Geriatrics

Bisphosphonate therapy minimizes bone loss and reduces fracture risk by up to 50% in patients with osteoporosis,¹ but it is also associated with increased risks of osteonecrosis of the jaw and atypical femoral fracture. Although atypical femoral fractures are rare, they can have a devastating effect. Patient concern about this complication has contributed to a decrease in bisphosphonate use by about half in the last decade or so,^2,3 and we fear this could result in an increase in hip fracture rates.

In this article, we examine the evidence on bisphosphonate-associated atypical femoral fractures, including risks, pathogenesis, treatment, and prevention.

ATYPICAL FRACTURES INVOLVE THE FEMORAL SHAFT, NOT THE HEAD

An atypical femoral fracture is a transverse fracture of the femoral shaft (diaphysis), defined by both clinical criteria and radiographic appearance.

To be defined as atypical, a femoral fracture must meet 4 of the following 5 criteria⁴:

• Occurs with minimal or no trauma
• Has a predominantly transverse fracture line, originating at the lateral cortex and sometimes becoming oblique as it progresses medially across the femur
• Extends through both cortices and may be associated with a medial spike (complete fractures); or involves only the lateral cortex (incomplete fractures)
• Is noncomminuted or minimally comminuted
• Shows localized periosteal or endosteal thickening (termed “beaking” or “flaring”) of the lateral cortex at the fracture site.

Several minor features are also important but are not required, eg:

• Cortical thickening of the femoral shaft
• Unilateral or bilateral prodromal pain preceding the fracture
• Bilateral incomplete or complete femoral diaphysis fractures
• Delayed fracture healing.

Atypical femoral fracture can occur anywhere along the shaft, from just distal to the lesser trochanter to just proximal to the supracondylar flare. However, most occur in 2 areas, with 1 cluster centered at about 41 mm from the lesser trochanter (more common in relatively younger patients) and the other at 187 mm.⁵

ABSOLUTE RISK IS LOW BUT INCREASES WITH LONGER USE

Atypical femoral fractures are rare. Schilcher et al⁶ reviewed radiographs of 1,234 women who had a subtrochanteric or shaft fracture and found 59 (4.6%) of fractures were atypical. In a systematic review of 14 studies,⁷ the incidence ranged from 3.0 to 9.8 cases per 100,000 patient-years.

Furthermore, not all atypical femoral fractures are in bisphosphonate users: 7.4% were in nonusers in 1 series⁸ and 22% in another.⁹

Nevertheless, most studies show that bis­phosphonate use increases the incidence of atypical femoral fracture, and the incidence increases with duration of use, especially after 3 years.⁷

An international task force of the American Society for Bone and Mineral Research listed the absolute risk as between 3.2 and 50 cases per 100,000 patient-years, with longer use (> 5 years) increasing the risk to about 100 per 100,000 patient-years.⁴ After stopping bis­phosphonate therapy, the risk diminished by 70% per year.⁹

In another study, for 0.1 to 1.9 years of therapy, the age-adjusted atypical fracture rates were 1.78 per 100,000 per year (95% confidence interval [CI] 1.5–2.0), increasing to 113.1 per 100,000 per year (95% CI 69.3–156.8) with exposure from 8 to 9.9 years.¹⁰

A case-control study found that more than 5 years of bisphosphonate use increased the fracture risk by an odds ratio of 2.74 (95% CI 1.25–6.02).¹¹

The incidence of typical femoral fracture was higher in those who adhered better to their oral bisphosphonate regimen in some studies,¹² but the opposite was true in others.¹³

The benefits of bisphosphonate therapy in reducing fracture risk, however, outweigh the risk of atypical fracture.⁴

We do not know whether the rate of atypical femoral fracture is increasing. A review of Kaiser Permanente Northwest records found that the rates of atypical femoral shaft fracture had remained stable from 1996 to 2009. However, 61.9% of patients who met the strict radiographic criteria had taken oral bisphosphonates.¹⁴ These data suggest that bisphosphonate use has not increased the overall population-based risk for subtrochanteric and femoral shaft fractures, but that bisphosphonates and other risk factors may have increased the likelihood that such fractures will exhibit atypical radiographic features.

A population-based study in Denmark¹³ found that alendronate use longer than 10 years was associated with an adjusted 30% lower risk of hip fracture and no increase in the risk of subtrochanteric and femoral shaft fracture. In addition, the risk of subtrochanteric and femoral shaft fracture was lower with high adherence to alendronate treatment (based on medication possession ratio > 80%) compared with low adherence (ratio < 50%) (odds ratio 0.88, 95% CI 0.77–0.99). The risk was not increased in current vs past users.

The Danish study¹³ used the coding of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) to identify subtrochanteric and femoral shaft fractures without radiologic review for atypical radiographic features. The lack of specific ICD-10 coding for subtrochanteric and femoral shaft fractures with atypical radiographic features has limited our knowledge of their incidence.

 

 

Contralateral fracture in more than one-fourth of cases

After an atypical femoral fracture, patients have a significant risk of fracture on the contralateral side. In a case-control study, 28% of patients with atypical femoral fracture suffered a contralateral fracture, compared with 0.9% of patients presenting with a typical fracture pattern (odds ratio 42.6, 95% CI 12.8–142.4).¹⁵

Contralateral fracture occurs from 1 month to 4 years after the index atypical femoral fracture.¹⁶

There are reports of bisphosphonate-related low-impact fractures in other sites such as the tibia¹⁷ and forearm.¹⁸ However, they may be too rare to warrant screening.

Mortality rates

A Swedish database study found that patients with atypical femoral fractures, whether bisphosphonate users or nonusers, do not have higher mortality rates than patients with ordinary subtrochanteric or femoral shaft fractures.¹⁹ Furthermore, the mortality rates for those with atypical femoral fracture were similar to rates in the general population. In contrast, patients with an ordinary femoral fracture had a higher mortality risk than the general population.¹⁹

Other studies suggest that atypical femoral fracture may be associated with a less favorable prognosis in older patients,²⁰ but this could be due to differences in demographics, treatment adherence, or postfracture care.²¹

In addition, functional outcomes as measured by independent mobility at discharge and at 3 months were comparable between patients with atypical fracture and those with typical fracture.²²

IMAGING STUDIES

If a long-term bisphosphonate user presents with hip, thigh, or groin pain, imaging studies are recommended.

Plain radiography

Radiography is usually the first step and should include a frontal view of the pelvis (Figure 1) and 2 views of the full length of each femur. If radiography is not conclusive, bone scan or magnetic resonance imaging (MRI) should be considered.

A linear cortex transverse fracture pattern and focal lateral cortical thickening are the most sensitive and specific radiographic features.^23,24 Because of the risk of fracture on the contralateral side, radiographic study of that side is recommended as well.

Computed tomography

Computed tomography (CT) is not sensitive for early stress fractures and, given the radiation burden, is not recommended in the workup of atypical fracture.

Bone scanning

Bone scanning using technetium 99m-labeled methylene diphosphonate with a gamma camera shows active bone turnover. Stress fractures and atypical femoral fractures are most easily identified in the third (delayed) phase of the bone scan. Although bone scanning is highly sensitive, the specificity is limited by lack of spatial resolution. Atypical femoral fracture appears as increased activity in the subtrochanteric region with a predilection for the lateral cortex.

Dual-energy x-ray absorptiometry

Conventional dual-energy x-ray absorptiometry (DXA) extends only to 1 to 2 cm below the lesser trochanter and can therefore miss atypical fractures, which usually occur farther down. The overall detection rate for DXA was 61% in a sample of 33 patients.²⁵

Newer scanners can look at the entire femoral shaft.²⁶ In addition, newer software can quantify focal thickening (beaking) of the lateral cortex and screen patients who have no symptoms. The results of serial measurements can be graphed so that the practitioner can view trends to help assess or rule out potential asymptomatic atypical femoral fracture.

A localized reaction (periosteal thickening of the lateral cortex or beaking) often precedes atypical femoral fracture. A 2017 study reported that patients with high localized reaction (mean height 3.3 mm) that was of the pointed type and was accompanied by prodromal pain had an increased risk of complete or incomplete atypical femoral fracture at that site.²⁷ This finding is used by the newer DXA software. The predictive value of beaking on extended femoral DXA may be as high as 83%.²⁶

Magnetic resonance imaging

The MRI characteristics of atypical femoral fracture are similar to those of other stress fractures except that there is a lateral-to-medial pattern rather than a medial pattern. The earliest findings include periosteal reaction about the lateral cortex with a normal marrow signal.

MRI may be of particular benefit in patients with known atypical femoral fracture to screen the contralateral leg. It should image the entire length of both femurs. Contrast enhancement is not needed.

Regardless of whether initial findings were discovered on conventional radiographs or DXA, MRI confirmation is needed. Radio­nuclide bone scanning is currently not recommended because it lacks specificity. Combination imaging is recommended, with either radiography plus MRI or DXA plus MRI.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of atypical femoral fracture includes stress fracture, pathologic fracture, hypophosphatasia, and osteogenesis imperfecta.²⁸ Hypophosphatemic osteomalacia can cause Looser zones, which can be confused with atypical femoral fractures but usually occur on the medial side.⁴ Stress fracture of the femur can occur below the lesser trochanter but usually begins in the medial, not the lateral, cortex.

Pathologic fractures from underlying osseous lesions can mimic the cortical beaking of bisphosphonate-related fracture, but they usually show the associated underlying lucent lesion and poorly defined margins. A sinus tract along the region of a chronic osteomyelitis may also appear similar.

Hypophosphatasia is an inborn error of metabolism caused by a loss-of-function mutation in the gene encoding alkaline phosphatase, resulting in pyrophosphate accumulation and causing osteomalacia from impaired mineralization. This can result in femoral pseudofracture that is often bilateral and occurs in the subtrochanteric region.²⁹

 

 

ADDITIONAL RISK FACTORS

Patients with atypical femoral fracture are generally a heterogeneous group, but there are risk factors to note other than bisphosphonate exposure.

Asian women had a risk 8 times higher than white women in 1 study.³⁰

Bone geometry. Mahjoub et al⁸ reported that compared with controls, patients with atypical femoral fracture had greater offset of the femoral shaft from the center of rotation of the femoral head, a more acute angle between the femoral neck and shaft, and greater proximal cortical thickness.

Medications. In addition to bisphosphonates, other drugs associated with atypical femoral fracture include RANK-ligand inhibitors such as denosumab (another drug for osteoporosis),³¹ glucocorticoids,^32,33 and proton pump inhibitors.^32,33

Genetics. Three sisters with atypical femoral fracture were found to have 37 rare mutations in 34 genes, including one in the GGPS1 gene, which codes for geranylgeranyl pyrophosphate synthase—an enzyme that bisphosphonates inhibit.³⁴

Medical conditions other than osteoporosis include collagen diseases, chronic pulmonary disease, asthma, rheumatoid arthritis, and diabetes.³⁵

Clinical recommendations

Current recommendations are to reevaluate bisphosphonate use in patients with osteoporosis after 5 or more years of therapy.³⁶

Given that patients with osteoporosis are at increased risk of typical fracture, those at higher risk should be considered for continued bisphosphonate therapy. Factors for high risk include the following:

• History of fracture on therapy
• Hip T score –2.5 or lower
• Older age (≥ 70)
• Other strong risk factors for fracture such as smoking, alcohol use, corticosteroid use, rheumatoid arthritis, and family history
• World Health Organization FRAX fracture risk score above the country-specific threshold.

Those at lower risk should be considered for a 2- to 3-year bisphosphonate holiday with periodic reevaluation of bone density and, possibly, bone markers.³⁶

WHAT IS THE UNDERLYING PATHOPHYSIOLOGY?

The mechanism by which bisphosphonates increase the risk of atypical femoral fracture is not clear. These drugs work by suppressing bone turnover; however, in theory, prolonged use could suppress it too much and increase bone fragility.

One hypothesis is that bisphosphonates impair the toughening of cortical bone, an important barrier to clinical fracture. This is supported by a study that found bisphosphonate users with atypical femoral fracture had deficits in intrinsic and extrinsic bone toughness, perhaps due to treatment-related increases in matrix mineralization.³⁷ Although this study and others showed an increase in matrix mineralization and reduced mineralization heterogeneity with bisphosphonate use,^38,39 it is unclear whether such changes contributed to reduced toughness or to atypical femoral fracture.

Changes in the skeletal geometry of the lower limb such as femoral neck-shaft angle and femoral curvature alter the stresses and strains experienced by the femoral diaphysis with loading. Because the incidence of incomplete atypical femoral fracture is much greater than that of complete fracture, most incomplete atypical femoral fractures heal before the fracture progresses.

Ultimately, all fractures, including atypical femoral fractures, occur when mechanical stress and strain exceed bone strength.

Antiresorptive drugs such as bisphosphonates, estrogen, calcitonin, and RANK ligand inhibitors prevent hip fracture by increasing the strength of the proximal femur—perhaps at the expense of the strength (or toughness) of the subtrochanteric shaft. It is also possible that treatment-related increases in hip strength (and reduced hip fracture rates) promote or sustain the transfer of stress and strain to femoral regions that experience lesser or no increases in strength from treatment, which likely includes the shaft.^40,41

CT studies in Japanese women with osteoporosis have shown that 2 years of zoledronate therapy had greater effects in the hip than in the femoral shaft, with significant increases in cortical thickness and volumetric bone mineral density at the femoral neck and intertrochanteric region compared with baseline.⁴² But zoledronate did not increase femoral shaft cortical thickness and caused only a minor increase in femoral shaft volumetric bone mineral density. Fracture patterns may have depended on damage and effects of bone turnover on mass and structure.

This hypothetical scenario portrays a possible “hip survival bias” mechanism for atypical femoral fracture, with the association with antiresorptive drugs arising from greater stress and strain in cortical regions where these fractures occur rather than from treatment-related reductions in cortical bone strength or toughness.

PRODROMAL PAIN IS COMMON

From 32% to 76% of patients who have incomplete or developing atypical femoral fracture present with a prodrome of groin or hip pain.^4,43 Prodromal pain occurs any time from 2 weeks to several years before the fracture, presenting as pain in the anterior or lateral thigh or in the groin.

Prodromal pain in a patient on antiresorptive therapy should be a signal for the clinician to obtain a radiograph of the hip and to look for contralateral symptoms and fractures. The most common mechanism of injury appears to be a ground-level fall or even a nontraumatic activity such as walking or stepping off a curb.

MEDICAL MANAGEMENT

In bisphosphonate users with radiographic evidence of atypical femoral fracture, the bis­phosphonate should be discontinued and the patient assessed for calcium and vitamin D deficiency, with supplements prescribed if needed.⁴

For patients with incomplete fracture and persistent pain after 3 months of medical management, prophylactic surgical nail fixation is recommended to prevent complete fracture.

Teriparatide, which has been associated with enhanced bone fracture healing, is a possible treatment to promote healing of atypical femoral fracture, either alone or as an adjunct to surgical fixation. A systematic review published in 2015 supported the use of teriparatide for enhancing fracture healing in atypical femoral fracture.⁴⁴ In addition, a 10-patient series⁴⁵ showed that incomplete fractures without radiolucent lines responded to teriparatide alone, whereas those with radiolucent lines needed intramedullary nailing.

These results suggest that teriparatide works best when the fracture site is stable, either inherently or with surgical fixation.

ORTHOPEDIC CARE

Orthopedic care for atypical femoral fracture differs depending on whether the patient experiences pain and whether the fracture is incomplete or complete. Figure 2 shows a treatment algorithm for atypical femoral fracture.

These are difficult fractures to manage, complicated by delayed healing in the elderly, complex displacement patterns, altered bone geometry, and risk of fracture in the opposite limb, all of which raise questions about recommending protected weight-bearing exercise.

Furthermore, atypical femoral fracture is often associated with increased anterolateral bowing of the femur, making it difficult to insert an intramedullary nail: the radius of curvature of the bone is shorter than that of a standard femoral nail. This mismatch can lead to intraoperative complications such as iatrogenic fracture during prophylactic nailing, malunion from excess straightening of the femur (which can itself lead to leg length discrepancy), and gapping of the fracture site, particularly on the medial side.

 

 

Intramedullary nailing for complete fracture

Intramedullary nailing is the first-line treatment for complete atypical femoral fracture, although the risk of delayed healing and revision surgery may be somewhat higher than with typical femoral fracture.⁴⁶ Prophylactic intramedullary nailing should be considered for a patient with intractable pain.²

A radiograph of the opposite leg should be obtained routinely, looking for an asymptomatic fracture. Bisphosphonates should be discontinued and calcium and vitamin D continued. Teriparatide therapy can be considered as an alternative treatment.

Conservative management for incomplete fracture without pain

Incomplete atypical femoral fracture unaccompanied by pain can be followed conservatively.⁴⁷ In addition to stopping antiresorptive therapy, patients need to avoid high-impact and repetitive-impact activities such as jumping or running. If pain occurs, patients should begin protected weight-bearing exercise.

Treatment is uncertain for incomplete fracture with pain

For patients with incomplete atypical femoral fracture and pain, treatment is controversial. Regimens that include 2 to 3 months of protected weight-bearing exercise, a full metabolic bone workup, calcium and vitamin D supplementation, and anabolic bone agents have produced some success. Some authors have reported poor results from conservative care, with few patients achieving pain relief or signs of complete healing.^48,49 Additionally, if an incomplete fracture is found in the opposite femur, protected weight-bearing of both legs may not be possible.

Patients with incomplete fracture should be monitored regularly with radiography and physical examination. If there is progression of the fracture, escalation of pain, or failure to heal within 2 to 3 months, then surgical treatment is necessary.

Prophylactic placement of an intramedullary nail to prevent completion of the fracture and allow a return to full weight-bearing is generally advised.⁵⁰ A long locking plate can be used if bone deformities make it difficult to place an intramedullary nail; however, nails are preferred because they allow formation of endochondral callus, which can be helpful in these difficult-to-heal fractures.

Results from retrospective reviews have shown that surgically treated patients with bis­phosphonate-associated incomplete atypical femoral fracture were more likely than those treated nonsurgically to be pain-free (81% vs 64%) and have radiographic healing (100% vs 18% at final follow-up).⁴⁶ Results have also been positive for those with complete atypical femoral fracture. At 6 months, 64% of surgically treated patients were pain-free and 98% were radiographically healed.⁵¹

The unusual geometry of the femur in patients with atypical femoral fracture and the presence of intramedullary cortical callus makes the placement of an intramedullary femoral rod more complex than in typical femoral fracture.⁸

Intramedullary nailing of atypical femoral fracture is a challenge for even the most experienced surgeon, and vigilance is imperative to avoid iatrogenic fracture and malunion.

MANY QUESTIONS REMAIN

We need more studies on the pathophysiology of bisphosphonate-associated atypical femoral fracture, the value of periodic screening with DXA, and which factors predict high risk (eg, Asian ethnicity, use of certain medications, femoral geometry). In addition, we need more data on the success of conservative management of incomplete fracture, including use of teriparatide.

Bisphosphonate therapy minimizes bone loss and reduces fracture risk by up to 50% in patients with osteoporosis,¹ but it is also associated with increased risks of osteonecrosis of the jaw and atypical femoral fracture. Although atypical femoral fractures are rare, they can have a devastating effect. Patient concern about this complication has contributed to a decrease in bisphosphonate use by about half in the last decade or so,^2,3 and we fear this could result in an increase in hip fracture rates.

In this article, we examine the evidence on bisphosphonate-associated atypical femoral fractures, including risks, pathogenesis, treatment, and prevention.

ATYPICAL FRACTURES INVOLVE THE FEMORAL SHAFT, NOT THE HEAD

An atypical femoral fracture is a transverse fracture of the femoral shaft (diaphysis), defined by both clinical criteria and radiographic appearance.

To be defined as atypical, a femoral fracture must meet 4 of the following 5 criteria⁴:

• Occurs with minimal or no trauma
• Has a predominantly transverse fracture line, originating at the lateral cortex and sometimes becoming oblique as it progresses medially across the femur
• Extends through both cortices and may be associated with a medial spike (complete fractures); or involves only the lateral cortex (incomplete fractures)
• Is noncomminuted or minimally comminuted
• Shows localized periosteal or endosteal thickening (termed “beaking” or “flaring”) of the lateral cortex at the fracture site.

