In 2014, the Society of Hospital Medicine endorsed the Interstate Medical Licensure Compact as a way to address divergent physician licensing requirements among states. The thrust of SHM’s reasoning was that differing licensing policies across state lines not only hinder the ability of hospitalists to quickly adjust staffing to meet the needs of hospitals and patients but also create extensive, costly, and often redundant administrative hurdles for individual hospitalists and hospital medicine groups. For hospitalists looking to relocate to another state, practice in multiple states, provide telemedicine services, or even take on some per diem work, the Interstate Medical Licensure Compact should be of great help.

To briefly summarize, states participating in the compact agree to share information with one another and work together in streamlining the licensing process. For example, the compact aims to reduce redundant licensing requirements by creating one place where physicians submit basic information such as their education credentials. The compact does not establish a national license; a license to practice medicine will still be issued by individual state medical boards. Physicians will still need to be licensed in the state where the patient is located, but the difference is that the process of obtaining a license will be streamlined significantly.

To join the Interstate Medical Licensure Compact, state legislatures must enact the compact into state law. Two years in, the compact is now being implemented in 12 states: Alabama, Idaho, Illinois, Iowa, Minnesota, Montana, Nevada, South Dakota, Utah, West Virginia, Wisconsin, and Wyoming. States where it has been introduced but not yet adopted include Alaska, Arizona, Colorado, Kansas, Maryland, Michigan, Mississippi, Nebraska, New Hampshire, Oklahoma, Pennsylvania, Rhode Island, Vermont, and Washington.

Licenses via the compact process are not currently being issued, but representatives from the 12 participating states have begun to formally meet and are working out the administrative procedures needed to begin expedited licensure processes. With a core group of states adopting and implementing the compact, it will be important for state officials to hear why adoption of the compact is important to physicians.

This presents an opportunity for hospitalists residing in holdout states to participate in some advocacy work at the state level—on their own, as a group, or even within one of SHM’s many state chapters. To find your local chapter and get involved, visit www.hospitalmedicine.org/chapters.

To assist, detailed information on the Interstate Medical Licensure Compact can be found at www.licenseportability.org, and SHM advocacy staff is available to address questions members may have about getting started. You can reach them via email at [email protected]. TH

Josh Boswell is SHM’s director of government affairs.

In 2014, the Society of Hospital Medicine endorsed the Interstate Medical Licensure Compact as a way to address divergent physician licensing requirements among states. The thrust of SHM’s reasoning was that differing licensing policies across state lines not only hinder the ability of hospitalists to quickly adjust staffing to meet the needs of hospitals and patients but also create extensive, costly, and often redundant administrative hurdles for individual hospitalists and hospital medicine groups. For hospitalists looking to relocate to another state, practice in multiple states, provide telemedicine services, or even take on some per diem work, the Interstate Medical Licensure Compact should be of great help.

To briefly summarize, states participating in the compact agree to share information with one another and work together in streamlining the licensing process. For example, the compact aims to reduce redundant licensing requirements by creating one place where physicians submit basic information such as their education credentials. The compact does not establish a national license; a license to practice medicine will still be issued by individual state medical boards. Physicians will still need to be licensed in the state where the patient is located, but the difference is that the process of obtaining a license will be streamlined significantly.

To join the Interstate Medical Licensure Compact, state legislatures must enact the compact into state law. Two years in, the compact is now being implemented in 12 states: Alabama, Idaho, Illinois, Iowa, Minnesota, Montana, Nevada, South Dakota, Utah, West Virginia, Wisconsin, and Wyoming. States where it has been introduced but not yet adopted include Alaska, Arizona, Colorado, Kansas, Maryland, Michigan, Mississippi, Nebraska, New Hampshire, Oklahoma, Pennsylvania, Rhode Island, Vermont, and Washington.

