Case

A 17-year-old adolescent girl with a history of depression and opioid dependence, for which she was taking buprenorphine until 2 weeks earlier, presented to the ED via emergency medical services (EMS) after her father found her lying on the couch unresponsive and with shallow respirations. Naloxone was administered by EMS and her mental status improved.

At presentation, the patient admitted to insufflation of an unknown amount of heroin and ingestion of 2 mg of alprazolam earlier in the day. She denied any past or current use of intravenous (IV) drugs. During monitoring, she began to complain of numbness in her legs and an inability to urinate. Examination revealed paralysis and decreased sensation of her bilateral lower extremities to the midthigh, with decreased rectal tone. Because of the patient’s history of drug use and temporal association with the heroin overdose, both neurosurgery and toxicology services were consulted.

What can cause lower extremity paralysis in a drug user?

The differential diagnosis for the patient at this point included toxin-induced myelopathy, Guillain-Barré syndrome, hypokalemic periodic paralysis, spinal compression, epidural abscess, cerebrovascular accident, spinal lesion, and spinal artery dissection or infarction.

Although Guillain-Barré syndrome presents with ascending paralysis, there is usually an antecedent respiratory or gastrointestinal infection. While epidural abscess with spinal compression is associated with IV drug use and can present similarly, the patient in this case denied IV use. In the absence of any risk factors, cerebrovascular accident and spinal artery dissection were also unlikely.

Case Continuation

A bladder catheter was placed due to the patient’s inability to urinate, and approximately 1 L of urine output was retrieved. Immediate magnetic resonance imaging (MRI) demonstrated increased T2 signal intensity and expansion of the distal thoracic cord and conus without mass lesion, consistent with transverse myelitis (TM).

What is transverse myelitis and why does it occur?

Transverse myelitis is an inflammatory demyelinating disorder that focally affects the spinal cord, resulting in a specific pattern of motor, sensory, and autonomic dysfunction.¹ Signs and symptoms include paresthesia, paralysis of the extremities, and loss of bladder and bowel control. The level of the spinal cord affected determines the clinical effects. Demyelination typically occurs at the thoracic segment, producing findings in the legs, as well as bladder and bowel dysfunction. 

The exact cause of TM is unknown, but the inflammation may result from a viral complication or an abnormal immune response. Infectious viral agents suspected of causing TM include varicella zoster, herpes simplex, cytomegalovirus, Epstein-Barr, influenza, human immunodeficiency virus, hepatitis A, and rubella. It has also been postulated that an autoimmune reaction is responsible for the condition.

In some individuals, TM represents the first manifestation of an underlying demyelinating disorder such as multiple sclerosis or neuromyelitis optica. A diagnosis of TM is made through patient history, physical examination, and characteristic findings on neuroimaging, specifically MRI.

Heroin use has long been associated with the development of TM, and is usually associated with IV administration of the drug after a period of abstinence.² This association strengthens the basis for an immunologic etiology—an initial sensitization and subsequent reexposure causing the effects of TM. There have also been cases of TM coexisting with rhabdomyolysis due to the patient being found in a contorted position.³ Another theory of the etiology of heroin-associated TM is a reaction to a possible adulterant or contaminant in the heroin.⁴

What is the treatment and prognosis of transverse myelitis?

Since there is no cure for TM, treatment is directed at reducing inflammation in the spinal cord. Initial therapy generally includes corticosteroids. In patients with a minimal response to corticosteroids, plasma exchange can be attempted. There are also limited data to suggest a beneficial role for the use of IV immunoglobulin.⁵ In addition to treatment, general supportive care must also be optimized, such as the use of prophylaxis for thrombophlebitis due to immobility and physical therapy, if possible.

The prognosis of patients with TM is variable, and up to two thirds of patients will have moderate-to-severe residual neurological disability.⁶ Recovery is slow, with most patients beginning to show improvement within the first 2 to 12 weeks from treatment and supportive care. The recovery process can continue for 2 years. However, if no improvement is made within the first 3 to 6 months, recovery is unlikely.⁷ Cases of heroin-associated TM may have a more favorable prognosis.⁸

A majority of individuals will only experience this clinical entity once, but there are rare causes of recurrent or relapsing TM.⁷ In these situations, a search for underlying demyelinating diseases should be performed.

Case Conclusion 

The patient was immediately started on IV corticosteroids, but as there was no improvement after 5 days, plasmapheresis was performed. She received 5 cycles of plasmapheresis and a 5-day course of IV immunoglobulin but still without any improvement. A repeat MRI of the thoracic spine was performed and raised the possibility of cord infarct, but infectious or inflammatory myelitis remained within differential consideration. The patient continued to make minimal improvement with physical therapy and, after a 3-week hospital course, she was transferred to inpatient rehabilitation for further care. Over the next 2 months, the loss of sensation and motor ability of her legs did not improve, but she did regain control of her bowels and bladder.

Dr Regina is a medical toxicology fellow in the department of emergency medicine at North Shore Long Island Jewish Health System, New York. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

Case

A 17-year-old adolescent girl with a history of depression and opioid dependence, for which she was taking buprenorphine until 2 weeks earlier, presented to the ED via emergency medical services (EMS) after her father found her lying on the couch unresponsive and with shallow respirations. Naloxone was administered by EMS and her mental status improved.

At presentation, the patient admitted to insufflation of an unknown amount of heroin and ingestion of 2 mg of alprazolam earlier in the day. She denied any past or current use of intravenous (IV) drugs. During monitoring, she began to complain of numbness in her legs and an inability to urinate. Examination revealed paralysis and decreased sensation of her bilateral lower extremities to the midthigh, with decreased rectal tone. Because of the patient’s history of drug use and temporal association with the heroin overdose, both neurosurgery and toxicology services were consulted.

What can cause lower extremity paralysis in a drug user?

The differential diagnosis for the patient at this point included toxin-induced myelopathy, Guillain-Barré syndrome, hypokalemic periodic paralysis, spinal compression, epidural abscess, cerebrovascular accident, spinal lesion, and spinal artery dissection or infarction.

Although Guillain-Barré syndrome presents with ascending paralysis, there is usually an antecedent respiratory or gastrointestinal infection. While epidural abscess with spinal compression is associated with IV drug use and can present similarly, the patient in this case denied IV use. In the absence of any risk factors, cerebrovascular accident and spinal artery dissection were also unlikely.

Case Continuation

A bladder catheter was placed due to the patient’s inability to urinate, and approximately 1 L of urine output was retrieved. Immediate magnetic resonance imaging (MRI) demonstrated increased T2 signal intensity and expansion of the distal thoracic cord and conus without mass lesion, consistent with transverse myelitis (TM).

What is transverse myelitis and why does it occur?

Transverse myelitis is an inflammatory demyelinating disorder that focally affects the spinal cord, resulting in a specific pattern of motor, sensory, and autonomic dysfunction.¹ Signs and symptoms include paresthesia, paralysis of the extremities, and loss of bladder and bowel control. The level of the spinal cord affected determines the clinical effects. Demyelination typically occurs at the thoracic segment, producing findings in the legs, as well as bladder and bowel dysfunction. 

The exact cause of TM is unknown, but the inflammation may result from a viral complication or an abnormal immune response. Infectious viral agents suspected of causing TM include varicella zoster, herpes simplex, cytomegalovirus, Epstein-Barr, influenza, human immunodeficiency virus, hepatitis A, and rubella. It has also been postulated that an autoimmune reaction is responsible for the condition.

In some individuals, TM represents the first manifestation of an underlying demyelinating disorder such as multiple sclerosis or neuromyelitis optica. A diagnosis of TM is made through patient history, physical examination, and characteristic findings on neuroimaging, specifically MRI.

Heroin use has long been associated with the development of TM, and is usually associated with IV administration of the drug after a period of abstinence.² This association strengthens the basis for an immunologic etiology—an initial sensitization and subsequent reexposure causing the effects of TM. There have also been cases of TM coexisting with rhabdomyolysis due to the patient being found in a contorted position.³ Another theory of the etiology of heroin-associated TM is a reaction to a possible adulterant or contaminant in the heroin.⁴

What is the treatment and prognosis of transverse myelitis?

Since there is no cure for TM, treatment is directed at reducing inflammation in the spinal cord. Initial therapy generally includes corticosteroids. In patients with a minimal response to corticosteroids, plasma exchange can be attempted. There are also limited data to suggest a beneficial role for the use of IV immunoglobulin.⁵ In addition to treatment, general supportive care must also be optimized, such as the use of prophylaxis for thrombophlebitis due to immobility and physical therapy, if possible.

The prognosis of patients with TM is variable, and up to two thirds of patients will have moderate-to-severe residual neurological disability.⁶ Recovery is slow, with most patients beginning to show improvement within the first 2 to 12 weeks from treatment and supportive care. The recovery process can continue for 2 years. However, if no improvement is made within the first 3 to 6 months, recovery is unlikely.⁷ Cases of heroin-associated TM may have a more favorable prognosis.⁸

A majority of individuals will only experience this clinical entity once, but there are rare causes of recurrent or relapsing TM.⁷ In these situations, a search for underlying demyelinating diseases should be performed.

Case Conclusion 

The patient was immediately started on IV corticosteroids, but as there was no improvement after 5 days, plasmapheresis was performed. She received 5 cycles of plasmapheresis and a 5-day course of IV immunoglobulin but still without any improvement. A repeat MRI of the thoracic spine was performed and raised the possibility of cord infarct, but infectious or inflammatory myelitis remained within differential consideration. The patient continued to make minimal improvement with physical therapy and, after a 3-week hospital course, she was transferred to inpatient rehabilitation for further care. Over the next 2 months, the loss of sensation and motor ability of her legs did not improve, but she did regain control of her bowels and bladder.

Dr Regina is a medical toxicology fellow in the department of emergency medicine at North Shore Long Island Jewish Health System, New York. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

Case

A 17-year-old adolescent girl with a history of depression and opioid dependence, for which she was taking buprenorphine until 2 weeks earlier, presented to the ED via emergency medical services (EMS) after her father found her lying on the couch unresponsive and with shallow respirations. Naloxone was administered by EMS and her mental status improved.

At presentation, the patient admitted to insufflation of an unknown amount of heroin and ingestion of 2 mg of alprazolam earlier in the day. She denied any past or current use of intravenous (IV) drugs. During monitoring, she began to complain of numbness in her legs and an inability to urinate. Examination revealed paralysis and decreased sensation of her bilateral lower extremities to the midthigh, with decreased rectal tone. Because of the patient’s history of drug use and temporal association with the heroin overdose, both neurosurgery and toxicology services were consulted.

What can cause lower extremity paralysis in a drug user?

