the ED with seizures; therefore, I would check a phenytoin level to assess whether she is at a therapeutic level and would consider administering another loading dose. In the absence of immunocompromise or unusual activities or exposures, North American travel does not bring to mind additional etiologies at this time.

On exam, temperature was 37.3C, blood pressure was 148/84 mm Hg, heart rate was 120 per minute, and respiratory rate was 16 per minute. The patient was stuporous and withdrew from painful stimuli. She was unable to speak. Pupils were 4 mm in diameter and reacted to light. No gaze preference or nystagmus was present. There was no meningismus. Deep tendon reflexes were 1+ and symmetrical in both upper and lower extremities. Plantar reflexes were extensor bilaterally. The tone in the right upper extremity was mildly increased compared to the left. The patient demonstrated semipurposeful movement of the limbs, such as reaching for the bed rails with her arms. Examination of the heart, lungs, abdomen, skin, and oropharynx was normal.

The white blood cell count was 22,300/mm³ with 50% neutrophils, 40% lymphocytes, 7% monocytes, and 3% eosinophils. Results of the chemistry panel including electrolytes, glucose, creatinine, and liver enzymes, urinalysis, and thyroid‐stimulating hormone were normal. Serum phenytoin level was 8.1 g/mL. Urine toxicology screen, obtained after the patient had received lorazepam, was positive only for benzodiazepines. A chest radiograph was normal.

The cerebrospinal fluid (CSF) was colorless, containing 35 white blood cells/mm³ (48% lymphocytes, 30% neutrophils, 22% monocytes), 3 red blood cells/mm³, 62 mg/dL protein, and 50 mg/dL glucose. There was no xanthochromia. The CSF was negative for cryptococcal antigen, antibodies to West Nile virus, PCR for herpes simplex viruses‐1 and ‐2, and PCR for Borrelia burgdorferi. CSF bacterial culture, cryptococcal antigen, and AFB stain were negative. The serum antinuclear antibody, rheumatoid factor, and rapid plasma reagin were negative. Serum antibodies to human immunodeficiency virus, hepatitis B and C viruses, Borrelia burgdorferi, and herpes simplex viruses were negative. The erythrocyte sedimentation rate was 25 mm/hr. There was no growth in her blood cultures.

These CSF findings have to be interpreted in light of her clinical picture, as they are congruent with both an aseptic meningitis and encephalitis. In practice, these can be hard to distinguish, but the early and dominant cortical findings (focal neurologic deficits, prominent altered mental status, bilateral extensor plantar reflexes) and absence of meningeal signs favor encephalitis. This CSF profile can be seen in a variety of disease processes causing a meningoencephalitis, including partially treated bacterial meningitis; meningitis due to viruses, fungi, mycobacteria, or atypical bacteria (eg, Listeria); neurosarcoidosis; carcinomatous meningitis; and infection or inflammation from a parameningeal focus in the sinuses, epidural space, or brain parenchyma. Seizure itself can lead to a postictal pleocytosis in the CSF, although this degree of inflammation would be unusual. Many tests can be sent, and the clinicians appropriately focused on some of the most treatable and serious etiologies first. The negative HIV test limits the list of opportunistic pathogens. The negative ANA substantially lowers the likelihood of systemic lupus, an important consideration in a young woman with an inflammatory disorder involving the central nervous system.

Magnetic resonance imaging (MRI) of the brain showed cortical T2 prolongation with significant enhancement with gadolinium in the cortex and leptomeninges of the left parietal and posterotemporal lobes and right cingulate gyrus region (Fig. 1). The patient was admitted to the intensive care unit, and phenytoin and levetiracetam were administered. Over the next several days, she remained afebrile, and her leukocytosis resolved. She continued to have seizures every day despite receiving phenytoin, levetiracetam, and lamotrigine. She was alert and complained about persistent right arm weakness and word‐finding difficulties. Posterior cervical lymphadenopathy at the base of her left occiput was detected on subsequent exam.

Figure 1

An excisional lymph node biopsy demonstrated extensive necrosis without evidence of granulomata, malignancy, or lymphoproliferative disease. Stains and cultures for bacteria, fungi, and mycobacteria were negative. The patient's electroencephalogram captured epileptiform activity over the left hemisphere 2 hours after a cluster of seizures. MR angiography and cerebral angiography demonstrated no abnormalities.

Despite this additional information, there is no distinguishing clue that points to a single diagnosis. This is a 26‐year‐old healthy, seemingly immunocompetent woman who has had a 2‐week progressive and refractory seizure disorder secondary to a multifocal neuroinvasive process with a CSF pleocytosis. She does not have evidence of a systemic underlying disorder, save for nonspecific localized lymphadenopathy and a transient episode of leukocytosis on admission, and has no distinguishing epidemiological factors or exposures.

Despite my initial concerns for infectious meningoencephalitis, the negative stains, serologies, and cultures of the blood, CSF, and lymph nodes in the setting of a normal immune system and no suspect exposure substantially lower this probability. Arthropod‐borne viruses are still possible, especially West Nile virus, because the serological tests are less sensitive early in the illness, acknowledging that the absence of fever, weakness, and known mosquito bites detracts from this diagnosis. Pathogens that cause regional lymphadenopathy and encephalitis such as Bartonella remain possibilities, as the history of exposure to a kitten can be easily overlooked.

Rheumatologic disorders merit close attention in a young woman, but the negative ANA makes lupus cerebritis unlikely, and the 2 angiograms did not detect evidence of vasculitis. Finally, there is the question of malignancy and other miscellaneous infiltrative disorders (such as sarcoid), which are of importance here because of the multifocal cortical involvement on imaging.

At this point, I would resample the CSF for viral etiologies (eg, West Nile virus) and cytology and would send serum Bartonella serologies. If these studies were negative, a brain biopsy, primarily to exclude malignancy but also to uncover an unsuspected process, would be indicated. I cannot make a definitive diagnosis or find a perfect fit here, but in the absence of strong evidence of an infection, I am concerned about a malignancy, perhaps a low‐grade primary brain tumor.

Brain biopsy of the leptomeninges and cortex of the left parietal lobe showed multiple blood vessels infiltrated by lymphocytes, neutrophils, and eosinophils (Fig. 2). The pattern of inflammation was consistent with primary angiitis of the central nervous system (PACNS). The patient received 1 g of intravenous methylprednisolone on 3 consecutive days, followed by oral prednisone and cyclophosphamide. The seizures ceased, and she made steady progress with rehabilitation therapy. Four months after discharge a cerebral angiogram (done to ensure there was no interval evidence of vasculitis prior to tapering therapy) demonstrated patency of all major intracranial arteries and venous sinuses.

Figure 2

COMMENTARY

When a patient presents with symptoms or signs referable to the central nervous system (CNS), hospitalists must simultaneously consider primary neurologic disorders and systemic diseases that involve the CNS. Initial evaluation includes a thorough history and physical examination, basic lab studies, routine CSF analysis, and neuroimaging (often a CT scan of the head). Complicated neurologic cases may warrant more elaborate testing including EEG, brain MRI, cerebral angiography, and specialized blood and CSF studies. Clinicians may still find themselves faced with a patient who has clear CNS dysfunction but no obvious diagnosis despite an exhaustive and expensive evaluation. Several disorders match this profile including intravascular lymphoma, prion diseases, paraneoplastic syndromes, and cerebritis. Primary angiitis of the central nervous system (PACNS), a rare disorder characterized by inflammation of the medium‐sized and small arteries of the CNS, is among these disorders. Although the aforementioned diseases may sometimes have suggestive or even pathognomonic features (eg, the string of beads angiographic appearance in vasculitides), they are challenging to diagnose when such findings are absent.

Like any vasculitis of the CNS, PACNS may present with a wide spectrum of clinical features.12 Although headache and altered mental status are the most common complaints, paresis, seizures, ataxia, visual changes, and aphasia have all been described. The onset of symptoms ranges from acute to chronic, and neurologic deficits can be focal or diffuse. Systemic manifestations such as fever and weight loss are rare. The average age of onset is 42 years, with no significant sex preponderance. The histopathology of PACNS is granulomatous inflammation of arteries in the parenchyma and leptomeninges of the brain and less commonly in the spinal cord. The narrowing of the affected vessels causes cerebral ischemia and the associated neurologic deficits. The trigger for this focal inflammation is unknown.

After common disorders have been excluded in cases of CNS dysfunction, compatible CSF findings and imaging results may prompt consideration of PACNS. CSF analysis in patients with PACNS typically demonstrates a lymphocytic pleocytosis. MRI abnormalities in PACNS include multiple infarcts in the cortex, deep white matter, or leptomeninges.34 Less specific findings are contrast enhancement in the leptomeninges and white matter disease, both of which may direct the site for meningeal and brain biopsy.

Both brain MRA and cerebral angiography have a limited role in the diagnosis of vasculitis within the CNS. In 18 patients with CNS vasculitis due to autoimmune disease, all had parenchymal abnormalities on MRA but only 65% had evidence of vasculitis on angiography. In 2 retrospective studies of patients with suspected PACNS, abnormal angiograms had a specificity less than 30% for PACNS, whereas brain biopsies had a negative predictive value of 70%.57 Although in practice patients with compatible clinical features are sometimes diagnosed with CNS vasculitis on the basis of angiographic findings, brain biopsy is necessary to differentiate vasculitis from other vasculopathies and to establish a definitive diagnosis.

Before a diagnosis of PACNS is made, care must be taken to exclude infections, neoplasms, and autoimmune processes that cause angiitis of the CNS (Table 1). The presence of any extracranial abnormalities (which were not present in this case) should prompt consideration of an underlying systemic disorder causing a secondary CNS vasculitis and should cast doubt on the diagnosis of PACNS. Meningovascular syphilis and tuberculosis are among the long list of infections that may cause inflammation of the CNS vasculature. Autoimmune disorders that may cause vasculitis inside the brain include polyarteritis nodosa and Wegener's granulomatosis. Reversible cerebral vasoconstrictive disease, which is most commonly seen in women ages 20 to 50, and sympathomimetic toxins such as cocaine and amphetamine may exhibit clinical and angiographic abnormalities indistinguishable from PACNS.89

There are no prospective trials investigating PACNS treatment. Aggressive immunosuppression with cyclophosphamide and glucocorticoids is the mainstay of treatment. The duration of treatment varies with the severity of the disease and response to therapy. One study suggests that treatment should be continued for 6 to 12 months.10 Neurologic deficits may remain irreversible because of scarring of the affected vessels. Serial brain MRI examinations are often used to follow radiographic resolution during and after the therapy, although radiographic changes do not predict clinical response.11 New abnormalities on MRI, however, delay any tapering of treatment. The availability of neuroimaging studies and immunosuppressive therapy has improved the prognosis of PACNS. One study reported a favorable outcome with a 29% relapse rate and a 10% mortality rate in 54 patients over a mean follow‐up period of 35 months.12

PACNS remains a challenging diagnosis because of its rarity, the wide range of neurologic manifestations, and the difficulty in establishing a diagnosis noninvasively. It is an extremely uncommon disease but should be considered in patients with unexplained neurologic deficits referable to the CNS alone after an exhaustive workup. Ultimately, the diagnosis is made by a thorough history and physical examination, exclusion of underlying conditions (particularly systemic vasculitides and infections), and histological confirmation.

Many hospitalists work with clinical coordinators and case managers.13 The descriptions of these roles often overlap4 and commonly include activities such as obtaining medical records, expediting tests and procedures, coordinating the plan of care with other health care providers, assessing postdischarge needs, completing discharge paperwork, and arranging follow‐up visits.2, 5, 6 Despite the potential to improve patient care and hospital efficiency, few studies have formally evaluated the impact of these roles. Moher et al. found that adding a clinical coordinator to a general medical team decreased length of stay (LOS) and improved patient satisfaction.5 However, this study was conducted at a time when the LOS was routinely longer than it is today. Forster et al. found that adding a clinical coordinator to a general medical team resulted in improved patient satisfaction but did not reduce length of stay or risk of adverse events occurring following hospital discharge.6 Both these studies evaluated the impact of adding a clinical coordinator to resident‐covered medical teams. Yet many hospitalists deliver care without residents, limiting the generalizability of the findings from these studies.

To date, no studies have evaluated the impact of clinical coordinators, case managers, or other nonphysician providers on the hospitalist work experience. This is surprising, as hospital medicine group leaders list daily workload and work hours among their top concerns.7 Clinical coordinators have the potential to improve patient care and hospital efficiency while simultaneously improving the experience of the hospitalists with whom they work. We conducted this study to evaluate the impact of a hospitalistcare coordinator team on hospitalist work experience, patient satisfaction, and hospital efficiency.

METHODS

RESULTS

There were 356 patients cared for by hospitalistHCC teams and 337 patients cared for by control hospitalists. Of the 60 weeks of hospitalist service of the study, hospitalistHCC teams accounted for 31 weeks (52%) and control hospitalists for 29 weeks (48%). Patients cared for by the hospitalistHCC teams were similar in age, sex, ethnicity, payer type, and DRG weight to those cared for by control hospitalists (see Table 2).

Sixty surveys were completed by hospitalists at the end of their week on service (response rate 100%). Of the 31 responses from hospitalists completing a hospitalistHCC team week, 28 (90%) reported that working with an HCC improved their efficiency and 28 (90%) that working with an HCC improved their job satisfaction. The hospitalists indicated that working with an HCC significantly improved the efficiency of most of their activities (see Table 3). Specifically, activities related to communication with nurses and patients and activities involving discharge planning and execution were improved with the use of an HCC. As would be expected, certain other activities did not improve. For example, there were no differences between the groups in the perceived efficiency of performing histories and physicals or placing admission orders. For activities that were significantly different, the Wilcoxon rank sum test and linear regression analysis adjusting for physician clustering showed identical results.

Seventy‐one of 196 eligible patients (36%) completed the discharge satisfaction interview. Of the 71 patients interviewed, 44 (62%) were cared for by hospitalistHCC teams and 27 (38%) were cared for by control hospitalists. Patient satisfaction with the clarity of the verbal and written discharge instructions and overall satisfaction with hospital discharge was similar between the 2 groups (see Table 4).

The unadjusted mean LOS for patients cared for by hospitalistHCC teams was 4.70 4.15 days compared with 5.07 3.99 days for patients cared for by control hospitalists (P = .005; see Table 5). The unadjusted mean cost for patients cared for by hospitalistHCC teams was $10,052.96 $11,708.73 compared with $11,703.19 $20,455.78 for patients cared for by control hospitalists (P = .008). In multivariate analysis using age, sex, ethnicity, payer type, and DRG weight as independent variables and adjusting for physician clustering, LOS remained lower for patients cared for by hospitalistHCC teams; however, this result was not statistically significant (0.28 days, P = .17). Similar multivariate regression analysis showed a trend toward lower cost for patients cared for by the hospitalistHCC teams (585.62, P = .15).

DISCUSSION

Our study found that hospitalists working in a team approach with an HCC rated the efficiency of their daily work and their job satisfaction significantly higher than did control hospitalists. Specific areas of improved efficiency included communication activities and activities related to hospital discharge. A prior study conducted by our group found that hospitalists spend a lot of time on indirect patient care activities such as communication and activities related to the discharge process, while spending relatively little time on direct patient care.8 Improving the efficiency of indirect patient care activities of hospitalists is likely to improve their job satisfaction. The importance of improving hospitalist workload and job satisfaction is underscored by the relatively high number of hospitalists at risk for burnout9 and the growing concern about daily workload among hospital medicine group leaders.7

Patient satisfaction was not significantly affected by the use of the hospitalistHCC team in our study. A priori, we postulated that patient satisfaction with the discharge process might improve with the use of the hospitalistHCC team. We therefore limited survey questions to assessing only satisfaction with hospital discharge rather than other aspects of patient hospital care. A recent study reported that patients rated the quality of discharge instructions significantly lower than they rated the overall quality of their hospital stay.10 However, the patients in our study gave high ratings to both discharge instructions and overall satisfaction with hospital discharge. This may explain why we were unable to detect a difference. Our study was limited by the relatively small number of patients we were able to contact to assess satisfaction. Previous studies evaluating the impact of care coordinators either did not assess patient satisfaction with discharge5 or found no difference in satisfaction with hospital discharge.6

Although our study did not find a difference in patient satisfaction with the discharge process, we believe the hospitalistHCC model has the potential to complement efforts to reduce the risk of adverse events as patients transition out of the hospital. It has been reported that 12% of patients have a preventable or ameliorable adverse event in the period immediately following hospital discharge.11, 12 Although Forster et al. did not find a reduction in the risk of adverse events with the addition of a clinical coordinator to a general medical team, they noted incongruence between the coordinator's role and the outcomes measured.6 Similarly, we would need to modify the role of the HCC from a position designed mainly to improve efficiency to one that complements efforts to improve the quality of the discharge process. Possible ways to enhance the HCC role in this regard include increasing the emphasis on and training in patient education skills. Several recently published articles have emphasized the need to redesign the discharge process in an effort to reduce the risk of adverse events following hospital discharge.1315 A modified HCC role might be an essential feature of a redesigned multidisciplinary discharge process.

We were unable to demonstrate improved efficiency for the hospital. Although LOS and cost were lower for patients cared for by the hospitalistHCC teams, the difference was not statistically significant. One possible explanation for why we did not observe a larger reduction in LOS is that our hospitalist service had a lower‐than‐average patient volume during the study period. The lower volume mirrored an unanticipated dip in hospital volume during the same period. Specifically, our service normally discharges an average of 338 patients per month, but during the study period we discharged an average of 235 patients per month. A potential LOS and cost benefit may have been attenuated by the relatively low volume, as hospitalists had ample time to dedicate to communication and coordination of discharge plans.

Our study had several limitations. It was conducted on a nonteaching hospitalist service at a single site. Hospitalist practices vary widely in their staffing and scheduling models. As previously mentioned, we were only able to perform patient satisfaction surveys during the second half of the study period. In addition, hospitalistHCC team patients made up a larger percentage of the patient survey responses (62%) than did control hospitalist patients (38%). This may have affected our ability to detect differences in satisfaction with the hospital discharge process. As also previously noted, our patient volume was lower than normal during the study period. We believe that a higher volume would have magnified differences in hospitalists' perceived efficiency and perhaps resulted in significant improvements in LOS and cost. Finally, the hospital provided funding for only a 12‐week study. This limited our sample size and the power of the study to detect important differences. It is possible that a larger sample size and/or longer study period may have been able to demonstrate a statistically significant improvement in LOS and cost.

Our findings are of particular importance in light of the persistent concerns about hospitalist workload and job satisfaction. Although many hospitalists work with clinical coordinators and case managers, we believe that having the formal structure of a hospitalistcare coordinator team was the key element to improving hospitalist efficiency and satisfaction. We hope that our study is a precursor to research evaluating models of delivering hospital care and their impact on hospitalist work experience, hospital efficiency, and patient outcomes.

