Most physicians know that migraine with aura is a risk factor for ischemic stroke and that the use of an estrogen-containing contraceptive further increases this risk.^1-3 Additional important and prevalent risk factors for ischemic stroke include cigarette smoking, hypertension, diabetes, and ischemic heart disease.¹ The American College of Obstetricians and Gynecologists (ACOG)² and the Centers for Disease Control and Prevention (CDC)³ recommend against the use of estrogen-containing contraceptives for women with migraine with aura because of the increased risk of ischemic stroke (Medical Eligibility Criteria [MEC] category 4—unacceptable health risk, method not to be used).

However, those who have migraine with aura can use nonhormonal and progestin-only forms of contraception, including copper- and levonorgestrel-intrauterine devices, the etonogestrel subdermal implant, depot medroxyprogesterone acetate, and progestin-only pills (MEC category 1—no restriction).^2,3 ACOG and the CDC advise that estrogen-containing contraceptives can be used for those with migraine without aura who have no other risk factors for stroke (MEC category 2—advantages generally outweigh theoretical or proven risks).^2,3 Given the high prevalence of migraine in reproductive-age women, accurate diagnosis of aura is of paramount importance in order to provide appropriate contraceptive counseling.

When is migraine with aura the right diagnosis?

In clinical practice, there is a high level of confusion about the migraine symptoms that warrant a diagnosis of migraine with aura. One approach to improving the accuracy of such a diagnosis is to refer every woman seeking contraceptive counseling who has migraine headaches to a neurologist for expert adjudication of the presence or absence of aura. But in the clinical context of contraceptive counseling, neurology consultation is not always readily available, and requiring consultation increases barriers to care. However, there are tools—such as the Visual Aura Rating Scale (VARS), which is discussed below—that may help non-neurologists identify migraine with aura.⁴ First, let us review the data that links migraine with aura with increased risk of ischemic stroke.

Migraine with aura is a risk factor for stroke

Multiple case-control studies report that migraine with aura is a risk factor for ischemic stroke.^1,5,6 Studies also report that women with migraine with aura who use estrogen-containing contraceptives have an even greater risk of ischemic stroke. For example, one recent case-control study used a commercial claims database of 1,884 cases of ischemic stroke among individuals who identify as women 15 to 49 years of age matched to 7,536 controls without ischemic stroke.¹ In this study, the risk of ischemic stroke was increased more than 2.5-fold by cigarette smoking (adjusted odds ratio [aOR], 2.59), hypertension (aOR, 2.73), diabetes (aOR, 2.78), migraine with aura (aOR, 2.89), and ischemic heart disease (aOR, 5.49). For those with migraine with aura who also used an estrogen-containing contraceptive, the aOR for ischemic stroke was 6.08. By contrast, the risk for stroke among those with migraine with aura who were not using an estrogen-containing contraceptive was 2.65. Furthermore, among those with migraine without aura, the risk of ischemic stroke was only 1.77 with the use of an estrogen-containing contraceptive.

Continue to: Although women with migraine...

Although women with migraine with and without aura are at increased risk for stroke, the absolute risk is still very low. For example, one review reported that the incidence of ischemic stroke per 100,000 person-years among women 20 to 44 years of age was 2.5 for those without migraine not taking estrogen-containing contraceptives, 5.9 for those with migraine with aura not taking estrogen-containing contraceptives, and 14.5 among those with migraine with aura and taking estrogen-containing contraceptives.⁶ Another important observation is that the incidence of thrombotic stroke dramatically increases from adolescence (3.4 per 100,000 person-years) to 45-49 years of age (64.4 per 100,000 person-years).⁷ Therefore, older women with migraine are at greater risk for stroke than adolescents.

Diagnostic criteria for migraine with and without aura

In contraceptive counseling, if an estrogen-containing contraceptive is being considered, it is important to identify women with migraine headache, determine migraine subtype, assess the frequency of migraines and identify other cardiovascular risk factors, such as hypertension and cigarette smoking. The International Headache Society has evolved the diagnostic criteria for migraine with and without aura, and now endorses the criteria published in the 3rd edition of the International Classification of Headache Disorders (ICHD-3; TABLES 1 and 2).⁸ For non-neurologists, these criteria may be difficult to remember and impractical to utilize in daily contraceptive counseling. Two simplified tools, the ID Migraine Questionnaire⁹ and the Visual Aura Rating Scale (TABLE 3)⁴ may help identify women who have migraine headaches and assess for the presence of aura.

The ID Migraine Questionnaire

In a study of 563 people seeking primary care who had headaches in the past 3 months, 3 questions were identified as being helpful in identifying women with migraine. This 3-question screening tool had reasonable sensitivity (81%), specificity (75%), and positive predictive value (93%) compared with expert diagnosis using the ICHD-3.⁹ The 3 questions in this screening tool, which are answered “Yes” or “No,” are:

During the last 3 months did you have the following symptoms with your headaches:

1. Feel nauseated or sick to your stomach?
2. Light bothered you?
3. Your headaches limited your ability to work, study or do what you needed to do for at least 1 day?

If two questions are answered “Yes” the patient may have migraine headaches.

Visual Aura Rating Scale for the diagnosis of migraine with aura

More than 90% of women with migraine with aura have visual auras, leaving only a minority with non–visual aura, such as tingling or numbness in a limb, speech or language problems, or muscle weakness. Hence for non-neurologists, it is reasonable to focus on the accurate diagnosis of visual aura to identify those with migraine with aura.

In the clinical context of contraceptive counseling, the Visual Aura Rating Scale (VARS) is especially useful because it has good sensitivity and specificity, and it is easy to use in practice (TABLE 3).⁴ VARS assesses for 5 characteristics of a visual aura, and each characteristic is associated with a weighted risk score. The 5 symptoms assessed include:

1. duration of visual symptom between 5 and 60 minutes (3 points)
2. visual symptom develops gradually over 5 minutes (2 points)
3. scotoma (2 points)
4. zig-zag line (2 points)
5. unilateral (1 point).

Continue to: Of note, visual aura is usually...

Of note, visual aura is usually slow-spreading and persists for more than 5 minutes but less than 60 minutes. If a visual symptom has a sudden onset and persists for much longer than 60 minutes, concern is heightened for a more serious neurologic diagnosis such as transient ischemic attack or stroke. A summed score of 5 or more points supports the diagnosis of migraine with aura. In one study, VARS had a sensitivity of 91% and specificity of 96% for identifying women with migraine with aura diagnosed by the ICHD-3 criteria.⁴

Consider using VARS to identify migraine with aura

Epidemiologic studies report that about 17% of adults have migraine, and about 5% have migraine with aura.^10,11 Consequently, migraine with aura is one of the most common medical conditions encountered during contraceptive counseling. The CDC MEC recommend against the use of estrogen-containing contraceptives in women with migraine with aura (Category 4 rating). The VARS may help clinicians identify those who have migraine with aura who should not be offered estrogen-containing contraceptives. Equally important, the use of VARS could help reduce the number of women who are inappropriately diagnosed as having migraine with aura based on fleeting visual symptoms lasting far less than 5 minutes during a migraine headache.

Most physicians know that migraine with aura is a risk factor for ischemic stroke and that the use of an estrogen-containing contraceptive further increases this risk.^1-3 Additional important and prevalent risk factors for ischemic stroke include cigarette smoking, hypertension, diabetes, and ischemic heart disease.¹ The American College of Obstetricians and Gynecologists (ACOG)² and the Centers for Disease Control and Prevention (CDC)³ recommend against the use of estrogen-containing contraceptives for women with migraine with aura because of the increased risk of ischemic stroke (Medical Eligibility Criteria [MEC] category 4—unacceptable health risk, method not to be used).

However, those who have migraine with aura can use nonhormonal and progestin-only forms of contraception, including copper- and levonorgestrel-intrauterine devices, the etonogestrel subdermal implant, depot medroxyprogesterone acetate, and progestin-only pills (MEC category 1—no restriction).^2,3 ACOG and the CDC advise that estrogen-containing contraceptives can be used for those with migraine without aura who have no other risk factors for stroke (MEC category 2—advantages generally outweigh theoretical or proven risks).^2,3 Given the high prevalence of migraine in reproductive-age women, accurate diagnosis of aura is of paramount importance in order to provide appropriate contraceptive counseling.

When is migraine with aura the right diagnosis?

In clinical practice, there is a high level of confusion about the migraine symptoms that warrant a diagnosis of migraine with aura. One approach to improving the accuracy of such a diagnosis is to refer every woman seeking contraceptive counseling who has migraine headaches to a neurologist for expert adjudication of the presence or absence of aura. But in the clinical context of contraceptive counseling, neurology consultation is not always readily available, and requiring consultation increases barriers to care. However, there are tools—such as the Visual Aura Rating Scale (VARS), which is discussed below—that may help non-neurologists identify migraine with aura.⁴ First, let us review the data that links migraine with aura with increased risk of ischemic stroke.

Migraine with aura is a risk factor for stroke

Multiple case-control studies report that migraine with aura is a risk factor for ischemic stroke.^1,5,6 Studies also report that women with migraine with aura who use estrogen-containing contraceptives have an even greater risk of ischemic stroke. For example, one recent case-control study used a commercial claims database of 1,884 cases of ischemic stroke among individuals who identify as women 15 to 49 years of age matched to 7,536 controls without ischemic stroke.¹ In this study, the risk of ischemic stroke was increased more than 2.5-fold by cigarette smoking (adjusted odds ratio [aOR], 2.59), hypertension (aOR, 2.73), diabetes (aOR, 2.78), migraine with aura (aOR, 2.89), and ischemic heart disease (aOR, 5.49). For those with migraine with aura who also used an estrogen-containing contraceptive, the aOR for ischemic stroke was 6.08. By contrast, the risk for stroke among those with migraine with aura who were not using an estrogen-containing contraceptive was 2.65. Furthermore, among those with migraine without aura, the risk of ischemic stroke was only 1.77 with the use of an estrogen-containing contraceptive.

Continue to: Although women with migraine...

Although women with migraine with and without aura are at increased risk for stroke, the absolute risk is still very low. For example, one review reported that the incidence of ischemic stroke per 100,000 person-years among women 20 to 44 years of age was 2.5 for those without migraine not taking estrogen-containing contraceptives, 5.9 for those with migraine with aura not taking estrogen-containing contraceptives, and 14.5 among those with migraine with aura and taking estrogen-containing contraceptives.⁶ Another important observation is that the incidence of thrombotic stroke dramatically increases from adolescence (3.4 per 100,000 person-years) to 45-49 years of age (64.4 per 100,000 person-years).⁷ Therefore, older women with migraine are at greater risk for stroke than adolescents.

Diagnostic criteria for migraine with and without aura

In contraceptive counseling, if an estrogen-containing contraceptive is being considered, it is important to identify women with migraine headache, determine migraine subtype, assess the frequency of migraines and identify other cardiovascular risk factors, such as hypertension and cigarette smoking. The International Headache Society has evolved the diagnostic criteria for migraine with and without aura, and now endorses the criteria published in the 3rd edition of the International Classification of Headache Disorders (ICHD-3; TABLES 1 and 2).⁸ For non-neurologists, these criteria may be difficult to remember and impractical to utilize in daily contraceptive counseling. Two simplified tools, the ID Migraine Questionnaire⁹ and the Visual Aura Rating Scale (TABLE 3)⁴ may help identify women who have migraine headaches and assess for the presence of aura.

The ID Migraine Questionnaire

In a study of 563 people seeking primary care who had headaches in the past 3 months, 3 questions were identified as being helpful in identifying women with migraine. This 3-question screening tool had reasonable sensitivity (81%), specificity (75%), and positive predictive value (93%) compared with expert diagnosis using the ICHD-3.⁹ The 3 questions in this screening tool, which are answered “Yes” or “No,” are:

During the last 3 months did you have the following symptoms with your headaches:

1. Feel nauseated or sick to your stomach?
2. Light bothered you?
3. Your headaches limited your ability to work, study or do what you needed to do for at least 1 day?

If two questions are answered “Yes” the patient may have migraine headaches.

Visual Aura Rating Scale for the diagnosis of migraine with aura

More than 90% of women with migraine with aura have visual auras, leaving only a minority with non–visual aura, such as tingling or numbness in a limb, speech or language problems, or muscle weakness. Hence for non-neurologists, it is reasonable to focus on the accurate diagnosis of visual aura to identify those with migraine with aura.

In the clinical context of contraceptive counseling, the Visual Aura Rating Scale (VARS) is especially useful because it has good sensitivity and specificity, and it is easy to use in practice (TABLE 3).⁴ VARS assesses for 5 characteristics of a visual aura, and each characteristic is associated with a weighted risk score. The 5 symptoms assessed include:

1. duration of visual symptom between 5 and 60 minutes (3 points)
2. visual symptom develops gradually over 5 minutes (2 points)
3. scotoma (2 points)
4. zig-zag line (2 points)
5. unilateral (1 point).

Continue to: Of note, visual aura is usually...

Of note, visual aura is usually slow-spreading and persists for more than 5 minutes but less than 60 minutes. If a visual symptom has a sudden onset and persists for much longer than 60 minutes, concern is heightened for a more serious neurologic diagnosis such as transient ischemic attack or stroke. A summed score of 5 or more points supports the diagnosis of migraine with aura. In one study, VARS had a sensitivity of 91% and specificity of 96% for identifying women with migraine with aura diagnosed by the ICHD-3 criteria.⁴

Consider using VARS to identify migraine with aura

Epidemiologic studies report that about 17% of adults have migraine, and about 5% have migraine with aura.^10,11 Consequently, migraine with aura is one of the most common medical conditions encountered during contraceptive counseling. The CDC MEC recommend against the use of estrogen-containing contraceptives in women with migraine with aura (Category 4 rating). The VARS may help clinicians identify those who have migraine with aura who should not be offered estrogen-containing contraceptives. Equally important, the use of VARS could help reduce the number of women who are inappropriately diagnosed as having migraine with aura based on fleeting visual symptoms lasting far less than 5 minutes during a migraine headache.

Most physicians know that migraine with aura is a risk factor for ischemic stroke and that the use of an estrogen-containing contraceptive further increases this risk.^1-3 Additional important and prevalent risk factors for ischemic stroke include cigarette smoking, hypertension, diabetes, and ischemic heart disease.¹ The American College of Obstetricians and Gynecologists (ACOG)² and the Centers for Disease Control and Prevention (CDC)³ recommend against the use of estrogen-containing contraceptives for women with migraine with aura because of the increased risk of ischemic stroke (Medical Eligibility Criteria [MEC] category 4—unacceptable health risk, method not to be used).

However, those who have migraine with aura can use nonhormonal and progestin-only forms of contraception, including copper- and levonorgestrel-intrauterine devices, the etonogestrel subdermal implant, depot medroxyprogesterone acetate, and progestin-only pills (MEC category 1—no restriction).^2,3 ACOG and the CDC advise that estrogen-containing contraceptives can be used for those with migraine without aura who have no other risk factors for stroke (MEC category 2—advantages generally outweigh theoretical or proven risks).^2,3 Given the high prevalence of migraine in reproductive-age women, accurate diagnosis of aura is of paramount importance in order to provide appropriate contraceptive counseling.

When is migraine with aura the right diagnosis?

In clinical practice, there is a high level of confusion about the migraine symptoms that warrant a diagnosis of migraine with aura. One approach to improving the accuracy of such a diagnosis is to refer every woman seeking contraceptive counseling who has migraine headaches to a neurologist for expert adjudication of the presence or absence of aura. But in the clinical context of contraceptive counseling, neurology consultation is not always readily available, and requiring consultation increases barriers to care. However, there are tools—such as the Visual Aura Rating Scale (VARS), which is discussed below—that may help non-neurologists identify migraine with aura.⁴ First, let us review the data that links migraine with aura with increased risk of ischemic stroke.

Migraine with aura is a risk factor for stroke

Multiple case-control studies report that migraine with aura is a risk factor for ischemic stroke.^1,5,6 Studies also report that women with migraine with aura who use estrogen-containing contraceptives have an even greater risk of ischemic stroke. For example, one recent case-control study used a commercial claims database of 1,884 cases of ischemic stroke among individuals who identify as women 15 to 49 years of age matched to 7,536 controls without ischemic stroke.¹ In this study, the risk of ischemic stroke was increased more than 2.5-fold by cigarette smoking (adjusted odds ratio [aOR], 2.59), hypertension (aOR, 2.73), diabetes (aOR, 2.78), migraine with aura (aOR, 2.89), and ischemic heart disease (aOR, 5.49). For those with migraine with aura who also used an estrogen-containing contraceptive, the aOR for ischemic stroke was 6.08. By contrast, the risk for stroke among those with migraine with aura who were not using an estrogen-containing contraceptive was 2.65. Furthermore, among those with migraine without aura, the risk of ischemic stroke was only 1.77 with the use of an estrogen-containing contraceptive.

