The Journal of Family Practice

ILLUSTRATIVE CASE

A 28-year-old G2P1001 at 28 weeks’ gestation presents to your clinic with 1 day of dyspnea and palpitations. Her pregnancy has been otherwise uncomplicated. She reports worsening dyspnea with mild exertion but denies other symptoms, including leg swelling.

The current incidence of venous thromboembolism (VTE) in pregnant women is estimated to be a relatively low 5 to 12 events per 10,000 pregnancies, yet the condition is the leading cause of maternal mortality in developed countries.^2,3,4 Currently, there are conflicting recommendations among relevant organization guidelines regarding the use of D-dimer testing to aid in the diagnosis of pulmonary embolism (PE) during pregnancy. Both the Working Group in Women’s Health of the Society of Thrombosis and Haemostasis (GTH) and the European Society of Cardiology (ESC) recommend using D-dimer testing to rule out PE in pregnant women (ESC Class IIa, level of evidence B based on small studies, retrospective studies, and observational studies; GTH provides no grade).^5,6

Conversely, the Royal College of Obstetricians and Gynaecologists (RCOG), the Society of Obstetricians and Gynaecologists of Canada (SOGC), and the American Thoracic Society (ATS)/Society of Thoracic Radiology recommend against the use of D-dimer testing in pregnant women because pregnant women were excluded from D-dimer validation studies (RCOG and SOGC Grade D; ATS weak recommendation).^4,7,8 The American College of Obstetricians and Gynecologists does not have specific recommendations regarding the use of D-dimer testing during pregnancy, but has endorsed the ATS guidelines.^4,9 In addition, SOGC recommends against the use of clinical prediction scores (Grade D), and RCOG states that there is no evidence to support their use (Grade C).^7,8 The remaining societies do not make a recommendation for or against the use of clinical prediction scores because of the absence of high-quality evidence regarding their use in the pregnant patient population.^4,5,6

STUDY SUMMARY

Prospective validation of a strategy to diagnose PE in pregnant women

This multicenter, multinational, prospective diagnostic study involving 395 pregnant women evaluated the accuracy of PE diagnosis across 11 centers in France and Switzerland from August 2008 through July 2016.¹ Patients with clinically suspected PE were evaluated in emergency departments. Patients were tested according to a diagnostic algorithm that included pretest clinical probability using the revised Geneva Score for Pulmonary Embolism (www.mdcalc.com/geneva-score-revised-pulmonary-­embolism), a clinical prediction tool that uses patient history, presenting symptoms, and clinical signs to classify patients as being at low (0-3/25), intermediate (4-10/25), or high (≥ 11/25) risk;¹⁰ high-sensitivity D-dimer testing; bilateral lower limb compression ultrasonography (CUS); computed tomography pulmonary angiography (CTPA); and a ventilation-perfusion (V/Q) scan.

PE was excluded in patients who had a low or intermediate pretest clinical probability score and a negative D-dimer test result (< 500 mcg/L). Patients with a high pretest probability score or positive D-dimer test result underwent CUS, and, if negative, subsequent CTPA. A V/Q scan was performed if the CTPA was inconclusive. If the work-up was negative, PE was excluded.

Untreated pregnant women had clinical follow-up at 3 months. Any cases of suspected VTE were evaluated by a 3-member independent adjudication committee blinded to the initial diagnostic work-up. The primary outcome was the rate of adjudicated VTE events during the 3-month follow-up period. PE was diagnosed in 28 patients (7.1%) and excluded in 367 (clinical probability score and negative D-dimer test result [n = 46], negative CTPA result [n = 290], normal or low-probability V/Q scan [n = 17], and other reason [n = 14]). Twenty-two women received anticoagulation during the follow-up period for other reasons (mainly history of previous VTE disease). No symptomatic VTE events occurred in any of the women after the diagnostic work-up was negative, including among those patients who were ruled out with only the clinical prediction tool and a negative D-dimer test result (rate 0.0%; 95% confidence interval [CI], 0.0%-1%).

WHAT’S NEW

Clinical probability and D-dimer rule out PE in pregnant women

This study ruled out PE in patients with low/intermediate risk as determined by the revised Geneva score and a D-dimer test, enabling patients to avoid further diagnostic testing. This low-cost strategy can be applied easily to the pregnant population.

CAVEATS

Additional research is still needed

From the results of this study, 11.6% of patients (n = 46) had a PE ruled out utilizing the revised Geneva score in conjunction with a D-dimer test result, with avoidance of chest imaging. However, this study was powered for the entire treatment algorithm and was not specifically powered for patients with low- or intermediate-risk pretest probability scores. Since this is the first published prospective diagnostic study of VTE in pregnancy, further research is needed to confirm the findings that a clinical prediction tool and a negative D-dimer test result can safely rule out PE in pregnant women.

This strategy ruled out PE in patients with low/ intermediate risk as determined by the revised Geneva score and a D-dimer test, enabling patients to avoid further diagnostic testing.

In addition, further research is needed to determine pregnancy-adapted D-dimer cut-off values, as the researchers of this study noted that < 500 mcg/L was useful in the first and second trimester, but that levels increased as gestational age increased.

CHALLENGES TO IMPLEMENTATION

None to speak of

Implementing a diagnostic algorithm that incorporates sequential assessment of pretest clinical probability based on the revised Geneva score and a D-dimer measurement should be relatively easy to implement, as both methods are readily available and relatively inexpensive.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 28-year-old G2P1001 at 28 weeks’ gestation presents to your clinic with 1 day of dyspnea and palpitations. Her pregnancy has been otherwise uncomplicated. She reports worsening dyspnea with mild exertion but denies other symptoms, including leg swelling.

The current incidence of venous thromboembolism (VTE) in pregnant women is estimated to be a relatively low 5 to 12 events per 10,000 pregnancies, yet the condition is the leading cause of maternal mortality in developed countries.^2,3,4 Currently, there are conflicting recommendations among relevant organization guidelines regarding the use of D-dimer testing to aid in the diagnosis of pulmonary embolism (PE) during pregnancy. Both the Working Group in Women’s Health of the Society of Thrombosis and Haemostasis (GTH) and the European Society of Cardiology (ESC) recommend using D-dimer testing to rule out PE in pregnant women (ESC Class IIa, level of evidence B based on small studies, retrospective studies, and observational studies; GTH provides no grade).^5,6

Conversely, the Royal College of Obstetricians and Gynaecologists (RCOG), the Society of Obstetricians and Gynaecologists of Canada (SOGC), and the American Thoracic Society (ATS)/Society of Thoracic Radiology recommend against the use of D-dimer testing in pregnant women because pregnant women were excluded from D-dimer validation studies (RCOG and SOGC Grade D; ATS weak recommendation).^4,7,8 The American College of Obstetricians and Gynecologists does not have specific recommendations regarding the use of D-dimer testing during pregnancy, but has endorsed the ATS guidelines.^4,9 In addition, SOGC recommends against the use of clinical prediction scores (Grade D), and RCOG states that there is no evidence to support their use (Grade C).^7,8 The remaining societies do not make a recommendation for or against the use of clinical prediction scores because of the absence of high-quality evidence regarding their use in the pregnant patient population.^4,5,6

STUDY SUMMARY

Prospective validation of a strategy to diagnose PE in pregnant women

This multicenter, multinational, prospective diagnostic study involving 395 pregnant women evaluated the accuracy of PE diagnosis across 11 centers in France and Switzerland from August 2008 through July 2016.¹ Patients with clinically suspected PE were evaluated in emergency departments. Patients were tested according to a diagnostic algorithm that included pretest clinical probability using the revised Geneva Score for Pulmonary Embolism (www.mdcalc.com/geneva-score-revised-pulmonary-­embolism), a clinical prediction tool that uses patient history, presenting symptoms, and clinical signs to classify patients as being at low (0-3/25), intermediate (4-10/25), or high (≥ 11/25) risk;¹⁰ high-sensitivity D-dimer testing; bilateral lower limb compression ultrasonography (CUS); computed tomography pulmonary angiography (CTPA); and a ventilation-perfusion (V/Q) scan.

PE was excluded in patients who had a low or intermediate pretest clinical probability score and a negative D-dimer test result (< 500 mcg/L). Patients with a high pretest probability score or positive D-dimer test result underwent CUS, and, if negative, subsequent CTPA. A V/Q scan was performed if the CTPA was inconclusive. If the work-up was negative, PE was excluded.

Untreated pregnant women had clinical follow-up at 3 months. Any cases of suspected VTE were evaluated by a 3-member independent adjudication committee blinded to the initial diagnostic work-up. The primary outcome was the rate of adjudicated VTE events during the 3-month follow-up period. PE was diagnosed in 28 patients (7.1%) and excluded in 367 (clinical probability score and negative D-dimer test result [n = 46], negative CTPA result [n = 290], normal or low-probability V/Q scan [n = 17], and other reason [n = 14]). Twenty-two women received anticoagulation during the follow-up period for other reasons (mainly history of previous VTE disease). No symptomatic VTE events occurred in any of the women after the diagnostic work-up was negative, including among those patients who were ruled out with only the clinical prediction tool and a negative D-dimer test result (rate 0.0%; 95% confidence interval [CI], 0.0%-1%).

WHAT’S NEW

Clinical probability and D-dimer rule out PE in pregnant women

This study ruled out PE in patients with low/intermediate risk as determined by the revised Geneva score and a D-dimer test, enabling patients to avoid further diagnostic testing. This low-cost strategy can be applied easily to the pregnant population.

CAVEATS

Additional research is still needed

From the results of this study, 11.6% of patients (n = 46) had a PE ruled out utilizing the revised Geneva score in conjunction with a D-dimer test result, with avoidance of chest imaging. However, this study was powered for the entire treatment algorithm and was not specifically powered for patients with low- or intermediate-risk pretest probability scores. Since this is the first published prospective diagnostic study of VTE in pregnancy, further research is needed to confirm the findings that a clinical prediction tool and a negative D-dimer test result can safely rule out PE in pregnant women.

This strategy ruled out PE in patients with low/ intermediate risk as determined by the revised Geneva score and a D-dimer test, enabling patients to avoid further diagnostic testing.

In addition, further research is needed to determine pregnancy-adapted D-dimer cut-off values, as the researchers of this study noted that < 500 mcg/L was useful in the first and second trimester, but that levels increased as gestational age increased.

CHALLENGES TO IMPLEMENTATION

None to speak of

Implementing a diagnostic algorithm that incorporates sequential assessment of pretest clinical probability based on the revised Geneva score and a D-dimer measurement should be relatively easy to implement, as both methods are readily available and relatively inexpensive.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 28-year-old G2P1001 at 28 weeks’ gestation presents to your clinic with 1 day of dyspnea and palpitations. Her pregnancy has been otherwise uncomplicated. She reports worsening dyspnea with mild exertion but denies other symptoms, including leg swelling.

The current incidence of venous thromboembolism (VTE) in pregnant women is estimated to be a relatively low 5 to 12 events per 10,000 pregnancies, yet the condition is the leading cause of maternal mortality in developed countries.^2,3,4 Currently, there are conflicting recommendations among relevant organization guidelines regarding the use of D-dimer testing to aid in the diagnosis of pulmonary embolism (PE) during pregnancy. Both the Working Group in Women’s Health of the Society of Thrombosis and Haemostasis (GTH) and the European Society of Cardiology (ESC) recommend using D-dimer testing to rule out PE in pregnant women (ESC Class IIa, level of evidence B based on small studies, retrospective studies, and observational studies; GTH provides no grade).^5,6

Conversely, the Royal College of Obstetricians and Gynaecologists (RCOG), the Society of Obstetricians and Gynaecologists of Canada (SOGC), and the American Thoracic Society (ATS)/Society of Thoracic Radiology recommend against the use of D-dimer testing in pregnant women because pregnant women were excluded from D-dimer validation studies (RCOG and SOGC Grade D; ATS weak recommendation).^4,7,8 The American College of Obstetricians and Gynecologists does not have specific recommendations regarding the use of D-dimer testing during pregnancy, but has endorsed the ATS guidelines.^4,9 In addition, SOGC recommends against the use of clinical prediction scores (Grade D), and RCOG states that there is no evidence to support their use (Grade C).^7,8 The remaining societies do not make a recommendation for or against the use of clinical prediction scores because of the absence of high-quality evidence regarding their use in the pregnant patient population.^4,5,6

STUDY SUMMARY

Prospective validation of a strategy to diagnose PE in pregnant women

This multicenter, multinational, prospective diagnostic study involving 395 pregnant women evaluated the accuracy of PE diagnosis across 11 centers in France and Switzerland from August 2008 through July 2016.¹ Patients with clinically suspected PE were evaluated in emergency departments. Patients were tested according to a diagnostic algorithm that included pretest clinical probability using the revised Geneva Score for Pulmonary Embolism (www.mdcalc.com/geneva-score-revised-pulmonary-­embolism), a clinical prediction tool that uses patient history, presenting symptoms, and clinical signs to classify patients as being at low (0-3/25), intermediate (4-10/25), or high (≥ 11/25) risk;¹⁰ high-sensitivity D-dimer testing; bilateral lower limb compression ultrasonography (CUS); computed tomography pulmonary angiography (CTPA); and a ventilation-perfusion (V/Q) scan.