Many hospitalists work with clinical coordinators and case managers.13 The descriptions of these roles often overlap4 and commonly include activities such as obtaining medical records, expediting tests and procedures, coordinating the plan of care with other health care providers, assessing postdischarge needs, completing discharge paperwork, and arranging follow‐up visits.2, 5, 6 Despite the potential to improve patient care and hospital efficiency, few studies have formally evaluated the impact of these roles. Moher et al. found that adding a clinical coordinator to a general medical team decreased length of stay (LOS) and improved patient satisfaction.5 However, this study was conducted at a time when the LOS was routinely longer than it is today. Forster et al. found that adding a clinical coordinator to a general medical team resulted in improved patient satisfaction but did not reduce length of stay or risk of adverse events occurring following hospital discharge.6 Both these studies evaluated the impact of adding a clinical coordinator to resident‐covered medical teams. Yet many hospitalists deliver care without residents, limiting the generalizability of the findings from these studies.

To date, no studies have evaluated the impact of clinical coordinators, case managers, or other nonphysician providers on the hospitalist work experience. This is surprising, as hospital medicine group leaders list daily workload and work hours among their top concerns.7 Clinical coordinators have the potential to improve patient care and hospital efficiency while simultaneously improving the experience of the hospitalists with whom they work. We conducted this study to evaluate the impact of a hospitalistcare coordinator team on hospitalist work experience, patient satisfaction, and hospital efficiency.

METHODS

RESULTS

There were 356 patients cared for by hospitalistHCC teams and 337 patients cared for by control hospitalists. Of the 60 weeks of hospitalist service of the study, hospitalistHCC teams accounted for 31 weeks (52%) and control hospitalists for 29 weeks (48%). Patients cared for by the hospitalistHCC teams were similar in age, sex, ethnicity, payer type, and DRG weight to those cared for by control hospitalists (see Table 2).

Sixty surveys were completed by hospitalists at the end of their week on service (response rate 100%). Of the 31 responses from hospitalists completing a hospitalistHCC team week, 28 (90%) reported that working with an HCC improved their efficiency and 28 (90%) that working with an HCC improved their job satisfaction. The hospitalists indicated that working with an HCC significantly improved the efficiency of most of their activities (see Table 3). Specifically, activities related to communication with nurses and patients and activities involving discharge planning and execution were improved with the use of an HCC. As would be expected, certain other activities did not improve. For example, there were no differences between the groups in the perceived efficiency of performing histories and physicals or placing admission orders. For activities that were significantly different, the Wilcoxon rank sum test and linear regression analysis adjusting for physician clustering showed identical results.

Seventy‐one of 196 eligible patients (36%) completed the discharge satisfaction interview. Of the 71 patients interviewed, 44 (62%) were cared for by hospitalistHCC teams and 27 (38%) were cared for by control hospitalists. Patient satisfaction with the clarity of the verbal and written discharge instructions and overall satisfaction with hospital discharge was similar between the 2 groups (see Table 4).

The unadjusted mean LOS for patients cared for by hospitalistHCC teams was 4.70 4.15 days compared with 5.07 3.99 days for patients cared for by control hospitalists (P = .005; see Table 5). The unadjusted mean cost for patients cared for by hospitalistHCC teams was $10,052.96 $11,708.73 compared with $11,703.19 $20,455.78 for patients cared for by control hospitalists (P = .008). In multivariate analysis using age, sex, ethnicity, payer type, and DRG weight as independent variables and adjusting for physician clustering, LOS remained lower for patients cared for by hospitalistHCC teams; however, this result was not statistically significant (0.28 days, P = .17). Similar multivariate regression analysis showed a trend toward lower cost for patients cared for by the hospitalistHCC teams (585.62, P = .15).

DISCUSSION

Our study found that hospitalists working in a team approach with an HCC rated the efficiency of their daily work and their job satisfaction significantly higher than did control hospitalists. Specific areas of improved efficiency included communication activities and activities related to hospital discharge. A prior study conducted by our group found that hospitalists spend a lot of time on indirect patient care activities such as communication and activities related to the discharge process, while spending relatively little time on direct patient care.8 Improving the efficiency of indirect patient care activities of hospitalists is likely to improve their job satisfaction. The importance of improving hospitalist workload and job satisfaction is underscored by the relatively high number of hospitalists at risk for burnout9 and the growing concern about daily workload among hospital medicine group leaders.7

Patient satisfaction was not significantly affected by the use of the hospitalistHCC team in our study. A priori, we postulated that patient satisfaction with the discharge process might improve with the use of the hospitalistHCC team. We therefore limited survey questions to assessing only satisfaction with hospital discharge rather than other aspects of patient hospital care. A recent study reported that patients rated the quality of discharge instructions significantly lower than they rated the overall quality of their hospital stay.10 However, the patients in our study gave high ratings to both discharge instructions and overall satisfaction with hospital discharge. This may explain why we were unable to detect a difference. Our study was limited by the relatively small number of patients we were able to contact to assess satisfaction. Previous studies evaluating the impact of care coordinators either did not assess patient satisfaction with discharge5 or found no difference in satisfaction with hospital discharge.6

Although our study did not find a difference in patient satisfaction with the discharge process, we believe the hospitalistHCC model has the potential to complement efforts to reduce the risk of adverse events as patients transition out of the hospital. It has been reported that 12% of patients have a preventable or ameliorable adverse event in the period immediately following hospital discharge.11, 12 Although Forster et al. did not find a reduction in the risk of adverse events with the addition of a clinical coordinator to a general medical team, they noted incongruence between the coordinator's role and the outcomes measured.6 Similarly, we would need to modify the role of the HCC from a position designed mainly to improve efficiency to one that complements efforts to improve the quality of the discharge process. Possible ways to enhance the HCC role in this regard include increasing the emphasis on and training in patient education skills. Several recently published articles have emphasized the need to redesign the discharge process in an effort to reduce the risk of adverse events following hospital discharge.1315 A modified HCC role might be an essential feature of a redesigned multidisciplinary discharge process.

We were unable to demonstrate improved efficiency for the hospital. Although LOS and cost were lower for patients cared for by the hospitalistHCC teams, the difference was not statistically significant. One possible explanation for why we did not observe a larger reduction in LOS is that our hospitalist service had a lower‐than‐average patient volume during the study period. The lower volume mirrored an unanticipated dip in hospital volume during the same period. Specifically, our service normally discharges an average of 338 patients per month, but during the study period we discharged an average of 235 patients per month. A potential LOS and cost benefit may have been attenuated by the relatively low volume, as hospitalists had ample time to dedicate to communication and coordination of discharge plans.

Our study had several limitations. It was conducted on a nonteaching hospitalist service at a single site. Hospitalist practices vary widely in their staffing and scheduling models. As previously mentioned, we were only able to perform patient satisfaction surveys during the second half of the study period. In addition, hospitalistHCC team patients made up a larger percentage of the patient survey responses (62%) than did control hospitalist patients (38%). This may have affected our ability to detect differences in satisfaction with the hospital discharge process. As also previously noted, our patient volume was lower than normal during the study period. We believe that a higher volume would have magnified differences in hospitalists' perceived efficiency and perhaps resulted in significant improvements in LOS and cost. Finally, the hospital provided funding for only a 12‐week study. This limited our sample size and the power of the study to detect important differences. It is possible that a larger sample size and/or longer study period may have been able to demonstrate a statistically significant improvement in LOS and cost.

Our findings are of particular importance in light of the persistent concerns about hospitalist workload and job satisfaction. Although many hospitalists work with clinical coordinators and case managers, we believe that having the formal structure of a hospitalistcare coordinator team was the key element to improving hospitalist efficiency and satisfaction. We hope that our study is a precursor to research evaluating models of delivering hospital care and their impact on hospitalist work experience, hospital efficiency, and patient outcomes.

Many hospitalists work with clinical coordinators and case managers.13 The descriptions of these roles often overlap4 and commonly include activities such as obtaining medical records, expediting tests and procedures, coordinating the plan of care with other health care providers, assessing postdischarge needs, completing discharge paperwork, and arranging follow‐up visits.2, 5, 6 Despite the potential to improve patient care and hospital efficiency, few studies have formally evaluated the impact of these roles. Moher et al. found that adding a clinical coordinator to a general medical team decreased length of stay (LOS) and improved patient satisfaction.5 However, this study was conducted at a time when the LOS was routinely longer than it is today. Forster et al. found that adding a clinical coordinator to a general medical team resulted in improved patient satisfaction but did not reduce length of stay or risk of adverse events occurring following hospital discharge.6 Both these studies evaluated the impact of adding a clinical coordinator to resident‐covered medical teams. Yet many hospitalists deliver care without residents, limiting the generalizability of the findings from these studies.

To date, no studies have evaluated the impact of clinical coordinators, case managers, or other nonphysician providers on the hospitalist work experience. This is surprising, as hospital medicine group leaders list daily workload and work hours among their top concerns.7 Clinical coordinators have the potential to improve patient care and hospital efficiency while simultaneously improving the experience of the hospitalists with whom they work. We conducted this study to evaluate the impact of a hospitalistcare coordinator team on hospitalist work experience, patient satisfaction, and hospital efficiency.

METHODS

RESULTS

There were 356 patients cared for by hospitalistHCC teams and 337 patients cared for by control hospitalists. Of the 60 weeks of hospitalist service of the study, hospitalistHCC teams accounted for 31 weeks (52%) and control hospitalists for 29 weeks (48%). Patients cared for by the hospitalistHCC teams were similar in age, sex, ethnicity, payer type, and DRG weight to those cared for by control hospitalists (see Table 2).

Sixty surveys were completed by hospitalists at the end of their week on service (response rate 100%). Of the 31 responses from hospitalists completing a hospitalistHCC team week, 28 (90%) reported that working with an HCC improved their efficiency and 28 (90%) that working with an HCC improved their job satisfaction. The hospitalists indicated that working with an HCC significantly improved the efficiency of most of their activities (see Table 3). Specifically, activities related to communication with nurses and patients and activities involving discharge planning and execution were improved with the use of an HCC. As would be expected, certain other activities did not improve. For example, there were no differences between the groups in the perceived efficiency of performing histories and physicals or placing admission orders. For activities that were significantly different, the Wilcoxon rank sum test and linear regression analysis adjusting for physician clustering showed identical results.

Seventy‐one of 196 eligible patients (36%) completed the discharge satisfaction interview. Of the 71 patients interviewed, 44 (62%) were cared for by hospitalistHCC teams and 27 (38%) were cared for by control hospitalists. Patient satisfaction with the clarity of the verbal and written discharge instructions and overall satisfaction with hospital discharge was similar between the 2 groups (see Table 4).

The unadjusted mean LOS for patients cared for by hospitalistHCC teams was 4.70 4.15 days compared with 5.07 3.99 days for patients cared for by control hospitalists (P = .005; see Table 5). The unadjusted mean cost for patients cared for by hospitalistHCC teams was $10,052.96 $11,708.73 compared with $11,703.19 $20,455.78 for patients cared for by control hospitalists (P = .008). In multivariate analysis using age, sex, ethnicity, payer type, and DRG weight as independent variables and adjusting for physician clustering, LOS remained lower for patients cared for by hospitalistHCC teams; however, this result was not statistically significant (0.28 days, P = .17). Similar multivariate regression analysis showed a trend toward lower cost for patients cared for by the hospitalistHCC teams (585.62, P = .15).

DISCUSSION

Our study found that hospitalists working in a team approach with an HCC rated the efficiency of their daily work and their job satisfaction significantly higher than did control hospitalists. Specific areas of improved efficiency included communication activities and activities related to hospital discharge. A prior study conducted by our group found that hospitalists spend a lot of time on indirect patient care activities such as communication and activities related to the discharge process, while spending relatively little time on direct patient care.8 Improving the efficiency of indirect patient care activities of hospitalists is likely to improve their job satisfaction. The importance of improving hospitalist workload and job satisfaction is underscored by the relatively high number of hospitalists at risk for burnout9 and the growing concern about daily workload among hospital medicine group leaders.7

Patient satisfaction was not significantly affected by the use of the hospitalistHCC team in our study. A priori, we postulated that patient satisfaction with the discharge process might improve with the use of the hospitalistHCC team. We therefore limited survey questions to assessing only satisfaction with hospital discharge rather than other aspects of patient hospital care. A recent study reported that patients rated the quality of discharge instructions significantly lower than they rated the overall quality of their hospital stay.10 However, the patients in our study gave high ratings to both discharge instructions and overall satisfaction with hospital discharge. This may explain why we were unable to detect a difference. Our study was limited by the relatively small number of patients we were able to contact to assess satisfaction. Previous studies evaluating the impact of care coordinators either did not assess patient satisfaction with discharge5 or found no difference in satisfaction with hospital discharge.6

Although our study did not find a difference in patient satisfaction with the discharge process, we believe the hospitalistHCC model has the potential to complement efforts to reduce the risk of adverse events as patients transition out of the hospital. It has been reported that 12% of patients have a preventable or ameliorable adverse event in the period immediately following hospital discharge.11, 12 Although Forster et al. did not find a reduction in the risk of adverse events with the addition of a clinical coordinator to a general medical team, they noted incongruence between the coordinator's role and the outcomes measured.6 Similarly, we would need to modify the role of the HCC from a position designed mainly to improve efficiency to one that complements efforts to improve the quality of the discharge process. Possible ways to enhance the HCC role in this regard include increasing the emphasis on and training in patient education skills. Several recently published articles have emphasized the need to redesign the discharge process in an effort to reduce the risk of adverse events following hospital discharge.1315 A modified HCC role might be an essential feature of a redesigned multidisciplinary discharge process.

We were unable to demonstrate improved efficiency for the hospital. Although LOS and cost were lower for patients cared for by the hospitalistHCC teams, the difference was not statistically significant. One possible explanation for why we did not observe a larger reduction in LOS is that our hospitalist service had a lower‐than‐average patient volume during the study period. The lower volume mirrored an unanticipated dip in hospital volume during the same period. Specifically, our service normally discharges an average of 338 patients per month, but during the study period we discharged an average of 235 patients per month. A potential LOS and cost benefit may have been attenuated by the relatively low volume, as hospitalists had ample time to dedicate to communication and coordination of discharge plans.

Our study had several limitations. It was conducted on a nonteaching hospitalist service at a single site. Hospitalist practices vary widely in their staffing and scheduling models. As previously mentioned, we were only able to perform patient satisfaction surveys during the second half of the study period. In addition, hospitalistHCC team patients made up a larger percentage of the patient survey responses (62%) than did control hospitalist patients (38%). This may have affected our ability to detect differences in satisfaction with the hospital discharge process. As also previously noted, our patient volume was lower than normal during the study period. We believe that a higher volume would have magnified differences in hospitalists' perceived efficiency and perhaps resulted in significant improvements in LOS and cost. Finally, the hospital provided funding for only a 12‐week study. This limited our sample size and the power of the study to detect important differences. It is possible that a larger sample size and/or longer study period may have been able to demonstrate a statistically significant improvement in LOS and cost.

Our findings are of particular importance in light of the persistent concerns about hospitalist workload and job satisfaction. Although many hospitalists work with clinical coordinators and case managers, we believe that having the formal structure of a hospitalistcare coordinator team was the key element to improving hospitalist efficiency and satisfaction. We hope that our study is a precursor to research evaluating models of delivering hospital care and their impact on hospitalist work experience, hospital efficiency, and patient outcomes.

Medications are central to managing the health of older patients. In 2006, more than 93% of adults 65 years or older reported taking at least 1 medication in the last week, 58% reported taking 5 or more medications, and 18% reported taking 10 or more.1 Medication use by older adults will likely increase further as the U.S. population ages, new drugs are developed, and new therapeutic and preventive uses for medications are discovered.2

Older patients, especially those who are chronically frail or acutely ill, may require special consideration when making prescribing decisions because of age‐related changes in the metabolism and clearance of medications and enhanced pharmacodynamic sensitivities.3 Thus, panels of experts in pharmacology and geriatrics have compiled lists of medications to avoid prescribing for patients 65 years of age or older. The most commonly used list is the Beers criteria, which were introduced in 1991 to serve researchers evaluating prescribing quality in nursing homes. The Beers criteria were updated in 1997 and again in 2003 to include 48 potentially inappropriate medications (PIMs) for which, according to the consensus panel, there are more effective or safer alternatives for older patients.4

Numerous studies in the last 15 years have found that PIMs continue to be used in 12% to 40% of older patients in community and nursing home settings.5 To address the continued use of PIMs, the Centers for Medicare and Medicaid Services incorporated the Beers criteria into federal safety regulations for long‐term care facilities in 1999.6 In 2006, the prescription rate of PIMs was introduced as a Health Plan and Employer Data and Information Set (HEDIS) quality measure for managed care plans.7 Despite adoption of the Beers criteria to monitor prescribing quality and safety in nursing homes and outpatient settings, there has been considerably less study of potentially inappropriate medication use in hospitalized patients.

In this issue of the Journal of Hospital Medicine, Rothberg and colleagues analyzed administrative data from nearly 400 hospitals across the United States and found that nearly half of all older patients hospitalized for 7 common conditions were prescribed at least 1 PIM.8 Thus, the incidence of PIM use in hospitalized older patients far exceeded that reported in most studies of community‐dwelling or nursing home patients. Most notable, however, was the variability found in prescribing rates based on a number of physician and hospital characteristics. For example, although hospitalists and geriatricians were found to be less likely to prescribe PIMs than cardiologists and general internists, among high‐volume cardiologists and internists, PIM prescribing rates ranged widely, from 0% to more than 90%. Similarly, hospitalwide prescribing rates varied by geographic region, and there were 7 hospitals in which not a single PIM was reportedly prescribed.

These findings raise three questions and bring to mind parallels with efforts to control inappropriate antimicrobial use. First question: Can inpatient use of PIMs truly be higher than outpatient use? Yes. The finding that more hospitalized patients are prescribed PIMs than ambulatory patients has face validity for several reasons. First, patients admitted for an acute hospitalization may have more comorbid diseases and take more medications than community‐dwelling older adults. Second, new medications are typically added to treat acutely ill patients on hospitalization. Third, previous studies estimating outpatient PIM use have typically used more narrowly defined lists of PIMs and have not captured over‐the‐counter use of PIMs, particularly antihistamines.9 Diphenhydramine alone accounted for 9% of PIM use in Rothberg's study. Finally, as Rothberg and colleagues point out, this study was limited to certain diagnoses such as acute myocardial infarction that may have protocol‐driven prescribing, which includes PIMs, that may be used only a single time such as promethazine.

Second question: Can PIM prescribing truly be so variable across regions, specialties, and individual hospitals and physicians? Yes. Using multivariable modeling, Rothberg and colleagues controlled for many patient, hospital, and physician characteristics and still found significant variation. John Wennberg and others have documented similar variations for a host of medical treatments; but although variation is interesting, it is unwarranted variation that matters for improving health care quality.10 It is not clear how much of the variation in prescribing rates of PIMs is unwarranted.