Continue to: Although women with migraine...

Although women with migraine with and without aura are at increased risk for stroke, the absolute risk is still very low. For example, one review reported that the incidence of ischemic stroke per 100,000 person-years among women 20 to 44 years of age was 2.5 for those without migraine not taking estrogen-containing contraceptives, 5.9 for those with migraine with aura not taking estrogen-containing contraceptives, and 14.5 among those with migraine with aura and taking estrogen-containing contraceptives.⁶ Another important observation is that the incidence of thrombotic stroke dramatically increases from adolescence (3.4 per 100,000 person-years) to 45-49 years of age (64.4 per 100,000 person-years).⁷ Therefore, older women with migraine are at greater risk for stroke than adolescents.

Diagnostic criteria for migraine with and without aura

In contraceptive counseling, if an estrogen-containing contraceptive is being considered, it is important to identify women with migraine headache, determine migraine subtype, assess the frequency of migraines and identify other cardiovascular risk factors, such as hypertension and cigarette smoking. The International Headache Society has evolved the diagnostic criteria for migraine with and without aura, and now endorses the criteria published in the 3rd edition of the International Classification of Headache Disorders (ICHD-3; TABLES 1 and 2).⁸ For non-neurologists, these criteria may be difficult to remember and impractical to utilize in daily contraceptive counseling. Two simplified tools, the ID Migraine Questionnaire⁹ and the Visual Aura Rating Scale (TABLE 3)⁴ may help identify women who have migraine headaches and assess for the presence of aura.

The ID Migraine Questionnaire

In a study of 563 people seeking primary care who had headaches in the past 3 months, 3 questions were identified as being helpful in identifying women with migraine. This 3-question screening tool had reasonable sensitivity (81%), specificity (75%), and positive predictive value (93%) compared with expert diagnosis using the ICHD-3.⁹ The 3 questions in this screening tool, which are answered “Yes” or “No,” are:

During the last 3 months did you have the following symptoms with your headaches:

1. Feel nauseated or sick to your stomach?
2. Light bothered you?
3. Your headaches limited your ability to work, study or do what you needed to do for at least 1 day?

If two questions are answered “Yes” the patient may have migraine headaches.

Visual Aura Rating Scale for the diagnosis of migraine with aura

More than 90% of women with migraine with aura have visual auras, leaving only a minority with non–visual aura, such as tingling or numbness in a limb, speech or language problems, or muscle weakness. Hence for non-neurologists, it is reasonable to focus on the accurate diagnosis of visual aura to identify those with migraine with aura.

In the clinical context of contraceptive counseling, the Visual Aura Rating Scale (VARS) is especially useful because it has good sensitivity and specificity, and it is easy to use in practice (TABLE 3).⁴ VARS assesses for 5 characteristics of a visual aura, and each characteristic is associated with a weighted risk score. The 5 symptoms assessed include:

1. duration of visual symptom between 5 and 60 minutes (3 points)
2. visual symptom develops gradually over 5 minutes (2 points)
3. scotoma (2 points)
4. zig-zag line (2 points)
5. unilateral (1 point).

Continue to: Of note, visual aura is usually...

Of note, visual aura is usually slow-spreading and persists for more than 5 minutes but less than 60 minutes. If a visual symptom has a sudden onset and persists for much longer than 60 minutes, concern is heightened for a more serious neurologic diagnosis such as transient ischemic attack or stroke. A summed score of 5 or more points supports the diagnosis of migraine with aura. In one study, VARS had a sensitivity of 91% and specificity of 96% for identifying women with migraine with aura diagnosed by the ICHD-3 criteria.⁴

Consider using VARS to identify migraine with aura

Epidemiologic studies report that about 17% of adults have migraine, and about 5% have migraine with aura.^10,11 Consequently, migraine with aura is one of the most common medical conditions encountered during contraceptive counseling. The CDC MEC recommend against the use of estrogen-containing contraceptives in women with migraine with aura (Category 4 rating). The VARS may help clinicians identify those who have migraine with aura who should not be offered estrogen-containing contraceptives. Equally important, the use of VARS could help reduce the number of women who are inappropriately diagnosed as having migraine with aura based on fleeting visual symptoms lasting far less than 5 minutes during a migraine headache.

In a recent systematic review, Fink and colleagues attempted to summarize the published evidence of the efficacy and safety of long-term (> 3 years) therapy for osteoporosis.¹ Unfortunately, they arrived at very limited and tentative conclusions because, as they point out, of the paucity of such evidence.

Why long-term studies stop short

Only 3 of the several tens of placebo-controlled fracture end-point studies (about 58 trials and observational studies) that Fink and colleagues reviewed evaluated treatment for more than 3 years. The nonavailability of longer-term studies is the direct consequence of a requirement by regulatory agencies for a 3-year fracture end-point study in order to register a new drug for osteoporosis. Hence, longer, placebo-controlled studies do not benefit the industry sponsor, and enrolling patients with osteoporosis or who are at high risk for fracture in any, much less long, placebo-controlled trials is now considered to be unethical.

What the authors did observe

From this limited set of information with which to evaluate, Fink and colleagues observed that long-term therapy with raloxifene reduces the risk of vertebral fractures but is associated with thromboembolic complications. In addition, treatment for more than 3 years with bisphosphonates reduces the risk of vertebral and nonvertebral fractures but may increase risk of rare adverse events (including femoral shaft fractures with atypical radiographic features).

The bisphosphonate holiday. The authors refer to the even more limited evidence about the effects of discontinuing bisphosphonate therapy. Unlike the rapid loss of bone mass density (BMD) and fracture protection upon stopping estrogen or denosumab, the offset of these treatment benefits is slower when bisphosphonates are discontinued. This, coupled with concern about increasing risk with long-term bisphosphonate therapy, led to the confusing concept of a “bisphosphonate holiday.” While recommendations to consider temporary discontinuation of bisphosphonates in patients at low risk for fracture have been made by expert panels,² very little information exists about the benefits/risks of this strategy, how long the treatment interruption should be, or how to decide when and with what to restart therapy. Unfortunately, overall, Fink and colleagues’ observations provide little practical guidance for clinicians.

Continue to: What we can learn from longer term and recent studies of ideal treatment...

What we can learn from longer term and recent studies of ideal treatment

Since we have no “cure” for osteoporosis, and since the benefits of therapy, including protection from fractures, abate upon stopping treatment (as they do when we stop treating hypertension or diabetes), very long term if not lifelong management is required for patients with osteoporosis. Persistent or even greater reduction of fracture risk with treatment up to 10 years, compared with the rate of fracture in the placebo or treated group during the first 3 years of the study, has been observed with zoledronate and denosumab.^3-5 Denosumab was not included in the systematic review by Fink and colleagues since the pivotal fracture trial with that agent was placebo-controlled for only 3 years.⁶

Sequential drug treatment may be best. Fink and colleagues also did not consider new evidence, which suggests that the use of osteoporosis drugs in sequence—rather than a single agent for a long time—may be the most effective management strategy.^7,8

More consideration should be given to the use of estrogen and raloxifene in younger postmenopausal women at risk for vertebral but not hip fracture.

Only treat high-risk patients. Using osteoporosis therapies to only treat patients at high risk for fracture will optimize the benefit:risk ratio and cost-effectiveness of therapy.

Bisphosphonate holidays may not be as important as once thought. BMD and fracture risk reduction does not improve after 5 years of bisphosphonate therapy, and longer treatment may increase the risk of atypical fractures, while switching to another agent can increase BMD and perhaps mitigate the safety concern, suggesting that there is little justification for continuous use of bisphosphonates for more than 5 years, thereby minimizing the importance of a bisphosphonate holiday.

Hip BMD may serve as indicator for treatment decisions. Recent evidence indicating that the change in hip BMD with treatment or the level of hip BMD achieved on treatment correlates with fracture risk reduction may provide a useful clinical target to guide treatment decisions.^9,10

Because we have a lack of pristine evidence does not mean that we shouldn’t treat osteoporosis; we have to do the best we can with the limited evidence we have. Therapy must be individualized, for we are not just treating osteoporosis, we are treating patients with osteoporosis.

In a recent systematic review, Fink and colleagues attempted to summarize the published evidence of the efficacy and safety of long-term (> 3 years) therapy for osteoporosis.¹ Unfortunately, they arrived at very limited and tentative conclusions because, as they point out, of the paucity of such evidence.

Why long-term studies stop short

Only 3 of the several tens of placebo-controlled fracture end-point studies (about 58 trials and observational studies) that Fink and colleagues reviewed evaluated treatment for more than 3 years. The nonavailability of longer-term studies is the direct consequence of a requirement by regulatory agencies for a 3-year fracture end-point study in order to register a new drug for osteoporosis. Hence, longer, placebo-controlled studies do not benefit the industry sponsor, and enrolling patients with osteoporosis or who are at high risk for fracture in any, much less long, placebo-controlled trials is now considered to be unethical.

What the authors did observe

From this limited set of information with which to evaluate, Fink and colleagues observed that long-term therapy with raloxifene reduces the risk of vertebral fractures but is associated with thromboembolic complications. In addition, treatment for more than 3 years with bisphosphonates reduces the risk of vertebral and nonvertebral fractures but may increase risk of rare adverse events (including femoral shaft fractures with atypical radiographic features).

The bisphosphonate holiday. The authors refer to the even more limited evidence about the effects of discontinuing bisphosphonate therapy. Unlike the rapid loss of bone mass density (BMD) and fracture protection upon stopping estrogen or denosumab, the offset of these treatment benefits is slower when bisphosphonates are discontinued. This, coupled with concern about increasing risk with long-term bisphosphonate therapy, led to the confusing concept of a “bisphosphonate holiday.” While recommendations to consider temporary discontinuation of bisphosphonates in patients at low risk for fracture have been made by expert panels,² very little information exists about the benefits/risks of this strategy, how long the treatment interruption should be, or how to decide when and with what to restart therapy. Unfortunately, overall, Fink and colleagues’ observations provide little practical guidance for clinicians.

Continue to: What we can learn from longer term and recent studies of ideal treatment...

What we can learn from longer term and recent studies of ideal treatment

Since we have no “cure” for osteoporosis, and since the benefits of therapy, including protection from fractures, abate upon stopping treatment (as they do when we stop treating hypertension or diabetes), very long term if not lifelong management is required for patients with osteoporosis. Persistent or even greater reduction of fracture risk with treatment up to 10 years, compared with the rate of fracture in the placebo or treated group during the first 3 years of the study, has been observed with zoledronate and denosumab.^3-5 Denosumab was not included in the systematic review by Fink and colleagues since the pivotal fracture trial with that agent was placebo-controlled for only 3 years.⁶

Sequential drug treatment may be best. Fink and colleagues also did not consider new evidence, which suggests that the use of osteoporosis drugs in sequence—rather than a single agent for a long time—may be the most effective management strategy.^7,8

More consideration should be given to the use of estrogen and raloxifene in younger postmenopausal women at risk for vertebral but not hip fracture.

Only treat high-risk patients. Using osteoporosis therapies to only treat patients at high risk for fracture will optimize the benefit:risk ratio and cost-effectiveness of therapy.

Bisphosphonate holidays may not be as important as once thought. BMD and fracture risk reduction does not improve after 5 years of bisphosphonate therapy, and longer treatment may increase the risk of atypical fractures, while switching to another agent can increase BMD and perhaps mitigate the safety concern, suggesting that there is little justification for continuous use of bisphosphonates for more than 5 years, thereby minimizing the importance of a bisphosphonate holiday.

Hip BMD may serve as indicator for treatment decisions. Recent evidence indicating that the change in hip BMD with treatment or the level of hip BMD achieved on treatment correlates with fracture risk reduction may provide a useful clinical target to guide treatment decisions.^9,10

Because we have a lack of pristine evidence does not mean that we shouldn’t treat osteoporosis; we have to do the best we can with the limited evidence we have. Therapy must be individualized, for we are not just treating osteoporosis, we are treating patients with osteoporosis.

In a recent systematic review, Fink and colleagues attempted to summarize the published evidence of the efficacy and safety of long-term (> 3 years) therapy for osteoporosis.¹ Unfortunately, they arrived at very limited and tentative conclusions because, as they point out, of the paucity of such evidence.

Why long-term studies stop short

Only 3 of the several tens of placebo-controlled fracture end-point studies (about 58 trials and observational studies) that Fink and colleagues reviewed evaluated treatment for more than 3 years. The nonavailability of longer-term studies is the direct consequence of a requirement by regulatory agencies for a 3-year fracture end-point study in order to register a new drug for osteoporosis. Hence, longer, placebo-controlled studies do not benefit the industry sponsor, and enrolling patients with osteoporosis or who are at high risk for fracture in any, much less long, placebo-controlled trials is now considered to be unethical.

What the authors did observe

From this limited set of information with which to evaluate, Fink and colleagues observed that long-term therapy with raloxifene reduces the risk of vertebral fractures but is associated with thromboembolic complications. In addition, treatment for more than 3 years with bisphosphonates reduces the risk of vertebral and nonvertebral fractures but may increase risk of rare adverse events (including femoral shaft fractures with atypical radiographic features).

The bisphosphonate holiday. The authors refer to the even more limited evidence about the effects of discontinuing bisphosphonate therapy. Unlike the rapid loss of bone mass density (BMD) and fracture protection upon stopping estrogen or denosumab, the offset of these treatment benefits is slower when bisphosphonates are discontinued. This, coupled with concern about increasing risk with long-term bisphosphonate therapy, led to the confusing concept of a “bisphosphonate holiday.” While recommendations to consider temporary discontinuation of bisphosphonates in patients at low risk for fracture have been made by expert panels,² very little information exists about the benefits/risks of this strategy, how long the treatment interruption should be, or how to decide when and with what to restart therapy. Unfortunately, overall, Fink and colleagues’ observations provide little practical guidance for clinicians.

Continue to: What we can learn from longer term and recent studies of ideal treatment...

What we can learn from longer term and recent studies of ideal treatment

Since we have no “cure” for osteoporosis, and since the benefits of therapy, including protection from fractures, abate upon stopping treatment (as they do when we stop treating hypertension or diabetes), very long term if not lifelong management is required for patients with osteoporosis. Persistent or even greater reduction of fracture risk with treatment up to 10 years, compared with the rate of fracture in the placebo or treated group during the first 3 years of the study, has been observed with zoledronate and denosumab.^3-5 Denosumab was not included in the systematic review by Fink and colleagues since the pivotal fracture trial with that agent was placebo-controlled for only 3 years.⁶

Sequential drug treatment may be best. Fink and colleagues also did not consider new evidence, which suggests that the use of osteoporosis drugs in sequence—rather than a single agent for a long time—may be the most effective management strategy.^7,8

More consideration should be given to the use of estrogen and raloxifene in younger postmenopausal women at risk for vertebral but not hip fracture.

Only treat high-risk patients. Using osteoporosis therapies to only treat patients at high risk for fracture will optimize the benefit:risk ratio and cost-effectiveness of therapy.

Bisphosphonate holidays may not be as important as once thought. BMD and fracture risk reduction does not improve after 5 years of bisphosphonate therapy, and longer treatment may increase the risk of atypical fractures, while switching to another agent can increase BMD and perhaps mitigate the safety concern, suggesting that there is little justification for continuous use of bisphosphonates for more than 5 years, thereby minimizing the importance of a bisphosphonate holiday.

Hip BMD may serve as indicator for treatment decisions. Recent evidence indicating that the change in hip BMD with treatment or the level of hip BMD achieved on treatment correlates with fracture risk reduction may provide a useful clinical target to guide treatment decisions.^9,10

Because we have a lack of pristine evidence does not mean that we shouldn’t treat osteoporosis; we have to do the best we can with the limited evidence we have. Therapy must be individualized, for we are not just treating osteoporosis, we are treating patients with osteoporosis.

Tumor markers are serum measures that are valuable in the discrimination of an adnexal mass. However, given the long list from which to choose, it can be confusing to know exactly which might best serve your diagnostic needs. I am commonly asked by obstetrician/gynecologists and primary care doctors for guidance on this subject. In this column I will explore some of the decision making that I use when determining which markers might be most helpful for individual patients.

Tumor markers typically are ordered to estimate the probability of malignancy and the need for referral to an oncology subspecialist.

So which tumor markers should you order when you have diagnosed an adnexal mass? Because tumor marker profiles can differ dramatically based on the cell type of the neoplasm, perhaps the first question to ask is what is the most likely category of neoplasm based on other clinical data? Ovarian neoplasms fit into the following subgroups: epithelial (including the most common cell type, serous ovarian cancer, but also the less common mucinous and low malignant potential tumors), sex cord-stromal tumors, germ cell tumors, and metastatic tumors. Table 1 summarizes which tumor markers should be considered based on the clinical setting.