Licenses via the compact process are not currently being issued, but representatives from the 12 participating states have begun to formally meet and are working out the administrative procedures needed to begin expedited licensure processes. With a core group of states adopting and implementing the compact, it will be important for state officials to hear why adoption of the compact is important to physicians.

This presents an opportunity for hospitalists residing in holdout states to participate in some advocacy work at the state level—on their own, as a group, or even within one of SHM’s many state chapters. To find your local chapter and get involved, visit www.hospitalmedicine.org/chapters.

To assist, detailed information on the Interstate Medical Licensure Compact can be found at www.licenseportability.org, and SHM advocacy staff is available to address questions members may have about getting started. You can reach them via email at [email protected]. TH

Josh Boswell is SHM’s director of government affairs.

In 2014, the Society of Hospital Medicine endorsed the Interstate Medical Licensure Compact as a way to address divergent physician licensing requirements among states. The thrust of SHM’s reasoning was that differing licensing policies across state lines not only hinder the ability of hospitalists to quickly adjust staffing to meet the needs of hospitals and patients but also create extensive, costly, and often redundant administrative hurdles for individual hospitalists and hospital medicine groups. For hospitalists looking to relocate to another state, practice in multiple states, provide telemedicine services, or even take on some per diem work, the Interstate Medical Licensure Compact should be of great help.

To briefly summarize, states participating in the compact agree to share information with one another and work together in streamlining the licensing process. For example, the compact aims to reduce redundant licensing requirements by creating one place where physicians submit basic information such as their education credentials. The compact does not establish a national license; a license to practice medicine will still be issued by individual state medical boards. Physicians will still need to be licensed in the state where the patient is located, but the difference is that the process of obtaining a license will be streamlined significantly.

To join the Interstate Medical Licensure Compact, state legislatures must enact the compact into state law. Two years in, the compact is now being implemented in 12 states: Alabama, Idaho, Illinois, Iowa, Minnesota, Montana, Nevada, South Dakota, Utah, West Virginia, Wisconsin, and Wyoming. States where it has been introduced but not yet adopted include Alaska, Arizona, Colorado, Kansas, Maryland, Michigan, Mississippi, Nebraska, New Hampshire, Oklahoma, Pennsylvania, Rhode Island, Vermont, and Washington.

Licenses via the compact process are not currently being issued, but representatives from the 12 participating states have begun to formally meet and are working out the administrative procedures needed to begin expedited licensure processes. With a core group of states adopting and implementing the compact, it will be important for state officials to hear why adoption of the compact is important to physicians.

This presents an opportunity for hospitalists residing in holdout states to participate in some advocacy work at the state level—on their own, as a group, or even within one of SHM’s many state chapters. To find your local chapter and get involved, visit www.hospitalmedicine.org/chapters.

To assist, detailed information on the Interstate Medical Licensure Compact can be found at www.licenseportability.org, and SHM advocacy staff is available to address questions members may have about getting started. You can reach them via email at [email protected]. TH

Josh Boswell is SHM’s director of government affairs.

CMV infection

The US Food and Drug Administration (FDA) has approved the first cytomegalovirus (CMV) test for use in hematopoietic stem cell transplant (HSCT) recipients.

With this approval, the COBAS® AmpliPrep/COBAS® TaqMan® CMV Test is available for monitoring CMV treatment in all types of transplant patients in the US.

The test, which was developed by Roche, is an in vitro nucleic acid amplification test that quantitates CMV DNA in human plasma.

It is intended to aid the management of HSCT recipients and solid-organ transplant recipients who are undergoing anti-CMV therapy.

In this population, serial DNA measurements can be used to assess virological response to antiviral treatment. The results from the test must be interpreted within the context of all relevant clinical and laboratory findings.

The COBAS® AmpliPrep/COBAS® TaqMan® CMV Test is not intended for use as a screening test for the presence of CMV DNA in blood or blood products.

The test is designed for use on the automated COBAS® AmpliPrep/COBAS® TaqMan® System, an established platform for viral load monitoring of multiple infectious diseases.