The differential diagnosis for the patient at this point included toxin-induced myelopathy, Guillain-Barré syndrome, hypokalemic periodic paralysis, spinal compression, epidural abscess, cerebrovascular accident, spinal lesion, and spinal artery dissection or infarction.

Although Guillain-Barré syndrome presents with ascending paralysis, there is usually an antecedent respiratory or gastrointestinal infection. While epidural abscess with spinal compression is associated with IV drug use and can present similarly, the patient in this case denied IV use. In the absence of any risk factors, cerebrovascular accident and spinal artery dissection were also unlikely.

Case Continuation

A bladder catheter was placed due to the patient’s inability to urinate, and approximately 1 L of urine output was retrieved. Immediate magnetic resonance imaging (MRI) demonstrated increased T2 signal intensity and expansion of the distal thoracic cord and conus without mass lesion, consistent with transverse myelitis (TM).

What is transverse myelitis and why does it occur?

Transverse myelitis is an inflammatory demyelinating disorder that focally affects the spinal cord, resulting in a specific pattern of motor, sensory, and autonomic dysfunction.¹ Signs and symptoms include paresthesia, paralysis of the extremities, and loss of bladder and bowel control. The level of the spinal cord affected determines the clinical effects. Demyelination typically occurs at the thoracic segment, producing findings in the legs, as well as bladder and bowel dysfunction. 

The exact cause of TM is unknown, but the inflammation may result from a viral complication or an abnormal immune response. Infectious viral agents suspected of causing TM include varicella zoster, herpes simplex, cytomegalovirus, Epstein-Barr, influenza, human immunodeficiency virus, hepatitis A, and rubella. It has also been postulated that an autoimmune reaction is responsible for the condition.

In some individuals, TM represents the first manifestation of an underlying demyelinating disorder such as multiple sclerosis or neuromyelitis optica. A diagnosis of TM is made through patient history, physical examination, and characteristic findings on neuroimaging, specifically MRI.

Heroin use has long been associated with the development of TM, and is usually associated with IV administration of the drug after a period of abstinence.² This association strengthens the basis for an immunologic etiology—an initial sensitization and subsequent reexposure causing the effects of TM. There have also been cases of TM coexisting with rhabdomyolysis due to the patient being found in a contorted position.³ Another theory of the etiology of heroin-associated TM is a reaction to a possible adulterant or contaminant in the heroin.⁴

What is the treatment and prognosis of transverse myelitis?

Since there is no cure for TM, treatment is directed at reducing inflammation in the spinal cord. Initial therapy generally includes corticosteroids. In patients with a minimal response to corticosteroids, plasma exchange can be attempted. There are also limited data to suggest a beneficial role for the use of IV immunoglobulin.⁵ In addition to treatment, general supportive care must also be optimized, such as the use of prophylaxis for thrombophlebitis due to immobility and physical therapy, if possible.

The prognosis of patients with TM is variable, and up to two thirds of patients will have moderate-to-severe residual neurological disability.⁶ Recovery is slow, with most patients beginning to show improvement within the first 2 to 12 weeks from treatment and supportive care. The recovery process can continue for 2 years. However, if no improvement is made within the first 3 to 6 months, recovery is unlikely.⁷ Cases of heroin-associated TM may have a more favorable prognosis.⁸

A majority of individuals will only experience this clinical entity once, but there are rare causes of recurrent or relapsing TM.⁷ In these situations, a search for underlying demyelinating diseases should be performed.

Case Conclusion 

The patient was immediately started on IV corticosteroids, but as there was no improvement after 5 days, plasmapheresis was performed. She received 5 cycles of plasmapheresis and a 5-day course of IV immunoglobulin but still without any improvement. A repeat MRI of the thoracic spine was performed and raised the possibility of cord infarct, but infectious or inflammatory myelitis remained within differential consideration. The patient continued to make minimal improvement with physical therapy and, after a 3-week hospital course, she was transferred to inpatient rehabilitation for further care. Over the next 2 months, the loss of sensation and motor ability of her legs did not improve, but she did regain control of her bowels and bladder.

Dr Regina is a medical toxicology fellow in the department of emergency medicine at North Shore Long Island Jewish Health System, New York. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board.

The patient’s physical examination was unremarkable. His vital signs were normal, and there was no obvious external evidence of trauma. The posterior cervical spine was tender to palpation in the midline, but no step-off signs were appreciated. The neurological examination, including strength and sensation in all four extremities, was normal.

Since the patient’s only complaint was neck pain and his physical examination and history were otherwise normal, the emergency physician (EP) ordered radiographs of the cervical spine. The imaging studies were interpreted as showing advanced degenerative changes but no fractures, and the patient was prescribed an analgesic and discharged home.

When the patient woke up the next morning, he was unable to move his extremities, and returned to the same ED via EMS. He was placed in a cervical collar and found to have flaccid extremities on examination. A computed tomography (CT) scan of the cervical spine revealed a transverse fracture through the C6 vertebra. Radiology services also reviewed the cervical spine X-rays from the previous day, noting the presence of fracture.

The patient was taken to the operating room by neurosurgery services but remained paralyzed postoperatively. He never recovered from his injury and died 6 months later. His family sued the EP and the hospital for missed diagnosis of cervical spine fracture at the first ED presentation and the resulting paralysis. The case was settled for $1.3 million prior to trial.

Discussion

The evaluation of suspected cervical spine injury secondary to blunt trauma is a frequent and important skill practiced by EPs. Motor vehicle accidents are the most common cause of spinal cord injury in the United States (42%), followed by falls (27%), acts of violence (15%), and sports-related injuries (8%).¹ A review by Sekon and Fehlings² showed that 55% of all spinal injuries involve the cervical spine. Interestingly, the majority of cervical spine injuries occur at the upper or lower ends of the cervical spine; C2 vertebral fractures account for 33%, while C6 and C7 vertebral fractures account for approximately 50%.¹

There are two commonly used criteria to clinically clear the cervical spine (ie, no imaging studies necessary) in blunt-trauma patients. The first is the National Emergency X-Radiography Use Study (NEXUS), which has a sensitivity of 99.6% of identifying cervical spine fractures.¹ According to the NEXUS criteria, no imaging studies are required if: (1) there is no midline cervical spine tenderness; (2) there are no focal neurological deficits; (3) the patient exhibits a normal level of alertness; (4) the patient is not intoxicated; and (5) there is no distracting injury.¹

The other set of criteria used to clear the cervical spine is the Canadian Cervical Spine Rule. In these criteria, a patient is considered at very low risk for cervical spine fracture in the following cases: (1) the patient is fully alert with a Glasgow Coma scale of 15; (2) the patient has no high-risk factors (ie, age >65 years, dangerous mechanism of injury, fall greater than five stairs, axial load to the head, high-speed vehicular crash, bicycle or motorcycle crash, or the presence of paresthesias in the extremities); (3) the patient has low-risk factors (eg, simple vehicle crash, sitting position in the ED, ambulatory at any time, delayed onset of neck pain, and the absence of midline cervical tenderness); and (4) the patient can actively rotate his or her neck 45 degrees to the left and to the right. The Canadian group found the above criteria to have 100% sensitivity for predicting the absence of cervical spine injury.¹

The patient in this case failed both sets of criteria (ie, presence of cervical spine tenderness and age >65 years) and therefore required imaging. Historically, cervical spine X-ray (three views, anteroposterior, lateral, and odontoid; or five views, three views plus obliques) has been the imaging study of choice for such patients. Unfortunately, however, cervical spine radiographs have severe limitations in identifying spinal injury. In a large retrospective review, Woodring and Lee,³ found that the standard three-view cervical spine series failed to demonstrate 61% of all fractures and 36% of all subluxation and dislocations. Similarly, in a prospective study of 1,006 patients with 72 injuries, Diaz et al,⁴ found a 52.3% missed fracture rate when five-view radiographs were used to identify cervical spine injury. In addition, radiographic evaluation of elderly patients was found to be even more challenging in identifying cervical spine injury due to age-related degenerative changes.

Given the abovementioned limitations associated with radiographic imaging, CT scan of the cervical spine has become the imaging study of choice in moderate-to-severe risk patients with blunt cervical spine trauma. This modality has been shown to have a higher sensitivity and specificity for evaluating cervical spine injury compared to plain X-ray films, with CT detecting 97% to 100% of cervical spine fractures.⁵

In addition to demonstrating a higher sensitivity, CT also has the advantage of speed—especially when the patient is undergoing other CT studies (eg, head, abdomen, pelvis). While some clinicians criticize the higher cost of CT versus plain films, CT has been shown to decrease institutional costs (when settlement costs are taken into account) due to the reduction of the incidence of paralysis resulting from false-negative imaging studies.⁶

Forgotten Tourniquet

The patient’s vital signs were: blood pressure, 138/82 mm Hg; heart rate, 102 beats/minute; respiratory rate, 18 breaths/minute; temperature 98.6˚F. Oxygen saturation was 99% on room air.

The patient appeared uncomfortable overall. The physical examination was remarkable only for mild left-sided costovertebral angle tenderness. Her abdomen was soft, nontender, and without guarding or rebound.

The EP ordered the placement of an intravenous (IV) line, through which the patient was administered normal saline and morphine and promethazine, respectively, for pain and nausea. A complete blood count, basic metabolic panel, urinalysis, and urine pregnancy test were ordered. All of the laboratory bloodwork results were normal, and the urine pregnancy test was negative. The urinalysis was remarkable for 50 to 100 red blood cells.

A noncontrast CT scan of the abdomen and pelvis revealed a 3-mm ureteral stone on the left side. When the patient returned from radiology services, her pain was significantly decreased and she felt much improved. She was diagnosed with a kidney stone and discharged home with an analgesic and a strainer, along with instructions to follow-up with urology services. The patient was in the ED for a total of 5 hours.

The plaintiff sued the EP and hospital, claiming that the tourniquet used to start the IV line and draw blood was never removed, which in turn caused nerve damage resulting in reflex sympathetic dystrophy and complex regional pain syndrome. The defense denied all of these allegations, and the ED personnel testified that the tourniquet was removed as soon as the IV was established. The defense cited the plaintiff’s medical records, which contained documentation that the tourniquet had been removed. The defense further argued that if the tourniquet had been left on as the patient alleged, she would have experienced obvious physical signs, such as swelling, redness, infiltration of fluids, pain, and numbness. A defense verdict was returned.

Discussion

It is very tempting to simply dismiss this case as absurd, with nothing to be learned from it. It does defy common sense that no one would have noticed the tourniquet or, at the very least, that the patient would not have spoken up about it during her stay in the ED. While the jury clearly came to the correct conclusion,  it does highlight a real problem: forgotten tourniquets.

