Diabetes mellitus and its management have become the center of controversy in recent years. More emphasis is being placed on the potential for adverse cardiovascular outcomes with more aggressive glycemic control as well as on the potential for adverse cardiovascular events with newer antidiabetic therapies, and less on the importance of glycemic control, particularly early in the disease course.

See related article

Although it is important to take new data into consideration when managing diabetes, it appears that the results of recent clinical trials are being misinterpreted and incorrectly applied to the wrong patient populations, and in the process, the results of older landmark clinical trials are being neglected. Inadequate glycemic control not only plays a role in cardiovascular risk, it also remains the leading cause of blindness, kidney failure, and nontraumatic lower-limb amputations in the United States.¹

Although we need to recognize the potential for adverse cardiovascular outcomes with diabetes and its management, we cannot lose sight of the big picture—ie, that inadequate glycemic control confers both microvascular and macrovascular risk, and that the available data show that restoring near-euglycemia in patients with diabetes considerably reduces the risk of microvascular and macrovascular complications.

Several recently published clinical trials—the Action to Control Cardiovascular Risk in Diabetes (ACCORD),² the Veterans Affairs Diabetes Trial (VADT),³ and the Action in Diabetes and Vascular Disease (ADVANCE)⁴—failed to demonstrate improved cardiovascular outcomes with improved glycemic control. However, we should not take this to mean that glycemic control is unimportant.

In this article, we will discuss why the results of these recent clinical trials are not valid for the general population of patients with diabetes. We will review evidence from landmark clinical trials that clearly demonstrates that better glycemic control reduces both microvascular and macrovascular complications of diabetes (the “glucose hypothesis”). We contend that excellent glycemic control clearly decreases the microvascular complications of diabetes, and that results from long-term follow-up studies in both type 1 and type 2 diabetes show reduced rates of heart attack and stroke in patients treated intensively earlier in the course of their disease.^5,6

EVIDENCE FOR THE GLUCOSE HYPOTHESIS

Diabetes Control and Complications Trial

The first major trial demonstrating that improved glycemic control provides benefit was the Diabetes Control and Complications Trial (DCCT).⁷ This study enrolled 1,441 patients with insulin-dependent diabetes mellitus, 726 of whom had no retinopathy at baseline (the primary-prevention cohort) and 715 of whom had mild retinopathy (the secondary-intervention cohort).

Patients were randomly assigned to intensive therapy (three or more insulin injections per day or an insulin pump) or to conventional therapy with one or two daily insulin injections. They were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.

During the study, the hemoglobin A_1c level averaged 9% in the control group and 7% in the intensively treated group. The cumulative incidence of retinopathy was defined as a change of three steps or more on fundus photography that was sustained over a 6-month period.

Effect on retinopathy. At study completion, the cumulative incidence of retinopathy in the intensive-therapy group was approximately 50% less than in the conventional-therapy group. Intensive therapy reduced the adjusted mean risk of retinopathy by 76% (95% confidence interval [CI] 62%–85%) in the primary-prevention cohort. In the secondary-prevention cohort, intensive therapy reduced the average risk of progression by 54% (95% CI 39%–66%). Intensive therapy reduced the adjusted risk of proliferative or severe nonproliferative retinopathy by 47% (P = .011) and that of treatment with photocoagulation by 56% (P = .002).

Effect on nephropathy. Intensive therapy reduced the mean adjusted risk of microalbuminuria by 34% (P = .04) in the primary-prevention cohort and by 43% (P = .001) in the secondary-intervention cohort. The risk of macroalbuminuria was reduced by 56% (P = .01) in the secondary-intervention cohort.

Effect on neuropathy. In the patients in the primary-prevention cohort who did not have neuropathy at baseline, intensive therapy reduced the incidence of neuropathy at 5 years by 69% (to 3%, vs 10% in the conventional-therapy group; P = .006). Similarly, in the secondary-intervention cohort, intensive therapy reduced the incidence of clinical neuropathy at 5 years by 57% (to 7%, vs 16%; P < .001).

Effect on macrovascular events. In the initial trial, a nonsignificant 41% reduction in combined cardiovascular and peripheral vascular disease events was observed.

DCCT long-term follow-up

After DCCT concluded, the control and treatment groups’ hemoglobin A_1c levels converged to approximately 8%. The two groups were then followed to determine the long-term effects of their prior separation of glycemic levels on micro- and macrovascular out comes.⁵ More than 90% of the original DCCT patients were followed for a mean of 17 years.

Intensive treatment reduced the risk of any cardiovascular disease event by 42% (95% CI 9%–63%; P = .02) and the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 57% (95% CI 12%– 79%; P = .02). This result was observed despite separation of glucose control in the two groups only for the first 6.5 years. This beneficial effect of intensive early glycemic control has been termed metabolic memory.

United Kingdom Prospective Diabetes Study

A second major trial, the United Kingdom Prospective Diabetes Study (UKPDS),⁸ assessed the effect of excellent diabetes control on diabetes complications in patients with type 2 diabetes. A total of 3,867 patients newly diagnosed with type 2 diabetes, median age 54, who after 3 months of diet treatment had mean fasting plasma glucose concentrations of 110 to 270 mg/dL, were randomly assigned to an intensive policy (with a sulfonylurea or insulin or, if overweight, metformin) or a conventional policy with diet. The aim in the intensive group was a fasting plasma glucose less than 108 mg/dL. In the conventional group, the aim was the best achievable fasting plasma glucose with diet alone; drugs were added only if there were hyperglycemic symptoms or a fasting plasma glucose greater than 270 mg/dL.

Over 10 years, the median hemoglobin A_1c level was 7.0% (interquartile range 6.2%–8.2%) in the intensive group compared with 7.9% (6.9%–8.8%) in the conventional group. Compared with the conventional group, the risk of any diabetes-related end point was 12% lower in the intensive group (95% CI 1%–21%, P = .029), the risk of any diabetes-related death was 10% lower (−11% to 27%, P = .34), and the rate of all-cause mortality was 6% lower (−10% to 20%, P = .44). Most of the reduction in risk of any diabetes-related end point was from a 25% risk reduction (95% CI 7%–40%, P = .0099) in microvascular end points, including the need for retinal photocoagulation.

UKPDS long-term follow-up

In 2008, Holman et al published the results of long-term follow-up of patients included in the UKPDS.⁶ In posttrial monitoring, 3,277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires.

Between-group differences in hemoglobin A_1c levels were lost after the first year. However, in the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P = .04) and microvascular disease (24%, P = .001), while risk reductions for myocardial infarction (15%, P = .01) and death from any cause (13%, P = .007) emerged over time as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P = .01), myocardial infarction (33%, P = .005), and death from any cause (27%, P = .002).

The long-term follow-up to the UKPDS, like the long-term follow-up to the DCCT, demonstrated metabolic memory: that is, despite an early loss of glycemic differences after completion of the trial, a continued reduction in microvascular risk and an emergent risk reduction for myocardial infarction and death from any cause were observed.

These long-term randomized prospective trials in patients with type 1 and type 2 diabetes clearly show that the glucose hypothesis is in fact correct: intensive glucose control lowers the risk of both microvascular and macrovascular complications of diabetes.

IS THERE DISCORDANCE BETWEEN OLDER AND MORE RECENT TRIALS?

If the results of these older landmark clinical trials are true, why did the more recent clinical trials fail to show cardiovascular benefit with stricter glycemic control, and in one trial² demonstrate the potential for harm? (ACCORD² found an increased death rate in patients who received intensive therapy, targeting a hemoglobin A_1c below 6.0%.)

The answer lies in the populations studied. ACCORD,² VADT,³ and ADVANCE⁴ were performed in older patients with prior cardiac events or with several risk factors for cardiovascular events. The study populations were picked to increase the number of cardiac events in a short time frame. Therefore, extrapolating the results of these studies to the younger population of patients with diabetes, most of whom have yet to develop macrovascular disease, is inappropriate.

The available evidence suggests that early aggressive management of diabetes reduces the risk of macrovascular disease, but that this benefit is delayed. In the UKPDS and DCCT trials, it took 10 to 17 years to show cardiac benefit in younger patients.

The results of ACCORD,² VADT,³ and ADVANCE⁴ are important when considered in the correct clinical context. Two of these trials did demonstrate some microvascular benefit as a result of better glycemic control in older patients, many of whom had longstanding diabetes. These studies suggest that, in patients who already have established cardiovascular disease or have several risk factors for cardiovascular events, a less-strict glycemic target may be warranted.

These trials should not be interpreted as saying that glycemic control is unimportant in older patients at higher risk. Rather, they suggest that an individualized approach to diabetes management, supported by the most recent American Diabetes Association guidelines,⁹ is more appropriate.

Physicians may reasonably suggest a stricter A_1c goal (ie, < 6.5%) in certain patients if it can be achieved without significant hypoglycemia. Stricter glycemic targets would seem appropriate in patients recently diagnosed with diabetes, those who have a long life expectancy, and those who have not yet developed significant cardiovascular disease.⁹

However, in patients who already have developed advanced microvascular and macrovascular complications, who have long-standing diabetes, who have a history of severe hypoglycemia (or hypoglycemia unawareness), or who have a limited life expectancy or numerous adverse comorbidities, a less strict glycemic target (hemoglobin A_1c < 8%) may be more appropriate.⁹

CARDIOVASCULAR RISK, HYPOGLYCEMIA, AND ATTAINING GLYCEMIC TARGETS

Metformin, in the absence of contraindications or intolerability, is generally the recommended first-line therapy to manage glycemia in patients with type 2 diabetes mellitus.^10,11 However, there are only limited data to direct clinicians as to which antidiabetic medication to use if further therapy is required to obtain glycemic control.

Much of the cardiovascular and mortality risk associated with aggressive diabetes management (ie, lower A_1c targets) is related to hypoglycemia. Thus, antidiabetic therapies that pose no risk or only a low risk of hypoglycemia should be chosen, particularly in older patients and in those with known cardiovascular disease. This may allow for better glycemic control without the risk of hypoglycemia and adverse cardiovascular outcomes.

However, in practice, clinicians continue to use a sulfonylurea as the second-line agent. Although sulfonylureas may appear to be a great option because of their low cost, they are associated with a higher risk of hypoglycemic episodes than other classes of diabetes drugs. We need to consider the frequency and cost of hypoglycemic episodes and the potential morbidity associated with them, because these episodes are a barrier to our efforts to achieve better glycemic control.

Budnitz et al¹² reported that from 2007 through 2009, in US adults age 65 and older, insulins were implicated in 13.9% of hospitalizations related to adverse drug events, and oral hypoglycemic agents (ie, insulin secretagogues) in 10.7%.

Quilliam et al¹³ reported that hypoglycemia resulted in a mean cost of $17,564 for an inpatient admission, $1,387 for an emergency department visit, and $394 for an outpatient visit. Thus, the cost savings associated with prescribing a sulfonylurea vs one of the newer oral antidiabetic agents that do not increase the risk of hypoglycemia (unless used concurrently with insulin or an insulin secretagogue) can quickly be eroded by severe hypoglycemic episodes requiring medical care.

Moreover, once patients start to experience hypoglycemic episodes, they are very reluctant, as are their physicians, to intensify therapy, even if it is indicated by their elevated A_1c.

There are now seven classes of oral antidiabetic therapies other than insulin secretagogues (ie, other than sulfonylureas and the meglitinides nateglinide and repaglinide), as well as a few noninsulin injectable therapies (glucagon-like peptide-1 agonists), that are not associated with hypoglycemia. We believe these agents should be tried before prescribing an agent that carries the risk of hypoglycemia (ie, sulfonylureas).

If agents that do not cause hypoglycemia are used, more-aggressive glycemic targets may be achieved safely. The ACCORD study,² which included patients at high cardiovascular risk and aimed at an aggressive glycemic target of 6%, may have yielded much different results had agents that carry a high risk of hypoglycemia been excluded.

Of importance, cardiovascular risk is also influenced by the common comorbidities seen in patients with diabetes, such as hypertension and hypercholesterolemia. Intensive, multifactorial interventions that address not only glycemic control but also blood pressure and lipids and that include low-dose aspirin therapy have been shown to lower the risk of death from cardiovascular causes and the risk of cardiovascular events.¹⁴ Likewise, smoking cessation is very important in reducing cardiovascular risk, especially in patients with diabetes.¹⁵

CLINICAL TRIALS IN CONTEXT

In conclusion, there is more to diabetes management than cardiovascular complications. Clearly, improved glycemic control decreases the risk of retinopathy, nephropathy, and neuropathy in patients with type 1 and type 2 diabetes. The DCCT and UKPDS extension studies further found that excellent glycemic control decreases rates of cardiac events.

The best way to treat diabetes may be different in otherwise healthy younger patients who have yet to develop significant complications than it is in older patients known to have cardiovascular disease or several risk factors for cardiovascular events. The available evidence suggests it would be reasonable to aim for stricter glycemic targets in the younger patients and less stringent targets in the older patients, particularly in those with long-standing diabetes who have already developed significant micro- and macrovascular complications.

We should interpret clinical trials within their narrow clinical context, emphasizing the actual population of patients included in the study, so as to avoid the inappropriate extrapolation of the results to all.

Diabetes mellitus and its management have become the center of controversy in recent years. More emphasis is being placed on the potential for adverse cardiovascular outcomes with more aggressive glycemic control as well as on the potential for adverse cardiovascular events with newer antidiabetic therapies, and less on the importance of glycemic control, particularly early in the disease course.

See related article

Although it is important to take new data into consideration when managing diabetes, it appears that the results of recent clinical trials are being misinterpreted and incorrectly applied to the wrong patient populations, and in the process, the results of older landmark clinical trials are being neglected. Inadequate glycemic control not only plays a role in cardiovascular risk, it also remains the leading cause of blindness, kidney failure, and nontraumatic lower-limb amputations in the United States.¹

Although we need to recognize the potential for adverse cardiovascular outcomes with diabetes and its management, we cannot lose sight of the big picture—ie, that inadequate glycemic control confers both microvascular and macrovascular risk, and that the available data show that restoring near-euglycemia in patients with diabetes considerably reduces the risk of microvascular and macrovascular complications.

Several recently published clinical trials—the Action to Control Cardiovascular Risk in Diabetes (ACCORD),² the Veterans Affairs Diabetes Trial (VADT),³ and the Action in Diabetes and Vascular Disease (ADVANCE)⁴—failed to demonstrate improved cardiovascular outcomes with improved glycemic control. However, we should not take this to mean that glycemic control is unimportant.

In this article, we will discuss why the results of these recent clinical trials are not valid for the general population of patients with diabetes. We will review evidence from landmark clinical trials that clearly demonstrates that better glycemic control reduces both microvascular and macrovascular complications of diabetes (the “glucose hypothesis”). We contend that excellent glycemic control clearly decreases the microvascular complications of diabetes, and that results from long-term follow-up studies in both type 1 and type 2 diabetes show reduced rates of heart attack and stroke in patients treated intensively earlier in the course of their disease.^5,6

EVIDENCE FOR THE GLUCOSE HYPOTHESIS

Diabetes Control and Complications Trial

The first major trial demonstrating that improved glycemic control provides benefit was the Diabetes Control and Complications Trial (DCCT).⁷ This study enrolled 1,441 patients with insulin-dependent diabetes mellitus, 726 of whom had no retinopathy at baseline (the primary-prevention cohort) and 715 of whom had mild retinopathy (the secondary-intervention cohort).

Patients were randomly assigned to intensive therapy (three or more insulin injections per day or an insulin pump) or to conventional therapy with one or two daily insulin injections. They were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.

During the study, the hemoglobin A_1c level averaged 9% in the control group and 7% in the intensively treated group. The cumulative incidence of retinopathy was defined as a change of three steps or more on fundus photography that was sustained over a 6-month period.

Effect on retinopathy. At study completion, the cumulative incidence of retinopathy in the intensive-therapy group was approximately 50% less than in the conventional-therapy group. Intensive therapy reduced the adjusted mean risk of retinopathy by 76% (95% confidence interval [CI] 62%–85%) in the primary-prevention cohort. In the secondary-prevention cohort, intensive therapy reduced the average risk of progression by 54% (95% CI 39%–66%). Intensive therapy reduced the adjusted risk of proliferative or severe nonproliferative retinopathy by 47% (P = .011) and that of treatment with photocoagulation by 56% (P = .002).

Effect on nephropathy. Intensive therapy reduced the mean adjusted risk of microalbuminuria by 34% (P = .04) in the primary-prevention cohort and by 43% (P = .001) in the secondary-intervention cohort. The risk of macroalbuminuria was reduced by 56% (P = .01) in the secondary-intervention cohort.

Effect on neuropathy. In the patients in the primary-prevention cohort who did not have neuropathy at baseline, intensive therapy reduced the incidence of neuropathy at 5 years by 69% (to 3%, vs 10% in the conventional-therapy group; P = .006). Similarly, in the secondary-intervention cohort, intensive therapy reduced the incidence of clinical neuropathy at 5 years by 57% (to 7%, vs 16%; P < .001).

Effect on macrovascular events. In the initial trial, a nonsignificant 41% reduction in combined cardiovascular and peripheral vascular disease events was observed.

DCCT long-term follow-up

After DCCT concluded, the control and treatment groups’ hemoglobin A_1c levels converged to approximately 8%. The two groups were then followed to determine the long-term effects of their prior separation of glycemic levels on micro- and macrovascular out comes.⁵ More than 90% of the original DCCT patients were followed for a mean of 17 years.

Intensive treatment reduced the risk of any cardiovascular disease event by 42% (95% CI 9%–63%; P = .02) and the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 57% (95% CI 12%– 79%; P = .02). This result was observed despite separation of glucose control in the two groups only for the first 6.5 years. This beneficial effect of intensive early glycemic control has been termed metabolic memory.