Several minor features are also important but are not required, eg:

• Cortical thickening of the femoral shaft
• Unilateral or bilateral prodromal pain preceding the fracture
• Bilateral incomplete or complete femoral diaphysis fractures
• Delayed fracture healing.

Atypical femoral fracture can occur anywhere along the shaft, from just distal to the lesser trochanter to just proximal to the supracondylar flare. However, most occur in 2 areas, with 1 cluster centered at about 41 mm from the lesser trochanter (more common in relatively younger patients) and the other at 187 mm.⁵

ABSOLUTE RISK IS LOW BUT INCREASES WITH LONGER USE

Atypical femoral fractures are rare. Schilcher et al⁶ reviewed radiographs of 1,234 women who had a subtrochanteric or shaft fracture and found 59 (4.6%) of fractures were atypical. In a systematic review of 14 studies,⁷ the incidence ranged from 3.0 to 9.8 cases per 100,000 patient-years.

Furthermore, not all atypical femoral fractures are in bisphosphonate users: 7.4% were in nonusers in 1 series⁸ and 22% in another.⁹

Nevertheless, most studies show that bis­phosphonate use increases the incidence of atypical femoral fracture, and the incidence increases with duration of use, especially after 3 years.⁷

An international task force of the American Society for Bone and Mineral Research listed the absolute risk as between 3.2 and 50 cases per 100,000 patient-years, with longer use (> 5 years) increasing the risk to about 100 per 100,000 patient-years.⁴ After stopping bis­phosphonate therapy, the risk diminished by 70% per year.⁹

In another study, for 0.1 to 1.9 years of therapy, the age-adjusted atypical fracture rates were 1.78 per 100,000 per year (95% confidence interval [CI] 1.5–2.0), increasing to 113.1 per 100,000 per year (95% CI 69.3–156.8) with exposure from 8 to 9.9 years.¹⁰

A case-control study found that more than 5 years of bisphosphonate use increased the fracture risk by an odds ratio of 2.74 (95% CI 1.25–6.02).¹¹

The incidence of typical femoral fracture was higher in those who adhered better to their oral bisphosphonate regimen in some studies,¹² but the opposite was true in others.¹³

The benefits of bisphosphonate therapy in reducing fracture risk, however, outweigh the risk of atypical fracture.⁴

We do not know whether the rate of atypical femoral fracture is increasing. A review of Kaiser Permanente Northwest records found that the rates of atypical femoral shaft fracture had remained stable from 1996 to 2009. However, 61.9% of patients who met the strict radiographic criteria had taken oral bisphosphonates.¹⁴ These data suggest that bisphosphonate use has not increased the overall population-based risk for subtrochanteric and femoral shaft fractures, but that bisphosphonates and other risk factors may have increased the likelihood that such fractures will exhibit atypical radiographic features.

A population-based study in Denmark¹³ found that alendronate use longer than 10 years was associated with an adjusted 30% lower risk of hip fracture and no increase in the risk of subtrochanteric and femoral shaft fracture. In addition, the risk of subtrochanteric and femoral shaft fracture was lower with high adherence to alendronate treatment (based on medication possession ratio > 80%) compared with low adherence (ratio < 50%) (odds ratio 0.88, 95% CI 0.77–0.99). The risk was not increased in current vs past users.

The Danish study¹³ used the coding of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) to identify subtrochanteric and femoral shaft fractures without radiologic review for atypical radiographic features. The lack of specific ICD-10 coding for subtrochanteric and femoral shaft fractures with atypical radiographic features has limited our knowledge of their incidence.

 

 

Contralateral fracture in more than one-fourth of cases

After an atypical femoral fracture, patients have a significant risk of fracture on the contralateral side. In a case-control study, 28% of patients with atypical femoral fracture suffered a contralateral fracture, compared with 0.9% of patients presenting with a typical fracture pattern (odds ratio 42.6, 95% CI 12.8–142.4).¹⁵

Contralateral fracture occurs from 1 month to 4 years after the index atypical femoral fracture.¹⁶

There are reports of bisphosphonate-related low-impact fractures in other sites such as the tibia¹⁷ and forearm.¹⁸ However, they may be too rare to warrant screening.

Mortality rates

A Swedish database study found that patients with atypical femoral fractures, whether bisphosphonate users or nonusers, do not have higher mortality rates than patients with ordinary subtrochanteric or femoral shaft fractures.¹⁹ Furthermore, the mortality rates for those with atypical femoral fracture were similar to rates in the general population. In contrast, patients with an ordinary femoral fracture had a higher mortality risk than the general population.¹⁹

Other studies suggest that atypical femoral fracture may be associated with a less favorable prognosis in older patients,²⁰ but this could be due to differences in demographics, treatment adherence, or postfracture care.²¹

In addition, functional outcomes as measured by independent mobility at discharge and at 3 months were comparable between patients with atypical fracture and those with typical fracture.²²

IMAGING STUDIES

If a long-term bisphosphonate user presents with hip, thigh, or groin pain, imaging studies are recommended.

Plain radiography

Radiography is usually the first step and should include a frontal view of the pelvis (Figure 1) and 2 views of the full length of each femur. If radiography is not conclusive, bone scan or magnetic resonance imaging (MRI) should be considered.

A linear cortex transverse fracture pattern and focal lateral cortical thickening are the most sensitive and specific radiographic features.^23,24 Because of the risk of fracture on the contralateral side, radiographic study of that side is recommended as well.

Computed tomography

Computed tomography (CT) is not sensitive for early stress fractures and, given the radiation burden, is not recommended in the workup of atypical fracture.

Bone scanning

Bone scanning using technetium 99m-labeled methylene diphosphonate with a gamma camera shows active bone turnover. Stress fractures and atypical femoral fractures are most easily identified in the third (delayed) phase of the bone scan. Although bone scanning is highly sensitive, the specificity is limited by lack of spatial resolution. Atypical femoral fracture appears as increased activity in the subtrochanteric region with a predilection for the lateral cortex.

Dual-energy x-ray absorptiometry

Conventional dual-energy x-ray absorptiometry (DXA) extends only to 1 to 2 cm below the lesser trochanter and can therefore miss atypical fractures, which usually occur farther down. The overall detection rate for DXA was 61% in a sample of 33 patients.²⁵

Newer scanners can look at the entire femoral shaft.²⁶ In addition, newer software can quantify focal thickening (beaking) of the lateral cortex and screen patients who have no symptoms. The results of serial measurements can be graphed so that the practitioner can view trends to help assess or rule out potential asymptomatic atypical femoral fracture.

A localized reaction (periosteal thickening of the lateral cortex or beaking) often precedes atypical femoral fracture. A 2017 study reported that patients with high localized reaction (mean height 3.3 mm) that was of the pointed type and was accompanied by prodromal pain had an increased risk of complete or incomplete atypical femoral fracture at that site.²⁷ This finding is used by the newer DXA software. The predictive value of beaking on extended femoral DXA may be as high as 83%.²⁶

Magnetic resonance imaging

The MRI characteristics of atypical femoral fracture are similar to those of other stress fractures except that there is a lateral-to-medial pattern rather than a medial pattern. The earliest findings include periosteal reaction about the lateral cortex with a normal marrow signal.

MRI may be of particular benefit in patients with known atypical femoral fracture to screen the contralateral leg. It should image the entire length of both femurs. Contrast enhancement is not needed.

Regardless of whether initial findings were discovered on conventional radiographs or DXA, MRI confirmation is needed. Radio­nuclide bone scanning is currently not recommended because it lacks specificity. Combination imaging is recommended, with either radiography plus MRI or DXA plus MRI.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of atypical femoral fracture includes stress fracture, pathologic fracture, hypophosphatasia, and osteogenesis imperfecta.²⁸ Hypophosphatemic osteomalacia can cause Looser zones, which can be confused with atypical femoral fractures but usually occur on the medial side.⁴ Stress fracture of the femur can occur below the lesser trochanter but usually begins in the medial, not the lateral, cortex.

Pathologic fractures from underlying osseous lesions can mimic the cortical beaking of bisphosphonate-related fracture, but they usually show the associated underlying lucent lesion and poorly defined margins. A sinus tract along the region of a chronic osteomyelitis may also appear similar.

Hypophosphatasia is an inborn error of metabolism caused by a loss-of-function mutation in the gene encoding alkaline phosphatase, resulting in pyrophosphate accumulation and causing osteomalacia from impaired mineralization. This can result in femoral pseudofracture that is often bilateral and occurs in the subtrochanteric region.²⁹

 

 

ADDITIONAL RISK FACTORS

Patients with atypical femoral fracture are generally a heterogeneous group, but there are risk factors to note other than bisphosphonate exposure.

Asian women had a risk 8 times higher than white women in 1 study.³⁰

Bone geometry. Mahjoub et al⁸ reported that compared with controls, patients with atypical femoral fracture had greater offset of the femoral shaft from the center of rotation of the femoral head, a more acute angle between the femoral neck and shaft, and greater proximal cortical thickness.

Medications. In addition to bisphosphonates, other drugs associated with atypical femoral fracture include RANK-ligand inhibitors such as denosumab (another drug for osteoporosis),³¹ glucocorticoids,^32,33 and proton pump inhibitors.^32,33

Genetics. Three sisters with atypical femoral fracture were found to have 37 rare mutations in 34 genes, including one in the GGPS1 gene, which codes for geranylgeranyl pyrophosphate synthase—an enzyme that bisphosphonates inhibit.³⁴

Medical conditions other than osteoporosis include collagen diseases, chronic pulmonary disease, asthma, rheumatoid arthritis, and diabetes.³⁵

Clinical recommendations

Current recommendations are to reevaluate bisphosphonate use in patients with osteoporosis after 5 or more years of therapy.³⁶

Given that patients with osteoporosis are at increased risk of typical fracture, those at higher risk should be considered for continued bisphosphonate therapy. Factors for high risk include the following:

• History of fracture on therapy
• Hip T score –2.5 or lower
• Older age (≥ 70)
• Other strong risk factors for fracture such as smoking, alcohol use, corticosteroid use, rheumatoid arthritis, and family history
• World Health Organization FRAX fracture risk score above the country-specific threshold.

Those at lower risk should be considered for a 2- to 3-year bisphosphonate holiday with periodic reevaluation of bone density and, possibly, bone markers.³⁶

WHAT IS THE UNDERLYING PATHOPHYSIOLOGY?

The mechanism by which bisphosphonates increase the risk of atypical femoral fracture is not clear. These drugs work by suppressing bone turnover; however, in theory, prolonged use could suppress it too much and increase bone fragility.

One hypothesis is that bisphosphonates impair the toughening of cortical bone, an important barrier to clinical fracture. This is supported by a study that found bisphosphonate users with atypical femoral fracture had deficits in intrinsic and extrinsic bone toughness, perhaps due to treatment-related increases in matrix mineralization.³⁷ Although this study and others showed an increase in matrix mineralization and reduced mineralization heterogeneity with bisphosphonate use,^38,39 it is unclear whether such changes contributed to reduced toughness or to atypical femoral fracture.

Changes in the skeletal geometry of the lower limb such as femoral neck-shaft angle and femoral curvature alter the stresses and strains experienced by the femoral diaphysis with loading. Because the incidence of incomplete atypical femoral fracture is much greater than that of complete fracture, most incomplete atypical femoral fractures heal before the fracture progresses.

Ultimately, all fractures, including atypical femoral fractures, occur when mechanical stress and strain exceed bone strength.

Antiresorptive drugs such as bisphosphonates, estrogen, calcitonin, and RANK ligand inhibitors prevent hip fracture by increasing the strength of the proximal femur—perhaps at the expense of the strength (or toughness) of the subtrochanteric shaft. It is also possible that treatment-related increases in hip strength (and reduced hip fracture rates) promote or sustain the transfer of stress and strain to femoral regions that experience lesser or no increases in strength from treatment, which likely includes the shaft.^40,41

CT studies in Japanese women with osteoporosis have shown that 2 years of zoledronate therapy had greater effects in the hip than in the femoral shaft, with significant increases in cortical thickness and volumetric bone mineral density at the femoral neck and intertrochanteric region compared with baseline.⁴² But zoledronate did not increase femoral shaft cortical thickness and caused only a minor increase in femoral shaft volumetric bone mineral density. Fracture patterns may have depended on damage and effects of bone turnover on mass and structure.

This hypothetical scenario portrays a possible “hip survival bias” mechanism for atypical femoral fracture, with the association with antiresorptive drugs arising from greater stress and strain in cortical regions where these fractures occur rather than from treatment-related reductions in cortical bone strength or toughness.

PRODROMAL PAIN IS COMMON

From 32% to 76% of patients who have incomplete or developing atypical femoral fracture present with a prodrome of groin or hip pain.^4,43 Prodromal pain occurs any time from 2 weeks to several years before the fracture, presenting as pain in the anterior or lateral thigh or in the groin.

Prodromal pain in a patient on antiresorptive therapy should be a signal for the clinician to obtain a radiograph of the hip and to look for contralateral symptoms and fractures. The most common mechanism of injury appears to be a ground-level fall or even a nontraumatic activity such as walking or stepping off a curb.

MEDICAL MANAGEMENT

In bisphosphonate users with radiographic evidence of atypical femoral fracture, the bis­phosphonate should be discontinued and the patient assessed for calcium and vitamin D deficiency, with supplements prescribed if needed.⁴

For patients with incomplete fracture and persistent pain after 3 months of medical management, prophylactic surgical nail fixation is recommended to prevent complete fracture.

Teriparatide, which has been associated with enhanced bone fracture healing, is a possible treatment to promote healing of atypical femoral fracture, either alone or as an adjunct to surgical fixation. A systematic review published in 2015 supported the use of teriparatide for enhancing fracture healing in atypical femoral fracture.⁴⁴ In addition, a 10-patient series⁴⁵ showed that incomplete fractures without radiolucent lines responded to teriparatide alone, whereas those with radiolucent lines needed intramedullary nailing.

These results suggest that teriparatide works best when the fracture site is stable, either inherently or with surgical fixation.

ORTHOPEDIC CARE

Orthopedic care for atypical femoral fracture differs depending on whether the patient experiences pain and whether the fracture is incomplete or complete. Figure 2 shows a treatment algorithm for atypical femoral fracture.

These are difficult fractures to manage, complicated by delayed healing in the elderly, complex displacement patterns, altered bone geometry, and risk of fracture in the opposite limb, all of which raise questions about recommending protected weight-bearing exercise.

Furthermore, atypical femoral fracture is often associated with increased anterolateral bowing of the femur, making it difficult to insert an intramedullary nail: the radius of curvature of the bone is shorter than that of a standard femoral nail. This mismatch can lead to intraoperative complications such as iatrogenic fracture during prophylactic nailing, malunion from excess straightening of the femur (which can itself lead to leg length discrepancy), and gapping of the fracture site, particularly on the medial side.

 

 

Intramedullary nailing for complete fracture

Intramedullary nailing is the first-line treatment for complete atypical femoral fracture, although the risk of delayed healing and revision surgery may be somewhat higher than with typical femoral fracture.⁴⁶ Prophylactic intramedullary nailing should be considered for a patient with intractable pain.²

A radiograph of the opposite leg should be obtained routinely, looking for an asymptomatic fracture. Bisphosphonates should be discontinued and calcium and vitamin D continued. Teriparatide therapy can be considered as an alternative treatment.

Conservative management for incomplete fracture without pain

Incomplete atypical femoral fracture unaccompanied by pain can be followed conservatively.⁴⁷ In addition to stopping antiresorptive therapy, patients need to avoid high-impact and repetitive-impact activities such as jumping or running. If pain occurs, patients should begin protected weight-bearing exercise.

Treatment is uncertain for incomplete fracture with pain

For patients with incomplete atypical femoral fracture and pain, treatment is controversial. Regimens that include 2 to 3 months of protected weight-bearing exercise, a full metabolic bone workup, calcium and vitamin D supplementation, and anabolic bone agents have produced some success. Some authors have reported poor results from conservative care, with few patients achieving pain relief or signs of complete healing.^48,49 Additionally, if an incomplete fracture is found in the opposite femur, protected weight-bearing of both legs may not be possible.

Patients with incomplete fracture should be monitored regularly with radiography and physical examination. If there is progression of the fracture, escalation of pain, or failure to heal within 2 to 3 months, then surgical treatment is necessary.

Prophylactic placement of an intramedullary nail to prevent completion of the fracture and allow a return to full weight-bearing is generally advised.⁵⁰ A long locking plate can be used if bone deformities make it difficult to place an intramedullary nail; however, nails are preferred because they allow formation of endochondral callus, which can be helpful in these difficult-to-heal fractures.

Results from retrospective reviews have shown that surgically treated patients with bis­phosphonate-associated incomplete atypical femoral fracture were more likely than those treated nonsurgically to be pain-free (81% vs 64%) and have radiographic healing (100% vs 18% at final follow-up).⁴⁶ Results have also been positive for those with complete atypical femoral fracture. At 6 months, 64% of surgically treated patients were pain-free and 98% were radiographically healed.⁵¹

The unusual geometry of the femur in patients with atypical femoral fracture and the presence of intramedullary cortical callus makes the placement of an intramedullary femoral rod more complex than in typical femoral fracture.⁸

Intramedullary nailing of atypical femoral fracture is a challenge for even the most experienced surgeon, and vigilance is imperative to avoid iatrogenic fracture and malunion.

MANY QUESTIONS REMAIN

We need more studies on the pathophysiology of bisphosphonate-associated atypical femoral fracture, the value of periodic screening with DXA, and which factors predict high risk (eg, Asian ethnicity, use of certain medications, femoral geometry). In addition, we need more data on the success of conservative management of incomplete fracture, including use of teriparatide.

Bisphosphonate therapy minimizes bone loss and reduces fracture risk by up to 50% in patients with osteoporosis,¹ but it is also associated with increased risks of osteonecrosis of the jaw and atypical femoral fracture. Although atypical femoral fractures are rare, they can have a devastating effect. Patient concern about this complication has contributed to a decrease in bisphosphonate use by about half in the last decade or so,^2,3 and we fear this could result in an increase in hip fracture rates.

In this article, we examine the evidence on bisphosphonate-associated atypical femoral fractures, including risks, pathogenesis, treatment, and prevention.

ATYPICAL FRACTURES INVOLVE THE FEMORAL SHAFT, NOT THE HEAD

An atypical femoral fracture is a transverse fracture of the femoral shaft (diaphysis), defined by both clinical criteria and radiographic appearance.

To be defined as atypical, a femoral fracture must meet 4 of the following 5 criteria⁴:

• Occurs with minimal or no trauma
• Has a predominantly transverse fracture line, originating at the lateral cortex and sometimes becoming oblique as it progresses medially across the femur
• Extends through both cortices and may be associated with a medial spike (complete fractures); or involves only the lateral cortex (incomplete fractures)
• Is noncomminuted or minimally comminuted
• Shows localized periosteal or endosteal thickening (termed “beaking” or “flaring”) of the lateral cortex at the fracture site.

Several minor features are also important but are not required, eg:

• Cortical thickening of the femoral shaft
• Unilateral or bilateral prodromal pain preceding the fracture
• Bilateral incomplete or complete femoral diaphysis fractures
• Delayed fracture healing.

Atypical femoral fracture can occur anywhere along the shaft, from just distal to the lesser trochanter to just proximal to the supracondylar flare. However, most occur in 2 areas, with 1 cluster centered at about 41 mm from the lesser trochanter (more common in relatively younger patients) and the other at 187 mm.⁵

ABSOLUTE RISK IS LOW BUT INCREASES WITH LONGER USE

Atypical femoral fractures are rare. Schilcher et al⁶ reviewed radiographs of 1,234 women who had a subtrochanteric or shaft fracture and found 59 (4.6%) of fractures were atypical. In a systematic review of 14 studies,⁷ the incidence ranged from 3.0 to 9.8 cases per 100,000 patient-years.