Some degree of variation in PIM prescribing rates is certainly acceptable. As the creators of the Beers criteria acknowledge, these medications are deemed only potentially inappropriate, and individual treatment decisions should be tailored to individual patients. However, others have taken the term potentially inappropriate one step further by recategorizing Beers medications as always avoid medications, rarely acceptable medications, and medications that indeed have some indications for use in older adults.8

Variation in prescribing practice may also be acceptable when there is not a clear consensus on the superiority of one practice over another. Indeed, the evidence that PIM prescribing causes large numbers of clinically significant adverse drug events and patient harm is weak and largely based on observational studies with inconsistent results. Although some studies demonstrated an epidemiological association between Beers criteria medications and general adverse outcomes (eg, hospitalizations),11 other studies did not.12 A recent systematic review concluded that Beers criteria medications were associated with some adverse health effects, but the studies analyzed were too heterogeneous to support formal meta‐analysis.13 Thus, variability in prescribing rates of Beers medications may simply reflect individual clinical judgment in the absence of conclusive outcomes data.

Third question: Can hospitalists use the findings of Rothberg and colleagues to improve the quality of medication prescribing for older adults in their institutions? Maybe. But hospitalists wishing to reduce PIM use in their institutions should draw lessons from other efforts to modify physician‐prescribing practice such as efforts to reduce inappropriate antimicrobial use. Although national data draw attention to the high frequency of potentially inappropriate medication use in hospitalized patients, the large variation in use across hospitals confirms the need for monitoring in individual facilities. For example, the National Healthcare Safety Network provides national benchmarks of antimicrobial use and resistance, but individual hospitals monitor antibiotic use and resistance in their own institutions to tailor local efforts to improve antimicrobial prescribing.14

Also, initiating a quality improvement effort targeting all 48 Beers criteria medications may be an inefficient use of resources. Using such a composite measure obscures the contribution of the component medications, each of which possesses unique and sometimes controversial profiles of efficacy and harm for older patients. Instead, a targeted intervention addressing the most commonly prescribed Beers medications that have widely accepted alternatives could be more practical. For instance, many antibiotic management programs focus on replacing a popular, extended‐spectrum antimicrobial with a narrow‐spectrum agent as soon as microbiological susceptibly results are available.

Propoxephene is a PIM that may be an attractive target for intervention. Propoxephene was the third most commonly prescribed PIM identified by Rothberg and colleagues, but meta‐analyses of controlled trials have concluded that propoxephene provides inferior analgesia for acute pain compared with that provided by other opioids with similar side effects, and has more adverse effects than nonopioid analgesics.15 Indeed, Rothberg found that just 3 of 48 PIMs (promethazine, diphenhydramine, and propoxyphene), each of which has viable alternative agents, accounted for approximately a quarter of all potentially inappropriate prescribing.

However, not all of the 48 Beers medications have alternatives with strong evidence of superiority. The Beers list includes medications (eg, amiodarone) that may not have equivalent alternative agents. On the other hand, some Beers medications have largely been supplanted (eg, ticlopidine or tripelennamine), and identifying these medications may be an inefficient use of scarce patient safety resources. As with antimicrobial stewardship programs, local surveillance of PIM use should be combined with local consensus on appropriate alternatives to target PIM interventions.

Of course, once specific PIM use is targeted for improvement, a specific intervention must be implemented. Only a handful of studies have examined the effectiveness of interventions (eg, computerized pharmacy alerts) to reduce PIM use, and most of these have focused on the outpatient setting rather than hospitalized patients.3 One study that included hospitalized patients utilized a team approach (geriatricians, nurses, social workers, and pharmacists) and demonstrated a reduction in potentially inappropriate medication use but no reduction in adverse drug reactions during hospitalization.16 In light of the scarcity of controlled intervention trials to reduce PIM use, initiatives to reduce inappropriate antimicrobial prescribing may provide useful insights into the strengths and limitations of approaches such as clinician education, formulary restrictions, pharmacist review, and computer‐based monitoring.17

Finally, any intervention to reduce PIM use should have reasonable expectations. The Beers criteria were developed to improve the effectiveness of medication therapy for older adults as well as to prevent harm, but it is unlikely that reducing PIM use in hospitalized patients will result in improvements that could be measured easily during an initial hospitalization. If preventing drug‐induced harm during the hospitalization of older patients is the primary concern, a shift in focus is required. Safety efforts should be concentrated on identifying and mitigating the most common and severe adverse drug events, rather than focusing efforts on reducing the use of PIMs. National data demonstrate that a handful of drugsinsulin, warfarin, and digoxinmost commonly cause severe adverse events in older outpatients.18 Optimizing the management of these medications may be another approach for improving drug safety in hospitalized patients. Regardless of the focus of a drug safety intervention, the experience of infection control and hospital epidemiology programs suggests that success will require dedicated professionals and the commitment of resources to examine patterns of local use, implement interventions, and monitor outcomes.

Medications are central to managing the health of older patients. In 2006, more than 93% of adults 65 years or older reported taking at least 1 medication in the last week, 58% reported taking 5 or more medications, and 18% reported taking 10 or more.1 Medication use by older adults will likely increase further as the U.S. population ages, new drugs are developed, and new therapeutic and preventive uses for medications are discovered.2

Older patients, especially those who are chronically frail or acutely ill, may require special consideration when making prescribing decisions because of age‐related changes in the metabolism and clearance of medications and enhanced pharmacodynamic sensitivities.3 Thus, panels of experts in pharmacology and geriatrics have compiled lists of medications to avoid prescribing for patients 65 years of age or older. The most commonly used list is the Beers criteria, which were introduced in 1991 to serve researchers evaluating prescribing quality in nursing homes. The Beers criteria were updated in 1997 and again in 2003 to include 48 potentially inappropriate medications (PIMs) for which, according to the consensus panel, there are more effective or safer alternatives for older patients.4

Numerous studies in the last 15 years have found that PIMs continue to be used in 12% to 40% of older patients in community and nursing home settings.5 To address the continued use of PIMs, the Centers for Medicare and Medicaid Services incorporated the Beers criteria into federal safety regulations for long‐term care facilities in 1999.6 In 2006, the prescription rate of PIMs was introduced as a Health Plan and Employer Data and Information Set (HEDIS) quality measure for managed care plans.7 Despite adoption of the Beers criteria to monitor prescribing quality and safety in nursing homes and outpatient settings, there has been considerably less study of potentially inappropriate medication use in hospitalized patients.

In this issue of the Journal of Hospital Medicine, Rothberg and colleagues analyzed administrative data from nearly 400 hospitals across the United States and found that nearly half of all older patients hospitalized for 7 common conditions were prescribed at least 1 PIM.8 Thus, the incidence of PIM use in hospitalized older patients far exceeded that reported in most studies of community‐dwelling or nursing home patients. Most notable, however, was the variability found in prescribing rates based on a number of physician and hospital characteristics. For example, although hospitalists and geriatricians were found to be less likely to prescribe PIMs than cardiologists and general internists, among high‐volume cardiologists and internists, PIM prescribing rates ranged widely, from 0% to more than 90%. Similarly, hospitalwide prescribing rates varied by geographic region, and there were 7 hospitals in which not a single PIM was reportedly prescribed.

These findings raise three questions and bring to mind parallels with efforts to control inappropriate antimicrobial use. First question: Can inpatient use of PIMs truly be higher than outpatient use? Yes. The finding that more hospitalized patients are prescribed PIMs than ambulatory patients has face validity for several reasons. First, patients admitted for an acute hospitalization may have more comorbid diseases and take more medications than community‐dwelling older adults. Second, new medications are typically added to treat acutely ill patients on hospitalization. Third, previous studies estimating outpatient PIM use have typically used more narrowly defined lists of PIMs and have not captured over‐the‐counter use of PIMs, particularly antihistamines.9 Diphenhydramine alone accounted for 9% of PIM use in Rothberg's study. Finally, as Rothberg and colleagues point out, this study was limited to certain diagnoses such as acute myocardial infarction that may have protocol‐driven prescribing, which includes PIMs, that may be used only a single time such as promethazine.

Second question: Can PIM prescribing truly be so variable across regions, specialties, and individual hospitals and physicians? Yes. Using multivariable modeling, Rothberg and colleagues controlled for many patient, hospital, and physician characteristics and still found significant variation. John Wennberg and others have documented similar variations for a host of medical treatments; but although variation is interesting, it is unwarranted variation that matters for improving health care quality.10 It is not clear how much of the variation in prescribing rates of PIMs is unwarranted.

Some degree of variation in PIM prescribing rates is certainly acceptable. As the creators of the Beers criteria acknowledge, these medications are deemed only potentially inappropriate, and individual treatment decisions should be tailored to individual patients. However, others have taken the term potentially inappropriate one step further by recategorizing Beers medications as always avoid medications, rarely acceptable medications, and medications that indeed have some indications for use in older adults.8

Variation in prescribing practice may also be acceptable when there is not a clear consensus on the superiority of one practice over another. Indeed, the evidence that PIM prescribing causes large numbers of clinically significant adverse drug events and patient harm is weak and largely based on observational studies with inconsistent results. Although some studies demonstrated an epidemiological association between Beers criteria medications and general adverse outcomes (eg, hospitalizations),11 other studies did not.12 A recent systematic review concluded that Beers criteria medications were associated with some adverse health effects, but the studies analyzed were too heterogeneous to support formal meta‐analysis.13 Thus, variability in prescribing rates of Beers medications may simply reflect individual clinical judgment in the absence of conclusive outcomes data.

Third question: Can hospitalists use the findings of Rothberg and colleagues to improve the quality of medication prescribing for older adults in their institutions? Maybe. But hospitalists wishing to reduce PIM use in their institutions should draw lessons from other efforts to modify physician‐prescribing practice such as efforts to reduce inappropriate antimicrobial use. Although national data draw attention to the high frequency of potentially inappropriate medication use in hospitalized patients, the large variation in use across hospitals confirms the need for monitoring in individual facilities. For example, the National Healthcare Safety Network provides national benchmarks of antimicrobial use and resistance, but individual hospitals monitor antibiotic use and resistance in their own institutions to tailor local efforts to improve antimicrobial prescribing.14

Also, initiating a quality improvement effort targeting all 48 Beers criteria medications may be an inefficient use of resources. Using such a composite measure obscures the contribution of the component medications, each of which possesses unique and sometimes controversial profiles of efficacy and harm for older patients. Instead, a targeted intervention addressing the most commonly prescribed Beers medications that have widely accepted alternatives could be more practical. For instance, many antibiotic management programs focus on replacing a popular, extended‐spectrum antimicrobial with a narrow‐spectrum agent as soon as microbiological susceptibly results are available.

Propoxephene is a PIM that may be an attractive target for intervention. Propoxephene was the third most commonly prescribed PIM identified by Rothberg and colleagues, but meta‐analyses of controlled trials have concluded that propoxephene provides inferior analgesia for acute pain compared with that provided by other opioids with similar side effects, and has more adverse effects than nonopioid analgesics.15 Indeed, Rothberg found that just 3 of 48 PIMs (promethazine, diphenhydramine, and propoxyphene), each of which has viable alternative agents, accounted for approximately a quarter of all potentially inappropriate prescribing.

However, not all of the 48 Beers medications have alternatives with strong evidence of superiority. The Beers list includes medications (eg, amiodarone) that may not have equivalent alternative agents. On the other hand, some Beers medications have largely been supplanted (eg, ticlopidine or tripelennamine), and identifying these medications may be an inefficient use of scarce patient safety resources. As with antimicrobial stewardship programs, local surveillance of PIM use should be combined with local consensus on appropriate alternatives to target PIM interventions.

Of course, once specific PIM use is targeted for improvement, a specific intervention must be implemented. Only a handful of studies have examined the effectiveness of interventions (eg, computerized pharmacy alerts) to reduce PIM use, and most of these have focused on the outpatient setting rather than hospitalized patients.3 One study that included hospitalized patients utilized a team approach (geriatricians, nurses, social workers, and pharmacists) and demonstrated a reduction in potentially inappropriate medication use but no reduction in adverse drug reactions during hospitalization.16 In light of the scarcity of controlled intervention trials to reduce PIM use, initiatives to reduce inappropriate antimicrobial prescribing may provide useful insights into the strengths and limitations of approaches such as clinician education, formulary restrictions, pharmacist review, and computer‐based monitoring.17

Finally, any intervention to reduce PIM use should have reasonable expectations. The Beers criteria were developed to improve the effectiveness of medication therapy for older adults as well as to prevent harm, but it is unlikely that reducing PIM use in hospitalized patients will result in improvements that could be measured easily during an initial hospitalization. If preventing drug‐induced harm during the hospitalization of older patients is the primary concern, a shift in focus is required. Safety efforts should be concentrated on identifying and mitigating the most common and severe adverse drug events, rather than focusing efforts on reducing the use of PIMs. National data demonstrate that a handful of drugsinsulin, warfarin, and digoxinmost commonly cause severe adverse events in older outpatients.18 Optimizing the management of these medications may be another approach for improving drug safety in hospitalized patients. Regardless of the focus of a drug safety intervention, the experience of infection control and hospital epidemiology programs suggests that success will require dedicated professionals and the commitment of resources to examine patterns of local use, implement interventions, and monitor outcomes.

Medications are central to managing the health of older patients. In 2006, more than 93% of adults 65 years or older reported taking at least 1 medication in the last week, 58% reported taking 5 or more medications, and 18% reported taking 10 or more.1 Medication use by older adults will likely increase further as the U.S. population ages, new drugs are developed, and new therapeutic and preventive uses for medications are discovered.2

Older patients, especially those who are chronically frail or acutely ill, may require special consideration when making prescribing decisions because of age‐related changes in the metabolism and clearance of medications and enhanced pharmacodynamic sensitivities.3 Thus, panels of experts in pharmacology and geriatrics have compiled lists of medications to avoid prescribing for patients 65 years of age or older. The most commonly used list is the Beers criteria, which were introduced in 1991 to serve researchers evaluating prescribing quality in nursing homes. The Beers criteria were updated in 1997 and again in 2003 to include 48 potentially inappropriate medications (PIMs) for which, according to the consensus panel, there are more effective or safer alternatives for older patients.4

Numerous studies in the last 15 years have found that PIMs continue to be used in 12% to 40% of older patients in community and nursing home settings.5 To address the continued use of PIMs, the Centers for Medicare and Medicaid Services incorporated the Beers criteria into federal safety regulations for long‐term care facilities in 1999.6 In 2006, the prescription rate of PIMs was introduced as a Health Plan and Employer Data and Information Set (HEDIS) quality measure for managed care plans.7 Despite adoption of the Beers criteria to monitor prescribing quality and safety in nursing homes and outpatient settings, there has been considerably less study of potentially inappropriate medication use in hospitalized patients.

In this issue of the Journal of Hospital Medicine, Rothberg and colleagues analyzed administrative data from nearly 400 hospitals across the United States and found that nearly half of all older patients hospitalized for 7 common conditions were prescribed at least 1 PIM.8 Thus, the incidence of PIM use in hospitalized older patients far exceeded that reported in most studies of community‐dwelling or nursing home patients. Most notable, however, was the variability found in prescribing rates based on a number of physician and hospital characteristics. For example, although hospitalists and geriatricians were found to be less likely to prescribe PIMs than cardiologists and general internists, among high‐volume cardiologists and internists, PIM prescribing rates ranged widely, from 0% to more than 90%. Similarly, hospitalwide prescribing rates varied by geographic region, and there were 7 hospitals in which not a single PIM was reportedly prescribed.

These findings raise three questions and bring to mind parallels with efforts to control inappropriate antimicrobial use. First question: Can inpatient use of PIMs truly be higher than outpatient use? Yes. The finding that more hospitalized patients are prescribed PIMs than ambulatory patients has face validity for several reasons. First, patients admitted for an acute hospitalization may have more comorbid diseases and take more medications than community‐dwelling older adults. Second, new medications are typically added to treat acutely ill patients on hospitalization. Third, previous studies estimating outpatient PIM use have typically used more narrowly defined lists of PIMs and have not captured over‐the‐counter use of PIMs, particularly antihistamines.9 Diphenhydramine alone accounted for 9% of PIM use in Rothberg's study. Finally, as Rothberg and colleagues point out, this study was limited to certain diagnoses such as acute myocardial infarction that may have protocol‐driven prescribing, which includes PIMs, that may be used only a single time such as promethazine.

Second question: Can PIM prescribing truly be so variable across regions, specialties, and individual hospitals and physicians? Yes. Using multivariable modeling, Rothberg and colleagues controlled for many patient, hospital, and physician characteristics and still found significant variation. John Wennberg and others have documented similar variations for a host of medical treatments; but although variation is interesting, it is unwarranted variation that matters for improving health care quality.10 It is not clear how much of the variation in prescribing rates of PIMs is unwarranted.

Some degree of variation in PIM prescribing rates is certainly acceptable. As the creators of the Beers criteria acknowledge, these medications are deemed only potentially inappropriate, and individual treatment decisions should be tailored to individual patients. However, others have taken the term potentially inappropriate one step further by recategorizing Beers medications as always avoid medications, rarely acceptable medications, and medications that indeed have some indications for use in older adults.8

Variation in prescribing practice may also be acceptable when there is not a clear consensus on the superiority of one practice over another. Indeed, the evidence that PIM prescribing causes large numbers of clinically significant adverse drug events and patient harm is weak and largely based on observational studies with inconsistent results. Although some studies demonstrated an epidemiological association between Beers criteria medications and general adverse outcomes (eg, hospitalizations),11 other studies did not.12 A recent systematic review concluded that Beers criteria medications were associated with some adverse health effects, but the studies analyzed were too heterogeneous to support formal meta‐analysis.13 Thus, variability in prescribing rates of Beers medications may simply reflect individual clinical judgment in the absence of conclusive outcomes data.

Third question: Can hospitalists use the findings of Rothberg and colleagues to improve the quality of medication prescribing for older adults in their institutions? Maybe. But hospitalists wishing to reduce PIM use in their institutions should draw lessons from other efforts to modify physician‐prescribing practice such as efforts to reduce inappropriate antimicrobial use. Although national data draw attention to the high frequency of potentially inappropriate medication use in hospitalized patients, the large variation in use across hospitals confirms the need for monitoring in individual facilities. For example, the National Healthcare Safety Network provides national benchmarks of antimicrobial use and resistance, but individual hospitals monitor antibiotic use and resistance in their own institutions to tailor local efforts to improve antimicrobial prescribing.14

Also, initiating a quality improvement effort targeting all 48 Beers criteria medications may be an inefficient use of resources. Using such a composite measure obscures the contribution of the component medications, each of which possesses unique and sometimes controversial profiles of efficacy and harm for older patients. Instead, a targeted intervention addressing the most commonly prescribed Beers medications that have widely accepted alternatives could be more practical. For instance, many antibiotic management programs focus on replacing a popular, extended‐spectrum antimicrobial with a narrow‐spectrum agent as soon as microbiological susceptibly results are available.