United Kingdom Prospective Diabetes Study

A second major trial, the United Kingdom Prospective Diabetes Study (UKPDS),⁸ assessed the effect of excellent diabetes control on diabetes complications in patients with type 2 diabetes. A total of 3,867 patients newly diagnosed with type 2 diabetes, median age 54, who after 3 months of diet treatment had mean fasting plasma glucose concentrations of 110 to 270 mg/dL, were randomly assigned to an intensive policy (with a sulfonylurea or insulin or, if overweight, metformin) or a conventional policy with diet. The aim in the intensive group was a fasting plasma glucose less than 108 mg/dL. In the conventional group, the aim was the best achievable fasting plasma glucose with diet alone; drugs were added only if there were hyperglycemic symptoms or a fasting plasma glucose greater than 270 mg/dL.

Over 10 years, the median hemoglobin A_1c level was 7.0% (interquartile range 6.2%–8.2%) in the intensive group compared with 7.9% (6.9%–8.8%) in the conventional group. Compared with the conventional group, the risk of any diabetes-related end point was 12% lower in the intensive group (95% CI 1%–21%, P = .029), the risk of any diabetes-related death was 10% lower (−11% to 27%, P = .34), and the rate of all-cause mortality was 6% lower (−10% to 20%, P = .44). Most of the reduction in risk of any diabetes-related end point was from a 25% risk reduction (95% CI 7%–40%, P = .0099) in microvascular end points, including the need for retinal photocoagulation.

UKPDS long-term follow-up

In 2008, Holman et al published the results of long-term follow-up of patients included in the UKPDS.⁶ In posttrial monitoring, 3,277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires.

Between-group differences in hemoglobin A_1c levels were lost after the first year. However, in the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P = .04) and microvascular disease (24%, P = .001), while risk reductions for myocardial infarction (15%, P = .01) and death from any cause (13%, P = .007) emerged over time as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P = .01), myocardial infarction (33%, P = .005), and death from any cause (27%, P = .002).

The long-term follow-up to the UKPDS, like the long-term follow-up to the DCCT, demonstrated metabolic memory: that is, despite an early loss of glycemic differences after completion of the trial, a continued reduction in microvascular risk and an emergent risk reduction for myocardial infarction and death from any cause were observed.

These long-term randomized prospective trials in patients with type 1 and type 2 diabetes clearly show that the glucose hypothesis is in fact correct: intensive glucose control lowers the risk of both microvascular and macrovascular complications of diabetes.

IS THERE DISCORDANCE BETWEEN OLDER AND MORE RECENT TRIALS?

If the results of these older landmark clinical trials are true, why did the more recent clinical trials fail to show cardiovascular benefit with stricter glycemic control, and in one trial² demonstrate the potential for harm? (ACCORD² found an increased death rate in patients who received intensive therapy, targeting a hemoglobin A_1c below 6.0%.)

The answer lies in the populations studied. ACCORD,² VADT,³ and ADVANCE⁴ were performed in older patients with prior cardiac events or with several risk factors for cardiovascular events. The study populations were picked to increase the number of cardiac events in a short time frame. Therefore, extrapolating the results of these studies to the younger population of patients with diabetes, most of whom have yet to develop macrovascular disease, is inappropriate.

The available evidence suggests that early aggressive management of diabetes reduces the risk of macrovascular disease, but that this benefit is delayed. In the UKPDS and DCCT trials, it took 10 to 17 years to show cardiac benefit in younger patients.

The results of ACCORD,² VADT,³ and ADVANCE⁴ are important when considered in the correct clinical context. Two of these trials did demonstrate some microvascular benefit as a result of better glycemic control in older patients, many of whom had longstanding diabetes. These studies suggest that, in patients who already have established cardiovascular disease or have several risk factors for cardiovascular events, a less-strict glycemic target may be warranted.

These trials should not be interpreted as saying that glycemic control is unimportant in older patients at higher risk. Rather, they suggest that an individualized approach to diabetes management, supported by the most recent American Diabetes Association guidelines,⁹ is more appropriate.

Physicians may reasonably suggest a stricter A_1c goal (ie, < 6.5%) in certain patients if it can be achieved without significant hypoglycemia. Stricter glycemic targets would seem appropriate in patients recently diagnosed with diabetes, those who have a long life expectancy, and those who have not yet developed significant cardiovascular disease.⁹

However, in patients who already have developed advanced microvascular and macrovascular complications, who have long-standing diabetes, who have a history of severe hypoglycemia (or hypoglycemia unawareness), or who have a limited life expectancy or numerous adverse comorbidities, a less strict glycemic target (hemoglobin A_1c < 8%) may be more appropriate.⁹

CARDIOVASCULAR RISK, HYPOGLYCEMIA, AND ATTAINING GLYCEMIC TARGETS

Metformin, in the absence of contraindications or intolerability, is generally the recommended first-line therapy to manage glycemia in patients with type 2 diabetes mellitus.^10,11 However, there are only limited data to direct clinicians as to which antidiabetic medication to use if further therapy is required to obtain glycemic control.

Much of the cardiovascular and mortality risk associated with aggressive diabetes management (ie, lower A_1c targets) is related to hypoglycemia. Thus, antidiabetic therapies that pose no risk or only a low risk of hypoglycemia should be chosen, particularly in older patients and in those with known cardiovascular disease. This may allow for better glycemic control without the risk of hypoglycemia and adverse cardiovascular outcomes.

However, in practice, clinicians continue to use a sulfonylurea as the second-line agent. Although sulfonylureas may appear to be a great option because of their low cost, they are associated with a higher risk of hypoglycemic episodes than other classes of diabetes drugs. We need to consider the frequency and cost of hypoglycemic episodes and the potential morbidity associated with them, because these episodes are a barrier to our efforts to achieve better glycemic control.

Budnitz et al¹² reported that from 2007 through 2009, in US adults age 65 and older, insulins were implicated in 13.9% of hospitalizations related to adverse drug events, and oral hypoglycemic agents (ie, insulin secretagogues) in 10.7%.

Quilliam et al¹³ reported that hypoglycemia resulted in a mean cost of $17,564 for an inpatient admission, $1,387 for an emergency department visit, and $394 for an outpatient visit. Thus, the cost savings associated with prescribing a sulfonylurea vs one of the newer oral antidiabetic agents that do not increase the risk of hypoglycemia (unless used concurrently with insulin or an insulin secretagogue) can quickly be eroded by severe hypoglycemic episodes requiring medical care.

Moreover, once patients start to experience hypoglycemic episodes, they are very reluctant, as are their physicians, to intensify therapy, even if it is indicated by their elevated A_1c.

There are now seven classes of oral antidiabetic therapies other than insulin secretagogues (ie, other than sulfonylureas and the meglitinides nateglinide and repaglinide), as well as a few noninsulin injectable therapies (glucagon-like peptide-1 agonists), that are not associated with hypoglycemia. We believe these agents should be tried before prescribing an agent that carries the risk of hypoglycemia (ie, sulfonylureas).

If agents that do not cause hypoglycemia are used, more-aggressive glycemic targets may be achieved safely. The ACCORD study,² which included patients at high cardiovascular risk and aimed at an aggressive glycemic target of 6%, may have yielded much different results had agents that carry a high risk of hypoglycemia been excluded.

Of importance, cardiovascular risk is also influenced by the common comorbidities seen in patients with diabetes, such as hypertension and hypercholesterolemia. Intensive, multifactorial interventions that address not only glycemic control but also blood pressure and lipids and that include low-dose aspirin therapy have been shown to lower the risk of death from cardiovascular causes and the risk of cardiovascular events.¹⁴ Likewise, smoking cessation is very important in reducing cardiovascular risk, especially in patients with diabetes.¹⁵

CLINICAL TRIALS IN CONTEXT

In conclusion, there is more to diabetes management than cardiovascular complications. Clearly, improved glycemic control decreases the risk of retinopathy, nephropathy, and neuropathy in patients with type 1 and type 2 diabetes. The DCCT and UKPDS extension studies further found that excellent glycemic control decreases rates of cardiac events.

The best way to treat diabetes may be different in otherwise healthy younger patients who have yet to develop significant complications than it is in older patients known to have cardiovascular disease or several risk factors for cardiovascular events. The available evidence suggests it would be reasonable to aim for stricter glycemic targets in the younger patients and less stringent targets in the older patients, particularly in those with long-standing diabetes who have already developed significant micro- and macrovascular complications.

We should interpret clinical trials within their narrow clinical context, emphasizing the actual population of patients included in the study, so as to avoid the inappropriate extrapolation of the results to all.

Diabetes mellitus and its management have become the center of controversy in recent years. More emphasis is being placed on the potential for adverse cardiovascular outcomes with more aggressive glycemic control as well as on the potential for adverse cardiovascular events with newer antidiabetic therapies, and less on the importance of glycemic control, particularly early in the disease course.

See related article

Although it is important to take new data into consideration when managing diabetes, it appears that the results of recent clinical trials are being misinterpreted and incorrectly applied to the wrong patient populations, and in the process, the results of older landmark clinical trials are being neglected. Inadequate glycemic control not only plays a role in cardiovascular risk, it also remains the leading cause of blindness, kidney failure, and nontraumatic lower-limb amputations in the United States.¹

Although we need to recognize the potential for adverse cardiovascular outcomes with diabetes and its management, we cannot lose sight of the big picture—ie, that inadequate glycemic control confers both microvascular and macrovascular risk, and that the available data show that restoring near-euglycemia in patients with diabetes considerably reduces the risk of microvascular and macrovascular complications.

Several recently published clinical trials—the Action to Control Cardiovascular Risk in Diabetes (ACCORD),² the Veterans Affairs Diabetes Trial (VADT),³ and the Action in Diabetes and Vascular Disease (ADVANCE)⁴—failed to demonstrate improved cardiovascular outcomes with improved glycemic control. However, we should not take this to mean that glycemic control is unimportant.

In this article, we will discuss why the results of these recent clinical trials are not valid for the general population of patients with diabetes. We will review evidence from landmark clinical trials that clearly demonstrates that better glycemic control reduces both microvascular and macrovascular complications of diabetes (the “glucose hypothesis”). We contend that excellent glycemic control clearly decreases the microvascular complications of diabetes, and that results from long-term follow-up studies in both type 1 and type 2 diabetes show reduced rates of heart attack and stroke in patients treated intensively earlier in the course of their disease.^5,6

EVIDENCE FOR THE GLUCOSE HYPOTHESIS

Diabetes Control and Complications Trial

The first major trial demonstrating that improved glycemic control provides benefit was the Diabetes Control and Complications Trial (DCCT).⁷ This study enrolled 1,441 patients with insulin-dependent diabetes mellitus, 726 of whom had no retinopathy at baseline (the primary-prevention cohort) and 715 of whom had mild retinopathy (the secondary-intervention cohort).

Patients were randomly assigned to intensive therapy (three or more insulin injections per day or an insulin pump) or to conventional therapy with one or two daily insulin injections. They were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.

During the study, the hemoglobin A_1c level averaged 9% in the control group and 7% in the intensively treated group. The cumulative incidence of retinopathy was defined as a change of three steps or more on fundus photography that was sustained over a 6-month period.

Effect on retinopathy. At study completion, the cumulative incidence of retinopathy in the intensive-therapy group was approximately 50% less than in the conventional-therapy group. Intensive therapy reduced the adjusted mean risk of retinopathy by 76% (95% confidence interval [CI] 62%–85%) in the primary-prevention cohort. In the secondary-prevention cohort, intensive therapy reduced the average risk of progression by 54% (95% CI 39%–66%). Intensive therapy reduced the adjusted risk of proliferative or severe nonproliferative retinopathy by 47% (P = .011) and that of treatment with photocoagulation by 56% (P = .002).

Effect on nephropathy. Intensive therapy reduced the mean adjusted risk of microalbuminuria by 34% (P = .04) in the primary-prevention cohort and by 43% (P = .001) in the secondary-intervention cohort. The risk of macroalbuminuria was reduced by 56% (P = .01) in the secondary-intervention cohort.

Effect on neuropathy. In the patients in the primary-prevention cohort who did not have neuropathy at baseline, intensive therapy reduced the incidence of neuropathy at 5 years by 69% (to 3%, vs 10% in the conventional-therapy group; P = .006). Similarly, in the secondary-intervention cohort, intensive therapy reduced the incidence of clinical neuropathy at 5 years by 57% (to 7%, vs 16%; P < .001).

Effect on macrovascular events. In the initial trial, a nonsignificant 41% reduction in combined cardiovascular and peripheral vascular disease events was observed.

DCCT long-term follow-up

After DCCT concluded, the control and treatment groups’ hemoglobin A_1c levels converged to approximately 8%. The two groups were then followed to determine the long-term effects of their prior separation of glycemic levels on micro- and macrovascular out comes.⁵ More than 90% of the original DCCT patients were followed for a mean of 17 years.

Intensive treatment reduced the risk of any cardiovascular disease event by 42% (95% CI 9%–63%; P = .02) and the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 57% (95% CI 12%– 79%; P = .02). This result was observed despite separation of glucose control in the two groups only for the first 6.5 years. This beneficial effect of intensive early glycemic control has been termed metabolic memory.

United Kingdom Prospective Diabetes Study

A second major trial, the United Kingdom Prospective Diabetes Study (UKPDS),⁸ assessed the effect of excellent diabetes control on diabetes complications in patients with type 2 diabetes. A total of 3,867 patients newly diagnosed with type 2 diabetes, median age 54, who after 3 months of diet treatment had mean fasting plasma glucose concentrations of 110 to 270 mg/dL, were randomly assigned to an intensive policy (with a sulfonylurea or insulin or, if overweight, metformin) or a conventional policy with diet. The aim in the intensive group was a fasting plasma glucose less than 108 mg/dL. In the conventional group, the aim was the best achievable fasting plasma glucose with diet alone; drugs were added only if there were hyperglycemic symptoms or a fasting plasma glucose greater than 270 mg/dL.

Over 10 years, the median hemoglobin A_1c level was 7.0% (interquartile range 6.2%–8.2%) in the intensive group compared with 7.9% (6.9%–8.8%) in the conventional group. Compared with the conventional group, the risk of any diabetes-related end point was 12% lower in the intensive group (95% CI 1%–21%, P = .029), the risk of any diabetes-related death was 10% lower (−11% to 27%, P = .34), and the rate of all-cause mortality was 6% lower (−10% to 20%, P = .44). Most of the reduction in risk of any diabetes-related end point was from a 25% risk reduction (95% CI 7%–40%, P = .0099) in microvascular end points, including the need for retinal photocoagulation.

UKPDS long-term follow-up

In 2008, Holman et al published the results of long-term follow-up of patients included in the UKPDS.⁶ In posttrial monitoring, 3,277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires.

Between-group differences in hemoglobin A_1c levels were lost after the first year. However, in the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P = .04) and microvascular disease (24%, P = .001), while risk reductions for myocardial infarction (15%, P = .01) and death from any cause (13%, P = .007) emerged over time as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P = .01), myocardial infarction (33%, P = .005), and death from any cause (27%, P = .002).

The long-term follow-up to the UKPDS, like the long-term follow-up to the DCCT, demonstrated metabolic memory: that is, despite an early loss of glycemic differences after completion of the trial, a continued reduction in microvascular risk and an emergent risk reduction for myocardial infarction and death from any cause were observed.

These long-term randomized prospective trials in patients with type 1 and type 2 diabetes clearly show that the glucose hypothesis is in fact correct: intensive glucose control lowers the risk of both microvascular and macrovascular complications of diabetes.

IS THERE DISCORDANCE BETWEEN OLDER AND MORE RECENT TRIALS?

If the results of these older landmark clinical trials are true, why did the more recent clinical trials fail to show cardiovascular benefit with stricter glycemic control, and in one trial² demonstrate the potential for harm? (ACCORD² found an increased death rate in patients who received intensive therapy, targeting a hemoglobin A_1c below 6.0%.)

The answer lies in the populations studied. ACCORD,² VADT,³ and ADVANCE⁴ were performed in older patients with prior cardiac events or with several risk factors for cardiovascular events. The study populations were picked to increase the number of cardiac events in a short time frame. Therefore, extrapolating the results of these studies to the younger population of patients with diabetes, most of whom have yet to develop macrovascular disease, is inappropriate.

The available evidence suggests that early aggressive management of diabetes reduces the risk of macrovascular disease, but that this benefit is delayed. In the UKPDS and DCCT trials, it took 10 to 17 years to show cardiac benefit in younger patients.

The results of ACCORD,² VADT,³ and ADVANCE⁴ are important when considered in the correct clinical context. Two of these trials did demonstrate some microvascular benefit as a result of better glycemic control in older patients, many of whom had longstanding diabetes. These studies suggest that, in patients who already have established cardiovascular disease or have several risk factors for cardiovascular events, a less-strict glycemic target may be warranted.

These trials should not be interpreted as saying that glycemic control is unimportant in older patients at higher risk. Rather, they suggest that an individualized approach to diabetes management, supported by the most recent American Diabetes Association guidelines,⁹ is more appropriate.

Physicians may reasonably suggest a stricter A_1c goal (ie, < 6.5%) in certain patients if it can be achieved without significant hypoglycemia. Stricter glycemic targets would seem appropriate in patients recently diagnosed with diabetes, those who have a long life expectancy, and those who have not yet developed significant cardiovascular disease.⁹

However, in patients who already have developed advanced microvascular and macrovascular complications, who have long-standing diabetes, who have a history of severe hypoglycemia (or hypoglycemia unawareness), or who have a limited life expectancy or numerous adverse comorbidities, a less strict glycemic target (hemoglobin A_1c < 8%) may be more appropriate.⁹

CARDIOVASCULAR RISK, HYPOGLYCEMIA, AND ATTAINING GLYCEMIC TARGETS

Metformin, in the absence of contraindications or intolerability, is generally the recommended first-line therapy to manage glycemia in patients with type 2 diabetes mellitus.^10,11 However, there are only limited data to direct clinicians as to which antidiabetic medication to use if further therapy is required to obtain glycemic control.