The system combines the COBAS® AmpliPrep Instrument for automated sample preparation and the COBAS® TaqMan® Analyzer or the smaller COBAS® TaqMan® 48 Analyzer for automated real-time PCR amplification and detection.

The COBAS® AmpliPrep/COBAS® TaqMan® System has parallel processing with other molecular diagnostics assays targeting other diseases. Roche’s AmpErase enzyme is also included in each test and is designed to prevent cross-contamination of samples and labs.

CMV infection

The US Food and Drug Administration (FDA) has approved the first cytomegalovirus (CMV) test for use in hematopoietic stem cell transplant (HSCT) recipients.

With this approval, the COBAS® AmpliPrep/COBAS® TaqMan® CMV Test is available for monitoring CMV treatment in all types of transplant patients in the US.

The test, which was developed by Roche, is an in vitro nucleic acid amplification test that quantitates CMV DNA in human plasma.

It is intended to aid the management of HSCT recipients and solid-organ transplant recipients who are undergoing anti-CMV therapy.

In this population, serial DNA measurements can be used to assess virological response to antiviral treatment. The results from the test must be interpreted within the context of all relevant clinical and laboratory findings.

The COBAS® AmpliPrep/COBAS® TaqMan® CMV Test is not intended for use as a screening test for the presence of CMV DNA in blood or blood products.

The test is designed for use on the automated COBAS® AmpliPrep/COBAS® TaqMan® System, an established platform for viral load monitoring of multiple infectious diseases.

The system combines the COBAS® AmpliPrep Instrument for automated sample preparation and the COBAS® TaqMan® Analyzer or the smaller COBAS® TaqMan® 48 Analyzer for automated real-time PCR amplification and detection.

The COBAS® AmpliPrep/COBAS® TaqMan® System has parallel processing with other molecular diagnostics assays targeting other diseases. Roche’s AmpErase enzyme is also included in each test and is designed to prevent cross-contamination of samples and labs.

CMV infection

The US Food and Drug Administration (FDA) has approved the first cytomegalovirus (CMV) test for use in hematopoietic stem cell transplant (HSCT) recipients.

With this approval, the COBAS® AmpliPrep/COBAS® TaqMan® CMV Test is available for monitoring CMV treatment in all types of transplant patients in the US.

The test, which was developed by Roche, is an in vitro nucleic acid amplification test that quantitates CMV DNA in human plasma.

It is intended to aid the management of HSCT recipients and solid-organ transplant recipients who are undergoing anti-CMV therapy.

In this population, serial DNA measurements can be used to assess virological response to antiviral treatment. The results from the test must be interpreted within the context of all relevant clinical and laboratory findings.

The COBAS® AmpliPrep/COBAS® TaqMan® CMV Test is not intended for use as a screening test for the presence of CMV DNA in blood or blood products.

The test is designed for use on the automated COBAS® AmpliPrep/COBAS® TaqMan® System, an established platform for viral load monitoring of multiple infectious diseases.

The system combines the COBAS® AmpliPrep Instrument for automated sample preparation and the COBAS® TaqMan® Analyzer or the smaller COBAS® TaqMan® 48 Analyzer for automated real-time PCR amplification and detection.

The COBAS® AmpliPrep/COBAS® TaqMan® System has parallel processing with other molecular diagnostics assays targeting other diseases. Roche’s AmpErase enzyme is also included in each test and is designed to prevent cross-contamination of samples and labs.

Doctor and patient

Photo courtesy of NIH

Worrying about wasting their doctor’s time is stopping people from reporting symptoms that might be related to cancer, according to a small study published in the British Journal of General Practice.

The goal of the study was to determine why some people are more likely than others to worry about wasting a general practitioner’s (GP’s) time and delay reporting possible cancer symptoms.

“People worrying about wasting their doctor’s time is one of the challenges we need to tackle when thinking about trying to diagnose cancer earlier,” said study author Katriina Whitaker, PhD, of the University of Surrey in the UK.