PE was excluded in patients who had a low or intermediate pretest clinical probability score and a negative D-dimer test result (< 500 mcg/L). Patients with a high pretest probability score or positive D-dimer test result underwent CUS, and, if negative, subsequent CTPA. A V/Q scan was performed if the CTPA was inconclusive. If the work-up was negative, PE was excluded.

Untreated pregnant women had clinical follow-up at 3 months. Any cases of suspected VTE were evaluated by a 3-member independent adjudication committee blinded to the initial diagnostic work-up. The primary outcome was the rate of adjudicated VTE events during the 3-month follow-up period. PE was diagnosed in 28 patients (7.1%) and excluded in 367 (clinical probability score and negative D-dimer test result [n = 46], negative CTPA result [n = 290], normal or low-probability V/Q scan [n = 17], and other reason [n = 14]). Twenty-two women received anticoagulation during the follow-up period for other reasons (mainly history of previous VTE disease). No symptomatic VTE events occurred in any of the women after the diagnostic work-up was negative, including among those patients who were ruled out with only the clinical prediction tool and a negative D-dimer test result (rate 0.0%; 95% confidence interval [CI], 0.0%-1%).

WHAT’S NEW

Clinical probability and D-dimer rule out PE in pregnant women

This study ruled out PE in patients with low/intermediate risk as determined by the revised Geneva score and a D-dimer test, enabling patients to avoid further diagnostic testing. This low-cost strategy can be applied easily to the pregnant population.

CAVEATS

Additional research is still needed

From the results of this study, 11.6% of patients (n = 46) had a PE ruled out utilizing the revised Geneva score in conjunction with a D-dimer test result, with avoidance of chest imaging. However, this study was powered for the entire treatment algorithm and was not specifically powered for patients with low- or intermediate-risk pretest probability scores. Since this is the first published prospective diagnostic study of VTE in pregnancy, further research is needed to confirm the findings that a clinical prediction tool and a negative D-dimer test result can safely rule out PE in pregnant women.

This strategy ruled out PE in patients with low/ intermediate risk as determined by the revised Geneva score and a D-dimer test, enabling patients to avoid further diagnostic testing.

In addition, further research is needed to determine pregnancy-adapted D-dimer cut-off values, as the researchers of this study noted that < 500 mcg/L was useful in the first and second trimester, but that levels increased as gestational age increased.

CHALLENGES TO IMPLEMENTATION

None to speak of

Implementing a diagnostic algorithm that incorporates sequential assessment of pretest clinical probability based on the revised Geneva score and a D-dimer measurement should be relatively easy to implement, as both methods are readily available and relatively inexpensive.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder that is estimated to occur in 1:2500 births and to have a prevalence of 1:2000 to 1:4000.^1,2 It was first described in 1882 by Friedrich Daniel Von Recklinghausen, who identified patients and their relatives with signs of neuroectodermal abnormalities (café-au-lait macules [CALMs], axillary and inguinal freckling, and neurofibromas).

NF1 may begin insidiously in childhood and evolves as the patient ages. It is associated with intracranial, intraspinal, and intraorbital neoplasms, although other organs and tissues can also be involved.

The family physician might be the first one to recognize the signs of this condition during a well-child exam and is in a unique position to coordinate a multidisciplinary approach to care.

A mutated allele and early manifestations on the skin

NF1 has been attributed to genetic mosaicism and is classified as segmental, generalized, or (less frequently) gonadal. The disorder results from germline mutations in the NF1 tumor-suppressor gene on chromosome 17, known to codify the cytoplasmic protein called neurofibromin.³ The penetrance of NF1 is complete, which means that 100% of patients with the mutated allele will develop the disease.

Patients typically have symptoms by the third decade of life, although many will show signs of the disease in early childhood. CALMs are the earliest expression of NF1. They manifest in the first 2 years of life and are found in almost all affected patients. The lesions are well defined and measure 10 to 40 mm. They are typically light brown, although they may darken with sun exposure.

Histologically, the lesions will show macromelanosomes and high concentrations of melanin but do not represent an increased risk for malignancy.⁴ Not all isolated CALMs are a sign of NF1. While children younger than 29 months with 6 or more CALMs have a high risk for NF1 (80.4%; 95% confidence interval [CI], 74.6% to 86.2%), those who are older than 29 months with at least 1 atypical CALM or fewer than 6 CALMs have just a 0.9% (95% CI, 0% to 2.6%) risk for constitutional NF1.⁵

Freckles are also observed in 90% of patients with NF1; these tend to develop after the third year of life. The breast and trunk are the most commonly affected areas in adults. The pathophysiology is unknown, but this freckling is believed to be related to skin friction, high humidity, and ambient temperature.⁶

Continue to: Neurofibromas are benign...

Some patients show disfiguration when hundreds of neurofibromas are present.

Neurofibromas are benign subcutaneous palpable lesions that grow within peripheral nerve tissue, including spinal, subcutaneous, plexiform, or dermal encapsulated nerves. Originating in Schwann cells, they are composed of fibroblasts, mast cells, macrophages, endothelial cells, and other perineural cells. Some patients show disfiguration when hundreds of these masses are present (FIGURE). These tumors increase in number as the patient ages or during pregnancy, which is thought to be secondary to hormonal changes.⁷ They are sometimes painful and can be pruritic. Their appearance can also cause patient distress.

The diagnosis is a clinical one

Suspicion for NF1 should be high in patients presenting with the dermatologic findings described, although CALMs and freckling are not exclusive to NF1. Diagnostic criteria for NF1, which distinguish it from other conditions, were first outlined in a National Institutes of Health Consensus Development Conference Statement in 1987.⁸ The list of criteria has subsequently been expanded.

While the presence of at least 2 criteria is required for diagnosis,² NF1 should be suspected in individuals who have any of the following findings^8,9:

• the presence of at least 6 CALMs that are > 5 mm in prepubertal children and > 15 mm in adults
• 2 or more neurofibromas of any type, or at least one plexiform neurofibroma
• axillary or groin freckling
• optic pathway glioma
• 2 or more Lisch nodules (iris hamartomas seen on slit-lamp examination)
• bony dysplasia (sphenoid wing dysplasia, bowing of long bone ± pseudarthrosis)
• first-degree relative with NF1.

What you’ll see as the disease progresses

NF1 can affect a variety of systems, and potential complications of the disease are numerous and varied (see TABLE⁹). Here is some of what you may see as the patient’s disease progresses to various organ systems:

Learning disabilities and other cognitive and behavioral problems, such as attention-deficit/hyperactivity disorder, may affect up to 70% of children with NF1. Additionally, children with NF1 have visual/spatial problems, impaired visual motor integration, and language deficits.¹⁰ The etiology of cognitive impairment in NF1 is unknown.¹¹  

Continue to: Hypertension

Hypertension is common and may contribute to premature death in patients with NF1. Up to 27% of patients will have significant cardiovascular anomalies, including pulmonary valve stenosis, hypertrophic cardiomyopathy in patients with complete deletions of the NF1 gene, intracardiac neurofibromas, renal artery stenosis, coarctation of the aorta, and cerebral infarctions.¹² Renal artery stenosis occurs in approximately 2% of the NF1 population, and the diagnosis should be considered in hypertensive children, young adults, pregnant women, older individuals with refractory hypertension, and those with an abdominal bruit.¹³

Psychological issues. The disfigurement caused by neurofibromas and the uncertainty of an unpredictable disease course can cause psychological manifestations for patients with NF1. Anxiety and depression are common. Not surprisingly, patients with more severe disease report more adverse psychological effects.

Orthopedic deformities. Spinal deformities are the most common skeletal manifestation of NF1, with an incidence estimated from 10% to 25% in various studies. Bone mineral density, as measured by age- and gender-adjusted Z-scores, is significantly lower in NF1 patients than in the general population.¹⁴ Children may develop bowing of the long bones, particularly the tibia, and pseudarthrosis, a false joint in a long bone. Children with NF1 need yearly assessment of the spine. Patients with clinical evidence of scoliosis should be referred to Orthopedics for further evaluation.

Eye issues. A majority of adult patients develop neurofibroma-like nodules in the iris known as Lisch nodules. The nodules are not thought to cause any ophthalmologic complications. Patients may also develop palpebral neurofibroma, which may become large and sporadically show malignant transformation. Optic nerve glioma may cause strabismus and proptosis, and a large number of patients will also develop glaucoma and globe enlargement.¹⁵

Gastrointestinal lesions and cancer. Neurofibromas can grow in the stomach, liver, mesentery, retroperitoneum, and bowel. Adenocarcinoma developed in 23% of patients.¹⁶ Gastrointestinal tract bleeding, pseudo-obstruction, and protein-losing enteropathy also may occur.¹⁷

Continue to: Central nervous system manifestations

Central nervous system manifestations. Neurological manifestations have been observed in 55% of patients with NF1.¹⁸ These include headache, hydrocephalus, epilepsy, lacunar stroke, white matter disease, intraspinal neurofibroma, facial palsy, radiculopathy, and polyneuropathy. Tumors include optic pathway tumors, meningioma, and cerebral glioma. Glioma is the predominant tumor type in NF1 and occurs in all parts of the nervous system, with a predilection for the optic pathways, brainstem, and cerebellum.¹⁸

Malignant peripheral nerve sheath tumors. There is an 8% to 13% lifetime risk for malignant peripheral nerve sheath tumors (MPNST), predominantly in individuals between the ages of 20 and 35.^19,20 Any change in neurofibroma from soft to hard, or a rapid increase in the size, is suspicious for MPNST. Other symptoms include persistent pain lasting for longer than a month, pain that disturbs sleep, and new neurological deficits. These cancers can be hard to detect, leading to poor prognosis secondary to metastasis.^19,20 The greatest risk factors for MPNST are pain associated with a mass and the presence of cutaneous and subcutaneous neurofibromas.²¹

Treatment is symptom based, but there is a new option

Treatment is individualized to the patient’s symptoms. Neurofibromas that are disfiguring, disruptive, or malignant may be surgically removed.

In April 2020, the US Food and Drug Administration (FDA) approved selumetinib (Koselugo) for the treatment of pediatric patients (ages ≥ 2 years) with NF1 who have symptomatic, inoperable plexiform neurofibromas (PNs).²² In a clinical trial, patients received selumetinib 25 mg/m² orally twice a day until they demonstrated disease progression or experienced “unacceptable” adverse events.^22,23 The overall response rate was 66%, defined as “the percentage of patients with a complete response and those who experienced more than a 20% reduction in PN volume on MRI that was confirmed on a subsequent MRI within 3 to 6 months.”²²

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms.

Of note, all patients had a partial, not complete, response. Common adverse effects included vomiting, rash, abdominal pain, diarrhea, and nausea.²³ Selumetinib may also cause more serious adverse effects, including cardiomyopathy and ocular toxicity. Prior to treatment initiation and at regular intervals during treatment, patients should undergo cardiac and ophthalmic evaluation.^22,23 Selumetinib was granted priority review and orphan drug status by the FDA.²²

Continue to: You play a key role in ongoing monitoring

 

 

You play a key role in ongoing monitoring

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms; optimization of quality of life; and identification and treatment of comorbidities. Family physicians are well positioned to monitor patients with NF1 for age-specific disease manifestations and potential complications.⁹ All patients require:

• an annual physical examination by a physician who is familiar with the individual and with the disease
• annual ophthalmologic examination in early childhood; less frequent examination in older children and adults
• regular blood pressure monitoring
• other studies (eg, MRI) only as indicated on the basis of clinically apparent signs or symptoms
• monitoring by an appropriate specialist if there are abnormalities of the central nervous, skeletal, or cardiovascular systems
• referral to a neurologist for any unexplained neurological signs and symptoms. Referral should be urgent if there are acute symptoms of progressive sensory disturbance, motor deficit and incoordination, or sphincter disturbances since these might indicate an intracranial lesion or spinal cord compression. Headaches on waking, morning vomiting, and altered consciousness are suggestive of raised intracranial pressure.