Much of the cardiovascular and mortality risk associated with aggressive diabetes management (ie, lower A_1c targets) is related to hypoglycemia. Thus, antidiabetic therapies that pose no risk or only a low risk of hypoglycemia should be chosen, particularly in older patients and in those with known cardiovascular disease. This may allow for better glycemic control without the risk of hypoglycemia and adverse cardiovascular outcomes.

However, in practice, clinicians continue to use a sulfonylurea as the second-line agent. Although sulfonylureas may appear to be a great option because of their low cost, they are associated with a higher risk of hypoglycemic episodes than other classes of diabetes drugs. We need to consider the frequency and cost of hypoglycemic episodes and the potential morbidity associated with them, because these episodes are a barrier to our efforts to achieve better glycemic control.

Budnitz et al¹² reported that from 2007 through 2009, in US adults age 65 and older, insulins were implicated in 13.9% of hospitalizations related to adverse drug events, and oral hypoglycemic agents (ie, insulin secretagogues) in 10.7%.

Quilliam et al¹³ reported that hypoglycemia resulted in a mean cost of $17,564 for an inpatient admission, $1,387 for an emergency department visit, and $394 for an outpatient visit. Thus, the cost savings associated with prescribing a sulfonylurea vs one of the newer oral antidiabetic agents that do not increase the risk of hypoglycemia (unless used concurrently with insulin or an insulin secretagogue) can quickly be eroded by severe hypoglycemic episodes requiring medical care.

Moreover, once patients start to experience hypoglycemic episodes, they are very reluctant, as are their physicians, to intensify therapy, even if it is indicated by their elevated A_1c.

There are now seven classes of oral antidiabetic therapies other than insulin secretagogues (ie, other than sulfonylureas and the meglitinides nateglinide and repaglinide), as well as a few noninsulin injectable therapies (glucagon-like peptide-1 agonists), that are not associated with hypoglycemia. We believe these agents should be tried before prescribing an agent that carries the risk of hypoglycemia (ie, sulfonylureas).

If agents that do not cause hypoglycemia are used, more-aggressive glycemic targets may be achieved safely. The ACCORD study,² which included patients at high cardiovascular risk and aimed at an aggressive glycemic target of 6%, may have yielded much different results had agents that carry a high risk of hypoglycemia been excluded.

Of importance, cardiovascular risk is also influenced by the common comorbidities seen in patients with diabetes, such as hypertension and hypercholesterolemia. Intensive, multifactorial interventions that address not only glycemic control but also blood pressure and lipids and that include low-dose aspirin therapy have been shown to lower the risk of death from cardiovascular causes and the risk of cardiovascular events.¹⁴ Likewise, smoking cessation is very important in reducing cardiovascular risk, especially in patients with diabetes.¹⁵

CLINICAL TRIALS IN CONTEXT

In conclusion, there is more to diabetes management than cardiovascular complications. Clearly, improved glycemic control decreases the risk of retinopathy, nephropathy, and neuropathy in patients with type 1 and type 2 diabetes. The DCCT and UKPDS extension studies further found that excellent glycemic control decreases rates of cardiac events.

The best way to treat diabetes may be different in otherwise healthy younger patients who have yet to develop significant complications than it is in older patients known to have cardiovascular disease or several risk factors for cardiovascular events. The available evidence suggests it would be reasonable to aim for stricter glycemic targets in the younger patients and less stringent targets in the older patients, particularly in those with long-standing diabetes who have already developed significant micro- and macrovascular complications.

We should interpret clinical trials within their narrow clinical context, emphasizing the actual population of patients included in the study, so as to avoid the inappropriate extrapolation of the results to all.

Yes, all patients with massive hemoptysis should undergo diagnostic bronchoscopy. The procedure plays an important role in protecting the airway, maintaining ventilation, finding the site and underlying cause of the bleeding, and in some cases stopping the bleeding, either temporarily or definitively.

Frightening to patients, massive hemoptysis is a medical emergency and demands immediate attention by an experienced pulmonary team.¹ Hemoptysis can be the initial presentation of an underlying infectious, autoimmune, or malignant disorder (Table 1).² Fortunately, most cases of hemoptysis are not massive or life-threatening.¹

WHAT IS ‘MASSIVE’ HEMOPTYSIS?

Numerous studies have defined massive hemoptysis on the basis of the volume of blood lost over time, eg, more than 1 L in 24 hours or more than 400 mL in 6 hours.

Ibrahim³ has proposed that we move away from using the word “massive,” which is not useful, and instead think in terms of “life-threatening” hemoptysis, defined as any of the following:

• More than 100 mL of blood lost in 24 hours (a low number, but blood loss is hard to estimate accurately)
• Causing abnormal gas exchange due to airway obstruction
• Causing hemodynamic instability.

In this article, we use the traditional “massive” terminology.

BRONCHOSCOPY IS SUPERIOR TO IMAGING FOR DIAGNOSIS

Radiography can help identify the side or the site of bleeding in 33% to 82% of patients, and computed tomography can in 70% to 88.5%.⁴ Magnetic resonance imaging may also have a role; one study found it useful in cases of thoracic endometriosis during the quiescent stage.⁵ However, transferring a patient who is actively bleeding out of the intensive care unit for imaging can be challenging.

Flexible bronchoscopy is superior to radiographic imaging in evaluating massive hemoptysis: it can be performed at the bed-side and can include therapeutic procedures to control the bleeding until the patient can undergo a definitive therapeutic procedure.⁶ It has been found helpful in identifying the side of bleeding in 73% to 93% of cases of massive hemoptysis.⁶

However, one should consider starting the procedure with a rigid bronchoscope, which protects the airway better and allows for better ventilation during the procedure than a flexible one. One can use it to isolate the nonbleeding lung and to apply pressure to the bleeding site if it is in the main bronchus.⁷ Measuring 12 mm in diameter, a rigid scope cannot go as far into the lung as a flexible bronchoscope (measuring 6.4 mm), but a flexible bronchoscope can be introduced through the rigid bronchoscope to go further in.

MANAGEMENT OPTIONS

The management team should include an anesthesiologist, an intensivist, a thoracic surgeon, an interventional radiologist, and an interventional pulmonologist.

In the intensive care unit, the patient should be placed in the lateral decubitus position on the bleeding side. To maintain ventilation, the nonbleeding lung should be intubated with a large-bore endotracheal tube (internal diameter 8.5–9.0 mm) or, ideally, with a rigid bronchoscope.⁶ Meanwhile, the patient’s circulatory status should be stabilized with adequate fluid resuscitation and transfusion of blood products, with close monitoring.

Once the bleeding site is found, a bronchoscopic treatment is selected based on the cause of the bleeding. Massive hemoptysis usually arises from high-pressure bronchial vessels (90%) or, less commonly, from non-bronchial vessels or capillaries (10%).⁸ A variety of agents (eg, cold saline lavage, epinephrine 1:20,000) can be instilled through the bronchoscope to slow the bleeding and offer better visualization of the airway.⁶

If a bleeding intrabronchial lesion is identified, such as a malignant tracheobronchial tumor, local coagulation therapy can be applied through the bronchoscope. Options include laser treatment, argon plasma coagulation, cryotherapy, and electrocautery (Figure 1).^9,10

If the bleeding persists or cannot be localized to a particular subsegment, an endobronchial balloon plug can be placed proximally (Figure 2). This can be left in place to isolate the bleeding and apply tamponade until a definitive procedure can be performed, such as bronchial artery embolization, radiation therapy, or surgery.

Yes, all patients with massive hemoptysis should undergo diagnostic bronchoscopy. The procedure plays an important role in protecting the airway, maintaining ventilation, finding the site and underlying cause of the bleeding, and in some cases stopping the bleeding, either temporarily or definitively.

Frightening to patients, massive hemoptysis is a medical emergency and demands immediate attention by an experienced pulmonary team.¹ Hemoptysis can be the initial presentation of an underlying infectious, autoimmune, or malignant disorder (Table 1).² Fortunately, most cases of hemoptysis are not massive or life-threatening.¹

WHAT IS ‘MASSIVE’ HEMOPTYSIS?

Numerous studies have defined massive hemoptysis on the basis of the volume of blood lost over time, eg, more than 1 L in 24 hours or more than 400 mL in 6 hours.

Ibrahim³ has proposed that we move away from using the word “massive,” which is not useful, and instead think in terms of “life-threatening” hemoptysis, defined as any of the following:

• More than 100 mL of blood lost in 24 hours (a low number, but blood loss is hard to estimate accurately)
• Causing abnormal gas exchange due to airway obstruction
• Causing hemodynamic instability.

In this article, we use the traditional “massive” terminology.

BRONCHOSCOPY IS SUPERIOR TO IMAGING FOR DIAGNOSIS

Radiography can help identify the side or the site of bleeding in 33% to 82% of patients, and computed tomography can in 70% to 88.5%.⁴ Magnetic resonance imaging may also have a role; one study found it useful in cases of thoracic endometriosis during the quiescent stage.⁵ However, transferring a patient who is actively bleeding out of the intensive care unit for imaging can be challenging.

Flexible bronchoscopy is superior to radiographic imaging in evaluating massive hemoptysis: it can be performed at the bed-side and can include therapeutic procedures to control the bleeding until the patient can undergo a definitive therapeutic procedure.⁶ It has been found helpful in identifying the side of bleeding in 73% to 93% of cases of massive hemoptysis.⁶

However, one should consider starting the procedure with a rigid bronchoscope, which protects the airway better and allows for better ventilation during the procedure than a flexible one. One can use it to isolate the nonbleeding lung and to apply pressure to the bleeding site if it is in the main bronchus.⁷ Measuring 12 mm in diameter, a rigid scope cannot go as far into the lung as a flexible bronchoscope (measuring 6.4 mm), but a flexible bronchoscope can be introduced through the rigid bronchoscope to go further in.

MANAGEMENT OPTIONS

The management team should include an anesthesiologist, an intensivist, a thoracic surgeon, an interventional radiologist, and an interventional pulmonologist.

In the intensive care unit, the patient should be placed in the lateral decubitus position on the bleeding side. To maintain ventilation, the nonbleeding lung should be intubated with a large-bore endotracheal tube (internal diameter 8.5–9.0 mm) or, ideally, with a rigid bronchoscope.⁶ Meanwhile, the patient’s circulatory status should be stabilized with adequate fluid resuscitation and transfusion of blood products, with close monitoring.

Once the bleeding site is found, a bronchoscopic treatment is selected based on the cause of the bleeding. Massive hemoptysis usually arises from high-pressure bronchial vessels (90%) or, less commonly, from non-bronchial vessels or capillaries (10%).⁸ A variety of agents (eg, cold saline lavage, epinephrine 1:20,000) can be instilled through the bronchoscope to slow the bleeding and offer better visualization of the airway.⁶

If a bleeding intrabronchial lesion is identified, such as a malignant tracheobronchial tumor, local coagulation therapy can be applied through the bronchoscope. Options include laser treatment, argon plasma coagulation, cryotherapy, and electrocautery (Figure 1).^9,10

If the bleeding persists or cannot be localized to a particular subsegment, an endobronchial balloon plug can be placed proximally (Figure 2). This can be left in place to isolate the bleeding and apply tamponade until a definitive procedure can be performed, such as bronchial artery embolization, radiation therapy, or surgery.

Yes, all patients with massive hemoptysis should undergo diagnostic bronchoscopy. The procedure plays an important role in protecting the airway, maintaining ventilation, finding the site and underlying cause of the bleeding, and in some cases stopping the bleeding, either temporarily or definitively.

Frightening to patients, massive hemoptysis is a medical emergency and demands immediate attention by an experienced pulmonary team.¹ Hemoptysis can be the initial presentation of an underlying infectious, autoimmune, or malignant disorder (Table 1).² Fortunately, most cases of hemoptysis are not massive or life-threatening.¹

WHAT IS ‘MASSIVE’ HEMOPTYSIS?

Numerous studies have defined massive hemoptysis on the basis of the volume of blood lost over time, eg, more than 1 L in 24 hours or more than 400 mL in 6 hours.

Ibrahim³ has proposed that we move away from using the word “massive,” which is not useful, and instead think in terms of “life-threatening” hemoptysis, defined as any of the following:

• More than 100 mL of blood lost in 24 hours (a low number, but blood loss is hard to estimate accurately)
• Causing abnormal gas exchange due to airway obstruction
• Causing hemodynamic instability.

In this article, we use the traditional “massive” terminology.

BRONCHOSCOPY IS SUPERIOR TO IMAGING FOR DIAGNOSIS

Radiography can help identify the side or the site of bleeding in 33% to 82% of patients, and computed tomography can in 70% to 88.5%.⁴ Magnetic resonance imaging may also have a role; one study found it useful in cases of thoracic endometriosis during the quiescent stage.⁵ However, transferring a patient who is actively bleeding out of the intensive care unit for imaging can be challenging.

Flexible bronchoscopy is superior to radiographic imaging in evaluating massive hemoptysis: it can be performed at the bed-side and can include therapeutic procedures to control the bleeding until the patient can undergo a definitive therapeutic procedure.⁶ It has been found helpful in identifying the side of bleeding in 73% to 93% of cases of massive hemoptysis.⁶

However, one should consider starting the procedure with a rigid bronchoscope, which protects the airway better and allows for better ventilation during the procedure than a flexible one. One can use it to isolate the nonbleeding lung and to apply pressure to the bleeding site if it is in the main bronchus.⁷ Measuring 12 mm in diameter, a rigid scope cannot go as far into the lung as a flexible bronchoscope (measuring 6.4 mm), but a flexible bronchoscope can be introduced through the rigid bronchoscope to go further in.

MANAGEMENT OPTIONS

The management team should include an anesthesiologist, an intensivist, a thoracic surgeon, an interventional radiologist, and an interventional pulmonologist.

In the intensive care unit, the patient should be placed in the lateral decubitus position on the bleeding side. To maintain ventilation, the nonbleeding lung should be intubated with a large-bore endotracheal tube (internal diameter 8.5–9.0 mm) or, ideally, with a rigid bronchoscope.⁶ Meanwhile, the patient’s circulatory status should be stabilized with adequate fluid resuscitation and transfusion of blood products, with close monitoring.

Once the bleeding site is found, a bronchoscopic treatment is selected based on the cause of the bleeding. Massive hemoptysis usually arises from high-pressure bronchial vessels (90%) or, less commonly, from non-bronchial vessels or capillaries (10%).⁸ A variety of agents (eg, cold saline lavage, epinephrine 1:20,000) can be instilled through the bronchoscope to slow the bleeding and offer better visualization of the airway.⁶

If a bleeding intrabronchial lesion is identified, such as a malignant tracheobronchial tumor, local coagulation therapy can be applied through the bronchoscope. Options include laser treatment, argon plasma coagulation, cryotherapy, and electrocautery (Figure 1).^9,10

If the bleeding persists or cannot be localized to a particular subsegment, an endobronchial balloon plug can be placed proximally (Figure 2). This can be left in place to isolate the bleeding and apply tamponade until a definitive procedure can be performed, such as bronchial artery embolization, radiation therapy, or surgery.

A 52-year-old woman presented with pain in both ears associated with redness and swelling. The symptoms appeared 3 weeks earlier. The pain had started on one side, then spread to the other over a period of 2 weeks. She denied fever, chills, rigor, rash, or upper respiratory symptoms. She had experienced similar but unilateral ear pain months before. Her medical history included bilateral knee pain and swelling (treated as osteoarthritis), hypertension, hyperlipidemia, and hypothyroidism. She also reported progressive bilateral hearing loss, for which she now uses hearing aids. She had no history of conjunctivitis or uveitis.

Physical examination showed swelling and erythema of both ears, sparing the earlobes (Figure 1), as well as bilateral knee-joint tenderness and restricted joint movement. The erythrocyte sedimentation rate was elevated at 52 mm/h (reference range 0–20); the complete blood cell count, creatinine, and liver enzyme levels were normal. An autoimmune panel was negative for antinuclear antibody, antineutrophil cytoplasmic antibody, and rheumatoid factor.

A clinical diagnosis of relapsing polychondritis was made based on the McAdam criteria.1 The patient was initially started on steroids and then was maintained on methotrexate. Her symptoms improved dramatically by 3 weeks.

RELAPSING POLYCHONDRITIS

Relapsing polychondritis is a rare, chronic, and potentially multisystem disorder characterized by recurrent episodes of cartilaginous inflammation that often lead to progressive destruction of the cartilage.^2,3

Auricular chondritis is the initial presentation in 43% of cases and eventually develops in 89% of patients.^2,4 The earlobes are spared, as they are devoid of cartilage, and this feature helps to differentiate the condition from an infection.

If the condition is not treated, recurrent attacks can result in irreversible cartilage damage and drooping of the pinna (ie, “cauliflower ear”). Biopsy is usually avoided, as it may further damage the ear. The diagnostic criteria for relapsing polychondritis formulated by McAdam et al¹ accommodate the different presentations in order to limit the need for biopsy. Systemic involvement may include external eye structures, vasculitis affecting the eighth cranial (vestibulocochlear) nerve, noninflammatory large-joint arthritis, and the trachea. There is also an association with myelodysplasia.

A 52-year-old woman presented with pain in both ears associated with redness and swelling. The symptoms appeared 3 weeks earlier. The pain had started on one side, then spread to the other over a period of 2 weeks. She denied fever, chills, rigor, rash, or upper respiratory symptoms. She had experienced similar but unilateral ear pain months before. Her medical history included bilateral knee pain and swelling (treated as osteoarthritis), hypertension, hyperlipidemia, and hypothyroidism. She also reported progressive bilateral hearing loss, for which she now uses hearing aids. She had no history of conjunctivitis or uveitis.