You should suspect an epithelial tumor if there is an adnexal mass with significant cystic components in older, postmenopausal patients, or the presence of peritoneal carcinomatosis on imaging. The tumor markers most commonly elevated in this clinical setting are cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), and possibly CA 19-9. The CA 125 antigen is a glycoprotein derived from the epithelium of peritoneum, pleura, pericardium, and Müllerian tissues. The multiple sites of origin of this glycoprotein speaks to the poor specificity associated with its elevation, as it is well known to be elevated in both benign conditions such as endometriosis, fibroids, pregnancy, ovulation, cirrhosis, and pericarditis as well as in nongynecologic malignancies, particularly those metastatic to the peritoneal cavity. Multiple different assays are available to measure CA 125, and each is associated with a slightly different reference range. Therefore, if measuring serial values, it is best to have these assessed by the same laboratory. Similarly, as it can be physiologically elevated during the menstrual cycle, premenopausal women should have serial assessments at the same point in their menstrual cycle or ideally within the first 2 weeks of their cycle.

The sensitivity of CA 125 in detecting ovarian cancer is only 78%, which is limited by the fact that not all epithelial ovarian cancer cell types (including some clear cell, carcinosarcoma, and mucinous) express elevations in this tumor marker, and because CA 125 is elevated in less than half of stage I ovarian cancers.¹ Therefore, given the lack of sensitivity and specificity for this tumor marker, you should integrate other clinical data, such as imaging findings, age of the patient, and associated benign medical conditions, when evaluating the likelihood of cancer. The American College of Obstetricians and Gynecologists (ACOG) recommends that in the setting of an adnexal mass, referral to gynecologic oncology is recommended when the CA 125 value is greater than 200 U/mL in premenopausal women, or greater than 35U/mL in postmenopausal women.²

CEA is a protein that can be expressed in the colon but not in other normal tissues after birth, and therefore its elevation is commonly associated with metastatic GI tumors to the ovary and peritoneum, or mucinous ovarian tumors, including borderline tumors. Metastatic GI tumors typically are suspected when there are bilateral ovarian solid masses. Right-sided ovarian cysts also can be associated with appendiceal pathology and checking a CEA level can be considered in these cases. I will commonly draw both CA 125 and CEA tumor markers in the setting of cystic +/– solid ovarian masses. This allows the recognition of CA 125-negative/CEA-positive ovarian cancers, such as mucinous tumors, which aids in later surveillance or increases my suspicion for an occult GI tumor (particularly if there is a disproportionately higher elevation in CEA than CA 125).³ If tumor marker profiles are suggestive of an occult GI tumor, I often will consider a preoperative colonoscopy and upper GI endoscopic assessment.

CA 19-9 is a much less specific tumor marker which can be elevated in a variety of solid organ tumors including pancreatic, hepatobiliary, gastric and ovarian tumors. I typically reserve adding this marker for atypical clinical presentations of ovarian cancer, such as carcinomatosis in the absence of pelvic masses.

Ovarian sex cord-stromal neoplasms most commonly present as solid tumors in the ovary. The ovarian stroma includes the bland fibroblasts and the hormone-producing sex-cord granulosa, Sertoli and Leydig cells. Therefore the sex cord-stromal tumors commonly are associated with elevations in serum inhibin, anti-Müllerian hormone, and potentially androstenedione and dehydroepiandrosterone.⁴ These tumors rarely have advanced disease at diagnosis. Granulosa cell tumors should be suspected in women with a solid ovarian mass and abnormal uterine bleeding (including postmenopausal bleeding), and the appropriate tumor markers (inhibin and anti-Müllerian hormone) can guide this diagnosis preoperatively.⁴ Androgen-secreting stromal tumors such as Sertoli-Leydig tumors often present with virilization or menstrual irregularities. Interestingly, these patients may have dramatic clinical symptoms with corresponding nonvisible or very small solid adnexal lesions seen on imaging. In the case of fibromas, these solid tumors have normal hormonal tumor markers but may present with ascites and pleural effusions as part of Meigs syndrome, which can confuse the clinician who may suspect advanced-stage epithelial cancer especially as this condition may be associated with elevated CA 125.

Germ cell tumors make up the other main group of primary ovarian tumors, and typically strongly express tumor markers. These tumors typically are solid and highly vascularized on imaging, can be bilateral, and may be very large at the time of diagnosis.⁵ They most commonly are unilateral and arise among younger women (including usually in the second and third decades of life). Table 1 demonstrates the different tumor markers associated with different germ cell tumors. It is my practice to order a panel of all of these germ cell markers in young women with solid adnexal masses in whom germ cell tumors are suspected, but I will not routinely draw this expansive panel for older women with cystic lesions.

Tumor marker panels (such as OVA 1, Overa, Risk of Malignancy Algorithm or ROMA) have become popular in recent years. These panels include multiple serum markers (such as CA 125, beta-2 microglobulin, human epididymis secretory protein 4, transferrin, etc.) evaluated in concert with the goal being a more nuanced assessment of likelihood for malignancy.^6,7 These assays typically are stratified by age or menopausal status given the physiologic differences in normal reference ranges that occur between these groups. While these studies do improve upon the sensitivity and specificity for identifying malignancy, compared with single-assay tests, they are not definitively diagnostic for this purpose. Therefore, I typically recommend these assays if a referring doctor needs additional risk stratification to guide whether or not to refer to an oncologist for surgery.

Not all tumor markers are of equal value in all patients with an adnexal mass. I recommend careful consideration of other clinical factors such as age, menopausal status, ultrasonographic features, and associated findings such as GI symptoms or manifestations of hormonal alterations when considering which markers to assess. 



Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email her at [email protected].

References

1. Hum Reprod. 1989 Jan;4(1):1-12.

2. Obstet Gynecol. 2016 Nov;128(5):e210-e26.

3. Dan Med Bull. 2011 Nov;58(11):A4331.

4. Int J Cancer. 2015 Oct 1;137(7):1661-71.

5. Obstet Gynecol. 2000 Jan;95(1):128-33.

6. Obstet Gynecol. 2011 Jun;117(6):1289-97.

7. Obstet Gynecol. 2011 Aug;118(2 Pt 1):280-8.

Tumor markers are serum measures that are valuable in the discrimination of an adnexal mass. However, given the long list from which to choose, it can be confusing to know exactly which might best serve your diagnostic needs. I am commonly asked by obstetrician/gynecologists and primary care doctors for guidance on this subject. In this column I will explore some of the decision making that I use when determining which markers might be most helpful for individual patients.

Tumor markers typically are ordered to estimate the probability of malignancy and the need for referral to an oncology subspecialist.

So which tumor markers should you order when you have diagnosed an adnexal mass? Because tumor marker profiles can differ dramatically based on the cell type of the neoplasm, perhaps the first question to ask is what is the most likely category of neoplasm based on other clinical data? Ovarian neoplasms fit into the following subgroups: epithelial (including the most common cell type, serous ovarian cancer, but also the less common mucinous and low malignant potential tumors), sex cord-stromal tumors, germ cell tumors, and metastatic tumors. Table 1 summarizes which tumor markers should be considered based on the clinical setting.

You should suspect an epithelial tumor if there is an adnexal mass with significant cystic components in older, postmenopausal patients, or the presence of peritoneal carcinomatosis on imaging. The tumor markers most commonly elevated in this clinical setting are cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), and possibly CA 19-9. The CA 125 antigen is a glycoprotein derived from the epithelium of peritoneum, pleura, pericardium, and Müllerian tissues. The multiple sites of origin of this glycoprotein speaks to the poor specificity associated with its elevation, as it is well known to be elevated in both benign conditions such as endometriosis, fibroids, pregnancy, ovulation, cirrhosis, and pericarditis as well as in nongynecologic malignancies, particularly those metastatic to the peritoneal cavity. Multiple different assays are available to measure CA 125, and each is associated with a slightly different reference range. Therefore, if measuring serial values, it is best to have these assessed by the same laboratory. Similarly, as it can be physiologically elevated during the menstrual cycle, premenopausal women should have serial assessments at the same point in their menstrual cycle or ideally within the first 2 weeks of their cycle.

The sensitivity of CA 125 in detecting ovarian cancer is only 78%, which is limited by the fact that not all epithelial ovarian cancer cell types (including some clear cell, carcinosarcoma, and mucinous) express elevations in this tumor marker, and because CA 125 is elevated in less than half of stage I ovarian cancers.¹ Therefore, given the lack of sensitivity and specificity for this tumor marker, you should integrate other clinical data, such as imaging findings, age of the patient, and associated benign medical conditions, when evaluating the likelihood of cancer. The American College of Obstetricians and Gynecologists (ACOG) recommends that in the setting of an adnexal mass, referral to gynecologic oncology is recommended when the CA 125 value is greater than 200 U/mL in premenopausal women, or greater than 35U/mL in postmenopausal women.²

CEA is a protein that can be expressed in the colon but not in other normal tissues after birth, and therefore its elevation is commonly associated with metastatic GI tumors to the ovary and peritoneum, or mucinous ovarian tumors, including borderline tumors. Metastatic GI tumors typically are suspected when there are bilateral ovarian solid masses. Right-sided ovarian cysts also can be associated with appendiceal pathology and checking a CEA level can be considered in these cases. I will commonly draw both CA 125 and CEA tumor markers in the setting of cystic +/– solid ovarian masses. This allows the recognition of CA 125-negative/CEA-positive ovarian cancers, such as mucinous tumors, which aids in later surveillance or increases my suspicion for an occult GI tumor (particularly if there is a disproportionately higher elevation in CEA than CA 125).³ If tumor marker profiles are suggestive of an occult GI tumor, I often will consider a preoperative colonoscopy and upper GI endoscopic assessment.

CA 19-9 is a much less specific tumor marker which can be elevated in a variety of solid organ tumors including pancreatic, hepatobiliary, gastric and ovarian tumors. I typically reserve adding this marker for atypical clinical presentations of ovarian cancer, such as carcinomatosis in the absence of pelvic masses.

Ovarian sex cord-stromal neoplasms most commonly present as solid tumors in the ovary. The ovarian stroma includes the bland fibroblasts and the hormone-producing sex-cord granulosa, Sertoli and Leydig cells. Therefore the sex cord-stromal tumors commonly are associated with elevations in serum inhibin, anti-Müllerian hormone, and potentially androstenedione and dehydroepiandrosterone.⁴ These tumors rarely have advanced disease at diagnosis. Granulosa cell tumors should be suspected in women with a solid ovarian mass and abnormal uterine bleeding (including postmenopausal bleeding), and the appropriate tumor markers (inhibin and anti-Müllerian hormone) can guide this diagnosis preoperatively.⁴ Androgen-secreting stromal tumors such as Sertoli-Leydig tumors often present with virilization or menstrual irregularities. Interestingly, these patients may have dramatic clinical symptoms with corresponding nonvisible or very small solid adnexal lesions seen on imaging. In the case of fibromas, these solid tumors have normal hormonal tumor markers but may present with ascites and pleural effusions as part of Meigs syndrome, which can confuse the clinician who may suspect advanced-stage epithelial cancer especially as this condition may be associated with elevated CA 125.

Germ cell tumors make up the other main group of primary ovarian tumors, and typically strongly express tumor markers. These tumors typically are solid and highly vascularized on imaging, can be bilateral, and may be very large at the time of diagnosis.⁵ They most commonly are unilateral and arise among younger women (including usually in the second and third decades of life). Table 1 demonstrates the different tumor markers associated with different germ cell tumors. It is my practice to order a panel of all of these germ cell markers in young women with solid adnexal masses in whom germ cell tumors are suspected, but I will not routinely draw this expansive panel for older women with cystic lesions.

Tumor marker panels (such as OVA 1, Overa, Risk of Malignancy Algorithm or ROMA) have become popular in recent years. These panels include multiple serum markers (such as CA 125, beta-2 microglobulin, human epididymis secretory protein 4, transferrin, etc.) evaluated in concert with the goal being a more nuanced assessment of likelihood for malignancy.^6,7 These assays typically are stratified by age or menopausal status given the physiologic differences in normal reference ranges that occur between these groups. While these studies do improve upon the sensitivity and specificity for identifying malignancy, compared with single-assay tests, they are not definitively diagnostic for this purpose. Therefore, I typically recommend these assays if a referring doctor needs additional risk stratification to guide whether or not to refer to an oncologist for surgery.

Not all tumor markers are of equal value in all patients with an adnexal mass. I recommend careful consideration of other clinical factors such as age, menopausal status, ultrasonographic features, and associated findings such as GI symptoms or manifestations of hormonal alterations when considering which markers to assess. 



Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email her at [email protected].

References

1. Hum Reprod. 1989 Jan;4(1):1-12.

2. Obstet Gynecol. 2016 Nov;128(5):e210-e26.

3. Dan Med Bull. 2011 Nov;58(11):A4331.

4. Int J Cancer. 2015 Oct 1;137(7):1661-71.

5. Obstet Gynecol. 2000 Jan;95(1):128-33.

6. Obstet Gynecol. 2011 Jun;117(6):1289-97.

7. Obstet Gynecol. 2011 Aug;118(2 Pt 1):280-8.

Tumor markers are serum measures that are valuable in the discrimination of an adnexal mass. However, given the long list from which to choose, it can be confusing to know exactly which might best serve your diagnostic needs. I am commonly asked by obstetrician/gynecologists and primary care doctors for guidance on this subject. In this column I will explore some of the decision making that I use when determining which markers might be most helpful for individual patients.

Tumor markers typically are ordered to estimate the probability of malignancy and the need for referral to an oncology subspecialist.

So which tumor markers should you order when you have diagnosed an adnexal mass? Because tumor marker profiles can differ dramatically based on the cell type of the neoplasm, perhaps the first question to ask is what is the most likely category of neoplasm based on other clinical data? Ovarian neoplasms fit into the following subgroups: epithelial (including the most common cell type, serous ovarian cancer, but also the less common mucinous and low malignant potential tumors), sex cord-stromal tumors, germ cell tumors, and metastatic tumors. Table 1 summarizes which tumor markers should be considered based on the clinical setting.

You should suspect an epithelial tumor if there is an adnexal mass with significant cystic components in older, postmenopausal patients, or the presence of peritoneal carcinomatosis on imaging. The tumor markers most commonly elevated in this clinical setting are cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), and possibly CA 19-9. The CA 125 antigen is a glycoprotein derived from the epithelium of peritoneum, pleura, pericardium, and Müllerian tissues. The multiple sites of origin of this glycoprotein speaks to the poor specificity associated with its elevation, as it is well known to be elevated in both benign conditions such as endometriosis, fibroids, pregnancy, ovulation, cirrhosis, and pericarditis as well as in nongynecologic malignancies, particularly those metastatic to the peritoneal cavity. Multiple different assays are available to measure CA 125, and each is associated with a slightly different reference range. Therefore, if measuring serial values, it is best to have these assessed by the same laboratory. Similarly, as it can be physiologically elevated during the menstrual cycle, premenopausal women should have serial assessments at the same point in their menstrual cycle or ideally within the first 2 weeks of their cycle.

The sensitivity of CA 125 in detecting ovarian cancer is only 78%, which is limited by the fact that not all epithelial ovarian cancer cell types (including some clear cell, carcinosarcoma, and mucinous) express elevations in this tumor marker, and because CA 125 is elevated in less than half of stage I ovarian cancers.¹ Therefore, given the lack of sensitivity and specificity for this tumor marker, you should integrate other clinical data, such as imaging findings, age of the patient, and associated benign medical conditions, when evaluating the likelihood of cancer. The American College of Obstetricians and Gynecologists (ACOG) recommends that in the setting of an adnexal mass, referral to gynecologic oncology is recommended when the CA 125 value is greater than 200 U/mL in premenopausal women, or greater than 35U/mL in postmenopausal women.²

CEA is a protein that can be expressed in the colon but not in other normal tissues after birth, and therefore its elevation is commonly associated with metastatic GI tumors to the ovary and peritoneum, or mucinous ovarian tumors, including borderline tumors. Metastatic GI tumors typically are suspected when there are bilateral ovarian solid masses. Right-sided ovarian cysts also can be associated with appendiceal pathology and checking a CEA level can be considered in these cases. I will commonly draw both CA 125 and CEA tumor markers in the setting of cystic +/– solid ovarian masses. This allows the recognition of CA 125-negative/CEA-positive ovarian cancers, such as mucinous tumors, which aids in later surveillance or increases my suspicion for an occult GI tumor (particularly if there is a disproportionately higher elevation in CEA than CA 125).³ If tumor marker profiles are suggestive of an occult GI tumor, I often will consider a preoperative colonoscopy and upper GI endoscopic assessment.