Children with NF1 benefit from coordinated care between the FP and a pediatrician or other specialist familiar with the disease. In addition to providing usual well care, perform regular assessment of development and school performance. Pay careful attention to the cardiovascular system (particularly blood pressure) and evaluate for scoliosis.

Young adults should be continually monitored for all complications, especially hypertension. This population requires continued education about NF1 and its possible complications and may benefit from counseling about disease inheritance. Screen for anxiety and depression; offer psychological support.

Provide adult patients with education about complications, especially malignant peripheral nerve sheath tumors and spinal cord compression.

Adults require monitoring based on patient preference and disease severity. For this population, blood pressure should be measured annually, or more frequently if the patient’s values indicate borderline hypertension. Provide education about complications, especially MPNSTs and spinal cord compression. Patients who have abnormalities of the central nervous, skeletal, or cardiovascular systems should be monitored by an appropriate specialist. If desired, the patient may be referred to a geneticist, especially if he or she expresses concern about inheritance. Cutaneous neurofibromas can be removed if they cause discomfort, although removal occasionally results in neurological deficit.

CORRESPONDENCE
T. Grant Phillips, MD, Associate Director, UPMC Altoona Family Physicians Residency, 501 Howard Avenue, Altoona, PA 16601-4899; [email protected]

Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder that is estimated to occur in 1:2500 births and to have a prevalence of 1:2000 to 1:4000.^1,2 It was first described in 1882 by Friedrich Daniel Von Recklinghausen, who identified patients and their relatives with signs of neuroectodermal abnormalities (café-au-lait macules [CALMs], axillary and inguinal freckling, and neurofibromas).

NF1 may begin insidiously in childhood and evolves as the patient ages. It is associated with intracranial, intraspinal, and intraorbital neoplasms, although other organs and tissues can also be involved.

The family physician might be the first one to recognize the signs of this condition during a well-child exam and is in a unique position to coordinate a multidisciplinary approach to care.

A mutated allele and early manifestations on the skin

NF1 has been attributed to genetic mosaicism and is classified as segmental, generalized, or (less frequently) gonadal. The disorder results from germline mutations in the NF1 tumor-suppressor gene on chromosome 17, known to codify the cytoplasmic protein called neurofibromin.³ The penetrance of NF1 is complete, which means that 100% of patients with the mutated allele will develop the disease.

Patients typically have symptoms by the third decade of life, although many will show signs of the disease in early childhood. CALMs are the earliest expression of NF1. They manifest in the first 2 years of life and are found in almost all affected patients. The lesions are well defined and measure 10 to 40 mm. They are typically light brown, although they may darken with sun exposure.

Histologically, the lesions will show macromelanosomes and high concentrations of melanin but do not represent an increased risk for malignancy.⁴ Not all isolated CALMs are a sign of NF1. While children younger than 29 months with 6 or more CALMs have a high risk for NF1 (80.4%; 95% confidence interval [CI], 74.6% to 86.2%), those who are older than 29 months with at least 1 atypical CALM or fewer than 6 CALMs have just a 0.9% (95% CI, 0% to 2.6%) risk for constitutional NF1.⁵

Freckles are also observed in 90% of patients with NF1; these tend to develop after the third year of life. The breast and trunk are the most commonly affected areas in adults. The pathophysiology is unknown, but this freckling is believed to be related to skin friction, high humidity, and ambient temperature.⁶

Continue to: Neurofibromas are benign...

Some patients show disfiguration when hundreds of neurofibromas are present.

Neurofibromas are benign subcutaneous palpable lesions that grow within peripheral nerve tissue, including spinal, subcutaneous, plexiform, or dermal encapsulated nerves. Originating in Schwann cells, they are composed of fibroblasts, mast cells, macrophages, endothelial cells, and other perineural cells. Some patients show disfiguration when hundreds of these masses are present (FIGURE). These tumors increase in number as the patient ages or during pregnancy, which is thought to be secondary to hormonal changes.⁷ They are sometimes painful and can be pruritic. Their appearance can also cause patient distress.

The diagnosis is a clinical one

Suspicion for NF1 should be high in patients presenting with the dermatologic findings described, although CALMs and freckling are not exclusive to NF1. Diagnostic criteria for NF1, which distinguish it from other conditions, were first outlined in a National Institutes of Health Consensus Development Conference Statement in 1987.⁸ The list of criteria has subsequently been expanded.

While the presence of at least 2 criteria is required for diagnosis,² NF1 should be suspected in individuals who have any of the following findings^8,9:

• the presence of at least 6 CALMs that are > 5 mm in prepubertal children and > 15 mm in adults
• 2 or more neurofibromas of any type, or at least one plexiform neurofibroma
• axillary or groin freckling
• optic pathway glioma
• 2 or more Lisch nodules (iris hamartomas seen on slit-lamp examination)
• bony dysplasia (sphenoid wing dysplasia, bowing of long bone ± pseudarthrosis)
• first-degree relative with NF1.

What you’ll see as the disease progresses

NF1 can affect a variety of systems, and potential complications of the disease are numerous and varied (see TABLE⁹). Here is some of what you may see as the patient’s disease progresses to various organ systems:

Learning disabilities and other cognitive and behavioral problems, such as attention-deficit/hyperactivity disorder, may affect up to 70% of children with NF1. Additionally, children with NF1 have visual/spatial problems, impaired visual motor integration, and language deficits.¹⁰ The etiology of cognitive impairment in NF1 is unknown.¹¹  

Continue to: Hypertension

Hypertension is common and may contribute to premature death in patients with NF1. Up to 27% of patients will have significant cardiovascular anomalies, including pulmonary valve stenosis, hypertrophic cardiomyopathy in patients with complete deletions of the NF1 gene, intracardiac neurofibromas, renal artery stenosis, coarctation of the aorta, and cerebral infarctions.¹² Renal artery stenosis occurs in approximately 2% of the NF1 population, and the diagnosis should be considered in hypertensive children, young adults, pregnant women, older individuals with refractory hypertension, and those with an abdominal bruit.¹³

Psychological issues. The disfigurement caused by neurofibromas and the uncertainty of an unpredictable disease course can cause psychological manifestations for patients with NF1. Anxiety and depression are common. Not surprisingly, patients with more severe disease report more adverse psychological effects.

Orthopedic deformities. Spinal deformities are the most common skeletal manifestation of NF1, with an incidence estimated from 10% to 25% in various studies. Bone mineral density, as measured by age- and gender-adjusted Z-scores, is significantly lower in NF1 patients than in the general population.¹⁴ Children may develop bowing of the long bones, particularly the tibia, and pseudarthrosis, a false joint in a long bone. Children with NF1 need yearly assessment of the spine. Patients with clinical evidence of scoliosis should be referred to Orthopedics for further evaluation.

Eye issues. A majority of adult patients develop neurofibroma-like nodules in the iris known as Lisch nodules. The nodules are not thought to cause any ophthalmologic complications. Patients may also develop palpebral neurofibroma, which may become large and sporadically show malignant transformation. Optic nerve glioma may cause strabismus and proptosis, and a large number of patients will also develop glaucoma and globe enlargement.¹⁵

Gastrointestinal lesions and cancer. Neurofibromas can grow in the stomach, liver, mesentery, retroperitoneum, and bowel. Adenocarcinoma developed in 23% of patients.¹⁶ Gastrointestinal tract bleeding, pseudo-obstruction, and protein-losing enteropathy also may occur.¹⁷

Continue to: Central nervous system manifestations

Central nervous system manifestations. Neurological manifestations have been observed in 55% of patients with NF1.¹⁸ These include headache, hydrocephalus, epilepsy, lacunar stroke, white matter disease, intraspinal neurofibroma, facial palsy, radiculopathy, and polyneuropathy. Tumors include optic pathway tumors, meningioma, and cerebral glioma. Glioma is the predominant tumor type in NF1 and occurs in all parts of the nervous system, with a predilection for the optic pathways, brainstem, and cerebellum.¹⁸

Malignant peripheral nerve sheath tumors. There is an 8% to 13% lifetime risk for malignant peripheral nerve sheath tumors (MPNST), predominantly in individuals between the ages of 20 and 35.^19,20 Any change in neurofibroma from soft to hard, or a rapid increase in the size, is suspicious for MPNST. Other symptoms include persistent pain lasting for longer than a month, pain that disturbs sleep, and new neurological deficits. These cancers can be hard to detect, leading to poor prognosis secondary to metastasis.^19,20 The greatest risk factors for MPNST are pain associated with a mass and the presence of cutaneous and subcutaneous neurofibromas.²¹

Treatment is symptom based, but there is a new option

Treatment is individualized to the patient’s symptoms. Neurofibromas that are disfiguring, disruptive, or malignant may be surgically removed.

In April 2020, the US Food and Drug Administration (FDA) approved selumetinib (Koselugo) for the treatment of pediatric patients (ages ≥ 2 years) with NF1 who have symptomatic, inoperable plexiform neurofibromas (PNs).²² In a clinical trial, patients received selumetinib 25 mg/m² orally twice a day until they demonstrated disease progression or experienced “unacceptable” adverse events.^22,23 The overall response rate was 66%, defined as “the percentage of patients with a complete response and those who experienced more than a 20% reduction in PN volume on MRI that was confirmed on a subsequent MRI within 3 to 6 months.”²²

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms.

Of note, all patients had a partial, not complete, response. Common adverse effects included vomiting, rash, abdominal pain, diarrhea, and nausea.²³ Selumetinib may also cause more serious adverse effects, including cardiomyopathy and ocular toxicity. Prior to treatment initiation and at regular intervals during treatment, patients should undergo cardiac and ophthalmic evaluation.^22,23 Selumetinib was granted priority review and orphan drug status by the FDA.²²

Continue to: You play a key role in ongoing monitoring

 

 

You play a key role in ongoing monitoring

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms; optimization of quality of life; and identification and treatment of comorbidities. Family physicians are well positioned to monitor patients with NF1 for age-specific disease manifestations and potential complications.⁹ All patients require:

• an annual physical examination by a physician who is familiar with the individual and with the disease
• annual ophthalmologic examination in early childhood; less frequent examination in older children and adults
• regular blood pressure monitoring
• other studies (eg, MRI) only as indicated on the basis of clinically apparent signs or symptoms
• monitoring by an appropriate specialist if there are abnormalities of the central nervous, skeletal, or cardiovascular systems
• referral to a neurologist for any unexplained neurological signs and symptoms. Referral should be urgent if there are acute symptoms of progressive sensory disturbance, motor deficit and incoordination, or sphincter disturbances since these might indicate an intracranial lesion or spinal cord compression. Headaches on waking, morning vomiting, and altered consciousness are suggestive of raised intracranial pressure.

Children with NF1 benefit from coordinated care between the FP and a pediatrician or other specialist familiar with the disease. In addition to providing usual well care, perform regular assessment of development and school performance. Pay careful attention to the cardiovascular system (particularly blood pressure) and evaluate for scoliosis.

Young adults should be continually monitored for all complications, especially hypertension. This population requires continued education about NF1 and its possible complications and may benefit from counseling about disease inheritance. Screen for anxiety and depression; offer psychological support.

Provide adult patients with education about complications, especially malignant peripheral nerve sheath tumors and spinal cord compression.

Adults require monitoring based on patient preference and disease severity. For this population, blood pressure should be measured annually, or more frequently if the patient’s values indicate borderline hypertension. Provide education about complications, especially MPNSTs and spinal cord compression. Patients who have abnormalities of the central nervous, skeletal, or cardiovascular systems should be monitored by an appropriate specialist. If desired, the patient may be referred to a geneticist, especially if he or she expresses concern about inheritance. Cutaneous neurofibromas can be removed if they cause discomfort, although removal occasionally results in neurological deficit.

CORRESPONDENCE
T. Grant Phillips, MD, Associate Director, UPMC Altoona Family Physicians Residency, 501 Howard Avenue, Altoona, PA 16601-4899; [email protected]

Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder that is estimated to occur in 1:2500 births and to have a prevalence of 1:2000 to 1:4000.^1,2 It was first described in 1882 by Friedrich Daniel Von Recklinghausen, who identified patients and their relatives with signs of neuroectodermal abnormalities (café-au-lait macules [CALMs], axillary and inguinal freckling, and neurofibromas).

NF1 may begin insidiously in childhood and evolves as the patient ages. It is associated with intracranial, intraspinal, and intraorbital neoplasms, although other organs and tissues can also be involved.

The family physician might be the first one to recognize the signs of this condition during a well-child exam and is in a unique position to coordinate a multidisciplinary approach to care.