According to the Pennsylvania Patient Safety Advisory (PPSA), there were 125 reports of tourniquets being left on patients in Pennsylvania healthcare facilities in 1 year alone.¹ In 5% of these cases, the tourniquet was discovered within a half hour of application. In approximately 66% of cases, the tourniquet was left on for up to 2 hours, and the remaining were left in place for 2 to 18 hours.

Few locations within the hospital are without risk for this type of accident. The PPSA further noted that approximately 30% of retained tourniquets occurred on medical/surgical units, 14% in the ED, and 14% on inpatient and ambulatory surgical services departments. Approximately 19% were discovered when patients were transferred from one department to another.¹

In the analysis of these incidents, contributing factors to forgotten tourniquets included staff failing to follow proper procedures, inadequate staff proficiency, and staff distractions and/or interruptions.¹ In addition, some patients appeared to be at increased risk of having a retained tourniquet than others. Sixty percent of 125 patients with a forgotten tourniquet were aged 70 years or older, whereas some patients were younger than age 2 years.¹ Not surprisingly, patients who were unable to verbally communicate (eg, patients who were intubated, under anesthesia, had expressive aphasia, severe dementia), were at the highest risk.

In a review of recovery room incidents, Salman and Asfar² identified two cases of forgotten tourniquets out of approximately 7,000 patients. Potential strategies to avoid this mistake include: (1) only documenting procedures after they have been completed (eg, tourniquet removal); (2) double-checking that the tourniquet has been removed prior to leaving patient bedside; and (3) the use of extra-long tourniquets so the ends are more clearly visible.

The patient’s physical examination was unremarkable. His vital signs were normal, and there was no obvious external evidence of trauma. The posterior cervical spine was tender to palpation in the midline, but no step-off signs were appreciated. The neurological examination, including strength and sensation in all four extremities, was normal.

Since the patient’s only complaint was neck pain and his physical examination and history were otherwise normal, the emergency physician (EP) ordered radiographs of the cervical spine. The imaging studies were interpreted as showing advanced degenerative changes but no fractures, and the patient was prescribed an analgesic and discharged home.

When the patient woke up the next morning, he was unable to move his extremities, and returned to the same ED via EMS. He was placed in a cervical collar and found to have flaccid extremities on examination. A computed tomography (CT) scan of the cervical spine revealed a transverse fracture through the C6 vertebra. Radiology services also reviewed the cervical spine X-rays from the previous day, noting the presence of fracture.

The patient was taken to the operating room by neurosurgery services but remained paralyzed postoperatively. He never recovered from his injury and died 6 months later. His family sued the EP and the hospital for missed diagnosis of cervical spine fracture at the first ED presentation and the resulting paralysis. The case was settled for $1.3 million prior to trial.

Discussion

The evaluation of suspected cervical spine injury secondary to blunt trauma is a frequent and important skill practiced by EPs. Motor vehicle accidents are the most common cause of spinal cord injury in the United States (42%), followed by falls (27%), acts of violence (15%), and sports-related injuries (8%).¹ A review by Sekon and Fehlings² showed that 55% of all spinal injuries involve the cervical spine. Interestingly, the majority of cervical spine injuries occur at the upper or lower ends of the cervical spine; C2 vertebral fractures account for 33%, while C6 and C7 vertebral fractures account for approximately 50%.¹

There are two commonly used criteria to clinically clear the cervical spine (ie, no imaging studies necessary) in blunt-trauma patients. The first is the National Emergency X-Radiography Use Study (NEXUS), which has a sensitivity of 99.6% of identifying cervical spine fractures.¹ According to the NEXUS criteria, no imaging studies are required if: (1) there is no midline cervical spine tenderness; (2) there are no focal neurological deficits; (3) the patient exhibits a normal level of alertness; (4) the patient is not intoxicated; and (5) there is no distracting injury.¹

The other set of criteria used to clear the cervical spine is the Canadian Cervical Spine Rule. In these criteria, a patient is considered at very low risk for cervical spine fracture in the following cases: (1) the patient is fully alert with a Glasgow Coma scale of 15; (2) the patient has no high-risk factors (ie, age >65 years, dangerous mechanism of injury, fall greater than five stairs, axial load to the head, high-speed vehicular crash, bicycle or motorcycle crash, or the presence of paresthesias in the extremities); (3) the patient has low-risk factors (eg, simple vehicle crash, sitting position in the ED, ambulatory at any time, delayed onset of neck pain, and the absence of midline cervical tenderness); and (4) the patient can actively rotate his or her neck 45 degrees to the left and to the right. The Canadian group found the above criteria to have 100% sensitivity for predicting the absence of cervical spine injury.¹

The patient in this case failed both sets of criteria (ie, presence of cervical spine tenderness and age >65 years) and therefore required imaging. Historically, cervical spine X-ray (three views, anteroposterior, lateral, and odontoid; or five views, three views plus obliques) has been the imaging study of choice for such patients. Unfortunately, however, cervical spine radiographs have severe limitations in identifying spinal injury. In a large retrospective review, Woodring and Lee,³ found that the standard three-view cervical spine series failed to demonstrate 61% of all fractures and 36% of all subluxation and dislocations. Similarly, in a prospective study of 1,006 patients with 72 injuries, Diaz et al,⁴ found a 52.3% missed fracture rate when five-view radiographs were used to identify cervical spine injury. In addition, radiographic evaluation of elderly patients was found to be even more challenging in identifying cervical spine injury due to age-related degenerative changes.

Given the abovementioned limitations associated with radiographic imaging, CT scan of the cervical spine has become the imaging study of choice in moderate-to-severe risk patients with blunt cervical spine trauma. This modality has been shown to have a higher sensitivity and specificity for evaluating cervical spine injury compared to plain X-ray films, with CT detecting 97% to 100% of cervical spine fractures.⁵

In addition to demonstrating a higher sensitivity, CT also has the advantage of speed—especially when the patient is undergoing other CT studies (eg, head, abdomen, pelvis). While some clinicians criticize the higher cost of CT versus plain films, CT has been shown to decrease institutional costs (when settlement costs are taken into account) due to the reduction of the incidence of paralysis resulting from false-negative imaging studies.⁶

Forgotten Tourniquet

The patient’s vital signs were: blood pressure, 138/82 mm Hg; heart rate, 102 beats/minute; respiratory rate, 18 breaths/minute; temperature 98.6˚F. Oxygen saturation was 99% on room air.

The patient appeared uncomfortable overall. The physical examination was remarkable only for mild left-sided costovertebral angle tenderness. Her abdomen was soft, nontender, and without guarding or rebound.

The EP ordered the placement of an intravenous (IV) line, through which the patient was administered normal saline and morphine and promethazine, respectively, for pain and nausea. A complete blood count, basic metabolic panel, urinalysis, and urine pregnancy test were ordered. All of the laboratory bloodwork results were normal, and the urine pregnancy test was negative. The urinalysis was remarkable for 50 to 100 red blood cells.

A noncontrast CT scan of the abdomen and pelvis revealed a 3-mm ureteral stone on the left side. When the patient returned from radiology services, her pain was significantly decreased and she felt much improved. She was diagnosed with a kidney stone and discharged home with an analgesic and a strainer, along with instructions to follow-up with urology services. The patient was in the ED for a total of 5 hours.

The plaintiff sued the EP and hospital, claiming that the tourniquet used to start the IV line and draw blood was never removed, which in turn caused nerve damage resulting in reflex sympathetic dystrophy and complex regional pain syndrome. The defense denied all of these allegations, and the ED personnel testified that the tourniquet was removed as soon as the IV was established. The defense cited the plaintiff’s medical records, which contained documentation that the tourniquet had been removed. The defense further argued that if the tourniquet had been left on as the patient alleged, she would have experienced obvious physical signs, such as swelling, redness, infiltration of fluids, pain, and numbness. A defense verdict was returned.

Discussion

It is very tempting to simply dismiss this case as absurd, with nothing to be learned from it. It does defy common sense that no one would have noticed the tourniquet or, at the very least, that the patient would not have spoken up about it during her stay in the ED. While the jury clearly came to the correct conclusion,  it does highlight a real problem: forgotten tourniquets.

According to the Pennsylvania Patient Safety Advisory (PPSA), there were 125 reports of tourniquets being left on patients in Pennsylvania healthcare facilities in 1 year alone.¹ In 5% of these cases, the tourniquet was discovered within a half hour of application. In approximately 66% of cases, the tourniquet was left on for up to 2 hours, and the remaining were left in place for 2 to 18 hours.

Few locations within the hospital are without risk for this type of accident. The PPSA further noted that approximately 30% of retained tourniquets occurred on medical/surgical units, 14% in the ED, and 14% on inpatient and ambulatory surgical services departments. Approximately 19% were discovered when patients were transferred from one department to another.¹

In the analysis of these incidents, contributing factors to forgotten tourniquets included staff failing to follow proper procedures, inadequate staff proficiency, and staff distractions and/or interruptions.¹ In addition, some patients appeared to be at increased risk of having a retained tourniquet than others. Sixty percent of 125 patients with a forgotten tourniquet were aged 70 years or older, whereas some patients were younger than age 2 years.¹ Not surprisingly, patients who were unable to verbally communicate (eg, patients who were intubated, under anesthesia, had expressive aphasia, severe dementia), were at the highest risk.

In a review of recovery room incidents, Salman and Asfar² identified two cases of forgotten tourniquets out of approximately 7,000 patients. Potential strategies to avoid this mistake include: (1) only documenting procedures after they have been completed (eg, tourniquet removal); (2) double-checking that the tourniquet has been removed prior to leaving patient bedside; and (3) the use of extra-long tourniquets so the ends are more clearly visible.

The patient’s physical examination was unremarkable. His vital signs were normal, and there was no obvious external evidence of trauma. The posterior cervical spine was tender to palpation in the midline, but no step-off signs were appreciated. The neurological examination, including strength and sensation in all four extremities, was normal.

Since the patient’s only complaint was neck pain and his physical examination and history were otherwise normal, the emergency physician (EP) ordered radiographs of the cervical spine. The imaging studies were interpreted as showing advanced degenerative changes but no fractures, and the patient was prescribed an analgesic and discharged home.

When the patient woke up the next morning, he was unable to move his extremities, and returned to the same ED via EMS. He was placed in a cervical collar and found to have flaccid extremities on examination. A computed tomography (CT) scan of the cervical spine revealed a transverse fracture through the C6 vertebra. Radiology services also reviewed the cervical spine X-rays from the previous day, noting the presence of fracture.