Furthermore, not all atypical femoral fractures are in bisphosphonate users: 7.4% were in nonusers in 1 series⁸ and 22% in another.⁹

Nevertheless, most studies show that bis­phosphonate use increases the incidence of atypical femoral fracture, and the incidence increases with duration of use, especially after 3 years.⁷

An international task force of the American Society for Bone and Mineral Research listed the absolute risk as between 3.2 and 50 cases per 100,000 patient-years, with longer use (> 5 years) increasing the risk to about 100 per 100,000 patient-years.⁴ After stopping bis­phosphonate therapy, the risk diminished by 70% per year.⁹

In another study, for 0.1 to 1.9 years of therapy, the age-adjusted atypical fracture rates were 1.78 per 100,000 per year (95% confidence interval [CI] 1.5–2.0), increasing to 113.1 per 100,000 per year (95% CI 69.3–156.8) with exposure from 8 to 9.9 years.¹⁰

A case-control study found that more than 5 years of bisphosphonate use increased the fracture risk by an odds ratio of 2.74 (95% CI 1.25–6.02).¹¹

The incidence of typical femoral fracture was higher in those who adhered better to their oral bisphosphonate regimen in some studies,¹² but the opposite was true in others.¹³

The benefits of bisphosphonate therapy in reducing fracture risk, however, outweigh the risk of atypical fracture.⁴

We do not know whether the rate of atypical femoral fracture is increasing. A review of Kaiser Permanente Northwest records found that the rates of atypical femoral shaft fracture had remained stable from 1996 to 2009. However, 61.9% of patients who met the strict radiographic criteria had taken oral bisphosphonates.¹⁴ These data suggest that bisphosphonate use has not increased the overall population-based risk for subtrochanteric and femoral shaft fractures, but that bisphosphonates and other risk factors may have increased the likelihood that such fractures will exhibit atypical radiographic features.

A population-based study in Denmark¹³ found that alendronate use longer than 10 years was associated with an adjusted 30% lower risk of hip fracture and no increase in the risk of subtrochanteric and femoral shaft fracture. In addition, the risk of subtrochanteric and femoral shaft fracture was lower with high adherence to alendronate treatment (based on medication possession ratio > 80%) compared with low adherence (ratio < 50%) (odds ratio 0.88, 95% CI 0.77–0.99). The risk was not increased in current vs past users.

The Danish study¹³ used the coding of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) to identify subtrochanteric and femoral shaft fractures without radiologic review for atypical radiographic features. The lack of specific ICD-10 coding for subtrochanteric and femoral shaft fractures with atypical radiographic features has limited our knowledge of their incidence.

 

 

Contralateral fracture in more than one-fourth of cases

After an atypical femoral fracture, patients have a significant risk of fracture on the contralateral side. In a case-control study, 28% of patients with atypical femoral fracture suffered a contralateral fracture, compared with 0.9% of patients presenting with a typical fracture pattern (odds ratio 42.6, 95% CI 12.8–142.4).¹⁵

Contralateral fracture occurs from 1 month to 4 years after the index atypical femoral fracture.¹⁶

There are reports of bisphosphonate-related low-impact fractures in other sites such as the tibia¹⁷ and forearm.¹⁸ However, they may be too rare to warrant screening.

Mortality rates

A Swedish database study found that patients with atypical femoral fractures, whether bisphosphonate users or nonusers, do not have higher mortality rates than patients with ordinary subtrochanteric or femoral shaft fractures.¹⁹ Furthermore, the mortality rates for those with atypical femoral fracture were similar to rates in the general population. In contrast, patients with an ordinary femoral fracture had a higher mortality risk than the general population.¹⁹

Other studies suggest that atypical femoral fracture may be associated with a less favorable prognosis in older patients,²⁰ but this could be due to differences in demographics, treatment adherence, or postfracture care.²¹

In addition, functional outcomes as measured by independent mobility at discharge and at 3 months were comparable between patients with atypical fracture and those with typical fracture.²²

IMAGING STUDIES

If a long-term bisphosphonate user presents with hip, thigh, or groin pain, imaging studies are recommended.

Plain radiography

Radiography is usually the first step and should include a frontal view of the pelvis (Figure 1) and 2 views of the full length of each femur. If radiography is not conclusive, bone scan or magnetic resonance imaging (MRI) should be considered.

A linear cortex transverse fracture pattern and focal lateral cortical thickening are the most sensitive and specific radiographic features.^23,24 Because of the risk of fracture on the contralateral side, radiographic study of that side is recommended as well.

Computed tomography

Computed tomography (CT) is not sensitive for early stress fractures and, given the radiation burden, is not recommended in the workup of atypical fracture.

Bone scanning

Bone scanning using technetium 99m-labeled methylene diphosphonate with a gamma camera shows active bone turnover. Stress fractures and atypical femoral fractures are most easily identified in the third (delayed) phase of the bone scan. Although bone scanning is highly sensitive, the specificity is limited by lack of spatial resolution. Atypical femoral fracture appears as increased activity in the subtrochanteric region with a predilection for the lateral cortex.

Dual-energy x-ray absorptiometry

Conventional dual-energy x-ray absorptiometry (DXA) extends only to 1 to 2 cm below the lesser trochanter and can therefore miss atypical fractures, which usually occur farther down. The overall detection rate for DXA was 61% in a sample of 33 patients.²⁵

Newer scanners can look at the entire femoral shaft.²⁶ In addition, newer software can quantify focal thickening (beaking) of the lateral cortex and screen patients who have no symptoms. The results of serial measurements can be graphed so that the practitioner can view trends to help assess or rule out potential asymptomatic atypical femoral fracture.

A localized reaction (periosteal thickening of the lateral cortex or beaking) often precedes atypical femoral fracture. A 2017 study reported that patients with high localized reaction (mean height 3.3 mm) that was of the pointed type and was accompanied by prodromal pain had an increased risk of complete or incomplete atypical femoral fracture at that site.²⁷ This finding is used by the newer DXA software. The predictive value of beaking on extended femoral DXA may be as high as 83%.²⁶

Magnetic resonance imaging

The MRI characteristics of atypical femoral fracture are similar to those of other stress fractures except that there is a lateral-to-medial pattern rather than a medial pattern. The earliest findings include periosteal reaction about the lateral cortex with a normal marrow signal.

MRI may be of particular benefit in patients with known atypical femoral fracture to screen the contralateral leg. It should image the entire length of both femurs. Contrast enhancement is not needed.

Regardless of whether initial findings were discovered on conventional radiographs or DXA, MRI confirmation is needed. Radio­nuclide bone scanning is currently not recommended because it lacks specificity. Combination imaging is recommended, with either radiography plus MRI or DXA plus MRI.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of atypical femoral fracture includes stress fracture, pathologic fracture, hypophosphatasia, and osteogenesis imperfecta.²⁸ Hypophosphatemic osteomalacia can cause Looser zones, which can be confused with atypical femoral fractures but usually occur on the medial side.⁴ Stress fracture of the femur can occur below the lesser trochanter but usually begins in the medial, not the lateral, cortex.

Pathologic fractures from underlying osseous lesions can mimic the cortical beaking of bisphosphonate-related fracture, but they usually show the associated underlying lucent lesion and poorly defined margins. A sinus tract along the region of a chronic osteomyelitis may also appear similar.

Hypophosphatasia is an inborn error of metabolism caused by a loss-of-function mutation in the gene encoding alkaline phosphatase, resulting in pyrophosphate accumulation and causing osteomalacia from impaired mineralization. This can result in femoral pseudofracture that is often bilateral and occurs in the subtrochanteric region.²⁹

 

 

ADDITIONAL RISK FACTORS

Patients with atypical femoral fracture are generally a heterogeneous group, but there are risk factors to note other than bisphosphonate exposure.

Asian women had a risk 8 times higher than white women in 1 study.³⁰

Bone geometry. Mahjoub et al⁸ reported that compared with controls, patients with atypical femoral fracture had greater offset of the femoral shaft from the center of rotation of the femoral head, a more acute angle between the femoral neck and shaft, and greater proximal cortical thickness.

Medications. In addition to bisphosphonates, other drugs associated with atypical femoral fracture include RANK-ligand inhibitors such as denosumab (another drug for osteoporosis),³¹ glucocorticoids,^32,33 and proton pump inhibitors.^32,33

Genetics. Three sisters with atypical femoral fracture were found to have 37 rare mutations in 34 genes, including one in the GGPS1 gene, which codes for geranylgeranyl pyrophosphate synthase—an enzyme that bisphosphonates inhibit.³⁴

Medical conditions other than osteoporosis include collagen diseases, chronic pulmonary disease, asthma, rheumatoid arthritis, and diabetes.³⁵

Clinical recommendations

Current recommendations are to reevaluate bisphosphonate use in patients with osteoporosis after 5 or more years of therapy.³⁶

Given that patients with osteoporosis are at increased risk of typical fracture, those at higher risk should be considered for continued bisphosphonate therapy. Factors for high risk include the following:

• History of fracture on therapy
• Hip T score –2.5 or lower
• Older age (≥ 70)
• Other strong risk factors for fracture such as smoking, alcohol use, corticosteroid use, rheumatoid arthritis, and family history
• World Health Organization FRAX fracture risk score above the country-specific threshold.

Those at lower risk should be considered for a 2- to 3-year bisphosphonate holiday with periodic reevaluation of bone density and, possibly, bone markers.³⁶

WHAT IS THE UNDERLYING PATHOPHYSIOLOGY?

The mechanism by which bisphosphonates increase the risk of atypical femoral fracture is not clear. These drugs work by suppressing bone turnover; however, in theory, prolonged use could suppress it too much and increase bone fragility.

One hypothesis is that bisphosphonates impair the toughening of cortical bone, an important barrier to clinical fracture. This is supported by a study that found bisphosphonate users with atypical femoral fracture had deficits in intrinsic and extrinsic bone toughness, perhaps due to treatment-related increases in matrix mineralization.³⁷ Although this study and others showed an increase in matrix mineralization and reduced mineralization heterogeneity with bisphosphonate use,^38,39 it is unclear whether such changes contributed to reduced toughness or to atypical femoral fracture.

Changes in the skeletal geometry of the lower limb such as femoral neck-shaft angle and femoral curvature alter the stresses and strains experienced by the femoral diaphysis with loading. Because the incidence of incomplete atypical femoral fracture is much greater than that of complete fracture, most incomplete atypical femoral fractures heal before the fracture progresses.

Ultimately, all fractures, including atypical femoral fractures, occur when mechanical stress and strain exceed bone strength.

Antiresorptive drugs such as bisphosphonates, estrogen, calcitonin, and RANK ligand inhibitors prevent hip fracture by increasing the strength of the proximal femur—perhaps at the expense of the strength (or toughness) of the subtrochanteric shaft. It is also possible that treatment-related increases in hip strength (and reduced hip fracture rates) promote or sustain the transfer of stress and strain to femoral regions that experience lesser or no increases in strength from treatment, which likely includes the shaft.^40,41

CT studies in Japanese women with osteoporosis have shown that 2 years of zoledronate therapy had greater effects in the hip than in the femoral shaft, with significant increases in cortical thickness and volumetric bone mineral density at the femoral neck and intertrochanteric region compared with baseline.⁴² But zoledronate did not increase femoral shaft cortical thickness and caused only a minor increase in femoral shaft volumetric bone mineral density. Fracture patterns may have depended on damage and effects of bone turnover on mass and structure.

This hypothetical scenario portrays a possible “hip survival bias” mechanism for atypical femoral fracture, with the association with antiresorptive drugs arising from greater stress and strain in cortical regions where these fractures occur rather than from treatment-related reductions in cortical bone strength or toughness.

PRODROMAL PAIN IS COMMON

From 32% to 76% of patients who have incomplete or developing atypical femoral fracture present with a prodrome of groin or hip pain.^4,43 Prodromal pain occurs any time from 2 weeks to several years before the fracture, presenting as pain in the anterior or lateral thigh or in the groin.

Prodromal pain in a patient on antiresorptive therapy should be a signal for the clinician to obtain a radiograph of the hip and to look for contralateral symptoms and fractures. The most common mechanism of injury appears to be a ground-level fall or even a nontraumatic activity such as walking or stepping off a curb.

MEDICAL MANAGEMENT

In bisphosphonate users with radiographic evidence of atypical femoral fracture, the bis­phosphonate should be discontinued and the patient assessed for calcium and vitamin D deficiency, with supplements prescribed if needed.⁴

For patients with incomplete fracture and persistent pain after 3 months of medical management, prophylactic surgical nail fixation is recommended to prevent complete fracture.

Teriparatide, which has been associated with enhanced bone fracture healing, is a possible treatment to promote healing of atypical femoral fracture, either alone or as an adjunct to surgical fixation. A systematic review published in 2015 supported the use of teriparatide for enhancing fracture healing in atypical femoral fracture.⁴⁴ In addition, a 10-patient series⁴⁵ showed that incomplete fractures without radiolucent lines responded to teriparatide alone, whereas those with radiolucent lines needed intramedullary nailing.

These results suggest that teriparatide works best when the fracture site is stable, either inherently or with surgical fixation.

ORTHOPEDIC CARE

Orthopedic care for atypical femoral fracture differs depending on whether the patient experiences pain and whether the fracture is incomplete or complete. Figure 2 shows a treatment algorithm for atypical femoral fracture.

These are difficult fractures to manage, complicated by delayed healing in the elderly, complex displacement patterns, altered bone geometry, and risk of fracture in the opposite limb, all of which raise questions about recommending protected weight-bearing exercise.

Furthermore, atypical femoral fracture is often associated with increased anterolateral bowing of the femur, making it difficult to insert an intramedullary nail: the radius of curvature of the bone is shorter than that of a standard femoral nail. This mismatch can lead to intraoperative complications such as iatrogenic fracture during prophylactic nailing, malunion from excess straightening of the femur (which can itself lead to leg length discrepancy), and gapping of the fracture site, particularly on the medial side.

 

 

Intramedullary nailing for complete fracture

Intramedullary nailing is the first-line treatment for complete atypical femoral fracture, although the risk of delayed healing and revision surgery may be somewhat higher than with typical femoral fracture.⁴⁶ Prophylactic intramedullary nailing should be considered for a patient with intractable pain.²

A radiograph of the opposite leg should be obtained routinely, looking for an asymptomatic fracture. Bisphosphonates should be discontinued and calcium and vitamin D continued. Teriparatide therapy can be considered as an alternative treatment.

Conservative management for incomplete fracture without pain

Incomplete atypical femoral fracture unaccompanied by pain can be followed conservatively.⁴⁷ In addition to stopping antiresorptive therapy, patients need to avoid high-impact and repetitive-impact activities such as jumping or running. If pain occurs, patients should begin protected weight-bearing exercise.

Treatment is uncertain for incomplete fracture with pain

For patients with incomplete atypical femoral fracture and pain, treatment is controversial. Regimens that include 2 to 3 months of protected weight-bearing exercise, a full metabolic bone workup, calcium and vitamin D supplementation, and anabolic bone agents have produced some success. Some authors have reported poor results from conservative care, with few patients achieving pain relief or signs of complete healing.^48,49 Additionally, if an incomplete fracture is found in the opposite femur, protected weight-bearing of both legs may not be possible.

Patients with incomplete fracture should be monitored regularly with radiography and physical examination. If there is progression of the fracture, escalation of pain, or failure to heal within 2 to 3 months, then surgical treatment is necessary.

Prophylactic placement of an intramedullary nail to prevent completion of the fracture and allow a return to full weight-bearing is generally advised.⁵⁰ A long locking plate can be used if bone deformities make it difficult to place an intramedullary nail; however, nails are preferred because they allow formation of endochondral callus, which can be helpful in these difficult-to-heal fractures.

Results from retrospective reviews have shown that surgically treated patients with bis­phosphonate-associated incomplete atypical femoral fracture were more likely than those treated nonsurgically to be pain-free (81% vs 64%) and have radiographic healing (100% vs 18% at final follow-up).⁴⁶ Results have also been positive for those with complete atypical femoral fracture. At 6 months, 64% of surgically treated patients were pain-free and 98% were radiographically healed.⁵¹

The unusual geometry of the femur in patients with atypical femoral fracture and the presence of intramedullary cortical callus makes the placement of an intramedullary femoral rod more complex than in typical femoral fracture.⁸

Intramedullary nailing of atypical femoral fracture is a challenge for even the most experienced surgeon, and vigilance is imperative to avoid iatrogenic fracture and malunion.

MANY QUESTIONS REMAIN

We need more studies on the pathophysiology of bisphosphonate-associated atypical femoral fracture, the value of periodic screening with DXA, and which factors predict high risk (eg, Asian ethnicity, use of certain medications, femoral geometry). In addition, we need more data on the success of conservative management of incomplete fracture, including use of teriparatide.

A 76-year-old man whose history included abdominal aortic aneurysm repair, bilateral femoral artery bypass for popliteal artery aneurysm, hypertension, and peptic ulcer disease was admitted to a community hospital with pleuritic chest pain and shortness of breath. Two days earlier, he had undergone repair of a ventral hernia.

At the time of that admission, he reported no fever, chills, night sweats, cough, or history of heart or lung disease. His vital signs were normal, and physical examination had revealed no apparent respiratory distress, no jugular venous distention, normal heart sounds, and no pedal edema; however, decreased air entry was noted in the right lung base. Initial serum levels of troponin and N-terminal pro-B-type natriuretic peptide were normal.

At that time, computed tomographic angiography of the chest showed segmental pulmonary emboli in the left upper and right lower lobes of the lungs and right pleural effusion. Transthoracic echocardiography showed normal atrial and ventricular sizes with no right or left ventricular systolic dysfunction and a left ventricular ejection fraction of 59%.

Treatment with intravenous heparin was started, and the patient was transferred to our hospital.

PLEURAL EFFUSION AND PULMONARY EMBOLISM

1. Which of the following is true about pleural effusion?

• It is rarely, if ever, associated with pulmonary embolism
• Most patients with pleural effusion due to pulmonary embolism do not have pleuritic chest pain
• Pulmonary embolism should be excluded in all cases of pleural effusion without a clear cause

Pulmonary embolism should be excluded in all cases of pleural effusion that do not have a clear cause. As for the other answer choices:

• Pulmonary embolism is the fourth leading cause of pleural effusion in the United States, after heart failure, pneumonia, and malignancy.¹
• About 75% of patients who develop pleural effusion in the setting of pulmonary embolism complain of pleuritic chest pain on the side of the effusion.² Most effusions are unilateral, small, and usually exudative.³

EVALUATION BEGINS: RESULTS OF THORACENTESIS

Our patient continued to receive intravenous heparin.

He underwent thoracentesis on hospital day 3, and 1,000 mL of turbid sanguineous pleural fluid was removed. Analysis of the fluid showed pH 7.27, white blood cell count 3.797 × 10⁹/L with 80% neutrophils, and lactate dehydrogenase (LDH) concentration 736 U/L (a ratio of pleural fluid LDH to a concurrent serum LDH > 0.6 is suggestive of an exudate); the fluid was also sent for culture and cytology. Thoracentesis was terminated early due to cough, and follow-up chest radiography showed a moderate-sized pneumothorax.

Computed tomography (CT) of the chest at this time showed a small wedge-shaped area of lung consolidation in the right lower lobe (also seen on CT done 1 day before admission to our hospital), with an intrinsic air-fluid level suggesting a focal infarct or lung abscess, now obscured by adjacent consolidation and atelectasis. In the interval since the previous CT, the multiloculated right pleural effusion had increased in size (Figure 1).

THE NEXT STEP

2. What is the most appropriate next step for this patient?

• Consult an interventional radiologist for chest tube placement
• Start empiric antibiotic therapy and ask an interventional radiologist to place a chest tube
• Start empiric antibiotic therapy, withhold anticoagulation, and consult a thoracic surgeon
• Start empiric antibiotic therapy and consult a thoracic surgeon while continuing anticoagulation

The most appropriate next step is to start empiric antibiotic therapy and consult a thoracic surgeon while continuing anticoagulation.

In this patient, it is appropriate to initiate antibiotics empirically on the basis of his significant pleural loculations, a wedge-shaped consolidation, and 80% neutrophils in the pleural fluid, all of which suggest infection. The unmasking of a wedge-shaped consolidation after thoracentesis, with a previously noted air-fluid level and an interval increase in multiloculated pleural fluid, raises suspicion of a necrotic infection that may have ruptured into the pleural space, a possible lung infarct, or a malignancy. Hence, simply placing a chest tube may not be enough.

Blood in the pleural fluid does not necessitate withholding anticoagulation unless the bleeding is heavy. A pleural fluid hematocrit greater than 50% of the peripheral blood hematocrit suggests hemothorax and is an indication to withhold anticoagulation.¹ Our patient’s pleural fluid was qualitatively sanguineous but not frankly bloody, and therefore we judged that it was not necessary to stop his heparin.