A mutated allele and early manifestations on the skin

NF1 has been attributed to genetic mosaicism and is classified as segmental, generalized, or (less frequently) gonadal. The disorder results from germline mutations in the NF1 tumor-suppressor gene on chromosome 17, known to codify the cytoplasmic protein called neurofibromin.³ The penetrance of NF1 is complete, which means that 100% of patients with the mutated allele will develop the disease.

Patients typically have symptoms by the third decade of life, although many will show signs of the disease in early childhood. CALMs are the earliest expression of NF1. They manifest in the first 2 years of life and are found in almost all affected patients. The lesions are well defined and measure 10 to 40 mm. They are typically light brown, although they may darken with sun exposure.

Histologically, the lesions will show macromelanosomes and high concentrations of melanin but do not represent an increased risk for malignancy.⁴ Not all isolated CALMs are a sign of NF1. While children younger than 29 months with 6 or more CALMs have a high risk for NF1 (80.4%; 95% confidence interval [CI], 74.6% to 86.2%), those who are older than 29 months with at least 1 atypical CALM or fewer than 6 CALMs have just a 0.9% (95% CI, 0% to 2.6%) risk for constitutional NF1.⁵

Freckles are also observed in 90% of patients with NF1; these tend to develop after the third year of life. The breast and trunk are the most commonly affected areas in adults. The pathophysiology is unknown, but this freckling is believed to be related to skin friction, high humidity, and ambient temperature.⁶

Continue to: Neurofibromas are benign...

Some patients show disfiguration when hundreds of neurofibromas are present.

Neurofibromas are benign subcutaneous palpable lesions that grow within peripheral nerve tissue, including spinal, subcutaneous, plexiform, or dermal encapsulated nerves. Originating in Schwann cells, they are composed of fibroblasts, mast cells, macrophages, endothelial cells, and other perineural cells. Some patients show disfiguration when hundreds of these masses are present (FIGURE). These tumors increase in number as the patient ages or during pregnancy, which is thought to be secondary to hormonal changes.⁷ They are sometimes painful and can be pruritic. Their appearance can also cause patient distress.

The diagnosis is a clinical one

Suspicion for NF1 should be high in patients presenting with the dermatologic findings described, although CALMs and freckling are not exclusive to NF1. Diagnostic criteria for NF1, which distinguish it from other conditions, were first outlined in a National Institutes of Health Consensus Development Conference Statement in 1987.⁸ The list of criteria has subsequently been expanded.

While the presence of at least 2 criteria is required for diagnosis,² NF1 should be suspected in individuals who have any of the following findings^8,9:

• the presence of at least 6 CALMs that are > 5 mm in prepubertal children and > 15 mm in adults
• 2 or more neurofibromas of any type, or at least one plexiform neurofibroma
• axillary or groin freckling
• optic pathway glioma
• 2 or more Lisch nodules (iris hamartomas seen on slit-lamp examination)
• bony dysplasia (sphenoid wing dysplasia, bowing of long bone ± pseudarthrosis)
• first-degree relative with NF1.

What you’ll see as the disease progresses

NF1 can affect a variety of systems, and potential complications of the disease are numerous and varied (see TABLE⁹). Here is some of what you may see as the patient’s disease progresses to various organ systems:

Learning disabilities and other cognitive and behavioral problems, such as attention-deficit/hyperactivity disorder, may affect up to 70% of children with NF1. Additionally, children with NF1 have visual/spatial problems, impaired visual motor integration, and language deficits.¹⁰ The etiology of cognitive impairment in NF1 is unknown.¹¹  

Continue to: Hypertension

Hypertension is common and may contribute to premature death in patients with NF1. Up to 27% of patients will have significant cardiovascular anomalies, including pulmonary valve stenosis, hypertrophic cardiomyopathy in patients with complete deletions of the NF1 gene, intracardiac neurofibromas, renal artery stenosis, coarctation of the aorta, and cerebral infarctions.¹² Renal artery stenosis occurs in approximately 2% of the NF1 population, and the diagnosis should be considered in hypertensive children, young adults, pregnant women, older individuals with refractory hypertension, and those with an abdominal bruit.¹³

Psychological issues. The disfigurement caused by neurofibromas and the uncertainty of an unpredictable disease course can cause psychological manifestations for patients with NF1. Anxiety and depression are common. Not surprisingly, patients with more severe disease report more adverse psychological effects.

Orthopedic deformities. Spinal deformities are the most common skeletal manifestation of NF1, with an incidence estimated from 10% to 25% in various studies. Bone mineral density, as measured by age- and gender-adjusted Z-scores, is significantly lower in NF1 patients than in the general population.¹⁴ Children may develop bowing of the long bones, particularly the tibia, and pseudarthrosis, a false joint in a long bone. Children with NF1 need yearly assessment of the spine. Patients with clinical evidence of scoliosis should be referred to Orthopedics for further evaluation.

Eye issues. A majority of adult patients develop neurofibroma-like nodules in the iris known as Lisch nodules. The nodules are not thought to cause any ophthalmologic complications. Patients may also develop palpebral neurofibroma, which may become large and sporadically show malignant transformation. Optic nerve glioma may cause strabismus and proptosis, and a large number of patients will also develop glaucoma and globe enlargement.¹⁵

Gastrointestinal lesions and cancer. Neurofibromas can grow in the stomach, liver, mesentery, retroperitoneum, and bowel. Adenocarcinoma developed in 23% of patients.¹⁶ Gastrointestinal tract bleeding, pseudo-obstruction, and protein-losing enteropathy also may occur.¹⁷

Continue to: Central nervous system manifestations

Central nervous system manifestations. Neurological manifestations have been observed in 55% of patients with NF1.¹⁸ These include headache, hydrocephalus, epilepsy, lacunar stroke, white matter disease, intraspinal neurofibroma, facial palsy, radiculopathy, and polyneuropathy. Tumors include optic pathway tumors, meningioma, and cerebral glioma. Glioma is the predominant tumor type in NF1 and occurs in all parts of the nervous system, with a predilection for the optic pathways, brainstem, and cerebellum.¹⁸

Malignant peripheral nerve sheath tumors. There is an 8% to 13% lifetime risk for malignant peripheral nerve sheath tumors (MPNST), predominantly in individuals between the ages of 20 and 35.^19,20 Any change in neurofibroma from soft to hard, or a rapid increase in the size, is suspicious for MPNST. Other symptoms include persistent pain lasting for longer than a month, pain that disturbs sleep, and new neurological deficits. These cancers can be hard to detect, leading to poor prognosis secondary to metastasis.^19,20 The greatest risk factors for MPNST are pain associated with a mass and the presence of cutaneous and subcutaneous neurofibromas.²¹

Treatment is symptom based, but there is a new option

Treatment is individualized to the patient’s symptoms. Neurofibromas that are disfiguring, disruptive, or malignant may be surgically removed.

In April 2020, the US Food and Drug Administration (FDA) approved selumetinib (Koselugo) for the treatment of pediatric patients (ages ≥ 2 years) with NF1 who have symptomatic, inoperable plexiform neurofibromas (PNs).²² In a clinical trial, patients received selumetinib 25 mg/m² orally twice a day until they demonstrated disease progression or experienced “unacceptable” adverse events.^22,23 The overall response rate was 66%, defined as “the percentage of patients with a complete response and those who experienced more than a 20% reduction in PN volume on MRI that was confirmed on a subsequent MRI within 3 to 6 months.”²²

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms.

Of note, all patients had a partial, not complete, response. Common adverse effects included vomiting, rash, abdominal pain, diarrhea, and nausea.²³ Selumetinib may also cause more serious adverse effects, including cardiomyopathy and ocular toxicity. Prior to treatment initiation and at regular intervals during treatment, patients should undergo cardiac and ophthalmic evaluation.^22,23 Selumetinib was granted priority review and orphan drug status by the FDA.²²

Continue to: You play a key role in ongoing monitoring

 

 

You play a key role in ongoing monitoring

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms; optimization of quality of life; and identification and treatment of comorbidities. Family physicians are well positioned to monitor patients with NF1 for age-specific disease manifestations and potential complications.⁹ All patients require:

• an annual physical examination by a physician who is familiar with the individual and with the disease
• annual ophthalmologic examination in early childhood; less frequent examination in older children and adults
• regular blood pressure monitoring
• other studies (eg, MRI) only as indicated on the basis of clinically apparent signs or symptoms
• monitoring by an appropriate specialist if there are abnormalities of the central nervous, skeletal, or cardiovascular systems
• referral to a neurologist for any unexplained neurological signs and symptoms. Referral should be urgent if there are acute symptoms of progressive sensory disturbance, motor deficit and incoordination, or sphincter disturbances since these might indicate an intracranial lesion or spinal cord compression. Headaches on waking, morning vomiting, and altered consciousness are suggestive of raised intracranial pressure.

Children with NF1 benefit from coordinated care between the FP and a pediatrician or other specialist familiar with the disease. In addition to providing usual well care, perform regular assessment of development and school performance. Pay careful attention to the cardiovascular system (particularly blood pressure) and evaluate for scoliosis.

Young adults should be continually monitored for all complications, especially hypertension. This population requires continued education about NF1 and its possible complications and may benefit from counseling about disease inheritance. Screen for anxiety and depression; offer psychological support.

Provide adult patients with education about complications, especially malignant peripheral nerve sheath tumors and spinal cord compression.

Adults require monitoring based on patient preference and disease severity. For this population, blood pressure should be measured annually, or more frequently if the patient’s values indicate borderline hypertension. Provide education about complications, especially MPNSTs and spinal cord compression. Patients who have abnormalities of the central nervous, skeletal, or cardiovascular systems should be monitored by an appropriate specialist. If desired, the patient may be referred to a geneticist, especially if he or she expresses concern about inheritance. Cutaneous neurofibromas can be removed if they cause discomfort, although removal occasionally results in neurological deficit.

CORRESPONDENCE
T. Grant Phillips, MD, Associate Director, UPMC Altoona Family Physicians Residency, 501 Howard Avenue, Altoona, PA 16601-4899; [email protected]

Venous thromboembolism (VTE) is a common and dangerous disease, affecting 0.1%-0.2% of the population annually—a rate that might be underreported.¹ VTE is a collective term for venous blood clots, including (1) deep vein thrombosis (DVT) of peripheral veins and (2) pulmonary embolism, which occurs after a clot travels through the heart and becomes lodged in the pulmonary vasculature. Two-thirds of VTE cases present clinically as DVT²; most mortality from VTE disease is caused by the 20% of cases of pulmonary embolism that present as sudden death.¹

VTE is comparable to myocardial infarction (MI) in incidence and severity. In 2008, 208 of every 100,000 people had an MI, with a 30-day mortality of 16/100,000³; VTE disease has an annual incidence of 161 of every 100,000 people and a 28-day mortality of 18/100,000.⁴ Although the incidence and severity of MI are steadily decreasing, the rate of VTE appears constant.^3,5 The high mortality of VTE suggests that primary prevention, which we discuss in this article, is valuable (see “Key points: Primary prevention of venous thromboembolism”).

Risk factors

Virchow’s triad of venous stasis, vascular injury, and hypercoagulability describes predisposing factors for VTE.⁶ Although venous valves promote blood flow, they produce isolated low-flow areas adjacent to valves that become concentrated and locally hypoxic, increasing the risk of clotting.⁷ The great majority of DVTs (≥ 96%) occur in the lower extremity,⁸ starting in the calf; there, 75% of cases resolve spontaneously before they extend into the deep veins of the proximal leg.⁷ One-half of DVTs that do move into the proximal leg eventually embolize.⁷

Major risk factors for VTE comprise inherited conditions, medical history, medical therapeutics, and behaviors (TABLE 1).^9-11 Unlike the preventive management of coronary artery disease (CAD), there is no simple, generalized prevention algorithm to address VTE risk factors.