Propoxephene is a PIM that may be an attractive target for intervention. Propoxephene was the third most commonly prescribed PIM identified by Rothberg and colleagues, but meta‐analyses of controlled trials have concluded that propoxephene provides inferior analgesia for acute pain compared with that provided by other opioids with similar side effects, and has more adverse effects than nonopioid analgesics.15 Indeed, Rothberg found that just 3 of 48 PIMs (promethazine, diphenhydramine, and propoxyphene), each of which has viable alternative agents, accounted for approximately a quarter of all potentially inappropriate prescribing.

However, not all of the 48 Beers medications have alternatives with strong evidence of superiority. The Beers list includes medications (eg, amiodarone) that may not have equivalent alternative agents. On the other hand, some Beers medications have largely been supplanted (eg, ticlopidine or tripelennamine), and identifying these medications may be an inefficient use of scarce patient safety resources. As with antimicrobial stewardship programs, local surveillance of PIM use should be combined with local consensus on appropriate alternatives to target PIM interventions.

Of course, once specific PIM use is targeted for improvement, a specific intervention must be implemented. Only a handful of studies have examined the effectiveness of interventions (eg, computerized pharmacy alerts) to reduce PIM use, and most of these have focused on the outpatient setting rather than hospitalized patients.3 One study that included hospitalized patients utilized a team approach (geriatricians, nurses, social workers, and pharmacists) and demonstrated a reduction in potentially inappropriate medication use but no reduction in adverse drug reactions during hospitalization.16 In light of the scarcity of controlled intervention trials to reduce PIM use, initiatives to reduce inappropriate antimicrobial prescribing may provide useful insights into the strengths and limitations of approaches such as clinician education, formulary restrictions, pharmacist review, and computer‐based monitoring.17

Finally, any intervention to reduce PIM use should have reasonable expectations. The Beers criteria were developed to improve the effectiveness of medication therapy for older adults as well as to prevent harm, but it is unlikely that reducing PIM use in hospitalized patients will result in improvements that could be measured easily during an initial hospitalization. If preventing drug‐induced harm during the hospitalization of older patients is the primary concern, a shift in focus is required. Safety efforts should be concentrated on identifying and mitigating the most common and severe adverse drug events, rather than focusing efforts on reducing the use of PIMs. National data demonstrate that a handful of drugsinsulin, warfarin, and digoxinmost commonly cause severe adverse events in older outpatients.18 Optimizing the management of these medications may be another approach for improving drug safety in hospitalized patients. Regardless of the focus of a drug safety intervention, the experience of infection control and hospital epidemiology programs suggests that success will require dedicated professionals and the commitment of resources to examine patterns of local use, implement interventions, and monitor outcomes.

A 23‐year‐old Chinese woman presented with worsening exertional dyspnea. Her medical history was notable for pulmonary tuberculosis treated at the age of 16. Over the past 3 years, she reported progressive respiratory symptoms resulting in marked exercise intolerance. She denied any fevers, cough, or weight loss. On examination, she had right‐sided tracheal deviation but spoke comfortably. Her heart sounds were displaced and right‐sided breath sounds nearly absent. Chest x‐ray (Fig. 1) and subsequent CT revealed complete collapse of the right lung with associated hyperexpansion of the left lung and left‐to‐right mediastinal shift (Fig. 2, with an asterisk denoting the aortic arch; an arrow, the right main‐stem bronchus, which would soon terminate; and arrowheads, the collapsed right lung). No lung masses or effusions were noted; active TB had been ruled out with AFB sputums. Bronchoscopy revealed a fibrotic and stenotic right main‐stem bronchus (Fig. 3, with an asterisk denoting a patent left main‐stem bronchus and an arrow denoting a stenotic right main‐stem bronchus). Pulmonary manifestations of TB include parenchymal and endobronchial disease. Patients more likely to develop endobronchial disease include those with extensive pulmonary involvement, particularly cavitary lesions. Between 10% and 20% of patients with endobronchial disease will have normal CXRs, though CT scans may reveal endobronchial lesions or narrowing. Complications of endobronchial disease include obstruction, bronchiectasis, and tracheal or bronchial stenosis. Some airway obstructions may be associated with enlarging peribronchial nodes, which may erode into the airways as broncholiths. Steroids have been used to prevent long‐term complications, but their efficacy is still unclear. Repeated dilation, stenting, and resection all serve as management options for advanced endobronchial disease. In our patient, the extensive bronchial scarring and stenosis were most likely complications from past endobronchial infection. Unfortunately, attempts at balloon dilatation of her right main‐stem bronchus were unsuccessful, and she continues to have considerable exercise limitation. More prompt recognition of the disease may have allowed for an earlier and more successful intervention.

Figure 1

Figure 2

Figure 3

A 23‐year‐old Chinese woman presented with worsening exertional dyspnea. Her medical history was notable for pulmonary tuberculosis treated at the age of 16. Over the past 3 years, she reported progressive respiratory symptoms resulting in marked exercise intolerance. She denied any fevers, cough, or weight loss. On examination, she had right‐sided tracheal deviation but spoke comfortably. Her heart sounds were displaced and right‐sided breath sounds nearly absent. Chest x‐ray (Fig. 1) and subsequent CT revealed complete collapse of the right lung with associated hyperexpansion of the left lung and left‐to‐right mediastinal shift (Fig. 2, with an asterisk denoting the aortic arch; an arrow, the right main‐stem bronchus, which would soon terminate; and arrowheads, the collapsed right lung). No lung masses or effusions were noted; active TB had been ruled out with AFB sputums. Bronchoscopy revealed a fibrotic and stenotic right main‐stem bronchus (Fig. 3, with an asterisk denoting a patent left main‐stem bronchus and an arrow denoting a stenotic right main‐stem bronchus). Pulmonary manifestations of TB include parenchymal and endobronchial disease. Patients more likely to develop endobronchial disease include those with extensive pulmonary involvement, particularly cavitary lesions. Between 10% and 20% of patients with endobronchial disease will have normal CXRs, though CT scans may reveal endobronchial lesions or narrowing. Complications of endobronchial disease include obstruction, bronchiectasis, and tracheal or bronchial stenosis. Some airway obstructions may be associated with enlarging peribronchial nodes, which may erode into the airways as broncholiths. Steroids have been used to prevent long‐term complications, but their efficacy is still unclear. Repeated dilation, stenting, and resection all serve as management options for advanced endobronchial disease. In our patient, the extensive bronchial scarring and stenosis were most likely complications from past endobronchial infection. Unfortunately, attempts at balloon dilatation of her right main‐stem bronchus were unsuccessful, and she continues to have considerable exercise limitation. More prompt recognition of the disease may have allowed for an earlier and more successful intervention.

Figure 1

Figure 2

Figure 3

A 23‐year‐old Chinese woman presented with worsening exertional dyspnea. Her medical history was notable for pulmonary tuberculosis treated at the age of 16. Over the past 3 years, she reported progressive respiratory symptoms resulting in marked exercise intolerance. She denied any fevers, cough, or weight loss. On examination, she had right‐sided tracheal deviation but spoke comfortably. Her heart sounds were displaced and right‐sided breath sounds nearly absent. Chest x‐ray (Fig. 1) and subsequent CT revealed complete collapse of the right lung with associated hyperexpansion of the left lung and left‐to‐right mediastinal shift (Fig. 2, with an asterisk denoting the aortic arch; an arrow, the right main‐stem bronchus, which would soon terminate; and arrowheads, the collapsed right lung). No lung masses or effusions were noted; active TB had been ruled out with AFB sputums. Bronchoscopy revealed a fibrotic and stenotic right main‐stem bronchus (Fig. 3, with an asterisk denoting a patent left main‐stem bronchus and an arrow denoting a stenotic right main‐stem bronchus). Pulmonary manifestations of TB include parenchymal and endobronchial disease. Patients more likely to develop endobronchial disease include those with extensive pulmonary involvement, particularly cavitary lesions. Between 10% and 20% of patients with endobronchial disease will have normal CXRs, though CT scans may reveal endobronchial lesions or narrowing. Complications of endobronchial disease include obstruction, bronchiectasis, and tracheal or bronchial stenosis. Some airway obstructions may be associated with enlarging peribronchial nodes, which may erode into the airways as broncholiths. Steroids have been used to prevent long‐term complications, but their efficacy is still unclear. Repeated dilation, stenting, and resection all serve as management options for advanced endobronchial disease. In our patient, the extensive bronchial scarring and stenosis were most likely complications from past endobronchial infection. Unfortunately, attempts at balloon dilatation of her right main‐stem bronchus were unsuccessful, and she continues to have considerable exercise limitation. More prompt recognition of the disease may have allowed for an earlier and more successful intervention.

Figure 1

Figure 2

Figure 3

Peripheral arterial disease (PAD) is defined by the presence of stenosis or occlusion in peripheral arterial beds.1, 2 Based on large population‐based screening surveys, the prevalence of this disease ranges between 5.5% and 26.7% and is dependent on age, atherothrombotic risk factors, and the coexistence of other atherothrombotic diseases.35 Symptoms of PAD include mild to intermittent claudication, ischemic rest pain, and tissue loss.2 Disease severity is classified according to either Fontaine's stages or Rutherford categories. These categorization schema have value in improving communication between physicians, which is important in ensuring continuity of care between the inpatient and outpatient settings (Table 1).2

Patients with PAD are at increased risk of dying from or experiencing a cardiovascular event.68 Among patients diagnosed with PAD, coronary artery disease (CAD), or cerebrovascular disease (CVD), those with PAD have the highest 1‐year rate of cardiovascular death, MI, stroke, or vascular‐related hospitalization (Fig. 1).8 This risk is attributable in part to the high rate of association of PAD with other atherothrombotic diseases. The Reduction of Atherothrombosis for Continued Health (REACH) Registry found that approximately 60% of participants with documented PAD have polyvascular disease, defined by the coexistence of CAD and/or CVD. In comparison, 25% of participants with CAD and 40% of participants with CVD have polyvascular disease.8 Thus, PAD can be considered a powerful indicator of systemic atherothrombotic disease and a predictor of cardiovascular and cerebrovascular morbidity and mortality.1

Figure 1

Unfortunately, asymptomatic PAD is more common than its symptomatic counterpart.3 In addition, symptomatic patients often fail to notify their physicians about PAD‐associated symptoms because they attribute them to aging.3 As a result, this disease is underdiagnosed and undertreated.1 Accordingly, several medical associations and physician task forces have called for an increase in screening for PAD in at‐risk populations that include: patients older than 70, patients older than 50 who have concomitant atherothrombotic risk factors, and patients with atherothrombotic disease of single or multiple vascular beds.1, 9 In many cases hospitalists encounter patients at high‐risk for PAD whose DRG for admission might be unrelated to this disease. Nonetheless, hospitalists have the opportunity to improve patient outcomes by being capable of screening for undiagnosed PAD and initiating appropriate interventions to reduce the risk of life‐threatening cardiovascular events.

DIAGNOSIS

Peripheral arterial disease can be diagnosed by either noninvasive or invasive methods. The ankle‐to‐brachial index (ABI) is an accurate, practical, inexpensive, and noninvasive method for detecting PAD.1 The sensitivity of ABI in detecting PAD is 95% with 99% specificity,10 which makes the method superior to other indicators (eg, absence of a pedal pulse, presence of a femoral arterial bruit, slow venous filling, or cold/abnormally colored skin) assessed during a physical examination.11 Under normal conditions, the systolic pressure at the ankle should be equal to or greater than that recorded from the upper arm. As PAD narrows arteries, the systolic pressure decreases at sites distal to the area of arterial narrowing. A resting ABI is quantified by taking 2 readings each of ankle and brachial blood pressures with a handheld Doppler device while the patient is supine and dividing the highest ankle systolic pressure by the highest brachial pressure.12

An ABI between 0.9 and 1.30 is considered normal. Ratios between 0.7 and 0.89 indicate mild PAD, 0.4 and 0.69 moderate PAD, and an ABI < 0.4 severe PAD when patients are more likely to have ischemic pain when at rest. An ABI > 1.3 usually indicates the presence of noncompressible vessels, which can be common in the elderly and patients with diabetes mellitus who have calcification of the distal arteries.1, 2 The ABI is also inversely related to the number of atherosclerotic risk factors and the risk of adverse cardiovascular events and death.6, 1316 To identify individuals with suspected or asymptomatic lower‐extremity PAD, ABI has a class I recommendation from the American College of Cardiology and American Heart Association (ACC/AHA) for patients who present with leg symptoms, who are 70 years and older, or who are 50 years and older with a history of smoking or diabetes.2 This enables physicians to make therapeutic interventions to reduce the risk of adverse vascular events in these patient cohorts.

Additional detection methods for PAD include measuring the ABI before and after exercise on a treadmill, if the patient is ambulatory, or exercise by performing 50 repetitions of raising the heels maximally off the floor, if the patient is not ambulatory. These tests determine the extent of claudication.2 Duplex ultrasound is used to establish the location and severity of stenosis and to follow PAD progression.2

Invasive evaluations for PAD are used primarily to confirm an initial diagnosis of PAD and assess its severity. These methods include a conventional angiogram, which is the most readily available and widely used technique for defining arterial stenosis. Magnetic resonance (MR) angiography with gadolinium and computed tomographic (CT) angiography are used to determine the location and degree of stenosis. Both MR and CT angiography have advantages and disadvantages but are considered interchangeable with one another in patients with contraindications to either method (Table 2).2

ANTIPLATELET THERAPY FOR REDUCTION OF VASCULAR EVENTS

Hospitalists utilize a wide array of therapies to treat and manage PAD. Acute complications of PAD may require interventions to prevent tissue loss or infection, revascularization procedures, or surgical amputation. Treatment of mild to moderate PAD focuses on atherothrombotic risk factor management, exercise therapy to improve limb function, and interventions to reduce the risk of adverse vascular events.2, 9 The remainder of this report focuses on the role of antiplatelet therapy (eg, aspirin and thienopyridines) in reducing the risk of vascular events in patients with PAD.

The Antiplatelet Trialists' Collaboration performed an overview analysis of randomized trials conducted prior to 1990 in order to determine the association of prolonged antiplatelet therapy with the occurrence of major vascular events. As a whole, therapies thought to act through inhibition of platelet aggregation, adhesion, or both reduced the incidence of vascular events by 33% in patients with PAD and those at high risk, and by 25% in all patient groups. Antiplatelet agents were also well tolerated; the absolute risk of fatal or nonmajor hemorrhage was low.17

A similar meta‐analysis was conducted of antiplatelet therapies in high‐risk patients with atherothrombosis by the Antithrombotic Trialists' Collaboration. Antiplatelet therapies taken together reduced the odds of patients experiencing vascular events by 22% (SE = 2%) across all trials and 23% (SE = 8%) in patients with PAD.18 Similar to the Antiplatelet Trialists' Collaboration study, the absolute risk of major and minor bleeding was low compared to the benefits of antiplatelet therapy.18 The results of these studies provide supporting evidence for the ACC/AHA class I recommendation for the use of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death in patients with PAD.

The Antithrombotic Trialists' Collaboration also examined the risk reduction associated with a specific antiplatelet agent, aspirin. All doses of aspirin (75‐150, 160‐325, and 500‐1500 mg/day) reduced the odds by 23% (SE = 2%); high doses were no more effective than medium or low doses.18 Although the effects of aspirin was not analyzed in a subgroup analysis of patients with PAD, this study and others support the ACC/AHA class I recommendations for the use of aspirin to reduce the risk of MI, stroke, or vascular death in patients with PAD.2, 1921

The CAPRIE trial compared the efficacy of another antiplatelet agent, clopidogrel, against aspirin in patients with PAD.22 Patients with a history of recent ischemic stroke, MI, or symptomatic PAD were randomized to receive either clopidogrel (75 mg/day) or aspirin (325 mg/day) for 1‐3 years (mean follow‐up time, 1.91 years). Study outcomes were the incidence of nonfatal MI, ischemic stroke, hemorrhagic stroke, leg amputation, and vascular deaths. The absolute risk reduction for all patients was 8.7% (95% confidence interval [CI], 0.3%‐16.5%) in favor of clopidogrel over aspirin. Moreover, subgroup analysis in patients with PAD revealed that clopidogrel reduced the risk of a vascular event by 23.8% (95% CI, 8.9%‐36.2%; P = 0.0028) compared with aspirin (Fig. 2). Clopidogrel and aspirin had similar safety profiles, but other studies have revealed bleeding incidence is numerically greater in patients treated with clopidogrel.2224 Although the CAPRIE trial is the only study to date to compare the efficacy of clopidogrel over aspirin in reducing vascular event in patients with PAD, its outcomes underlie the class I ACC/AHA recommendation for clopidogrel (75 mg/day) as an effective alternative to aspirin to reduce the risk of MI, stroke, or death in patients with PAD.2

Figure 2

CONCLUSIONS

Despite the availability of accurate, practical, and inexpensive diagnostic testing, PAD remains underdiagnosed and undertreated. Early detection of PAD and subsequent intervention by hospitalists are important because peripheral arterial disease is strongly associated with an increased risk of mortality and morbidity from adverse vascular events. The ACC/AHA recommends screening for asymptomatic patients at risk for this disease so that therapies that reduce the risk of an MI, stroke, or vascular death can be administered immediately. Antiplatelet agents reduce the risk of adverse vascular events in patients with PAD. The use of aspirin or clopidogrel is recommended in this cohort of patients. However, further study is necessary to determine the efficacy and safety of combination therapy with aspirin and clopidogrel in patients with PAD. It is also important to note that coordination of care between hospitalists and cardiologists is critical in the management of patients with this disease. However, the appropriate handoff of patients between these 2 groups of physicians depends on the local expertise and support structure of these health care professionals. Thus, an interdisciplinary approach utilizing guideline‐based patient care will allow hospitalists to refer patients accordingly, ensuring optimal outcomes in patients with PAD.