The patient was taken to the operating room by neurosurgery services but remained paralyzed postoperatively. He never recovered from his injury and died 6 months later. His family sued the EP and the hospital for missed diagnosis of cervical spine fracture at the first ED presentation and the resulting paralysis. The case was settled for $1.3 million prior to trial.

Discussion

The evaluation of suspected cervical spine injury secondary to blunt trauma is a frequent and important skill practiced by EPs. Motor vehicle accidents are the most common cause of spinal cord injury in the United States (42%), followed by falls (27%), acts of violence (15%), and sports-related injuries (8%).¹ A review by Sekon and Fehlings² showed that 55% of all spinal injuries involve the cervical spine. Interestingly, the majority of cervical spine injuries occur at the upper or lower ends of the cervical spine; C2 vertebral fractures account for 33%, while C6 and C7 vertebral fractures account for approximately 50%.¹

There are two commonly used criteria to clinically clear the cervical spine (ie, no imaging studies necessary) in blunt-trauma patients. The first is the National Emergency X-Radiography Use Study (NEXUS), which has a sensitivity of 99.6% of identifying cervical spine fractures.¹ According to the NEXUS criteria, no imaging studies are required if: (1) there is no midline cervical spine tenderness; (2) there are no focal neurological deficits; (3) the patient exhibits a normal level of alertness; (4) the patient is not intoxicated; and (5) there is no distracting injury.¹

The other set of criteria used to clear the cervical spine is the Canadian Cervical Spine Rule. In these criteria, a patient is considered at very low risk for cervical spine fracture in the following cases: (1) the patient is fully alert with a Glasgow Coma scale of 15; (2) the patient has no high-risk factors (ie, age >65 years, dangerous mechanism of injury, fall greater than five stairs, axial load to the head, high-speed vehicular crash, bicycle or motorcycle crash, or the presence of paresthesias in the extremities); (3) the patient has low-risk factors (eg, simple vehicle crash, sitting position in the ED, ambulatory at any time, delayed onset of neck pain, and the absence of midline cervical tenderness); and (4) the patient can actively rotate his or her neck 45 degrees to the left and to the right. The Canadian group found the above criteria to have 100% sensitivity for predicting the absence of cervical spine injury.¹

The patient in this case failed both sets of criteria (ie, presence of cervical spine tenderness and age >65 years) and therefore required imaging. Historically, cervical spine X-ray (three views, anteroposterior, lateral, and odontoid; or five views, three views plus obliques) has been the imaging study of choice for such patients. Unfortunately, however, cervical spine radiographs have severe limitations in identifying spinal injury. In a large retrospective review, Woodring and Lee,³ found that the standard three-view cervical spine series failed to demonstrate 61% of all fractures and 36% of all subluxation and dislocations. Similarly, in a prospective study of 1,006 patients with 72 injuries, Diaz et al,⁴ found a 52.3% missed fracture rate when five-view radiographs were used to identify cervical spine injury. In addition, radiographic evaluation of elderly patients was found to be even more challenging in identifying cervical spine injury due to age-related degenerative changes.

Given the abovementioned limitations associated with radiographic imaging, CT scan of the cervical spine has become the imaging study of choice in moderate-to-severe risk patients with blunt cervical spine trauma. This modality has been shown to have a higher sensitivity and specificity for evaluating cervical spine injury compared to plain X-ray films, with CT detecting 97% to 100% of cervical spine fractures.⁵

In addition to demonstrating a higher sensitivity, CT also has the advantage of speed—especially when the patient is undergoing other CT studies (eg, head, abdomen, pelvis). While some clinicians criticize the higher cost of CT versus plain films, CT has been shown to decrease institutional costs (when settlement costs are taken into account) due to the reduction of the incidence of paralysis resulting from false-negative imaging studies.⁶

Forgotten Tourniquet

The patient’s vital signs were: blood pressure, 138/82 mm Hg; heart rate, 102 beats/minute; respiratory rate, 18 breaths/minute; temperature 98.6˚F. Oxygen saturation was 99% on room air.

The patient appeared uncomfortable overall. The physical examination was remarkable only for mild left-sided costovertebral angle tenderness. Her abdomen was soft, nontender, and without guarding or rebound.

The EP ordered the placement of an intravenous (IV) line, through which the patient was administered normal saline and morphine and promethazine, respectively, for pain and nausea. A complete blood count, basic metabolic panel, urinalysis, and urine pregnancy test were ordered. All of the laboratory bloodwork results were normal, and the urine pregnancy test was negative. The urinalysis was remarkable for 50 to 100 red blood cells.

A noncontrast CT scan of the abdomen and pelvis revealed a 3-mm ureteral stone on the left side. When the patient returned from radiology services, her pain was significantly decreased and she felt much improved. She was diagnosed with a kidney stone and discharged home with an analgesic and a strainer, along with instructions to follow-up with urology services. The patient was in the ED for a total of 5 hours.

The plaintiff sued the EP and hospital, claiming that the tourniquet used to start the IV line and draw blood was never removed, which in turn caused nerve damage resulting in reflex sympathetic dystrophy and complex regional pain syndrome. The defense denied all of these allegations, and the ED personnel testified that the tourniquet was removed as soon as the IV was established. The defense cited the plaintiff’s medical records, which contained documentation that the tourniquet had been removed. The defense further argued that if the tourniquet had been left on as the patient alleged, she would have experienced obvious physical signs, such as swelling, redness, infiltration of fluids, pain, and numbness. A defense verdict was returned.

Discussion

It is very tempting to simply dismiss this case as absurd, with nothing to be learned from it. It does defy common sense that no one would have noticed the tourniquet or, at the very least, that the patient would not have spoken up about it during her stay in the ED. While the jury clearly came to the correct conclusion,  it does highlight a real problem: forgotten tourniquets.

According to the Pennsylvania Patient Safety Advisory (PPSA), there were 125 reports of tourniquets being left on patients in Pennsylvania healthcare facilities in 1 year alone.¹ In 5% of these cases, the tourniquet was discovered within a half hour of application. In approximately 66% of cases, the tourniquet was left on for up to 2 hours, and the remaining were left in place for 2 to 18 hours.

Few locations within the hospital are without risk for this type of accident. The PPSA further noted that approximately 30% of retained tourniquets occurred on medical/surgical units, 14% in the ED, and 14% on inpatient and ambulatory surgical services departments. Approximately 19% were discovered when patients were transferred from one department to another.¹

In the analysis of these incidents, contributing factors to forgotten tourniquets included staff failing to follow proper procedures, inadequate staff proficiency, and staff distractions and/or interruptions.¹ In addition, some patients appeared to be at increased risk of having a retained tourniquet than others. Sixty percent of 125 patients with a forgotten tourniquet were aged 70 years or older, whereas some patients were younger than age 2 years.¹ Not surprisingly, patients who were unable to verbally communicate (eg, patients who were intubated, under anesthesia, had expressive aphasia, severe dementia), were at the highest risk.

In a review of recovery room incidents, Salman and Asfar² identified two cases of forgotten tourniquets out of approximately 7,000 patients. Potential strategies to avoid this mistake include: (1) only documenting procedures after they have been completed (eg, tourniquet removal); (2) double-checking that the tourniquet has been removed prior to leaving patient bedside; and (3) the use of extra-long tourniquets so the ends are more clearly visible.

VALENCIA, SPAIN—A history of childhood sexual abuse is nearly fourfold more common among patients with chronic migraine than in those with episodic migraine, according to research presented at the International Headache Congress. This association raises the possibility that prior sexual abuse is a contributing factor in the transformation from episodic migraine to chronic migraine, said Brad Torphy, MD, of Diamond Headache Clinic in Chicago.

“The clinical implication of these findings, and what I’m stressing, is the importance of intervention—such as psychological counseling—in episodic migraine patients who have a history of abuse,” he said in an interview. “The other key point is that patients who have episodic migraine may warrant more aggressive therapy, including going on preventive medications sooner, if they have a history of sexual abuse, because they’re probably at risk for progression to chronic migraine.”

Dr. Torphy presented a retrospective study of all new patients seen at the Diamond Headache Clinic during the final four months of last year. The new-patient questionnaire includes a section about past sexual abuse. Such a history was reported by six (4.4%) of the 135 patients with episodic migraine, compared with 30 (15.5%) of the 194 patients with chronic migraine.

Based upon his experience in the clinic, Dr. Torphy suspects that the true proportion of patients with a positive history for sexual abuse is considerably higher than the rates the new-patient questionnaire would suggest.

“A lot of factors would lead to that being a very low number,” Dr. Torphy continued. “It’s the patient’s first visit, and it’s a paper questionnaire, so patients may not be comfortable checking that box when they don’t know who’s going to see the results. I’ve had cases where patients shared with me only after two or three visits that, yes, I do have that history. I think it’s underreported across the board.”

In his review of the literature, he found that other investigators have tended either to lump together all kinds of abuse—physical, emotional, and sexual—in analyzing an association with migraine, or if they looked at sexual abuse in particular, it was in association with all types of chronic pain, not specifically migraine.

—Bruce Jancin

VALENCIA, SPAIN—A history of childhood sexual abuse is nearly fourfold more common among patients with chronic migraine than in those with episodic migraine, according to research presented at the International Headache Congress. This association raises the possibility that prior sexual abuse is a contributing factor in the transformation from episodic migraine to chronic migraine, said Brad Torphy, MD, of Diamond Headache Clinic in Chicago.

“The clinical implication of these findings, and what I’m stressing, is the importance of intervention—such as psychological counseling—in episodic migraine patients who have a history of abuse,” he said in an interview. “The other key point is that patients who have episodic migraine may warrant more aggressive therapy, including going on preventive medications sooner, if they have a history of sexual abuse, because they’re probably at risk for progression to chronic migraine.”

Dr. Torphy presented a retrospective study of all new patients seen at the Diamond Headache Clinic during the final four months of last year. The new-patient questionnaire includes a section about past sexual abuse. Such a history was reported by six (4.4%) of the 135 patients with episodic migraine, compared with 30 (15.5%) of the 194 patients with chronic migraine.

Based upon his experience in the clinic, Dr. Torphy suspects that the true proportion of patients with a positive history for sexual abuse is considerably higher than the rates the new-patient questionnaire would suggest.

“A lot of factors would lead to that being a very low number,” Dr. Torphy continued. “It’s the patient’s first visit, and it’s a paper questionnaire, so patients may not be comfortable checking that box when they don’t know who’s going to see the results. I’ve had cases where patients shared with me only after two or three visits that, yes, I do have that history. I think it’s underreported across the board.”

In his review of the literature, he found that other investigators have tended either to lump together all kinds of abuse—physical, emotional, and sexual—in analyzing an association with migraine, or if they looked at sexual abuse in particular, it was in association with all types of chronic pain, not specifically migraine.