Risk factors for VTE and CAD overlap. Risk factors for atherosclerosis—­obesity, diabetes, smoking, hypertension, ­hyperlipidemia—also increase the risk of VTE (TABLE 1).^9-11 The association between risk factors for VTE and atherosclerosis is demonstrated by a doubling of the risk of MI and stroke in the year following VTE.¹¹ Lifestyle changes are expected to reduce the risk of VTE, as they do for acute CAD, but studies are lacking to confirm this connection. There is no prospective evidence showing that weight loss or control of diabetes or hypertension reduces the risk of VTE.¹² Smoking cessation does appear to reduce risk: Former smokers have the same VTE risk as never-smokers.¹³

Thrombophilia testing: Not generally useful

Inherited and acquired thrombophilic conditions define a group of disorders in which the risk of VTE is increased. Although thrombophilia testing was once considered for primary and secondary prevention of VTE, such testing is rarely used now because proof of benefit is lacking: A large case–control study showed that thrombophilia testing did not predict recurrence after a first VTE.¹⁴ Guidelines of the American College of Chest Physicians (ACCP) do not address thrombophilia, and the American Society of Hematology recommends against thrombophilia testing after a provoked VTE.^15,16

Primary prophylaxis of patients with a family history of VTE and inherited thrombophilia is controversial. Patients with both a family history of VTE and demonstrated thrombophilia do have double the average incidence of VTE, but this increased risk does not offset the significant bleeding risk associated with anticoagulation.¹⁷ Recommendations for thrombophilia testing are limited to certain situations in pregnancy, discussed in a bit.^16,18,19

Continue to: Primary prevention of VTE in the clinic

 

 

Primary prevention of VTE in the clinic

There is no single, overarching preventive strategy for VTE in an ambulatory patient (although statins, discussed in a moment, offer some benefit, broadly). There are, however, distinct behavioral characteristics and medical circumstances for which opportunities exist to reduce VTE risk—for example, when a person engages in long-distance travel, receives hormonal therapy, is pregnant, or has cancer. In each scenario, recognizing and mitigating risk are important.

Statins offer a (slight) benefit

There is evidence that statins reduce the risk of VTE—slightly^20-23:

• A large randomized, controlled trial showed that rosuvastatin, 20 mg/d, reduced the rate of VTE, compared to placebo; however, the 2-year number needed to treat (NNT) was 349.²⁰ The VTE benefit is minimal, however, compared to primary prevention of cardiovascular disease with statins (5-year NNT = 56).²¹ The sole significant adverse event associated with statins was new-onset type 2 diabetes (5-year number needed to harm = 235).²¹
• A subsequent meta-analysis confirmed a small reduction in VTE risk with statins.²² In its 2012 guidelines, ACCP declined to issue a recommendation on the use of statins for VTE prevention.²³ When considering statins for primary cardiovascular disease prevention, take the additional VTE prevention into account.

Simple strategies can help prevent travel-related VTE

Travel is a common inciting factor for VTE. A systematic review showed that VTE risk triples after travel of ≥ 4 hours, increasing by 20% with each additional 2 hours.²⁴ Most VTE occurs in travelers who have other VTE risk factors.²⁵ Based on case–control studies,²³ guidelines recommend these preventive measures:

• frequent calf exercises
• sitting in an aisle seat during air travel
• keeping hydrated.

A Cochrane review showed that graded compression stockings reduce asymptomatic DVT in travelers by a factor of 10, in high- and low-risk patients.²⁶

VTE risk varies with type of hormonal contraception

Most contraceptives increase VTE risk (TABLE 2^27,28). Risk with combined oral contraceptives varies with the amount of estrogen and progesterone. To reduce VTE risk with oral contraceptives, patients can use an agent that contains a lower dose of estrogen or one in which levonorgestrel replaces other progesterones.²⁷

Continue to: Studies suggest that the levonorgestrel-releasing...

Studies suggest that the levonorgestrel-releasing intrauterine device and progestin-only pills are not associated with an increase in VTE risk.²⁷ Although the quality of evidence varies, most nonoral hormonal contraceptives have been determined to carry a risk of VTE that is similar to that of combined oral contraceptives.²⁸

In hormone replacement, avoid pills to lower risk

Hormone replacement therapy (HRT) for postmenopausal women increases VTE risk when administered in oral form, with combined estrogen and progestin HRT doubling the risk and estrogen-only formulations having a lower risk.²⁹ VTE risk is highest in the first 6 months of HRT, declining to that of a non-HRT user within 5 years.²⁹ Neither transdermal HRT nor estrogen creams increase the risk of VTE, according to a systematic review.³⁰ The estradiol-containing vaginal ring also does not confer increased risk.²⁹

Pregnancy, thrombophilia, and VTE prevention

VTE affects as many as 0.2% of pregnancies but causes 9% of pregnancy-related deaths.¹⁸ The severity of VTE in pregnancy led the American College of Obstetricians and Gynecologists (ACOG) to recommend primary VTE prophylaxis in patients with certain thrombophilias.¹⁸ Thrombophilia testing is recommended in patients with proven high-risk thrombophilia in a first-degree relative.¹⁸ ACOG recognizes 5 thrombophilias considered to carry a high risk of VTE in pregnancy¹⁸:

• homozygous Factor V Leiden
• homozygous prothrombin G20210A mutation
• antithrombin deficiency
• heterozygous Factor V Leiden and prothrombin G20210A mutation
• antiphospholipid antibody syndrome.

ACOG recommends limiting thrombophilia testing to (1) any specific thrombophilia carried by a relative and (2) possibly, the antiphospholipid antibodies anticardiolipin and lupus anticoagulant.^18,19 Antiphospholipid testing is recommended when there is a history of stillbirth, 3 early pregnancy losses, or delivery earlier than 34 weeks secondary to preeclampsia.¹⁹

Primary VTE prophylaxis is recommended for pregnant patients with a high-risk thrombophilia; low-molecular-weight heparin (LMWH) is safe and its effects are predictable.¹⁸ Because postpartum risk of VTE is higher than antepartum risk, postpartum prophylaxis is also recommended with lower-risk thrombophilias¹⁸; a vitamin K antagonist or LMWH can be used.¹⁸ ACCP and ACOG recommendations for VTE prophylaxis in pregnancy differ slightly (TABLE 3^16,18,19).

Continue to: Cancer increases risks of VTE and bleeding

 

 

Cancer increases risks of VTE and bleeding

Cancer increases VTE risk > 6-fold³¹; metastases, chemotherapy, and radiotherapy further increase risk. Cancer also greatly increases the risk of bleeding: Cancer patients with VTE have an annual major bleeding rate ≥ 20%.³² Guidelines do not recommend primary VTE prophylaxis for cancer, although American Society of Clinical Oncology guidelines discuss consideration of prophylaxis for select, high-risk patients,^33,34 including those with multiple myeloma, metastatic gastrointestinal cancer, or metastatic brain cancer.^31,34 Recent evidence (discussed in a moment) supports the use of apixaban for primary VTE prevention during chemotherapy for high-risk cancer.

The Khorana Risk Score (TABLE 4^35,36) for VTE was developed and validated for use in patients with solid cancer³⁵: A score of 2 conveys nearly a 10% risk of VTE over 6 months.³⁶ A recent study of 550 cancer patients with a Khorana score of ≥ 2—the first evidence of risk-guided primary VTE prevention in cancer—showed that primary prophylaxis with 2.5 mg of apixaban, bid, reduced the risk of VTE (NNT = 17); however, the number needed to harm (for major bleeding) was 59.³⁷ Mortality was not changed with apixaban treatment.³⁷

Primary VTE prevention in med-surg hospitalizations

The risk of VTE increases significantly during hospitalization, although not enough to justify universal prophylaxis. Recommended prevention strategies for different classes of hospitalized patients are summarized below.

In medically hospitalized patients, risk is stratified with a risk-assessment model. Medically hospitalized patients have, on average, a VTE risk of 1.2%²³; 12 risk-assessment models designed to stratify risk were recently compared.³⁸ Two models, the Caprini Score (TABLE 5)³⁹ and the IMPROVE VTE Risk Calculator,⁴⁰ were best able to identify low-risk patients (negative predictive value, > 99%).³⁸ American Society of Hematology guidelines recommend IMPROVE VTE or the Padua Prediction Score for risk stratification.⁴¹ While the Caprini score only designates 11% of eventual VTE cases as low risk, both the IMPROVE VTE and Padua scores miss more than 35% of eventual VTE.³⁸

There is no prospective evidence that weight loss or control of diabetes or hypertension reduces the risk of VTE; smoking cessation does appear to reduce risk.

Because LMWH prophylaxis has been shown to reduce VTE by 40% without increasing the risk of major bleeding, using Caprini should prevent 2 VTEs for every 1000 patients, without an increase in major bleeding and with 13 additional minor bleeding events.⁴²

Continue to: Critically ill patients

Critically ill patients are assumed to be at high risk of VTE and do not require stratification.²³ For high-risk patients, prophylaxis with LMWH, low-dose unfractionated heparin (LDUH), or fondaparinux is recommended for the duration of admission.²³ For patients at high risk of both VTE and bleeding, mechanical prophylaxis with intermittent pneumatic compression (IPC) is recommended instead of LMWH, LDUH, or fondaparinux.²³

Surgery, like trauma (see next page), increases the risk of VTE and has been well studied. Prophylaxis after orthopedic surgery differs from that of other types of surgery.

In orthopedic surgery, risk depends on the procedure. For major orthopedic surgery, including total hip or knee arthroplasty and hip fracture surgery, VTE prophylaxis is recommended for 35 days postsurgically.⁴³ LMWH is the preferred agent, although many other means have been shown to be beneficial.⁴⁴ A recent systematic review demonstrated that aspirin is not inferior to other medications after hip or knee arthroplasty.⁴⁵ No mechanical or pharmacotherapeutic prophylaxis is generally recommended after nonmajor orthopedic surgery.⁴³

Taking a statin can reduce the risk of VTE— slightly.

Nonorthopedic surgery is stratified by risk factors, using Caprini⁴⁴ (TABLE 5³⁹). For medium-risk patients (Caprini score, 3-4) LDUH, LMWH, or IPC is recommended; for high-risk patients (Caprini score, ≥ 5) preventive treatment should combine pharmacotherapeutic and mechanical prophylaxis.⁴⁶ A recent meta-analysis, comprising 14,776 patients, showed that surgical patients with a Caprini score ≥ 7 had a reduced incidence of VTE when given chemoprophylaxis, whereas patients whose score is < 7 do not benefit from chemoprophylaxis.⁴³ When bleeding risk is high, IPC is recommended as sole therapy.⁴³ Prophylaxis is not recommended when risk (determined by the Caprini score) is low.⁴⁶

Post-hospitalization. Risk of VTE can persist for as long as 90 days after hospitalization; this finding has led to evaluation of the benefit of prolonged chemoprophylaxis.²³ Extended-duration LMWH prophylaxis decreases the incidence of VTE, but at the cost of increased risk of major bleeding.⁴⁷ Based on this evidence, guidelines recommend against prolonged-duration anticoagulation.²³ A 2016 trial showed that 35 days of the direct-acting anticoagulant betrixaban reduced the risk of symptomatic VTE events, compared to 10 days of LMWH (NNT = 167), without increased risk of bleeding.⁴⁸ This is a limited benefit, however, that is unlikely to change guideline recommendations.

Continue to: Trauma

Trauma: VTE risk increases with severity

Trauma increases the risk of VTE considerably. A national study showed that 1.5% of admitted trauma patients experienced VTE during hospitalization and that 1.2% were readmitted for VTE within 1 year.⁴⁹ As many as 32% of trauma patients admitted to the intensive care unit experience VTE despite appropriate prophylaxis.⁵⁰ A Cochrane Review⁵¹ found that:

• prophylaxis significantly reduces DVT risk
• pharmacotherapeutic prophylaxis is more effective than mechanical prophylaxis
• LMWH is more effective than LDUH.

Guidelines recommend that major trauma patients receive prophylaxis with LMWH, LDUH, or IPC.⁴⁶

CORRESPONDENCE
Michael J. Arnold, MD, CDR, MC, USN; Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Jacksonville, FL 32214; [email protected].

Venous thromboembolism (VTE) is a common and dangerous disease, affecting 0.1%-0.2% of the population annually—a rate that might be underreported.¹ VTE is a collective term for venous blood clots, including (1) deep vein thrombosis (DVT) of peripheral veins and (2) pulmonary embolism, which occurs after a clot travels through the heart and becomes lodged in the pulmonary vasculature. Two-thirds of VTE cases present clinically as DVT²; most mortality from VTE disease is caused by the 20% of cases of pulmonary embolism that present as sudden death.¹

VTE is comparable to myocardial infarction (MI) in incidence and severity. In 2008, 208 of every 100,000 people had an MI, with a 30-day mortality of 16/100,000³; VTE disease has an annual incidence of 161 of every 100,000 people and a 28-day mortality of 18/100,000.⁴ Although the incidence and severity of MI are steadily decreasing, the rate of VTE appears constant.^3,5 The high mortality of VTE suggests that primary prevention, which we discuss in this article, is valuable (see “Key points: Primary prevention of venous thromboembolism”).