Physical examination showed swelling and erythema of both ears, sparing the earlobes (Figure 1), as well as bilateral knee-joint tenderness and restricted joint movement. The erythrocyte sedimentation rate was elevated at 52 mm/h (reference range 0–20); the complete blood cell count, creatinine, and liver enzyme levels were normal. An autoimmune panel was negative for antinuclear antibody, antineutrophil cytoplasmic antibody, and rheumatoid factor.

A clinical diagnosis of relapsing polychondritis was made based on the McAdam criteria.1 The patient was initially started on steroids and then was maintained on methotrexate. Her symptoms improved dramatically by 3 weeks.

RELAPSING POLYCHONDRITIS

Relapsing polychondritis is a rare, chronic, and potentially multisystem disorder characterized by recurrent episodes of cartilaginous inflammation that often lead to progressive destruction of the cartilage.^2,3

Auricular chondritis is the initial presentation in 43% of cases and eventually develops in 89% of patients.^2,4 The earlobes are spared, as they are devoid of cartilage, and this feature helps to differentiate the condition from an infection.

If the condition is not treated, recurrent attacks can result in irreversible cartilage damage and drooping of the pinna (ie, “cauliflower ear”). Biopsy is usually avoided, as it may further damage the ear. The diagnostic criteria for relapsing polychondritis formulated by McAdam et al¹ accommodate the different presentations in order to limit the need for biopsy. Systemic involvement may include external eye structures, vasculitis affecting the eighth cranial (vestibulocochlear) nerve, noninflammatory large-joint arthritis, and the trachea. There is also an association with myelodysplasia.

A 52-year-old woman presented with pain in both ears associated with redness and swelling. The symptoms appeared 3 weeks earlier. The pain had started on one side, then spread to the other over a period of 2 weeks. She denied fever, chills, rigor, rash, or upper respiratory symptoms. She had experienced similar but unilateral ear pain months before. Her medical history included bilateral knee pain and swelling (treated as osteoarthritis), hypertension, hyperlipidemia, and hypothyroidism. She also reported progressive bilateral hearing loss, for which she now uses hearing aids. She had no history of conjunctivitis or uveitis.

Physical examination showed swelling and erythema of both ears, sparing the earlobes (Figure 1), as well as bilateral knee-joint tenderness and restricted joint movement. The erythrocyte sedimentation rate was elevated at 52 mm/h (reference range 0–20); the complete blood cell count, creatinine, and liver enzyme levels were normal. An autoimmune panel was negative for antinuclear antibody, antineutrophil cytoplasmic antibody, and rheumatoid factor.

A clinical diagnosis of relapsing polychondritis was made based on the McAdam criteria.1 The patient was initially started on steroids and then was maintained on methotrexate. Her symptoms improved dramatically by 3 weeks.

RELAPSING POLYCHONDRITIS

Relapsing polychondritis is a rare, chronic, and potentially multisystem disorder characterized by recurrent episodes of cartilaginous inflammation that often lead to progressive destruction of the cartilage.^2,3

Auricular chondritis is the initial presentation in 43% of cases and eventually develops in 89% of patients.^2,4 The earlobes are spared, as they are devoid of cartilage, and this feature helps to differentiate the condition from an infection.

If the condition is not treated, recurrent attacks can result in irreversible cartilage damage and drooping of the pinna (ie, “cauliflower ear”). Biopsy is usually avoided, as it may further damage the ear. The diagnostic criteria for relapsing polychondritis formulated by McAdam et al¹ accommodate the different presentations in order to limit the need for biopsy. Systemic involvement may include external eye structures, vasculitis affecting the eighth cranial (vestibulocochlear) nerve, noninflammatory large-joint arthritis, and the trachea. There is also an association with myelodysplasia.

Medical screening consists of trying to detect an occult disease at a point in its course—earlier than if diagnosed by clinical manifestations—when treatment offers a meaningful benefit to the patient. If the cost is acceptable, one would think that most care providers and patients would embrace the concept. So why are there such heated controversies surrounding screening for breast, prostate, and lung cancer?

The answer to that question is interpretive and philosophical and depends in part on the frame of reference. Are we looking at screening from the perspective of the health care system or from the perspective of the individual patient who is contemplating being screened?

The US Preventive Services Task Force (USPSTF), whose guidelines on screening are reviewed by Dr. Craig Nielsen in this issue of the Journal, went to great lengths to generate evidence-based guidelines based on rigorously conducted trials. They did not consider observational information or the emotional contextual biases of individual patients. Since their guidelines carry great weight, they have a big impact, sometimes including effects on insurance reimbursement for certain screening tests.

As with all “evidence-based” decisions, when applying guidelines or trial data in the clinic, we weigh the effect of our recommendations on individual patients, not on populations. Is a test worthwhile if it offers a 1 in 250 (or fill in your own number) chance of prolonging a specific patient’s life but is expensive and uncomfortable and poses the possible stress of a false-positive result that will warrant more testing? Which is actually more stressful: undergoing additional testing (with expense and discomfort) or not knowing whether you have a potentially lethal tumor? What is a reasonable cost to the patient and to a financially failing health system in attempting to delay the end of life to some time in the future when the patient may well be frail and perhaps even incapacitated?

People may differ in how they answer these questions, some of which may not even be answerable. The USPSTF guidelines, I believe, offer solid scaffolding for informed discussion. But we and our patients should use the offered evidence-based guidelines, and perhaps assume some costs, within a personalized context. Guidelines are only guidelines.

Medical screening consists of trying to detect an occult disease at a point in its course—earlier than if diagnosed by clinical manifestations—when treatment offers a meaningful benefit to the patient. If the cost is acceptable, one would think that most care providers and patients would embrace the concept. So why are there such heated controversies surrounding screening for breast, prostate, and lung cancer?

The answer to that question is interpretive and philosophical and depends in part on the frame of reference. Are we looking at screening from the perspective of the health care system or from the perspective of the individual patient who is contemplating being screened?

The US Preventive Services Task Force (USPSTF), whose guidelines on screening are reviewed by Dr. Craig Nielsen in this issue of the Journal, went to great lengths to generate evidence-based guidelines based on rigorously conducted trials. They did not consider observational information or the emotional contextual biases of individual patients. Since their guidelines carry great weight, they have a big impact, sometimes including effects on insurance reimbursement for certain screening tests.

As with all “evidence-based” decisions, when applying guidelines or trial data in the clinic, we weigh the effect of our recommendations on individual patients, not on populations. Is a test worthwhile if it offers a 1 in 250 (or fill in your own number) chance of prolonging a specific patient’s life but is expensive and uncomfortable and poses the possible stress of a false-positive result that will warrant more testing? Which is actually more stressful: undergoing additional testing (with expense and discomfort) or not knowing whether you have a potentially lethal tumor? What is a reasonable cost to the patient and to a financially failing health system in attempting to delay the end of life to some time in the future when the patient may well be frail and perhaps even incapacitated?

People may differ in how they answer these questions, some of which may not even be answerable. The USPSTF guidelines, I believe, offer solid scaffolding for informed discussion. But we and our patients should use the offered evidence-based guidelines, and perhaps assume some costs, within a personalized context. Guidelines are only guidelines.

Medical screening consists of trying to detect an occult disease at a point in its course—earlier than if diagnosed by clinical manifestations—when treatment offers a meaningful benefit to the patient. If the cost is acceptable, one would think that most care providers and patients would embrace the concept. So why are there such heated controversies surrounding screening for breast, prostate, and lung cancer?

The answer to that question is interpretive and philosophical and depends in part on the frame of reference. Are we looking at screening from the perspective of the health care system or from the perspective of the individual patient who is contemplating being screened?

The US Preventive Services Task Force (USPSTF), whose guidelines on screening are reviewed by Dr. Craig Nielsen in this issue of the Journal, went to great lengths to generate evidence-based guidelines based on rigorously conducted trials. They did not consider observational information or the emotional contextual biases of individual patients. Since their guidelines carry great weight, they have a big impact, sometimes including effects on insurance reimbursement for certain screening tests.

As with all “evidence-based” decisions, when applying guidelines or trial data in the clinic, we weigh the effect of our recommendations on individual patients, not on populations. Is a test worthwhile if it offers a 1 in 250 (or fill in your own number) chance of prolonging a specific patient’s life but is expensive and uncomfortable and poses the possible stress of a false-positive result that will warrant more testing? Which is actually more stressful: undergoing additional testing (with expense and discomfort) or not knowing whether you have a potentially lethal tumor? What is a reasonable cost to the patient and to a financially failing health system in attempting to delay the end of life to some time in the future when the patient may well be frail and perhaps even incapacitated?

People may differ in how they answer these questions, some of which may not even be answerable. The USPSTF guidelines, I believe, offer solid scaffolding for informed discussion. But we and our patients should use the offered evidence-based guidelines, and perhaps assume some costs, within a personalized context. Guidelines are only guidelines.

A 68-year-old man with a history of hyperlipidemia is evaluated during a routine examination. He has a 25-pack-year cigarette smoking history but quit 12 years ago. He has no history of hypertension, diabetes mellitus, or stroke. A review of systems is unremarkable, and he has no family history of heart disease or cancer. He has noted no change in his bowel movements, and his most recent screening colonoscopy, done at age 60, was normal. His only current medication is lovastatin.

Physical examination reveals no abnormalities. His blood pressure is 130/82 mm Hg, and his body mass index is 24 kg/m². His total cholesterol level is 213 mg/dL, and his high-density lipoprotein level is 48 mg/dL.

Which screening tests, if any, would be appropriate for this patient?

The advent in recent years of several new screening tests, along with changing and conflicting screening recommendations, has made it a challenge to manage this aspect of patient care. This article reviews six common screening tests and presents the current recommendations for their use (Table 1).

SCREENING CAN HARM

Screening is used to detect a disease in people who have no signs or symptoms of that disease; if signs or symptoms are present, diagnostic testing is indicated instead. Ideally, screening allows for early treatment to reduce the risk of illness and death associated with a disease.

Problems with screening relate to lead-time bias (detection of disease earlier in its course without actually affecting survival time), length-time bias (detection of indolent and benign cancers rather than aggressive ones), and overdiagnosis (detection of abnormalities that would not cause a problem in the patient’s lifetime, causing unnecessary concern, cost, or treatment).

The leading advisory groups on screening are the US Preventive Services Task Force (USPSTF),¹ which is stringently evidence-based in its recommendations, and subspecialty societies, which often rely on expert opinion.^2,3

ULTRASONOGRAPHY FOR ABDOMINAL AORTIC ANEURYSM

In 2005, the USPSTF gave a grade-B recommendation (recommended; benefit outweighs harm) for one-time ultrasonographic screening for abdominal aortic aneurysm in men ages 65 to 75 who have ever smoked at least 100 cigarettes over a lifetime. For men in the same age range who have never smoked, they gave a grade-C recommendation (no recommendation; small net benefit). The USPSTF updated its recommendation in 2014. For women ages 65 to 75 who smoke, the USPSTF thinks the evidence is insufficient to recommend for or against screening (grade-I recommendation).

Our patient described above—male, age 68, and with a 25 pack-year smoking history—is a candidate for screening for abdominal aortic aneurysm.

CT SCREENING FOR LUNG CANCER

In December 2013, the USPSTF gave a B-grade recommendation for annual screening for lung cancer with low-dose computed tomography (CT) for adults ages 55 to 80 who have a 30-pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that limits life expectancy or the ability to undergo curative lung surgery.

These recommendations were based on the outcomes of the National Lung Screening Trial.⁴ However, whereas this trial was in people ages 55 to 74, the USPSTF boosted the upper age limit to 80 based on computer modeling, a decision that was somewhat controversial.

Patz et al⁵ analyzed data from the National Lung Screening Trial and found that about 18% of lung cancers detected by low-dose CT appeared to be indolent and were unlikely to become clinically apparent during the patient’s lifetime. The authors concluded that overdiagnosis should be considered when guidelines for mass screening programs are developed.

Our 68-year-old patient would not qualify for CT screening for lung cancer, since his smoking history is less than 30 pack-years.

COLORECTAL CANCER SCREENING AND PREVENTION

Unlike other cancer screening tests, colorectal cancer screening can also be a preventive measure; removing polyps found during screening with colonoscopy or sigmoidoscopy is an effective strategy in preventing colon cancer.

The USPSTF last updated its colorectal screening recommendations in 2008, giving a grade-A recommendation (strongly recommended; benefit far outweighs harm) to screening using fecal occult blood testing, sigmoidoscopy, or colonoscopy for adults ages 50 to 75. The risks and benefits of these screening methods vary. For adults ages 76 to 85, the task force recommends against routine screening but gives a grade-C recommendation for screening in that age group in some circumstances. They give a grade-D recommendation for screening after age 85.

The USPSTF concluded that the evidence is insufficient to assess the benefits and harms of CT colonography and fecal DNA testing for colorectal cancer screening.

The American Cancer Society issued similar guidelines in 2013, recommending that starting at age 50, men and women at low risk of colorectal cancer should be screened using one of the following schedules (the first four methods help detect both polyps and cancers, and the others detect only cancer)⁶:

• Colonoscopy every 10 years
• Flexible sigmoidoscopy every 5 years
• A double-contrast barium enema every 5 years
• CT colonography (“virtual colonoscopy”) every 5 years
• A guaiac-based fecal occult blood test annually
• A fecal immunochemical test annually.

Those at moderate or high risk of colorectal cancer are advised to talk with a doctor about a different testing schedule. (eg, colonoscopy every 5 years in patients with a significant family history of colon cancer).

Our patient last underwent colonoscopy 8 years ago and so does not need to be screened again for another 2 years.

CERVICAL CANCER SCREENING: MOVING TOWARD HPV TESTING FIRST?

Cervical cancer screening recommendations are fairly uniform across the major guideline-setting organizations.⁷ In general, they are:

• Ages 21–29: Check cytology every 3 years
• Ages 30–65: Cytology plus human papillomavirus (HPV) testing every 5 years (or cytology alone every 3 years)
• After age 65: Stop screening if prior screenings have been adequate and negative over the past 20 years.

Women who have been vaccinated against HPV have the same screening recommendations as above. Women who have had a hysterectomy for benign reasons do not need further screening.

The future of cervical cancer screening may be “reflex testing.” Rather than checking cervical samples for cytologic study (Papanicolaou smear) and HPV status together, we may one day screen samples first for HPV and, if that is positive, follow up with cytologic study. Easy-to-use home tests for HPV will likely be developed and should increase screening rates.

PROSTATE CANCER SCREENING: A SHARED DECISION

Prostate cancer screening remains controversial. Different guideline-setting bodies have different recommendations, creating confusion for patients. Physicians must follow what fits their own practice and beliefs.

The USPSTF in 2012 gave a grade-D recommendation to prostate-specific antigen (PSA) testing to screen for prostate cancer, stating that it did more harm than good. However, some men continue to be screened for PSA.

The American Cancer Society in 2013 recommended against routine testing for prostate cancer without a full discussion between physician and patient of the pros and cons of testing.⁸ If screening is decided upon, it should be done with annual PSA measurement or digital rectal examination, or both, starting at age 50. Men at high risk (ie, African American men, and men with a first-degree relative diagnosed with prostate cancer before age 65) should begin screening at age 45.

The American College of Physicians in 2013 issued a statement that clinicians should inform men between the ages of 50 and 69 about the limited potential benefits and substantial harms of prostate cancer screening.⁹ They recommended against PSA screening in men of average risk who are younger than age 50 or older than age 69, or those whose life expectancy is less than 10 to 15 years.

The American Urological Association in 2013 advised that¹⁰:

• PSA screening is not recommended in men younger than 40.
• Routine screening is not recommended in men between ages 40 and 54 at average risk.
• In men ages 55 to 69, decisions about PSA screening should be shared and based on each patient’s values and preferences. The decision to undergo PSA screening involves weighing the benefits of preventing death from prostate cancer in 1 man for every 1,000 men screened over a decade against the known potential harms associated with screening and treatment.
• To reduce the harm of screening, a routine interval of 2 years may be chosen over annual screening; such a schedule may preserve most benefits and reduce overdiagnosis and false-positive results.
• Routine PSA screening is not recommended in men ages 70 and older or with less than a 10- to 15-year life expectancy.

Shared decision-making. Many of the guidelines for prostate cancer screening are based on the concept of shared decision-making. However, studies indicate that many patients do not receive a full discussion of the issue,¹¹ and in any event, patient education may make little difference in PSA testing rates.^12,13

On the horizon for prostate cancer screening is the hope of finding a more predictable test. There is also discussion of using the PSA test earlier: some evidence shows that a very low result at age 45 predicts a less than 1% chance of developing metastatic prostate cancer by age 75, so it is possible that screening could stop in that population.

BREAST CANCER SCREENING: DIVERGENT RECOMMENDATIONS

The USPSTF created considerable controversy a few years ago when it recommended screening mammography from ages 50 to 74, and then only every 2 years—a departure from the traditional practice of starting screening at age 40. Few doctors heed the USPSTF guideline: most of the other guideline-setting organizations (eg, the American Cancer Society, the American Congress of Obstetricians and Gynecologists) recommend annual mammography for women starting at age 40.

Overdiagnosis is an especially pertinent issue with screening mammography for breast cancer because some cancers are indolent and will not cause a problem during a lifetime. Falk et al¹⁴ analyzed a Norwegian breast cancer screening program and found that overdiagnosis occurred in 10% to 20% of cases. Welch and Passow¹⁵ quantified the benefits and harms of screening mammography in 50-year-old women in the United States and found that of 1,000 women screened annually for a decade, 0.3 to 3.2 will avoid a breast cancer death, 490 to 670 will have at least one false alarm, and 3 to 14 will be overdiagnosed and treated needlessly.

Mammography screening for breast cancer will likely stay controversial for some time as we await additional data.

OTHER CANCERS: SCREENING NOT RECOMMENDED

The USPSTF currently does not recommend screening for ovarian cancer (guideline issued in 2012), pancreatic cancer (2004), or testicular cancer (2011), giving each a grade-D recommendation, indicating that screening does more harm than good. It also stated that there is insufficient evidence to recommend screening for oral cancer (2013), skin cancer (2009), and bladder cancer (2011).