—Bruce Jancin

VALENCIA, SPAIN—A history of childhood sexual abuse is nearly fourfold more common among patients with chronic migraine than in those with episodic migraine, according to research presented at the International Headache Congress. This association raises the possibility that prior sexual abuse is a contributing factor in the transformation from episodic migraine to chronic migraine, said Brad Torphy, MD, of Diamond Headache Clinic in Chicago.

“The clinical implication of these findings, and what I’m stressing, is the importance of intervention—such as psychological counseling—in episodic migraine patients who have a history of abuse,” he said in an interview. “The other key point is that patients who have episodic migraine may warrant more aggressive therapy, including going on preventive medications sooner, if they have a history of sexual abuse, because they’re probably at risk for progression to chronic migraine.”

Dr. Torphy presented a retrospective study of all new patients seen at the Diamond Headache Clinic during the final four months of last year. The new-patient questionnaire includes a section about past sexual abuse. Such a history was reported by six (4.4%) of the 135 patients with episodic migraine, compared with 30 (15.5%) of the 194 patients with chronic migraine.

Based upon his experience in the clinic, Dr. Torphy suspects that the true proportion of patients with a positive history for sexual abuse is considerably higher than the rates the new-patient questionnaire would suggest.

“A lot of factors would lead to that being a very low number,” Dr. Torphy continued. “It’s the patient’s first visit, and it’s a paper questionnaire, so patients may not be comfortable checking that box when they don’t know who’s going to see the results. I’ve had cases where patients shared with me only after two or three visits that, yes, I do have that history. I think it’s underreported across the board.”

In his review of the literature, he found that other investigators have tended either to lump together all kinds of abuse—physical, emotional, and sexual—in analyzing an association with migraine, or if they looked at sexual abuse in particular, it was in association with all types of chronic pain, not specifically migraine.

—Bruce Jancin

Sphingolipid metabolism is altered in women with episodic migraine, according to a study published online ahead of print September 9 in Neurology. According to the study authors, serum sphingolipid panels may have the potential to differentiate episodic migraine presence and absence. “While more research is needed to confirm these initial findings, the possibility of discovering a new biomarker for migraine is exciting,” said lead author B. Lee Peterlin, DO, Director of Johns Hopkins Headache Research and Associate Professor of Neurology at Johns Hopkins University School of Medicine in Baltimore.

Case–Control Study

In this study, 88 female participants, 52 with episodic migraine and 36 without, were evaluated on the basis of demographic and health-related criteria, including marital status, BMI, and neuronal functioning. The patients also submitted blood samples, which were tested for lipid concentrations among other things.

The findings suggest that migraineurs had a decreased de novo synthesis of ceramides, which, paired with an independent downstream increase in the conversion of ceramide metabolic products, resulted in a major deficit. Women with migraines had an average concentration of ceramide levels of 6,000 ng/mL, a 43% decrease when compared with controls, who had an average of 10,500 ng/mL of ceramide in their blood.

There was also a marked difference in sphingolipid concentrations in those with migraines, with some species increasing while others were decreased. Dr. Peterlin and colleagues used the difference in blood lipid levels to create a list of 10 sphingolipids thought to classify episodic migraine. In a later test, this constructed biomarker evaluative list was 100% effective in identifying women with and without episodic migraine for a small group of eight migraineurs and six controls.

“This study is an important contribution to our understanding of the pathophysiology of migraine and may have vast practical, clinical, and therapeutic implications if it is supported by further studies,” said Karl Ekbom, PhD, a neurologist at the Karolinska Institutet in Stockholm, in an accompanying commentary.

The study suggests that the presence of migraines is a neurologic disorder of sphingolipid dsymetabolism. With the positive identification of these biomarkers comes the potential of targeted drug therapies directed against the specific sphingolipid pathways 
involved.

—Adaeze Stephanie Onyechi

Sphingolipid metabolism is altered in women with episodic migraine, according to a study published online ahead of print September 9 in Neurology. According to the study authors, serum sphingolipid panels may have the potential to differentiate episodic migraine presence and absence. “While more research is needed to confirm these initial findings, the possibility of discovering a new biomarker for migraine is exciting,” said lead author B. Lee Peterlin, DO, Director of Johns Hopkins Headache Research and Associate Professor of Neurology at Johns Hopkins University School of Medicine in Baltimore.

Case–Control Study

In this study, 88 female participants, 52 with episodic migraine and 36 without, were evaluated on the basis of demographic and health-related criteria, including marital status, BMI, and neuronal functioning. The patients also submitted blood samples, which were tested for lipid concentrations among other things.

The findings suggest that migraineurs had a decreased de novo synthesis of ceramides, which, paired with an independent downstream increase in the conversion of ceramide metabolic products, resulted in a major deficit. Women with migraines had an average concentration of ceramide levels of 6,000 ng/mL, a 43% decrease when compared with controls, who had an average of 10,500 ng/mL of ceramide in their blood.

There was also a marked difference in sphingolipid concentrations in those with migraines, with some species increasing while others were decreased. Dr. Peterlin and colleagues used the difference in blood lipid levels to create a list of 10 sphingolipids thought to classify episodic migraine. In a later test, this constructed biomarker evaluative list was 100% effective in identifying women with and without episodic migraine for a small group of eight migraineurs and six controls.

“This study is an important contribution to our understanding of the pathophysiology of migraine and may have vast practical, clinical, and therapeutic implications if it is supported by further studies,” said Karl Ekbom, PhD, a neurologist at the Karolinska Institutet in Stockholm, in an accompanying commentary.

The study suggests that the presence of migraines is a neurologic disorder of sphingolipid dsymetabolism. With the positive identification of these biomarkers comes the potential of targeted drug therapies directed against the specific sphingolipid pathways 
involved.

—Adaeze Stephanie Onyechi

Sphingolipid metabolism is altered in women with episodic migraine, according to a study published online ahead of print September 9 in Neurology. According to the study authors, serum sphingolipid panels may have the potential to differentiate episodic migraine presence and absence. “While more research is needed to confirm these initial findings, the possibility of discovering a new biomarker for migraine is exciting,” said lead author B. Lee Peterlin, DO, Director of Johns Hopkins Headache Research and Associate Professor of Neurology at Johns Hopkins University School of Medicine in Baltimore.

Case–Control Study

In this study, 88 female participants, 52 with episodic migraine and 36 without, were evaluated on the basis of demographic and health-related criteria, including marital status, BMI, and neuronal functioning. The patients also submitted blood samples, which were tested for lipid concentrations among other things.

The findings suggest that migraineurs had a decreased de novo synthesis of ceramides, which, paired with an independent downstream increase in the conversion of ceramide metabolic products, resulted in a major deficit. Women with migraines had an average concentration of ceramide levels of 6,000 ng/mL, a 43% decrease when compared with controls, who had an average of 10,500 ng/mL of ceramide in their blood.

There was also a marked difference in sphingolipid concentrations in those with migraines, with some species increasing while others were decreased. Dr. Peterlin and colleagues used the difference in blood lipid levels to create a list of 10 sphingolipids thought to classify episodic migraine. In a later test, this constructed biomarker evaluative list was 100% effective in identifying women with and without episodic migraine for a small group of eight migraineurs and six controls.

“This study is an important contribution to our understanding of the pathophysiology of migraine and may have vast practical, clinical, and therapeutic implications if it is supported by further studies,” said Karl Ekbom, PhD, a neurologist at the Karolinska Institutet in Stockholm, in an accompanying commentary.

The study suggests that the presence of migraines is a neurologic disorder of sphingolipid dsymetabolism. With the positive identification of these biomarkers comes the potential of targeted drug therapies directed against the specific sphingolipid pathways 
involved.

—Adaeze Stephanie Onyechi

Three decades ago, the only drugs we had for treating chronic heart failure were digitalis and loop diuretics. The mortality rate was very high, and heart transplantation was a newly developing treatment that could help only a very few patients.

See related article

The early 80s heralded new hope for patients with heart failure, with the introduction of angiotensin-converting enzyme (ACE) inhibitors^1–5 and, later, beta-blockers. Beta-blockers were considered contraindicated in heart failure until new trials provided evidence of dramatic benefit such as better quality of life and longer survival.^6–8 ACE inhibitors, along with beta-blockers, quickly became the standard of care for all patients with systolic heart failure.

The implantable cardioverter-defibrillator (ICD) required numerous clinical trials in ischemic and nonischemic cardiomyopathy to define its role.^9,10 Cardiac resynchronization therapy did not arrive until 15 years ago and is now indicated in a specific niche of patients with left bundle branch block.^11,12 Mineralocorticoid antagonists required three pivotal clinical trials before their important role in the treatment of systolic heart failure was defined.^13–16

And in the current decade, the roles of ACE inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, mineralocorticoid antagonists, ICDs, and cardiac resynchronization therapy have been further defined, as reflected in the latest guidelines for the treatment of systolic heart failure.¹⁷

It was hard to believe that any new additional therapy would make a significant difference

Guideline-directed medical therapy for systolic heart failure with the agents and devices mentioned above improves quality of life and extends survival. It was therefore hard to imagine that any new additive therapy could offer significant incremental improvement. However, more than 5 years ago, in an ambitious effort, the largest global clinical trial ever performed in chronic heart failure was launched with a novel agent.¹⁸

THE PARADIGM-HF TRIAL

In this issue of the Journal, Sabe et al¹⁹ describe the results of the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial of the novel combination drug sacubitril-valsartan, designated LCZ696 during its development and now available as Entresto.²⁰

The mean age of the 8,442 patients in PARADIGM-HF was 64, and 78% were men. Despite guideline-directed medical therapy (93% of the patients were receiving a beta-blocker, and 60% were receiving a mineralocorticoid receptor antagonist), patients had persistent symptoms and signs of heart failure, diminished health-related quality of life, reduced ejection fraction (mean 29%), and elevated n-terminal pro-B-type natriuretic peptide levels (median 1,608 pg/mL, interquartile range 886–3,221).

The investigators reported a remarkable 20% reduction in the primary outcome of death from cardiovascular causes or hospitalization for heart failure in the patients who received sacubitril-valsartan compared with enalapril.²⁰

Sacubitril-valsartan was reviewed under a US Food and Drug Administration (FDA) program that provides expedited review of drugs that are intended to treat a serious disease or condition and that may provide a significant improvement over available therapy. It was also granted a fast-track designation, which supports FDA efforts to facilitate the development and expedite the review of drugs to treat serious and life-threatening conditions and fill an unmet medical need. The FDA approved sacubitril-valsartan on July 7, 2015, for use in place of an ACE inhibitor or ARB in patients with New York Heart Association class II, III, or IV heart failure with reduced ejection fraction.²¹

WHAT WE STILL NEED TO KNOW

The results of PARADIGM-HF are generalizable, and sacubitril-valsartan was well tolerated in patients whose blood pressure was acceptable and who were able to tolerate ACE inhibitors in target doses. More than 90% of patients were receiving a beta-blocker. The dosing of enalapril (target 10 mg twice a day) is the guideline-directed target dose, and ACE inhibition is considered the gold standard for heart failure with reduced ejection fraction. Sacubitril-valsartan vs enalapril was a very appropriate comparison.