Risk factors

Virchow’s triad of venous stasis, vascular injury, and hypercoagulability describes predisposing factors for VTE.⁶ Although venous valves promote blood flow, they produce isolated low-flow areas adjacent to valves that become concentrated and locally hypoxic, increasing the risk of clotting.⁷ The great majority of DVTs (≥ 96%) occur in the lower extremity,⁸ starting in the calf; there, 75% of cases resolve spontaneously before they extend into the deep veins of the proximal leg.⁷ One-half of DVTs that do move into the proximal leg eventually embolize.⁷

Major risk factors for VTE comprise inherited conditions, medical history, medical therapeutics, and behaviors (TABLE 1).^9-11 Unlike the preventive management of coronary artery disease (CAD), there is no simple, generalized prevention algorithm to address VTE risk factors.

Risk factors for VTE and CAD overlap. Risk factors for atherosclerosis—­obesity, diabetes, smoking, hypertension, ­hyperlipidemia—also increase the risk of VTE (TABLE 1).^9-11 The association between risk factors for VTE and atherosclerosis is demonstrated by a doubling of the risk of MI and stroke in the year following VTE.¹¹ Lifestyle changes are expected to reduce the risk of VTE, as they do for acute CAD, but studies are lacking to confirm this connection. There is no prospective evidence showing that weight loss or control of diabetes or hypertension reduces the risk of VTE.¹² Smoking cessation does appear to reduce risk: Former smokers have the same VTE risk as never-smokers.¹³

Thrombophilia testing: Not generally useful

Inherited and acquired thrombophilic conditions define a group of disorders in which the risk of VTE is increased. Although thrombophilia testing was once considered for primary and secondary prevention of VTE, such testing is rarely used now because proof of benefit is lacking: A large case–control study showed that thrombophilia testing did not predict recurrence after a first VTE.¹⁴ Guidelines of the American College of Chest Physicians (ACCP) do not address thrombophilia, and the American Society of Hematology recommends against thrombophilia testing after a provoked VTE.^15,16

Primary prophylaxis of patients with a family history of VTE and inherited thrombophilia is controversial. Patients with both a family history of VTE and demonstrated thrombophilia do have double the average incidence of VTE, but this increased risk does not offset the significant bleeding risk associated with anticoagulation.¹⁷ Recommendations for thrombophilia testing are limited to certain situations in pregnancy, discussed in a bit.^16,18,19

Continue to: Primary prevention of VTE in the clinic

 

 

Primary prevention of VTE in the clinic

There is no single, overarching preventive strategy for VTE in an ambulatory patient (although statins, discussed in a moment, offer some benefit, broadly). There are, however, distinct behavioral characteristics and medical circumstances for which opportunities exist to reduce VTE risk—for example, when a person engages in long-distance travel, receives hormonal therapy, is pregnant, or has cancer. In each scenario, recognizing and mitigating risk are important.

Statins offer a (slight) benefit

There is evidence that statins reduce the risk of VTE—slightly^20-23:

• A large randomized, controlled trial showed that rosuvastatin, 20 mg/d, reduced the rate of VTE, compared to placebo; however, the 2-year number needed to treat (NNT) was 349.²⁰ The VTE benefit is minimal, however, compared to primary prevention of cardiovascular disease with statins (5-year NNT = 56).²¹ The sole significant adverse event associated with statins was new-onset type 2 diabetes (5-year number needed to harm = 235).²¹
• A subsequent meta-analysis confirmed a small reduction in VTE risk with statins.²² In its 2012 guidelines, ACCP declined to issue a recommendation on the use of statins for VTE prevention.²³ When considering statins for primary cardiovascular disease prevention, take the additional VTE prevention into account.

Simple strategies can help prevent travel-related VTE

Travel is a common inciting factor for VTE. A systematic review showed that VTE risk triples after travel of ≥ 4 hours, increasing by 20% with each additional 2 hours.²⁴ Most VTE occurs in travelers who have other VTE risk factors.²⁵ Based on case–control studies,²³ guidelines recommend these preventive measures:

• frequent calf exercises
• sitting in an aisle seat during air travel
• keeping hydrated.

A Cochrane review showed that graded compression stockings reduce asymptomatic DVT in travelers by a factor of 10, in high- and low-risk patients.²⁶

VTE risk varies with type of hormonal contraception

Most contraceptives increase VTE risk (TABLE 2^27,28). Risk with combined oral contraceptives varies with the amount of estrogen and progesterone. To reduce VTE risk with oral contraceptives, patients can use an agent that contains a lower dose of estrogen or one in which levonorgestrel replaces other progesterones.²⁷

Continue to: Studies suggest that the levonorgestrel-releasing...

Studies suggest that the levonorgestrel-releasing intrauterine device and progestin-only pills are not associated with an increase in VTE risk.²⁷ Although the quality of evidence varies, most nonoral hormonal contraceptives have been determined to carry a risk of VTE that is similar to that of combined oral contraceptives.²⁸

In hormone replacement, avoid pills to lower risk

Hormone replacement therapy (HRT) for postmenopausal women increases VTE risk when administered in oral form, with combined estrogen and progestin HRT doubling the risk and estrogen-only formulations having a lower risk.²⁹ VTE risk is highest in the first 6 months of HRT, declining to that of a non-HRT user within 5 years.²⁹ Neither transdermal HRT nor estrogen creams increase the risk of VTE, according to a systematic review.³⁰ The estradiol-containing vaginal ring also does not confer increased risk.²⁹

Pregnancy, thrombophilia, and VTE prevention

VTE affects as many as 0.2% of pregnancies but causes 9% of pregnancy-related deaths.¹⁸ The severity of VTE in pregnancy led the American College of Obstetricians and Gynecologists (ACOG) to recommend primary VTE prophylaxis in patients with certain thrombophilias.¹⁸ Thrombophilia testing is recommended in patients with proven high-risk thrombophilia in a first-degree relative.¹⁸ ACOG recognizes 5 thrombophilias considered to carry a high risk of VTE in pregnancy¹⁸:

• homozygous Factor V Leiden
• homozygous prothrombin G20210A mutation
• antithrombin deficiency
• heterozygous Factor V Leiden and prothrombin G20210A mutation
• antiphospholipid antibody syndrome.

ACOG recommends limiting thrombophilia testing to (1) any specific thrombophilia carried by a relative and (2) possibly, the antiphospholipid antibodies anticardiolipin and lupus anticoagulant.^18,19 Antiphospholipid testing is recommended when there is a history of stillbirth, 3 early pregnancy losses, or delivery earlier than 34 weeks secondary to preeclampsia.¹⁹

Primary VTE prophylaxis is recommended for pregnant patients with a high-risk thrombophilia; low-molecular-weight heparin (LMWH) is safe and its effects are predictable.¹⁸ Because postpartum risk of VTE is higher than antepartum risk, postpartum prophylaxis is also recommended with lower-risk thrombophilias¹⁸; a vitamin K antagonist or LMWH can be used.¹⁸ ACCP and ACOG recommendations for VTE prophylaxis in pregnancy differ slightly (TABLE 3^16,18,19).

Continue to: Cancer increases risks of VTE and bleeding

 

 

Cancer increases risks of VTE and bleeding

Cancer increases VTE risk > 6-fold³¹; metastases, chemotherapy, and radiotherapy further increase risk. Cancer also greatly increases the risk of bleeding: Cancer patients with VTE have an annual major bleeding rate ≥ 20%.³² Guidelines do not recommend primary VTE prophylaxis for cancer, although American Society of Clinical Oncology guidelines discuss consideration of prophylaxis for select, high-risk patients,^33,34 including those with multiple myeloma, metastatic gastrointestinal cancer, or metastatic brain cancer.^31,34 Recent evidence (discussed in a moment) supports the use of apixaban for primary VTE prevention during chemotherapy for high-risk cancer.

The Khorana Risk Score (TABLE 4^35,36) for VTE was developed and validated for use in patients with solid cancer³⁵: A score of 2 conveys nearly a 10% risk of VTE over 6 months.³⁶ A recent study of 550 cancer patients with a Khorana score of ≥ 2—the first evidence of risk-guided primary VTE prevention in cancer—showed that primary prophylaxis with 2.5 mg of apixaban, bid, reduced the risk of VTE (NNT = 17); however, the number needed to harm (for major bleeding) was 59.³⁷ Mortality was not changed with apixaban treatment.³⁷

Primary VTE prevention in med-surg hospitalizations

The risk of VTE increases significantly during hospitalization, although not enough to justify universal prophylaxis. Recommended prevention strategies for different classes of hospitalized patients are summarized below.

In medically hospitalized patients, risk is stratified with a risk-assessment model. Medically hospitalized patients have, on average, a VTE risk of 1.2%²³; 12 risk-assessment models designed to stratify risk were recently compared.³⁸ Two models, the Caprini Score (TABLE 5)³⁹ and the IMPROVE VTE Risk Calculator,⁴⁰ were best able to identify low-risk patients (negative predictive value, > 99%).³⁸ American Society of Hematology guidelines recommend IMPROVE VTE or the Padua Prediction Score for risk stratification.⁴¹ While the Caprini score only designates 11% of eventual VTE cases as low risk, both the IMPROVE VTE and Padua scores miss more than 35% of eventual VTE.³⁸

There is no prospective evidence that weight loss or control of diabetes or hypertension reduces the risk of VTE; smoking cessation does appear to reduce risk.

Because LMWH prophylaxis has been shown to reduce VTE by 40% without increasing the risk of major bleeding, using Caprini should prevent 2 VTEs for every 1000 patients, without an increase in major bleeding and with 13 additional minor bleeding events.⁴²

Continue to: Critically ill patients

Critically ill patients are assumed to be at high risk of VTE and do not require stratification.²³ For high-risk patients, prophylaxis with LMWH, low-dose unfractionated heparin (LDUH), or fondaparinux is recommended for the duration of admission.²³ For patients at high risk of both VTE and bleeding, mechanical prophylaxis with intermittent pneumatic compression (IPC) is recommended instead of LMWH, LDUH, or fondaparinux.²³

Surgery, like trauma (see next page), increases the risk of VTE and has been well studied. Prophylaxis after orthopedic surgery differs from that of other types of surgery.

In orthopedic surgery, risk depends on the procedure. For major orthopedic surgery, including total hip or knee arthroplasty and hip fracture surgery, VTE prophylaxis is recommended for 35 days postsurgically.⁴³ LMWH is the preferred agent, although many other means have been shown to be beneficial.⁴⁴ A recent systematic review demonstrated that aspirin is not inferior to other medications after hip or knee arthroplasty.⁴⁵ No mechanical or pharmacotherapeutic prophylaxis is generally recommended after nonmajor orthopedic surgery.⁴³

Taking a statin can reduce the risk of VTE— slightly.

Nonorthopedic surgery is stratified by risk factors, using Caprini⁴⁴ (TABLE 5³⁹). For medium-risk patients (Caprini score, 3-4) LDUH, LMWH, or IPC is recommended; for high-risk patients (Caprini score, ≥ 5) preventive treatment should combine pharmacotherapeutic and mechanical prophylaxis.⁴⁶ A recent meta-analysis, comprising 14,776 patients, showed that surgical patients with a Caprini score ≥ 7 had a reduced incidence of VTE when given chemoprophylaxis, whereas patients whose score is < 7 do not benefit from chemoprophylaxis.⁴³ When bleeding risk is high, IPC is recommended as sole therapy.⁴³ Prophylaxis is not recommended when risk (determined by the Caprini score) is low.⁴⁶

Post-hospitalization. Risk of VTE can persist for as long as 90 days after hospitalization; this finding has led to evaluation of the benefit of prolonged chemoprophylaxis.²³ Extended-duration LMWH prophylaxis decreases the incidence of VTE, but at the cost of increased risk of major bleeding.⁴⁷ Based on this evidence, guidelines recommend against prolonged-duration anticoagulation.²³ A 2016 trial showed that 35 days of the direct-acting anticoagulant betrixaban reduced the risk of symptomatic VTE events, compared to 10 days of LMWH (NNT = 167), without increased risk of bleeding.⁴⁸ This is a limited benefit, however, that is unlikely to change guideline recommendations.

Continue to: Trauma

Trauma: VTE risk increases with severity

Trauma increases the risk of VTE considerably. A national study showed that 1.5% of admitted trauma patients experienced VTE during hospitalization and that 1.2% were readmitted for VTE within 1 year.⁴⁹ As many as 32% of trauma patients admitted to the intensive care unit experience VTE despite appropriate prophylaxis.⁵⁰ A Cochrane Review⁵¹ found that:

• prophylaxis significantly reduces DVT risk
• pharmacotherapeutic prophylaxis is more effective than mechanical prophylaxis
• LMWH is more effective than LDUH.

Guidelines recommend that major trauma patients receive prophylaxis with LMWH, LDUH, or IPC.⁴⁶

CORRESPONDENCE
Michael J. Arnold, MD, CDR, MC, USN; Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Jacksonville, FL 32214; [email protected].