“We need to get to the root of the problem and find out why people are feeling worried. Not a lot of work has been done on this so far. Our study draws attention to some reasons patients put off going to their GP to check out possible cancer symptoms.”

For this study, Dr Whitaker and her colleagues conducted interviews with subjects in London, South East England, and North West England.

The subjects were recruited from a sample of 2042 adults, age 50 and older, who completed a survey that included a list of “cancer alarm symptoms.”

Ultimately, the researchers interviewed 62 subjects who had reported symptoms at baseline, were still present at the 3-month follow-up, and had agreed to be contacted.

The interviews revealed a few reasons why subjects were hesitant to report symptoms to their GP.

Some subjects felt that long waiting times for appointments indicated GPs were very busy, so they shouldn’t bother making an appointment unless symptoms seemed very serious.

Other subjects felt that seeking help when their symptoms did not seem serious—ie, persistent, worsening, or life-threatening—was a waste of a doctor’s time.

Still other subjects were hesitant to seek help because their doctors had been dismissive about symptoms in the past.

On the other hand, subjects who reported positive interactions with GPs or good relationships with them were less worried about time-wasting.

And other subjects weren’t worried about wasting their doctor’s time because they think of GPs as fulfilling a service financed by taxpayers.

“We’ve all had times where we’ve wondered if we should go to see a GP, but getting unusual or persistent changes checked out is really important,” said Julie Sharp, head of health and patient information at Cancer Research UK, which funded this study.

“Worrying about wasting a GP’s time should not put people off. Doctors are there to help spot cancer symptoms early when treatment is more likely to be successful, and delaying a visit could save up bigger problems for later. So if you’ve noticed anything that isn’t normal for you, make an appointment to see your doctor.”

Doctor and patient

Photo courtesy of NIH

Worrying about wasting their doctor’s time is stopping people from reporting symptoms that might be related to cancer, according to a small study published in the British Journal of General Practice.

The goal of the study was to determine why some people are more likely than others to worry about wasting a general practitioner’s (GP’s) time and delay reporting possible cancer symptoms.

“People worrying about wasting their doctor’s time is one of the challenges we need to tackle when thinking about trying to diagnose cancer earlier,” said study author Katriina Whitaker, PhD, of the University of Surrey in the UK.

“We need to get to the root of the problem and find out why people are feeling worried. Not a lot of work has been done on this so far. Our study draws attention to some reasons patients put off going to their GP to check out possible cancer symptoms.”

For this study, Dr Whitaker and her colleagues conducted interviews with subjects in London, South East England, and North West England.

The subjects were recruited from a sample of 2042 adults, age 50 and older, who completed a survey that included a list of “cancer alarm symptoms.”

Ultimately, the researchers interviewed 62 subjects who had reported symptoms at baseline, were still present at the 3-month follow-up, and had agreed to be contacted.

The interviews revealed a few reasons why subjects were hesitant to report symptoms to their GP.

Some subjects felt that long waiting times for appointments indicated GPs were very busy, so they shouldn’t bother making an appointment unless symptoms seemed very serious.

Other subjects felt that seeking help when their symptoms did not seem serious—ie, persistent, worsening, or life-threatening—was a waste of a doctor’s time.

Still other subjects were hesitant to seek help because their doctors had been dismissive about symptoms in the past.

On the other hand, subjects who reported positive interactions with GPs or good relationships with them were less worried about time-wasting.

And other subjects weren’t worried about wasting their doctor’s time because they think of GPs as fulfilling a service financed by taxpayers.

“We’ve all had times where we’ve wondered if we should go to see a GP, but getting unusual or persistent changes checked out is really important,” said Julie Sharp, head of health and patient information at Cancer Research UK, which funded this study.

“Worrying about wasting a GP’s time should not put people off. Doctors are there to help spot cancer symptoms early when treatment is more likely to be successful, and delaying a visit could save up bigger problems for later. So if you’ve noticed anything that isn’t normal for you, make an appointment to see your doctor.”