HOW DOES PULMONARY INFARCTION PRESENT CLINICALLY?

3. Which of the following statements about pulmonary infarction is incorrect?

• Cavitation and infarction are more common with larger emboli
• Cavitation occurs in fewer than 10% of pulmonary infarctions
• Lung abscess develops in more than 50% of pulmonary infarctions
• Pulmonary thromboembolism is the most common cause of pulmonary infarction

Lung abscess develops in far fewer than 50% of cases of pulmonary infarction. The rest of the statements are correct.

Cavitation complicates about 4% to 7% of infarctions and is more common when the infarction is 4 cm or greater in diameter.⁴ These cavities are usually single and predominantly on the right side in the apical or posterior segment of the upper lobe or the apical segment of the right lower lobe, as in our patient.^5–8 CT demonstrating scalloped inner margins and cross-cavity band shadows suggests a cavitary pulmonary infarction.^9,10

Infection and abscess in pulmonary infarction are poorly understood but have been linked to larger infarctions, coexistent congestion or atelectasis, and dental or oropharyngeal infection. In an early series of 550 cases of pulmonary infarction, 23 patients (4.2%) developed lung abscess and 6 (1.1%) developed empyema.¹¹ The mean time to cavitation for an infected pulmonary infarction has been reported to be 18 days.¹²

A reversed halo sign, generally described as a focal, rounded area of ground-glass opacity surrounded by a nearly complete ring of consolidation, has been reported to be more frequent with pulmonary infarction than with other diseases, especially when in the lower lobes.¹³

CASE CONTINUED: THORACOSCOPY

A cardiothoracic surgeon was consulted, intravenous heparin was discontinued, an inferior vena cava filter was placed, and the patient underwent video-assisted thoracoscopy.

Purulent fluid was noted on the lateral aspect of right lower lobe; this appeared to be the ruptured cavitary lesion functioning like an uncontrolled bronchopleural fistula. Two chest tubes, sizes 32F and 28F, were placed after decortication, resection of the lung abscess, and closure of the bronchopleural fistula. No significant air leak was noted after resection of this segment of lung.

Pathologic study showed acute organizing pneumonia with abscess formation; no malignant cells or granulomas were seen (Figure 2). Pleural fluid cultures grew Streptococcus intermedius, while the tissue culture was negative for any growth, including acid-fast bacilli and fungi.

On 3 different occasions, both chest tubes were shortened, backed out 2 cm, and resecured with sutures and pins, and Heimlich valves were applied before the patient was discharged.

Intravenous piperacillin-tazobactam was started on the fifth hospital day. On discharge, the patient was advised to continue this treatment for 3 weeks at home.

The patient was receiving enoxaparin subcutaneously in prophylactic doses; 72 hours after the thorascopic procedure this was increased to therapeutic doses, continuing after discharge. Bridging to warfarin was not advised in view of his chest tubes.

Our patient appeared to have developed a right lower lobe infarction that cavitated and ruptured into the pleural space, causing a bronchopleural fistula with empyema after a recent pulmonary embolism. Other reported causes of pulmonary infarction in pulmonary embolism are malignancy and heavy clot burden,⁶ but these have not been confirmed in subsequent studies.⁵ Malignancy was ruled out by biopsy of the resected portion of the lung, and our patient did not have a history of heart failure. A clear cavity was not noted (because it ruptured into the pleura), but an air-fluid level was described in a wedge-shaped consolidation, suggesting infarction.

How common is pulmonary infarction after pulmonary embolism?

Pulmonary infarction occurs in few patients with pulmonary embolism.¹³ Since the lungs receive oxygen from the airways and have a dual blood supply from the pulmonary and bronchial arteries, they are not particularly vulnerable to ischemia. However, the reported incidence of pulmonary infarction in patients with pulmonary embolism has ranged from 10% to higher than 30%.^5,14,15

The reasons behind pulmonary infarction with complications after pulmonary embolism have varied in different case series in different eras. CT, biopsy, or autopsy studies reveal pulmonary infarction after pulmonary embolism to be more common than suspected by clinical symptoms.

In a Mayo Clinic series of 43 cases of pulmonary infarction diagnosed over a 6-year period by surgical lung biopsy, 18 (42%) of the patients had underlying pulmonary thromboembolism, which was the most common cause.¹⁶

 

 

RISK FACTORS FOR PULMONARY INFARCTION

4. Which statement about risk factors for pulmonary infarction in pulmonary embolism is incorrect?

• Heart failure may be a risk factor for pulmonary infarction
• Pulmonary hemorrhage is a risk factor for pulmonary infarction
• Pulmonary infarction is more common with more proximal sites of pulmonary embolism
• Collateral circulation may protect against pulmonary infarction

Infarction is more common with emboli that are distal rather than proximal.

Dalen et al¹⁵ suggested that after pulmonary embolism, pulmonary hemorrhage is an important contributor to the development of pulmonary infarction independent of the presence or absence of associated cardiac or pulmonary disease, but that the effect depends on the site of obstruction.

This idea was first proposed in 1913, when Karsner and Ghoreyeb¹⁷ showed that when pulmonary arteries are completely obstructed, the bronchial arteries take over, except when the embolism is present in a small branch of the pulmonary artery. This is because the physiologic anastomosis between the pulmonary artery and the bronchial arteries is located at the precapillary level of the pulmonary artery, and the bronchial circulation does not take over until the pulmonary arterial pressure in the area of the embolism drops to zero.

Using CT data, Kirchner et al⁵ confirmed that the risk of pulmonary infarction is higher if the obstruction is peripheral, ie, distal.

Using autopsy data, Tsao et al¹⁸ reported a higher risk of pulmonary infarction in embolic occlusion of pulmonary vessels less than 3 mm in diameter.

Collateral circulation has been shown to protect against pulmonary infarction. For example, Miniati et al¹⁴ showed that healthy young patients with pulmonary embolism were more prone to develop pulmonary infarction, probably because they had less efficient collateral systems in the peripheral lung fields. In lung transplant recipients, it has been shown that the risk of infarction decreased with development of collateral circulation.¹⁹

Dalen et al,¹⁵ however, attributed delayed resolution of pulmonary hemorrhage (as measured by resolution of infiltrate on chest radiography) to higher underlying pulmonary venous pressure in patients with heart failure and consequent pulmonary infarction. In comparison, healthy patients without cardiac or pulmonary disease have faster resolution of pulmonary hemorrhage when present, and less likelihood of pulmonary infarction (and death in submassive pulmonary embolism).

Data on the management of infected pulmonary infarction are limited. Mortality rates have been as high as 41% with noninfected and 73% with infected cavitary infarctions.⁴ Some authors have advocated early surgical resection in view of high rates of failure of medical treatment due to lack of blood supply within the cavity and continued risk of infection.

KEY POINTS

In patients with a recently diagnosed pulmonary embolism and concurrent symptoms of bacterial pneumonia, a diagnosis of cavitary pulmonary infarction should be considered.

Consolidations that are pleural-based with sharp, rounded margins and with focal areas of central hyperlucencies representing hemorrhage on the mediastinal windows on CT are more likely to represent a pulmonary infarct.²⁰

A 76-year-old man whose history included abdominal aortic aneurysm repair, bilateral femoral artery bypass for popliteal artery aneurysm, hypertension, and peptic ulcer disease was admitted to a community hospital with pleuritic chest pain and shortness of breath. Two days earlier, he had undergone repair of a ventral hernia.

At the time of that admission, he reported no fever, chills, night sweats, cough, or history of heart or lung disease. His vital signs were normal, and physical examination had revealed no apparent respiratory distress, no jugular venous distention, normal heart sounds, and no pedal edema; however, decreased air entry was noted in the right lung base. Initial serum levels of troponin and N-terminal pro-B-type natriuretic peptide were normal.

At that time, computed tomographic angiography of the chest showed segmental pulmonary emboli in the left upper and right lower lobes of the lungs and right pleural effusion. Transthoracic echocardiography showed normal atrial and ventricular sizes with no right or left ventricular systolic dysfunction and a left ventricular ejection fraction of 59%.

Treatment with intravenous heparin was started, and the patient was transferred to our hospital.

PLEURAL EFFUSION AND PULMONARY EMBOLISM

1. Which of the following is true about pleural effusion?

• It is rarely, if ever, associated with pulmonary embolism
• Most patients with pleural effusion due to pulmonary embolism do not have pleuritic chest pain
• Pulmonary embolism should be excluded in all cases of pleural effusion without a clear cause

Pulmonary embolism should be excluded in all cases of pleural effusion that do not have a clear cause. As for the other answer choices:

• Pulmonary embolism is the fourth leading cause of pleural effusion in the United States, after heart failure, pneumonia, and malignancy.¹
• About 75% of patients who develop pleural effusion in the setting of pulmonary embolism complain of pleuritic chest pain on the side of the effusion.² Most effusions are unilateral, small, and usually exudative.³

EVALUATION BEGINS: RESULTS OF THORACENTESIS

Our patient continued to receive intravenous heparin.

He underwent thoracentesis on hospital day 3, and 1,000 mL of turbid sanguineous pleural fluid was removed. Analysis of the fluid showed pH 7.27, white blood cell count 3.797 × 10⁹/L with 80% neutrophils, and lactate dehydrogenase (LDH) concentration 736 U/L (a ratio of pleural fluid LDH to a concurrent serum LDH > 0.6 is suggestive of an exudate); the fluid was also sent for culture and cytology. Thoracentesis was terminated early due to cough, and follow-up chest radiography showed a moderate-sized pneumothorax.

Computed tomography (CT) of the chest at this time showed a small wedge-shaped area of lung consolidation in the right lower lobe (also seen on CT done 1 day before admission to our hospital), with an intrinsic air-fluid level suggesting a focal infarct or lung abscess, now obscured by adjacent consolidation and atelectasis. In the interval since the previous CT, the multiloculated right pleural effusion had increased in size (Figure 1).

THE NEXT STEP

2. What is the most appropriate next step for this patient?

• Consult an interventional radiologist for chest tube placement
• Start empiric antibiotic therapy and ask an interventional radiologist to place a chest tube
• Start empiric antibiotic therapy, withhold anticoagulation, and consult a thoracic surgeon
• Start empiric antibiotic therapy and consult a thoracic surgeon while continuing anticoagulation

The most appropriate next step is to start empiric antibiotic therapy and consult a thoracic surgeon while continuing anticoagulation.

In this patient, it is appropriate to initiate antibiotics empirically on the basis of his significant pleural loculations, a wedge-shaped consolidation, and 80% neutrophils in the pleural fluid, all of which suggest infection. The unmasking of a wedge-shaped consolidation after thoracentesis, with a previously noted air-fluid level and an interval increase in multiloculated pleural fluid, raises suspicion of a necrotic infection that may have ruptured into the pleural space, a possible lung infarct, or a malignancy. Hence, simply placing a chest tube may not be enough.

Blood in the pleural fluid does not necessitate withholding anticoagulation unless the bleeding is heavy. A pleural fluid hematocrit greater than 50% of the peripheral blood hematocrit suggests hemothorax and is an indication to withhold anticoagulation.¹ Our patient’s pleural fluid was qualitatively sanguineous but not frankly bloody, and therefore we judged that it was not necessary to stop his heparin.

HOW DOES PULMONARY INFARCTION PRESENT CLINICALLY?

3. Which of the following statements about pulmonary infarction is incorrect?

• Cavitation and infarction are more common with larger emboli
• Cavitation occurs in fewer than 10% of pulmonary infarctions
• Lung abscess develops in more than 50% of pulmonary infarctions
• Pulmonary thromboembolism is the most common cause of pulmonary infarction

Lung abscess develops in far fewer than 50% of cases of pulmonary infarction. The rest of the statements are correct.

Cavitation complicates about 4% to 7% of infarctions and is more common when the infarction is 4 cm or greater in diameter.⁴ These cavities are usually single and predominantly on the right side in the apical or posterior segment of the upper lobe or the apical segment of the right lower lobe, as in our patient.^5–8 CT demonstrating scalloped inner margins and cross-cavity band shadows suggests a cavitary pulmonary infarction.^9,10

Infection and abscess in pulmonary infarction are poorly understood but have been linked to larger infarctions, coexistent congestion or atelectasis, and dental or oropharyngeal infection. In an early series of 550 cases of pulmonary infarction, 23 patients (4.2%) developed lung abscess and 6 (1.1%) developed empyema.¹¹ The mean time to cavitation for an infected pulmonary infarction has been reported to be 18 days.¹²

A reversed halo sign, generally described as a focal, rounded area of ground-glass opacity surrounded by a nearly complete ring of consolidation, has been reported to be more frequent with pulmonary infarction than with other diseases, especially when in the lower lobes.¹³

CASE CONTINUED: THORACOSCOPY

A cardiothoracic surgeon was consulted, intravenous heparin was discontinued, an inferior vena cava filter was placed, and the patient underwent video-assisted thoracoscopy.

Purulent fluid was noted on the lateral aspect of right lower lobe; this appeared to be the ruptured cavitary lesion functioning like an uncontrolled bronchopleural fistula. Two chest tubes, sizes 32F and 28F, were placed after decortication, resection of the lung abscess, and closure of the bronchopleural fistula. No significant air leak was noted after resection of this segment of lung.

Pathologic study showed acute organizing pneumonia with abscess formation; no malignant cells or granulomas were seen (Figure 2). Pleural fluid cultures grew Streptococcus intermedius, while the tissue culture was negative for any growth, including acid-fast bacilli and fungi.

On 3 different occasions, both chest tubes were shortened, backed out 2 cm, and resecured with sutures and pins, and Heimlich valves were applied before the patient was discharged.

Intravenous piperacillin-tazobactam was started on the fifth hospital day. On discharge, the patient was advised to continue this treatment for 3 weeks at home.

The patient was receiving enoxaparin subcutaneously in prophylactic doses; 72 hours after the thorascopic procedure this was increased to therapeutic doses, continuing after discharge. Bridging to warfarin was not advised in view of his chest tubes.

Our patient appeared to have developed a right lower lobe infarction that cavitated and ruptured into the pleural space, causing a bronchopleural fistula with empyema after a recent pulmonary embolism. Other reported causes of pulmonary infarction in pulmonary embolism are malignancy and heavy clot burden,⁶ but these have not been confirmed in subsequent studies.⁵ Malignancy was ruled out by biopsy of the resected portion of the lung, and our patient did not have a history of heart failure. A clear cavity was not noted (because it ruptured into the pleura), but an air-fluid level was described in a wedge-shaped consolidation, suggesting infarction.

How common is pulmonary infarction after pulmonary embolism?

Pulmonary infarction occurs in few patients with pulmonary embolism.¹³ Since the lungs receive oxygen from the airways and have a dual blood supply from the pulmonary and bronchial arteries, they are not particularly vulnerable to ischemia. However, the reported incidence of pulmonary infarction in patients with pulmonary embolism has ranged from 10% to higher than 30%.^5,14,15

The reasons behind pulmonary infarction with complications after pulmonary embolism have varied in different case series in different eras. CT, biopsy, or autopsy studies reveal pulmonary infarction after pulmonary embolism to be more common than suspected by clinical symptoms.

In a Mayo Clinic series of 43 cases of pulmonary infarction diagnosed over a 6-year period by surgical lung biopsy, 18 (42%) of the patients had underlying pulmonary thromboembolism, which was the most common cause.¹⁶

 

 

RISK FACTORS FOR PULMONARY INFARCTION

4. Which statement about risk factors for pulmonary infarction in pulmonary embolism is incorrect?

• Heart failure may be a risk factor for pulmonary infarction
• Pulmonary hemorrhage is a risk factor for pulmonary infarction
• Pulmonary infarction is more common with more proximal sites of pulmonary embolism
• Collateral circulation may protect against pulmonary infarction

Infarction is more common with emboli that are distal rather than proximal.

Dalen et al¹⁵ suggested that after pulmonary embolism, pulmonary hemorrhage is an important contributor to the development of pulmonary infarction independent of the presence or absence of associated cardiac or pulmonary disease, but that the effect depends on the site of obstruction.

This idea was first proposed in 1913, when Karsner and Ghoreyeb¹⁷ showed that when pulmonary arteries are completely obstructed, the bronchial arteries take over, except when the embolism is present in a small branch of the pulmonary artery. This is because the physiologic anastomosis between the pulmonary artery and the bronchial arteries is located at the precapillary level of the pulmonary artery, and the bronchial circulation does not take over until the pulmonary arterial pressure in the area of the embolism drops to zero.

Using CT data, Kirchner et al⁵ confirmed that the risk of pulmonary infarction is higher if the obstruction is peripheral, ie, distal.

Using autopsy data, Tsao et al¹⁸ reported a higher risk of pulmonary infarction in embolic occlusion of pulmonary vessels less than 3 mm in diameter.

Collateral circulation has been shown to protect against pulmonary infarction. For example, Miniati et al¹⁴ showed that healthy young patients with pulmonary embolism were more prone to develop pulmonary infarction, probably because they had less efficient collateral systems in the peripheral lung fields. In lung transplant recipients, it has been shown that the risk of infarction decreased with development of collateral circulation.¹⁹

Dalen et al,¹⁵ however, attributed delayed resolution of pulmonary hemorrhage (as measured by resolution of infiltrate on chest radiography) to higher underlying pulmonary venous pressure in patients with heart failure and consequent pulmonary infarction. In comparison, healthy patients without cardiac or pulmonary disease have faster resolution of pulmonary hemorrhage when present, and less likelihood of pulmonary infarction (and death in submassive pulmonary embolism).

Data on the management of infected pulmonary infarction are limited. Mortality rates have been as high as 41% with noninfected and 73% with infected cavitary infarctions.⁴ Some authors have advocated early surgical resection in view of high rates of failure of medical treatment due to lack of blood supply within the cavity and continued risk of infection.

KEY POINTS

In patients with a recently diagnosed pulmonary embolism and concurrent symptoms of bacterial pneumonia, a diagnosis of cavitary pulmonary infarction should be considered.

Consolidations that are pleural-based with sharp, rounded margins and with focal areas of central hyperlucencies representing hemorrhage on the mediastinal windows on CT are more likely to represent a pulmonary infarct.²⁰

A 76-year-old man whose history included abdominal aortic aneurysm repair, bilateral femoral artery bypass for popliteal artery aneurysm, hypertension, and peptic ulcer disease was admitted to a community hospital with pleuritic chest pain and shortness of breath. Two days earlier, he had undergone repair of a ventral hernia.

At the time of that admission, he reported no fever, chills, night sweats, cough, or history of heart or lung disease. His vital signs were normal, and physical examination had revealed no apparent respiratory distress, no jugular venous distention, normal heart sounds, and no pedal edema; however, decreased air entry was noted in the right lung base. Initial serum levels of troponin and N-terminal pro-B-type natriuretic peptide were normal.

At that time, computed tomographic angiography of the chest showed segmental pulmonary emboli in the left upper and right lower lobes of the lungs and right pleural effusion. Transthoracic echocardiography showed normal atrial and ventricular sizes with no right or left ventricular systolic dysfunction and a left ventricular ejection fraction of 59%.

Treatment with intravenous heparin was started, and the patient was transferred to our hospital.

PLEURAL EFFUSION AND PULMONARY EMBOLISM

1. Which of the following is true about pleural effusion?

• It is rarely, if ever, associated with pulmonary embolism
• Most patients with pleural effusion due to pulmonary embolism do not have pleuritic chest pain
• Pulmonary embolism should be excluded in all cases of pleural effusion without a clear cause

Pulmonary embolism should be excluded in all cases of pleural effusion that do not have a clear cause. As for the other answer choices:

• Pulmonary embolism is the fourth leading cause of pleural effusion in the United States, after heart failure, pneumonia, and malignancy.¹
• About 75% of patients who develop pleural effusion in the setting of pulmonary embolism complain of pleuritic chest pain on the side of the effusion.² Most effusions are unilateral, small, and usually exudative.³

EVALUATION BEGINS: RESULTS OF THORACENTESIS

Our patient continued to receive intravenous heparin.

He underwent thoracentesis on hospital day 3, and 1,000 mL of turbid sanguineous pleural fluid was removed. Analysis of the fluid showed pH 7.27, white blood cell count 3.797 × 10⁹/L with 80% neutrophils, and lactate dehydrogenase (LDH) concentration 736 U/L (a ratio of pleural fluid LDH to a concurrent serum LDH > 0.6 is suggestive of an exudate); the fluid was also sent for culture and cytology. Thoracentesis was terminated early due to cough, and follow-up chest radiography showed a moderate-sized pneumothorax.