CA 19-9 is a much less specific tumor marker which can be elevated in a variety of solid organ tumors including pancreatic, hepatobiliary, gastric and ovarian tumors. I typically reserve adding this marker for atypical clinical presentations of ovarian cancer, such as carcinomatosis in the absence of pelvic masses.

Ovarian sex cord-stromal neoplasms most commonly present as solid tumors in the ovary. The ovarian stroma includes the bland fibroblasts and the hormone-producing sex-cord granulosa, Sertoli and Leydig cells. Therefore the sex cord-stromal tumors commonly are associated with elevations in serum inhibin, anti-Müllerian hormone, and potentially androstenedione and dehydroepiandrosterone.⁴ These tumors rarely have advanced disease at diagnosis. Granulosa cell tumors should be suspected in women with a solid ovarian mass and abnormal uterine bleeding (including postmenopausal bleeding), and the appropriate tumor markers (inhibin and anti-Müllerian hormone) can guide this diagnosis preoperatively.⁴ Androgen-secreting stromal tumors such as Sertoli-Leydig tumors often present with virilization or menstrual irregularities. Interestingly, these patients may have dramatic clinical symptoms with corresponding nonvisible or very small solid adnexal lesions seen on imaging. In the case of fibromas, these solid tumors have normal hormonal tumor markers but may present with ascites and pleural effusions as part of Meigs syndrome, which can confuse the clinician who may suspect advanced-stage epithelial cancer especially as this condition may be associated with elevated CA 125.

Germ cell tumors make up the other main group of primary ovarian tumors, and typically strongly express tumor markers. These tumors typically are solid and highly vascularized on imaging, can be bilateral, and may be very large at the time of diagnosis.⁵ They most commonly are unilateral and arise among younger women (including usually in the second and third decades of life). Table 1 demonstrates the different tumor markers associated with different germ cell tumors. It is my practice to order a panel of all of these germ cell markers in young women with solid adnexal masses in whom germ cell tumors are suspected, but I will not routinely draw this expansive panel for older women with cystic lesions.

Tumor marker panels (such as OVA 1, Overa, Risk of Malignancy Algorithm or ROMA) have become popular in recent years. These panels include multiple serum markers (such as CA 125, beta-2 microglobulin, human epididymis secretory protein 4, transferrin, etc.) evaluated in concert with the goal being a more nuanced assessment of likelihood for malignancy.^6,7 These assays typically are stratified by age or menopausal status given the physiologic differences in normal reference ranges that occur between these groups. While these studies do improve upon the sensitivity and specificity for identifying malignancy, compared with single-assay tests, they are not definitively diagnostic for this purpose. Therefore, I typically recommend these assays if a referring doctor needs additional risk stratification to guide whether or not to refer to an oncologist for surgery.

Not all tumor markers are of equal value in all patients with an adnexal mass. I recommend careful consideration of other clinical factors such as age, menopausal status, ultrasonographic features, and associated findings such as GI symptoms or manifestations of hormonal alterations when considering which markers to assess. 



Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email her at [email protected].

References

1. Hum Reprod. 1989 Jan;4(1):1-12.

2. Obstet Gynecol. 2016 Nov;128(5):e210-e26.

3. Dan Med Bull. 2011 Nov;58(11):A4331.

4. Int J Cancer. 2015 Oct 1;137(7):1661-71.

5. Obstet Gynecol. 2000 Jan;95(1):128-33.

6. Obstet Gynecol. 2011 Jun;117(6):1289-97.

7. Obstet Gynecol. 2011 Aug;118(2 Pt 1):280-8.

De Vivo V, Carbone L, Saccone G, et al. Early amniotomy after cervical ripening for induction of labor: a systematic review and meta-analysis of randomized controlled trials. Am J Obstet Gynecol. 2019. doi: 10.1016/j.ajog.2019.07.049.

EXPERT COMMENTARY

Induction of labor has doubled over the past 2 decades, with almost 25% of parturients currently undergoing induction in the United States.¹ Labor induction at term is associated with perinatal outcomes similar to those with spontaneous labor, without an increase in the CD rate.^1-3 Although numerous methods for cervical ripening have been evaluated, the safest and most effective method has yet to be determined.²

Amniotomy—or artificial rupture of membranes (AROM)—has long been used as a technique for labor induction and for augmentation in women in spontaneous labor. Purported benefits include an increased responsiveness to exogenous oxytocin, decreased interval to delivery, and an increased likelihood of spontaneous vaginal delivery. Risks of amniotomy include injury to the fetus or surrounding tissues, bleeding, nonreassuring fetal testing, cord prolapse, and prolonged rupture of membranes (defined as longer than 18 hours), which is a risk factor for intra-amniotic infection.

The optimal timing of amniotomy is not known. The recent study by De Vivo and colleagues was designed to better understand the risk/benefit ratio of early amniotomy after cervical ripening in women undergoing induction of labor.

Details of the study

The authors conducted a systematic review and meta-analysis that included 1,273 women in 4 randomized controlled trials to determine the effectiveness of routine early amniotomy versus late amniotomy/spontaneous rupture of membranes after cervical ripening (with either a Foley catheter or prostaglandins) in women with a singleton vertex fetus undergoing induction of labor in the term or late preterm period.

Early amniotomy was defined as AROM “soon after cervical ripening” (cases); late amniotomy was defined as AROM after the active phase of labor or spontaneous rupture of membranes (controls).

The primary outcome was the incidence of CD. Secondary outcomes included the overall length of labor, latency from induction to delivery, and neonatal morbidity (a composite of birth weight, Apgar scores, meconium-stained amniotic fluid, neonatal sepsis, need for resuscitation, and admission to the neonatal intensive care unit).

Continue to: Findings...

Findings. Women randomly assigned to early amniotomy had a similar risk of CD compared with controls (31.1% vs 30.9% [relative risk (RR), 1.05; 95% confidence interval (CI), 0.71–1.56]) and a shorter interval from induction to delivery of about 5 hours (mean difference, -4.95 hours [95% CI, -8.12 to -1.78]).

There was no difference in any of the secondary outcome measures, although the number of events was small. Specifically, there was no significant difference in rates of chorioamnionitis between the early and late amniotomy cohorts (7.3% vs 4.8% [RR, 1.47; 95% CI, 0.95–2.28]).

Study strengths and limitations

This is the first systematic review to evaluate early versus late amniotomy after cervical ripening for induction of labor. “Systematic review and meta-analysis” is not synonymous with a review of the literature. It has its own methodology and is regarded as original research. A strength of this study is that it was performed by a highly credible team who followed established Cochrane and PRISMA methodological and reporting guidelines.

Study weaknesses include the fact that the meta-analysis contained a relatively small number of trials and study participants. It was significantly underpowered to address issues related to neonatal outcome. The 4 trials included were highly variable in terms of maternal parity and indications for labor induction and CD. The definition of “early amniotomy” was inconsistent, and the overall rate of CD varied greatly among the studies (7.9%–41.1%). Multiple pregnancies were excluded. Taken together, these findings may have limited generalizability.

De Vivo V, Carbone L, Saccone G, et al. Early amniotomy after cervical ripening for induction of labor: a systematic review and meta-analysis of randomized controlled trials. Am J Obstet Gynecol. 2019. doi: 10.1016/j.ajog.2019.07.049.

EXPERT COMMENTARY

Induction of labor has doubled over the past 2 decades, with almost 25% of parturients currently undergoing induction in the United States.¹ Labor induction at term is associated with perinatal outcomes similar to those with spontaneous labor, without an increase in the CD rate.^1-3 Although numerous methods for cervical ripening have been evaluated, the safest and most effective method has yet to be determined.²

Amniotomy—or artificial rupture of membranes (AROM)—has long been used as a technique for labor induction and for augmentation in women in spontaneous labor. Purported benefits include an increased responsiveness to exogenous oxytocin, decreased interval to delivery, and an increased likelihood of spontaneous vaginal delivery. Risks of amniotomy include injury to the fetus or surrounding tissues, bleeding, nonreassuring fetal testing, cord prolapse, and prolonged rupture of membranes (defined as longer than 18 hours), which is a risk factor for intra-amniotic infection.

The optimal timing of amniotomy is not known. The recent study by De Vivo and colleagues was designed to better understand the risk/benefit ratio of early amniotomy after cervical ripening in women undergoing induction of labor.

Details of the study

The authors conducted a systematic review and meta-analysis that included 1,273 women in 4 randomized controlled trials to determine the effectiveness of routine early amniotomy versus late amniotomy/spontaneous rupture of membranes after cervical ripening (with either a Foley catheter or prostaglandins) in women with a singleton vertex fetus undergoing induction of labor in the term or late preterm period.

Early amniotomy was defined as AROM “soon after cervical ripening” (cases); late amniotomy was defined as AROM after the active phase of labor or spontaneous rupture of membranes (controls).

The primary outcome was the incidence of CD. Secondary outcomes included the overall length of labor, latency from induction to delivery, and neonatal morbidity (a composite of birth weight, Apgar scores, meconium-stained amniotic fluid, neonatal sepsis, need for resuscitation, and admission to the neonatal intensive care unit).

Continue to: Findings...

Findings. Women randomly assigned to early amniotomy had a similar risk of CD compared with controls (31.1% vs 30.9% [relative risk (RR), 1.05; 95% confidence interval (CI), 0.71–1.56]) and a shorter interval from induction to delivery of about 5 hours (mean difference, -4.95 hours [95% CI, -8.12 to -1.78]).

There was no difference in any of the secondary outcome measures, although the number of events was small. Specifically, there was no significant difference in rates of chorioamnionitis between the early and late amniotomy cohorts (7.3% vs 4.8% [RR, 1.47; 95% CI, 0.95–2.28]).

Study strengths and limitations

This is the first systematic review to evaluate early versus late amniotomy after cervical ripening for induction of labor. “Systematic review and meta-analysis” is not synonymous with a review of the literature. It has its own methodology and is regarded as original research. A strength of this study is that it was performed by a highly credible team who followed established Cochrane and PRISMA methodological and reporting guidelines.

Study weaknesses include the fact that the meta-analysis contained a relatively small number of trials and study participants. It was significantly underpowered to address issues related to neonatal outcome. The 4 trials included were highly variable in terms of maternal parity and indications for labor induction and CD. The definition of “early amniotomy” was inconsistent, and the overall rate of CD varied greatly among the studies (7.9%–41.1%). Multiple pregnancies were excluded. Taken together, these findings may have limited generalizability.

De Vivo V, Carbone L, Saccone G, et al. Early amniotomy after cervical ripening for induction of labor: a systematic review and meta-analysis of randomized controlled trials. Am J Obstet Gynecol. 2019. doi: 10.1016/j.ajog.2019.07.049.

EXPERT COMMENTARY

Induction of labor has doubled over the past 2 decades, with almost 25% of parturients currently undergoing induction in the United States.¹ Labor induction at term is associated with perinatal outcomes similar to those with spontaneous labor, without an increase in the CD rate.^1-3 Although numerous methods for cervical ripening have been evaluated, the safest and most effective method has yet to be determined.²

Amniotomy—or artificial rupture of membranes (AROM)—has long been used as a technique for labor induction and for augmentation in women in spontaneous labor. Purported benefits include an increased responsiveness to exogenous oxytocin, decreased interval to delivery, and an increased likelihood of spontaneous vaginal delivery. Risks of amniotomy include injury to the fetus or surrounding tissues, bleeding, nonreassuring fetal testing, cord prolapse, and prolonged rupture of membranes (defined as longer than 18 hours), which is a risk factor for intra-amniotic infection.

The optimal timing of amniotomy is not known. The recent study by De Vivo and colleagues was designed to better understand the risk/benefit ratio of early amniotomy after cervical ripening in women undergoing induction of labor.

Details of the study

The authors conducted a systematic review and meta-analysis that included 1,273 women in 4 randomized controlled trials to determine the effectiveness of routine early amniotomy versus late amniotomy/spontaneous rupture of membranes after cervical ripening (with either a Foley catheter or prostaglandins) in women with a singleton vertex fetus undergoing induction of labor in the term or late preterm period.

Early amniotomy was defined as AROM “soon after cervical ripening” (cases); late amniotomy was defined as AROM after the active phase of labor or spontaneous rupture of membranes (controls).

The primary outcome was the incidence of CD. Secondary outcomes included the overall length of labor, latency from induction to delivery, and neonatal morbidity (a composite of birth weight, Apgar scores, meconium-stained amniotic fluid, neonatal sepsis, need for resuscitation, and admission to the neonatal intensive care unit).

Continue to: Findings...

Findings. Women randomly assigned to early amniotomy had a similar risk of CD compared with controls (31.1% vs 30.9% [relative risk (RR), 1.05; 95% confidence interval (CI), 0.71–1.56]) and a shorter interval from induction to delivery of about 5 hours (mean difference, -4.95 hours [95% CI, -8.12 to -1.78]).

There was no difference in any of the secondary outcome measures, although the number of events was small. Specifically, there was no significant difference in rates of chorioamnionitis between the early and late amniotomy cohorts (7.3% vs 4.8% [RR, 1.47; 95% CI, 0.95–2.28]).

Study strengths and limitations

This is the first systematic review to evaluate early versus late amniotomy after cervical ripening for induction of labor. “Systematic review and meta-analysis” is not synonymous with a review of the literature. It has its own methodology and is regarded as original research. A strength of this study is that it was performed by a highly credible team who followed established Cochrane and PRISMA methodological and reporting guidelines.

Study weaknesses include the fact that the meta-analysis contained a relatively small number of trials and study participants. It was significantly underpowered to address issues related to neonatal outcome. The 4 trials included were highly variable in terms of maternal parity and indications for labor induction and CD. The definition of “early amniotomy” was inconsistent, and the overall rate of CD varied greatly among the studies (7.9%–41.1%). Multiple pregnancies were excluded. Taken together, these findings may have limited generalizability.

These are challenging, and sometimes tragic, times in the history of the United States. The image of a father and child face down in the Rio Grande River, drowning as they tried to cross from Mexico into Texas, is heart breaking. Irrespective of your political affiliation, we can agree that the immigration process is far from ideal and that no one should die in pursuit of a better life.

The United States has a complicated history with equity and inclusion, for all persons, and we are now living in times when the scab is being ripped off and these wounds are raw. What role can the Society of Hospital Medicine play to help heal these wounds?

I am a first-generation immigrant to the United States. I remember walking down the streets of my neighborhood in Uganda when my attention was drawn to a plane flying overhead. I thought to myself, “Some lucky duck is going to the U.S.” The United States was the land of opportunity and I was determined to come here. Through hard work and some luck, I arrived in the United States on June 15, 1991, with a single suitcase packed full of hope, dreams, and $3,000.

Fast-forward 28 years. I am now a hospitalist and faculty at the Johns Hopkins University, Baltimore, the associate director of the division of hospital medicine, and the vice chair for clinical operations at Johns Hopkins Bayview Medical Center. I learned about hospital medicine during my third year of medical school at the University of Minnesota, Minneapolis. While I loved general medicine, I could not see myself practicing anywhere outside of the hospital.

Following residency at Johns Hopkins Bayview, I still felt that a hospital-based practice was tailor-made for me. As I matured professionally, I worked to improve the provision of care within my hospital, and then started developing educational and practice programs in hospital medicine, both locally and internationally. My passion for hospital medicine led me to serve on committees for SHM, and this year, I was honored to join the SHM Board of Directors.

It is hard to answer the question of why, or how, one person immigrates to the United States and finds success while another loses their life. A quote attributed to Edmund Burke says, “the only thing necessary for the triumph of evil is for good [wo]men to do nothing.” One of SHM’s core values is to promote diversity and inclusion. A major step taken by the society to promote work in this area was to establish the diversity and inclusion Special Interest Group in 2018. I am the board liaison for the diversity and inclusion SIG and will work alongside this group, which aims to:

• Foster diversity, equity, and inclusion in SHM.
• Increase visibility of diversity, equity, and inclusion to the broader hospital medicine community.
• Support hospital medicine groups in matching their work forces to their diverse patient populations.
• Develop tool kits to improve the provision of care for our diverse patient population.
• Engender diversity among hospitalists.
• Develop opportunities for expanding the fund of knowledge on diversity in hospital medicine through research and discovery.
• Participate in SHM’s advocacy efforts related to diversity and inclusion.
• Develop partnerships with other key organizations to advance diversity, equity, and inclusion platforms so as to increase the scalability of SHM’s efforts.

We have been successful at Hopkins with diversity and inclusion, but that did not occur by chance. I believe that diversity and inclusion is a team sport and that everyone can be an important part of that team. In my hospitalist group, we actively engage women, men, doctors, NPs, PAs, administrators, minorities, and nonminorities. We recruit to – and cherish members of – our group irrespective of religious beliefs or sexual orientation. We believe that a heterogeneous group of people leads to an engaged and high-performing culture.