Doctor and patient

Photo courtesy of NIH

Worrying about wasting their doctor’s time is stopping people from reporting symptoms that might be related to cancer, according to a small study published in the British Journal of General Practice.

The goal of the study was to determine why some people are more likely than others to worry about wasting a general practitioner’s (GP’s) time and delay reporting possible cancer symptoms.

“People worrying about wasting their doctor’s time is one of the challenges we need to tackle when thinking about trying to diagnose cancer earlier,” said study author Katriina Whitaker, PhD, of the University of Surrey in the UK.

“We need to get to the root of the problem and find out why people are feeling worried. Not a lot of work has been done on this so far. Our study draws attention to some reasons patients put off going to their GP to check out possible cancer symptoms.”

For this study, Dr Whitaker and her colleagues conducted interviews with subjects in London, South East England, and North West England.

The subjects were recruited from a sample of 2042 adults, age 50 and older, who completed a survey that included a list of “cancer alarm symptoms.”

Ultimately, the researchers interviewed 62 subjects who had reported symptoms at baseline, were still present at the 3-month follow-up, and had agreed to be contacted.

The interviews revealed a few reasons why subjects were hesitant to report symptoms to their GP.

Some subjects felt that long waiting times for appointments indicated GPs were very busy, so they shouldn’t bother making an appointment unless symptoms seemed very serious.

Other subjects felt that seeking help when their symptoms did not seem serious—ie, persistent, worsening, or life-threatening—was a waste of a doctor’s time.

Still other subjects were hesitant to seek help because their doctors had been dismissive about symptoms in the past.

On the other hand, subjects who reported positive interactions with GPs or good relationships with them were less worried about time-wasting.

And other subjects weren’t worried about wasting their doctor’s time because they think of GPs as fulfilling a service financed by taxpayers.

“We’ve all had times where we’ve wondered if we should go to see a GP, but getting unusual or persistent changes checked out is really important,” said Julie Sharp, head of health and patient information at Cancer Research UK, which funded this study.

“Worrying about wasting a GP’s time should not put people off. Doctors are there to help spot cancer symptoms early when treatment is more likely to be successful, and delaying a visit could save up bigger problems for later. So if you’ve noticed anything that isn’t normal for you, make an appointment to see your doctor.”

Red blood cells

Recent studies have suggested that roughly half of patients hospitalized with traumatic brain injuries (TBIs) are anemic, but it hasn’t been clear how the anemia affects patients’ recovery.

Now, researchers have found evidence suggesting that low hemoglobin levels can negatively influence the outcomes of patients with TBIs.

The team detailed this evidence in a paper published in World Neurosurgery.

“More research is needed to develop treatment protocols for anemic patients with traumatic brain injuries,” said study author N. Scott Litofsky, MD, of the University of Missouri School of Medicine in Columbia.

“There has been a lack of consensus among physicians regarding the relationship of anemia and traumatic brain injuries on a patient’s health. Because of this uncertainty, treatment protocols are unclear and inconsistent. Our observational study found that a patient’s outcome is worse when he or she is anemic.”

The researchers studied 939 TBI patients with anemia who were admitted to a Level I trauma center.

The team assessed the relationships between patients’ initial hemoglobin level and lowest hemoglobin level during hospitalization at threshold values of ≤7, ≤8, ≤9, and ≤10 g/dL relative to their Glasgow Outcome Score within a year of surgery.

The data suggested that both initial hemoglobin levels and lowest hemoglobin levels were independent predictors of poor outcome (P<0.0001).

For each increase in initial hemoglobin level of 1 g/dL, the odds of a patient achieving a good outcome increased by 32%. For each increase in lowest hemoglobin level of 1 g/dL, the probability of a good outcome increased by 35.6%.