Computed tomography (CT) of the chest at this time showed a small wedge-shaped area of lung consolidation in the right lower lobe (also seen on CT done 1 day before admission to our hospital), with an intrinsic air-fluid level suggesting a focal infarct or lung abscess, now obscured by adjacent consolidation and atelectasis. In the interval since the previous CT, the multiloculated right pleural effusion had increased in size (Figure 1).

THE NEXT STEP

2. What is the most appropriate next step for this patient?

• Consult an interventional radiologist for chest tube placement
• Start empiric antibiotic therapy and ask an interventional radiologist to place a chest tube
• Start empiric antibiotic therapy, withhold anticoagulation, and consult a thoracic surgeon
• Start empiric antibiotic therapy and consult a thoracic surgeon while continuing anticoagulation

The most appropriate next step is to start empiric antibiotic therapy and consult a thoracic surgeon while continuing anticoagulation.

In this patient, it is appropriate to initiate antibiotics empirically on the basis of his significant pleural loculations, a wedge-shaped consolidation, and 80% neutrophils in the pleural fluid, all of which suggest infection. The unmasking of a wedge-shaped consolidation after thoracentesis, with a previously noted air-fluid level and an interval increase in multiloculated pleural fluid, raises suspicion of a necrotic infection that may have ruptured into the pleural space, a possible lung infarct, or a malignancy. Hence, simply placing a chest tube may not be enough.

Blood in the pleural fluid does not necessitate withholding anticoagulation unless the bleeding is heavy. A pleural fluid hematocrit greater than 50% of the peripheral blood hematocrit suggests hemothorax and is an indication to withhold anticoagulation.¹ Our patient’s pleural fluid was qualitatively sanguineous but not frankly bloody, and therefore we judged that it was not necessary to stop his heparin.

HOW DOES PULMONARY INFARCTION PRESENT CLINICALLY?

3. Which of the following statements about pulmonary infarction is incorrect?

• Cavitation and infarction are more common with larger emboli
• Cavitation occurs in fewer than 10% of pulmonary infarctions
• Lung abscess develops in more than 50% of pulmonary infarctions
• Pulmonary thromboembolism is the most common cause of pulmonary infarction

Lung abscess develops in far fewer than 50% of cases of pulmonary infarction. The rest of the statements are correct.

Cavitation complicates about 4% to 7% of infarctions and is more common when the infarction is 4 cm or greater in diameter.⁴ These cavities are usually single and predominantly on the right side in the apical or posterior segment of the upper lobe or the apical segment of the right lower lobe, as in our patient.^5–8 CT demonstrating scalloped inner margins and cross-cavity band shadows suggests a cavitary pulmonary infarction.^9,10

Infection and abscess in pulmonary infarction are poorly understood but have been linked to larger infarctions, coexistent congestion or atelectasis, and dental or oropharyngeal infection. In an early series of 550 cases of pulmonary infarction, 23 patients (4.2%) developed lung abscess and 6 (1.1%) developed empyema.¹¹ The mean time to cavitation for an infected pulmonary infarction has been reported to be 18 days.¹²

A reversed halo sign, generally described as a focal, rounded area of ground-glass opacity surrounded by a nearly complete ring of consolidation, has been reported to be more frequent with pulmonary infarction than with other diseases, especially when in the lower lobes.¹³

CASE CONTINUED: THORACOSCOPY

A cardiothoracic surgeon was consulted, intravenous heparin was discontinued, an inferior vena cava filter was placed, and the patient underwent video-assisted thoracoscopy.

Purulent fluid was noted on the lateral aspect of right lower lobe; this appeared to be the ruptured cavitary lesion functioning like an uncontrolled bronchopleural fistula. Two chest tubes, sizes 32F and 28F, were placed after decortication, resection of the lung abscess, and closure of the bronchopleural fistula. No significant air leak was noted after resection of this segment of lung.

Pathologic study showed acute organizing pneumonia with abscess formation; no malignant cells or granulomas were seen (Figure 2). Pleural fluid cultures grew Streptococcus intermedius, while the tissue culture was negative for any growth, including acid-fast bacilli and fungi.

On 3 different occasions, both chest tubes were shortened, backed out 2 cm, and resecured with sutures and pins, and Heimlich valves were applied before the patient was discharged.

Intravenous piperacillin-tazobactam was started on the fifth hospital day. On discharge, the patient was advised to continue this treatment for 3 weeks at home.

The patient was receiving enoxaparin subcutaneously in prophylactic doses; 72 hours after the thorascopic procedure this was increased to therapeutic doses, continuing after discharge. Bridging to warfarin was not advised in view of his chest tubes.

Our patient appeared to have developed a right lower lobe infarction that cavitated and ruptured into the pleural space, causing a bronchopleural fistula with empyema after a recent pulmonary embolism. Other reported causes of pulmonary infarction in pulmonary embolism are malignancy and heavy clot burden,⁶ but these have not been confirmed in subsequent studies.⁵ Malignancy was ruled out by biopsy of the resected portion of the lung, and our patient did not have a history of heart failure. A clear cavity was not noted (because it ruptured into the pleura), but an air-fluid level was described in a wedge-shaped consolidation, suggesting infarction.

How common is pulmonary infarction after pulmonary embolism?

Pulmonary infarction occurs in few patients with pulmonary embolism.¹³ Since the lungs receive oxygen from the airways and have a dual blood supply from the pulmonary and bronchial arteries, they are not particularly vulnerable to ischemia. However, the reported incidence of pulmonary infarction in patients with pulmonary embolism has ranged from 10% to higher than 30%.^5,14,15

The reasons behind pulmonary infarction with complications after pulmonary embolism have varied in different case series in different eras. CT, biopsy, or autopsy studies reveal pulmonary infarction after pulmonary embolism to be more common than suspected by clinical symptoms.

In a Mayo Clinic series of 43 cases of pulmonary infarction diagnosed over a 6-year period by surgical lung biopsy, 18 (42%) of the patients had underlying pulmonary thromboembolism, which was the most common cause.¹⁶

 

 

RISK FACTORS FOR PULMONARY INFARCTION

4. Which statement about risk factors for pulmonary infarction in pulmonary embolism is incorrect?

• Heart failure may be a risk factor for pulmonary infarction
• Pulmonary hemorrhage is a risk factor for pulmonary infarction
• Pulmonary infarction is more common with more proximal sites of pulmonary embolism
• Collateral circulation may protect against pulmonary infarction

Infarction is more common with emboli that are distal rather than proximal.

Dalen et al¹⁵ suggested that after pulmonary embolism, pulmonary hemorrhage is an important contributor to the development of pulmonary infarction independent of the presence or absence of associated cardiac or pulmonary disease, but that the effect depends on the site of obstruction.

This idea was first proposed in 1913, when Karsner and Ghoreyeb¹⁷ showed that when pulmonary arteries are completely obstructed, the bronchial arteries take over, except when the embolism is present in a small branch of the pulmonary artery. This is because the physiologic anastomosis between the pulmonary artery and the bronchial arteries is located at the precapillary level of the pulmonary artery, and the bronchial circulation does not take over until the pulmonary arterial pressure in the area of the embolism drops to zero.

Using CT data, Kirchner et al⁵ confirmed that the risk of pulmonary infarction is higher if the obstruction is peripheral, ie, distal.

Using autopsy data, Tsao et al¹⁸ reported a higher risk of pulmonary infarction in embolic occlusion of pulmonary vessels less than 3 mm in diameter.

Collateral circulation has been shown to protect against pulmonary infarction. For example, Miniati et al¹⁴ showed that healthy young patients with pulmonary embolism were more prone to develop pulmonary infarction, probably because they had less efficient collateral systems in the peripheral lung fields. In lung transplant recipients, it has been shown that the risk of infarction decreased with development of collateral circulation.¹⁹

Dalen et al,¹⁵ however, attributed delayed resolution of pulmonary hemorrhage (as measured by resolution of infiltrate on chest radiography) to higher underlying pulmonary venous pressure in patients with heart failure and consequent pulmonary infarction. In comparison, healthy patients without cardiac or pulmonary disease have faster resolution of pulmonary hemorrhage when present, and less likelihood of pulmonary infarction (and death in submassive pulmonary embolism).

Data on the management of infected pulmonary infarction are limited. Mortality rates have been as high as 41% with noninfected and 73% with infected cavitary infarctions.⁴ Some authors have advocated early surgical resection in view of high rates of failure of medical treatment due to lack of blood supply within the cavity and continued risk of infection.

KEY POINTS

In patients with a recently diagnosed pulmonary embolism and concurrent symptoms of bacterial pneumonia, a diagnosis of cavitary pulmonary infarction should be considered.

Consolidations that are pleural-based with sharp, rounded margins and with focal areas of central hyperlucencies representing hemorrhage on the mediastinal windows on CT are more likely to represent a pulmonary infarct.²⁰

Although I look forward to receiving JFP each month, I was initially disappointed in Dr. Jonathon M. Firnhaber’s article, “Newer cholesterol-lowering agents: What you must know” (J Fam Pract. 2018;67:339-341,344,345), because of what appeared to be a superficial discussion of the medication ezetimibe. The potential role of PCSK9 inhibitors in extremely high-risk individuals was well discussed, but my first read left me with the impression that ezetimibe should be used more widely.

It seemed that in the section for ezetimibe, the author was suggesting using it for primary prevention. The line, “Consider adding ezetimibe to maximally tolerated statin therapy for patients not meeting LDL-C goals with a statin alone” left me a bit confused, as the most widely used guideline (that by the American College of Cardiology/American Heart Association Task Force on Practice Guidelines) states that there is no goal low-density lipoprotein cholesterol (LDL-C) level for primary prevention in patients without known cardiovascular disease (CVD) because studies have not been done to support this concept.¹

But upon rereading the article, I realized the statement was placed at the end of a section that discussed secondary prevention based on the IMPROVE-IT study.² This trial included only patients with previous acute coronary syndrome, one of the populations at highest risk.

I write just to reinforce the importance of considering what evidence we have for primary prevention. Although there is a value to rechecking LDL-C levels to assess compliance, there really is no convincing evidence that we should treat to a goal LDL-C level in someone who does not already have CVD. So the addition of ezetimibe to a statin in these patients is not recommended. Thus, the often-quoted strategy: “Start them on the right statin, and don’t look back.”

Bill Crump, MD
Madisonville, Ky

1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(suppl 2):S1-S45.

2. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.

Continue to: Authors' response

Author’s response:

Thank you, Dr. Crump, for your feedback. I suspect that most clinicians would welcome more robust outcomes data on ezetimibe, but to date none have been published.

The IMPROVE-IT trial¹ offers the best supportive evidence for the use of ezetimibe, but still finds only a 2% absolute risk reduction (ARR) in a composite endpoint (cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization ≥30 days after randomization, or nonfatal stroke), equating to a number needed to treat (NNT) of 50.

Most clinicians would welcome more robust outcomes data on ezetimibe, but to date none have been published.

The largest meta-analysis of ezetimibe trials—published prior to IMPROVE-IT—combined 31,048 patients to find an ARR for myocardial infarction of 1.1% (NNT=91) and an ARR for stroke of 0.6% (NNT=167), with no difference in cardiovascular death.²

Because of its limited outcomes data, ezetimibe is best reserved for patients unable to tolerate statin therapy, for those in whom statin therapy is contraindicated, or for those not meeting LDL-C reduction goals with a statin alone. This position is also supported by the United Kingdom’s National Institute for Health and Care Excellence (NICE).³

Finally, you are correct that the 2013 American College of Cardiology/American Heart Association Guideline on the Assessment of Cardiovascular Risk does not advocate a number-driven LDL-C goal, but rather recommends a risk-based moderate (30%-50%) or high-intensity (>50%) LDL-C reduction goal.⁴

Jonathon Firnhaber, MD
Greenville, NC

1. Cannon C, Blazing M, Giugliano R, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.

2. Savarese G, Ferrari G, Rosano G, et al. Safety and efficacy of ezetimibe: a meta-analysis. Int J Cardiol. 2015;201:247-252.

3. National Institute for Health and Care Excellence. Ezetimibe for treating primary heterozygous-familial and non-familial hypercholesterolaemia. Technology appraisal guidance [TA385]. February 24, 2016. www.nice.org.uk/guidance/ta385. Accessed September 12, 2018.

4. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2935-2959. 

Although I look forward to receiving JFP each month, I was initially disappointed in Dr. Jonathon M. Firnhaber’s article, “Newer cholesterol-lowering agents: What you must know” (J Fam Pract. 2018;67:339-341,344,345), because of what appeared to be a superficial discussion of the medication ezetimibe. The potential role of PCSK9 inhibitors in extremely high-risk individuals was well discussed, but my first read left me with the impression that ezetimibe should be used more widely.

It seemed that in the section for ezetimibe, the author was suggesting using it for primary prevention. The line, “Consider adding ezetimibe to maximally tolerated statin therapy for patients not meeting LDL-C goals with a statin alone” left me a bit confused, as the most widely used guideline (that by the American College of Cardiology/American Heart Association Task Force on Practice Guidelines) states that there is no goal low-density lipoprotein cholesterol (LDL-C) level for primary prevention in patients without known cardiovascular disease (CVD) because studies have not been done to support this concept.¹

But upon rereading the article, I realized the statement was placed at the end of a section that discussed secondary prevention based on the IMPROVE-IT study.² This trial included only patients with previous acute coronary syndrome, one of the populations at highest risk.

I write just to reinforce the importance of considering what evidence we have for primary prevention. Although there is a value to rechecking LDL-C levels to assess compliance, there really is no convincing evidence that we should treat to a goal LDL-C level in someone who does not already have CVD. So the addition of ezetimibe to a statin in these patients is not recommended. Thus, the often-quoted strategy: “Start them on the right statin, and don’t look back.”

Bill Crump, MD
Madisonville, Ky

1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(suppl 2):S1-S45.

2. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.

Continue to: Authors' response

Author’s response:

Thank you, Dr. Crump, for your feedback. I suspect that most clinicians would welcome more robust outcomes data on ezetimibe, but to date none have been published.

The IMPROVE-IT trial¹ offers the best supportive evidence for the use of ezetimibe, but still finds only a 2% absolute risk reduction (ARR) in a composite endpoint (cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization ≥30 days after randomization, or nonfatal stroke), equating to a number needed to treat (NNT) of 50.

Most clinicians would welcome more robust outcomes data on ezetimibe, but to date none have been published.

The largest meta-analysis of ezetimibe trials—published prior to IMPROVE-IT—combined 31,048 patients to find an ARR for myocardial infarction of 1.1% (NNT=91) and an ARR for stroke of 0.6% (NNT=167), with no difference in cardiovascular death.²

Because of its limited outcomes data, ezetimibe is best reserved for patients unable to tolerate statin therapy, for those in whom statin therapy is contraindicated, or for those not meeting LDL-C reduction goals with a statin alone. This position is also supported by the United Kingdom’s National Institute for Health and Care Excellence (NICE).³

Finally, you are correct that the 2013 American College of Cardiology/American Heart Association Guideline on the Assessment of Cardiovascular Risk does not advocate a number-driven LDL-C goal, but rather recommends a risk-based moderate (30%-50%) or high-intensity (>50%) LDL-C reduction goal.⁴

Jonathon Firnhaber, MD
Greenville, NC

1. Cannon C, Blazing M, Giugliano R, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.

2. Savarese G, Ferrari G, Rosano G, et al. Safety and efficacy of ezetimibe: a meta-analysis. Int J Cardiol. 2015;201:247-252.

3. National Institute for Health and Care Excellence. Ezetimibe for treating primary heterozygous-familial and non-familial hypercholesterolaemia. Technology appraisal guidance [TA385]. February 24, 2016. www.nice.org.uk/guidance/ta385. Accessed September 12, 2018.

4. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2935-2959. 

Although I look forward to receiving JFP each month, I was initially disappointed in Dr. Jonathon M. Firnhaber’s article, “Newer cholesterol-lowering agents: What you must know” (J Fam Pract. 2018;67:339-341,344,345), because of what appeared to be a superficial discussion of the medication ezetimibe. The potential role of PCSK9 inhibitors in extremely high-risk individuals was well discussed, but my first read left me with the impression that ezetimibe should be used more widely.

It seemed that in the section for ezetimibe, the author was suggesting using it for primary prevention. The line, “Consider adding ezetimibe to maximally tolerated statin therapy for patients not meeting LDL-C goals with a statin alone” left me a bit confused, as the most widely used guideline (that by the American College of Cardiology/American Heart Association Task Force on Practice Guidelines) states that there is no goal low-density lipoprotein cholesterol (LDL-C) level for primary prevention in patients without known cardiovascular disease (CVD) because studies have not been done to support this concept.¹

But upon rereading the article, I realized the statement was placed at the end of a section that discussed secondary prevention based on the IMPROVE-IT study.² This trial included only patients with previous acute coronary syndrome, one of the populations at highest risk.

I write just to reinforce the importance of considering what evidence we have for primary prevention. Although there is a value to rechecking LDL-C levels to assess compliance, there really is no convincing evidence that we should treat to a goal LDL-C level in someone who does not already have CVD. So the addition of ezetimibe to a statin in these patients is not recommended. Thus, the often-quoted strategy: “Start them on the right statin, and don’t look back.”

Bill Crump, MD
Madisonville, Ky

1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(suppl 2):S1-S45.

2. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.

Continue to: Authors' response

Author’s response:

Thank you, Dr. Crump, for your feedback. I suspect that most clinicians would welcome more robust outcomes data on ezetimibe, but to date none have been published.

The IMPROVE-IT trial¹ offers the best supportive evidence for the use of ezetimibe, but still finds only a 2% absolute risk reduction (ARR) in a composite endpoint (cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization ≥30 days after randomization, or nonfatal stroke), equating to a number needed to treat (NNT) of 50.

Most clinicians would welcome more robust outcomes data on ezetimibe, but to date none have been published.

The largest meta-analysis of ezetimibe trials—published prior to IMPROVE-IT—combined 31,048 patients to find an ARR for myocardial infarction of 1.1% (NNT=91) and an ARR for stroke of 0.6% (NNT=167), with no difference in cardiovascular death.²

Because of its limited outcomes data, ezetimibe is best reserved for patients unable to tolerate statin therapy, for those in whom statin therapy is contraindicated, or for those not meeting LDL-C reduction goals with a statin alone. This position is also supported by the United Kingdom’s National Institute for Health and Care Excellence (NICE).³

Finally, you are correct that the 2013 American College of Cardiology/American Heart Association Guideline on the Assessment of Cardiovascular Risk does not advocate a number-driven LDL-C goal, but rather recommends a risk-based moderate (30%-50%) or high-intensity (>50%) LDL-C reduction goal.⁴

Jonathon Firnhaber, MD
Greenville, NC

1. Cannon C, Blazing M, Giugliano R, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.

2. Savarese G, Ferrari G, Rosano G, et al. Safety and efficacy of ezetimibe: a meta-analysis. Int J Cardiol. 2015;201:247-252.

3. National Institute for Health and Care Excellence. Ezetimibe for treating primary heterozygous-familial and non-familial hypercholesterolaemia. Technology appraisal guidance [TA385]. February 24, 2016. www.nice.org.uk/guidance/ta385. Accessed September 12, 2018.

4. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2935-2959. 

Frailty defined as functional dependence is a predictor of mortality risk in elderly patients having major vascular surgery, a meta-analysis of studies has found

“Functional dependency may be recommended for use in rapid screening for frailty in major vascular surgery because of the high quality of associated evidence. Additionally, information on central muscle mass also adds incremental predictive value to long-term survival of elderly patients after major vascular surgery,” the study investigaters stated. However, they pointed out that “other newly developed frailty tools require further validation in more studies” before they should be adopted.

The report, published in the European Journal of Vascular and Endovascular Surgery, evaluated the effect of frailty in major vascular surgery from a search of MEDLINE, Embase, Cochrane Database, and Scopus through May 2018. Data were extracted from the articles related to surgery for abdominal aortic aneurysms (AAA) and lower extremity artery disease (LEAD), and a modified Newcastle-Ottawa scale was used to assess the quality of the included studies, according to Jiarong Wang, MD, of the department of vascular surgery, Sichuan University, Sichuan Province, China, and colleagues. A total of 22 cohort studies and one randomized controlled trial was used in the final analysis. The reviewers expressed the impact of frailty on outcomes as odds ratios (OR) or hazard ratios (HR) using a random effects model.