Far fewer PARADIGM-HF patients outside the United States had an ICD than those in the United States, which is a common finding in global clinical trials. However, Desai et al reported that sacubitril-valsartan reduced rates of cardiovascular mortality both from worsening heart failure and from sudden cardiac death, independent of whether the patient had an ICD.²²

Sacubitril-valsartan is taken twice a day, but most heart failure patients already take medications at several times during the day, so this should not pose a problem.

Sacubitril-valsartan ushers in a new era in treating heart failure with reduced ejection fraction

More information is needed on the use of this new drug in patients with New York Heart Association class IV symptoms, as only 60 patients with class IV symptoms were included in the PARADIGM-HF trial. Also, the efficacy of the drug in patients unable to tolerate a full dose will need to be analyzed.

PARADIGM-HF was conducted in stable, nonhospitalized patients with chronic heart failure; the use of the drug in new-onset heart failure and its initiation in hospitalized patients will require further study. In addition, the PARAGON-HF trial²³ will examine the efficacy of sacubitril-valsartan in patients with heart failure and an ejection fraction of 45% or higher.

Sacubitril-valsartan ushers in a new era in heart failure treatment for patients with reduced ejection fraction and will certainly prompt quick revision of heart failure guidelines.

Three decades ago, the only drugs we had for treating chronic heart failure were digitalis and loop diuretics. The mortality rate was very high, and heart transplantation was a newly developing treatment that could help only a very few patients.

See related article

The early 80s heralded new hope for patients with heart failure, with the introduction of angiotensin-converting enzyme (ACE) inhibitors^1–5 and, later, beta-blockers. Beta-blockers were considered contraindicated in heart failure until new trials provided evidence of dramatic benefit such as better quality of life and longer survival.^6–8 ACE inhibitors, along with beta-blockers, quickly became the standard of care for all patients with systolic heart failure.

The implantable cardioverter-defibrillator (ICD) required numerous clinical trials in ischemic and nonischemic cardiomyopathy to define its role.^9,10 Cardiac resynchronization therapy did not arrive until 15 years ago and is now indicated in a specific niche of patients with left bundle branch block.^11,12 Mineralocorticoid antagonists required three pivotal clinical trials before their important role in the treatment of systolic heart failure was defined.^13–16

And in the current decade, the roles of ACE inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, mineralocorticoid antagonists, ICDs, and cardiac resynchronization therapy have been further defined, as reflected in the latest guidelines for the treatment of systolic heart failure.¹⁷

It was hard to believe that any new additional therapy would make a significant difference

Guideline-directed medical therapy for systolic heart failure with the agents and devices mentioned above improves quality of life and extends survival. It was therefore hard to imagine that any new additive therapy could offer significant incremental improvement. However, more than 5 years ago, in an ambitious effort, the largest global clinical trial ever performed in chronic heart failure was launched with a novel agent.¹⁸

THE PARADIGM-HF TRIAL

In this issue of the Journal, Sabe et al¹⁹ describe the results of the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial of the novel combination drug sacubitril-valsartan, designated LCZ696 during its development and now available as Entresto.²⁰

The mean age of the 8,442 patients in PARADIGM-HF was 64, and 78% were men. Despite guideline-directed medical therapy (93% of the patients were receiving a beta-blocker, and 60% were receiving a mineralocorticoid receptor antagonist), patients had persistent symptoms and signs of heart failure, diminished health-related quality of life, reduced ejection fraction (mean 29%), and elevated n-terminal pro-B-type natriuretic peptide levels (median 1,608 pg/mL, interquartile range 886–3,221).

The investigators reported a remarkable 20% reduction in the primary outcome of death from cardiovascular causes or hospitalization for heart failure in the patients who received sacubitril-valsartan compared with enalapril.²⁰

Sacubitril-valsartan was reviewed under a US Food and Drug Administration (FDA) program that provides expedited review of drugs that are intended to treat a serious disease or condition and that may provide a significant improvement over available therapy. It was also granted a fast-track designation, which supports FDA efforts to facilitate the development and expedite the review of drugs to treat serious and life-threatening conditions and fill an unmet medical need. The FDA approved sacubitril-valsartan on July 7, 2015, for use in place of an ACE inhibitor or ARB in patients with New York Heart Association class II, III, or IV heart failure with reduced ejection fraction.²¹

WHAT WE STILL NEED TO KNOW

The results of PARADIGM-HF are generalizable, and sacubitril-valsartan was well tolerated in patients whose blood pressure was acceptable and who were able to tolerate ACE inhibitors in target doses. More than 90% of patients were receiving a beta-blocker. The dosing of enalapril (target 10 mg twice a day) is the guideline-directed target dose, and ACE inhibition is considered the gold standard for heart failure with reduced ejection fraction. Sacubitril-valsartan vs enalapril was a very appropriate comparison.

Far fewer PARADIGM-HF patients outside the United States had an ICD than those in the United States, which is a common finding in global clinical trials. However, Desai et al reported that sacubitril-valsartan reduced rates of cardiovascular mortality both from worsening heart failure and from sudden cardiac death, independent of whether the patient had an ICD.²²

Sacubitril-valsartan is taken twice a day, but most heart failure patients already take medications at several times during the day, so this should not pose a problem.

Sacubitril-valsartan ushers in a new era in treating heart failure with reduced ejection fraction

More information is needed on the use of this new drug in patients with New York Heart Association class IV symptoms, as only 60 patients with class IV symptoms were included in the PARADIGM-HF trial. Also, the efficacy of the drug in patients unable to tolerate a full dose will need to be analyzed.

PARADIGM-HF was conducted in stable, nonhospitalized patients with chronic heart failure; the use of the drug in new-onset heart failure and its initiation in hospitalized patients will require further study. In addition, the PARAGON-HF trial²³ will examine the efficacy of sacubitril-valsartan in patients with heart failure and an ejection fraction of 45% or higher.

Sacubitril-valsartan ushers in a new era in heart failure treatment for patients with reduced ejection fraction and will certainly prompt quick revision of heart failure guidelines.

Three decades ago, the only drugs we had for treating chronic heart failure were digitalis and loop diuretics. The mortality rate was very high, and heart transplantation was a newly developing treatment that could help only a very few patients.

See related article

The early 80s heralded new hope for patients with heart failure, with the introduction of angiotensin-converting enzyme (ACE) inhibitors^1–5 and, later, beta-blockers. Beta-blockers were considered contraindicated in heart failure until new trials provided evidence of dramatic benefit such as better quality of life and longer survival.^6–8 ACE inhibitors, along with beta-blockers, quickly became the standard of care for all patients with systolic heart failure.

The implantable cardioverter-defibrillator (ICD) required numerous clinical trials in ischemic and nonischemic cardiomyopathy to define its role.^9,10 Cardiac resynchronization therapy did not arrive until 15 years ago and is now indicated in a specific niche of patients with left bundle branch block.^11,12 Mineralocorticoid antagonists required three pivotal clinical trials before their important role in the treatment of systolic heart failure was defined.^13–16

And in the current decade, the roles of ACE inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, mineralocorticoid antagonists, ICDs, and cardiac resynchronization therapy have been further defined, as reflected in the latest guidelines for the treatment of systolic heart failure.¹⁷

It was hard to believe that any new additional therapy would make a significant difference

Guideline-directed medical therapy for systolic heart failure with the agents and devices mentioned above improves quality of life and extends survival. It was therefore hard to imagine that any new additive therapy could offer significant incremental improvement. However, more than 5 years ago, in an ambitious effort, the largest global clinical trial ever performed in chronic heart failure was launched with a novel agent.¹⁸

THE PARADIGM-HF TRIAL

In this issue of the Journal, Sabe et al¹⁹ describe the results of the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial of the novel combination drug sacubitril-valsartan, designated LCZ696 during its development and now available as Entresto.²⁰

The mean age of the 8,442 patients in PARADIGM-HF was 64, and 78% were men. Despite guideline-directed medical therapy (93% of the patients were receiving a beta-blocker, and 60% were receiving a mineralocorticoid receptor antagonist), patients had persistent symptoms and signs of heart failure, diminished health-related quality of life, reduced ejection fraction (mean 29%), and elevated n-terminal pro-B-type natriuretic peptide levels (median 1,608 pg/mL, interquartile range 886–3,221).

The investigators reported a remarkable 20% reduction in the primary outcome of death from cardiovascular causes or hospitalization for heart failure in the patients who received sacubitril-valsartan compared with enalapril.²⁰

Sacubitril-valsartan was reviewed under a US Food and Drug Administration (FDA) program that provides expedited review of drugs that are intended to treat a serious disease or condition and that may provide a significant improvement over available therapy. It was also granted a fast-track designation, which supports FDA efforts to facilitate the development and expedite the review of drugs to treat serious and life-threatening conditions and fill an unmet medical need. The FDA approved sacubitril-valsartan on July 7, 2015, for use in place of an ACE inhibitor or ARB in patients with New York Heart Association class II, III, or IV heart failure with reduced ejection fraction.²¹

WHAT WE STILL NEED TO KNOW

The results of PARADIGM-HF are generalizable, and sacubitril-valsartan was well tolerated in patients whose blood pressure was acceptable and who were able to tolerate ACE inhibitors in target doses. More than 90% of patients were receiving a beta-blocker. The dosing of enalapril (target 10 mg twice a day) is the guideline-directed target dose, and ACE inhibition is considered the gold standard for heart failure with reduced ejection fraction. Sacubitril-valsartan vs enalapril was a very appropriate comparison.

Far fewer PARADIGM-HF patients outside the United States had an ICD than those in the United States, which is a common finding in global clinical trials. However, Desai et al reported that sacubitril-valsartan reduced rates of cardiovascular mortality both from worsening heart failure and from sudden cardiac death, independent of whether the patient had an ICD.²²

Sacubitril-valsartan is taken twice a day, but most heart failure patients already take medications at several times during the day, so this should not pose a problem.

Sacubitril-valsartan ushers in a new era in treating heart failure with reduced ejection fraction

More information is needed on the use of this new drug in patients with New York Heart Association class IV symptoms, as only 60 patients with class IV symptoms were included in the PARADIGM-HF trial. Also, the efficacy of the drug in patients unable to tolerate a full dose will need to be analyzed.