Female patients had worse outcomes than male patients if their initial hemoglobin levels were between 7 g/dL and 8 g/dL (P<0.05).

And receiving a blood transfusion was associated with poorer outcomes at hemoglobin levels ≤9 g/dL and ≤10 g/dL (P<0.05) but not at the lower hemoglobin thresholds.

The researchers said these data suggest clinicians may want to consider giving blood transfusions in TBI patients with hemoglobin levels of 8 g/dL or lower.

However, Dr Litofsky noted that the purpose of this study was not to propose transfusion guidelines. It was to determine the effects of anemia on TBI outcomes.

“Now that we have shown that anemia affects a patient’s recovery, further studies are needed to determine the best way to correct it,” he said. “The ultimate goal of this research is to help patients recover more quickly from traumatic brain injuries.”

Red blood cells

Recent studies have suggested that roughly half of patients hospitalized with traumatic brain injuries (TBIs) are anemic, but it hasn’t been clear how the anemia affects patients’ recovery.

Now, researchers have found evidence suggesting that low hemoglobin levels can negatively influence the outcomes of patients with TBIs.

The team detailed this evidence in a paper published in World Neurosurgery.

“More research is needed to develop treatment protocols for anemic patients with traumatic brain injuries,” said study author N. Scott Litofsky, MD, of the University of Missouri School of Medicine in Columbia.

“There has been a lack of consensus among physicians regarding the relationship of anemia and traumatic brain injuries on a patient’s health. Because of this uncertainty, treatment protocols are unclear and inconsistent. Our observational study found that a patient’s outcome is worse when he or she is anemic.”

The researchers studied 939 TBI patients with anemia who were admitted to a Level I trauma center.

The team assessed the relationships between patients’ initial hemoglobin level and lowest hemoglobin level during hospitalization at threshold values of ≤7, ≤8, ≤9, and ≤10 g/dL relative to their Glasgow Outcome Score within a year of surgery.

The data suggested that both initial hemoglobin levels and lowest hemoglobin levels were independent predictors of poor outcome (P<0.0001).

For each increase in initial hemoglobin level of 1 g/dL, the odds of a patient achieving a good outcome increased by 32%. For each increase in lowest hemoglobin level of 1 g/dL, the probability of a good outcome increased by 35.6%.

Female patients had worse outcomes than male patients if their initial hemoglobin levels were between 7 g/dL and 8 g/dL (P<0.05).

And receiving a blood transfusion was associated with poorer outcomes at hemoglobin levels ≤9 g/dL and ≤10 g/dL (P<0.05) but not at the lower hemoglobin thresholds.

The researchers said these data suggest clinicians may want to consider giving blood transfusions in TBI patients with hemoglobin levels of 8 g/dL or lower.

However, Dr Litofsky noted that the purpose of this study was not to propose transfusion guidelines. It was to determine the effects of anemia on TBI outcomes.

“Now that we have shown that anemia affects a patient’s recovery, further studies are needed to determine the best way to correct it,” he said. “The ultimate goal of this research is to help patients recover more quickly from traumatic brain injuries.”

Red blood cells

Recent studies have suggested that roughly half of patients hospitalized with traumatic brain injuries (TBIs) are anemic, but it hasn’t been clear how the anemia affects patients’ recovery.

Now, researchers have found evidence suggesting that low hemoglobin levels can negatively influence the outcomes of patients with TBIs.

The team detailed this evidence in a paper published in World Neurosurgery.

“More research is needed to develop treatment protocols for anemic patients with traumatic brain injuries,” said study author N. Scott Litofsky, MD, of the University of Missouri School of Medicine in Columbia.

“There has been a lack of consensus among physicians regarding the relationship of anemia and traumatic brain injuries on a patient’s health. Because of this uncertainty, treatment protocols are unclear and inconsistent. Our observational study found that a patient’s outcome is worse when he or she is anemic.”

The researchers studied 939 TBI patients with anemia who were admitted to a Level I trauma center.