Peripheral arterial disease (PAD) is defined by the presence of stenosis or occlusion in peripheral arterial beds.1, 2 Based on large population‐based screening surveys, the prevalence of this disease ranges between 5.5% and 26.7% and is dependent on age, atherothrombotic risk factors, and the coexistence of other atherothrombotic diseases.35 Symptoms of PAD include mild to intermittent claudication, ischemic rest pain, and tissue loss.2 Disease severity is classified according to either Fontaine's stages or Rutherford categories. These categorization schema have value in improving communication between physicians, which is important in ensuring continuity of care between the inpatient and outpatient settings (Table 1).2

Patients with PAD are at increased risk of dying from or experiencing a cardiovascular event.68 Among patients diagnosed with PAD, coronary artery disease (CAD), or cerebrovascular disease (CVD), those with PAD have the highest 1‐year rate of cardiovascular death, MI, stroke, or vascular‐related hospitalization (Fig. 1).8 This risk is attributable in part to the high rate of association of PAD with other atherothrombotic diseases. The Reduction of Atherothrombosis for Continued Health (REACH) Registry found that approximately 60% of participants with documented PAD have polyvascular disease, defined by the coexistence of CAD and/or CVD. In comparison, 25% of participants with CAD and 40% of participants with CVD have polyvascular disease.8 Thus, PAD can be considered a powerful indicator of systemic atherothrombotic disease and a predictor of cardiovascular and cerebrovascular morbidity and mortality.1

Figure 1

Unfortunately, asymptomatic PAD is more common than its symptomatic counterpart.3 In addition, symptomatic patients often fail to notify their physicians about PAD‐associated symptoms because they attribute them to aging.3 As a result, this disease is underdiagnosed and undertreated.1 Accordingly, several medical associations and physician task forces have called for an increase in screening for PAD in at‐risk populations that include: patients older than 70, patients older than 50 who have concomitant atherothrombotic risk factors, and patients with atherothrombotic disease of single or multiple vascular beds.1, 9 In many cases hospitalists encounter patients at high‐risk for PAD whose DRG for admission might be unrelated to this disease. Nonetheless, hospitalists have the opportunity to improve patient outcomes by being capable of screening for undiagnosed PAD and initiating appropriate interventions to reduce the risk of life‐threatening cardiovascular events.

DIAGNOSIS

Peripheral arterial disease can be diagnosed by either noninvasive or invasive methods. The ankle‐to‐brachial index (ABI) is an accurate, practical, inexpensive, and noninvasive method for detecting PAD.1 The sensitivity of ABI in detecting PAD is 95% with 99% specificity,10 which makes the method superior to other indicators (eg, absence of a pedal pulse, presence of a femoral arterial bruit, slow venous filling, or cold/abnormally colored skin) assessed during a physical examination.11 Under normal conditions, the systolic pressure at the ankle should be equal to or greater than that recorded from the upper arm. As PAD narrows arteries, the systolic pressure decreases at sites distal to the area of arterial narrowing. A resting ABI is quantified by taking 2 readings each of ankle and brachial blood pressures with a handheld Doppler device while the patient is supine and dividing the highest ankle systolic pressure by the highest brachial pressure.12

An ABI between 0.9 and 1.30 is considered normal. Ratios between 0.7 and 0.89 indicate mild PAD, 0.4 and 0.69 moderate PAD, and an ABI < 0.4 severe PAD when patients are more likely to have ischemic pain when at rest. An ABI > 1.3 usually indicates the presence of noncompressible vessels, which can be common in the elderly and patients with diabetes mellitus who have calcification of the distal arteries.1, 2 The ABI is also inversely related to the number of atherosclerotic risk factors and the risk of adverse cardiovascular events and death.6, 1316 To identify individuals with suspected or asymptomatic lower‐extremity PAD, ABI has a class I recommendation from the American College of Cardiology and American Heart Association (ACC/AHA) for patients who present with leg symptoms, who are 70 years and older, or who are 50 years and older with a history of smoking or diabetes.2 This enables physicians to make therapeutic interventions to reduce the risk of adverse vascular events in these patient cohorts.

Additional detection methods for PAD include measuring the ABI before and after exercise on a treadmill, if the patient is ambulatory, or exercise by performing 50 repetitions of raising the heels maximally off the floor, if the patient is not ambulatory. These tests determine the extent of claudication.2 Duplex ultrasound is used to establish the location and severity of stenosis and to follow PAD progression.2

Invasive evaluations for PAD are used primarily to confirm an initial diagnosis of PAD and assess its severity. These methods include a conventional angiogram, which is the most readily available and widely used technique for defining arterial stenosis. Magnetic resonance (MR) angiography with gadolinium and computed tomographic (CT) angiography are used to determine the location and degree of stenosis. Both MR and CT angiography have advantages and disadvantages but are considered interchangeable with one another in patients with contraindications to either method (Table 2).2

ANTIPLATELET THERAPY FOR REDUCTION OF VASCULAR EVENTS

Hospitalists utilize a wide array of therapies to treat and manage PAD. Acute complications of PAD may require interventions to prevent tissue loss or infection, revascularization procedures, or surgical amputation. Treatment of mild to moderate PAD focuses on atherothrombotic risk factor management, exercise therapy to improve limb function, and interventions to reduce the risk of adverse vascular events.2, 9 The remainder of this report focuses on the role of antiplatelet therapy (eg, aspirin and thienopyridines) in reducing the risk of vascular events in patients with PAD.

The Antiplatelet Trialists' Collaboration performed an overview analysis of randomized trials conducted prior to 1990 in order to determine the association of prolonged antiplatelet therapy with the occurrence of major vascular events. As a whole, therapies thought to act through inhibition of platelet aggregation, adhesion, or both reduced the incidence of vascular events by 33% in patients with PAD and those at high risk, and by 25% in all patient groups. Antiplatelet agents were also well tolerated; the absolute risk of fatal or nonmajor hemorrhage was low.17

A similar meta‐analysis was conducted of antiplatelet therapies in high‐risk patients with atherothrombosis by the Antithrombotic Trialists' Collaboration. Antiplatelet therapies taken together reduced the odds of patients experiencing vascular events by 22% (SE = 2%) across all trials and 23% (SE = 8%) in patients with PAD.18 Similar to the Antiplatelet Trialists' Collaboration study, the absolute risk of major and minor bleeding was low compared to the benefits of antiplatelet therapy.18 The results of these studies provide supporting evidence for the ACC/AHA class I recommendation for the use of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death in patients with PAD.

The Antithrombotic Trialists' Collaboration also examined the risk reduction associated with a specific antiplatelet agent, aspirin. All doses of aspirin (75‐150, 160‐325, and 500‐1500 mg/day) reduced the odds by 23% (SE = 2%); high doses were no more effective than medium or low doses.18 Although the effects of aspirin was not analyzed in a subgroup analysis of patients with PAD, this study and others support the ACC/AHA class I recommendations for the use of aspirin to reduce the risk of MI, stroke, or vascular death in patients with PAD.2, 1921

The CAPRIE trial compared the efficacy of another antiplatelet agent, clopidogrel, against aspirin in patients with PAD.22 Patients with a history of recent ischemic stroke, MI, or symptomatic PAD were randomized to receive either clopidogrel (75 mg/day) or aspirin (325 mg/day) for 1‐3 years (mean follow‐up time, 1.91 years). Study outcomes were the incidence of nonfatal MI, ischemic stroke, hemorrhagic stroke, leg amputation, and vascular deaths. The absolute risk reduction for all patients was 8.7% (95% confidence interval [CI], 0.3%‐16.5%) in favor of clopidogrel over aspirin. Moreover, subgroup analysis in patients with PAD revealed that clopidogrel reduced the risk of a vascular event by 23.8% (95% CI, 8.9%‐36.2%; P = 0.0028) compared with aspirin (Fig. 2). Clopidogrel and aspirin had similar safety profiles, but other studies have revealed bleeding incidence is numerically greater in patients treated with clopidogrel.2224 Although the CAPRIE trial is the only study to date to compare the efficacy of clopidogrel over aspirin in reducing vascular event in patients with PAD, its outcomes underlie the class I ACC/AHA recommendation for clopidogrel (75 mg/day) as an effective alternative to aspirin to reduce the risk of MI, stroke, or death in patients with PAD.2

Figure 2

CONCLUSIONS

Despite the availability of accurate, practical, and inexpensive diagnostic testing, PAD remains underdiagnosed and undertreated. Early detection of PAD and subsequent intervention by hospitalists are important because peripheral arterial disease is strongly associated with an increased risk of mortality and morbidity from adverse vascular events. The ACC/AHA recommends screening for asymptomatic patients at risk for this disease so that therapies that reduce the risk of an MI, stroke, or vascular death can be administered immediately. Antiplatelet agents reduce the risk of adverse vascular events in patients with PAD. The use of aspirin or clopidogrel is recommended in this cohort of patients. However, further study is necessary to determine the efficacy and safety of combination therapy with aspirin and clopidogrel in patients with PAD. It is also important to note that coordination of care between hospitalists and cardiologists is critical in the management of patients with this disease. However, the appropriate handoff of patients between these 2 groups of physicians depends on the local expertise and support structure of these health care professionals. Thus, an interdisciplinary approach utilizing guideline‐based patient care will allow hospitalists to refer patients accordingly, ensuring optimal outcomes in patients with PAD.

Peripheral arterial disease (PAD) is defined by the presence of stenosis or occlusion in peripheral arterial beds.1, 2 Based on large population‐based screening surveys, the prevalence of this disease ranges between 5.5% and 26.7% and is dependent on age, atherothrombotic risk factors, and the coexistence of other atherothrombotic diseases.35 Symptoms of PAD include mild to intermittent claudication, ischemic rest pain, and tissue loss.2 Disease severity is classified according to either Fontaine's stages or Rutherford categories. These categorization schema have value in improving communication between physicians, which is important in ensuring continuity of care between the inpatient and outpatient settings (Table 1).2

Patients with PAD are at increased risk of dying from or experiencing a cardiovascular event.68 Among patients diagnosed with PAD, coronary artery disease (CAD), or cerebrovascular disease (CVD), those with PAD have the highest 1‐year rate of cardiovascular death, MI, stroke, or vascular‐related hospitalization (Fig. 1).8 This risk is attributable in part to the high rate of association of PAD with other atherothrombotic diseases. The Reduction of Atherothrombosis for Continued Health (REACH) Registry found that approximately 60% of participants with documented PAD have polyvascular disease, defined by the coexistence of CAD and/or CVD. In comparison, 25% of participants with CAD and 40% of participants with CVD have polyvascular disease.8 Thus, PAD can be considered a powerful indicator of systemic atherothrombotic disease and a predictor of cardiovascular and cerebrovascular morbidity and mortality.1

Figure 1

Unfortunately, asymptomatic PAD is more common than its symptomatic counterpart.3 In addition, symptomatic patients often fail to notify their physicians about PAD‐associated symptoms because they attribute them to aging.3 As a result, this disease is underdiagnosed and undertreated.1 Accordingly, several medical associations and physician task forces have called for an increase in screening for PAD in at‐risk populations that include: patients older than 70, patients older than 50 who have concomitant atherothrombotic risk factors, and patients with atherothrombotic disease of single or multiple vascular beds.1, 9 In many cases hospitalists encounter patients at high‐risk for PAD whose DRG for admission might be unrelated to this disease. Nonetheless, hospitalists have the opportunity to improve patient outcomes by being capable of screening for undiagnosed PAD and initiating appropriate interventions to reduce the risk of life‐threatening cardiovascular events.

DIAGNOSIS

Peripheral arterial disease can be diagnosed by either noninvasive or invasive methods. The ankle‐to‐brachial index (ABI) is an accurate, practical, inexpensive, and noninvasive method for detecting PAD.1 The sensitivity of ABI in detecting PAD is 95% with 99% specificity,10 which makes the method superior to other indicators (eg, absence of a pedal pulse, presence of a femoral arterial bruit, slow venous filling, or cold/abnormally colored skin) assessed during a physical examination.11 Under normal conditions, the systolic pressure at the ankle should be equal to or greater than that recorded from the upper arm. As PAD narrows arteries, the systolic pressure decreases at sites distal to the area of arterial narrowing. A resting ABI is quantified by taking 2 readings each of ankle and brachial blood pressures with a handheld Doppler device while the patient is supine and dividing the highest ankle systolic pressure by the highest brachial pressure.12

An ABI between 0.9 and 1.30 is considered normal. Ratios between 0.7 and 0.89 indicate mild PAD, 0.4 and 0.69 moderate PAD, and an ABI < 0.4 severe PAD when patients are more likely to have ischemic pain when at rest. An ABI > 1.3 usually indicates the presence of noncompressible vessels, which can be common in the elderly and patients with diabetes mellitus who have calcification of the distal arteries.1, 2 The ABI is also inversely related to the number of atherosclerotic risk factors and the risk of adverse cardiovascular events and death.6, 1316 To identify individuals with suspected or asymptomatic lower‐extremity PAD, ABI has a class I recommendation from the American College of Cardiology and American Heart Association (ACC/AHA) for patients who present with leg symptoms, who are 70 years and older, or who are 50 years and older with a history of smoking or diabetes.2 This enables physicians to make therapeutic interventions to reduce the risk of adverse vascular events in these patient cohorts.

Additional detection methods for PAD include measuring the ABI before and after exercise on a treadmill, if the patient is ambulatory, or exercise by performing 50 repetitions of raising the heels maximally off the floor, if the patient is not ambulatory. These tests determine the extent of claudication.2 Duplex ultrasound is used to establish the location and severity of stenosis and to follow PAD progression.2

Invasive evaluations for PAD are used primarily to confirm an initial diagnosis of PAD and assess its severity. These methods include a conventional angiogram, which is the most readily available and widely used technique for defining arterial stenosis. Magnetic resonance (MR) angiography with gadolinium and computed tomographic (CT) angiography are used to determine the location and degree of stenosis. Both MR and CT angiography have advantages and disadvantages but are considered interchangeable with one another in patients with contraindications to either method (Table 2).2

ANTIPLATELET THERAPY FOR REDUCTION OF VASCULAR EVENTS

Hospitalists utilize a wide array of therapies to treat and manage PAD. Acute complications of PAD may require interventions to prevent tissue loss or infection, revascularization procedures, or surgical amputation. Treatment of mild to moderate PAD focuses on atherothrombotic risk factor management, exercise therapy to improve limb function, and interventions to reduce the risk of adverse vascular events.2, 9 The remainder of this report focuses on the role of antiplatelet therapy (eg, aspirin and thienopyridines) in reducing the risk of vascular events in patients with PAD.

The Antiplatelet Trialists' Collaboration performed an overview analysis of randomized trials conducted prior to 1990 in order to determine the association of prolonged antiplatelet therapy with the occurrence of major vascular events. As a whole, therapies thought to act through inhibition of platelet aggregation, adhesion, or both reduced the incidence of vascular events by 33% in patients with PAD and those at high risk, and by 25% in all patient groups. Antiplatelet agents were also well tolerated; the absolute risk of fatal or nonmajor hemorrhage was low.17

A similar meta‐analysis was conducted of antiplatelet therapies in high‐risk patients with atherothrombosis by the Antithrombotic Trialists' Collaboration. Antiplatelet therapies taken together reduced the odds of patients experiencing vascular events by 22% (SE = 2%) across all trials and 23% (SE = 8%) in patients with PAD.18 Similar to the Antiplatelet Trialists' Collaboration study, the absolute risk of major and minor bleeding was low compared to the benefits of antiplatelet therapy.18 The results of these studies provide supporting evidence for the ACC/AHA class I recommendation for the use of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death in patients with PAD.

The Antithrombotic Trialists' Collaboration also examined the risk reduction associated with a specific antiplatelet agent, aspirin. All doses of aspirin (75‐150, 160‐325, and 500‐1500 mg/day) reduced the odds by 23% (SE = 2%); high doses were no more effective than medium or low doses.18 Although the effects of aspirin was not analyzed in a subgroup analysis of patients with PAD, this study and others support the ACC/AHA class I recommendations for the use of aspirin to reduce the risk of MI, stroke, or vascular death in patients with PAD.2, 1921

The CAPRIE trial compared the efficacy of another antiplatelet agent, clopidogrel, against aspirin in patients with PAD.22 Patients with a history of recent ischemic stroke, MI, or symptomatic PAD were randomized to receive either clopidogrel (75 mg/day) or aspirin (325 mg/day) for 1‐3 years (mean follow‐up time, 1.91 years). Study outcomes were the incidence of nonfatal MI, ischemic stroke, hemorrhagic stroke, leg amputation, and vascular deaths. The absolute risk reduction for all patients was 8.7% (95% confidence interval [CI], 0.3%‐16.5%) in favor of clopidogrel over aspirin. Moreover, subgroup analysis in patients with PAD revealed that clopidogrel reduced the risk of a vascular event by 23.8% (95% CI, 8.9%‐36.2%; P = 0.0028) compared with aspirin (Fig. 2). Clopidogrel and aspirin had similar safety profiles, but other studies have revealed bleeding incidence is numerically greater in patients treated with clopidogrel.2224 Although the CAPRIE trial is the only study to date to compare the efficacy of clopidogrel over aspirin in reducing vascular event in patients with PAD, its outcomes underlie the class I ACC/AHA recommendation for clopidogrel (75 mg/day) as an effective alternative to aspirin to reduce the risk of MI, stroke, or death in patients with PAD.2

Figure 2

CONCLUSIONS

Despite the availability of accurate, practical, and inexpensive diagnostic testing, PAD remains underdiagnosed and undertreated. Early detection of PAD and subsequent intervention by hospitalists are important because peripheral arterial disease is strongly associated with an increased risk of mortality and morbidity from adverse vascular events. The ACC/AHA recommends screening for asymptomatic patients at risk for this disease so that therapies that reduce the risk of an MI, stroke, or vascular death can be administered immediately. Antiplatelet agents reduce the risk of adverse vascular events in patients with PAD. The use of aspirin or clopidogrel is recommended in this cohort of patients. However, further study is necessary to determine the efficacy and safety of combination therapy with aspirin and clopidogrel in patients with PAD. It is also important to note that coordination of care between hospitalists and cardiologists is critical in the management of patients with this disease. However, the appropriate handoff of patients between these 2 groups of physicians depends on the local expertise and support structure of these health care professionals. Thus, an interdisciplinary approach utilizing guideline‐based patient care will allow hospitalists to refer patients accordingly, ensuring optimal outcomes in patients with PAD.

Stroke is the leading cause of disability and the third leading cause of death in the United States.1, 2 Each year approximately 700,000 strokes occur, 88% of which are considered ischemic; they predominately arise from atherothrombotic events in large or small cerebral vessels. Moreover, approximately 200,000 of these events are classified as recurrent.1 Patients who have had a stroke frequently also have coronary artery disease (CAD) and/or peripheral artery disease (PAD), putting them at high risk of adverse vascular events such as myocardial infarction (MI) or sudden vascular death.35 Hospitalists initiate and coordinate aggressive and rapid interventions in the acute care setting in order to minimize stroke progression and thus optimize outcomes. They also initiate long‐term treatments to prevent recurrence and secondary vascular events in the outpatient setting. Thus, the treatment plan developed by the hospitalist on admission is as important as the one created on discharge.

The hospitalist plays a central role in managing stroke. Prior to having an event, patients are at risk. The goal of clinical management is prevention. This is mainly focused on risk factor reduction and aspirin therapy. Outpatient medical providers direct this care. Once a stroke occurs and the victim is admitted to the hospital, the hospitalist becomes this patient's medical care coordinator. In the very acute phase, the goal of management is optimizing outcomes by restoring perfusion to ischemic tissue and minimizing injury progression. There are a number of interventions available to the hospitalist. If patients present within 3 hours of ictus, they may qualify for IV thrombolytic therapy and if within 6 hours for intra‐arterial therapy. If later, aspirin can have beneficial effects on outcomes. Also during this time, it is important to maintain adequate systemic perfusion, oxygenation/ventilation, cardiovascular function, and, importantly, close clinical monitoring.