Venous thromboembolism (VTE) is a common and dangerous disease, affecting 0.1%-0.2% of the population annually—a rate that might be underreported.¹ VTE is a collective term for venous blood clots, including (1) deep vein thrombosis (DVT) of peripheral veins and (2) pulmonary embolism, which occurs after a clot travels through the heart and becomes lodged in the pulmonary vasculature. Two-thirds of VTE cases present clinically as DVT²; most mortality from VTE disease is caused by the 20% of cases of pulmonary embolism that present as sudden death.¹

VTE is comparable to myocardial infarction (MI) in incidence and severity. In 2008, 208 of every 100,000 people had an MI, with a 30-day mortality of 16/100,000³; VTE disease has an annual incidence of 161 of every 100,000 people and a 28-day mortality of 18/100,000.⁴ Although the incidence and severity of MI are steadily decreasing, the rate of VTE appears constant.^3,5 The high mortality of VTE suggests that primary prevention, which we discuss in this article, is valuable (see “Key points: Primary prevention of venous thromboembolism”).

Risk factors

Virchow’s triad of venous stasis, vascular injury, and hypercoagulability describes predisposing factors for VTE.⁶ Although venous valves promote blood flow, they produce isolated low-flow areas adjacent to valves that become concentrated and locally hypoxic, increasing the risk of clotting.⁷ The great majority of DVTs (≥ 96%) occur in the lower extremity,⁸ starting in the calf; there, 75% of cases resolve spontaneously before they extend into the deep veins of the proximal leg.⁷ One-half of DVTs that do move into the proximal leg eventually embolize.⁷

Major risk factors for VTE comprise inherited conditions, medical history, medical therapeutics, and behaviors (TABLE 1).^9-11 Unlike the preventive management of coronary artery disease (CAD), there is no simple, generalized prevention algorithm to address VTE risk factors.

Risk factors for VTE and CAD overlap. Risk factors for atherosclerosis—­obesity, diabetes, smoking, hypertension, ­hyperlipidemia—also increase the risk of VTE (TABLE 1).^9-11 The association between risk factors for VTE and atherosclerosis is demonstrated by a doubling of the risk of MI and stroke in the year following VTE.¹¹ Lifestyle changes are expected to reduce the risk of VTE, as they do for acute CAD, but studies are lacking to confirm this connection. There is no prospective evidence showing that weight loss or control of diabetes or hypertension reduces the risk of VTE.¹² Smoking cessation does appear to reduce risk: Former smokers have the same VTE risk as never-smokers.¹³

Thrombophilia testing: Not generally useful

Inherited and acquired thrombophilic conditions define a group of disorders in which the risk of VTE is increased. Although thrombophilia testing was once considered for primary and secondary prevention of VTE, such testing is rarely used now because proof of benefit is lacking: A large case–control study showed that thrombophilia testing did not predict recurrence after a first VTE.¹⁴ Guidelines of the American College of Chest Physicians (ACCP) do not address thrombophilia, and the American Society of Hematology recommends against thrombophilia testing after a provoked VTE.^15,16

Primary prophylaxis of patients with a family history of VTE and inherited thrombophilia is controversial. Patients with both a family history of VTE and demonstrated thrombophilia do have double the average incidence of VTE, but this increased risk does not offset the significant bleeding risk associated with anticoagulation.¹⁷ Recommendations for thrombophilia testing are limited to certain situations in pregnancy, discussed in a bit.^16,18,19

Continue to: Primary prevention of VTE in the clinic

 

 

Primary prevention of VTE in the clinic

There is no single, overarching preventive strategy for VTE in an ambulatory patient (although statins, discussed in a moment, offer some benefit, broadly). There are, however, distinct behavioral characteristics and medical circumstances for which opportunities exist to reduce VTE risk—for example, when a person engages in long-distance travel, receives hormonal therapy, is pregnant, or has cancer. In each scenario, recognizing and mitigating risk are important.

Statins offer a (slight) benefit

There is evidence that statins reduce the risk of VTE—slightly^20-23:

• A large randomized, controlled trial showed that rosuvastatin, 20 mg/d, reduced the rate of VTE, compared to placebo; however, the 2-year number needed to treat (NNT) was 349.²⁰ The VTE benefit is minimal, however, compared to primary prevention of cardiovascular disease with statins (5-year NNT = 56).²¹ The sole significant adverse event associated with statins was new-onset type 2 diabetes (5-year number needed to harm = 235).²¹
• A subsequent meta-analysis confirmed a small reduction in VTE risk with statins.²² In its 2012 guidelines, ACCP declined to issue a recommendation on the use of statins for VTE prevention.²³ When considering statins for primary cardiovascular disease prevention, take the additional VTE prevention into account.

Simple strategies can help prevent travel-related VTE

Travel is a common inciting factor for VTE. A systematic review showed that VTE risk triples after travel of ≥ 4 hours, increasing by 20% with each additional 2 hours.²⁴ Most VTE occurs in travelers who have other VTE risk factors.²⁵ Based on case–control studies,²³ guidelines recommend these preventive measures:

• frequent calf exercises
• sitting in an aisle seat during air travel
• keeping hydrated.

A Cochrane review showed that graded compression stockings reduce asymptomatic DVT in travelers by a factor of 10, in high- and low-risk patients.²⁶

VTE risk varies with type of hormonal contraception

Most contraceptives increase VTE risk (TABLE 2^27,28). Risk with combined oral contraceptives varies with the amount of estrogen and progesterone. To reduce VTE risk with oral contraceptives, patients can use an agent that contains a lower dose of estrogen or one in which levonorgestrel replaces other progesterones.²⁷

Continue to: Studies suggest that the levonorgestrel-releasing...

Studies suggest that the levonorgestrel-releasing intrauterine device and progestin-only pills are not associated with an increase in VTE risk.²⁷ Although the quality of evidence varies, most nonoral hormonal contraceptives have been determined to carry a risk of VTE that is similar to that of combined oral contraceptives.²⁸

In hormone replacement, avoid pills to lower risk

Hormone replacement therapy (HRT) for postmenopausal women increases VTE risk when administered in oral form, with combined estrogen and progestin HRT doubling the risk and estrogen-only formulations having a lower risk.²⁹ VTE risk is highest in the first 6 months of HRT, declining to that of a non-HRT user within 5 years.²⁹ Neither transdermal HRT nor estrogen creams increase the risk of VTE, according to a systematic review.³⁰ The estradiol-containing vaginal ring also does not confer increased risk.²⁹

Pregnancy, thrombophilia, and VTE prevention

VTE affects as many as 0.2% of pregnancies but causes 9% of pregnancy-related deaths.¹⁸ The severity of VTE in pregnancy led the American College of Obstetricians and Gynecologists (ACOG) to recommend primary VTE prophylaxis in patients with certain thrombophilias.¹⁸ Thrombophilia testing is recommended in patients with proven high-risk thrombophilia in a first-degree relative.¹⁸ ACOG recognizes 5 thrombophilias considered to carry a high risk of VTE in pregnancy¹⁸:

• homozygous Factor V Leiden
• homozygous prothrombin G20210A mutation
• antithrombin deficiency
• heterozygous Factor V Leiden and prothrombin G20210A mutation
• antiphospholipid antibody syndrome.

ACOG recommends limiting thrombophilia testing to (1) any specific thrombophilia carried by a relative and (2) possibly, the antiphospholipid antibodies anticardiolipin and lupus anticoagulant.^18,19 Antiphospholipid testing is recommended when there is a history of stillbirth, 3 early pregnancy losses, or delivery earlier than 34 weeks secondary to preeclampsia.¹⁹

Primary VTE prophylaxis is recommended for pregnant patients with a high-risk thrombophilia; low-molecular-weight heparin (LMWH) is safe and its effects are predictable.¹⁸ Because postpartum risk of VTE is higher than antepartum risk, postpartum prophylaxis is also recommended with lower-risk thrombophilias¹⁸; a vitamin K antagonist or LMWH can be used.¹⁸ ACCP and ACOG recommendations for VTE prophylaxis in pregnancy differ slightly (TABLE 3^16,18,19).

Continue to: Cancer increases risks of VTE and bleeding

 

 

Cancer increases risks of VTE and bleeding

Cancer increases VTE risk > 6-fold³¹; metastases, chemotherapy, and radiotherapy further increase risk. Cancer also greatly increases the risk of bleeding: Cancer patients with VTE have an annual major bleeding rate ≥ 20%.³² Guidelines do not recommend primary VTE prophylaxis for cancer, although American Society of Clinical Oncology guidelines discuss consideration of prophylaxis for select, high-risk patients,^33,34 including those with multiple myeloma, metastatic gastrointestinal cancer, or metastatic brain cancer.^31,34 Recent evidence (discussed in a moment) supports the use of apixaban for primary VTE prevention during chemotherapy for high-risk cancer.

The Khorana Risk Score (TABLE 4^35,36) for VTE was developed and validated for use in patients with solid cancer³⁵: A score of 2 conveys nearly a 10% risk of VTE over 6 months.³⁶ A recent study of 550 cancer patients with a Khorana score of ≥ 2—the first evidence of risk-guided primary VTE prevention in cancer—showed that primary prophylaxis with 2.5 mg of apixaban, bid, reduced the risk of VTE (NNT = 17); however, the number needed to harm (for major bleeding) was 59.³⁷ Mortality was not changed with apixaban treatment.³⁷

Primary VTE prevention in med-surg hospitalizations

The risk of VTE increases significantly during hospitalization, although not enough to justify universal prophylaxis. Recommended prevention strategies for different classes of hospitalized patients are summarized below.

In medically hospitalized patients, risk is stratified with a risk-assessment model. Medically hospitalized patients have, on average, a VTE risk of 1.2%²³; 12 risk-assessment models designed to stratify risk were recently compared.³⁸ Two models, the Caprini Score (TABLE 5)³⁹ and the IMPROVE VTE Risk Calculator,⁴⁰ were best able to identify low-risk patients (negative predictive value, > 99%).³⁸ American Society of Hematology guidelines recommend IMPROVE VTE or the Padua Prediction Score for risk stratification.⁴¹ While the Caprini score only designates 11% of eventual VTE cases as low risk, both the IMPROVE VTE and Padua scores miss more than 35% of eventual VTE.³⁸

There is no prospective evidence that weight loss or control of diabetes or hypertension reduces the risk of VTE; smoking cessation does appear to reduce risk.

Because LMWH prophylaxis has been shown to reduce VTE by 40% without increasing the risk of major bleeding, using Caprini should prevent 2 VTEs for every 1000 patients, without an increase in major bleeding and with 13 additional minor bleeding events.⁴²

Continue to: Critically ill patients

Critically ill patients are assumed to be at high risk of VTE and do not require stratification.²³ For high-risk patients, prophylaxis with LMWH, low-dose unfractionated heparin (LDUH), or fondaparinux is recommended for the duration of admission.²³ For patients at high risk of both VTE and bleeding, mechanical prophylaxis with intermittent pneumatic compression (IPC) is recommended instead of LMWH, LDUH, or fondaparinux.²³

Surgery, like trauma (see next page), increases the risk of VTE and has been well studied. Prophylaxis after orthopedic surgery differs from that of other types of surgery.

In orthopedic surgery, risk depends on the procedure. For major orthopedic surgery, including total hip or knee arthroplasty and hip fracture surgery, VTE prophylaxis is recommended for 35 days postsurgically.⁴³ LMWH is the preferred agent, although many other means have been shown to be beneficial.⁴⁴ A recent systematic review demonstrated that aspirin is not inferior to other medications after hip or knee arthroplasty.⁴⁵ No mechanical or pharmacotherapeutic prophylaxis is generally recommended after nonmajor orthopedic surgery.⁴³

Taking a statin can reduce the risk of VTE— slightly.

Nonorthopedic surgery is stratified by risk factors, using Caprini⁴⁴ (TABLE 5³⁹). For medium-risk patients (Caprini score, 3-4) LDUH, LMWH, or IPC is recommended; for high-risk patients (Caprini score, ≥ 5) preventive treatment should combine pharmacotherapeutic and mechanical prophylaxis.⁴⁶ A recent meta-analysis, comprising 14,776 patients, showed that surgical patients with a Caprini score ≥ 7 had a reduced incidence of VTE when given chemoprophylaxis, whereas patients whose score is < 7 do not benefit from chemoprophylaxis.⁴³ When bleeding risk is high, IPC is recommended as sole therapy.⁴³ Prophylaxis is not recommended when risk (determined by the Caprini score) is low.⁴⁶

Post-hospitalization. Risk of VTE can persist for as long as 90 days after hospitalization; this finding has led to evaluation of the benefit of prolonged chemoprophylaxis.²³ Extended-duration LMWH prophylaxis decreases the incidence of VTE, but at the cost of increased risk of major bleeding.⁴⁷ Based on this evidence, guidelines recommend against prolonged-duration anticoagulation.²³ A 2016 trial showed that 35 days of the direct-acting anticoagulant betrixaban reduced the risk of symptomatic VTE events, compared to 10 days of LMWH (NNT = 167), without increased risk of bleeding.⁴⁸ This is a limited benefit, however, that is unlikely to change guideline recommendations.