The team assessed the relationships between patients’ initial hemoglobin level and lowest hemoglobin level during hospitalization at threshold values of ≤7, ≤8, ≤9, and ≤10 g/dL relative to their Glasgow Outcome Score within a year of surgery.

The data suggested that both initial hemoglobin levels and lowest hemoglobin levels were independent predictors of poor outcome (P<0.0001).

For each increase in initial hemoglobin level of 1 g/dL, the odds of a patient achieving a good outcome increased by 32%. For each increase in lowest hemoglobin level of 1 g/dL, the probability of a good outcome increased by 35.6%.

Female patients had worse outcomes than male patients if their initial hemoglobin levels were between 7 g/dL and 8 g/dL (P<0.05).

And receiving a blood transfusion was associated with poorer outcomes at hemoglobin levels ≤9 g/dL and ≤10 g/dL (P<0.05) but not at the lower hemoglobin thresholds.

The researchers said these data suggest clinicians may want to consider giving blood transfusions in TBI patients with hemoglobin levels of 8 g/dL or lower.

However, Dr Litofsky noted that the purpose of this study was not to propose transfusion guidelines. It was to determine the effects of anemia on TBI outcomes.

“Now that we have shown that anemia affects a patient’s recovery, further studies are needed to determine the best way to correct it,” he said. “The ultimate goal of this research is to help patients recover more quickly from traumatic brain injuries.”

Antihemophilic factor

The source of factor VIII (FVIII) replacement therapy affects the risk of inhibitor development in previously untreated patients with severe hemophilia A, according to the SIPPET study.

The data indicated that receiving recombinant FVIII (rFVIII) is associated with a nearly 2-fold higher risk of developing inhibitory alloantibodies than receiving plasma-derived FVIII.

Flora Peyvandi, MD, PhD, of Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, Italy, and her colleagues reported this discovery in NEJM.

Dr Peyvandi previously presented results from the SIPPET at the 2015 ASH Annual Meeting.

The study included 251 patients (all males) who were younger than age 6 at enrollment. They had severe hemophilia A, negative inhibitor measurement at enrollment, and no or minimal exposure (less than 5 exposure days) to blood products.

The patients were randomized to either a single plasma-derived FVIII product containing von Willebrand factor (n=125) or a single rFVIII product (n=126). The treatment was at the discretion of the local physician.

Confounders—such as family history, previous exposure, and surgery—were equally distributed between the treatment arms. The same was true for the treatment type—on-demand, standard prophylaxis, etc.

Patients were treated for 50 exposure days, 3 years, or until inhibitor development. They were assessed every 3 to 5 exposure days in the first 20 exposure days, then every 10 exposure days or every 3 months and every 2 weeks during prophylaxis.

Results

The primary outcome was any FVIII inhibitor at titers ≥ 0.4 BU/mL. High-titer inhibitors (≥ 5 BU/mL) were a secondary outcome. Transient inhibitors were defined as those that spontaneously disappeared within 6 months.

Overall, 76 patients developed inhibitors, for a cumulative incidence of 35.4%. Fifty patients had high-titer inhibitors, for a cumulative incidence of 23.3%.

The cumulative incidence of all inhibitors was 44.5% (n=47) in the rFVIII arm and 26.8% (n=29) in the plasma-derived FVIII arm. The cumulative incidence of high-titer inhibitors was 28.4% (n=30) and 18.6% (n=20), respectively.

More than 73% of all inhibitors were non-transient in both arms.

By univariate Cox regression analysis, rFVIII was associated with an 87% higher incidence of inhibitors than plasma-derived FVIII (hazard ratio [HR]=1.87). And rFVIII was associated with a 69% higher incidence of high-titer inhibitors (HR=1.69).

A previous study published in NEJM in 2013 suggested that second-generation, full-length FVIII products are associated with an increased risk of inhibitor development when compared to third-generation FVIII products.