A 68-year-old man with a history of hyperlipidemia is evaluated during a routine examination. He has a 25-pack-year cigarette smoking history but quit 12 years ago. He has no history of hypertension, diabetes mellitus, or stroke. A review of systems is unremarkable, and he has no family history of heart disease or cancer. He has noted no change in his bowel movements, and his most recent screening colonoscopy, done at age 60, was normal. His only current medication is lovastatin.

Physical examination reveals no abnormalities. His blood pressure is 130/82 mm Hg, and his body mass index is 24 kg/m². His total cholesterol level is 213 mg/dL, and his high-density lipoprotein level is 48 mg/dL.

Which screening tests, if any, would be appropriate for this patient?

The advent in recent years of several new screening tests, along with changing and conflicting screening recommendations, has made it a challenge to manage this aspect of patient care. This article reviews six common screening tests and presents the current recommendations for their use (Table 1).

SCREENING CAN HARM

Screening is used to detect a disease in people who have no signs or symptoms of that disease; if signs or symptoms are present, diagnostic testing is indicated instead. Ideally, screening allows for early treatment to reduce the risk of illness and death associated with a disease.

Problems with screening relate to lead-time bias (detection of disease earlier in its course without actually affecting survival time), length-time bias (detection of indolent and benign cancers rather than aggressive ones), and overdiagnosis (detection of abnormalities that would not cause a problem in the patient’s lifetime, causing unnecessary concern, cost, or treatment).

The leading advisory groups on screening are the US Preventive Services Task Force (USPSTF),¹ which is stringently evidence-based in its recommendations, and subspecialty societies, which often rely on expert opinion.^2,3

ULTRASONOGRAPHY FOR ABDOMINAL AORTIC ANEURYSM

In 2005, the USPSTF gave a grade-B recommendation (recommended; benefit outweighs harm) for one-time ultrasonographic screening for abdominal aortic aneurysm in men ages 65 to 75 who have ever smoked at least 100 cigarettes over a lifetime. For men in the same age range who have never smoked, they gave a grade-C recommendation (no recommendation; small net benefit). The USPSTF updated its recommendation in 2014. For women ages 65 to 75 who smoke, the USPSTF thinks the evidence is insufficient to recommend for or against screening (grade-I recommendation).

Our patient described above—male, age 68, and with a 25 pack-year smoking history—is a candidate for screening for abdominal aortic aneurysm.

CT SCREENING FOR LUNG CANCER

In December 2013, the USPSTF gave a B-grade recommendation for annual screening for lung cancer with low-dose computed tomography (CT) for adults ages 55 to 80 who have a 30-pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that limits life expectancy or the ability to undergo curative lung surgery.

These recommendations were based on the outcomes of the National Lung Screening Trial.⁴ However, whereas this trial was in people ages 55 to 74, the USPSTF boosted the upper age limit to 80 based on computer modeling, a decision that was somewhat controversial.

Patz et al⁵ analyzed data from the National Lung Screening Trial and found that about 18% of lung cancers detected by low-dose CT appeared to be indolent and were unlikely to become clinically apparent during the patient’s lifetime. The authors concluded that overdiagnosis should be considered when guidelines for mass screening programs are developed.

Our 68-year-old patient would not qualify for CT screening for lung cancer, since his smoking history is less than 30 pack-years.

COLORECTAL CANCER SCREENING AND PREVENTION

Unlike other cancer screening tests, colorectal cancer screening can also be a preventive measure; removing polyps found during screening with colonoscopy or sigmoidoscopy is an effective strategy in preventing colon cancer.

The USPSTF last updated its colorectal screening recommendations in 2008, giving a grade-A recommendation (strongly recommended; benefit far outweighs harm) to screening using fecal occult blood testing, sigmoidoscopy, or colonoscopy for adults ages 50 to 75. The risks and benefits of these screening methods vary. For adults ages 76 to 85, the task force recommends against routine screening but gives a grade-C recommendation for screening in that age group in some circumstances. They give a grade-D recommendation for screening after age 85.

The USPSTF concluded that the evidence is insufficient to assess the benefits and harms of CT colonography and fecal DNA testing for colorectal cancer screening.

The American Cancer Society issued similar guidelines in 2013, recommending that starting at age 50, men and women at low risk of colorectal cancer should be screened using one of the following schedules (the first four methods help detect both polyps and cancers, and the others detect only cancer)⁶:

• Colonoscopy every 10 years
• Flexible sigmoidoscopy every 5 years
• A double-contrast barium enema every 5 years
• CT colonography (“virtual colonoscopy”) every 5 years
• A guaiac-based fecal occult blood test annually
• A fecal immunochemical test annually.

Those at moderate or high risk of colorectal cancer are advised to talk with a doctor about a different testing schedule. (eg, colonoscopy every 5 years in patients with a significant family history of colon cancer).

Our patient last underwent colonoscopy 8 years ago and so does not need to be screened again for another 2 years.

CERVICAL CANCER SCREENING: MOVING TOWARD HPV TESTING FIRST?

Cervical cancer screening recommendations are fairly uniform across the major guideline-setting organizations.⁷ In general, they are:

• Ages 21–29: Check cytology every 3 years
• Ages 30–65: Cytology plus human papillomavirus (HPV) testing every 5 years (or cytology alone every 3 years)
• After age 65: Stop screening if prior screenings have been adequate and negative over the past 20 years.

Women who have been vaccinated against HPV have the same screening recommendations as above. Women who have had a hysterectomy for benign reasons do not need further screening.

The future of cervical cancer screening may be “reflex testing.” Rather than checking cervical samples for cytologic study (Papanicolaou smear) and HPV status together, we may one day screen samples first for HPV and, if that is positive, follow up with cytologic study. Easy-to-use home tests for HPV will likely be developed and should increase screening rates.

PROSTATE CANCER SCREENING: A SHARED DECISION

Prostate cancer screening remains controversial. Different guideline-setting bodies have different recommendations, creating confusion for patients. Physicians must follow what fits their own practice and beliefs.

The USPSTF in 2012 gave a grade-D recommendation to prostate-specific antigen (PSA) testing to screen for prostate cancer, stating that it did more harm than good. However, some men continue to be screened for PSA.

The American Cancer Society in 2013 recommended against routine testing for prostate cancer without a full discussion between physician and patient of the pros and cons of testing.⁸ If screening is decided upon, it should be done with annual PSA measurement or digital rectal examination, or both, starting at age 50. Men at high risk (ie, African American men, and men with a first-degree relative diagnosed with prostate cancer before age 65) should begin screening at age 45.

The American College of Physicians in 2013 issued a statement that clinicians should inform men between the ages of 50 and 69 about the limited potential benefits and substantial harms of prostate cancer screening.⁹ They recommended against PSA screening in men of average risk who are younger than age 50 or older than age 69, or those whose life expectancy is less than 10 to 15 years.

The American Urological Association in 2013 advised that¹⁰:

• PSA screening is not recommended in men younger than 40.
• Routine screening is not recommended in men between ages 40 and 54 at average risk.
• In men ages 55 to 69, decisions about PSA screening should be shared and based on each patient’s values and preferences. The decision to undergo PSA screening involves weighing the benefits of preventing death from prostate cancer in 1 man for every 1,000 men screened over a decade against the known potential harms associated with screening and treatment.
• To reduce the harm of screening, a routine interval of 2 years may be chosen over annual screening; such a schedule may preserve most benefits and reduce overdiagnosis and false-positive results.
• Routine PSA screening is not recommended in men ages 70 and older or with less than a 10- to 15-year life expectancy.

Shared decision-making. Many of the guidelines for prostate cancer screening are based on the concept of shared decision-making. However, studies indicate that many patients do not receive a full discussion of the issue,¹¹ and in any event, patient education may make little difference in PSA testing rates.^12,13

On the horizon for prostate cancer screening is the hope of finding a more predictable test. There is also discussion of using the PSA test earlier: some evidence shows that a very low result at age 45 predicts a less than 1% chance of developing metastatic prostate cancer by age 75, so it is possible that screening could stop in that population.

BREAST CANCER SCREENING: DIVERGENT RECOMMENDATIONS

The USPSTF created considerable controversy a few years ago when it recommended screening mammography from ages 50 to 74, and then only every 2 years—a departure from the traditional practice of starting screening at age 40. Few doctors heed the USPSTF guideline: most of the other guideline-setting organizations (eg, the American Cancer Society, the American Congress of Obstetricians and Gynecologists) recommend annual mammography for women starting at age 40.

Overdiagnosis is an especially pertinent issue with screening mammography for breast cancer because some cancers are indolent and will not cause a problem during a lifetime. Falk et al¹⁴ analyzed a Norwegian breast cancer screening program and found that overdiagnosis occurred in 10% to 20% of cases. Welch and Passow¹⁵ quantified the benefits and harms of screening mammography in 50-year-old women in the United States and found that of 1,000 women screened annually for a decade, 0.3 to 3.2 will avoid a breast cancer death, 490 to 670 will have at least one false alarm, and 3 to 14 will be overdiagnosed and treated needlessly.

Mammography screening for breast cancer will likely stay controversial for some time as we await additional data.

OTHER CANCERS: SCREENING NOT RECOMMENDED

The USPSTF currently does not recommend screening for ovarian cancer (guideline issued in 2012), pancreatic cancer (2004), or testicular cancer (2011), giving each a grade-D recommendation, indicating that screening does more harm than good. It also stated that there is insufficient evidence to recommend screening for oral cancer (2013), skin cancer (2009), and bladder cancer (2011).

A 68-year-old man with a history of hyperlipidemia is evaluated during a routine examination. He has a 25-pack-year cigarette smoking history but quit 12 years ago. He has no history of hypertension, diabetes mellitus, or stroke. A review of systems is unremarkable, and he has no family history of heart disease or cancer. He has noted no change in his bowel movements, and his most recent screening colonoscopy, done at age 60, was normal. His only current medication is lovastatin.

Physical examination reveals no abnormalities. His blood pressure is 130/82 mm Hg, and his body mass index is 24 kg/m². His total cholesterol level is 213 mg/dL, and his high-density lipoprotein level is 48 mg/dL.

Which screening tests, if any, would be appropriate for this patient?

The advent in recent years of several new screening tests, along with changing and conflicting screening recommendations, has made it a challenge to manage this aspect of patient care. This article reviews six common screening tests and presents the current recommendations for their use (Table 1).

SCREENING CAN HARM

Screening is used to detect a disease in people who have no signs or symptoms of that disease; if signs or symptoms are present, diagnostic testing is indicated instead. Ideally, screening allows for early treatment to reduce the risk of illness and death associated with a disease.

Problems with screening relate to lead-time bias (detection of disease earlier in its course without actually affecting survival time), length-time bias (detection of indolent and benign cancers rather than aggressive ones), and overdiagnosis (detection of abnormalities that would not cause a problem in the patient’s lifetime, causing unnecessary concern, cost, or treatment).

The leading advisory groups on screening are the US Preventive Services Task Force (USPSTF),¹ which is stringently evidence-based in its recommendations, and subspecialty societies, which often rely on expert opinion.^2,3

ULTRASONOGRAPHY FOR ABDOMINAL AORTIC ANEURYSM

In 2005, the USPSTF gave a grade-B recommendation (recommended; benefit outweighs harm) for one-time ultrasonographic screening for abdominal aortic aneurysm in men ages 65 to 75 who have ever smoked at least 100 cigarettes over a lifetime. For men in the same age range who have never smoked, they gave a grade-C recommendation (no recommendation; small net benefit). The USPSTF updated its recommendation in 2014. For women ages 65 to 75 who smoke, the USPSTF thinks the evidence is insufficient to recommend for or against screening (grade-I recommendation).

Our patient described above—male, age 68, and with a 25 pack-year smoking history—is a candidate for screening for abdominal aortic aneurysm.

CT SCREENING FOR LUNG CANCER

In December 2013, the USPSTF gave a B-grade recommendation for annual screening for lung cancer with low-dose computed tomography (CT) for adults ages 55 to 80 who have a 30-pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that limits life expectancy or the ability to undergo curative lung surgery.

These recommendations were based on the outcomes of the National Lung Screening Trial.⁴ However, whereas this trial was in people ages 55 to 74, the USPSTF boosted the upper age limit to 80 based on computer modeling, a decision that was somewhat controversial.

Patz et al⁵ analyzed data from the National Lung Screening Trial and found that about 18% of lung cancers detected by low-dose CT appeared to be indolent and were unlikely to become clinically apparent during the patient’s lifetime. The authors concluded that overdiagnosis should be considered when guidelines for mass screening programs are developed.

Our 68-year-old patient would not qualify for CT screening for lung cancer, since his smoking history is less than 30 pack-years.

COLORECTAL CANCER SCREENING AND PREVENTION

Unlike other cancer screening tests, colorectal cancer screening can also be a preventive measure; removing polyps found during screening with colonoscopy or sigmoidoscopy is an effective strategy in preventing colon cancer.

The USPSTF last updated its colorectal screening recommendations in 2008, giving a grade-A recommendation (strongly recommended; benefit far outweighs harm) to screening using fecal occult blood testing, sigmoidoscopy, or colonoscopy for adults ages 50 to 75. The risks and benefits of these screening methods vary. For adults ages 76 to 85, the task force recommends against routine screening but gives a grade-C recommendation for screening in that age group in some circumstances. They give a grade-D recommendation for screening after age 85.

The USPSTF concluded that the evidence is insufficient to assess the benefits and harms of CT colonography and fecal DNA testing for colorectal cancer screening.

The American Cancer Society issued similar guidelines in 2013, recommending that starting at age 50, men and women at low risk of colorectal cancer should be screened using one of the following schedules (the first four methods help detect both polyps and cancers, and the others detect only cancer)⁶:

• Colonoscopy every 10 years
• Flexible sigmoidoscopy every 5 years
• A double-contrast barium enema every 5 years
• CT colonography (“virtual colonoscopy”) every 5 years
• A guaiac-based fecal occult blood test annually
• A fecal immunochemical test annually.

Those at moderate or high risk of colorectal cancer are advised to talk with a doctor about a different testing schedule. (eg, colonoscopy every 5 years in patients with a significant family history of colon cancer).

Our patient last underwent colonoscopy 8 years ago and so does not need to be screened again for another 2 years.

CERVICAL CANCER SCREENING: MOVING TOWARD HPV TESTING FIRST?

Cervical cancer screening recommendations are fairly uniform across the major guideline-setting organizations.⁷ In general, they are:

• Ages 21–29: Check cytology every 3 years
• Ages 30–65: Cytology plus human papillomavirus (HPV) testing every 5 years (or cytology alone every 3 years)
• After age 65: Stop screening if prior screenings have been adequate and negative over the past 20 years.

Women who have been vaccinated against HPV have the same screening recommendations as above. Women who have had a hysterectomy for benign reasons do not need further screening.

The future of cervical cancer screening may be “reflex testing.” Rather than checking cervical samples for cytologic study (Papanicolaou smear) and HPV status together, we may one day screen samples first for HPV and, if that is positive, follow up with cytologic study. Easy-to-use home tests for HPV will likely be developed and should increase screening rates.

PROSTATE CANCER SCREENING: A SHARED DECISION

Prostate cancer screening remains controversial. Different guideline-setting bodies have different recommendations, creating confusion for patients. Physicians must follow what fits their own practice and beliefs.

The USPSTF in 2012 gave a grade-D recommendation to prostate-specific antigen (PSA) testing to screen for prostate cancer, stating that it did more harm than good. However, some men continue to be screened for PSA.

The American Cancer Society in 2013 recommended against routine testing for prostate cancer without a full discussion between physician and patient of the pros and cons of testing.⁸ If screening is decided upon, it should be done with annual PSA measurement or digital rectal examination, or both, starting at age 50. Men at high risk (ie, African American men, and men with a first-degree relative diagnosed with prostate cancer before age 65) should begin screening at age 45.

The American College of Physicians in 2013 issued a statement that clinicians should inform men between the ages of 50 and 69 about the limited potential benefits and substantial harms of prostate cancer screening.⁹ They recommended against PSA screening in men of average risk who are younger than age 50 or older than age 69, or those whose life expectancy is less than 10 to 15 years.

The American Urological Association in 2013 advised that¹⁰:

• PSA screening is not recommended in men younger than 40.
• Routine screening is not recommended in men between ages 40 and 54 at average risk.
• In men ages 55 to 69, decisions about PSA screening should be shared and based on each patient’s values and preferences. The decision to undergo PSA screening involves weighing the benefits of preventing death from prostate cancer in 1 man for every 1,000 men screened over a decade against the known potential harms associated with screening and treatment.
• To reduce the harm of screening, a routine interval of 2 years may be chosen over annual screening; such a schedule may preserve most benefits and reduce overdiagnosis and false-positive results.
• Routine PSA screening is not recommended in men ages 70 and older or with less than a 10- to 15-year life expectancy.

Shared decision-making. Many of the guidelines for prostate cancer screening are based on the concept of shared decision-making. However, studies indicate that many patients do not receive a full discussion of the issue,¹¹ and in any event, patient education may make little difference in PSA testing rates.^12,13

On the horizon for prostate cancer screening is the hope of finding a more predictable test. There is also discussion of using the PSA test earlier: some evidence shows that a very low result at age 45 predicts a less than 1% chance of developing metastatic prostate cancer by age 75, so it is possible that screening could stop in that population.

BREAST CANCER SCREENING: DIVERGENT RECOMMENDATIONS

The USPSTF created considerable controversy a few years ago when it recommended screening mammography from ages 50 to 74, and then only every 2 years—a departure from the traditional practice of starting screening at age 40. Few doctors heed the USPSTF guideline: most of the other guideline-setting organizations (eg, the American Cancer Society, the American Congress of Obstetricians and Gynecologists) recommend annual mammography for women starting at age 40.