STROKE MORTALITY

Stroke is a deadly diseaseas deadly as many malignancies. Most patients die of complications of vascular disease (eg, cerebrovascular, cardiovascular, and peripheral vascular diseases). The Oxfordshire Community Stroke Project and Perth Community Stroke Study has indicated that at least 50% of patients die within 5 years of a first‐time acute ischemic or hemorrhagic stroke. The highest risk of death occurs during the first year, with a mortality rate ranging between 31% and 36.5% (95% confidence interval [CI], 27%34% and 31.5%41.4%, respectively).6, 7 Moreover, the risk of death within 30 days after stroke was approximately 20%. The annual risk of death for patients who survived 1 year was 7% and 10% according to the Oxfordshire and Perth studies, respectively, which was approximately 2‐fold higher than that for stroke‐free patients of the same age and sex.6, 7

The proportion of death caused by stroke, recurrent stroke, cardiovascular events, or nonvascular events changes over time (Fig. 1). The Perth study showed that the predominant causes of death within the first 30 days were complications from the incident stroke and, to a lesser degree, recurrent stroke. Over time, cardiovascular events (eg, myocardial infarction, ruptured aortic aneurysms, PAD) become the most common cause of mortality in patients who have had a stroke. However, the risk of death from a recurrent stroke only diminishes slightly with time.7 This trend is consistent with the findings of the Oxfordshire study and the Northern Manhattan Stroke Study, which focused on long‐term survival after first‐ever ischemic stroke.6, 8 Thus, the short‐term goals of treatment implemented by hospitalists are to ensure survival and recovery from the index stroke, and the long‐term goals are to protect against recurrent stroke or secondary vascular events.

Figure 1

MANAGEMENT OF ACUTE ISCHEMIC STROKE

Stroke is no longer an untreatable disease. The introduction of thrombolytic therapy has provided an opportunity for medical providers to significantly improve short‐ and long‐term survival rates and functional outcomes of patients. Most ischemic strokes are caused by thrombotic arterial occlusions. Hence, thrombolytic therapy has been tested and approved for use in patients with acute ischemic stroke.9 The efficacy and safety of the thrombolytic agent, recombinant tissue plasminogen activator (rtPA), were demonstrated in the landmark National Institute of Neurological Disorders and Stroke (NINDS) rtPA Stroke Study.

When compared with patients who received placebo, the odds of a favorable treatment outcome increased by at least 30% in those who received rtPA within 3 hours of the onset of symptoms of an acute ischemic stroke. This benefit was sustained for 612 months.10, 11 Patients who received rtPA were at an increased risk for intracerebral hemorrhage, but this did not translate to an increased risk of death.10 Currently, this thrombolytic agent has a class I recommendation from the American Heart Association and American Stroke Association (AHA/ASA) for its administration within 3 hours of onset of ischemic stroke symptoms in patients who have no sign or history of subarachnoid hemorrhage and who meet the other 21 criteria based on those used in the NINDS study.9

Patients who arrive at the hospital 36 hours after symptom onset or those who have contraindications for IV rtPA may benefit from intra‐arterial administration of thrombolytic agents.12 However, there is no consensus on the optimal dose that should be delivered by intra‐arterial administration.13 In addition, this course of treatment requires rapid access to cerebral angiography and a qualified interventionalist, both of which may not be available to all hospitalists.9

If a patient presents beyond 6 hours, the hospitalist may initiate aspirin therapy, which has been shown to improve outcomes following acute stroke if therapy is begun within 48 hours. A planned meta‐analysis of approximately 40,000 patients with suspected ischemic stroke demonstrated that aspirin therapy proportionally reduces the risk of recurrent stroke and mortality from recurrent stroke or any other cause by 11% 3%. This benefit was apparent as early as 06 hours and as late as 2548 hours following stroke onset (Fig. 2), with only a slight increase in the risk of hemorrhagic stroke.14 The studies analyzed in the meta‐analysis underlie the AHA/ASA recommendations that aspirin (325 mg) be administered within 2448 hours of stroke onset or within 24 hours after thrombolytic therapy for the early management of ischemic stroke in adults.9 By contrast, heparin therapy is not a recommended treatment for acute ischemic stroke; its clinical benefits do not outweigh the risk of bleeding complications.9 In addition, clinical trial data do not support the use of heparin for cardioembolic stroke.13

Figure 2

The AHA/ASA has made several recommendations to enhance outcomes and to prevent complications after an acute ischemic stroke. These include the stabilization and management of blood pressure (BP) and blood glucose levels and protection against deep vein thrombosis.9 Hypertension in the peristroke period is expected and is generally not treated. The rationale is that cerebral blood flow (CBF) is autoregulated in healthy brain tissue. As such, CBF remains constant at 50 cc/100 g of tissue per minute over a wide range of mean arterial pressures: 60150 mm Hg. However, in ischemic brain regions, autoregulation is lost, resulting in a pressure passive perfusion state (ie, local CBF is dependent on systemic blood pressure). As an injured brain is hypermetabolic, CBF adequate to meet its needs is dependent on a higher than normal blood pressure. Thus, reduction of high BP might worsen ischemia.

From a clinical practice standpoint, patients' outpatient antihypertensive medications are frequently held, with no additional treatment given for blood pressure elevation. The exception is, should the patient become encephalopathic, blood pressure may need to be reduced, as this may represent a state of hypertensive encephalopathy or luxury perfusion. There are no data indicating the use of a specific hypertensive agent in reducing blood pressure in such a setting. The AHA/ASA guidelines for early management of ischemic stroke recommend the use of antihypertensive agents on a case‐by‐case basis; although as recommended by consensus, there may be IV administration of labetalol or nicardipine if there is evidence of hypertensive encephalopathy, the diastolic BP is >120 mm Hg or the systolic BP is >220 mm Hg.9

Blood glucose should be kept stable, between 80 and 120 mg/dL. This can be achieved with either an oral hypoglycemic agent or sliding‐scale insulin regimen. Venous thrombus formation after stroke is a very serious concern as it can result in pulmonary embolism. As soon as possible, sequential compression devices and agents such as unfractionated heparin, low‐molecular‐weight heparin (ie, enoxaparin, dalteparin), fondaparinux, warfarin, or aspirin should be initiated.9

Hyperthermia has been shown to worsen functional outcome following stroke.15 Thus, maintenance of normal body temperature is recommended. This can be achieved with acetaminophen. Causes other than acute brain injury such as infection need to be investigated and treated as appropriate. Induced hypothermia has long been considered a potential therapy for improving outcome from acute stroke. Although preclinical studies in animals support induced hypothermia as a beneficial approach, there has not yet been a successful human clinical trial demonstrating efficacy. In addition, hypotonic intravenous solutions have the potential to worsen cerebral edema. Thus, normal saline without dextrose may be preferable. However, conclusive evidence supporting the use of hypertonic and colloid solutions remains insufficient.

Other important issues are gastrointestinal prophylaxis, early mobilization, and nutrition. The nutritional needs of acute brain‐injured patients cannot be overemphasized. Caloric intake should be maintained at 140% to compensate for the hypermetabolic state of the brain and to avoid weight loss. Patients should not be fed or treated with oral medications until a speech and swallow study is conducted to determine the extent of dysphagia and dysarthria or aphasia.9 However, in general, patients who are alert can usually be administered their oral medications, but only after a swallow evaluation has been passed.

ANTIPLATELET THERAPY FOR STROKE PREVENTION

LONG‐TERM MANAGEMENT FOR SECONDARY PREVENTION OF NONSTROKE VASCULAR EVENTS

In the subacute period, the hospitalist transitions the patient from acute to chronic care. Here, the goals are optimizing functional outcome and preventing recurrence. Still, during the first few days after ictus, the patient remains at risk for recurrent stroke, cerebral edema, and hemorrhagic transformation, so continued hospitalization is required. By 57 days later, the most significant risk period has elapsed. Physical and occupational therapy are initiated while patients are still hospitalized. Patient and family education about stroke and related diseases is done. A rational and comprehensive plan to reduce risk of secondary stroke is critical. This plan must include diet, tobacco, diabetes, blood pressure and excessive weight interventions. These may require care from a specialized team with members such as dieticians, exercise therapists, and tobacco interventionalists. Especially critical is instituting a discharge plan that highlights continued control of all modifiable risk factors and antiplatelet therapy. Finally, coordination with the patient's outpatient provider is paramount.

There is a developing awareness of the importance of the overlapping syndrome of combined stroke and cardiovascular and peripheral vascular risk. In leading clinical trials, the coexistence of coronary artery disease and cerebral artery disease is as high as 40%; thus, patients who have had a stroke are at high risk for other vascular events such as MI, critical limb ischemia, or vascular death. The AHA/ASA scientific statement on coronary risk evaluation recommends testing for CAD after ischemic stroke, as it has been suggested that asymptomatic CAD is highly prevalent among these patients.4 Diagnostic testing for CAD should be conducted outside the acute stroke setting and optimized based on stroke subtype and the health status of individual patients.4 Testing for PAD should also be done in patients with ischemic stroke when not otherwise contraindicated.27 Thus, the hospitalist should determine the stroke patient's risk of having coexisting CAD and/or PAD. If significant, then appropriate follow‐up testing either during the hospitalization or after discharge should be arranged.

To prevent secondary vascular events including stroke, effective management of common risk factors shared by stroke, CAD, and PAD is recommended. Long‐term treatment goals include control of hypertension, lipid and glucose management, smoking cessation, weight control, and integration of physical activity.4, 5, 27 Except for blood pressure control, many of these should be initiated while still in the hospital. Acute hospitalization is also an opportunity for patient and family education regarding risk factor reduction.

Antiplatelet therapies are also recommended and are associated with an absolute risk reduction of serious vascular events of 36 6 per 1000 persons with previous stroke or transient ischemic attack.20 Aspirin use in patients at high risk for atherothrombotic events has been shown to be effective in reducing the risk of myocardial infarction and other vascular events.20 The AHA‐recommended dose of aspirin for preventing sudden coronary syndrome is 81 mg/day or higher. Clopidogrel has been shown to be effective in reducing the risk of recurrent sudden coronary artery syndrome and progression of peripheral vascular disease.22 When combined with aspirin, clopidogrel has been shown to reduce recurrent sudden coronary syndrome.28, 29

CONCLUSIONS

The hospitalist is involved in the spectrum of stroke care, from management of stroke in the acute care setting to establishing long‐term treatments for prevention of secondary vascular events. As such, hospitalists can significantly affect the lives of patients with ischemic stroke. Current treatment guidelines for stroke recommend aggressive and rapid response in the acute setting. Long‐term treatments focus on risk reduction for recurrent stroke or for other vascular events such as MI or critical limb ischemia. Antiplatelet therapies are a component of long‐term treatments. Current research suggests that antiplatelet agents differ in reducing recurrent strokes versus nonstroke events. Thus, treatments should be based on a patient's individual risk factors for recurrent stroke and/or CAD or PAD. Although hospitalists will transfer care back to outpatient providers, the interventions initiated in the hospital will optimize the patient's future. In many ways, the patient's first step to a better health began when crossing the entrance of the hospital.

Stroke is the leading cause of disability and the third leading cause of death in the United States.1, 2 Each year approximately 700,000 strokes occur, 88% of which are considered ischemic; they predominately arise from atherothrombotic events in large or small cerebral vessels. Moreover, approximately 200,000 of these events are classified as recurrent.1 Patients who have had a stroke frequently also have coronary artery disease (CAD) and/or peripheral artery disease (PAD), putting them at high risk of adverse vascular events such as myocardial infarction (MI) or sudden vascular death.35 Hospitalists initiate and coordinate aggressive and rapid interventions in the acute care setting in order to minimize stroke progression and thus optimize outcomes. They also initiate long‐term treatments to prevent recurrence and secondary vascular events in the outpatient setting. Thus, the treatment plan developed by the hospitalist on admission is as important as the one created on discharge.

The hospitalist plays a central role in managing stroke. Prior to having an event, patients are at risk. The goal of clinical management is prevention. This is mainly focused on risk factor reduction and aspirin therapy. Outpatient medical providers direct this care. Once a stroke occurs and the victim is admitted to the hospital, the hospitalist becomes this patient's medical care coordinator. In the very acute phase, the goal of management is optimizing outcomes by restoring perfusion to ischemic tissue and minimizing injury progression. There are a number of interventions available to the hospitalist. If patients present within 3 hours of ictus, they may qualify for IV thrombolytic therapy and if within 6 hours for intra‐arterial therapy. If later, aspirin can have beneficial effects on outcomes. Also during this time, it is important to maintain adequate systemic perfusion, oxygenation/ventilation, cardiovascular function, and, importantly, close clinical monitoring.

STROKE MORTALITY

Stroke is a deadly diseaseas deadly as many malignancies. Most patients die of complications of vascular disease (eg, cerebrovascular, cardiovascular, and peripheral vascular diseases). The Oxfordshire Community Stroke Project and Perth Community Stroke Study has indicated that at least 50% of patients die within 5 years of a first‐time acute ischemic or hemorrhagic stroke. The highest risk of death occurs during the first year, with a mortality rate ranging between 31% and 36.5% (95% confidence interval [CI], 27%34% and 31.5%41.4%, respectively).6, 7 Moreover, the risk of death within 30 days after stroke was approximately 20%. The annual risk of death for patients who survived 1 year was 7% and 10% according to the Oxfordshire and Perth studies, respectively, which was approximately 2‐fold higher than that for stroke‐free patients of the same age and sex.6, 7

The proportion of death caused by stroke, recurrent stroke, cardiovascular events, or nonvascular events changes over time (Fig. 1). The Perth study showed that the predominant causes of death within the first 30 days were complications from the incident stroke and, to a lesser degree, recurrent stroke. Over time, cardiovascular events (eg, myocardial infarction, ruptured aortic aneurysms, PAD) become the most common cause of mortality in patients who have had a stroke. However, the risk of death from a recurrent stroke only diminishes slightly with time.7 This trend is consistent with the findings of the Oxfordshire study and the Northern Manhattan Stroke Study, which focused on long‐term survival after first‐ever ischemic stroke.6, 8 Thus, the short‐term goals of treatment implemented by hospitalists are to ensure survival and recovery from the index stroke, and the long‐term goals are to protect against recurrent stroke or secondary vascular events.

Figure 1

MANAGEMENT OF ACUTE ISCHEMIC STROKE

Stroke is no longer an untreatable disease. The introduction of thrombolytic therapy has provided an opportunity for medical providers to significantly improve short‐ and long‐term survival rates and functional outcomes of patients. Most ischemic strokes are caused by thrombotic arterial occlusions. Hence, thrombolytic therapy has been tested and approved for use in patients with acute ischemic stroke.9 The efficacy and safety of the thrombolytic agent, recombinant tissue plasminogen activator (rtPA), were demonstrated in the landmark National Institute of Neurological Disorders and Stroke (NINDS) rtPA Stroke Study.

When compared with patients who received placebo, the odds of a favorable treatment outcome increased by at least 30% in those who received rtPA within 3 hours of the onset of symptoms of an acute ischemic stroke. This benefit was sustained for 612 months.10, 11 Patients who received rtPA were at an increased risk for intracerebral hemorrhage, but this did not translate to an increased risk of death.10 Currently, this thrombolytic agent has a class I recommendation from the American Heart Association and American Stroke Association (AHA/ASA) for its administration within 3 hours of onset of ischemic stroke symptoms in patients who have no sign or history of subarachnoid hemorrhage and who meet the other 21 criteria based on those used in the NINDS study.9

Patients who arrive at the hospital 36 hours after symptom onset or those who have contraindications for IV rtPA may benefit from intra‐arterial administration of thrombolytic agents.12 However, there is no consensus on the optimal dose that should be delivered by intra‐arterial administration.13 In addition, this course of treatment requires rapid access to cerebral angiography and a qualified interventionalist, both of which may not be available to all hospitalists.9

If a patient presents beyond 6 hours, the hospitalist may initiate aspirin therapy, which has been shown to improve outcomes following acute stroke if therapy is begun within 48 hours. A planned meta‐analysis of approximately 40,000 patients with suspected ischemic stroke demonstrated that aspirin therapy proportionally reduces the risk of recurrent stroke and mortality from recurrent stroke or any other cause by 11% 3%. This benefit was apparent as early as 06 hours and as late as 2548 hours following stroke onset (Fig. 2), with only a slight increase in the risk of hemorrhagic stroke.14 The studies analyzed in the meta‐analysis underlie the AHA/ASA recommendations that aspirin (325 mg) be administered within 2448 hours of stroke onset or within 24 hours after thrombolytic therapy for the early management of ischemic stroke in adults.9 By contrast, heparin therapy is not a recommended treatment for acute ischemic stroke; its clinical benefits do not outweigh the risk of bleeding complications.9 In addition, clinical trial data do not support the use of heparin for cardioembolic stroke.13

Figure 2

The AHA/ASA has made several recommendations to enhance outcomes and to prevent complications after an acute ischemic stroke. These include the stabilization and management of blood pressure (BP) and blood glucose levels and protection against deep vein thrombosis.9 Hypertension in the peristroke period is expected and is generally not treated. The rationale is that cerebral blood flow (CBF) is autoregulated in healthy brain tissue. As such, CBF remains constant at 50 cc/100 g of tissue per minute over a wide range of mean arterial pressures: 60150 mm Hg. However, in ischemic brain regions, autoregulation is lost, resulting in a pressure passive perfusion state (ie, local CBF is dependent on systemic blood pressure). As an injured brain is hypermetabolic, CBF adequate to meet its needs is dependent on a higher than normal blood pressure. Thus, reduction of high BP might worsen ischemia.

From a clinical practice standpoint, patients' outpatient antihypertensive medications are frequently held, with no additional treatment given for blood pressure elevation. The exception is, should the patient become encephalopathic, blood pressure may need to be reduced, as this may represent a state of hypertensive encephalopathy or luxury perfusion. There are no data indicating the use of a specific hypertensive agent in reducing blood pressure in such a setting. The AHA/ASA guidelines for early management of ischemic stroke recommend the use of antihypertensive agents on a case‐by‐case basis; although as recommended by consensus, there may be IV administration of labetalol or nicardipine if there is evidence of hypertensive encephalopathy, the diastolic BP is >120 mm Hg or the systolic BP is >220 mm Hg.9

Blood glucose should be kept stable, between 80 and 120 mg/dL. This can be achieved with either an oral hypoglycemic agent or sliding‐scale insulin regimen. Venous thrombus formation after stroke is a very serious concern as it can result in pulmonary embolism. As soon as possible, sequential compression devices and agents such as unfractionated heparin, low‐molecular‐weight heparin (ie, enoxaparin, dalteparin), fondaparinux, warfarin, or aspirin should be initiated.9

Hyperthermia has been shown to worsen functional outcome following stroke.15 Thus, maintenance of normal body temperature is recommended. This can be achieved with acetaminophen. Causes other than acute brain injury such as infection need to be investigated and treated as appropriate. Induced hypothermia has long been considered a potential therapy for improving outcome from acute stroke. Although preclinical studies in animals support induced hypothermia as a beneficial approach, there has not yet been a successful human clinical trial demonstrating efficacy. In addition, hypotonic intravenous solutions have the potential to worsen cerebral edema. Thus, normal saline without dextrose may be preferable. However, conclusive evidence supporting the use of hypertonic and colloid solutions remains insufficient.