PARADIGM-HF was conducted in stable, nonhospitalized patients with chronic heart failure; the use of the drug in new-onset heart failure and its initiation in hospitalized patients will require further study. In addition, the PARAGON-HF trial²³ will examine the efficacy of sacubitril-valsartan in patients with heart failure and an ejection fraction of 45% or higher.

Sacubitril-valsartan ushers in a new era in heart failure treatment for patients with reduced ejection fraction and will certainly prompt quick revision of heart failure guidelines.

In a large phase trial, a combination drug that contains the angiotensin II receptor blocker (ARB) valsartan and the neprilysin inhibitor sacubitril was found to be superior to the angiotensin-converting enzyme (ACE) inhibitor enalapril in terms of important end points, including death and hospitalization for heart failure, in patients with heart failure with reduced ejection fraction.¹

See related editorial

Recently approved by the US Food and Drug Administration, this combination drug, marketed under the brand name Entresto, represents a new drug class, angiotensin receptor-neprilysin inhibitors, or ARNIs.

This article is an overview of the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial¹ and the implications it may have on the care of patients with chronic heart failure.

NEED FOR NEW HEART FAILURE DRUGS

Heart failure is a major public health problem, and the care of patients with heart failure is challenging.

Almost 6 million US adults have heart failure, and the prevalence is projected to increase in the next few decades as the population continues to age.² Furthermore, the total healthcare cost for heart failure patients was almost $31 billion in 2012 and is projected to rise to $70 billion by 2030.²

The care of patients with severely decompensated heart failure has changed dramatically in the last few decades with advances in heart transplantation and mechanical support devices. But day-to-day management of patients with chronic mildly to moderately symptomatic heart failure continues to pose a clinical challenge.

The drugs currently available for these patients include beta-blockers, ACE inhibitors, ARBs, aldosterone antagonists, digoxin, diuretics, and vasodilators. But even with these drugs, the death and readmission rates of patients with heart failure with reduced ejection fraction remain high. More than 50% of patients with heart failure die within 5 years of diagnosis,³ and 25% of patients hospitalized with heart failure are readmitted within 30 days of discharge.² Furthermore, death rates are higher in those patients who have a history of heart failure hospitalization.⁴

Although heart failure with preserved ejection fraction encompasses an important group of heart failure patients with high morbidity, the focus of this article will be on patients with heart failure with reduced ejection fraction.

Available drugs to date

The cornerstone drugs that lower the odds of death in patients with heart failure with reduced ejection fraction are ACE inhibitors, ARBs, beta-blockers, and mineralocorticoid antagonists.

ACE inhibitors were the first class of drugs shown to reduce the death rate in patients with heart failure with reduced ejection fraction. The landmark CONSENSUS trial,⁵ published in 1987, found that the death rate in patients who received enalapril was 27% lower than in those receiving placebo, an effect driven entirely by a reduction in progressive heart failure. Similarly, the SOLVD trial,⁶ published in 1991, showed a 26% reduction in heart failure hospitalization and a 16% lower rate of death with enalapril compared with placebo, an effect driven predominantly by a decrease in the progression of heart failure.

ARBs have also been shown to decrease the rate of death, although not by as much as ACE inhibitors. In the CHARM trial,⁷ compared with placebo, candesartan significantly decreased the risk of death from any cause, of death from cardiovascular causes, and of hospitalization related to heart failure.⁷

Beta-blockers. The MERIT-HF trial,⁸ published in 1999, was stopped early because fewer patients were dying in the group receiving metoprolol succinate than in the group receiving placebo (relative risk 0.66). Similarly, in 2001, the COPERNICUS trial⁹ reported a 34% reduction in deaths in patients receiving carvedilol in addition to an ACE inhibitor compared with those receiving an ACE inhibitor alone.

Mineralocorticoid receptor antagonists were found to be beneficial when added to standard therapy for chronic symptomatic heart failure in the RALES¹⁰ and EMPHASIS-HF¹¹ trials.

Vasodilators (specifically, the combination of isosorbide dinitrate and hydralazine) were found to have benefit in terms of mortality when added to standard therapy in African American patients in the A-HeEFT trial.¹²

WHY INHIBIT BOTH ANGIOTENSIN AND NEPRILYSIN?

The renin-angiotensin-aldosterone system is a major focus in treating heart failure, as overactivity of this system plays a key role in the pathophysiology of this disease. Therefore, essential drugs for heart failure patients include those that inhibit overactivity of this system such as ACE inhibitors, ARBs, and aldosterone antagonists.

The natriuretic peptide system is another important pathway that can be targeted in patients with heart failure. Natriuretic peptides are key molecules that counteract heart failure, as they contribute to diuresis and vasodilation and protect against vascular remodeling.¹³ An increased understanding of the importance of this system in slowing the progression of heart failure has motivated evaluation of drugs such as nesiritide in patients with symptomatic heart failure. However, these drugs can cause hypotension and have limited bioavailability.¹⁴

Neprilysin is an endopeptidase—an endogenous enzyme that degrades vasoactive peptides such as bradykinin and natriuretic peptides.¹⁴ Drugs that inhibit neprilysin increase the levels of these peptides and thus counteract neurohormonal stimuli that lead to cardiac remodeling, sodium retention, and vasoconstriction.¹⁵

However, neprilysin also hydrolyzes angiotensin I to angiotensin (1–7), an inhibitor of angiotensin II. Thus, inhibition of neprilysin alone could lead to increased activity of angiotensin II and so have an overall neutral effect. To be beneficial, neprilysin inhibition needs to be combined with renin-angiotensin system inhibition. Furthermore, the benefit of renin-angiotensin-aldosterone system blockade may be amplified by up-regulation of the endogenous natriuretic peptide system.¹⁵

Omapatrilat, the most studied combination neprilysin inhibitor and ACE inhibitor, improved cardiac function and decreased cardiac mass in animal experiments.¹⁵ In addition, this drug showed promise in terms of blood pressure, heart failure readmissions, death, and preservation of renal function when compared with ACE inhibitors in patients with heart failure.^15–17 But in clinical trials this drug posed a greater risk of hypotension, dizziness, and, its major shortcoming, an unacceptably high incidence of angioedema compared with ACE inhibitors.^15,16,18 This higher risk of angioedema is thought to be from inhibition of three enzymes that break down bradykinin: ACE, neprilysin, and aminopeptidase P.¹⁹

ARNIs contain an angiotensin receptor blocker rather than an ACE inhibitor, and thus in theory they may be associated with a lower risk of angioedema.¹⁹ Sacubitril-valsartan, the first drug of this class, contains its two constitutive drugs in a one-to-one molecular ratio (Figure 1).

PARADIGM-HF investigated the benefit of this drug in patients with systolic heart failure.¹

STUDY DESIGN AND OBJECTIVES

PARADIGM-HF was a double-blind, randomized controlled trial comparing sacubitril-valsartan and enalapril in patients with chronic systolic heart failure. As such, it was the first trial in recent years to study a new drug in comparison with a well-established heart failure drug rather than as an add-on strategy.¹

Inclusion criteria

To be included in the PARADIGM-HF trial, patients had to have:

• A left ventricular ejection fraction of 40% or less (later changed to ≤ 35%)
• New York Heart Association class II, III, or IV symptoms
• A B-type natriuretic peptide (BNP) level of at least 150 pg/mL or an N-terminal proBNP (NT-proBNP) level of at least 600 pg/mL; for patients hospitalized for heart failure within the previous 12 months, the cut points were lower (BNP ≥ 100 pg/mL or NT-proBNP ≥ 400 pg/mL).

End points

The primary end point was the composite of cardiovascular death or first hospitalization for heart failure. Other outcomes assessed were time to death from any cause, the change from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score at 8 months, time to new-onset atrial fibrillation, and the time to decline in renal function (defined as end-stage renal disease or a decrease in estimated glomerular filtration rate of at least 50% from randomization). All end points were blindly adjudicated by a clinical end points committee.

Two run-in periods

The study enrolled 10,521 patients from 1,043 centers in 47 countries, who entered the initial run-in period consisting of 2 weeks of treatment with enalapril at the study dosage (10 mg twice daily) in order to ensure no unacceptable side effects. At this point, 1,102 patients exited the study, leaving 9,419 who entered the second run-in period.

The second run-in period consisted of 4 weeks of treatment with sacubitril-valsartan, initially at half the study regimen (100 mg twice daily) and eventually at the full study dosage (200 mg twice daily). During the second run-in period, 977 participants left the study, leaving a total of 8,442 patients who underwent randomization. Forty-three patients were then excluded (6 because of invalid randomization and 37 because of four sites that closed because of major violations of good clinical practice).

Of those randomized, 4,187 patients were assigned to the sacubitril-valsartan treatment group and 4,212 were assigned to the enalapril group. The investigators used an intention-to-treat analysis for this study.

Most patients had NYHA class II symptoms

The randomized patients had a mean age of 64 years, 75% were men, 66% were white, and 58% were from Europe (only 7% were from North America). The mean left ventricular ejection fraction was about 30%, and 60% of the study participants had an ischemic cause for their cardiomyopathy. Although one of the inclusion criteria was New York Heart Association class II, III, or IV symptoms, about 5% of the patients had class I symptoms. Seventy percent had class II symptoms, 24% had class III, and less than 1% had class IV symptoms.

At the time of randomization, 78% of the patients were taking an ACE inhibitor and 93% were taking a beta-blocker, but only a little more than half were taking a mineralocorticoid antagonist and only about 15% had an implantable cardioverter-defibrillator.

STUDY OUTCOMES

This study was designed to detect a 15% lower risk of cardiovascular death in the sacubitril-valsartan group. It was projected to continue for at least 34 months but was stopped early because of an overwhelming benefit of the new drug at a median follow-up of 27 months.

Major findings

The primary composite outcome (cardiovascular death or first hospitalization for heart failure)¹ occurred in 21.8% of the patients in the sacubitril-valsartan group vs 26.5% of patients in the enalapril group (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.73–0.87, P < .001). The number of patients who needed to be treated to prevent one occurrence of the primary composite outcome (100/absolute risk reduction) was only 21. The benefit was strong and consistent across both of the individual components of the composite outcome:

• Cardiovascular death 13.3% vs 16.5%, HR 0.80 (95% CI 0.71–0.89), P < .001
• First hospitalization for worsening heart failure 12.8% vs 15.6%, HR 0.79 (95% CI 0.71–0.89), P < .001.