Overdiagnosis is an especially pertinent issue with screening mammography for breast cancer because some cancers are indolent and will not cause a problem during a lifetime. Falk et al¹⁴ analyzed a Norwegian breast cancer screening program and found that overdiagnosis occurred in 10% to 20% of cases. Welch and Passow¹⁵ quantified the benefits and harms of screening mammography in 50-year-old women in the United States and found that of 1,000 women screened annually for a decade, 0.3 to 3.2 will avoid a breast cancer death, 490 to 670 will have at least one false alarm, and 3 to 14 will be overdiagnosed and treated needlessly.

Mammography screening for breast cancer will likely stay controversial for some time as we await additional data.

OTHER CANCERS: SCREENING NOT RECOMMENDED

The USPSTF currently does not recommend screening for ovarian cancer (guideline issued in 2012), pancreatic cancer (2004), or testicular cancer (2011), giving each a grade-D recommendation, indicating that screening does more harm than good. It also stated that there is insufficient evidence to recommend screening for oral cancer (2013), skin cancer (2009), and bladder cancer (2011).

PHILADELPHIA—Head trauma among ice hockey players may produce abnormalities in brain function, as assessed by neuropsychologic testing, diffusion tensor imaging, quantitative EEG, and postmortem studies, according to research reported at the 66th Annual Meeting of the American Academy of Neurology (AAN).

“The relationship between these measures in the short term and midterm and postmortem findings of chronic traumatic encephalopathy (CTE) is still unclear,” stated Ozan Toy, a medical student at the Commonwealth Medical College in Scranton, Pennsylvania, and colleagues.

Head Impact Injuries in Hockey
The researchers conducted a literature review regarding the effect of concussions in male ice hockey players. In addition, a Google search was performed to obtain information regarding professional hockey players who have been diagnosed with CTE.

In one of the studies reviewed, Gaetz and colleagues reported that electrophysiologic evidence from a cohort of junior hockey players showed that multiple concussions can lead to long-term neurologic symptoms, including headache, decreased memory, and decreased thinking speed, which correlate with electrophysiologic deficits related to attention, working memory, and mental processing. The study authors concluded that multiple concussions in hockey players can lead to neurologic deficits that can linger for at least six months postconcussion.

In 2012, Koerte et al found that diffusion tensor imaging revealed changes in white matter diffusivity in 17 male ice hockey players (ages 20 to 26) throughout the course of one season. Also in 2012, Bazarian and colleagues found that two high school ice hockey players who had multiple subconcussive head blows had significant changes in a percentage of their white matter that was more than three times higher than in controls.

Furthermore, in 2013 McKee and colleagues found that in eight subjects who were examined postmortem for CTE and who had a history of playing amateur and professional ice hockey, five had a presence of CTE on examination. Of the five players who underwent neuropathologic analysis, four showed signs of CTE. Three of the former National Hockey League players had stage II CTE, and one had stage III CTE and Lewy body disease; one of the four was nonsymptomatic at the time of death.

CNS Injuries in Ice Hockey
In a related study presented at the AAN Meeting, Mr. Toy and colleagues found that concussion (0.2 to 6.6 per 1,000 player hours) and spinal cord injury (five per 1,000 player hours) were the most common CNS injuries among ice hockey players.

Other reported injuries were second impact syndrome, subarachnoid hemorrhage, subdural hematoma, epidural hematoma, spinal cord concussion, and vertebral hemorrhage.

“Although numerous measures have been taken to decrease the incidence of CNS injuries in ice hockey, it has been difficult to measure the impact of those changes,” stated Mr. Toy. “Nonetheless, knowledge of the potential for CNS injuries and the mechanisms of those injuries helps inform the athletes and trainers to make more informed decisions regarding play.”

—Colby Stong

PHILADELPHIA—Head trauma among ice hockey players may produce abnormalities in brain function, as assessed by neuropsychologic testing, diffusion tensor imaging, quantitative EEG, and postmortem studies, according to research reported at the 66th Annual Meeting of the American Academy of Neurology (AAN).

“The relationship between these measures in the short term and midterm and postmortem findings of chronic traumatic encephalopathy (CTE) is still unclear,” stated Ozan Toy, a medical student at the Commonwealth Medical College in Scranton, Pennsylvania, and colleagues.

Head Impact Injuries in Hockey
The researchers conducted a literature review regarding the effect of concussions in male ice hockey players. In addition, a Google search was performed to obtain information regarding professional hockey players who have been diagnosed with CTE.

In one of the studies reviewed, Gaetz and colleagues reported that electrophysiologic evidence from a cohort of junior hockey players showed that multiple concussions can lead to long-term neurologic symptoms, including headache, decreased memory, and decreased thinking speed, which correlate with electrophysiologic deficits related to attention, working memory, and mental processing. The study authors concluded that multiple concussions in hockey players can lead to neurologic deficits that can linger for at least six months postconcussion.

In 2012, Koerte et al found that diffusion tensor imaging revealed changes in white matter diffusivity in 17 male ice hockey players (ages 20 to 26) throughout the course of one season. Also in 2012, Bazarian and colleagues found that two high school ice hockey players who had multiple subconcussive head blows had significant changes in a percentage of their white matter that was more than three times higher than in controls.

Furthermore, in 2013 McKee and colleagues found that in eight subjects who were examined postmortem for CTE and who had a history of playing amateur and professional ice hockey, five had a presence of CTE on examination. Of the five players who underwent neuropathologic analysis, four showed signs of CTE. Three of the former National Hockey League players had stage II CTE, and one had stage III CTE and Lewy body disease; one of the four was nonsymptomatic at the time of death.

CNS Injuries in Ice Hockey
In a related study presented at the AAN Meeting, Mr. Toy and colleagues found that concussion (0.2 to 6.6 per 1,000 player hours) and spinal cord injury (five per 1,000 player hours) were the most common CNS injuries among ice hockey players.

Other reported injuries were second impact syndrome, subarachnoid hemorrhage, subdural hematoma, epidural hematoma, spinal cord concussion, and vertebral hemorrhage.

“Although numerous measures have been taken to decrease the incidence of CNS injuries in ice hockey, it has been difficult to measure the impact of those changes,” stated Mr. Toy. “Nonetheless, knowledge of the potential for CNS injuries and the mechanisms of those injuries helps inform the athletes and trainers to make more informed decisions regarding play.”

—Colby Stong

PHILADELPHIA—Head trauma among ice hockey players may produce abnormalities in brain function, as assessed by neuropsychologic testing, diffusion tensor imaging, quantitative EEG, and postmortem studies, according to research reported at the 66th Annual Meeting of the American Academy of Neurology (AAN).

“The relationship between these measures in the short term and midterm and postmortem findings of chronic traumatic encephalopathy (CTE) is still unclear,” stated Ozan Toy, a medical student at the Commonwealth Medical College in Scranton, Pennsylvania, and colleagues.

Head Impact Injuries in Hockey
The researchers conducted a literature review regarding the effect of concussions in male ice hockey players. In addition, a Google search was performed to obtain information regarding professional hockey players who have been diagnosed with CTE.

In one of the studies reviewed, Gaetz and colleagues reported that electrophysiologic evidence from a cohort of junior hockey players showed that multiple concussions can lead to long-term neurologic symptoms, including headache, decreased memory, and decreased thinking speed, which correlate with electrophysiologic deficits related to attention, working memory, and mental processing. The study authors concluded that multiple concussions in hockey players can lead to neurologic deficits that can linger for at least six months postconcussion.

In 2012, Koerte et al found that diffusion tensor imaging revealed changes in white matter diffusivity in 17 male ice hockey players (ages 20 to 26) throughout the course of one season. Also in 2012, Bazarian and colleagues found that two high school ice hockey players who had multiple subconcussive head blows had significant changes in a percentage of their white matter that was more than three times higher than in controls.

Furthermore, in 2013 McKee and colleagues found that in eight subjects who were examined postmortem for CTE and who had a history of playing amateur and professional ice hockey, five had a presence of CTE on examination. Of the five players who underwent neuropathologic analysis, four showed signs of CTE. Three of the former National Hockey League players had stage II CTE, and one had stage III CTE and Lewy body disease; one of the four was nonsymptomatic at the time of death.

CNS Injuries in Ice Hockey
In a related study presented at the AAN Meeting, Mr. Toy and colleagues found that concussion (0.2 to 6.6 per 1,000 player hours) and spinal cord injury (five per 1,000 player hours) were the most common CNS injuries among ice hockey players.

Other reported injuries were second impact syndrome, subarachnoid hemorrhage, subdural hematoma, epidural hematoma, spinal cord concussion, and vertebral hemorrhage.

“Although numerous measures have been taken to decrease the incidence of CNS injuries in ice hockey, it has been difficult to measure the impact of those changes,” stated Mr. Toy. “Nonetheless, knowledge of the potential for CNS injuries and the mechanisms of those injuries helps inform the athletes and trainers to make more informed decisions regarding play.”

—Colby Stong

Photo by Nina Matthews

PHILADELPHIA—Results of a single-center study suggest that, when it comes to massive transfusion in pregnancy, a 1:1 ratio of red blood cells (RBCs) to plasma is not needed to maintain adequate hemostasis.

A 2:1 ratio produces prothrombin times (PTs), activated partial thromboplastin times (PTTs), and fibrinogen levels within references ranges.

Vanessa Plasencia, MLS (ASCP)^CM, of Texas Children’s Hospital in Houston, presented these findings at the AABB Annual Meeting 2014 (abstract S43-030G).

She noted that hospital staff perform approximately 4500 to 5000 deliveries per year, and they define massive transfusion as 4 or more RBC units in 1 hour or 10 or more RBC units in 24 hours.

The hospital’s initial obstetric massive transfusion protocol was 4 units of RBCs and 4 units of plasma to be issued in a cooler. Four units of group AB thawed plasma or liquid plasma were always available.

To determine if this protocol is optimal, Plasencia and her colleagues conducted a retrospective review of patient records from April 2012 to June 2014. During this time, there were 28 cases of massive transfusion.

Two of these patients died and were excluded from the study. One, who had placental abruption, received 131 RBC units and 48 plasma units (ratio=2.7:1). The other, who had placenta percreta, received 90 RBC units and 52 plasma units (ratio=1.7:1).

The median age of the remaining 26 patients was 34 years (range, 24-44). Four of these patients had placenta accreta, 2 had placenta increta, 14 had placenta percreta, and 6 had other complications (such as placental abruption, diabetes, and risks due to advanced-age pregnancy).

A median of 12 RBC units (range, 9-20) and 9 plasma units (range, 5-19) were issued. And a median of 8 RBC units (range, 6-12) and 5 plasma units (range, 4-8) were actually transfused. That translates to RBC-to-plasma ratios of 1.4:1 (range, 1.0-2.0) and 1.7:1 (1.3-2.5), respectively.

So despite the hospital’s protocol of a 1:1 RBC-to-plasma ratio, the actual ratio of transfusion in practice was approximately 2:1, Plasencia noted. And the patients had PT, PTT, and fibrinogen values within reference ranges.

Coagulation data were collected after transfusions took place, once patients were stable. The median PT was 14.8 seconds (range, 14.1-15.2), the median PTT was 29.9 seconds (range, 27.6-33.3), and the median fibrinogen was 283 mg/dL (range, 225-325).

Because of these results, Texas Children’s Hospital decided to change its massive transfusion protocol for obstetrics to a 2:1 RBC-to-plasma ratio. Now, the hospital issues 4 units of RBCs and 2 units of plasma in its initial blood package.

Photo by Nina Matthews

PHILADELPHIA—Results of a single-center study suggest that, when it comes to massive transfusion in pregnancy, a 1:1 ratio of red blood cells (RBCs) to plasma is not needed to maintain adequate hemostasis.

A 2:1 ratio produces prothrombin times (PTs), activated partial thromboplastin times (PTTs), and fibrinogen levels within references ranges.

Vanessa Plasencia, MLS (ASCP)^CM, of Texas Children’s Hospital in Houston, presented these findings at the AABB Annual Meeting 2014 (abstract S43-030G).

She noted that hospital staff perform approximately 4500 to 5000 deliveries per year, and they define massive transfusion as 4 or more RBC units in 1 hour or 10 or more RBC units in 24 hours.

The hospital’s initial obstetric massive transfusion protocol was 4 units of RBCs and 4 units of plasma to be issued in a cooler. Four units of group AB thawed plasma or liquid plasma were always available.

To determine if this protocol is optimal, Plasencia and her colleagues conducted a retrospective review of patient records from April 2012 to June 2014. During this time, there were 28 cases of massive transfusion.

Two of these patients died and were excluded from the study. One, who had placental abruption, received 131 RBC units and 48 plasma units (ratio=2.7:1). The other, who had placenta percreta, received 90 RBC units and 52 plasma units (ratio=1.7:1).

The median age of the remaining 26 patients was 34 years (range, 24-44). Four of these patients had placenta accreta, 2 had placenta increta, 14 had placenta percreta, and 6 had other complications (such as placental abruption, diabetes, and risks due to advanced-age pregnancy).

A median of 12 RBC units (range, 9-20) and 9 plasma units (range, 5-19) were issued. And a median of 8 RBC units (range, 6-12) and 5 plasma units (range, 4-8) were actually transfused. That translates to RBC-to-plasma ratios of 1.4:1 (range, 1.0-2.0) and 1.7:1 (1.3-2.5), respectively.

So despite the hospital’s protocol of a 1:1 RBC-to-plasma ratio, the actual ratio of transfusion in practice was approximately 2:1, Plasencia noted. And the patients had PT, PTT, and fibrinogen values within reference ranges.

Coagulation data were collected after transfusions took place, once patients were stable. The median PT was 14.8 seconds (range, 14.1-15.2), the median PTT was 29.9 seconds (range, 27.6-33.3), and the median fibrinogen was 283 mg/dL (range, 225-325).

Because of these results, Texas Children’s Hospital decided to change its massive transfusion protocol for obstetrics to a 2:1 RBC-to-plasma ratio. Now, the hospital issues 4 units of RBCs and 2 units of plasma in its initial blood package.

Photo by Nina Matthews

PHILADELPHIA—Results of a single-center study suggest that, when it comes to massive transfusion in pregnancy, a 1:1 ratio of red blood cells (RBCs) to plasma is not needed to maintain adequate hemostasis.

A 2:1 ratio produces prothrombin times (PTs), activated partial thromboplastin times (PTTs), and fibrinogen levels within references ranges.

Vanessa Plasencia, MLS (ASCP)^CM, of Texas Children’s Hospital in Houston, presented these findings at the AABB Annual Meeting 2014 (abstract S43-030G).

She noted that hospital staff perform approximately 4500 to 5000 deliveries per year, and they define massive transfusion as 4 or more RBC units in 1 hour or 10 or more RBC units in 24 hours.

The hospital’s initial obstetric massive transfusion protocol was 4 units of RBCs and 4 units of plasma to be issued in a cooler. Four units of group AB thawed plasma or liquid plasma were always available.

To determine if this protocol is optimal, Plasencia and her colleagues conducted a retrospective review of patient records from April 2012 to June 2014. During this time, there were 28 cases of massive transfusion.

Two of these patients died and were excluded from the study. One, who had placental abruption, received 131 RBC units and 48 plasma units (ratio=2.7:1). The other, who had placenta percreta, received 90 RBC units and 52 plasma units (ratio=1.7:1).

The median age of the remaining 26 patients was 34 years (range, 24-44). Four of these patients had placenta accreta, 2 had placenta increta, 14 had placenta percreta, and 6 had other complications (such as placental abruption, diabetes, and risks due to advanced-age pregnancy).

A median of 12 RBC units (range, 9-20) and 9 plasma units (range, 5-19) were issued. And a median of 8 RBC units (range, 6-12) and 5 plasma units (range, 4-8) were actually transfused. That translates to RBC-to-plasma ratios of 1.4:1 (range, 1.0-2.0) and 1.7:1 (1.3-2.5), respectively.

So despite the hospital’s protocol of a 1:1 RBC-to-plasma ratio, the actual ratio of transfusion in practice was approximately 2:1, Plasencia noted. And the patients had PT, PTT, and fibrinogen values within reference ranges.

Coagulation data were collected after transfusions took place, once patients were stable. The median PT was 14.8 seconds (range, 14.1-15.2), the median PTT was 29.9 seconds (range, 27.6-33.3), and the median fibrinogen was 283 mg/dL (range, 225-325).

Because of these results, Texas Children’s Hospital decided to change its massive transfusion protocol for obstetrics to a 2:1 RBC-to-plasma ratio. Now, the hospital issues 4 units of RBCs and 2 units of plasma in its initial blood package.

BALTIMORE—Patients with clinically isolated syndrome (CIS) who received early treatment with interferon beta-1b had a more favorable outcome after 11 years than did patients who had delayed treatment, Ludwig Kappos, MD, and colleagues reported.

Patients in the early treatment arm of the Betaferon/Betaseron in Newly Emerging MS For Initial Treatment (BENEFIT) trial had a longer time to clinically definite multiple sclerosis (MS) (hazard ratio [HR], 0.67), compared with patients in the delayed treatment group. Patients who had early treatment also had a longer time to first relapse (HR, 0.655) and a lower annualized relapse rate (relative risk, 0.8094), compared with those in the delayed treatment group.

Patients in BENEFIT 11 were randomized to receive either 250 µg of interferon beta-1b as early treatment or placebo as delayed treatment subcutaneously every other day. All participants had CIS and two or more MRI lesions suggestive of MS. After two years or conversion to clinically definite MS, patients who had received placebo were offered treatment with interferon beta-1b but could take another medication or no medication for MS. In the delayed treatment group, the mean delay in start of interferon beta-1b treatment was 1.33 years.