The researchers found that frailty, in terms of functional dependence, was associated with a significantly increased 30-day mortality risk in patients with AAA without heterogeneity (OR 5.15) and also in LEAD patients (OR 3.29). Functionally dependent patients also had a significantly increased 30-day mortality risk, compared with independent patients (OR 4.49), and similar results were observed after stratifying those who underwent AAA repair (OR 5.14) or lower extremity revascularization (OR 4.18). Even for patients who underwent endovascular procedures rather than open surgery, functional dependency was also associated with a significantly increased 30-day mortality risk (OR 4.90). In addition, with regard to 30-day morbidity, frailty was associated with a significantly increased risk in both AAA (OR 2.79) and LEAD (OR 1.40) patients.

As far as long-term outcomes were concerned, frailty was associated with a significantly increased risk of long-term all-cause mortality in the overall studied population (HR 2.22), as well as in patients with AAA repair (HR 2.10) and LEAD revascularization (HR 2.46). Dr. Wang and colleagues found that central muscle mass was the only tool with moderate quality of evidence predicting long-term survival after major vascular surgery (HR .48), with other single-domain tools such as nutrition or cognition scoring being of low quality. The modified Frailty Index was the only multi-domain tool with moderate quality in predicting mortality for AAA, while others were scored as low or very low, the authors added.

“Future research is warranted to establish consensus on how to select the optimal frailty tool for certain clinical settings,” they concluded.

The authors reported that they had no conflicts of interest and no funding sources for the study.
 

SOURCE: Wang, J et al. Eur J Vasc Endovasc Surg. 2018;56:591-602.

Frailty defined as functional dependence is a predictor of mortality risk in elderly patients having major vascular surgery, a meta-analysis of studies has found

“Functional dependency may be recommended for use in rapid screening for frailty in major vascular surgery because of the high quality of associated evidence. Additionally, information on central muscle mass also adds incremental predictive value to long-term survival of elderly patients after major vascular surgery,” the study investigaters stated. However, they pointed out that “other newly developed frailty tools require further validation in more studies” before they should be adopted.

The report, published in the European Journal of Vascular and Endovascular Surgery, evaluated the effect of frailty in major vascular surgery from a search of MEDLINE, Embase, Cochrane Database, and Scopus through May 2018. Data were extracted from the articles related to surgery for abdominal aortic aneurysms (AAA) and lower extremity artery disease (LEAD), and a modified Newcastle-Ottawa scale was used to assess the quality of the included studies, according to Jiarong Wang, MD, of the department of vascular surgery, Sichuan University, Sichuan Province, China, and colleagues. A total of 22 cohort studies and one randomized controlled trial was used in the final analysis. The reviewers expressed the impact of frailty on outcomes as odds ratios (OR) or hazard ratios (HR) using a random effects model.

The researchers found that frailty, in terms of functional dependence, was associated with a significantly increased 30-day mortality risk in patients with AAA without heterogeneity (OR 5.15) and also in LEAD patients (OR 3.29). Functionally dependent patients also had a significantly increased 30-day mortality risk, compared with independent patients (OR 4.49), and similar results were observed after stratifying those who underwent AAA repair (OR 5.14) or lower extremity revascularization (OR 4.18). Even for patients who underwent endovascular procedures rather than open surgery, functional dependency was also associated with a significantly increased 30-day mortality risk (OR 4.90). In addition, with regard to 30-day morbidity, frailty was associated with a significantly increased risk in both AAA (OR 2.79) and LEAD (OR 1.40) patients.

As far as long-term outcomes were concerned, frailty was associated with a significantly increased risk of long-term all-cause mortality in the overall studied population (HR 2.22), as well as in patients with AAA repair (HR 2.10) and LEAD revascularization (HR 2.46). Dr. Wang and colleagues found that central muscle mass was the only tool with moderate quality of evidence predicting long-term survival after major vascular surgery (HR .48), with other single-domain tools such as nutrition or cognition scoring being of low quality. The modified Frailty Index was the only multi-domain tool with moderate quality in predicting mortality for AAA, while others were scored as low or very low, the authors added.

“Future research is warranted to establish consensus on how to select the optimal frailty tool for certain clinical settings,” they concluded.

The authors reported that they had no conflicts of interest and no funding sources for the study.
 

SOURCE: Wang, J et al. Eur J Vasc Endovasc Surg. 2018;56:591-602.

Frailty defined as functional dependence is a predictor of mortality risk in elderly patients having major vascular surgery, a meta-analysis of studies has found

“Functional dependency may be recommended for use in rapid screening for frailty in major vascular surgery because of the high quality of associated evidence. Additionally, information on central muscle mass also adds incremental predictive value to long-term survival of elderly patients after major vascular surgery,” the study investigaters stated. However, they pointed out that “other newly developed frailty tools require further validation in more studies” before they should be adopted.

The report, published in the European Journal of Vascular and Endovascular Surgery, evaluated the effect of frailty in major vascular surgery from a search of MEDLINE, Embase, Cochrane Database, and Scopus through May 2018. Data were extracted from the articles related to surgery for abdominal aortic aneurysms (AAA) and lower extremity artery disease (LEAD), and a modified Newcastle-Ottawa scale was used to assess the quality of the included studies, according to Jiarong Wang, MD, of the department of vascular surgery, Sichuan University, Sichuan Province, China, and colleagues. A total of 22 cohort studies and one randomized controlled trial was used in the final analysis. The reviewers expressed the impact of frailty on outcomes as odds ratios (OR) or hazard ratios (HR) using a random effects model.

The researchers found that frailty, in terms of functional dependence, was associated with a significantly increased 30-day mortality risk in patients with AAA without heterogeneity (OR 5.15) and also in LEAD patients (OR 3.29). Functionally dependent patients also had a significantly increased 30-day mortality risk, compared with independent patients (OR 4.49), and similar results were observed after stratifying those who underwent AAA repair (OR 5.14) or lower extremity revascularization (OR 4.18). Even for patients who underwent endovascular procedures rather than open surgery, functional dependency was also associated with a significantly increased 30-day mortality risk (OR 4.90). In addition, with regard to 30-day morbidity, frailty was associated with a significantly increased risk in both AAA (OR 2.79) and LEAD (OR 1.40) patients.

As far as long-term outcomes were concerned, frailty was associated with a significantly increased risk of long-term all-cause mortality in the overall studied population (HR 2.22), as well as in patients with AAA repair (HR 2.10) and LEAD revascularization (HR 2.46). Dr. Wang and colleagues found that central muscle mass was the only tool with moderate quality of evidence predicting long-term survival after major vascular surgery (HR .48), with other single-domain tools such as nutrition or cognition scoring being of low quality. The modified Frailty Index was the only multi-domain tool with moderate quality in predicting mortality for AAA, while others were scored as low or very low, the authors added.

“Future research is warranted to establish consensus on how to select the optimal frailty tool for certain clinical settings,” they concluded.

The authors reported that they had no conflicts of interest and no funding sources for the study.
 

SOURCE: Wang, J et al. Eur J Vasc Endovasc Surg. 2018;56:591-602.

BARCELONA – Amyloid PET brain imaging changed clinical management in 60% of patients with a diagnosis of mild cognitive impairment or dementia and confirmed a presumptive Alzheimer’s diagnosis in 95% of those with positive scans.

But the scans also benefited amyloid-negative patients, Gil Rabinovici, MD, said at the Clinical Trials on Alzheimer’s Disease conference. Before the test, 71% carried an Alzheimer’s disease (AD) diagnosis; after the test, just 10% did, opening the way for an accurate diagnosis and more effective treatment.

“These patients were saved from unnecessary treatment for Alzheimer’s,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. They received more suitable care plans because of the confirmation.

He presented final results of aim one of the IDEAS (Imaging Dementia–Evidence for Amyloid Scanning) study, which seeks to prove that amyloid imaging changes clinical management and improves health outcomes in Medicare beneficiaries who have been diagnosed with mild cognitive impairment (MCI) or dementia of uncertain cause. Its two aims are to show that amyloid PET imaging affects a patient’s care plan within 3 months of the scan and that this impacts major medical outcomes 12 months later. In diagnostically uncertain cases, investigators theorized, amyloid PET imaging would lead to significant changes in patient management, which would then translate into improved medical outcomes.

Ultimately, investigators hope the U.S.-wide, open-label study will prove the clinical value of amyloid PET scanning and convince the Centers for Medicare & Medicaid Services to make the test a fully covered service.

So far, IDEAS has accrued data on 11,409 patients and is quickly closing in on the 18,000-patient target. The patients reported on at CTAD were aged a mean of 75 years and were largely white; only 4% were black and 4% Hispanic. The mean Mini-Mental Scale Exam score was 26. AD was the leading suspect pathology in 73% of the 6,905 with MCI and in 83% of those with dementia of uncertain etiology. Overall, 44% were taking AD medications at baseline.

Scans were positive in 55% of those with MCI and in 70% of those with dementia. Overall, the scans changed clinical management in 61% (7,018), including 60% of those with MCI and 63% of those with dementia.

“We also asked physicians how much the scan results contributed to these changes, and 86.7% replied that they ‘contributed significantly,’ ” Dr. Rabinovici said.

Most changes involved adjustments to medication. AD drugs were started in 44% of MCI patients and in 45% of dementia patients, and non-AD drugs started in 22% and 25%, respectively. About a fifth of the patients received counseling in wake of the scan results.

Medication adjustments also varied by scan result. Among amyloid-positive MCI patients, AD drug use increased from 40% before imaging to 81% after; among amyloid-negative MCI patients, drug use decreased slightly from 27% to 24%. Among amyloid-positive dementia patients, AD drug use increased from 63% to 91%, and among amyloid-negative patients, it dropped from 50% to 44%. All these changes were statistically significant.

The primary diagnosis changed from AD to non-AD in 25%, and from non-AD to AD in 10%. Among amyloid-positive patients, the diagnosis prevalence jumped from 80.0% to 95.5%; among amyloid-negative patients, it dropped from 71% to just 10%.

“IDEAS now provides the strongest data we have supporting the beneficial impact of amyloid PET on patient management,” said Dr. Rabinovici. “Aim two, which is the 12-month health outcomes, we expect to be completed by the end of next year.”

The IDEAS team is also looking at a furthering the investigation with a study called, aptly, “NEW IDEAS.” That would reach out to recruit the minorities that were so underrepresented in the main study and include patients with early-onset MCI or dementia. Building up a library of DNA and blood plasma samples might also fit into the new project.

IDEAS is a funding collaboration of the CMS, the Alzheimer’s Association, Avid Radiopharmaceuticals/Eli Lilly, General Electric Healthcare, Piramal Imaging, and the American College of Radiology. Dr. Rabinovici had no financial disclosures.

msullivan@mdedge.com

BARCELONA – Amyloid PET brain imaging changed clinical management in 60% of patients with a diagnosis of mild cognitive impairment or dementia and confirmed a presumptive Alzheimer’s diagnosis in 95% of those with positive scans.

But the scans also benefited amyloid-negative patients, Gil Rabinovici, MD, said at the Clinical Trials on Alzheimer’s Disease conference. Before the test, 71% carried an Alzheimer’s disease (AD) diagnosis; after the test, just 10% did, opening the way for an accurate diagnosis and more effective treatment.

“These patients were saved from unnecessary treatment for Alzheimer’s,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. They received more suitable care plans because of the confirmation.

He presented final results of aim one of the IDEAS (Imaging Dementia–Evidence for Amyloid Scanning) study, which seeks to prove that amyloid imaging changes clinical management and improves health outcomes in Medicare beneficiaries who have been diagnosed with mild cognitive impairment (MCI) or dementia of uncertain cause. Its two aims are to show that amyloid PET imaging affects a patient’s care plan within 3 months of the scan and that this impacts major medical outcomes 12 months later. In diagnostically uncertain cases, investigators theorized, amyloid PET imaging would lead to significant changes in patient management, which would then translate into improved medical outcomes.

Ultimately, investigators hope the U.S.-wide, open-label study will prove the clinical value of amyloid PET scanning and convince the Centers for Medicare & Medicaid Services to make the test a fully covered service.

So far, IDEAS has accrued data on 11,409 patients and is quickly closing in on the 18,000-patient target. The patients reported on at CTAD were aged a mean of 75 years and were largely white; only 4% were black and 4% Hispanic. The mean Mini-Mental Scale Exam score was 26. AD was the leading suspect pathology in 73% of the 6,905 with MCI and in 83% of those with dementia of uncertain etiology. Overall, 44% were taking AD medications at baseline.

Scans were positive in 55% of those with MCI and in 70% of those with dementia. Overall, the scans changed clinical management in 61% (7,018), including 60% of those with MCI and 63% of those with dementia.

“We also asked physicians how much the scan results contributed to these changes, and 86.7% replied that they ‘contributed significantly,’ ” Dr. Rabinovici said.

Most changes involved adjustments to medication. AD drugs were started in 44% of MCI patients and in 45% of dementia patients, and non-AD drugs started in 22% and 25%, respectively. About a fifth of the patients received counseling in wake of the scan results.

Medication adjustments also varied by scan result. Among amyloid-positive MCI patients, AD drug use increased from 40% before imaging to 81% after; among amyloid-negative MCI patients, drug use decreased slightly from 27% to 24%. Among amyloid-positive dementia patients, AD drug use increased from 63% to 91%, and among amyloid-negative patients, it dropped from 50% to 44%. All these changes were statistically significant.

The primary diagnosis changed from AD to non-AD in 25%, and from non-AD to AD in 10%. Among amyloid-positive patients, the diagnosis prevalence jumped from 80.0% to 95.5%; among amyloid-negative patients, it dropped from 71% to just 10%.

“IDEAS now provides the strongest data we have supporting the beneficial impact of amyloid PET on patient management,” said Dr. Rabinovici. “Aim two, which is the 12-month health outcomes, we expect to be completed by the end of next year.”

The IDEAS team is also looking at a furthering the investigation with a study called, aptly, “NEW IDEAS.” That would reach out to recruit the minorities that were so underrepresented in the main study and include patients with early-onset MCI or dementia. Building up a library of DNA and blood plasma samples might also fit into the new project.

IDEAS is a funding collaboration of the CMS, the Alzheimer’s Association, Avid Radiopharmaceuticals/Eli Lilly, General Electric Healthcare, Piramal Imaging, and the American College of Radiology. Dr. Rabinovici had no financial disclosures.

msullivan@mdedge.com

BARCELONA – Amyloid PET brain imaging changed clinical management in 60% of patients with a diagnosis of mild cognitive impairment or dementia and confirmed a presumptive Alzheimer’s diagnosis in 95% of those with positive scans.

But the scans also benefited amyloid-negative patients, Gil Rabinovici, MD, said at the Clinical Trials on Alzheimer’s Disease conference. Before the test, 71% carried an Alzheimer’s disease (AD) diagnosis; after the test, just 10% did, opening the way for an accurate diagnosis and more effective treatment.

“These patients were saved from unnecessary treatment for Alzheimer’s,” said Dr. Rabinovici, the Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging at the University of California, San Francisco. They received more suitable care plans because of the confirmation.

He presented final results of aim one of the IDEAS (Imaging Dementia–Evidence for Amyloid Scanning) study, which seeks to prove that amyloid imaging changes clinical management and improves health outcomes in Medicare beneficiaries who have been diagnosed with mild cognitive impairment (MCI) or dementia of uncertain cause. Its two aims are to show that amyloid PET imaging affects a patient’s care plan within 3 months of the scan and that this impacts major medical outcomes 12 months later. In diagnostically uncertain cases, investigators theorized, amyloid PET imaging would lead to significant changes in patient management, which would then translate into improved medical outcomes.

Ultimately, investigators hope the U.S.-wide, open-label study will prove the clinical value of amyloid PET scanning and convince the Centers for Medicare & Medicaid Services to make the test a fully covered service.

So far, IDEAS has accrued data on 11,409 patients and is quickly closing in on the 18,000-patient target. The patients reported on at CTAD were aged a mean of 75 years and were largely white; only 4% were black and 4% Hispanic. The mean Mini-Mental Scale Exam score was 26. AD was the leading suspect pathology in 73% of the 6,905 with MCI and in 83% of those with dementia of uncertain etiology. Overall, 44% were taking AD medications at baseline.

Scans were positive in 55% of those with MCI and in 70% of those with dementia. Overall, the scans changed clinical management in 61% (7,018), including 60% of those with MCI and 63% of those with dementia.

“We also asked physicians how much the scan results contributed to these changes, and 86.7% replied that they ‘contributed significantly,’ ” Dr. Rabinovici said.

Most changes involved adjustments to medication. AD drugs were started in 44% of MCI patients and in 45% of dementia patients, and non-AD drugs started in 22% and 25%, respectively. About a fifth of the patients received counseling in wake of the scan results.

Medication adjustments also varied by scan result. Among amyloid-positive MCI patients, AD drug use increased from 40% before imaging to 81% after; among amyloid-negative MCI patients, drug use decreased slightly from 27% to 24%. Among amyloid-positive dementia patients, AD drug use increased from 63% to 91%, and among amyloid-negative patients, it dropped from 50% to 44%. All these changes were statistically significant.

The primary diagnosis changed from AD to non-AD in 25%, and from non-AD to AD in 10%. Among amyloid-positive patients, the diagnosis prevalence jumped from 80.0% to 95.5%; among amyloid-negative patients, it dropped from 71% to just 10%.

“IDEAS now provides the strongest data we have supporting the beneficial impact of amyloid PET on patient management,” said Dr. Rabinovici. “Aim two, which is the 12-month health outcomes, we expect to be completed by the end of next year.”

The IDEAS team is also looking at a furthering the investigation with a study called, aptly, “NEW IDEAS.” That would reach out to recruit the minorities that were so underrepresented in the main study and include patients with early-onset MCI or dementia. Building up a library of DNA and blood plasma samples might also fit into the new project.

IDEAS is a funding collaboration of the CMS, the Alzheimer’s Association, Avid Radiopharmaceuticals/Eli Lilly, General Electric Healthcare, Piramal Imaging, and the American College of Radiology. Dr. Rabinovici had no financial disclosures.

msullivan@mdedge.com

ATLANTA – Acute myocardial infarction is associated with a risk of stroke that extends beyond the 1-month time window currently considered the at-risk period, according to an analysis of Medicare data.

“The results of our study may allow clinicians to more accurately counsel patients regarding their stroke etiology and may allow refinement of stroke etiology classification systems and clinical trial selection criteria,” lead study author Alexander E. Merkler, MD, said in an interview in advance of the annual meeting of the American Neurological Association.

In an effort to better understand the duration of heightened stroke risk after acute myocardial infarction, Dr. Merkler, a neurologist at New York–based Weill Cornell Medicine, and his colleagues conducted a retrospective cohort study using inpatient and outpatient claims during 2008-2015 from a nationally representative 5% sample of Medicare beneficiaries who were at least 66 years old. They used previously validated ICD-9-CM diagnosis codes to ascertain the exposure variable of acute MI and the outcome of ischemic stroke but excluded strokes that occurred during an acute MI hospitalization.


Patients were censored at the time of ischemic stroke, death, end of Medicare coverage, or by Sept. 30, 2015. The researchers fit Cox regression models separately for the groups with and without acute MI to examine its association with ischemic stroke after adjusting for demographics, stroke risk factors, and Charlson comorbidities. Next, they used the corresponding survival probabilities to compute the hazard ratio (HR) in each 4-week interval after discharge, up to week 12. They also conducted a subgroup analysis to evaluate the duration of heightened ischemic stroke risk by MI type: ST-segment elevation MI (STEMI) versus non-STEMI (NSTEMI).

Dr. Merkler and his colleagues drew from data on 1.7 million eligible beneficiaries. Of these, 46,182 were hospitalized for acute MI and 80,466 for ischemic stroke. After they adjusted for demographics, stroke risk factors, and Charlson comorbidities, the researchers found that the risk of ischemic stroke was highest in the first 4 weeks after discharge from the MI hospitalization (HR, 2.7), yet remained elevated during weeks 5-8 (HR, 2.0) and weeks 9-12 (HR, 1.6). It was no longer significantly elevated afterward. The prolonged period of heightened ischemic stroke risk was evident in patients with both STEMI and NSTEMI.