Secondary outcomes. The sacubitril-valsartan group had a significantly lower rate of death from any cause (17.0% vs 19.8%, HR 0.84, 95% CI 0.76–0.93, P < .001) and a lower mean decrease in KCCQ clinical summary scores at 8 months (2.99 points vs 4.63 points, mean difference 1.64, 95% CI 0.63–2.65, P = .001). The KCCQ score measures subjective symptoms and physical limitations caused by heart failure; possible scores range from 0 to 100, with a higher score indicating better functional status. Notably, sacubitril-valsartan did not increase the KCCQ score in these patients; rather, sacubitril-valsartan recipients had a lower decrease in their scores than those in the enalapril group.

The incidence of new-onset atrial fibrillation was the same in both groups (3.1% and 3.1%).¹ A decline in renal function (defined as end-stage renal disease, a decrease of 50% or more in estimated glomerular filtration rate from the value at randomization or a decrease in the estimated glomerular filtration rate of more than 30 mL/min/1.73 m² to less than 60 mL/min/1.73 m²) occurred in 2.2% of the valsartan-sacubitril group and 2.6% of the enalapril group (P = .28).

The effects of the study drug on the primary composite outcome and on death from a cardiovascular cause were similar in all prespecified subgroups except for NYHA class: the reduction in the risk of the composite outcome was lower in sacubitril-valsartan recipients with NYHA I or II symptoms than in those with NYHA III or IV symptoms (P for interaction .03). However, there were no differences in the other prespecified subgroups, defined by age, sex, race, region, estimated glomerular filtration rate, diabetes, systolic blood pressure, ejection fraction, atrial fibrillation, NT-proBNP, hypertension, previous use of an ACE inhibitor, previous use of an aldosterone antagonist, previous heart failure hospitalization, and time since diagnosis of heart failure.

SAFETY: ANGIOEDEMA, HYPOTENSION, AND RENAL DYSFUNCTION

Angioedema

As noted above, the combination of neprilysin inhibitors and ACE inhibitors has been associated with an increased risk of angioedema. That was an important consideration before starting this study, which used a combination of a neprilysin inhibitor and an ARB in an attempt to avoid this serious side effect.

As it happened, there was no increased risk of significant angioedema with sacubitril-valsartan use compared with enalapril. Rates were similar to those in other studies, which showed a less than 1% risk of angioedema caused by ACE inhibitors.^20,21 Only 19 patients (0.5%) in the sacubitril-valsartan group and 10 patients (0.2%) in the enalapril group experienced any angioedema. Of these, just three patients in the sacubitril-valsartan group and one patient in the enalapril group experienced angioedema that required hospitalization (P = .31). None of these patients had airway compromise due to angioedema.

Hypotension, cough, renal dysfunction, hyperkalemia

Other safety issues that were assessed included hypotension, worsening renal function, increase in potassium levels, and cough. Patients in the sacubitril-valsartan group were more likely to have symptomatic hypotension than patients in the enalapril group (14.0% vs 9.2%, P < .001); however, the authors noted that this was a rare cause of drug discontinuation.

Patients in the sacubitril-valsartan group were less likely to develop cough (11.3% vs 14.3%, P < .001), a serum creatinine level of 2.5 mg/dL or more (3.3% vs 4.5%, P = .007), or a serum potassium level of more than 6.0 mmol/L (11.3% vs 14.3%, P = .007).¹

During the two run-in periods combined, 12% of the patients in the study withdrew because of adverse events, including cough, renal dysfunction, hyperkalemia, and symptomatic hypotension. During the enalapril run-in period, 591 patients (5.6%) withdrew due to adverse events, and 547 patients (5.8%) withdrew due to these events during the sacubitril-valsartan run-in period. After adjusting for the shorter time on enalapril, there was a higher rate of withdrawal because of adverse events from enalapril than from sacubitril-valsartan.

LOWER RISK OF CLINICAL PROGRESSION

In a separate paper,²² the PARADIGM-HF investigators reported that, among the survivors in the study, those who received sacubitril-valsartan fared better in terms of a number of markers of progression of heart failure, with lower rates of:

• Intensification of medical treatment for heart failure
• Emergency department visits for worsening heart failure
• Hospitalization for worsening heart failure
• Need for intensive care
• Need for intravenous inotropic agents
• Need for cardiac devices or heart transplants
• Worsening symptom scores
• Elevation of biomarkers of myocardial injury.

QUESTIONS AND CONCERNS

Although this study, which was funded by the manufacturer, showed consistent benefit for sacubitril-valsartan over enalapril, questions remain.

Are the findings generalizable?

Despite the study’s rigorous run-in period, 12% of patients dropped out because of adverse events, and thus the patients who completed the study may not be representative of the general population of heart failure patients. The authors included this double-level wash-out to ensure patient tolerance of both drugs. But in everyday practice, a significant number of patients may be unable to tolerate one of these drugs.

Moreover, after adjusting for the difference in the run-in periods, patients actually withdrew more often during the enalapril run-in period than during the sacubitril-valsartan run-in period. However, there may be overlap in tolerability in these two drugs, which both affect the renin-angiotensin-aldosterone system. Thus, the enalapril run-in period may have contributed to the lower tolerability of this drug compared with sacubitril-valsartan.

Were patients receiving the best possible therapy?

Another important point when considering how we treat heart failure patients in the United States is how few patients in this study were using cardiac implantable electronic devices. Only 15% of the patients in this study had an implantable cardioverter-defibrillator despite a mean left ventricular ejection fraction less than 30%. This likely reflects differences in practice internationally; however, based on American College of Cardiology, American Heart Association, and Heart Rhythm Society guidelines, these patients would have a class I indication for an implantable cardioverter-defibrillator for primary prevention of sudden cardiac death.²³

Therefore, based on these recommendations, the patients in this study were not necessarily on optimal medical and device therapy and furthermore may not be representative of heart failure patients in the United States.

Was enalapril 10 mg twice a day a fair comparison?

Another concern about the results of this study relates to the dosages used in the two treatment groups. The sacubitril-valsartan formulation included full-dose valsartan, whereas the ACE inhibitor group received enalapril at less than a full dose.

Although the authors explained that the dose of enalapril chosen for the study was based on the one used in previous studies that showed survival benefit, this raises the question of whether the significant difference in outcomes in this trial was due to a greater inhibition of the renin-angiotensin-aldosterone system related to a higher dose of drug in the sacubitril-valsartan group.

What about black patients taking hydralazine-isosorbide?

Only about 5% of patients in the PARADIGM-HF trial were black. Based on the A-HeFT study results, black patients can be prescribed an ACE inhibitor as well as hydralazine and isosorbide dinitrate as tolerated to decrease the risk of death. Does sacubitril-valsartan offer benefit to these patients compared with a regimen of an ACE inhibitor, hydralazine, and isosorbide dinitrate?

Another concern is that the incidence of angioedema observed with ACE inhibitors and omapatrilat is higher in black patients.^15,21 Thus, it would be prudent to investigate whether the risk of angioedema with sacubitril-valsartan would be higher if more black patients are studied.

IMPLICATIONS AND CONSIDERATIONS

In this study, sacubitril-valsartan showed impressive and consistent results, with an almost 20% decrease in the composite end point of heart failure hospitalization or cardiovascular death and a similar decrease in the composite outcomes with a very low number needed to treat (21 patients). It did not show a decrease in the incidence of new-onset atrial fibrillation; however, only 80 cases of atrial fibrillation were reported, so there may have been a lack of statistical power to detect a difference.

To avoid angioedema, wait at least 36 hours after stopping an ACE inhibitor. Sacubitril-valsartan was not associated with an increased risk of severe angioedema, and no patients experienced life-threatening angioedema. In the trial, the sacubitril-valsartan run-in period was started at least 24 hours after enalapril was stopped, and thus the authors recommended at least a 1-day washout period after discontinuing an ACE inhibitor to avoid angioedema in patients starting sacubitril-valsartan.

Hypotension is a concern. Although there was actually a decreased risk of renal dysfunction, hyperkalemia, and cough compared with enalapril, there was a significantly increased rate of symptomatic hypotension in the sacubitril-valsartan group, which raises the question of patient tolerance and physician comfort when prescribing and titrating this drug in clinical practice. This side effect will be an important consideration when attempting to titrate the drug to target doses.

Start treatment early. This trial largely consisted of patients with NYHA class II or III symptoms, with about 70% of patients with class II symptoms. Since this drug showed benefit in patients with mildly to moderately symptomatic heart failure, clinicians who are considering prescribing this drug should not wait until the patient is closer to end-stage disease. Patients with mildly symptomatic heart failure may be followed by a general cardiologist, internist, or both, and thus it is important to emphasize to the entire medical community the need to start this medication early on.

How much will it cost? Cost is a concern that could heavily weigh on the decision to prescribe this drug. Generic ACE inhibitors are relatively inexpensive, and it may difficult to switch from an affordable generic drug to a new drug that is likely to be much more expensive. Arguably, this drug may be cost-effective in the long run owing to a large decrease in heart failure readmissions. We await further analyses to evaluate this issue.

Will patients take a twice-a-day drug as prescribed? Most patients who are prescribed an ACE inhibitor take it just once a day, and switching from a daily to a twice-daily drug may present a challenge for some.

What about other outcomes? Based on this study, it is unclear what effect sacubitril-valsartan has on the incidence of fatal arrhythmias, sudden cardiac death, and pump failure. Furthermore, the effect on quality of life is still uncertain. Quality of life is an integral component in the evaluation of heart failure patients, and in this study the changes in KCCQ scores were not impressive. We hope to see further evaluations of this drug’s impact on quality of life of patients with heart failure. Furthermore, it would be interesting to study if this drug has any long-term effects on the need for advanced therapies such as left ventricular assist devices and orthotopic heart transplant.

What about patients with heart failure with preserved ejection fraction? This study included only patients with heart failure with reduced ejection fraction. However PARAMOUNT, a phase 2 study that evaluated the benefit of sacubitril-valsartan in patients with heart failure with preserved ejection fraction, has shown encouraging results.²⁴ We look forward to further investigation of this agent in patients with heart failure with preserved ejection fraction.

Sacubitril-valsartan, the first ARNI to be studied in humans, has a dual action in that it enhances the activity of the natriuretic peptide system and inhibits that of the renin-angiotensin-aldosterone system. It is the first drug in over a decade to show mortality benefit in patients with chronic systolic heart failure when compared with an already well-established heart failure medication. It appears to decrease rates of mortality and heart failure hospitalization without increasing the risk of severe angioedema in patients with mild or moderate chronic systolic heart failure. Symptomatic hypotension and high cost may pose the largest barriers to the use of this new drug. And we have yet to see how the clinical community and patients with heart failure will respond to it.