Eleven years after the initial randomization, all patients were asked to complete a comprehensive reassessment. A total of 167 patients received early treatment with interferon beta-1b, and 111 received placebo in BENEFIT 11.

Scores on the Expanded Disability Status Scale (EDSS) “remained low and stable,” with a median of 2.0 and a median change from baseline of 0.5 in both groups, noted Dr. Kappos, Chair in Neurology at the University Hospital Basel, Switzerland. Kaplan–Meier estimates of risk of secondary progressive MS at 11 years were 4.5% in the early treatment group and 8.3% in the delayed treatment groups.

“The 11-year follow-up of the BENEFIT trial includes a sizeable proportion of the originally randomized patients from the participating centers and shows that relapse-related clinical outcomes—time to clinically definite MS, time to first relapse, and annualized relapse rate—still favor patients who had early treatment with interferon beta-1b, relative to those in the delayed interferon beta-1b treatment arm,” stated Dr. Kappos.

The differences between the treatment groups remained after 11 years “despite the relatively small differences in interferon beta-1b exposure between the treatment arms,” noted Dr. Kappos. All patients in the delayed treatment group began their treatment within a maximum of two years following a first demyelinating event.

“BENEFIT 11 provides evidence that the early treatment of patients with CIS had a positive impact on clinical outcomes, even 11 years postrandomization, and supports the importance of starting therapy with interferon beta-1b early in the course of disease,” Dr. Kappos concluded. “Disability data from BENEFIT 11 also appear to suggest a positive effect of interferon beta-1b on EDSS progression.”

Are Patients With Ischemic Stroke Receiving Guideline-Concordant Cardiac Stress Testing?
Guideline-concordant cardiac screening is underused in patients who have had an ischemic stroke without evidence of previous cardiac stress testing, researchers reported.

“Current guidelines recommend screening for coronary heart disease using cardiac stress testing for ischemic stroke patients at high risk of future cardiac events,” stated Jason J. Sico, MD, Assistant Professor of Neurology at the Yale University School of Medicine and Director of Stroke Care at the VA Connecticut Healthcare System in New Haven. “Whether high-risk stroke patients routinely receive guideline-concordant cardiac stress testing is not known.”

Dr. Sico and colleagues analyzed the medical records of 3,965 veterans from 131 Veterans Health Administration facilities who were admitted with a confirmed diagnosis of ischemic stroke in 2007. The investigators used a Framingham Risk Score of 20 or greater to define patients who had a high risk of coronary heart disease. The study authors used logistic regression analysis to assess whether cardiac stress testing had been performed more frequently among patients who were at high risk for stroke.

Among the 2,337 patients who were included in the analysis, 664 (28%) had a Framingham Risk Score of 20 or greater. A total of 140 patients (6%) had cardiac stress testing within six months of discharge.

“High-risk patients were as likely to have received cardiac stress testing as were those with a low Framingham Risk Score (odds ratio, 0.90),” Dr. Sico reported.

Mild TBI Is a More Common Risk Factor for Early-Onset Alzheimer’s Disease Than for Late-Onset Alzheimer’s Disease
Mild traumatic brain injury (TBI) occurring two or more years before the initial diagnosis of dementia is more common in patients with early-onset Alzheimer’s disease, compared with patients who have late-onset Alzheimer’s disease, according to research presented.

Ugur Sener, MD, of the Department of Neurology, University of Oklahoma Medical Center in Oklahoma City, and colleagues conducted a retrospective chart review that compared patients with early-onset Alzheimer’s disease with those who had late-onset Alzheimer’s disease, regarding vascular risk factors, depression, excessive use of alcohol, TBI, education, and family history of dementia. Neuroimaging tests and laboratory screening tests were performed according to guidelines from the American Academy of Neurology.

The investigators found that 35 patients had early-onset Alzheimer’s disease and 103 patients had late-onset Alzheimer’s disease during the study period of September 1, 2010, through September 1, 2013. Seven of the 35 patients with early-onset Alzheimer’s disease had had a concussion two years or more before their initial visit, compared with five of the 103 patients with late-onset Alzheimer’s disease.

“There were no significant differences in any of the other risk factors,” stated Dr. Sener.

Sodium Channel–Blocking AEDs Linked to Better Adherence
Patients with epilepsy who use a sodium channel–blocking antiepileptic drug (AED) have a higher likelihood of treatment adherence for 12 months, compared with patients who use AEDs with other mechanisms, researchers reported.

Jennifer S. Korsnes, Senior Health Outcomes Scientist, RTI Health Solutions in Research Triangle Park, North Carolina, and colleagues based their findings on a review of a US commercial claims database of adult patients with epilepsy, ages 18 to 65. Patients were required to have six or more months of continuous health plan enrollment before their index date and 12 or more months of continuous enrollment after their index date, as well as a monotherapy index AED. Patients were considered to be adherent if they had a proportion of days covered greater than or equal to 80% with an AED during the 12-month follow-up. The investigators performed logistic regression analysis to assess the relationship between AED mechanism and adherence.

A total of 53,338 patients were included in the study—40.2% had been taking a sodium channel blocker, 15.8% were using a gamma-aminobutyric acid (GABA) enhancer, 23.3% were using a synaptic vesicle protein 2A (SV2A) binding agent, 10.1% had been taking a glutamate blocker, and 10.6% had been using a multiple-mechanism index AED.

Compared with patients who were using a sodium-channel blocker, the one-year odds of being adherent were 57.2% lower for patients taking a GABA enhancer, 8.3% lower for patients taking an SV2A-binding agent, 6.8% lower for patients taking a glutamate blocker, and 12% lower for patients using a multiple-mechanism AED.

—Colby Stong

BALTIMORE—Patients with clinically isolated syndrome (CIS) who received early treatment with interferon beta-1b had a more favorable outcome after 11 years than did patients who had delayed treatment, Ludwig Kappos, MD, and colleagues reported.

Patients in the early treatment arm of the Betaferon/Betaseron in Newly Emerging MS For Initial Treatment (BENEFIT) trial had a longer time to clinically definite multiple sclerosis (MS) (hazard ratio [HR], 0.67), compared with patients in the delayed treatment group. Patients who had early treatment also had a longer time to first relapse (HR, 0.655) and a lower annualized relapse rate (relative risk, 0.8094), compared with those in the delayed treatment group.

Patients in BENEFIT 11 were randomized to receive either 250 µg of interferon beta-1b as early treatment or placebo as delayed treatment subcutaneously every other day. All participants had CIS and two or more MRI lesions suggestive of MS. After two years or conversion to clinically definite MS, patients who had received placebo were offered treatment with interferon beta-1b but could take another medication or no medication for MS. In the delayed treatment group, the mean delay in start of interferon beta-1b treatment was 1.33 years.

Eleven years after the initial randomization, all patients were asked to complete a comprehensive reassessment. A total of 167 patients received early treatment with interferon beta-1b, and 111 received placebo in BENEFIT 11.

Scores on the Expanded Disability Status Scale (EDSS) “remained low and stable,” with a median of 2.0 and a median change from baseline of 0.5 in both groups, noted Dr. Kappos, Chair in Neurology at the University Hospital Basel, Switzerland. Kaplan–Meier estimates of risk of secondary progressive MS at 11 years were 4.5% in the early treatment group and 8.3% in the delayed treatment groups.

“The 11-year follow-up of the BENEFIT trial includes a sizeable proportion of the originally randomized patients from the participating centers and shows that relapse-related clinical outcomes—time to clinically definite MS, time to first relapse, and annualized relapse rate—still favor patients who had early treatment with interferon beta-1b, relative to those in the delayed interferon beta-1b treatment arm,” stated Dr. Kappos.

The differences between the treatment groups remained after 11 years “despite the relatively small differences in interferon beta-1b exposure between the treatment arms,” noted Dr. Kappos. All patients in the delayed treatment group began their treatment within a maximum of two years following a first demyelinating event.

“BENEFIT 11 provides evidence that the early treatment of patients with CIS had a positive impact on clinical outcomes, even 11 years postrandomization, and supports the importance of starting therapy with interferon beta-1b early in the course of disease,” Dr. Kappos concluded. “Disability data from BENEFIT 11 also appear to suggest a positive effect of interferon beta-1b on EDSS progression.”

Are Patients With Ischemic Stroke Receiving Guideline-Concordant Cardiac Stress Testing?
Guideline-concordant cardiac screening is underused in patients who have had an ischemic stroke without evidence of previous cardiac stress testing, researchers reported.

“Current guidelines recommend screening for coronary heart disease using cardiac stress testing for ischemic stroke patients at high risk of future cardiac events,” stated Jason J. Sico, MD, Assistant Professor of Neurology at the Yale University School of Medicine and Director of Stroke Care at the VA Connecticut Healthcare System in New Haven. “Whether high-risk stroke patients routinely receive guideline-concordant cardiac stress testing is not known.”

Dr. Sico and colleagues analyzed the medical records of 3,965 veterans from 131 Veterans Health Administration facilities who were admitted with a confirmed diagnosis of ischemic stroke in 2007. The investigators used a Framingham Risk Score of 20 or greater to define patients who had a high risk of coronary heart disease. The study authors used logistic regression analysis to assess whether cardiac stress testing had been performed more frequently among patients who were at high risk for stroke.

Among the 2,337 patients who were included in the analysis, 664 (28%) had a Framingham Risk Score of 20 or greater. A total of 140 patients (6%) had cardiac stress testing within six months of discharge.

“High-risk patients were as likely to have received cardiac stress testing as were those with a low Framingham Risk Score (odds ratio, 0.90),” Dr. Sico reported.

Mild TBI Is a More Common Risk Factor for Early-Onset Alzheimer’s Disease Than for Late-Onset Alzheimer’s Disease
Mild traumatic brain injury (TBI) occurring two or more years before the initial diagnosis of dementia is more common in patients with early-onset Alzheimer’s disease, compared with patients who have late-onset Alzheimer’s disease, according to research presented.

Ugur Sener, MD, of the Department of Neurology, University of Oklahoma Medical Center in Oklahoma City, and colleagues conducted a retrospective chart review that compared patients with early-onset Alzheimer’s disease with those who had late-onset Alzheimer’s disease, regarding vascular risk factors, depression, excessive use of alcohol, TBI, education, and family history of dementia. Neuroimaging tests and laboratory screening tests were performed according to guidelines from the American Academy of Neurology.

The investigators found that 35 patients had early-onset Alzheimer’s disease and 103 patients had late-onset Alzheimer’s disease during the study period of September 1, 2010, through September 1, 2013. Seven of the 35 patients with early-onset Alzheimer’s disease had had a concussion two years or more before their initial visit, compared with five of the 103 patients with late-onset Alzheimer’s disease.

“There were no significant differences in any of the other risk factors,” stated Dr. Sener.

Sodium Channel–Blocking AEDs Linked to Better Adherence
Patients with epilepsy who use a sodium channel–blocking antiepileptic drug (AED) have a higher likelihood of treatment adherence for 12 months, compared with patients who use AEDs with other mechanisms, researchers reported.

Jennifer S. Korsnes, Senior Health Outcomes Scientist, RTI Health Solutions in Research Triangle Park, North Carolina, and colleagues based their findings on a review of a US commercial claims database of adult patients with epilepsy, ages 18 to 65. Patients were required to have six or more months of continuous health plan enrollment before their index date and 12 or more months of continuous enrollment after their index date, as well as a monotherapy index AED. Patients were considered to be adherent if they had a proportion of days covered greater than or equal to 80% with an AED during the 12-month follow-up. The investigators performed logistic regression analysis to assess the relationship between AED mechanism and adherence.

A total of 53,338 patients were included in the study—40.2% had been taking a sodium channel blocker, 15.8% were using a gamma-aminobutyric acid (GABA) enhancer, 23.3% were using a synaptic vesicle protein 2A (SV2A) binding agent, 10.1% had been taking a glutamate blocker, and 10.6% had been using a multiple-mechanism index AED.

Compared with patients who were using a sodium-channel blocker, the one-year odds of being adherent were 57.2% lower for patients taking a GABA enhancer, 8.3% lower for patients taking an SV2A-binding agent, 6.8% lower for patients taking a glutamate blocker, and 12% lower for patients using a multiple-mechanism AED.

—Colby Stong

BALTIMORE—Patients with clinically isolated syndrome (CIS) who received early treatment with interferon beta-1b had a more favorable outcome after 11 years than did patients who had delayed treatment, Ludwig Kappos, MD, and colleagues reported.

Patients in the early treatment arm of the Betaferon/Betaseron in Newly Emerging MS For Initial Treatment (BENEFIT) trial had a longer time to clinically definite multiple sclerosis (MS) (hazard ratio [HR], 0.67), compared with patients in the delayed treatment group. Patients who had early treatment also had a longer time to first relapse (HR, 0.655) and a lower annualized relapse rate (relative risk, 0.8094), compared with those in the delayed treatment group.

Patients in BENEFIT 11 were randomized to receive either 250 µg of interferon beta-1b as early treatment or placebo as delayed treatment subcutaneously every other day. All participants had CIS and two or more MRI lesions suggestive of MS. After two years or conversion to clinically definite MS, patients who had received placebo were offered treatment with interferon beta-1b but could take another medication or no medication for MS. In the delayed treatment group, the mean delay in start of interferon beta-1b treatment was 1.33 years.

Eleven years after the initial randomization, all patients were asked to complete a comprehensive reassessment. A total of 167 patients received early treatment with interferon beta-1b, and 111 received placebo in BENEFIT 11.

Scores on the Expanded Disability Status Scale (EDSS) “remained low and stable,” with a median of 2.0 and a median change from baseline of 0.5 in both groups, noted Dr. Kappos, Chair in Neurology at the University Hospital Basel, Switzerland. Kaplan–Meier estimates of risk of secondary progressive MS at 11 years were 4.5% in the early treatment group and 8.3% in the delayed treatment groups.

“The 11-year follow-up of the BENEFIT trial includes a sizeable proportion of the originally randomized patients from the participating centers and shows that relapse-related clinical outcomes—time to clinically definite MS, time to first relapse, and annualized relapse rate—still favor patients who had early treatment with interferon beta-1b, relative to those in the delayed interferon beta-1b treatment arm,” stated Dr. Kappos.

The differences between the treatment groups remained after 11 years “despite the relatively small differences in interferon beta-1b exposure between the treatment arms,” noted Dr. Kappos. All patients in the delayed treatment group began their treatment within a maximum of two years following a first demyelinating event.

“BENEFIT 11 provides evidence that the early treatment of patients with CIS had a positive impact on clinical outcomes, even 11 years postrandomization, and supports the importance of starting therapy with interferon beta-1b early in the course of disease,” Dr. Kappos concluded. “Disability data from BENEFIT 11 also appear to suggest a positive effect of interferon beta-1b on EDSS progression.”

Are Patients With Ischemic Stroke Receiving Guideline-Concordant Cardiac Stress Testing?
Guideline-concordant cardiac screening is underused in patients who have had an ischemic stroke without evidence of previous cardiac stress testing, researchers reported.

“Current guidelines recommend screening for coronary heart disease using cardiac stress testing for ischemic stroke patients at high risk of future cardiac events,” stated Jason J. Sico, MD, Assistant Professor of Neurology at the Yale University School of Medicine and Director of Stroke Care at the VA Connecticut Healthcare System in New Haven. “Whether high-risk stroke patients routinely receive guideline-concordant cardiac stress testing is not known.”

Dr. Sico and colleagues analyzed the medical records of 3,965 veterans from 131 Veterans Health Administration facilities who were admitted with a confirmed diagnosis of ischemic stroke in 2007. The investigators used a Framingham Risk Score of 20 or greater to define patients who had a high risk of coronary heart disease. The study authors used logistic regression analysis to assess whether cardiac stress testing had been performed more frequently among patients who were at high risk for stroke.

Among the 2,337 patients who were included in the analysis, 664 (28%) had a Framingham Risk Score of 20 or greater. A total of 140 patients (6%) had cardiac stress testing within six months of discharge.

“High-risk patients were as likely to have received cardiac stress testing as were those with a low Framingham Risk Score (odds ratio, 0.90),” Dr. Sico reported.

Mild TBI Is a More Common Risk Factor for Early-Onset Alzheimer’s Disease Than for Late-Onset Alzheimer’s Disease
Mild traumatic brain injury (TBI) occurring two or more years before the initial diagnosis of dementia is more common in patients with early-onset Alzheimer’s disease, compared with patients who have late-onset Alzheimer’s disease, according to research presented.

Ugur Sener, MD, of the Department of Neurology, University of Oklahoma Medical Center in Oklahoma City, and colleagues conducted a retrospective chart review that compared patients with early-onset Alzheimer’s disease with those who had late-onset Alzheimer’s disease, regarding vascular risk factors, depression, excessive use of alcohol, TBI, education, and family history of dementia. Neuroimaging tests and laboratory screening tests were performed according to guidelines from the American Academy of Neurology.

The investigators found that 35 patients had early-onset Alzheimer’s disease and 103 patients had late-onset Alzheimer’s disease during the study period of September 1, 2010, through September 1, 2013. Seven of the 35 patients with early-onset Alzheimer’s disease had had a concussion two years or more before their initial visit, compared with five of the 103 patients with late-onset Alzheimer’s disease.

“There were no significant differences in any of the other risk factors,” stated Dr. Sener.

Sodium Channel–Blocking AEDs Linked to Better Adherence
Patients with epilepsy who use a sodium channel–blocking antiepileptic drug (AED) have a higher likelihood of treatment adherence for 12 months, compared with patients who use AEDs with other mechanisms, researchers reported.

Jennifer S. Korsnes, Senior Health Outcomes Scientist, RTI Health Solutions in Research Triangle Park, North Carolina, and colleagues based their findings on a review of a US commercial claims database of adult patients with epilepsy, ages 18 to 65. Patients were required to have six or more months of continuous health plan enrollment before their index date and 12 or more months of continuous enrollment after their index date, as well as a monotherapy index AED. Patients were considered to be adherent if they had a proportion of days covered greater than or equal to 80% with an AED during the 12-month follow-up. The investigators performed logistic regression analysis to assess the relationship between AED mechanism and adherence.