Other important issues are gastrointestinal prophylaxis, early mobilization, and nutrition. The nutritional needs of acute brain‐injured patients cannot be overemphasized. Caloric intake should be maintained at 140% to compensate for the hypermetabolic state of the brain and to avoid weight loss. Patients should not be fed or treated with oral medications until a speech and swallow study is conducted to determine the extent of dysphagia and dysarthria or aphasia.9 However, in general, patients who are alert can usually be administered their oral medications, but only after a swallow evaluation has been passed.

ANTIPLATELET THERAPY FOR STROKE PREVENTION

LONG‐TERM MANAGEMENT FOR SECONDARY PREVENTION OF NONSTROKE VASCULAR EVENTS

In the subacute period, the hospitalist transitions the patient from acute to chronic care. Here, the goals are optimizing functional outcome and preventing recurrence. Still, during the first few days after ictus, the patient remains at risk for recurrent stroke, cerebral edema, and hemorrhagic transformation, so continued hospitalization is required. By 57 days later, the most significant risk period has elapsed. Physical and occupational therapy are initiated while patients are still hospitalized. Patient and family education about stroke and related diseases is done. A rational and comprehensive plan to reduce risk of secondary stroke is critical. This plan must include diet, tobacco, diabetes, blood pressure and excessive weight interventions. These may require care from a specialized team with members such as dieticians, exercise therapists, and tobacco interventionalists. Especially critical is instituting a discharge plan that highlights continued control of all modifiable risk factors and antiplatelet therapy. Finally, coordination with the patient's outpatient provider is paramount.

There is a developing awareness of the importance of the overlapping syndrome of combined stroke and cardiovascular and peripheral vascular risk. In leading clinical trials, the coexistence of coronary artery disease and cerebral artery disease is as high as 40%; thus, patients who have had a stroke are at high risk for other vascular events such as MI, critical limb ischemia, or vascular death. The AHA/ASA scientific statement on coronary risk evaluation recommends testing for CAD after ischemic stroke, as it has been suggested that asymptomatic CAD is highly prevalent among these patients.4 Diagnostic testing for CAD should be conducted outside the acute stroke setting and optimized based on stroke subtype and the health status of individual patients.4 Testing for PAD should also be done in patients with ischemic stroke when not otherwise contraindicated.27 Thus, the hospitalist should determine the stroke patient's risk of having coexisting CAD and/or PAD. If significant, then appropriate follow‐up testing either during the hospitalization or after discharge should be arranged.

To prevent secondary vascular events including stroke, effective management of common risk factors shared by stroke, CAD, and PAD is recommended. Long‐term treatment goals include control of hypertension, lipid and glucose management, smoking cessation, weight control, and integration of physical activity.4, 5, 27 Except for blood pressure control, many of these should be initiated while still in the hospital. Acute hospitalization is also an opportunity for patient and family education regarding risk factor reduction.

Antiplatelet therapies are also recommended and are associated with an absolute risk reduction of serious vascular events of 36 6 per 1000 persons with previous stroke or transient ischemic attack.20 Aspirin use in patients at high risk for atherothrombotic events has been shown to be effective in reducing the risk of myocardial infarction and other vascular events.20 The AHA‐recommended dose of aspirin for preventing sudden coronary syndrome is 81 mg/day or higher. Clopidogrel has been shown to be effective in reducing the risk of recurrent sudden coronary artery syndrome and progression of peripheral vascular disease.22 When combined with aspirin, clopidogrel has been shown to reduce recurrent sudden coronary syndrome.28, 29

CONCLUSIONS

The hospitalist is involved in the spectrum of stroke care, from management of stroke in the acute care setting to establishing long‐term treatments for prevention of secondary vascular events. As such, hospitalists can significantly affect the lives of patients with ischemic stroke. Current treatment guidelines for stroke recommend aggressive and rapid response in the acute setting. Long‐term treatments focus on risk reduction for recurrent stroke or for other vascular events such as MI or critical limb ischemia. Antiplatelet therapies are a component of long‐term treatments. Current research suggests that antiplatelet agents differ in reducing recurrent strokes versus nonstroke events. Thus, treatments should be based on a patient's individual risk factors for recurrent stroke and/or CAD or PAD. Although hospitalists will transfer care back to outpatient providers, the interventions initiated in the hospital will optimize the patient's future. In many ways, the patient's first step to a better health began when crossing the entrance of the hospital.

Stroke is the leading cause of disability and the third leading cause of death in the United States.1, 2 Each year approximately 700,000 strokes occur, 88% of which are considered ischemic; they predominately arise from atherothrombotic events in large or small cerebral vessels. Moreover, approximately 200,000 of these events are classified as recurrent.1 Patients who have had a stroke frequently also have coronary artery disease (CAD) and/or peripheral artery disease (PAD), putting them at high risk of adverse vascular events such as myocardial infarction (MI) or sudden vascular death.35 Hospitalists initiate and coordinate aggressive and rapid interventions in the acute care setting in order to minimize stroke progression and thus optimize outcomes. They also initiate long‐term treatments to prevent recurrence and secondary vascular events in the outpatient setting. Thus, the treatment plan developed by the hospitalist on admission is as important as the one created on discharge.

The hospitalist plays a central role in managing stroke. Prior to having an event, patients are at risk. The goal of clinical management is prevention. This is mainly focused on risk factor reduction and aspirin therapy. Outpatient medical providers direct this care. Once a stroke occurs and the victim is admitted to the hospital, the hospitalist becomes this patient's medical care coordinator. In the very acute phase, the goal of management is optimizing outcomes by restoring perfusion to ischemic tissue and minimizing injury progression. There are a number of interventions available to the hospitalist. If patients present within 3 hours of ictus, they may qualify for IV thrombolytic therapy and if within 6 hours for intra‐arterial therapy. If later, aspirin can have beneficial effects on outcomes. Also during this time, it is important to maintain adequate systemic perfusion, oxygenation/ventilation, cardiovascular function, and, importantly, close clinical monitoring.

STROKE MORTALITY

Stroke is a deadly diseaseas deadly as many malignancies. Most patients die of complications of vascular disease (eg, cerebrovascular, cardiovascular, and peripheral vascular diseases). The Oxfordshire Community Stroke Project and Perth Community Stroke Study has indicated that at least 50% of patients die within 5 years of a first‐time acute ischemic or hemorrhagic stroke. The highest risk of death occurs during the first year, with a mortality rate ranging between 31% and 36.5% (95% confidence interval [CI], 27%34% and 31.5%41.4%, respectively).6, 7 Moreover, the risk of death within 30 days after stroke was approximately 20%. The annual risk of death for patients who survived 1 year was 7% and 10% according to the Oxfordshire and Perth studies, respectively, which was approximately 2‐fold higher than that for stroke‐free patients of the same age and sex.6, 7

The proportion of death caused by stroke, recurrent stroke, cardiovascular events, or nonvascular events changes over time (Fig. 1). The Perth study showed that the predominant causes of death within the first 30 days were complications from the incident stroke and, to a lesser degree, recurrent stroke. Over time, cardiovascular events (eg, myocardial infarction, ruptured aortic aneurysms, PAD) become the most common cause of mortality in patients who have had a stroke. However, the risk of death from a recurrent stroke only diminishes slightly with time.7 This trend is consistent with the findings of the Oxfordshire study and the Northern Manhattan Stroke Study, which focused on long‐term survival after first‐ever ischemic stroke.6, 8 Thus, the short‐term goals of treatment implemented by hospitalists are to ensure survival and recovery from the index stroke, and the long‐term goals are to protect against recurrent stroke or secondary vascular events.

Figure 1

MANAGEMENT OF ACUTE ISCHEMIC STROKE

Stroke is no longer an untreatable disease. The introduction of thrombolytic therapy has provided an opportunity for medical providers to significantly improve short‐ and long‐term survival rates and functional outcomes of patients. Most ischemic strokes are caused by thrombotic arterial occlusions. Hence, thrombolytic therapy has been tested and approved for use in patients with acute ischemic stroke.9 The efficacy and safety of the thrombolytic agent, recombinant tissue plasminogen activator (rtPA), were demonstrated in the landmark National Institute of Neurological Disorders and Stroke (NINDS) rtPA Stroke Study.

When compared with patients who received placebo, the odds of a favorable treatment outcome increased by at least 30% in those who received rtPA within 3 hours of the onset of symptoms of an acute ischemic stroke. This benefit was sustained for 612 months.10, 11 Patients who received rtPA were at an increased risk for intracerebral hemorrhage, but this did not translate to an increased risk of death.10 Currently, this thrombolytic agent has a class I recommendation from the American Heart Association and American Stroke Association (AHA/ASA) for its administration within 3 hours of onset of ischemic stroke symptoms in patients who have no sign or history of subarachnoid hemorrhage and who meet the other 21 criteria based on those used in the NINDS study.9

Patients who arrive at the hospital 36 hours after symptom onset or those who have contraindications for IV rtPA may benefit from intra‐arterial administration of thrombolytic agents.12 However, there is no consensus on the optimal dose that should be delivered by intra‐arterial administration.13 In addition, this course of treatment requires rapid access to cerebral angiography and a qualified interventionalist, both of which may not be available to all hospitalists.9

If a patient presents beyond 6 hours, the hospitalist may initiate aspirin therapy, which has been shown to improve outcomes following acute stroke if therapy is begun within 48 hours. A planned meta‐analysis of approximately 40,000 patients with suspected ischemic stroke demonstrated that aspirin therapy proportionally reduces the risk of recurrent stroke and mortality from recurrent stroke or any other cause by 11% 3%. This benefit was apparent as early as 06 hours and as late as 2548 hours following stroke onset (Fig. 2), with only a slight increase in the risk of hemorrhagic stroke.14 The studies analyzed in the meta‐analysis underlie the AHA/ASA recommendations that aspirin (325 mg) be administered within 2448 hours of stroke onset or within 24 hours after thrombolytic therapy for the early management of ischemic stroke in adults.9 By contrast, heparin therapy is not a recommended treatment for acute ischemic stroke; its clinical benefits do not outweigh the risk of bleeding complications.9 In addition, clinical trial data do not support the use of heparin for cardioembolic stroke.13

Figure 2

The AHA/ASA has made several recommendations to enhance outcomes and to prevent complications after an acute ischemic stroke. These include the stabilization and management of blood pressure (BP) and blood glucose levels and protection against deep vein thrombosis.9 Hypertension in the peristroke period is expected and is generally not treated. The rationale is that cerebral blood flow (CBF) is autoregulated in healthy brain tissue. As such, CBF remains constant at 50 cc/100 g of tissue per minute over a wide range of mean arterial pressures: 60150 mm Hg. However, in ischemic brain regions, autoregulation is lost, resulting in a pressure passive perfusion state (ie, local CBF is dependent on systemic blood pressure). As an injured brain is hypermetabolic, CBF adequate to meet its needs is dependent on a higher than normal blood pressure. Thus, reduction of high BP might worsen ischemia.

From a clinical practice standpoint, patients' outpatient antihypertensive medications are frequently held, with no additional treatment given for blood pressure elevation. The exception is, should the patient become encephalopathic, blood pressure may need to be reduced, as this may represent a state of hypertensive encephalopathy or luxury perfusion. There are no data indicating the use of a specific hypertensive agent in reducing blood pressure in such a setting. The AHA/ASA guidelines for early management of ischemic stroke recommend the use of antihypertensive agents on a case‐by‐case basis; although as recommended by consensus, there may be IV administration of labetalol or nicardipine if there is evidence of hypertensive encephalopathy, the diastolic BP is >120 mm Hg or the systolic BP is >220 mm Hg.9

Blood glucose should be kept stable, between 80 and 120 mg/dL. This can be achieved with either an oral hypoglycemic agent or sliding‐scale insulin regimen. Venous thrombus formation after stroke is a very serious concern as it can result in pulmonary embolism. As soon as possible, sequential compression devices and agents such as unfractionated heparin, low‐molecular‐weight heparin (ie, enoxaparin, dalteparin), fondaparinux, warfarin, or aspirin should be initiated.9

Hyperthermia has been shown to worsen functional outcome following stroke.15 Thus, maintenance of normal body temperature is recommended. This can be achieved with acetaminophen. Causes other than acute brain injury such as infection need to be investigated and treated as appropriate. Induced hypothermia has long been considered a potential therapy for improving outcome from acute stroke. Although preclinical studies in animals support induced hypothermia as a beneficial approach, there has not yet been a successful human clinical trial demonstrating efficacy. In addition, hypotonic intravenous solutions have the potential to worsen cerebral edema. Thus, normal saline without dextrose may be preferable. However, conclusive evidence supporting the use of hypertonic and colloid solutions remains insufficient.

Other important issues are gastrointestinal prophylaxis, early mobilization, and nutrition. The nutritional needs of acute brain‐injured patients cannot be overemphasized. Caloric intake should be maintained at 140% to compensate for the hypermetabolic state of the brain and to avoid weight loss. Patients should not be fed or treated with oral medications until a speech and swallow study is conducted to determine the extent of dysphagia and dysarthria or aphasia.9 However, in general, patients who are alert can usually be administered their oral medications, but only after a swallow evaluation has been passed.

ANTIPLATELET THERAPY FOR STROKE PREVENTION

LONG‐TERM MANAGEMENT FOR SECONDARY PREVENTION OF NONSTROKE VASCULAR EVENTS

In the subacute period, the hospitalist transitions the patient from acute to chronic care. Here, the goals are optimizing functional outcome and preventing recurrence. Still, during the first few days after ictus, the patient remains at risk for recurrent stroke, cerebral edema, and hemorrhagic transformation, so continued hospitalization is required. By 57 days later, the most significant risk period has elapsed. Physical and occupational therapy are initiated while patients are still hospitalized. Patient and family education about stroke and related diseases is done. A rational and comprehensive plan to reduce risk of secondary stroke is critical. This plan must include diet, tobacco, diabetes, blood pressure and excessive weight interventions. These may require care from a specialized team with members such as dieticians, exercise therapists, and tobacco interventionalists. Especially critical is instituting a discharge plan that highlights continued control of all modifiable risk factors and antiplatelet therapy. Finally, coordination with the patient's outpatient provider is paramount.

There is a developing awareness of the importance of the overlapping syndrome of combined stroke and cardiovascular and peripheral vascular risk. In leading clinical trials, the coexistence of coronary artery disease and cerebral artery disease is as high as 40%; thus, patients who have had a stroke are at high risk for other vascular events such as MI, critical limb ischemia, or vascular death. The AHA/ASA scientific statement on coronary risk evaluation recommends testing for CAD after ischemic stroke, as it has been suggested that asymptomatic CAD is highly prevalent among these patients.4 Diagnostic testing for CAD should be conducted outside the acute stroke setting and optimized based on stroke subtype and the health status of individual patients.4 Testing for PAD should also be done in patients with ischemic stroke when not otherwise contraindicated.27 Thus, the hospitalist should determine the stroke patient's risk of having coexisting CAD and/or PAD. If significant, then appropriate follow‐up testing either during the hospitalization or after discharge should be arranged.

To prevent secondary vascular events including stroke, effective management of common risk factors shared by stroke, CAD, and PAD is recommended. Long‐term treatment goals include control of hypertension, lipid and glucose management, smoking cessation, weight control, and integration of physical activity.4, 5, 27 Except for blood pressure control, many of these should be initiated while still in the hospital. Acute hospitalization is also an opportunity for patient and family education regarding risk factor reduction.

Antiplatelet therapies are also recommended and are associated with an absolute risk reduction of serious vascular events of 36 6 per 1000 persons with previous stroke or transient ischemic attack.20 Aspirin use in patients at high risk for atherothrombotic events has been shown to be effective in reducing the risk of myocardial infarction and other vascular events.20 The AHA‐recommended dose of aspirin for preventing sudden coronary syndrome is 81 mg/day or higher. Clopidogrel has been shown to be effective in reducing the risk of recurrent sudden coronary artery syndrome and progression of peripheral vascular disease.22 When combined with aspirin, clopidogrel has been shown to reduce recurrent sudden coronary syndrome.28, 29

CONCLUSIONS

The hospitalist is involved in the spectrum of stroke care, from management of stroke in the acute care setting to establishing long‐term treatments for prevention of secondary vascular events. As such, hospitalists can significantly affect the lives of patients with ischemic stroke. Current treatment guidelines for stroke recommend aggressive and rapid response in the acute setting. Long‐term treatments focus on risk reduction for recurrent stroke or for other vascular events such as MI or critical limb ischemia. Antiplatelet therapies are a component of long‐term treatments. Current research suggests that antiplatelet agents differ in reducing recurrent strokes versus nonstroke events. Thus, treatments should be based on a patient's individual risk factors for recurrent stroke and/or CAD or PAD. Although hospitalists will transfer care back to outpatient providers, the interventions initiated in the hospital will optimize the patient's future. In many ways, the patient's first step to a better health began when crossing the entrance of the hospital.

Acute atherothrombotic events associated with ischemic heart disease and stroke are the first and third most common causes of death in the United States, respectively.1 Despite an overall decrease in age‐adjusted mortality since 1970 in the United States, the worldwide prevalence of these diseases is anticipated to sharply increase by 2020.1, 2 Caring for patients with atherothrombosis is now within the purview of hospitalists to a larger extent than ever before. In recognition of the expanding role of these health care professionals and to reduce the risk of adverse cardiovascular events in the outpatient setting, the Society of Hospital Medicine held a symposium during its 10th Annual Meeting.

Rules of Engagement: The Hospitalist and Atherothrombosis took place on May 24, 2007, in Dallas, Texas. This supplement summarizes the highlights from this symposium and reviews the causes and polyvascular nature of atherothrombosis. The role of the hospitalist in managing atherothrombotic disease and evidence‐based practices for the evaluation and treatment of patients with various manifestations of atherothrombotic disease are also discussed.