I have traveled a convoluted path since my arrival in 1991. Along the way, I was blessed with a husband and son who anchor me. Every day they remind me that the hard work I do is to build on the past to improve the future. My husband, an immigrant from Uganda like me, reminds me that we are lucky to have made it to the United States and that the ability and freedom to work hard and be rewarded for that hard work is a great privilege. My son reminds me of the many other children who look at me and know that they too can dare to dream. Occasionally, I still look up and see a plane, and I am reminded of that day many years ago. Hospital medicine is my suitcase packed with hopes and dreams for me, for this specialty, and for this country.

Dr. Kisuule is associate director of the division of hospital medicine at Johns Hopkins Bayview and assistant professor at Johns Hopkins University, both in Baltimore, and a member of the SHM Board of Directors.

These are challenging, and sometimes tragic, times in the history of the United States. The image of a father and child face down in the Rio Grande River, drowning as they tried to cross from Mexico into Texas, is heart breaking. Irrespective of your political affiliation, we can agree that the immigration process is far from ideal and that no one should die in pursuit of a better life.

The United States has a complicated history with equity and inclusion, for all persons, and we are now living in times when the scab is being ripped off and these wounds are raw. What role can the Society of Hospital Medicine play to help heal these wounds?

I am a first-generation immigrant to the United States. I remember walking down the streets of my neighborhood in Uganda when my attention was drawn to a plane flying overhead. I thought to myself, “Some lucky duck is going to the U.S.” The United States was the land of opportunity and I was determined to come here. Through hard work and some luck, I arrived in the United States on June 15, 1991, with a single suitcase packed full of hope, dreams, and $3,000.

Fast-forward 28 years. I am now a hospitalist and faculty at the Johns Hopkins University, Baltimore, the associate director of the division of hospital medicine, and the vice chair for clinical operations at Johns Hopkins Bayview Medical Center. I learned about hospital medicine during my third year of medical school at the University of Minnesota, Minneapolis. While I loved general medicine, I could not see myself practicing anywhere outside of the hospital.

Following residency at Johns Hopkins Bayview, I still felt that a hospital-based practice was tailor-made for me. As I matured professionally, I worked to improve the provision of care within my hospital, and then started developing educational and practice programs in hospital medicine, both locally and internationally. My passion for hospital medicine led me to serve on committees for SHM, and this year, I was honored to join the SHM Board of Directors.

It is hard to answer the question of why, or how, one person immigrates to the United States and finds success while another loses their life. A quote attributed to Edmund Burke says, “the only thing necessary for the triumph of evil is for good [wo]men to do nothing.” One of SHM’s core values is to promote diversity and inclusion. A major step taken by the society to promote work in this area was to establish the diversity and inclusion Special Interest Group in 2018. I am the board liaison for the diversity and inclusion SIG and will work alongside this group, which aims to:

• Foster diversity, equity, and inclusion in SHM.
• Increase visibility of diversity, equity, and inclusion to the broader hospital medicine community.
• Support hospital medicine groups in matching their work forces to their diverse patient populations.
• Develop tool kits to improve the provision of care for our diverse patient population.
• Engender diversity among hospitalists.
• Develop opportunities for expanding the fund of knowledge on diversity in hospital medicine through research and discovery.
• Participate in SHM’s advocacy efforts related to diversity and inclusion.
• Develop partnerships with other key organizations to advance diversity, equity, and inclusion platforms so as to increase the scalability of SHM’s efforts.

We have been successful at Hopkins with diversity and inclusion, but that did not occur by chance. I believe that diversity and inclusion is a team sport and that everyone can be an important part of that team. In my hospitalist group, we actively engage women, men, doctors, NPs, PAs, administrators, minorities, and nonminorities. We recruit to – and cherish members of – our group irrespective of religious beliefs or sexual orientation. We believe that a heterogeneous group of people leads to an engaged and high-performing culture.

I have traveled a convoluted path since my arrival in 1991. Along the way, I was blessed with a husband and son who anchor me. Every day they remind me that the hard work I do is to build on the past to improve the future. My husband, an immigrant from Uganda like me, reminds me that we are lucky to have made it to the United States and that the ability and freedom to work hard and be rewarded for that hard work is a great privilege. My son reminds me of the many other children who look at me and know that they too can dare to dream. Occasionally, I still look up and see a plane, and I am reminded of that day many years ago. Hospital medicine is my suitcase packed with hopes and dreams for me, for this specialty, and for this country.

Dr. Kisuule is associate director of the division of hospital medicine at Johns Hopkins Bayview and assistant professor at Johns Hopkins University, both in Baltimore, and a member of the SHM Board of Directors.

These are challenging, and sometimes tragic, times in the history of the United States. The image of a father and child face down in the Rio Grande River, drowning as they tried to cross from Mexico into Texas, is heart breaking. Irrespective of your political affiliation, we can agree that the immigration process is far from ideal and that no one should die in pursuit of a better life.

The United States has a complicated history with equity and inclusion, for all persons, and we are now living in times when the scab is being ripped off and these wounds are raw. What role can the Society of Hospital Medicine play to help heal these wounds?

I am a first-generation immigrant to the United States. I remember walking down the streets of my neighborhood in Uganda when my attention was drawn to a plane flying overhead. I thought to myself, “Some lucky duck is going to the U.S.” The United States was the land of opportunity and I was determined to come here. Through hard work and some luck, I arrived in the United States on June 15, 1991, with a single suitcase packed full of hope, dreams, and $3,000.

Fast-forward 28 years. I am now a hospitalist and faculty at the Johns Hopkins University, Baltimore, the associate director of the division of hospital medicine, and the vice chair for clinical operations at Johns Hopkins Bayview Medical Center. I learned about hospital medicine during my third year of medical school at the University of Minnesota, Minneapolis. While I loved general medicine, I could not see myself practicing anywhere outside of the hospital.

Following residency at Johns Hopkins Bayview, I still felt that a hospital-based practice was tailor-made for me. As I matured professionally, I worked to improve the provision of care within my hospital, and then started developing educational and practice programs in hospital medicine, both locally and internationally. My passion for hospital medicine led me to serve on committees for SHM, and this year, I was honored to join the SHM Board of Directors.

It is hard to answer the question of why, or how, one person immigrates to the United States and finds success while another loses their life. A quote attributed to Edmund Burke says, “the only thing necessary for the triumph of evil is for good [wo]men to do nothing.” One of SHM’s core values is to promote diversity and inclusion. A major step taken by the society to promote work in this area was to establish the diversity and inclusion Special Interest Group in 2018. I am the board liaison for the diversity and inclusion SIG and will work alongside this group, which aims to:

• Foster diversity, equity, and inclusion in SHM.
• Increase visibility of diversity, equity, and inclusion to the broader hospital medicine community.
• Support hospital medicine groups in matching their work forces to their diverse patient populations.
• Develop tool kits to improve the provision of care for our diverse patient population.
• Engender diversity among hospitalists.
• Develop opportunities for expanding the fund of knowledge on diversity in hospital medicine through research and discovery.
• Participate in SHM’s advocacy efforts related to diversity and inclusion.
• Develop partnerships with other key organizations to advance diversity, equity, and inclusion platforms so as to increase the scalability of SHM’s efforts.

We have been successful at Hopkins with diversity and inclusion, but that did not occur by chance. I believe that diversity and inclusion is a team sport and that everyone can be an important part of that team. In my hospitalist group, we actively engage women, men, doctors, NPs, PAs, administrators, minorities, and nonminorities. We recruit to – and cherish members of – our group irrespective of religious beliefs or sexual orientation. We believe that a heterogeneous group of people leads to an engaged and high-performing culture.

I have traveled a convoluted path since my arrival in 1991. Along the way, I was blessed with a husband and son who anchor me. Every day they remind me that the hard work I do is to build on the past to improve the future. My husband, an immigrant from Uganda like me, reminds me that we are lucky to have made it to the United States and that the ability and freedom to work hard and be rewarded for that hard work is a great privilege. My son reminds me of the many other children who look at me and know that they too can dare to dream. Occasionally, I still look up and see a plane, and I am reminded of that day many years ago. Hospital medicine is my suitcase packed with hopes and dreams for me, for this specialty, and for this country.

Dr. Kisuule is associate director of the division of hospital medicine at Johns Hopkins Bayview and assistant professor at Johns Hopkins University, both in Baltimore, and a member of the SHM Board of Directors.

BARCELONA – Ivosidenib, a first-in-class, oral, small-molecule inhibitor of the mutant isocitrate dehydrogenase 1 (mIDH1) protein, significantly improved progression-free survival, compared with placebo, for the treatment of advanced cholangiocarcinoma in the global, randomized, phase 3 ClarIDHy trial.

A trend toward favorable overall survival was also seen in the pivotal double-blind trial, Ghassan K. Abou-Alfa, MD, of Memorial Sloan-Kettering Cancer Center, New York, reported at the European Society for Medical Oncology Congress.

Median progression-free survival (PFS) in 124 patients randomized to receive 500 mg of ivosidenib (IVO) once daily was 2.7 months, compared with 1.4 months in 61 patients who received placebo (hazard ratio, 0.37).

The primary study endpoint – PFS by central review – was reached, Dr. Abou-Alfa said, noting that the PFS rates at 6 and 12 months were 32% and 22% in the IVO arm, whereas none of the patients in the placebo arm were progression-free for 6 or more months.

Although the 1.3-month difference in PFS between the treatment and placebo arms “may seem short and some people may question whether this is clinically meaningful,” this outcome actually represents an important breakthrough for patients with a disease that has few treatment options, Angela Lamarca, MD, PhD, of the Christie NHS Foundation Trust, Manchester, England, explained in a press release about the study.

“A treatment that increases the chance of being free from progression by 32% at 6 months after starting treatment and that prolongs survival from 6 months with placebo to 10.8 months with ivosidenib, after adjusting for crossover, is definitely meaningful for our patients with cholangiocarcinoma and their families,” said Dr. Lamarca, representing the ESMO Press & Media Affairs Committee.

Indeed, the overall response rate in the IVO arm was 2.4%, representing three partial responses, and the stable disease rate was 50.8%. The overall response rate and stable disease rates in the placebo arm were 0% and 28%, Dr. Abou-Alfa said.

Median overall survival in the intent-to-treat population, including the 57% of placebo arm patients who crossed over to the treatment arm at the time of radiographic progression as allowed by study protocol, was 10.8 months, compared with 9.7 months in the placebo arm, respectively (HR, 0.69), Dr. Abou-Alfa said.

Crossover-adjusted overall survival was 6 months for the placebo arm (HR, 0.46) as assessed using rank-preserving structural failure time analysis, which suggested that the overall survival benefit would have been statistically significant had there been no crossover.

Study subjects had unresectable or metastatic mIDH1 cholangiocarcinoma, good performance status, and measurable disease. They had a median age of 62 years, and 68 were men. Most had intrahepatic disease (91%) and metastatic disease (92%), and 43% had two prior therapies, he noted.

They were randomized 2:1 to the treatment and placebo arms, respectively.

Since IVO targets mIDH1, which occurs in about 20% of patients with cholangiocarcinoma and results in production of the oncogenesis-promoting oncometabolite D-2-hydroxyglutarate, and since the IVO has shown encouraging activity in smaller prior studies, ClarIDHy was designed to evaluate it in the advanced mIDH1 cholangiocarcinoma setting because patients with this aggressive disease have generally poor prognosis and few treatment options beyond chemotherapy, he explained.

In addition to providing significant, clinically meaningful survival benefit, the treatment also was generally well tolerated, he noted.

Treatment-emergent adverse events occurring in more than 15% of patients in the IVO arm included nausea (32.1%), diarrhea (28.8%), fatigue (23.7%), cough (19.2%), abdominal pain (18.6%), ascites (18.6%), decreased appetite (17.3%), anemia (16.0%), and vomiting (16.0%). Grade 3 or higher adverse events were reported in 46% and 36% of the IVO and placebo patients, respectively.

The findings are notable, in part because of the unmet need and also because this is the first pivotal study demonstrating the clinical benefit of targeting mIDH1 in patients with advanced mIDH1 cholangiocarcinoma, he said, concluding that “these pivotal data demonstrate the clinical relevance and benefit of ivosidenib in mIDH1 cholangiocarcinoma ... [and] establish the role for genomic testing in this rare cancer with a high unmet need.”

He also said studies should investigate IVO in the first-line setting for IDH1-mutated cholangiocarcinoma, in addition to its use in combination therapy and as adjuvant therapy.

In the ESMO press release, Chris Verslype, MD, of University Hospital Leuven (Belgium) called the findings of this study unprecedented given the lack of treatment options in those who fail systemic therapy, which has led to very limited survival.

The findings are “very likely to change clinical practice” and “will, for sure, drive the further development of targeted therapy for the disease,” he said.

Despite being limited by the requirement that patients have good performance status after prior chemotherapy (which means the findings may not be representative of all patients), ClarIDHy is “still a strong study because of the randomization to placebo.”

“It showed a real effect,” he said.

ClarIDHy was funded by Agios Pharmaceuticals. Dr. Abou-Alfa reported both personal and institutional relationships with industry. These include advisory /consulting roles and research grants/funding from numerous pharmaceutical companies.

SOURCE: Abou-Alfa GK et al. ESMO 2019, Abstract LBA10-PR.

BARCELONA – Ivosidenib, a first-in-class, oral, small-molecule inhibitor of the mutant isocitrate dehydrogenase 1 (mIDH1) protein, significantly improved progression-free survival, compared with placebo, for the treatment of advanced cholangiocarcinoma in the global, randomized, phase 3 ClarIDHy trial.

A trend toward favorable overall survival was also seen in the pivotal double-blind trial, Ghassan K. Abou-Alfa, MD, of Memorial Sloan-Kettering Cancer Center, New York, reported at the European Society for Medical Oncology Congress.

Median progression-free survival (PFS) in 124 patients randomized to receive 500 mg of ivosidenib (IVO) once daily was 2.7 months, compared with 1.4 months in 61 patients who received placebo (hazard ratio, 0.37).

The primary study endpoint – PFS by central review – was reached, Dr. Abou-Alfa said, noting that the PFS rates at 6 and 12 months were 32% and 22% in the IVO arm, whereas none of the patients in the placebo arm were progression-free for 6 or more months.

Although the 1.3-month difference in PFS between the treatment and placebo arms “may seem short and some people may question whether this is clinically meaningful,” this outcome actually represents an important breakthrough for patients with a disease that has few treatment options, Angela Lamarca, MD, PhD, of the Christie NHS Foundation Trust, Manchester, England, explained in a press release about the study.

“A treatment that increases the chance of being free from progression by 32% at 6 months after starting treatment and that prolongs survival from 6 months with placebo to 10.8 months with ivosidenib, after adjusting for crossover, is definitely meaningful for our patients with cholangiocarcinoma and their families,” said Dr. Lamarca, representing the ESMO Press & Media Affairs Committee.

Indeed, the overall response rate in the IVO arm was 2.4%, representing three partial responses, and the stable disease rate was 50.8%. The overall response rate and stable disease rates in the placebo arm were 0% and 28%, Dr. Abou-Alfa said.

Median overall survival in the intent-to-treat population, including the 57% of placebo arm patients who crossed over to the treatment arm at the time of radiographic progression as allowed by study protocol, was 10.8 months, compared with 9.7 months in the placebo arm, respectively (HR, 0.69), Dr. Abou-Alfa said.

Crossover-adjusted overall survival was 6 months for the placebo arm (HR, 0.46) as assessed using rank-preserving structural failure time analysis, which suggested that the overall survival benefit would have been statistically significant had there been no crossover.

Study subjects had unresectable or metastatic mIDH1 cholangiocarcinoma, good performance status, and measurable disease. They had a median age of 62 years, and 68 were men. Most had intrahepatic disease (91%) and metastatic disease (92%), and 43% had two prior therapies, he noted.

They were randomized 2:1 to the treatment and placebo arms, respectively.

Since IVO targets mIDH1, which occurs in about 20% of patients with cholangiocarcinoma and results in production of the oncogenesis-promoting oncometabolite D-2-hydroxyglutarate, and since the IVO has shown encouraging activity in smaller prior studies, ClarIDHy was designed to evaluate it in the advanced mIDH1 cholangiocarcinoma setting because patients with this aggressive disease have generally poor prognosis and few treatment options beyond chemotherapy, he explained.

In addition to providing significant, clinically meaningful survival benefit, the treatment also was generally well tolerated, he noted.

Treatment-emergent adverse events occurring in more than 15% of patients in the IVO arm included nausea (32.1%), diarrhea (28.8%), fatigue (23.7%), cough (19.2%), abdominal pain (18.6%), ascites (18.6%), decreased appetite (17.3%), anemia (16.0%), and vomiting (16.0%). Grade 3 or higher adverse events were reported in 46% and 36% of the IVO and placebo patients, respectively.