“We were surprised by how long the risk of stroke lasts after MI,” Dr. Merkler said. He acknowledged certain limitations of the analysis, including the fact that patients were all over the age of 65 years. “In addition, we lack granular detail such as severity of MI [and] the extent of stroke work-up,” he said.

Dr. Merkler disclosed that he is supported by a grant from the National Institutes of Health and by the Leon Levy Foundation in Neuroscience. Most of his coauthors are also supported by NIH grants.

dbrunk@mdedge.com

Source: Ann Neurol. 2018;84[S22]:S146-7, Abstract M122.

ATLANTA – Acute myocardial infarction is associated with a risk of stroke that extends beyond the 1-month time window currently considered the at-risk period, according to an analysis of Medicare data.

“The results of our study may allow clinicians to more accurately counsel patients regarding their stroke etiology and may allow refinement of stroke etiology classification systems and clinical trial selection criteria,” lead study author Alexander E. Merkler, MD, said in an interview in advance of the annual meeting of the American Neurological Association.

In an effort to better understand the duration of heightened stroke risk after acute myocardial infarction, Dr. Merkler, a neurologist at New York–based Weill Cornell Medicine, and his colleagues conducted a retrospective cohort study using inpatient and outpatient claims during 2008-2015 from a nationally representative 5% sample of Medicare beneficiaries who were at least 66 years old. They used previously validated ICD-9-CM diagnosis codes to ascertain the exposure variable of acute MI and the outcome of ischemic stroke but excluded strokes that occurred during an acute MI hospitalization.


Patients were censored at the time of ischemic stroke, death, end of Medicare coverage, or by Sept. 30, 2015. The researchers fit Cox regression models separately for the groups with and without acute MI to examine its association with ischemic stroke after adjusting for demographics, stroke risk factors, and Charlson comorbidities. Next, they used the corresponding survival probabilities to compute the hazard ratio (HR) in each 4-week interval after discharge, up to week 12. They also conducted a subgroup analysis to evaluate the duration of heightened ischemic stroke risk by MI type: ST-segment elevation MI (STEMI) versus non-STEMI (NSTEMI).

Dr. Merkler and his colleagues drew from data on 1.7 million eligible beneficiaries. Of these, 46,182 were hospitalized for acute MI and 80,466 for ischemic stroke. After they adjusted for demographics, stroke risk factors, and Charlson comorbidities, the researchers found that the risk of ischemic stroke was highest in the first 4 weeks after discharge from the MI hospitalization (HR, 2.7), yet remained elevated during weeks 5-8 (HR, 2.0) and weeks 9-12 (HR, 1.6). It was no longer significantly elevated afterward. The prolonged period of heightened ischemic stroke risk was evident in patients with both STEMI and NSTEMI.

“We were surprised by how long the risk of stroke lasts after MI,” Dr. Merkler said. He acknowledged certain limitations of the analysis, including the fact that patients were all over the age of 65 years. “In addition, we lack granular detail such as severity of MI [and] the extent of stroke work-up,” he said.

Dr. Merkler disclosed that he is supported by a grant from the National Institutes of Health and by the Leon Levy Foundation in Neuroscience. Most of his coauthors are also supported by NIH grants.

dbrunk@mdedge.com

Source: Ann Neurol. 2018;84[S22]:S146-7, Abstract M122.

ATLANTA – Acute myocardial infarction is associated with a risk of stroke that extends beyond the 1-month time window currently considered the at-risk period, according to an analysis of Medicare data.

“The results of our study may allow clinicians to more accurately counsel patients regarding their stroke etiology and may allow refinement of stroke etiology classification systems and clinical trial selection criteria,” lead study author Alexander E. Merkler, MD, said in an interview in advance of the annual meeting of the American Neurological Association.

In an effort to better understand the duration of heightened stroke risk after acute myocardial infarction, Dr. Merkler, a neurologist at New York–based Weill Cornell Medicine, and his colleagues conducted a retrospective cohort study using inpatient and outpatient claims during 2008-2015 from a nationally representative 5% sample of Medicare beneficiaries who were at least 66 years old. They used previously validated ICD-9-CM diagnosis codes to ascertain the exposure variable of acute MI and the outcome of ischemic stroke but excluded strokes that occurred during an acute MI hospitalization.


Patients were censored at the time of ischemic stroke, death, end of Medicare coverage, or by Sept. 30, 2015. The researchers fit Cox regression models separately for the groups with and without acute MI to examine its association with ischemic stroke after adjusting for demographics, stroke risk factors, and Charlson comorbidities. Next, they used the corresponding survival probabilities to compute the hazard ratio (HR) in each 4-week interval after discharge, up to week 12. They also conducted a subgroup analysis to evaluate the duration of heightened ischemic stroke risk by MI type: ST-segment elevation MI (STEMI) versus non-STEMI (NSTEMI).

Dr. Merkler and his colleagues drew from data on 1.7 million eligible beneficiaries. Of these, 46,182 were hospitalized for acute MI and 80,466 for ischemic stroke. After they adjusted for demographics, stroke risk factors, and Charlson comorbidities, the researchers found that the risk of ischemic stroke was highest in the first 4 weeks after discharge from the MI hospitalization (HR, 2.7), yet remained elevated during weeks 5-8 (HR, 2.0) and weeks 9-12 (HR, 1.6). It was no longer significantly elevated afterward. The prolonged period of heightened ischemic stroke risk was evident in patients with both STEMI and NSTEMI.

“We were surprised by how long the risk of stroke lasts after MI,” Dr. Merkler said. He acknowledged certain limitations of the analysis, including the fact that patients were all over the age of 65 years. “In addition, we lack granular detail such as severity of MI [and] the extent of stroke work-up,” he said.

Dr. Merkler disclosed that he is supported by a grant from the National Institutes of Health and by the Leon Levy Foundation in Neuroscience. Most of his coauthors are also supported by NIH grants.

dbrunk@mdedge.com

Source: Ann Neurol. 2018;84[S22]:S146-7, Abstract M122.

ATLANTA – Following an acute stroke, optimizing stroke secondary prevention measures, medical complications, and transitions of care is essential to reducing 30-day readmissions and improving patient outcomes, a large analysis of national data showed.

Doug Brunk/MDedge News

“Care that is fragmented with readmissions to other hospitals results not only in more expensive care and longer length of stay but also increased mortality for our acute stroke patients,” lead study author Laura K. Stein, MD, said in an interview in advance of the annual meeting of the American Neurological Association.

In 2017, a study of the Nationwide Readmissions Database demonstrated that 12.1% of patients with acute ischemic stroke were readmitted within 30 days (Stroke 2017;48:1386-8). It cited that 89.6% were unplanned and 12.9% were preventable. “However, this study did not examine whether patients were admitted to the discharging hospital or a different hospital,” said Dr. Stein, a neurologist at the Icahn School of Medicine at Mount Sinai, New York. “Furthermore, it did not include metrics such as cost, length of stay, and mortality with 30-day readmissions. Hospitals are increasingly held accountable and penalized for metrics such as length of stay and 30-day readmissions.”

In 2010, the Centers for Medicare & Medicaid Services introduced the Hospital Readmissions Reduction Program in an attempt to decrease readmissions following hospitalizations for acute myocardial infarction, heart failure, and pneumonia. “In 2012, CMS started reducing Medicare payments for hospitals with excess readmissions,” said Dr. Stein, who is a fellowship-trained stroke specialist. “While readmission to the same hospital has great implications for hospital systems, any readmission has great implications for patients.”

In what is believed to be the first study of its kind, Dr. Stein and her colleagues drew from the 2013 Nationwide Readmissions Database to examine in-hospital outcomes associated with 30-day readmission to a different hospital for acute ischemic stroke. They used ICD-9 codes to identify index stroke admissions and all-cause readmissions. Outcomes of interest were length of stay, total charges, and in-hospital mortality during the 30-day readmission. The main predictor was readmission to another hospital, compared with readmission to the same hospital as the index acute stroke admission. The researchers used linear regression for the outcomes of length of stay and charges, and logistic regression for in-hospital mortality. They adjusted for several variables during the index admission, including age, sex, vascular risk factors, hospital bed size, teaching hospital status, insurance status, discharge destination, National Center for Health Statistics urban-rural location classification, length of stay, and total charges.

Of 24,545 acute stroke patients readmitted within 30 days, 7,274 (30%) were readmitted to a different hospital. The top three reasons for readmission were acute cerebrovascular disease, septicemia, and renal failure. In fully adjusted models, readmission to a different hospital was associated with an increased length of stay of 0.97 days (P less than .0001) and a mean of $7,677.28 greater total charges, compared with readmission to the same hospital (P less than .0001). The fully adjusted odds ratio for in-hospital mortality during readmission was 1.17 for readmission to another hospital vs. readmission to the same hospital (P = .0079).

“While it is conceivable that cost and length of stay could be higher with readmission to a different hospital because of a need for additional testing with a lack of familiarity with the patient, it is concerning that mortality is higher,” Dr. Stein said. “These findings emphasize the importance of optimizing secondary stroke prevention and medical complications following acute stroke before discharge. Additionally, they emphasize the importance of good transitions of care from the inpatient to outpatient setting (whether that’s to a rehabilitation facility, skilled nursing facility, or home) and accessibility of the discharging stroke team after discharge.”

She acknowledged certain limitations of the analysis, including its reliance of administrative data, which could include misclassification of diagnoses and comorbidities based on ICD-9 codes. “However, we have chosen ICD-9 codes for stroke that have been previously validated in the literature,” Dr. Stein said. “For instance, the validated codes for stroke as the primary discharge diagnosis have a sensitivity of 74%, specificity of 95%, and positive predictive value of 88%. Second, we do not know stroke subtype or severity of stroke. Third, we do not know what the transitions of care plan were when the patients left the hospital following index acute ischemic stroke admission and why these patients ended up being readmitted to a different hospital rather than the one that treated them for their acute stroke.”

The researchers reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Stein L et al. Ann Neurol. 2018;84[S22]:S149. Abstract M127.

ATLANTA – Following an acute stroke, optimizing stroke secondary prevention measures, medical complications, and transitions of care is essential to reducing 30-day readmissions and improving patient outcomes, a large analysis of national data showed.

Doug Brunk/MDedge News

“Care that is fragmented with readmissions to other hospitals results not only in more expensive care and longer length of stay but also increased mortality for our acute stroke patients,” lead study author Laura K. Stein, MD, said in an interview in advance of the annual meeting of the American Neurological Association.

In 2017, a study of the Nationwide Readmissions Database demonstrated that 12.1% of patients with acute ischemic stroke were readmitted within 30 days (Stroke 2017;48:1386-8). It cited that 89.6% were unplanned and 12.9% were preventable. “However, this study did not examine whether patients were admitted to the discharging hospital or a different hospital,” said Dr. Stein, a neurologist at the Icahn School of Medicine at Mount Sinai, New York. “Furthermore, it did not include metrics such as cost, length of stay, and mortality with 30-day readmissions. Hospitals are increasingly held accountable and penalized for metrics such as length of stay and 30-day readmissions.”

In 2010, the Centers for Medicare & Medicaid Services introduced the Hospital Readmissions Reduction Program in an attempt to decrease readmissions following hospitalizations for acute myocardial infarction, heart failure, and pneumonia. “In 2012, CMS started reducing Medicare payments for hospitals with excess readmissions,” said Dr. Stein, who is a fellowship-trained stroke specialist. “While readmission to the same hospital has great implications for hospital systems, any readmission has great implications for patients.”

In what is believed to be the first study of its kind, Dr. Stein and her colleagues drew from the 2013 Nationwide Readmissions Database to examine in-hospital outcomes associated with 30-day readmission to a different hospital for acute ischemic stroke. They used ICD-9 codes to identify index stroke admissions and all-cause readmissions. Outcomes of interest were length of stay, total charges, and in-hospital mortality during the 30-day readmission. The main predictor was readmission to another hospital, compared with readmission to the same hospital as the index acute stroke admission. The researchers used linear regression for the outcomes of length of stay and charges, and logistic regression for in-hospital mortality. They adjusted for several variables during the index admission, including age, sex, vascular risk factors, hospital bed size, teaching hospital status, insurance status, discharge destination, National Center for Health Statistics urban-rural location classification, length of stay, and total charges.

Of 24,545 acute stroke patients readmitted within 30 days, 7,274 (30%) were readmitted to a different hospital. The top three reasons for readmission were acute cerebrovascular disease, septicemia, and renal failure. In fully adjusted models, readmission to a different hospital was associated with an increased length of stay of 0.97 days (P less than .0001) and a mean of $7,677.28 greater total charges, compared with readmission to the same hospital (P less than .0001). The fully adjusted odds ratio for in-hospital mortality during readmission was 1.17 for readmission to another hospital vs. readmission to the same hospital (P = .0079).

“While it is conceivable that cost and length of stay could be higher with readmission to a different hospital because of a need for additional testing with a lack of familiarity with the patient, it is concerning that mortality is higher,” Dr. Stein said. “These findings emphasize the importance of optimizing secondary stroke prevention and medical complications following acute stroke before discharge. Additionally, they emphasize the importance of good transitions of care from the inpatient to outpatient setting (whether that’s to a rehabilitation facility, skilled nursing facility, or home) and accessibility of the discharging stroke team after discharge.”

She acknowledged certain limitations of the analysis, including its reliance of administrative data, which could include misclassification of diagnoses and comorbidities based on ICD-9 codes. “However, we have chosen ICD-9 codes for stroke that have been previously validated in the literature,” Dr. Stein said. “For instance, the validated codes for stroke as the primary discharge diagnosis have a sensitivity of 74%, specificity of 95%, and positive predictive value of 88%. Second, we do not know stroke subtype or severity of stroke. Third, we do not know what the transitions of care plan were when the patients left the hospital following index acute ischemic stroke admission and why these patients ended up being readmitted to a different hospital rather than the one that treated them for their acute stroke.”

The researchers reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Stein L et al. Ann Neurol. 2018;84[S22]:S149. Abstract M127.

ATLANTA – Following an acute stroke, optimizing stroke secondary prevention measures, medical complications, and transitions of care is essential to reducing 30-day readmissions and improving patient outcomes, a large analysis of national data showed.

Doug Brunk/MDedge News

“Care that is fragmented with readmissions to other hospitals results not only in more expensive care and longer length of stay but also increased mortality for our acute stroke patients,” lead study author Laura K. Stein, MD, said in an interview in advance of the annual meeting of the American Neurological Association.

In 2017, a study of the Nationwide Readmissions Database demonstrated that 12.1% of patients with acute ischemic stroke were readmitted within 30 days (Stroke 2017;48:1386-8). It cited that 89.6% were unplanned and 12.9% were preventable. “However, this study did not examine whether patients were admitted to the discharging hospital or a different hospital,” said Dr. Stein, a neurologist at the Icahn School of Medicine at Mount Sinai, New York. “Furthermore, it did not include metrics such as cost, length of stay, and mortality with 30-day readmissions. Hospitals are increasingly held accountable and penalized for metrics such as length of stay and 30-day readmissions.”

In 2010, the Centers for Medicare & Medicaid Services introduced the Hospital Readmissions Reduction Program in an attempt to decrease readmissions following hospitalizations for acute myocardial infarction, heart failure, and pneumonia. “In 2012, CMS started reducing Medicare payments for hospitals with excess readmissions,” said Dr. Stein, who is a fellowship-trained stroke specialist. “While readmission to the same hospital has great implications for hospital systems, any readmission has great implications for patients.”

In what is believed to be the first study of its kind, Dr. Stein and her colleagues drew from the 2013 Nationwide Readmissions Database to examine in-hospital outcomes associated with 30-day readmission to a different hospital for acute ischemic stroke. They used ICD-9 codes to identify index stroke admissions and all-cause readmissions. Outcomes of interest were length of stay, total charges, and in-hospital mortality during the 30-day readmission. The main predictor was readmission to another hospital, compared with readmission to the same hospital as the index acute stroke admission. The researchers used linear regression for the outcomes of length of stay and charges, and logistic regression for in-hospital mortality. They adjusted for several variables during the index admission, including age, sex, vascular risk factors, hospital bed size, teaching hospital status, insurance status, discharge destination, National Center for Health Statistics urban-rural location classification, length of stay, and total charges.

Of 24,545 acute stroke patients readmitted within 30 days, 7,274 (30%) were readmitted to a different hospital. The top three reasons for readmission were acute cerebrovascular disease, septicemia, and renal failure. In fully adjusted models, readmission to a different hospital was associated with an increased length of stay of 0.97 days (P less than .0001) and a mean of $7,677.28 greater total charges, compared with readmission to the same hospital (P less than .0001). The fully adjusted odds ratio for in-hospital mortality during readmission was 1.17 for readmission to another hospital vs. readmission to the same hospital (P = .0079).

“While it is conceivable that cost and length of stay could be higher with readmission to a different hospital because of a need for additional testing with a lack of familiarity with the patient, it is concerning that mortality is higher,” Dr. Stein said. “These findings emphasize the importance of optimizing secondary stroke prevention and medical complications following acute stroke before discharge. Additionally, they emphasize the importance of good transitions of care from the inpatient to outpatient setting (whether that’s to a rehabilitation facility, skilled nursing facility, or home) and accessibility of the discharging stroke team after discharge.”

She acknowledged certain limitations of the analysis, including its reliance of administrative data, which could include misclassification of diagnoses and comorbidities based on ICD-9 codes. “However, we have chosen ICD-9 codes for stroke that have been previously validated in the literature,” Dr. Stein said. “For instance, the validated codes for stroke as the primary discharge diagnosis have a sensitivity of 74%, specificity of 95%, and positive predictive value of 88%. Second, we do not know stroke subtype or severity of stroke. Third, we do not know what the transitions of care plan were when the patients left the hospital following index acute ischemic stroke admission and why these patients ended up being readmitted to a different hospital rather than the one that treated them for their acute stroke.”

The researchers reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Stein L et al. Ann Neurol. 2018;84[S22]:S149. Abstract M127.

Adults aged 65 years and older with a self-harm history are more likely to die from unnatural causes – specifically suicide – than are those who do not self-harm, according to what researchers called the first study of self-harm that exclusively focused on older adults from the perspective of primary care.

giocalde/Thinkstock

“This work should alert policy makers and primary health care professionals to progress towards implementing preventive measures among older adults who consult with a GP,” lead author Catharine Morgan, PhD, and her coauthors, wrote in the Lancet Psychiatry.

The study, which reviewed the primary care records of 4,124 older adults in the United Kingdom with incidents of self-harm, found that older adults were infrequently referred to mental health specialists while being prescribed potentially toxic tricyclic antidepressants at a high proportion, said Dr. Morgan, of the National Institute for Health Research (NIHR) Greater Manchester (England) Patient Safety Translational Research Centre at the University of Manchester, and her coauthors. They also noted that, “compared with their peers who had not harmed themselves, adults in the self-harm cohort were an estimated 20 times more likely to die unnaturally during the first year after a self-harm episode and three or four times more likely to die unnaturally in subsequent years.”

The coauthors also found that, compared with a comparison cohort, the prevalence of a previous mental illness was twice as high among older adults who had engaged in self-harm (hazard ratio, 2.10; 95% confidence interval, 2.03-2.17). Older adults with a self-harm history also had a 20% higher prevalence of a physical illness (HR, 1.20; 95% CI, 1.17-1.23), compared with those without such a history.

Dr. Morgan and her coauthors also uncovered differing likelihoods of referral to specialists, depending on socioeconomic status of the surrounding area. Older patients in “more socially deprived localities” were less likely to be referred to mental health services. Women also were more likely than men were to be referred, highlighting “an important target for improvement across the health care system.” They also recommended avoiding tricyclics for older patients and encouraged maintaining “frequent medication reviews after self-harm.”

The coauthors noted potential limitations in their study, including reliance on clinicians who entered the primary care records and reluctance of coroners to report suicide as the cause of death in certain scenarios. However, they strongly encouraged general practitioners to intervene early and consider alternative medications when treating older patients who exhibit risk factors.

“Health care professionals should take the opportunity to consider the risk of self-harm when an older person consults with other health problems, especially when major physical illnesses and psychopathology are both present, to reduce the risk of an escalation in self-harming behaviour and associated mortality,” they wrote.