Continue to: Trauma

Trauma: VTE risk increases with severity

Trauma increases the risk of VTE considerably. A national study showed that 1.5% of admitted trauma patients experienced VTE during hospitalization and that 1.2% were readmitted for VTE within 1 year.⁴⁹ As many as 32% of trauma patients admitted to the intensive care unit experience VTE despite appropriate prophylaxis.⁵⁰ A Cochrane Review⁵¹ found that:

• prophylaxis significantly reduces DVT risk
• pharmacotherapeutic prophylaxis is more effective than mechanical prophylaxis
• LMWH is more effective than LDUH.

Guidelines recommend that major trauma patients receive prophylaxis with LMWH, LDUH, or IPC.⁴⁶

CORRESPONDENCE
Michael J. Arnold, MD, CDR, MC, USN; Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Jacksonville, FL 32214; [email protected].

CASE

Jessica F is a new 23-year-old patient at your clinic who is seeing you to discuss her severe anxiety. She also has asthma and reports during your exploration of her family history that her father has been diagnosed with schizophrenia. She has been using 3 cartridges of cannabis vape daily to help “calm her mind” but has never tried other psychotropic medications and has never been referred to a psychiatrist.

How would you proceed with this patient?

Despite emerging evidence of the harmful effects of cannabis consumption, public perception of harm has steadily declined over the past 10 years.^1,2 More adults are using cannabis than before and using it more frequently. Among primary care patients who consume cannabis recreationally, about half report less than monthly consumption; 15% use it weekly, and 20% daily.³ The potency of cannabis products has also increased. In the past 2 decades, the average tetrahydrocannabinol (THC) content of recreational cannabis rose from 3% to 19%, and high-THC content delivery modalities such as vaporizer pens (“vapes”) were introduced.^4,5

Health hazards of cannabis use include gastrointestinal dysfunction (eg, cannabinoid hyperemesis syndrome), acute psychosis or exacerbation of an existing mood, anxiety, or psychotic disorder, and cardiovascular sequelae such as myocardial infarction or dysrhythmia.⁶ Potential long-term effects include neurocognitive impairment among adolescents who use cannabis,^7-9 worse outcomes in anxiety and mood disorders,¹⁰ schizophrenia,¹¹ cardiovascular sequelae,¹² chronic bronchitis,¹³ negative impact on reproductive function,¹⁴ and poor birth outcomes.^15-17

Hidden in plain sight. Many patients who use cannabis report that their primary care physicians are unaware of their cannabis consumption.¹⁸ Inadequate screening for cannabis can be attributed to time constraints, inconsistent definitions for problematic or risky cannabis use, and lack of guidance.^19,20 This article offers a more inclusive definition of “problematic cannabis use,” presents an up-to-date framework for evaluating it in the outpatient setting, and outlines potential interventions.

Your patient doesn’t meetthe DSM criteria, but …

Although it is important to identify cannabis use disorder (CUD) as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5; TABLE 1^21,22), consider also the immediate and long-term consequences of cannabis use for individuals who do not meet criteria for CUD. “Problematic cannabis use,” as we define it, may also involve (a) high-risk behaviors or (b) contraindicating medical or psychiatric comorbidities (TABLE 2^6-9).

CASE

The patient in our case exhibited 4 factors indicative of problematic cannabis use: heavy vape use, cannabis use more than twice a week, asthma, and a family history of schizophrenia.

Continue to: Guidelines for screening and evaluation

 

 

Guidelines for screening and evaluation

All primary care patients should be screened for problematic cannabis use, but especially teenagers, young adults, pregnant women, and patients with a mental health or substance use history. A variation of the single question used to screen for alcohol use disorder can be applied to cannabis use.²³ We recommend asking the initial question, “Over the past month, how many days a week on average have you used cannabis and products that contain THC?” Although some guidelines emphasize frequency of cannabis use when identifying problematic consumption,^24,25 duration of behavior and content of THC are also important indicators.¹⁹ Inquire about cannabis consumption over 1 month to differentiate sporadic use from longstanding persistent use.

Many patients who use cannabis report that their primary care physicians are unaware of their cannabis consumption.

Explore what types of cannabis the patient is ingesting and whether the patient uses cannabis heavily (4 or more times a week on average). Also determine the method of ingestion (eg, eating, vaping, smoking), THC-content (%, if known), and estimated weight of daily cannabis use in grams (TABLE 3²⁶). Although patients may not always be able to provide accurate answers, you can gain a sense of the quantity and forms of cannabis a patient is ingesting to inform future conversations on risk and harm reduction.²⁷

Assess a patient’s risk for harm

Cannabis use has the potential to cause immediate harm (linked to a single event of problematic cannabis use) and long-term harm (linked to a recurring pattern of problematic consumption). Cannabis can be especially harmful for patients with the following medical comorbidities or psychosocial factors, and should be avoided.

Cardiovascular disease. Cannabis is associated with an elevated risk for acute coronary syndrome and cardiovascular disease.²⁸ Long-term cannabis use is linked to increased frequency of anginal events, development of cardiac arrhythmias, peripheral arteritis, coronary vasospasms, and problems with platelet aggregation.^29,30 Strongly caution against cannabis use with patients who have a history of cardiovascular disease, orthostatic hypotension, tachyarrhythmia, or hypertension.

Pulmonary disease. Patients with pulmonary disease such as asthma may find cannabis helpful as a short-term bronchodilator.³¹ However, for patients with underlying pulmonary disease who also smoke cigarettes, strongly discourage the smoking of cannabis or hashish, as that may worsen asthma symptoms,³² increase risk of chronic bronchitis,³³ and increase cough, sputum production, and wheezing.³¹ There is currently insufficient evidence to suggest a positive association between cannabis use and the development of chronic obstructive pulmonary disease.³⁴

Continue to: Family history of psychotic disorders

Family history of psychotic disorders. Cannabis is associated with a dose-­dependent risk of schizophrenia, which is especially pronounced in patients with a family history of schizophrenia.³⁵ Among patients with a history of psychosis, heavy cannabis use has been associated with increased hospitalizations, increased positive symptoms, and more frequent relapses.^36-38

Pregnancy, current or planned. Some women turn to cannabis during pregnancy due to its antiemetic properties. However, perinatal exposure to cannabis is associated with significant risk to the offspring. Maternal cannabis use during the first and second trimesters of pregnancy is associated with decreased performance of the child on measures of function at 3 years of age.³⁹ In addition, cannabis consumption during pregnancy is linked to increased frequency of childhood behavioral issues, inattention, hyperactivity, and impulsivity.⁴⁰ Peripartum cannabis exposure can affect birth outcomes and is correlated with lower birth weight, incidence of preterm labor, and neonatal intensive care unit admission.^15-17,41 Of note, the THC concentration in breast milk peaks at 1 hour after the nursing mother inhales cannabis and typically dissipates after 4 hours.⁴²

Age < 25 years. Chronic heavy use of cannabis in those younger than 25 is associated with higher likelihood of developing CUD, lower IQ,⁹ lower level of educational attainment, lower income,⁴³ and decreased executive function.⁸

Substance use disorder history. Recreational cannabis use can hinder recovery from other substance use disorders.⁴⁴

Consider these 5 interventions

Physicians can address problematic cannabis use with a 5-pronged approach: (1) harm reduction, (2) motivational interviewing, (3) addressing underlying conditions, (4) mitigating withdrawal symptoms, and (5) referring to an addiction specialist (FIGURE).

Continue to: Harm reduction

 

 

Harm reduction

Harm reduction applies to all individuals who use cannabis but especially to problematic cannabis users. Ask users to abstain from cannabis for limited periods of time to see how such abstinence affects other areas of their life. While abstinence is a goal, be prepared to perform non-abstinence-based interventions. The goal of harm reduction is to encourage behaviors that minimize health risks to which cannabis users are exposed. Encourage patients to:

Abstain from driving while intoxicated. Cannabis use while driving slows reaction time,⁴⁵ impairs road tracking (driving with correct road position),⁴⁶ increases weaving,⁴⁷ and causes a loss of anticipatory reactions learned in driving practice.⁴⁸ Risk of crashing is significantly increased with elevated levels of THC, and driving within 1 hour of cannabis ingestion nearly doubles the risk of a crash.^49-51

Abstain from vaping THC-containing products. The Centers for Disease Control and Prevention recommends that patients minimize the use of THC-containing e-cigarette or vaping products in light of the thousands of reports in the United States of product-associated lung injury, which in some cases have led to death.⁵²

Clarify serving sizes and recognize delayed effects. Inexperienced cannabis users often are confused by recommended serving sizes for edible cannabis products. A typical cannabis-infused brownie may contain 100 mg of THC when the recommended serving size typically is 10 mg. THC content is included on the label of cannabis edibles purchased in state-regulated stores; these products are tested regularly in laboratories designated by the state.

To screen, ask, “Over the past month, how many days a week on average have you used cannabis and products that contain THC?”

Due to the delayed onset of THC’s effect, there have been numerous cases of patients taking a higher-than-intended dose of edible cannabis that caused acute intoxication and psychomedical sequelae leading to emergency hospital visits and, in some cases, death.^6,53 Individuals should start at a low dose and gradually work up to a higher dose as tolerated. Patients naïve to cannabis should be especially cautious when ingesting edible products.

Continue to: Abstain from cannabis with high THC content

Abstain from cannabis with high THC content. High-potency cannabis (> 10% THC) is associated with earlier onset of first-episode psychosis.^54,55

Motivational interviewing

Motivational interviewing (MI) is a psychosocial approach that emphasizes a patient’s self-efficacy and an interviewer’s positive feedback to collaboratively address substance use.⁵⁶ MI can be performed in short, discrete sessions. Such interventions can reduce the average number of days of cannabis use. One large-scale Cochrane review found that cognitive behavioral therapy (CBT), motivational enhancement therapy, or the 2 therapies combined most consistently reduced the frequency of cannabis use reported by patients at early follow-up.⁵⁷

Address underlying conditions

Some patients use cannabis to self-medicate for pain, insomnia, nausea, and anxiety. Identify these conditions and address them with first-line pharmacologic or psychotherapeutic interventions when possible. This is especially important for conditions in which long-term cannabis use may adversely impact outcomes, such as in posttraumatic stress disorder, anxiety, and mood disorders.^58-60 Little evidence exists for the use of cannabis as treatment of any primary psychiatric disorder.^61,62 Family physicians who are uncomfortable treating a specific underlying condition can consult specialists in pain management, sleep medicine, psychiatry, and neurology.

Mitigate withdrawal symptoms

Discontinuation of cannabis use may lead to withdrawal symptoms such as waxing and waning irritability, restlessness, sweating, aggression, anxiety, depressed mood, sleep disturbance, or changes in appetite.^63,64 These symptoms typically emerge within the first couple days of abstinence and can last up to 28 days.^63,64 Although the US Food and Drug Administration has not approved any medications for CUD treatment, and there are no established protocols for detoxification, there is evidence that CBT or medications such as gabapentin or zolpidem can reduce the intensity of withdrawal symptoms.^65,66

Refer to an addiction specialist

Consider referring patients with problematic cannabis use to an addiction specialist with expertise in psychopharmacologic and psychotherapeutic approaches to managing substance use.

Continue to: CASE

CASE

You renew Ms. F’s asthma medications, discuss her cannabis use, start her on a selective serotonin reuptake inhibitor, and refer her to an outpatient psychiatrist. Over the next few weeks, you and the outpatient psychiatrist employ brief motivational interviewing around cannabis use, and you provide psychoeducation around potential harms of use when driving and in light of the patient’s asthma.

Factors to consider in cannabis use include the method of ingestion, percentage of THC content, and times of day cannabis is used.

The patient’s anxiety symptoms decrease with up-titration of the SSRI by the outpatient psychiatrist and with enrollment in individual CBT. She is slowly able to taper off cannabis vaping with continued motivational interviewing and encouragement, despite withdrawal-induced anxiety and sleep disturbance.

CORRESPONDENCE
Michael Hsu, MD, Brigham & Women’s Hospital, 75 Francis Street, Boston, MA 02215; [email protected].