ARTERIAL THROMBOSIS AND ITS POLYVASCULAR NATURE

Atherothrombosis refers to the formation of large and occlusive mural thrombi that arise from the rupture of an atherosclerotic plaque. Myocardial infarction (MI), ischemic stroke, and acute limb ischemia are the most severe manifestations of this disease.3, 4 This process begins when denuded or inflamed endothelial cells develop properties that permit platelet adhesion. At the site of endothelial dysfunction, activation of adherent platelet results in the release of inflammatory and mitogenic factors. After a series of dynamic and repetitive processes including amplified platelet activation, monocyte chemotaxis, adhesion, transmigration, and lipoprotein retention, plaque formation occurs.5 Consequently, the rupture or erosion of an atherosclerotic plaque produces a higher degree of platelet adhesion, activation, and aggregation, causing the fibrotic organization of a mural thrombus.3

The number of persons with multiple, concomitant cardiovascular disease (CAD), cerebrovascular disease (CVD), and peripheral arterial disease (PAD) accentuates the polyvascular nature of atherothrombosis (Fig. 1). The international Reduction of Atherothrombosis for Continued Health (REACH) Registry demonstrated that 1‐year incidence rates of major cardiovascular events (eg, MI, stroke, death) were high in patients with an established atherothrombotic disease and increased with the number of concomitant vascular diseases.6 These data infer that the burden on the vascular system is considered extensive on diagnosis of a single atherothrombotic disease. Thus, aggressive therapies are needed to reduce the risk of recurrent or other cardiovascular events. The management of risk factors for atherothrombosis such as hypercholesterolemia, dyslipidemia, hypertension, and diabetes mellitus fall under specific disease‐specific guidelines for patients presenting with atherothrombotic diseases.712

Figure 1

ANTIPLATELET THERAPIES

Antiplatelet therapies are used for the acute and long‐term treatment of patients after a thrombic event. Antiplatelet agents target the molecular mechanisms responsible for platelet activation and aggregation, such as the synthesis of thromboxane A₂. On platelet activation, free arachidonic acid is converted to prostaglandin H₂ (PGH₂) by cyclooxygenase‐1 (COX‐1; Fig. 2). Further metabolism of PGH₂ by thromboxane synthase produces thromboxane A₂, which induces vasoconstriction (Fig. 2). Fortunately, the ability of platelets to produce COX‐1 is limited, and irreversible inhibition of this enzyme can impair thromboxane A₂ synthesis for approximately 10 days.

Figure 2

Aspirin is a potent COX‐1 inhibitor, whose effects are evident 1 hour after dosing (Fig. 2).4, 13 Aspirin effectively prevents fatal and nonfatal vascular events in healthy individuals and in patients who present with acute MI or ischemic stroke.13 Unfortunately, a proportion of patients are aspirin resistant. Recent studies have indicated that interactions with the nonsteroidal anti‐inflammatory drug (NSAID) ibuprofen may diminish the primary and secondary protective effects of aspirin and may contribute to aspirin resistance, although the origin of this remains unclear.

The results of a post hoc subgroup analysis of 22,071 apparently healthy male physicians randomized to take aspirin or placebo for 5 years indicated that individuals who used NSAIDs for at least 60 days/year increased their risk of MI by more than 2‐fold compared with those who did not use NSAIDs.14 A second study conducted in patients following a major adverse cardiovascular event showed that the combination of aspirin plus ibuprofen increased the adjusted relative risk of cardiovascular mortality over an 8‐year period compared with aspirin alone.15 However, the effects of NSAIDS on aspirin's ability to inhibit COX‐1 are reversible and only last for the dosing interval and body clearance time of the drug.16

Adeonsine diphosphate (ADP)dependent stimulation of the P2Y₁₂ receptor is another target for antiplatelet therapy. On its release, ADP binds to the P2Y₁₂ receptor on platelets, resulting in activation and aggregation (Fig. 2). Ticlopidine and clopidogrel are thienopyridines that may irreversibly modify the P2Y₁₂ receptor (Fig. 2).13 Safety concerns associated with ticlopidine use, including severe neutropenia, have limited its administration. Conversely, clopidogrel is relatively well‐tolerated and can prevent cardiovascular events in patients with CAD, ischemic stroke, and PAD. This agent is an orally administered prodrug requiring activation by hepatic cytochrome P450 enzymes.13

Aspirin and thienopyridines do not inhibit platelet aggregation induced by the binding of fibrinogen to the platelet glycoprotein (GP) IIb/IIIa receptor (Fig. 2).4, 13 However, there are 3 commonly administered GP IIb/IIIa inhibitors: abciximab, eptifibatide, and tirofiban (Fig. 2).4 Abciximab is the fab fragment of the chimeric monoclonal antibody 7E3 and irreversibly inhibits the GP IIb/IIIa receptor. By contrast, eptifibatide is a cyclic heptapeptide, tirofiban is a nonpeptide, and both agents are reversible inhibitors. These agents are administered intravenously, and boluses are reserved for the short‐term treatment of atherothrombosis in patients undergoing percutaneous coronary intervention.13

CONCLUSIONS

Atherothrombosis is a systemic disease that often affects coronary, intracranial, and peripheral arterial beds concomitantly, which increases the probability of a thrombotic event. Aggressive treatments, including acute and long‐term antiplatelet therapies, are required to reduce the risks associated with atherothrombosis. This supplement reviews the evidence‐based approaches for managing atherothrombosis. It will provide hospitalists with the knowledge needed to treat patients with PAD, stroke, and acute coronary syndrome. First, the administration of antiplatelet therapies to patients with acute coronary syndrome will be described. Then, guidelines for the management of patients with acute ischemic stroke and the use of antiplatelet therapies to reduce mortality due to primary and secondary ischemic events will be reviewed. Finally, the role of the hospitalist in the diagnosis of PAD in asymptomatic patients and in those with confirmed atherothrombosis will be discussed.

Acute atherothrombotic events associated with ischemic heart disease and stroke are the first and third most common causes of death in the United States, respectively.1 Despite an overall decrease in age‐adjusted mortality since 1970 in the United States, the worldwide prevalence of these diseases is anticipated to sharply increase by 2020.1, 2 Caring for patients with atherothrombosis is now within the purview of hospitalists to a larger extent than ever before. In recognition of the expanding role of these health care professionals and to reduce the risk of adverse cardiovascular events in the outpatient setting, the Society of Hospital Medicine held a symposium during its 10th Annual Meeting.

Rules of Engagement: The Hospitalist and Atherothrombosis took place on May 24, 2007, in Dallas, Texas. This supplement summarizes the highlights from this symposium and reviews the causes and polyvascular nature of atherothrombosis. The role of the hospitalist in managing atherothrombotic disease and evidence‐based practices for the evaluation and treatment of patients with various manifestations of atherothrombotic disease are also discussed.

ARTERIAL THROMBOSIS AND ITS POLYVASCULAR NATURE

Atherothrombosis refers to the formation of large and occlusive mural thrombi that arise from the rupture of an atherosclerotic plaque. Myocardial infarction (MI), ischemic stroke, and acute limb ischemia are the most severe manifestations of this disease.3, 4 This process begins when denuded or inflamed endothelial cells develop properties that permit platelet adhesion. At the site of endothelial dysfunction, activation of adherent platelet results in the release of inflammatory and mitogenic factors. After a series of dynamic and repetitive processes including amplified platelet activation, monocyte chemotaxis, adhesion, transmigration, and lipoprotein retention, plaque formation occurs.5 Consequently, the rupture or erosion of an atherosclerotic plaque produces a higher degree of platelet adhesion, activation, and aggregation, causing the fibrotic organization of a mural thrombus.3

The number of persons with multiple, concomitant cardiovascular disease (CAD), cerebrovascular disease (CVD), and peripheral arterial disease (PAD) accentuates the polyvascular nature of atherothrombosis (Fig. 1). The international Reduction of Atherothrombosis for Continued Health (REACH) Registry demonstrated that 1‐year incidence rates of major cardiovascular events (eg, MI, stroke, death) were high in patients with an established atherothrombotic disease and increased with the number of concomitant vascular diseases.6 These data infer that the burden on the vascular system is considered extensive on diagnosis of a single atherothrombotic disease. Thus, aggressive therapies are needed to reduce the risk of recurrent or other cardiovascular events. The management of risk factors for atherothrombosis such as hypercholesterolemia, dyslipidemia, hypertension, and diabetes mellitus fall under specific disease‐specific guidelines for patients presenting with atherothrombotic diseases.712

Figure 1

ANTIPLATELET THERAPIES

Antiplatelet therapies are used for the acute and long‐term treatment of patients after a thrombic event. Antiplatelet agents target the molecular mechanisms responsible for platelet activation and aggregation, such as the synthesis of thromboxane A₂. On platelet activation, free arachidonic acid is converted to prostaglandin H₂ (PGH₂) by cyclooxygenase‐1 (COX‐1; Fig. 2). Further metabolism of PGH₂ by thromboxane synthase produces thromboxane A₂, which induces vasoconstriction (Fig. 2). Fortunately, the ability of platelets to produce COX‐1 is limited, and irreversible inhibition of this enzyme can impair thromboxane A₂ synthesis for approximately 10 days.

Figure 2

Aspirin is a potent COX‐1 inhibitor, whose effects are evident 1 hour after dosing (Fig. 2).4, 13 Aspirin effectively prevents fatal and nonfatal vascular events in healthy individuals and in patients who present with acute MI or ischemic stroke.13 Unfortunately, a proportion of patients are aspirin resistant. Recent studies have indicated that interactions with the nonsteroidal anti‐inflammatory drug (NSAID) ibuprofen may diminish the primary and secondary protective effects of aspirin and may contribute to aspirin resistance, although the origin of this remains unclear.

The results of a post hoc subgroup analysis of 22,071 apparently healthy male physicians randomized to take aspirin or placebo for 5 years indicated that individuals who used NSAIDs for at least 60 days/year increased their risk of MI by more than 2‐fold compared with those who did not use NSAIDs.14 A second study conducted in patients following a major adverse cardiovascular event showed that the combination of aspirin plus ibuprofen increased the adjusted relative risk of cardiovascular mortality over an 8‐year period compared with aspirin alone.15 However, the effects of NSAIDS on aspirin's ability to inhibit COX‐1 are reversible and only last for the dosing interval and body clearance time of the drug.16

Adeonsine diphosphate (ADP)dependent stimulation of the P2Y₁₂ receptor is another target for antiplatelet therapy. On its release, ADP binds to the P2Y₁₂ receptor on platelets, resulting in activation and aggregation (Fig. 2). Ticlopidine and clopidogrel are thienopyridines that may irreversibly modify the P2Y₁₂ receptor (Fig. 2).13 Safety concerns associated with ticlopidine use, including severe neutropenia, have limited its administration. Conversely, clopidogrel is relatively well‐tolerated and can prevent cardiovascular events in patients with CAD, ischemic stroke, and PAD. This agent is an orally administered prodrug requiring activation by hepatic cytochrome P450 enzymes.13

Aspirin and thienopyridines do not inhibit platelet aggregation induced by the binding of fibrinogen to the platelet glycoprotein (GP) IIb/IIIa receptor (Fig. 2).4, 13 However, there are 3 commonly administered GP IIb/IIIa inhibitors: abciximab, eptifibatide, and tirofiban (Fig. 2).4 Abciximab is the fab fragment of the chimeric monoclonal antibody 7E3 and irreversibly inhibits the GP IIb/IIIa receptor. By contrast, eptifibatide is a cyclic heptapeptide, tirofiban is a nonpeptide, and both agents are reversible inhibitors. These agents are administered intravenously, and boluses are reserved for the short‐term treatment of atherothrombosis in patients undergoing percutaneous coronary intervention.13

CONCLUSIONS

Atherothrombosis is a systemic disease that often affects coronary, intracranial, and peripheral arterial beds concomitantly, which increases the probability of a thrombotic event. Aggressive treatments, including acute and long‐term antiplatelet therapies, are required to reduce the risks associated with atherothrombosis. This supplement reviews the evidence‐based approaches for managing atherothrombosis. It will provide hospitalists with the knowledge needed to treat patients with PAD, stroke, and acute coronary syndrome. First, the administration of antiplatelet therapies to patients with acute coronary syndrome will be described. Then, guidelines for the management of patients with acute ischemic stroke and the use of antiplatelet therapies to reduce mortality due to primary and secondary ischemic events will be reviewed. Finally, the role of the hospitalist in the diagnosis of PAD in asymptomatic patients and in those with confirmed atherothrombosis will be discussed.

Acute atherothrombotic events associated with ischemic heart disease and stroke are the first and third most common causes of death in the United States, respectively.1 Despite an overall decrease in age‐adjusted mortality since 1970 in the United States, the worldwide prevalence of these diseases is anticipated to sharply increase by 2020.1, 2 Caring for patients with atherothrombosis is now within the purview of hospitalists to a larger extent than ever before. In recognition of the expanding role of these health care professionals and to reduce the risk of adverse cardiovascular events in the outpatient setting, the Society of Hospital Medicine held a symposium during its 10th Annual Meeting.

Rules of Engagement: The Hospitalist and Atherothrombosis took place on May 24, 2007, in Dallas, Texas. This supplement summarizes the highlights from this symposium and reviews the causes and polyvascular nature of atherothrombosis. The role of the hospitalist in managing atherothrombotic disease and evidence‐based practices for the evaluation and treatment of patients with various manifestations of atherothrombotic disease are also discussed.

ARTERIAL THROMBOSIS AND ITS POLYVASCULAR NATURE

Atherothrombosis refers to the formation of large and occlusive mural thrombi that arise from the rupture of an atherosclerotic plaque. Myocardial infarction (MI), ischemic stroke, and acute limb ischemia are the most severe manifestations of this disease.3, 4 This process begins when denuded or inflamed endothelial cells develop properties that permit platelet adhesion. At the site of endothelial dysfunction, activation of adherent platelet results in the release of inflammatory and mitogenic factors. After a series of dynamic and repetitive processes including amplified platelet activation, monocyte chemotaxis, adhesion, transmigration, and lipoprotein retention, plaque formation occurs.5 Consequently, the rupture or erosion of an atherosclerotic plaque produces a higher degree of platelet adhesion, activation, and aggregation, causing the fibrotic organization of a mural thrombus.3

The number of persons with multiple, concomitant cardiovascular disease (CAD), cerebrovascular disease (CVD), and peripheral arterial disease (PAD) accentuates the polyvascular nature of atherothrombosis (Fig. 1). The international Reduction of Atherothrombosis for Continued Health (REACH) Registry demonstrated that 1‐year incidence rates of major cardiovascular events (eg, MI, stroke, death) were high in patients with an established atherothrombotic disease and increased with the number of concomitant vascular diseases.6 These data infer that the burden on the vascular system is considered extensive on diagnosis of a single atherothrombotic disease. Thus, aggressive therapies are needed to reduce the risk of recurrent or other cardiovascular events. The management of risk factors for atherothrombosis such as hypercholesterolemia, dyslipidemia, hypertension, and diabetes mellitus fall under specific disease‐specific guidelines for patients presenting with atherothrombotic diseases.712

Figure 1

ANTIPLATELET THERAPIES

Antiplatelet therapies are used for the acute and long‐term treatment of patients after a thrombic event. Antiplatelet agents target the molecular mechanisms responsible for platelet activation and aggregation, such as the synthesis of thromboxane A₂. On platelet activation, free arachidonic acid is converted to prostaglandin H₂ (PGH₂) by cyclooxygenase‐1 (COX‐1; Fig. 2). Further metabolism of PGH₂ by thromboxane synthase produces thromboxane A₂, which induces vasoconstriction (Fig. 2). Fortunately, the ability of platelets to produce COX‐1 is limited, and irreversible inhibition of this enzyme can impair thromboxane A₂ synthesis for approximately 10 days.

Figure 2

Aspirin is a potent COX‐1 inhibitor, whose effects are evident 1 hour after dosing (Fig. 2).4, 13 Aspirin effectively prevents fatal and nonfatal vascular events in healthy individuals and in patients who present with acute MI or ischemic stroke.13 Unfortunately, a proportion of patients are aspirin resistant. Recent studies have indicated that interactions with the nonsteroidal anti‐inflammatory drug (NSAID) ibuprofen may diminish the primary and secondary protective effects of aspirin and may contribute to aspirin resistance, although the origin of this remains unclear.

The results of a post hoc subgroup analysis of 22,071 apparently healthy male physicians randomized to take aspirin or placebo for 5 years indicated that individuals who used NSAIDs for at least 60 days/year increased their risk of MI by more than 2‐fold compared with those who did not use NSAIDs.14 A second study conducted in patients following a major adverse cardiovascular event showed that the combination of aspirin plus ibuprofen increased the adjusted relative risk of cardiovascular mortality over an 8‐year period compared with aspirin alone.15 However, the effects of NSAIDS on aspirin's ability to inhibit COX‐1 are reversible and only last for the dosing interval and body clearance time of the drug.16

Adeonsine diphosphate (ADP)dependent stimulation of the P2Y₁₂ receptor is another target for antiplatelet therapy. On its release, ADP binds to the P2Y₁₂ receptor on platelets, resulting in activation and aggregation (Fig. 2). Ticlopidine and clopidogrel are thienopyridines that may irreversibly modify the P2Y₁₂ receptor (Fig. 2).13 Safety concerns associated with ticlopidine use, including severe neutropenia, have limited its administration. Conversely, clopidogrel is relatively well‐tolerated and can prevent cardiovascular events in patients with CAD, ischemic stroke, and PAD. This agent is an orally administered prodrug requiring activation by hepatic cytochrome P450 enzymes.13

Aspirin and thienopyridines do not inhibit platelet aggregation induced by the binding of fibrinogen to the platelet glycoprotein (GP) IIb/IIIa receptor (Fig. 2).4, 13 However, there are 3 commonly administered GP IIb/IIIa inhibitors: abciximab, eptifibatide, and tirofiban (Fig. 2).4 Abciximab is the fab fragment of the chimeric monoclonal antibody 7E3 and irreversibly inhibits the GP IIb/IIIa receptor. By contrast, eptifibatide is a cyclic heptapeptide, tirofiban is a nonpeptide, and both agents are reversible inhibitors. These agents are administered intravenously, and boluses are reserved for the short‐term treatment of atherothrombosis in patients undergoing percutaneous coronary intervention.13

CONCLUSIONS

Atherothrombosis is a systemic disease that often affects coronary, intracranial, and peripheral arterial beds concomitantly, which increases the probability of a thrombotic event. Aggressive treatments, including acute and long‐term antiplatelet therapies, are required to reduce the risks associated with atherothrombosis. This supplement reviews the evidence‐based approaches for managing atherothrombosis. It will provide hospitalists with the knowledge needed to treat patients with PAD, stroke, and acute coronary syndrome. First, the administration of antiplatelet therapies to patients with acute coronary syndrome will be described. Then, guidelines for the management of patients with acute ischemic stroke and the use of antiplatelet therapies to reduce mortality due to primary and secondary ischemic events will be reviewed. Finally, the role of the hospitalist in the diagnosis of PAD in asymptomatic patients and in those with confirmed atherothrombosis will be discussed.