The NIHR Greater Manchester Patient Safety Translational Research Centre funded the study. Dr. Morgan and three of her coauthors declared no conflicts of interest. Two authors reported grants from the NIHR, and one author reported grants from the Department of Health and Social Care and the Healthcare Quality Improvement Partnership.

SOURCE: Morgan C et al. Lancet Psychiatry. 2018 Oct 15. doi: 10.1016/S2215-0366(18)30348-1.

Adults aged 65 years and older with a self-harm history are more likely to die from unnatural causes – specifically suicide – than are those who do not self-harm, according to what researchers called the first study of self-harm that exclusively focused on older adults from the perspective of primary care.

giocalde/Thinkstock

“This work should alert policy makers and primary health care professionals to progress towards implementing preventive measures among older adults who consult with a GP,” lead author Catharine Morgan, PhD, and her coauthors, wrote in the Lancet Psychiatry.

The study, which reviewed the primary care records of 4,124 older adults in the United Kingdom with incidents of self-harm, found that older adults were infrequently referred to mental health specialists while being prescribed potentially toxic tricyclic antidepressants at a high proportion, said Dr. Morgan, of the National Institute for Health Research (NIHR) Greater Manchester (England) Patient Safety Translational Research Centre at the University of Manchester, and her coauthors. They also noted that, “compared with their peers who had not harmed themselves, adults in the self-harm cohort were an estimated 20 times more likely to die unnaturally during the first year after a self-harm episode and three or four times more likely to die unnaturally in subsequent years.”

The coauthors also found that, compared with a comparison cohort, the prevalence of a previous mental illness was twice as high among older adults who had engaged in self-harm (hazard ratio, 2.10; 95% confidence interval, 2.03-2.17). Older adults with a self-harm history also had a 20% higher prevalence of a physical illness (HR, 1.20; 95% CI, 1.17-1.23), compared with those without such a history.

Dr. Morgan and her coauthors also uncovered differing likelihoods of referral to specialists, depending on socioeconomic status of the surrounding area. Older patients in “more socially deprived localities” were less likely to be referred to mental health services. Women also were more likely than men were to be referred, highlighting “an important target for improvement across the health care system.” They also recommended avoiding tricyclics for older patients and encouraged maintaining “frequent medication reviews after self-harm.”

The coauthors noted potential limitations in their study, including reliance on clinicians who entered the primary care records and reluctance of coroners to report suicide as the cause of death in certain scenarios. However, they strongly encouraged general practitioners to intervene early and consider alternative medications when treating older patients who exhibit risk factors.

“Health care professionals should take the opportunity to consider the risk of self-harm when an older person consults with other health problems, especially when major physical illnesses and psychopathology are both present, to reduce the risk of an escalation in self-harming behaviour and associated mortality,” they wrote.

The NIHR Greater Manchester Patient Safety Translational Research Centre funded the study. Dr. Morgan and three of her coauthors declared no conflicts of interest. Two authors reported grants from the NIHR, and one author reported grants from the Department of Health and Social Care and the Healthcare Quality Improvement Partnership.

SOURCE: Morgan C et al. Lancet Psychiatry. 2018 Oct 15. doi: 10.1016/S2215-0366(18)30348-1.

Adults aged 65 years and older with a self-harm history are more likely to die from unnatural causes – specifically suicide – than are those who do not self-harm, according to what researchers called the first study of self-harm that exclusively focused on older adults from the perspective of primary care.

giocalde/Thinkstock

“This work should alert policy makers and primary health care professionals to progress towards implementing preventive measures among older adults who consult with a GP,” lead author Catharine Morgan, PhD, and her coauthors, wrote in the Lancet Psychiatry.

The study, which reviewed the primary care records of 4,124 older adults in the United Kingdom with incidents of self-harm, found that older adults were infrequently referred to mental health specialists while being prescribed potentially toxic tricyclic antidepressants at a high proportion, said Dr. Morgan, of the National Institute for Health Research (NIHR) Greater Manchester (England) Patient Safety Translational Research Centre at the University of Manchester, and her coauthors. They also noted that, “compared with their peers who had not harmed themselves, adults in the self-harm cohort were an estimated 20 times more likely to die unnaturally during the first year after a self-harm episode and three or four times more likely to die unnaturally in subsequent years.”

The coauthors also found that, compared with a comparison cohort, the prevalence of a previous mental illness was twice as high among older adults who had engaged in self-harm (hazard ratio, 2.10; 95% confidence interval, 2.03-2.17). Older adults with a self-harm history also had a 20% higher prevalence of a physical illness (HR, 1.20; 95% CI, 1.17-1.23), compared with those without such a history.

Dr. Morgan and her coauthors also uncovered differing likelihoods of referral to specialists, depending on socioeconomic status of the surrounding area. Older patients in “more socially deprived localities” were less likely to be referred to mental health services. Women also were more likely than men were to be referred, highlighting “an important target for improvement across the health care system.” They also recommended avoiding tricyclics for older patients and encouraged maintaining “frequent medication reviews after self-harm.”

The coauthors noted potential limitations in their study, including reliance on clinicians who entered the primary care records and reluctance of coroners to report suicide as the cause of death in certain scenarios. However, they strongly encouraged general practitioners to intervene early and consider alternative medications when treating older patients who exhibit risk factors.

“Health care professionals should take the opportunity to consider the risk of self-harm when an older person consults with other health problems, especially when major physical illnesses and psychopathology are both present, to reduce the risk of an escalation in self-harming behaviour and associated mortality,” they wrote.

The NIHR Greater Manchester Patient Safety Translational Research Centre funded the study. Dr. Morgan and three of her coauthors declared no conflicts of interest. Two authors reported grants from the NIHR, and one author reported grants from the Department of Health and Social Care and the Healthcare Quality Improvement Partnership.

SOURCE: Morgan C et al. Lancet Psychiatry. 2018 Oct 15. doi: 10.1016/S2215-0366(18)30348-1.

SAN FRANCISCO – An adjuvanted trivalent flu vaccine cuts the risk of hospitalizations in nursing home residents by about 6%, according to a new study presented at an annual scientific meeting on infectious diseases.

“It’s one thing to say you have a more immunogenic vaccine, it’s another thing to be able to say it offers clinical benefit, especially in the oldest old and the frailest frail,” says Stefan Gravenstein, MD, professor of medicine and health services, policy and practice at the Brown University School of Public Health, Providence, R.I. Dr. Gravenstein presented a poster outlying a randomized, clinical trial of the Fluad vaccine in nursing homes.

The study randomized the nursing homes so that some facilities would offer Fluad as part of their standard of care. The design helped address the problem of consent. Any clinical trial that requires individual consent would likely exclude many of the frailest patients, leading to an unrepresentative sample. “So if you want to have a generalizable result, you’d like to have it applied to the population the way you would in the real world, so randomizing the nursing homes rather than the people makes a lot of sense,” said Dr. Gravenstein.

Dr. Gravenstein chose to test the vaccine in nursing home residents, hoping to see a signal in a population in which flu complications are more common. “If you can get a difference in a nursing home population, that’s clinically important, that gives you hope that you can see it in all the other populations, too,” he said.

SOURCE: Gravenstein S et al. IDWeek 2018, Abstract 996.

SAN FRANCISCO – An adjuvanted trivalent flu vaccine cuts the risk of hospitalizations in nursing home residents by about 6%, according to a new study presented at an annual scientific meeting on infectious diseases.

“It’s one thing to say you have a more immunogenic vaccine, it’s another thing to be able to say it offers clinical benefit, especially in the oldest old and the frailest frail,” says Stefan Gravenstein, MD, professor of medicine and health services, policy and practice at the Brown University School of Public Health, Providence, R.I. Dr. Gravenstein presented a poster outlying a randomized, clinical trial of the Fluad vaccine in nursing homes.

The study randomized the nursing homes so that some facilities would offer Fluad as part of their standard of care. The design helped address the problem of consent. Any clinical trial that requires individual consent would likely exclude many of the frailest patients, leading to an unrepresentative sample. “So if you want to have a generalizable result, you’d like to have it applied to the population the way you would in the real world, so randomizing the nursing homes rather than the people makes a lot of sense,” said Dr. Gravenstein.

Dr. Gravenstein chose to test the vaccine in nursing home residents, hoping to see a signal in a population in which flu complications are more common. “If you can get a difference in a nursing home population, that’s clinically important, that gives you hope that you can see it in all the other populations, too,” he said.

SOURCE: Gravenstein S et al. IDWeek 2018, Abstract 996.

SAN FRANCISCO – An adjuvanted trivalent flu vaccine cuts the risk of hospitalizations in nursing home residents by about 6%, according to a new study presented at an annual scientific meeting on infectious diseases.

“It’s one thing to say you have a more immunogenic vaccine, it’s another thing to be able to say it offers clinical benefit, especially in the oldest old and the frailest frail,” says Stefan Gravenstein, MD, professor of medicine and health services, policy and practice at the Brown University School of Public Health, Providence, R.I. Dr. Gravenstein presented a poster outlying a randomized, clinical trial of the Fluad vaccine in nursing homes.

The study randomized the nursing homes so that some facilities would offer Fluad as part of their standard of care. The design helped address the problem of consent. Any clinical trial that requires individual consent would likely exclude many of the frailest patients, leading to an unrepresentative sample. “So if you want to have a generalizable result, you’d like to have it applied to the population the way you would in the real world, so randomizing the nursing homes rather than the people makes a lot of sense,” said Dr. Gravenstein.

Dr. Gravenstein chose to test the vaccine in nursing home residents, hoping to see a signal in a population in which flu complications are more common. “If you can get a difference in a nursing home population, that’s clinically important, that gives you hope that you can see it in all the other populations, too,” he said.

SOURCE: Gravenstein S et al. IDWeek 2018, Abstract 996.

ATLANTA – Postlicensure surveillance of a trivalent adjuvanted influenza vaccine approved in 2015 for adults aged 65 years and older revealed no new or unexpected patterns of adverse events, according to an analysis of reports to the Vaccine Adverse Event Reporting System (VAERS) during July 2016 through March 2018.

Wavebreakmedia/Thinkstock

VAERS received 630 reports related to the vaccine (aIIV3; FLUAD) during the study period, of which 521 involved adults aged 65 years and older.

“Eighteen (3%) were serious reports, including two death reports (0.4%), all in adults aged [at least] 65 years,” Penina Haber and her colleagues at the Immunization Safety Office at the Centers for Disease Control and Prevention reported in a poster at the International Conference on Emerging Infectious Diseases.

The deaths included a 75-year-old man who died from Sjögren’s syndrome and a 65-year-old man who died from a myocardial infarction. The other serious events included five neurologic disorders (two cases of Guillain-Barré syndrome and one each of Bell’s palsy, Bickerstaff encephalitis, and lower-extremity weakness), five musculoskeletal and connective tissue disorders (three with shoulder pain and two with arm pain), three general disorders and administration site conditions (two cases of fever/chills and one case of cellulitis/bursitis), and one case each of a gastrointestinal disorder (acute diarrhea/gastroenteritis), an injury (a fall), and a skin/subcutaneous tissue disorder (keratosis pilaris rubra), according to the investigators.

There were no reports of anaphylaxis.

For the sake of comparison, the investigators also looked at reports associated with IIV3-HD and IIV3/IIV4 vaccines in adults aged 65 years and older during the same time period; they found that patient characteristics and reported events were similar for all the vaccines. For example, the percentages of reports involving patients aged 65 years and older were 65% or 66% for each, and those involving patients aged 75-84 years were 27%-29%. Further, 0.2%-0.6% of reports for each vaccine involved death.

The most frequently reported events for aIIV3, IIV3-HD, and IIV3/IIV4, respectively, were extremity pain (21%, 17%, and 15%, respectively), injection site erythema (18%, 19%, and 15%), and injection site pain (15%, 16%, and 16%), they said.

The aIIV3 vaccine – the first seasonal inactivated trivalent influenza vaccine produced from three influenza virus strains (two subtype A strains and one type B strain) – was approved by the Food and Drug Administration in 2015 for adults aged 65 years and older. It was the first influenza vaccine containing the adjuvant MF59 – a purified oil-in-water emulsion of squalene oil added to boost immune response in that population. Its safety was assessed in 15 randomized, controlled clinical studies, and several trials in older adults supported its efficacy and safety over nonadjuvanted influenza vaccines, the investigators reported. They noted that the Advisory Committee on Immunization Practices (ACIP) recommended the vaccine as an option for routine use in adults aged 65 years and older during the 2016-2017 flu seasons.

For the 2018-2019 flu season, ACIP determined that “For persons aged ≥65 years, any age-appropriate IIV formulation (standard-dose or high-dose, trivalent or quadrivalent, unadjuvanted or adjuvanted) or RIV4 are acceptable options.”

The findings of the analysis of the 2017-2018 flu season data are consistent with prelicensure studies, Ms. Haber and her colleagues concluded, noting that data mining did not detect disproportional reporting of any unexpected adverse event.

“[There were] no safety concerns following aIIV3 when compared to the nonadjuvanted influenza vaccines (IIV3-HD or IIV3/IIV4),” they wrote, adding that the “CDC and FDA will continue to monitor and ensure the safety of aIIV3.”

Ms. Haber reported having no disclosures

sworcester@frontlinemedcom.com

SOURCE: Haber P et al. ICEID 2018, Board 320.

ATLANTA – Postlicensure surveillance of a trivalent adjuvanted influenza vaccine approved in 2015 for adults aged 65 years and older revealed no new or unexpected patterns of adverse events, according to an analysis of reports to the Vaccine Adverse Event Reporting System (VAERS) during July 2016 through March 2018.

Wavebreakmedia/Thinkstock

VAERS received 630 reports related to the vaccine (aIIV3; FLUAD) during the study period, of which 521 involved adults aged 65 years and older.

“Eighteen (3%) were serious reports, including two death reports (0.4%), all in adults aged [at least] 65 years,” Penina Haber and her colleagues at the Immunization Safety Office at the Centers for Disease Control and Prevention reported in a poster at the International Conference on Emerging Infectious Diseases.

The deaths included a 75-year-old man who died from Sjögren’s syndrome and a 65-year-old man who died from a myocardial infarction. The other serious events included five neurologic disorders (two cases of Guillain-Barré syndrome and one each of Bell’s palsy, Bickerstaff encephalitis, and lower-extremity weakness), five musculoskeletal and connective tissue disorders (three with shoulder pain and two with arm pain), three general disorders and administration site conditions (two cases of fever/chills and one case of cellulitis/bursitis), and one case each of a gastrointestinal disorder (acute diarrhea/gastroenteritis), an injury (a fall), and a skin/subcutaneous tissue disorder (keratosis pilaris rubra), according to the investigators.

There were no reports of anaphylaxis.

For the sake of comparison, the investigators also looked at reports associated with IIV3-HD and IIV3/IIV4 vaccines in adults aged 65 years and older during the same time period; they found that patient characteristics and reported events were similar for all the vaccines. For example, the percentages of reports involving patients aged 65 years and older were 65% or 66% for each, and those involving patients aged 75-84 years were 27%-29%. Further, 0.2%-0.6% of reports for each vaccine involved death.

The most frequently reported events for aIIV3, IIV3-HD, and IIV3/IIV4, respectively, were extremity pain (21%, 17%, and 15%, respectively), injection site erythema (18%, 19%, and 15%), and injection site pain (15%, 16%, and 16%), they said.

The aIIV3 vaccine – the first seasonal inactivated trivalent influenza vaccine produced from three influenza virus strains (two subtype A strains and one type B strain) – was approved by the Food and Drug Administration in 2015 for adults aged 65 years and older. It was the first influenza vaccine containing the adjuvant MF59 – a purified oil-in-water emulsion of squalene oil added to boost immune response in that population. Its safety was assessed in 15 randomized, controlled clinical studies, and several trials in older adults supported its efficacy and safety over nonadjuvanted influenza vaccines, the investigators reported. They noted that the Advisory Committee on Immunization Practices (ACIP) recommended the vaccine as an option for routine use in adults aged 65 years and older during the 2016-2017 flu seasons.

For the 2018-2019 flu season, ACIP determined that “For persons aged ≥65 years, any age-appropriate IIV formulation (standard-dose or high-dose, trivalent or quadrivalent, unadjuvanted or adjuvanted) or RIV4 are acceptable options.”

The findings of the analysis of the 2017-2018 flu season data are consistent with prelicensure studies, Ms. Haber and her colleagues concluded, noting that data mining did not detect disproportional reporting of any unexpected adverse event.

“[There were] no safety concerns following aIIV3 when compared to the nonadjuvanted influenza vaccines (IIV3-HD or IIV3/IIV4),” they wrote, adding that the “CDC and FDA will continue to monitor and ensure the safety of aIIV3.”

Ms. Haber reported having no disclosures

sworcester@frontlinemedcom.com

SOURCE: Haber P et al. ICEID 2018, Board 320.

ATLANTA – Postlicensure surveillance of a trivalent adjuvanted influenza vaccine approved in 2015 for adults aged 65 years and older revealed no new or unexpected patterns of adverse events, according to an analysis of reports to the Vaccine Adverse Event Reporting System (VAERS) during July 2016 through March 2018.

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VAERS received 630 reports related to the vaccine (aIIV3; FLUAD) during the study period, of which 521 involved adults aged 65 years and older.

“Eighteen (3%) were serious reports, including two death reports (0.4%), all in adults aged [at least] 65 years,” Penina Haber and her colleagues at the Immunization Safety Office at the Centers for Disease Control and Prevention reported in a poster at the International Conference on Emerging Infectious Diseases.

The deaths included a 75-year-old man who died from Sjögren’s syndrome and a 65-year-old man who died from a myocardial infarction. The other serious events included five neurologic disorders (two cases of Guillain-Barré syndrome and one each of Bell’s palsy, Bickerstaff encephalitis, and lower-extremity weakness), five musculoskeletal and connective tissue disorders (three with shoulder pain and two with arm pain), three general disorders and administration site conditions (two cases of fever/chills and one case of cellulitis/bursitis), and one case each of a gastrointestinal disorder (acute diarrhea/gastroenteritis), an injury (a fall), and a skin/subcutaneous tissue disorder (keratosis pilaris rubra), according to the investigators.

There were no reports of anaphylaxis.

For the sake of comparison, the investigators also looked at reports associated with IIV3-HD and IIV3/IIV4 vaccines in adults aged 65 years and older during the same time period; they found that patient characteristics and reported events were similar for all the vaccines. For example, the percentages of reports involving patients aged 65 years and older were 65% or 66% for each, and those involving patients aged 75-84 years were 27%-29%. Further, 0.2%-0.6% of reports for each vaccine involved death.

The most frequently reported events for aIIV3, IIV3-HD, and IIV3/IIV4, respectively, were extremity pain (21%, 17%, and 15%, respectively), injection site erythema (18%, 19%, and 15%), and injection site pain (15%, 16%, and 16%), they said.

The aIIV3 vaccine – the first seasonal inactivated trivalent influenza vaccine produced from three influenza virus strains (two subtype A strains and one type B strain) – was approved by the Food and Drug Administration in 2015 for adults aged 65 years and older. It was the first influenza vaccine containing the adjuvant MF59 – a purified oil-in-water emulsion of squalene oil added to boost immune response in that population. Its safety was assessed in 15 randomized, controlled clinical studies, and several trials in older adults supported its efficacy and safety over nonadjuvanted influenza vaccines, the investigators reported. They noted that the Advisory Committee on Immunization Practices (ACIP) recommended the vaccine as an option for routine use in adults aged 65 years and older during the 2016-2017 flu seasons.

For the 2018-2019 flu season, ACIP determined that “For persons aged ≥65 years, any age-appropriate IIV formulation (standard-dose or high-dose, trivalent or quadrivalent, unadjuvanted or adjuvanted) or RIV4 are acceptable options.”

The findings of the analysis of the 2017-2018 flu season data are consistent with prelicensure studies, Ms. Haber and her colleagues concluded, noting that data mining did not detect disproportional reporting of any unexpected adverse event.

“[There were] no safety concerns following aIIV3 when compared to the nonadjuvanted influenza vaccines (IIV3-HD or IIV3/IIV4),” they wrote, adding that the “CDC and FDA will continue to monitor and ensure the safety of aIIV3.”

Ms. Haber reported having no disclosures

sworcester@frontlinemedcom.com

SOURCE: Haber P et al. ICEID 2018, Board 320.