The findings are notable, in part because of the unmet need and also because this is the first pivotal study demonstrating the clinical benefit of targeting mIDH1 in patients with advanced mIDH1 cholangiocarcinoma, he said, concluding that “these pivotal data demonstrate the clinical relevance and benefit of ivosidenib in mIDH1 cholangiocarcinoma ... [and] establish the role for genomic testing in this rare cancer with a high unmet need.”

He also said studies should investigate IVO in the first-line setting for IDH1-mutated cholangiocarcinoma, in addition to its use in combination therapy and as adjuvant therapy.

In the ESMO press release, Chris Verslype, MD, of University Hospital Leuven (Belgium) called the findings of this study unprecedented given the lack of treatment options in those who fail systemic therapy, which has led to very limited survival.

The findings are “very likely to change clinical practice” and “will, for sure, drive the further development of targeted therapy for the disease,” he said.

Despite being limited by the requirement that patients have good performance status after prior chemotherapy (which means the findings may not be representative of all patients), ClarIDHy is “still a strong study because of the randomization to placebo.”

“It showed a real effect,” he said.

ClarIDHy was funded by Agios Pharmaceuticals. Dr. Abou-Alfa reported both personal and institutional relationships with industry. These include advisory /consulting roles and research grants/funding from numerous pharmaceutical companies.

SOURCE: Abou-Alfa GK et al. ESMO 2019, Abstract LBA10-PR.

BARCELONA – Ivosidenib, a first-in-class, oral, small-molecule inhibitor of the mutant isocitrate dehydrogenase 1 (mIDH1) protein, significantly improved progression-free survival, compared with placebo, for the treatment of advanced cholangiocarcinoma in the global, randomized, phase 3 ClarIDHy trial.

A trend toward favorable overall survival was also seen in the pivotal double-blind trial, Ghassan K. Abou-Alfa, MD, of Memorial Sloan-Kettering Cancer Center, New York, reported at the European Society for Medical Oncology Congress.

Median progression-free survival (PFS) in 124 patients randomized to receive 500 mg of ivosidenib (IVO) once daily was 2.7 months, compared with 1.4 months in 61 patients who received placebo (hazard ratio, 0.37).

The primary study endpoint – PFS by central review – was reached, Dr. Abou-Alfa said, noting that the PFS rates at 6 and 12 months were 32% and 22% in the IVO arm, whereas none of the patients in the placebo arm were progression-free for 6 or more months.

Although the 1.3-month difference in PFS between the treatment and placebo arms “may seem short and some people may question whether this is clinically meaningful,” this outcome actually represents an important breakthrough for patients with a disease that has few treatment options, Angela Lamarca, MD, PhD, of the Christie NHS Foundation Trust, Manchester, England, explained in a press release about the study.

“A treatment that increases the chance of being free from progression by 32% at 6 months after starting treatment and that prolongs survival from 6 months with placebo to 10.8 months with ivosidenib, after adjusting for crossover, is definitely meaningful for our patients with cholangiocarcinoma and their families,” said Dr. Lamarca, representing the ESMO Press & Media Affairs Committee.

Indeed, the overall response rate in the IVO arm was 2.4%, representing three partial responses, and the stable disease rate was 50.8%. The overall response rate and stable disease rates in the placebo arm were 0% and 28%, Dr. Abou-Alfa said.

Median overall survival in the intent-to-treat population, including the 57% of placebo arm patients who crossed over to the treatment arm at the time of radiographic progression as allowed by study protocol, was 10.8 months, compared with 9.7 months in the placebo arm, respectively (HR, 0.69), Dr. Abou-Alfa said.

Crossover-adjusted overall survival was 6 months for the placebo arm (HR, 0.46) as assessed using rank-preserving structural failure time analysis, which suggested that the overall survival benefit would have been statistically significant had there been no crossover.

Study subjects had unresectable or metastatic mIDH1 cholangiocarcinoma, good performance status, and measurable disease. They had a median age of 62 years, and 68 were men. Most had intrahepatic disease (91%) and metastatic disease (92%), and 43% had two prior therapies, he noted.

They were randomized 2:1 to the treatment and placebo arms, respectively.

Since IVO targets mIDH1, which occurs in about 20% of patients with cholangiocarcinoma and results in production of the oncogenesis-promoting oncometabolite D-2-hydroxyglutarate, and since the IVO has shown encouraging activity in smaller prior studies, ClarIDHy was designed to evaluate it in the advanced mIDH1 cholangiocarcinoma setting because patients with this aggressive disease have generally poor prognosis and few treatment options beyond chemotherapy, he explained.

In addition to providing significant, clinically meaningful survival benefit, the treatment also was generally well tolerated, he noted.

Treatment-emergent adverse events occurring in more than 15% of patients in the IVO arm included nausea (32.1%), diarrhea (28.8%), fatigue (23.7%), cough (19.2%), abdominal pain (18.6%), ascites (18.6%), decreased appetite (17.3%), anemia (16.0%), and vomiting (16.0%). Grade 3 or higher adverse events were reported in 46% and 36% of the IVO and placebo patients, respectively.

The findings are notable, in part because of the unmet need and also because this is the first pivotal study demonstrating the clinical benefit of targeting mIDH1 in patients with advanced mIDH1 cholangiocarcinoma, he said, concluding that “these pivotal data demonstrate the clinical relevance and benefit of ivosidenib in mIDH1 cholangiocarcinoma ... [and] establish the role for genomic testing in this rare cancer with a high unmet need.”

He also said studies should investigate IVO in the first-line setting for IDH1-mutated cholangiocarcinoma, in addition to its use in combination therapy and as adjuvant therapy.

In the ESMO press release, Chris Verslype, MD, of University Hospital Leuven (Belgium) called the findings of this study unprecedented given the lack of treatment options in those who fail systemic therapy, which has led to very limited survival.

The findings are “very likely to change clinical practice” and “will, for sure, drive the further development of targeted therapy for the disease,” he said.

Despite being limited by the requirement that patients have good performance status after prior chemotherapy (which means the findings may not be representative of all patients), ClarIDHy is “still a strong study because of the randomization to placebo.”

“It showed a real effect,” he said.

ClarIDHy was funded by Agios Pharmaceuticals. Dr. Abou-Alfa reported both personal and institutional relationships with industry. These include advisory /consulting roles and research grants/funding from numerous pharmaceutical companies.

SOURCE: Abou-Alfa GK et al. ESMO 2019, Abstract LBA10-PR.

SAN FRANCISCO – Several factors must be considered when extrapolating biosimilar results, according to a speaker at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Jennifer Smith/MDedge News

In this context, “extrapolation” means expanding the use of an approved biosimilar from one indication to another, based on efficacy and safety data from the first indication, Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, explained at the meeting.

To determine if extrapolation is appropriate, regulatory agencies consider the biosimilar’s mechanism of action in each indication; pharmacokinetics, pharmacodynamics, and immunogenicity in the different patient populations; differences in expected toxicities for each condition and population; and any other factor that may affect safety or efficacy.

To illustrate the process, Dr. Zelenetz explained how results with a rituximab biosimilar in rheumatoid arthritis (RA) cannot be extrapolated to B‐cell non‐Hodgkin lymphoma (NHL), but results with that same biosimilar in follicular lymphoma can be extrapolated to other types of B-cell NHL.

The biosimilar is rituximab-abbs (CT‐P10, Truxima). In a phase 1 trial of patients with RA, rituximab-abbs demonstrated biosimilarity to the reference product (Ann Rheum Dis. 2017;76[3]:566‐70).

The RA results cannot be extrapolated to B-cell NHL for a few reasons, according to Dr. Zelenetz. He noted that rituximab’s mechanism of action is antibody-dependent cell‐mediated cytotoxicity in both RA and NHL. However, the target in RA is the normal B cell, and the target in NHL is the malignant B cell.

In addition, the pharmacokinetics of rituximab are “drastically different” in RA and NHL, Dr. Zelenetz said. Differences in pharmacokinetics support different dosing approaches in the two diseases.

Another big difference is immunogenicity. Anti‐CD20 antibodies develop in 15%-17% of RA patients, Dr. Zelenetz said, but the risk of antibody development is less than 1% in lymphoma.

Though extrapolation from RA to B‐cell NHL was not possible, it was possible to extrapolate results with rituximab-abbs in follicular lymphoma to other B-cell NHLs.

The study used was a phase 3 trial comparing rituximab-abbs to rituximab – both in combination with cyclophosphamide, vincristine, and prednisone – in patients with newly diagnosed, advanced stage follicular lymphoma.

This study showed no difference in pharmacokinetics or pharmacodynamics between rituximab-abbs and rituximab. The two agents also had comparable safety profiles and produced similar response rates (Lancet Haematol. 2017 Jul 13;4:e362‐73).

Rituximab‐abbs was approved in the United States based on these data, and results from this trial were extrapolated to other types of B-cell NHL. The results were extrapolated because the mechanism of action, pharmacokinetics, pharmacodynamics, and immunogenicity of rituximab are the same across B-cell NHLs, Dr. Zelenetz noted.

“Extrapolation is a critical part of biosimilarity development,” he said. “As long as scientific justification for extrapolation exists, I believe that extrapolation makes good sense.”

Dr. Zelenetz reported relationships with AbbVie, Adaptive Biotechnologies, Amgen, AstraZeneca, BeiGene, Celgene, Genentech, Gilead Sciences, Janssen, MEI Pharma, MorphoSys AG, Novartis, Pharmacyclics, and Roche.

[email protected]

SAN FRANCISCO – Several factors must be considered when extrapolating biosimilar results, according to a speaker at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Jennifer Smith/MDedge News

In this context, “extrapolation” means expanding the use of an approved biosimilar from one indication to another, based on efficacy and safety data from the first indication, Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, explained at the meeting.

To determine if extrapolation is appropriate, regulatory agencies consider the biosimilar’s mechanism of action in each indication; pharmacokinetics, pharmacodynamics, and immunogenicity in the different patient populations; differences in expected toxicities for each condition and population; and any other factor that may affect safety or efficacy.

To illustrate the process, Dr. Zelenetz explained how results with a rituximab biosimilar in rheumatoid arthritis (RA) cannot be extrapolated to B‐cell non‐Hodgkin lymphoma (NHL), but results with that same biosimilar in follicular lymphoma can be extrapolated to other types of B-cell NHL.

The biosimilar is rituximab-abbs (CT‐P10, Truxima). In a phase 1 trial of patients with RA, rituximab-abbs demonstrated biosimilarity to the reference product (Ann Rheum Dis. 2017;76[3]:566‐70).

The RA results cannot be extrapolated to B-cell NHL for a few reasons, according to Dr. Zelenetz. He noted that rituximab’s mechanism of action is antibody-dependent cell‐mediated cytotoxicity in both RA and NHL. However, the target in RA is the normal B cell, and the target in NHL is the malignant B cell.

In addition, the pharmacokinetics of rituximab are “drastically different” in RA and NHL, Dr. Zelenetz said. Differences in pharmacokinetics support different dosing approaches in the two diseases.

Another big difference is immunogenicity. Anti‐CD20 antibodies develop in 15%-17% of RA patients, Dr. Zelenetz said, but the risk of antibody development is less than 1% in lymphoma.

Though extrapolation from RA to B‐cell NHL was not possible, it was possible to extrapolate results with rituximab-abbs in follicular lymphoma to other B-cell NHLs.

The study used was a phase 3 trial comparing rituximab-abbs to rituximab – both in combination with cyclophosphamide, vincristine, and prednisone – in patients with newly diagnosed, advanced stage follicular lymphoma.

This study showed no difference in pharmacokinetics or pharmacodynamics between rituximab-abbs and rituximab. The two agents also had comparable safety profiles and produced similar response rates (Lancet Haematol. 2017 Jul 13;4:e362‐73).

Rituximab‐abbs was approved in the United States based on these data, and results from this trial were extrapolated to other types of B-cell NHL. The results were extrapolated because the mechanism of action, pharmacokinetics, pharmacodynamics, and immunogenicity of rituximab are the same across B-cell NHLs, Dr. Zelenetz noted.

“Extrapolation is a critical part of biosimilarity development,” he said. “As long as scientific justification for extrapolation exists, I believe that extrapolation makes good sense.”

Dr. Zelenetz reported relationships with AbbVie, Adaptive Biotechnologies, Amgen, AstraZeneca, BeiGene, Celgene, Genentech, Gilead Sciences, Janssen, MEI Pharma, MorphoSys AG, Novartis, Pharmacyclics, and Roche.

[email protected]

SAN FRANCISCO – Several factors must be considered when extrapolating biosimilar results, according to a speaker at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Jennifer Smith/MDedge News

In this context, “extrapolation” means expanding the use of an approved biosimilar from one indication to another, based on efficacy and safety data from the first indication, Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, explained at the meeting.

To determine if extrapolation is appropriate, regulatory agencies consider the biosimilar’s mechanism of action in each indication; pharmacokinetics, pharmacodynamics, and immunogenicity in the different patient populations; differences in expected toxicities for each condition and population; and any other factor that may affect safety or efficacy.

To illustrate the process, Dr. Zelenetz explained how results with a rituximab biosimilar in rheumatoid arthritis (RA) cannot be extrapolated to B‐cell non‐Hodgkin lymphoma (NHL), but results with that same biosimilar in follicular lymphoma can be extrapolated to other types of B-cell NHL.

The biosimilar is rituximab-abbs (CT‐P10, Truxima). In a phase 1 trial of patients with RA, rituximab-abbs demonstrated biosimilarity to the reference product (Ann Rheum Dis. 2017;76[3]:566‐70).

The RA results cannot be extrapolated to B-cell NHL for a few reasons, according to Dr. Zelenetz. He noted that rituximab’s mechanism of action is antibody-dependent cell‐mediated cytotoxicity in both RA and NHL. However, the target in RA is the normal B cell, and the target in NHL is the malignant B cell.

In addition, the pharmacokinetics of rituximab are “drastically different” in RA and NHL, Dr. Zelenetz said. Differences in pharmacokinetics support different dosing approaches in the two diseases.

Another big difference is immunogenicity. Anti‐CD20 antibodies develop in 15%-17% of RA patients, Dr. Zelenetz said, but the risk of antibody development is less than 1% in lymphoma.

Though extrapolation from RA to B‐cell NHL was not possible, it was possible to extrapolate results with rituximab-abbs in follicular lymphoma to other B-cell NHLs.

The study used was a phase 3 trial comparing rituximab-abbs to rituximab – both in combination with cyclophosphamide, vincristine, and prednisone – in patients with newly diagnosed, advanced stage follicular lymphoma.

This study showed no difference in pharmacokinetics or pharmacodynamics between rituximab-abbs and rituximab. The two agents also had comparable safety profiles and produced similar response rates (Lancet Haematol. 2017 Jul 13;4:e362‐73).

Rituximab‐abbs was approved in the United States based on these data, and results from this trial were extrapolated to other types of B-cell NHL. The results were extrapolated because the mechanism of action, pharmacokinetics, pharmacodynamics, and immunogenicity of rituximab are the same across B-cell NHLs, Dr. Zelenetz noted.

“Extrapolation is a critical part of biosimilarity development,” he said. “As long as scientific justification for extrapolation exists, I believe that extrapolation makes good sense.”

Dr. Zelenetz reported relationships with AbbVie, Adaptive Biotechnologies, Amgen, AstraZeneca, BeiGene, Celgene, Genentech, Gilead Sciences, Janssen, MEI Pharma, MorphoSys AG, Novartis, Pharmacyclics, and Roche.

[email protected]

BOSTON — There is “no standard of care and no clear pattern” for discontinuing treatment in multiple myeloma, according to a speaker at the International Myeloma Workshop.

Jennifer Smith/MDedge News

Data from a large, observational study revealed that a wide range of treatment regimens are used for first-, second-, and third-line therapy in multiple myeloma. The duration of therapy and time to next treatment were shorter in this real-world study than in prior clinical trials, and reasons for treatment discontinuation varied by regimen and line of therapy.

Katja Weisel, MD, of University Medical Center Hamburg-Eppendorf in Germany, presented these findings at the workshop, held by the International Myeloma Society.

The study, INSIGHT MM, is the largest global, prospective, observational study of multiple myeloma to date, according to Dr. Weisel. The study, which began July 1, 2016, has enrolled patients in the United States (n = 1,004), Europe (n = 1,612), Latin America (n = 367), and Asia (n = 218).

Dr. Weisel and her colleagues evaluated duration of therapy, reasons for treatment discontinuation, and subsequent therapies in a subset of patients on INSIGHT MM. The researchers’ analysis revealed “broad heterogeneity” across lines of therapy, Dr. Weisel said, adding that patients are receiving multiple regimens in addition to the most commonly prescribed regimens in myeloma.