A total of 53,338 patients were included in the study—40.2% had been taking a sodium channel blocker, 15.8% were using a gamma-aminobutyric acid (GABA) enhancer, 23.3% were using a synaptic vesicle protein 2A (SV2A) binding agent, 10.1% had been taking a glutamate blocker, and 10.6% had been using a multiple-mechanism index AED.

Compared with patients who were using a sodium-channel blocker, the one-year odds of being adherent were 57.2% lower for patients taking a GABA enhancer, 8.3% lower for patients taking an SV2A-binding agent, 6.8% lower for patients taking a glutamate blocker, and 12% lower for patients using a multiple-mechanism AED.

—Colby Stong

In his monthly podcast for The Journal of Community and Supportive Oncology for October, David Henry examines two research articles that focus on patient-provider communication: one article looks at patient and provider concordance on symptoms and the other discusses the informational needs and the quality of life of patients after being diagnosed with metastatic breast cancer. Two other original research articles on weight change in breast cancer patients on third-generation adjuvant chemotherapy and the quality of supportive care in patients with advanced lung cancer in the Veterans Health Administration plus a Case Report about breast cancer with brain metastases in pregnancy round off the clinical portion of the line-up. A feature article details the current state of biomarker development and challenges that temper their clinical potential.

In his monthly podcast for The Journal of Community and Supportive Oncology for October, David Henry examines two research articles that focus on patient-provider communication: one article looks at patient and provider concordance on symptoms and the other discusses the informational needs and the quality of life of patients after being diagnosed with metastatic breast cancer. Two other original research articles on weight change in breast cancer patients on third-generation adjuvant chemotherapy and the quality of supportive care in patients with advanced lung cancer in the Veterans Health Administration plus a Case Report about breast cancer with brain metastases in pregnancy round off the clinical portion of the line-up. A feature article details the current state of biomarker development and challenges that temper their clinical potential.

In his monthly podcast for The Journal of Community and Supportive Oncology for October, David Henry examines two research articles that focus on patient-provider communication: one article looks at patient and provider concordance on symptoms and the other discusses the informational needs and the quality of life of patients after being diagnosed with metastatic breast cancer. Two other original research articles on weight change in breast cancer patients on third-generation adjuvant chemotherapy and the quality of supportive care in patients with advanced lung cancer in the Veterans Health Administration plus a Case Report about breast cancer with brain metastases in pregnancy round off the clinical portion of the line-up. A feature article details the current state of biomarker development and challenges that temper their clinical potential.

RELIZEN: NONHORMONAL TX FOR HOT FLASHES
RELIZEN^® is a patented, nonhormonal therapy for the relief of hot flashes associated with menopause from JDS Therapeutics.New to the United States, Relizen has been used by women and physicians in Europe for more than 15 years, according to the manufacturer, and has clinical efficacy data established in a placebo-controlled trial published in Climacteric. The active ingredient is a non-estrogenic, purified Swedish pollen extract that has pollen allergens removed. The daily dose is 2 pills/day.
FOR MORE INFORMATION, VISIT www.relizen.com

RISK ASSESSMENT FOR SPORADIC BREAST CA
BREVAGenplus, from Phenogen Sciences, Inc, assesses clinical risk factors (Gail score) and genetic markers (SNP profile) to determine 5-year and lifetime risks of developing sporadic (nonhereditary) breast cancer. The test is for Caucasian, Hispanic, and African-American women, aged 35 years and older, who have not had breast cancer but have one or more risk factors for developing breast cancer.
FOR MORE INFORMATION, VISIT http://phenogensciences.com

3 NEW DEVICE LENGTHS FOR DISSECTION
Covidien has added 13-cm, 26-cm, and 48-cm lengths to its Sonicision^tm Cordless Ultrasonic Dissection Device portfolio. Covidien reports that Sonicision offers surgeons faster dissection with increased mobility without having to manage electrical cords. Single-use and reusable components available.
FOR MORE INFORMATION, VISIT www.covidien.com

ROBOTICS SIMULATOR
Simbionix has launched RobotiX Mentor, a comprehensive educational tool for surgeons of all levels to practice the skills required to perform robotic surgery. By using basic task modules and cross-specialty clinical procedure simulations, surgeons can experience partial or entire robotic procedures.
FOR MORE INFORMATION, VISIT www.simbionix.com

NATURAL PRODUCTS FOR PREGNANCY
Fairhaven Health’s PregnancyPlus Line includes Prenatal Vitamins, Omega-3, and Cal-Mag (calcium, magnesium, and vitamin D3) natural supplements. Fairhaven Health claims that the Belly Rest Pregnancy Pillow provides back-pain relief during sleep. All products are BPA-free, with no artificial flavors, colors, or preservatives.
FOR MORE INFORMATION, VISIT www.fairhavenhealth.com

OPTIMIZE OFFICE WORKFLOW
Comtron offers Medgen EHR, a customized electronic health record (EHR) system. Comtron claims the Medgen EHR system is easily adaptable and is cost-effective by offering increased efficiency, decreased overhead, and improved patient care.
FOR MORE INFORMATION, VISIT www.medgenehr.com

VISUALIZATION ENHANCEMENT TOOLS
Karl Storz launched the Image1^® SPIES^tm visualization enhancement modular system for endoscopic surgery. SPIES, an acronym for Storz Professional Image Enhancement System, has three components: video software, a modular camera control unit, and a graphic user interface. Karl Storz reports that the modular design allows customization to individual needs. The combined camera heads and visualization tools offer homogenous illumination and contrast enhancement.
FOR MORE INFORMATION, VISIT www.karlstorz.com

NONINVASIVE PRENATAL GENETIC BLOOD TEST
Synapse Diagnostics offers Materni T21 PLUS, a test for specific chromosomal conditions in a fetus that are associated with birth defects. Conducted on blood drawn from the mother as early as 10 weeks’ gestation, the test uses genomic sequencing. Synapse Diagnostics claims that this is the only test that not only detects abnormalities like Down syndrome but also reveals defects called “microdeletions” caused by a missing gene that are otherwise difficult to discover early in pregnancy.
FOR MORE INFORMATION, VISIT www.synapsediagnostics.com

NEW ULTRASOUND SYSTEM
Samsung Electronics America, Inc. has introduced the UGEO WS80A ultrasound system for ObGyn applications. Key features: 21.5"-wide LED monitor with touch panel, 5D technologies, FRV^tm (Feto Realistic View) with 3D visualization, and piezoelectric crystal design for high resolution. Samsung reports that the UGEO WS80A has improved gray scale and color with a more precise signal, speckle reduction, and edge and contrast enhancement.
FOR MORE INFORMATION, VISIT www.samsung.com/healthcare

SEAL & CUT TECHNOLOGY
Aesculap has expanded its line of Caiman 5 Seal and Cut Technology to include 24-cm and 44-cm lengths of vessel sealing devices in addition to its original 36-cm device. Aesculap claims that the extended jaw design provides uniform pressure distribution across a variety of tissue thicknesses. These bipolar electrosurgical RF energy instruments are intended for open and laparoscopic surgery.
FOR MORE INFORMATION, VISIT www.caimansurgery.com

DETECTING RUPTURED MEMBRANES
ROM Plus^®is a rapid qualitative test for in vitro detection of amniotic proteins in vaginal secretions of pregnant women for possible diagnosis of premature rupture of membranes (PROM). ROM Plus uses a monoclonal/polyclonal antibody approach to detect two amniotic proteins, AFP and PP12. Accurate and prompt diagnosis of PROM helps decrease or avoid serious complications for mother and fetus.
FOR MORE INFORMATION, VISIT www.clinicalinnovations.com

RELIZEN: NONHORMONAL TX FOR HOT FLASHES
RELIZEN^® is a patented, nonhormonal therapy for the relief of hot flashes associated with menopause from JDS Therapeutics.New to the United States, Relizen has been used by women and physicians in Europe for more than 15 years, according to the manufacturer, and has clinical efficacy data established in a placebo-controlled trial published in Climacteric. The active ingredient is a non-estrogenic, purified Swedish pollen extract that has pollen allergens removed. The daily dose is 2 pills/day.
FOR MORE INFORMATION, VISIT www.relizen.com

RISK ASSESSMENT FOR SPORADIC BREAST CA
BREVAGenplus, from Phenogen Sciences, Inc, assesses clinical risk factors (Gail score) and genetic markers (SNP profile) to determine 5-year and lifetime risks of developing sporadic (nonhereditary) breast cancer. The test is for Caucasian, Hispanic, and African-American women, aged 35 years and older, who have not had breast cancer but have one or more risk factors for developing breast cancer.
FOR MORE INFORMATION, VISIT http://phenogensciences.com

3 NEW DEVICE LENGTHS FOR DISSECTION
Covidien has added 13-cm, 26-cm, and 48-cm lengths to its Sonicision^tm Cordless Ultrasonic Dissection Device portfolio. Covidien reports that Sonicision offers surgeons faster dissection with increased mobility without having to manage electrical cords. Single-use and reusable components available.
FOR MORE INFORMATION, VISIT www.covidien.com

ROBOTICS SIMULATOR
Simbionix has launched RobotiX Mentor, a comprehensive educational tool for surgeons of all levels to practice the skills required to perform robotic surgery. By using basic task modules and cross-specialty clinical procedure simulations, surgeons can experience partial or entire robotic procedures.
FOR MORE INFORMATION, VISIT www.simbionix.com

NATURAL PRODUCTS FOR PREGNANCY
Fairhaven Health’s PregnancyPlus Line includes Prenatal Vitamins, Omega-3, and Cal-Mag (calcium, magnesium, and vitamin D3) natural supplements. Fairhaven Health claims that the Belly Rest Pregnancy Pillow provides back-pain relief during sleep. All products are BPA-free, with no artificial flavors, colors, or preservatives.
FOR MORE INFORMATION, VISIT www.fairhavenhealth.com

OPTIMIZE OFFICE WORKFLOW
Comtron offers Medgen EHR, a customized electronic health record (EHR) system. Comtron claims the Medgen EHR system is easily adaptable and is cost-effective by offering increased efficiency, decreased overhead, and improved patient care.
FOR MORE INFORMATION, VISIT www.medgenehr.com

VISUALIZATION ENHANCEMENT TOOLS
Karl Storz launched the Image1^® SPIES^tm visualization enhancement modular system for endoscopic surgery. SPIES, an acronym for Storz Professional Image Enhancement System, has three components: video software, a modular camera control unit, and a graphic user interface. Karl Storz reports that the modular design allows customization to individual needs. The combined camera heads and visualization tools offer homogenous illumination and contrast enhancement.
FOR MORE INFORMATION, VISIT www.karlstorz.com

NONINVASIVE PRENATAL GENETIC BLOOD TEST
Synapse Diagnostics offers Materni T21 PLUS, a test for specific chromosomal conditions in a fetus that are associated with birth defects. Conducted on blood drawn from the mother as early as 10 weeks’ gestation, the test uses genomic sequencing. Synapse Diagnostics claims that this is the only test that not only detects abnormalities like Down syndrome but also reveals defects called “microdeletions” caused by a missing gene that are otherwise difficult to discover early in pregnancy.
FOR MORE INFORMATION, VISIT www.synapsediagnostics.com

NEW ULTRASOUND SYSTEM
Samsung Electronics America, Inc. has introduced the UGEO WS80A ultrasound system for ObGyn applications. Key features: 21.5"-wide LED monitor with touch panel, 5D technologies, FRV^tm (Feto Realistic View) with 3D visualization, and piezoelectric crystal design for high resolution. Samsung reports that the UGEO WS80A has improved gray scale and color with a more precise signal, speckle reduction, and edge and contrast enhancement.
FOR MORE INFORMATION, VISIT www.samsung.com/healthcare

SEAL & CUT TECHNOLOGY
Aesculap has expanded its line of Caiman 5 Seal and Cut Technology to include 24-cm and 44-cm lengths of vessel sealing devices in addition to its original 36-cm device. Aesculap claims that the extended jaw design provides uniform pressure distribution across a variety of tissue thicknesses. These bipolar electrosurgical RF energy instruments are intended for open and laparoscopic surgery.
FOR MORE INFORMATION, VISIT www.caimansurgery.com

DETECTING RUPTURED MEMBRANES
ROM Plus^®is a rapid qualitative test for in vitro detection of amniotic proteins in vaginal secretions of pregnant women for possible diagnosis of premature rupture of membranes (PROM). ROM Plus uses a monoclonal/polyclonal antibody approach to detect two amniotic proteins, AFP and PP12. Accurate and prompt diagnosis of PROM helps decrease or avoid serious complications for mother and fetus.
FOR MORE INFORMATION, VISIT www.clinicalinnovations.com

RELIZEN: NONHORMONAL TX FOR HOT FLASHES
RELIZEN^® is a patented, nonhormonal therapy for the relief of hot flashes associated with menopause from JDS Therapeutics.New to the United States, Relizen has been used by women and physicians in Europe for more than 15 years, according to the manufacturer, and has clinical efficacy data established in a placebo-controlled trial published in Climacteric. The active ingredient is a non-estrogenic, purified Swedish pollen extract that has pollen allergens removed. The daily dose is 2 pills/day.
FOR MORE INFORMATION, VISIT www.relizen.com

RISK ASSESSMENT FOR SPORADIC BREAST CA
BREVAGenplus, from Phenogen Sciences, Inc, assesses clinical risk factors (Gail score) and genetic markers (SNP profile) to determine 5-year and lifetime risks of developing sporadic (nonhereditary) breast cancer. The test is for Caucasian, Hispanic, and African-American women, aged 35 years and older, who have not had breast cancer but have one or more risk factors for developing breast cancer.
FOR MORE INFORMATION, VISIT http://phenogensciences.com

3 NEW DEVICE LENGTHS FOR DISSECTION
Covidien has added 13-cm, 26-cm, and 48-cm lengths to its Sonicision^tm Cordless Ultrasonic Dissection Device portfolio. Covidien reports that Sonicision offers surgeons faster dissection with increased mobility without having to manage electrical cords. Single-use and reusable components available.
FOR MORE INFORMATION, VISIT www.covidien.com

ROBOTICS SIMULATOR
Simbionix has launched RobotiX Mentor, a comprehensive educational tool for surgeons of all levels to practice the skills required to perform robotic surgery. By using basic task modules and cross-specialty clinical procedure simulations, surgeons can experience partial or entire robotic procedures.
FOR MORE INFORMATION, VISIT www.simbionix.com

NATURAL PRODUCTS FOR PREGNANCY
Fairhaven Health’s PregnancyPlus Line includes Prenatal Vitamins, Omega-3, and Cal-Mag (calcium, magnesium, and vitamin D3) natural supplements. Fairhaven Health claims that the Belly Rest Pregnancy Pillow provides back-pain relief during sleep. All products are BPA-free, with no artificial flavors, colors, or preservatives.
FOR MORE INFORMATION, VISIT www.fairhavenhealth.com

OPTIMIZE OFFICE WORKFLOW
Comtron offers Medgen EHR, a customized electronic health record (EHR) system. Comtron claims the Medgen EHR system is easily adaptable and is cost-effective by offering increased efficiency, decreased overhead, and improved patient care.
FOR MORE INFORMATION, VISIT www.medgenehr.com

VISUALIZATION ENHANCEMENT TOOLS
Karl Storz launched the Image1^® SPIES^tm visualization enhancement modular system for endoscopic surgery. SPIES, an acronym for Storz Professional Image Enhancement System, has three components: video software, a modular camera control unit, and a graphic user interface. Karl Storz reports that the modular design allows customization to individual needs. The combined camera heads and visualization tools offer homogenous illumination and contrast enhancement.
FOR MORE INFORMATION, VISIT www.karlstorz.com

NONINVASIVE PRENATAL GENETIC BLOOD TEST
Synapse Diagnostics offers Materni T21 PLUS, a test for specific chromosomal conditions in a fetus that are associated with birth defects. Conducted on blood drawn from the mother as early as 10 weeks’ gestation, the test uses genomic sequencing. Synapse Diagnostics claims that this is the only test that not only detects abnormalities like Down syndrome but also reveals defects called “microdeletions” caused by a missing gene that are otherwise difficult to discover early in pregnancy.
FOR MORE INFORMATION, VISIT www.synapsediagnostics.com

NEW ULTRASOUND SYSTEM
Samsung Electronics America, Inc. has introduced the UGEO WS80A ultrasound system for ObGyn applications. Key features: 21.5"-wide LED monitor with touch panel, 5D technologies, FRV^tm (Feto Realistic View) with 3D visualization, and piezoelectric crystal design for high resolution. Samsung reports that the UGEO WS80A has improved gray scale and color with a more precise signal, speckle reduction, and edge and contrast enhancement.
FOR MORE INFORMATION, VISIT www.samsung.com/healthcare

SEAL & CUT TECHNOLOGY
Aesculap has expanded its line of Caiman 5 Seal and Cut Technology to include 24-cm and 44-cm lengths of vessel sealing devices in addition to its original 36-cm device. Aesculap claims that the extended jaw design provides uniform pressure distribution across a variety of tissue thicknesses. These bipolar electrosurgical RF energy instruments are intended for open and laparoscopic surgery.
FOR MORE INFORMATION, VISIT www.caimansurgery.com

DETECTING RUPTURED MEMBRANES
ROM Plus^®is a rapid qualitative test for in vitro detection of amniotic proteins in vaginal secretions of pregnant women for possible diagnosis of premature rupture of membranes (PROM). ROM Plus uses a monoclonal/polyclonal antibody approach to detect two amniotic proteins, AFP and PP12. Accurate and prompt diagnosis of PROM helps decrease or avoid serious complications for mother and fetus.
FOR MORE INFORMATION, VISIT www.clinicalinnovations.com