First-line therapy

“In first-line treatment, we see predominantly bortezomib-based triplets ... regardless of transplant-eligible or transplant-ineligible patients,” Dr. Weisel said. “This is followed by doublets and other more rarely [applied] regimens.”

First-line therapies in 1,175 patients included:

• Bortezomib, cyclophosphamide, and dexamethasone (VCd) – 323 patients.
• Bortezomib, lenalidomide, and dexamethasone (VRd) – 321 patients.
• Bortezomib, thalidomide, and dexamethasone (VTd) – 200 patients.
• Bortezomib and dexamethasone (Vd) – 102 patients.
• Lenalidomide and dexamethasone (Rd) – 90 patients.
• Bortezomib, melphalan, and prednisone (VMP) – 53 patients.
• Carfilzomib, lenalidomide, and dexamethasone (KRd) – 47 patients.
• Daratumumab-based regimens (Dara) – 32 patients.
• Carfilzomib and dexamethasone (Kd) – 5 patients.
• Ixazomib, lenalidomide, and dexamethasone (IRd) – 2 patients.

Of the 1,175 newly diagnosed patients, 894 did not proceed to transplant after first-line therapy, but 281 did. Most of the patients who went on to transplant had received VRd (n = 82), VTd (n = 76), or VCd (n = 75).

Second- and third-line therapies

“In second-line treatment, we have still a dominance of the len-dex regimen all over the world,” Dr. Weisel said. “There is an emerging use of daratumumab in various combinations, and then you see the whole spectrum of approved triplet and doublet regimens.”

In the third line, the most commonly used regimens are daratumumab-based combinations and Rd.

There were 548 patients who received second-line treatment and 332 who received third-line therapy. The regimens used were:

• Rd – 130 patients second line, 71 third line.
• Dara – 121 patients second line, 105 third line.
• KRd – 61 patients second line, 17 third line.
• VCd – 57 patients second line, 19 third line.
• Vd – 48 patients second line, 29 third line.
• VRd – 36 patients second line, 8 third line.
• Kd – 33 patients for both second and third line.
• IRd – 29 patients second line, 43 third line.
• VTd – 25 patients second line, 4 third line.
• VMP – 8 patients second line, 3 third line.

Most transplant-eligible patients received any first-line therapy (VRd, VTd, or VCd) for longer than 12 months. Among transplant-ineligible patients, Rd was the first-line therapy most likely to be given for 12 months or more.

None of the second-line regimens lasted longer than 12 months in a majority of patients, but daratumumab-based regimens and IRd were the therapies most likely to exceed 12 months’ duration in both second- and third-line treatment.

Time to next treatment

“The vast majority of [transplant-eligible] patients, close to 90% ... do not need a second-line treatment during the first year of treatment,” Dr. Weisel said. “However, for transplant-ineligible patients, this accounts only for the most effective regimens, VMP and Rd.”

For second- and third-line therapies, a 12-month or longer time to next treatment was most likely among patients who received IRd or daratumumab-based regimens.

“Planned end of therapy only accounts for a small proportion of treatment discontinuations, especially in the relapsed setting,” Dr. Weisel said. “Patients are discontinuing treatment due to reasons other than relapse, ultimately receiving fixed-duration therapy.”

The most common reasons for discontinuation of first-line therapy were:

• Relapse for VCd.
• Planned end of therapy for VRd.
• Adverse events (AEs) for VD and VTd.
• AEs and “other reasons” for Rd.

The most common reasons for discontinuation of second-line therapy were:

• Planned end of therapy for VCd.
• AEs, relapse, and other reasons for VRd.
• Relapse for VD, KRd, and Dara.
• AEs for Rd and IRd.
• AEs and other reasons for Kd.

The most common reasons for discontinuation of third-line therapy were:

• AEs for VCd, Vd, and KRd.
• Relapse for Kd, IRd, and Dara.
• Relapse and other reasons for VRd.
• AEs and other reasons for Rd.

The most common AE leading to discontinuation, across all treatment regimens, was peripheral neuropathy. This suggests peripheral neuropathy is still the “biggest impediment for continuous treatment,” Dr. Weisel said.

INSIGHT MM is sponsored by Takeda. Dr. Weisel reported relationships with Takeda and several other companies.

[email protected]

SOURCE: Weisel K et al. IMW 2019, Abstract OAB-005.

BOSTON — There is “no standard of care and no clear pattern” for discontinuing treatment in multiple myeloma, according to a speaker at the International Myeloma Workshop.

Jennifer Smith/MDedge News

Data from a large, observational study revealed that a wide range of treatment regimens are used for first-, second-, and third-line therapy in multiple myeloma. The duration of therapy and time to next treatment were shorter in this real-world study than in prior clinical trials, and reasons for treatment discontinuation varied by regimen and line of therapy.

Katja Weisel, MD, of University Medical Center Hamburg-Eppendorf in Germany, presented these findings at the workshop, held by the International Myeloma Society.

The study, INSIGHT MM, is the largest global, prospective, observational study of multiple myeloma to date, according to Dr. Weisel. The study, which began July 1, 2016, has enrolled patients in the United States (n = 1,004), Europe (n = 1,612), Latin America (n = 367), and Asia (n = 218).

Dr. Weisel and her colleagues evaluated duration of therapy, reasons for treatment discontinuation, and subsequent therapies in a subset of patients on INSIGHT MM. The researchers’ analysis revealed “broad heterogeneity” across lines of therapy, Dr. Weisel said, adding that patients are receiving multiple regimens in addition to the most commonly prescribed regimens in myeloma.

First-line therapy

“In first-line treatment, we see predominantly bortezomib-based triplets ... regardless of transplant-eligible or transplant-ineligible patients,” Dr. Weisel said. “This is followed by doublets and other more rarely [applied] regimens.”

First-line therapies in 1,175 patients included:

• Bortezomib, cyclophosphamide, and dexamethasone (VCd) – 323 patients.
• Bortezomib, lenalidomide, and dexamethasone (VRd) – 321 patients.
• Bortezomib, thalidomide, and dexamethasone (VTd) – 200 patients.
• Bortezomib and dexamethasone (Vd) – 102 patients.
• Lenalidomide and dexamethasone (Rd) – 90 patients.
• Bortezomib, melphalan, and prednisone (VMP) – 53 patients.
• Carfilzomib, lenalidomide, and dexamethasone (KRd) – 47 patients.
• Daratumumab-based regimens (Dara) – 32 patients.
• Carfilzomib and dexamethasone (Kd) – 5 patients.
• Ixazomib, lenalidomide, and dexamethasone (IRd) – 2 patients.

Of the 1,175 newly diagnosed patients, 894 did not proceed to transplant after first-line therapy, but 281 did. Most of the patients who went on to transplant had received VRd (n = 82), VTd (n = 76), or VCd (n = 75).

Second- and third-line therapies

“In second-line treatment, we have still a dominance of the len-dex regimen all over the world,” Dr. Weisel said. “There is an emerging use of daratumumab in various combinations, and then you see the whole spectrum of approved triplet and doublet regimens.”

In the third line, the most commonly used regimens are daratumumab-based combinations and Rd.

There were 548 patients who received second-line treatment and 332 who received third-line therapy. The regimens used were:

• Rd – 130 patients second line, 71 third line.
• Dara – 121 patients second line, 105 third line.
• KRd – 61 patients second line, 17 third line.
• VCd – 57 patients second line, 19 third line.
• Vd – 48 patients second line, 29 third line.
• VRd – 36 patients second line, 8 third line.
• Kd – 33 patients for both second and third line.
• IRd – 29 patients second line, 43 third line.
• VTd – 25 patients second line, 4 third line.
• VMP – 8 patients second line, 3 third line.

Most transplant-eligible patients received any first-line therapy (VRd, VTd, or VCd) for longer than 12 months. Among transplant-ineligible patients, Rd was the first-line therapy most likely to be given for 12 months or more.

None of the second-line regimens lasted longer than 12 months in a majority of patients, but daratumumab-based regimens and IRd were the therapies most likely to exceed 12 months’ duration in both second- and third-line treatment.

Time to next treatment

“The vast majority of [transplant-eligible] patients, close to 90% ... do not need a second-line treatment during the first year of treatment,” Dr. Weisel said. “However, for transplant-ineligible patients, this accounts only for the most effective regimens, VMP and Rd.”

For second- and third-line therapies, a 12-month or longer time to next treatment was most likely among patients who received IRd or daratumumab-based regimens.

“Planned end of therapy only accounts for a small proportion of treatment discontinuations, especially in the relapsed setting,” Dr. Weisel said. “Patients are discontinuing treatment due to reasons other than relapse, ultimately receiving fixed-duration therapy.”

The most common reasons for discontinuation of first-line therapy were:

• Relapse for VCd.
• Planned end of therapy for VRd.
• Adverse events (AEs) for VD and VTd.
• AEs and “other reasons” for Rd.

The most common reasons for discontinuation of second-line therapy were:

• Planned end of therapy for VCd.
• AEs, relapse, and other reasons for VRd.
• Relapse for VD, KRd, and Dara.
• AEs for Rd and IRd.
• AEs and other reasons for Kd.

The most common reasons for discontinuation of third-line therapy were:

• AEs for VCd, Vd, and KRd.
• Relapse for Kd, IRd, and Dara.
• Relapse and other reasons for VRd.
• AEs and other reasons for Rd.

The most common AE leading to discontinuation, across all treatment regimens, was peripheral neuropathy. This suggests peripheral neuropathy is still the “biggest impediment for continuous treatment,” Dr. Weisel said.

INSIGHT MM is sponsored by Takeda. Dr. Weisel reported relationships with Takeda and several other companies.

[email protected]

SOURCE: Weisel K et al. IMW 2019, Abstract OAB-005.

BOSTON — There is “no standard of care and no clear pattern” for discontinuing treatment in multiple myeloma, according to a speaker at the International Myeloma Workshop.

Jennifer Smith/MDedge News

Data from a large, observational study revealed that a wide range of treatment regimens are used for first-, second-, and third-line therapy in multiple myeloma. The duration of therapy and time to next treatment were shorter in this real-world study than in prior clinical trials, and reasons for treatment discontinuation varied by regimen and line of therapy.

Katja Weisel, MD, of University Medical Center Hamburg-Eppendorf in Germany, presented these findings at the workshop, held by the International Myeloma Society.

The study, INSIGHT MM, is the largest global, prospective, observational study of multiple myeloma to date, according to Dr. Weisel. The study, which began July 1, 2016, has enrolled patients in the United States (n = 1,004), Europe (n = 1,612), Latin America (n = 367), and Asia (n = 218).

Dr. Weisel and her colleagues evaluated duration of therapy, reasons for treatment discontinuation, and subsequent therapies in a subset of patients on INSIGHT MM. The researchers’ analysis revealed “broad heterogeneity” across lines of therapy, Dr. Weisel said, adding that patients are receiving multiple regimens in addition to the most commonly prescribed regimens in myeloma.

First-line therapy

“In first-line treatment, we see predominantly bortezomib-based triplets ... regardless of transplant-eligible or transplant-ineligible patients,” Dr. Weisel said. “This is followed by doublets and other more rarely [applied] regimens.”

First-line therapies in 1,175 patients included:

• Bortezomib, cyclophosphamide, and dexamethasone (VCd) – 323 patients.
• Bortezomib, lenalidomide, and dexamethasone (VRd) – 321 patients.
• Bortezomib, thalidomide, and dexamethasone (VTd) – 200 patients.
• Bortezomib and dexamethasone (Vd) – 102 patients.
• Lenalidomide and dexamethasone (Rd) – 90 patients.
• Bortezomib, melphalan, and prednisone (VMP) – 53 patients.
• Carfilzomib, lenalidomide, and dexamethasone (KRd) – 47 patients.
• Daratumumab-based regimens (Dara) – 32 patients.
• Carfilzomib and dexamethasone (Kd) – 5 patients.
• Ixazomib, lenalidomide, and dexamethasone (IRd) – 2 patients.

Of the 1,175 newly diagnosed patients, 894 did not proceed to transplant after first-line therapy, but 281 did. Most of the patients who went on to transplant had received VRd (n = 82), VTd (n = 76), or VCd (n = 75).

Second- and third-line therapies

“In second-line treatment, we have still a dominance of the len-dex regimen all over the world,” Dr. Weisel said. “There is an emerging use of daratumumab in various combinations, and then you see the whole spectrum of approved triplet and doublet regimens.”

In the third line, the most commonly used regimens are daratumumab-based combinations and Rd.

There were 548 patients who received second-line treatment and 332 who received third-line therapy. The regimens used were:

• Rd – 130 patients second line, 71 third line.
• Dara – 121 patients second line, 105 third line.
• KRd – 61 patients second line, 17 third line.
• VCd – 57 patients second line, 19 third line.
• Vd – 48 patients second line, 29 third line.
• VRd – 36 patients second line, 8 third line.
• Kd – 33 patients for both second and third line.
• IRd – 29 patients second line, 43 third line.
• VTd – 25 patients second line, 4 third line.
• VMP – 8 patients second line, 3 third line.

Most transplant-eligible patients received any first-line therapy (VRd, VTd, or VCd) for longer than 12 months. Among transplant-ineligible patients, Rd was the first-line therapy most likely to be given for 12 months or more.

None of the second-line regimens lasted longer than 12 months in a majority of patients, but daratumumab-based regimens and IRd were the therapies most likely to exceed 12 months’ duration in both second- and third-line treatment.

Time to next treatment

“The vast majority of [transplant-eligible] patients, close to 90% ... do not need a second-line treatment during the first year of treatment,” Dr. Weisel said. “However, for transplant-ineligible patients, this accounts only for the most effective regimens, VMP and Rd.”

For second- and third-line therapies, a 12-month or longer time to next treatment was most likely among patients who received IRd or daratumumab-based regimens.

“Planned end of therapy only accounts for a small proportion of treatment discontinuations, especially in the relapsed setting,” Dr. Weisel said. “Patients are discontinuing treatment due to reasons other than relapse, ultimately receiving fixed-duration therapy.”

The most common reasons for discontinuation of first-line therapy were:

• Relapse for VCd.
• Planned end of therapy for VRd.
• Adverse events (AEs) for VD and VTd.
• AEs and “other reasons” for Rd.

The most common reasons for discontinuation of second-line therapy were:

• Planned end of therapy for VCd.
• AEs, relapse, and other reasons for VRd.
• Relapse for VD, KRd, and Dara.
• AEs for Rd and IRd.
• AEs and other reasons for Kd.

The most common reasons for discontinuation of third-line therapy were:

• AEs for VCd, Vd, and KRd.
• Relapse for Kd, IRd, and Dara.
• Relapse and other reasons for VRd.
• AEs and other reasons for Rd.

The most common AE leading to discontinuation, across all treatment regimens, was peripheral neuropathy. This suggests peripheral neuropathy is still the “biggest impediment for continuous treatment,” Dr. Weisel said.

INSIGHT MM is sponsored by Takeda. Dr. Weisel reported relationships with Takeda and several other companies.

[email protected]

SOURCE: Weisel K et al. IMW 2019, Abstract OAB-005.

Persistent high rates of bacterial resistance to current treatments have created the need for more options, especially for the treatment of community-acquired bacterial pneumonia (CABP), which remains a leading cause of hospitalization and death in the United States, wrote Elizabeth Alexander, MD, of Nabriva Therapeutics in King of Prussia, Penn., and colleagues. Lefamulin, “the first pleuromutilin antibiotic approved for intravenous and oral use in humans,” has demonstrated activity against many CABP-causing pathogens, including some not susceptible to other classes of antimicrobials, they noted.

Findings of Lefamulin Evaluation Against Pneumonia 2 (LEAP2) were published in JAMA. In this study, the researchers randomized 370 patients to 600 mg of oral lefamulin every 12 hours for 5 days and 368 patients to 400 mg of oral moxifloxacin every 24 hours for 7 days.

Early clinical response rates at 96 hours were 90.8% for both medications (difference of 0.1%). In addition, the rates of clinical response success were similar between the groups in both the modified intent-to-treat population (87.5% with lefamulin and 89.1% with moxifloxacin) and the clinically evaluable population (89.7% with lefamulin and 93.6% with moxifloxacin).

Gastrointestinal issues of diarrhea and nausea were the two most frequently reported treatment-emergent adverse events in both groups. Both conditions occurred more often in the lefamulin group, compared with the moxifloxacin group, but the differences were not significant (12.2% vs. 1.1% and 5.2% vs. 1.9%, respectively).

The study findings were limited by several factors including strict exclusion criteria that may limit the generalizability of the results, as well as a lack of testing for viral copathogens, low recovery of resistant pathogens, and possible misclassification of patient ethnicity, the researchers noted.

However, the results were strengthened by the randomized design, inclusion of patients with more severe CABP, and low rate of discontinuation, they said. The data support previous studies of lefamulin. Its lack of cross-resistance to other drug classes, coverage of typical and atypical CABP pathogens, and options for both oral and intravenous use suggest that it “may provide an alternative approach for the treatment of vulnerable patients,” the researchers said.

The study was supported by Nabriva Therapeutics. Dr. Alexander and several coauthors are employees of Nabriva Therapeutics and own stock in the company.

SOURCE: Alexander E et al. JAMA. 2019 Sep 27. doi:10.1001/jama.2019.15468.

Persistent high rates of bacterial resistance to current treatments have created the need for more options, especially for the treatment of community-acquired bacterial pneumonia (CABP), which remains a leading cause of hospitalization and death in the United States, wrote Elizabeth Alexander, MD, of Nabriva Therapeutics in King of Prussia, Penn., and colleagues. Lefamulin, “the first pleuromutilin antibiotic approved for intravenous and oral use in humans,” has demonstrated activity against many CABP-causing pathogens, including some not susceptible to other classes of antimicrobials, they noted.

Findings of Lefamulin Evaluation Against Pneumonia 2 (LEAP2) were published in JAMA. In this study, the researchers randomized 370 patients to 600 mg of oral lefamulin every 12 hours for 5 days and 368 patients to 400 mg of oral moxifloxacin every 24 hours for 7 days.

Early clinical response rates at 96 hours were 90.8% for both medications (difference of 0.1%). In addition, the rates of clinical response success were similar between the groups in both the modified intent-to-treat population (87.5% with lefamulin and 89.1% with moxifloxacin) and the clinically evaluable population (89.7% with lefamulin and 93.6% with moxifloxacin).

Gastrointestinal issues of diarrhea and nausea were the two most frequently reported treatment-emergent adverse events in both groups. Both conditions occurred more often in the lefamulin group, compared with the moxifloxacin group, but the differences were not significant (12.2% vs. 1.1% and 5.2% vs. 1.9%, respectively).

The study findings were limited by several factors including strict exclusion criteria that may limit the generalizability of the results, as well as a lack of testing for viral copathogens, low recovery of resistant pathogens, and possible misclassification of patient ethnicity, the researchers noted.

However, the results were strengthened by the randomized design, inclusion of patients with more severe CABP, and low rate of discontinuation, they said. The data support previous studies of lefamulin. Its lack of cross-resistance to other drug classes, coverage of typical and atypical CABP pathogens, and options for both oral and intravenous use suggest that it “may provide an alternative approach for the treatment of vulnerable patients,” the researchers said.

The study was supported by Nabriva Therapeutics. Dr. Alexander and several coauthors are employees of Nabriva Therapeutics and own stock in the company.

SOURCE: Alexander E et al. JAMA. 2019 Sep 27. doi:10.1001/jama.2019.15468.

Persistent high rates of bacterial resistance to current treatments have created the need for more options, especially for the treatment of community-acquired bacterial pneumonia (CABP), which remains a leading cause of hospitalization and death in the United States, wrote Elizabeth Alexander, MD, of Nabriva Therapeutics in King of Prussia, Penn., and colleagues. Lefamulin, “the first pleuromutilin antibiotic approved for intravenous and oral use in humans,” has demonstrated activity against many CABP-causing pathogens, including some not susceptible to other classes of antimicrobials, they noted.

Findings of Lefamulin Evaluation Against Pneumonia 2 (LEAP2) were published in JAMA. In this study, the researchers randomized 370 patients to 600 mg of oral lefamulin every 12 hours for 5 days and 368 patients to 400 mg of oral moxifloxacin every 24 hours for 7 days.

Early clinical response rates at 96 hours were 90.8% for both medications (difference of 0.1%). In addition, the rates of clinical response success were similar between the groups in both the modified intent-to-treat population (87.5% with lefamulin and 89.1% with moxifloxacin) and the clinically evaluable population (89.7% with lefamulin and 93.6% with moxifloxacin).

Gastrointestinal issues of diarrhea and nausea were the two most frequently reported treatment-emergent adverse events in both groups. Both conditions occurred more often in the lefamulin group, compared with the moxifloxacin group, but the differences were not significant (12.2% vs. 1.1% and 5.2% vs. 1.9%, respectively).

The study findings were limited by several factors including strict exclusion criteria that may limit the generalizability of the results, as well as a lack of testing for viral copathogens, low recovery of resistant pathogens, and possible misclassification of patient ethnicity, the researchers noted.

However, the results were strengthened by the randomized design, inclusion of patients with more severe CABP, and low rate of discontinuation, they said. The data support previous studies of lefamulin. Its lack of cross-resistance to other drug classes, coverage of typical and atypical CABP pathogens, and options for both oral and intravenous use suggest that it “may provide an alternative approach for the treatment of vulnerable patients,” the researchers said.

The study was supported by Nabriva Therapeutics. Dr. Alexander and several coauthors are employees of Nabriva Therapeutics and own stock in the company.

SOURCE: Alexander E et al. JAMA. 2019 Sep 27. doi:10.1001/jama.2019.15468.

PARIS – All lifestyle-related cardiovascular risk factors aren’t equal in power when it comes to secondary prevention after a first acute MI, according to a massive Swedish registry study.

Insufficient physical activity and current smoking were consistently the strongest risk factors for all-cause mortality, major adverse cardiovascular events, and other key adverse outcomes in an analysis from the SWEDEHEART registry. The study included 65,002 patients discharged after a first MI and 325,010 age- and sex-matched controls with no prior MI followed for a median of 5.5 years and maximum of 12, Emil Hagstrom, MD, PhD, reported at the annual congress of the European Society of Cardiology.

Strongest lifestyle risk factors

The study examined the long-term relative importance of control of six major lifestyle risk factors for secondary cardiovascular prevention: current smoking, insufficient physical activity, blood pressure of 140/90 mm Hg or more, obesity, a fasting blood glucose of at least 126 mg/dL, and an LDL cholesterol of 70 mg/dL or more. Notably, two risk factors that physicians often emphasize in working with their patients with known coronary heart disease – an elevated LDL cholesterol and obesity – barely moved the needle. Out of the six risk factors scrutinized, those two consistently showed the weakest association with long-term risk of adverse outcomes. Occupying the middle ground in terms of predictive strength were hypertension and elevated blood glucose, according to Dr. Hagstrom, a cardiologist at Uppsala (Sweden) University.

Risk factor status was assessed 6-10 weeks post MI. Insufficient physical activity was defined as not engaging in at least 30 minutes of moderate-intensity exercise on at least 5 days per week. And when Dr. Hagstrom recalculated the risk of adverse outcomes using an LDL cholesterol threshold of 55 mg/dL rather than using 70 mg/dL, as recommended in new ESC secondary prevention guidelines released during the congress, the study results remained unchanged.

Cumulative effects

A key SWEDEHEART finding underscoring the importance of lifestyle in secondary prevention was that a linear stepwise relationship existed between the number of risk factors at target levels and the risk of all of the various adverse outcomes assessed, including stroke and heart failure hospitalization as well as all-cause mortality, cardiovascular mortality, and major bleeding.

Moreover, patients with none of the six risk factors outside of target when assessed after their MI had the same risks of all-cause mortality, cardiovascular mortality, and stroke as the matched controls.

For example, in an analysis adjusted for comorbid cancer, chronic obstructive pulmonary disease, and dementia, post-MI patients with zero risk factors had the same long-term risk of cardiovascular mortality as controls without a history of MI at baseline. With one risk factor not at target, a patient had a 41% increased risk compared with controls, a statistically significant difference. With two out-of-whack risk factors, the risk climbed to 102%. With three, 185%. With four risk factors not at target, the all-cause mortality risk jumped to 291%. And patients with more than four of the six risk factors not at target had a 409% greater risk of all-cause mortality than controls who had never had a heart attack.

When Dr. Hagstrom stratified subjects by age at baseline – up to 55, 56-64, 65-70, and 70-75 years – he discovered that, regardless of age, patients with zero risk factors had the same risk of all-cause mortality and other adverse outcomes as controls. However, when risk factors were present, younger patients consistently had a higher risk of all adverse outcomes than older patients with the same number of risk factors. When asked for an explanation of this phenomenon, Dr. Hagstrom noted that younger patients with multiple risk factors have a longer time to be exposed to and accumulate risk.

Follow-up of the study cohort will continue for years to come, the cardiologist promised.

At an ESC congress highlights session that closed out the meeting, Eva Prescott, MD, put the SWEDEHEART study at the top of her list of important developments in preventive cardiology arising from the congress.

“This is an excellent national registry I think we’re all envious of,” commented Dr. Prescott, a cardiologist at Copenhagen University. “The conclusion of this registry-based data, I think, is that lifestyle really remains at the core of prevention of cardiovascular events still today.”

The SWEDEHEART study analysis was funded free of commercial support. Dr. Hagstrom reported serving as a consultant to or receiving speakers’ fees from Amgen, AstraZeneca, Bayer, Novo Nordisk, and Sanofi.

[email protected]

PARIS – All lifestyle-related cardiovascular risk factors aren’t equal in power when it comes to secondary prevention after a first acute MI, according to a massive Swedish registry study.

Insufficient physical activity and current smoking were consistently the strongest risk factors for all-cause mortality, major adverse cardiovascular events, and other key adverse outcomes in an analysis from the SWEDEHEART registry. The study included 65,002 patients discharged after a first MI and 325,010 age- and sex-matched controls with no prior MI followed for a median of 5.5 years and maximum of 12, Emil Hagstrom, MD, PhD, reported at the annual congress of the European Society of Cardiology.

Strongest lifestyle risk factors

The study examined the long-term relative importance of control of six major lifestyle risk factors for secondary cardiovascular prevention: current smoking, insufficient physical activity, blood pressure of 140/90 mm Hg or more, obesity, a fasting blood glucose of at least 126 mg/dL, and an LDL cholesterol of 70 mg/dL or more. Notably, two risk factors that physicians often emphasize in working with their patients with known coronary heart disease – an elevated LDL cholesterol and obesity – barely moved the needle. Out of the six risk factors scrutinized, those two consistently showed the weakest association with long-term risk of adverse outcomes. Occupying the middle ground in terms of predictive strength were hypertension and elevated blood glucose, according to Dr. Hagstrom, a cardiologist at Uppsala (Sweden) University.

Risk factor status was assessed 6-10 weeks post MI. Insufficient physical activity was defined as not engaging in at least 30 minutes of moderate-intensity exercise on at least 5 days per week. And when Dr. Hagstrom recalculated the risk of adverse outcomes using an LDL cholesterol threshold of 55 mg/dL rather than using 70 mg/dL, as recommended in new ESC secondary prevention guidelines released during the congress, the study results remained unchanged.

Cumulative effects

A key SWEDEHEART finding underscoring the importance of lifestyle in secondary prevention was that a linear stepwise relationship existed between the number of risk factors at target levels and the risk of all of the various adverse outcomes assessed, including stroke and heart failure hospitalization as well as all-cause mortality, cardiovascular mortality, and major bleeding.

Moreover, patients with none of the six risk factors outside of target when assessed after their MI had the same risks of all-cause mortality, cardiovascular mortality, and stroke as the matched controls.

For example, in an analysis adjusted for comorbid cancer, chronic obstructive pulmonary disease, and dementia, post-MI patients with zero risk factors had the same long-term risk of cardiovascular mortality as controls without a history of MI at baseline. With one risk factor not at target, a patient had a 41% increased risk compared with controls, a statistically significant difference. With two out-of-whack risk factors, the risk climbed to 102%. With three, 185%. With four risk factors not at target, the all-cause mortality risk jumped to 291%. And patients with more than four of the six risk factors not at target had a 409% greater risk of all-cause mortality than controls who had never had a heart attack.

When Dr. Hagstrom stratified subjects by age at baseline – up to 55, 56-64, 65-70, and 70-75 years – he discovered that, regardless of age, patients with zero risk factors had the same risk of all-cause mortality and other adverse outcomes as controls. However, when risk factors were present, younger patients consistently had a higher risk of all adverse outcomes than older patients with the same number of risk factors. When asked for an explanation of this phenomenon, Dr. Hagstrom noted that younger patients with multiple risk factors have a longer time to be exposed to and accumulate risk.

Follow-up of the study cohort will continue for years to come, the cardiologist promised.

At an ESC congress highlights session that closed out the meeting, Eva Prescott, MD, put the SWEDEHEART study at the top of her list of important developments in preventive cardiology arising from the congress.

“This is an excellent national registry I think we’re all envious of,” commented Dr. Prescott, a cardiologist at Copenhagen University. “The conclusion of this registry-based data, I think, is that lifestyle really remains at the core of prevention of cardiovascular events still today.”

The SWEDEHEART study analysis was funded free of commercial support. Dr. Hagstrom reported serving as a consultant to or receiving speakers’ fees from Amgen, AstraZeneca, Bayer, Novo Nordisk, and Sanofi.

[email protected]

PARIS – All lifestyle-related cardiovascular risk factors aren’t equal in power when it comes to secondary prevention after a first acute MI, according to a massive Swedish registry study.

Insufficient physical activity and current smoking were consistently the strongest risk factors for all-cause mortality, major adverse cardiovascular events, and other key adverse outcomes in an analysis from the SWEDEHEART registry. The study included 65,002 patients discharged after a first MI and 325,010 age- and sex-matched controls with no prior MI followed for a median of 5.5 years and maximum of 12, Emil Hagstrom, MD, PhD, reported at the annual congress of the European Society of Cardiology.

Strongest lifestyle risk factors

The study examined the long-term relative importance of control of six major lifestyle risk factors for secondary cardiovascular prevention: current smoking, insufficient physical activity, blood pressure of 140/90 mm Hg or more, obesity, a fasting blood glucose of at least 126 mg/dL, and an LDL cholesterol of 70 mg/dL or more. Notably, two risk factors that physicians often emphasize in working with their patients with known coronary heart disease – an elevated LDL cholesterol and obesity – barely moved the needle. Out of the six risk factors scrutinized, those two consistently showed the weakest association with long-term risk of adverse outcomes. Occupying the middle ground in terms of predictive strength were hypertension and elevated blood glucose, according to Dr. Hagstrom, a cardiologist at Uppsala (Sweden) University.

Risk factor status was assessed 6-10 weeks post MI. Insufficient physical activity was defined as not engaging in at least 30 minutes of moderate-intensity exercise on at least 5 days per week. And when Dr. Hagstrom recalculated the risk of adverse outcomes using an LDL cholesterol threshold of 55 mg/dL rather than using 70 mg/dL, as recommended in new ESC secondary prevention guidelines released during the congress, the study results remained unchanged.

Cumulative effects

A key SWEDEHEART finding underscoring the importance of lifestyle in secondary prevention was that a linear stepwise relationship existed between the number of risk factors at target levels and the risk of all of the various adverse outcomes assessed, including stroke and heart failure hospitalization as well as all-cause mortality, cardiovascular mortality, and major bleeding.

Moreover, patients with none of the six risk factors outside of target when assessed after their MI had the same risks of all-cause mortality, cardiovascular mortality, and stroke as the matched controls.

For example, in an analysis adjusted for comorbid cancer, chronic obstructive pulmonary disease, and dementia, post-MI patients with zero risk factors had the same long-term risk of cardiovascular mortality as controls without a history of MI at baseline. With one risk factor not at target, a patient had a 41% increased risk compared with controls, a statistically significant difference. With two out-of-whack risk factors, the risk climbed to 102%. With three, 185%. With four risk factors not at target, the all-cause mortality risk jumped to 291%. And patients with more than four of the six risk factors not at target had a 409% greater risk of all-cause mortality than controls who had never had a heart attack.

When Dr. Hagstrom stratified subjects by age at baseline – up to 55, 56-64, 65-70, and 70-75 years – he discovered that, regardless of age, patients with zero risk factors had the same risk of all-cause mortality and other adverse outcomes as controls. However, when risk factors were present, younger patients consistently had a higher risk of all adverse outcomes than older patients with the same number of risk factors. When asked for an explanation of this phenomenon, Dr. Hagstrom noted that younger patients with multiple risk factors have a longer time to be exposed to and accumulate risk.

Follow-up of the study cohort will continue for years to come, the cardiologist promised.

At an ESC congress highlights session that closed out the meeting, Eva Prescott, MD, put the SWEDEHEART study at the top of her list of important developments in preventive cardiology arising from the congress.

“This is an excellent national registry I think we’re all envious of,” commented Dr. Prescott, a cardiologist at Copenhagen University. “The conclusion of this registry-based data, I think, is that lifestyle really remains at the core of prevention of cardiovascular events still today.”

The SWEDEHEART study analysis was funded free of commercial support. Dr. Hagstrom reported serving as a consultant to or receiving speakers’ fees from Amgen, AstraZeneca, Bayer, Novo Nordisk, and Sanofi.

[email protected]