So Dr Peyvandi and her colleagues stopped using second-generation FVIII products during the course of the SIPPET study. And they adjusted their analysis to ensure their observations were not due to any confounding effects of the products.

After excluding second-generation, full-length rFVIII from their analysis, the researchers still observed an increased risk of inhibitor development with rFVIII. The HRs were 1.98 for all inhibitors and 2.59 for high-titer inhibitors.

Antihemophilic factor

The source of factor VIII (FVIII) replacement therapy affects the risk of inhibitor development in previously untreated patients with severe hemophilia A, according to the SIPPET study.

The data indicated that receiving recombinant FVIII (rFVIII) is associated with a nearly 2-fold higher risk of developing inhibitory alloantibodies than receiving plasma-derived FVIII.

Flora Peyvandi, MD, PhD, of Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, Italy, and her colleagues reported this discovery in NEJM.

Dr Peyvandi previously presented results from the SIPPET at the 2015 ASH Annual Meeting.

The study included 251 patients (all males) who were younger than age 6 at enrollment. They had severe hemophilia A, negative inhibitor measurement at enrollment, and no or minimal exposure (less than 5 exposure days) to blood products.

The patients were randomized to either a single plasma-derived FVIII product containing von Willebrand factor (n=125) or a single rFVIII product (n=126). The treatment was at the discretion of the local physician.

Confounders—such as family history, previous exposure, and surgery—were equally distributed between the treatment arms. The same was true for the treatment type—on-demand, standard prophylaxis, etc.

Patients were treated for 50 exposure days, 3 years, or until inhibitor development. They were assessed every 3 to 5 exposure days in the first 20 exposure days, then every 10 exposure days or every 3 months and every 2 weeks during prophylaxis.

Results

The primary outcome was any FVIII inhibitor at titers ≥ 0.4 BU/mL. High-titer inhibitors (≥ 5 BU/mL) were a secondary outcome. Transient inhibitors were defined as those that spontaneously disappeared within 6 months.

Overall, 76 patients developed inhibitors, for a cumulative incidence of 35.4%. Fifty patients had high-titer inhibitors, for a cumulative incidence of 23.3%.

The cumulative incidence of all inhibitors was 44.5% (n=47) in the rFVIII arm and 26.8% (n=29) in the plasma-derived FVIII arm. The cumulative incidence of high-titer inhibitors was 28.4% (n=30) and 18.6% (n=20), respectively.

More than 73% of all inhibitors were non-transient in both arms.

By univariate Cox regression analysis, rFVIII was associated with an 87% higher incidence of inhibitors than plasma-derived FVIII (hazard ratio [HR]=1.87). And rFVIII was associated with a 69% higher incidence of high-titer inhibitors (HR=1.69).

A previous study published in NEJM in 2013 suggested that second-generation, full-length FVIII products are associated with an increased risk of inhibitor development when compared to third-generation FVIII products.

So Dr Peyvandi and her colleagues stopped using second-generation FVIII products during the course of the SIPPET study. And they adjusted their analysis to ensure their observations were not due to any confounding effects of the products.

After excluding second-generation, full-length rFVIII from their analysis, the researchers still observed an increased risk of inhibitor development with rFVIII. The HRs were 1.98 for all inhibitors and 2.59 for high-titer inhibitors.

Antihemophilic factor

The source of factor VIII (FVIII) replacement therapy affects the risk of inhibitor development in previously untreated patients with severe hemophilia A, according to the SIPPET study.

The data indicated that receiving recombinant FVIII (rFVIII) is associated with a nearly 2-fold higher risk of developing inhibitory alloantibodies than receiving plasma-derived FVIII.

Flora Peyvandi, MD, PhD, of Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, Italy, and her colleagues reported this discovery in NEJM.

Dr Peyvandi previously presented results from the SIPPET at the 2015 ASH Annual Meeting.

The study included 251 patients (all males) who were younger than age 6 at enrollment. They had severe hemophilia A, negative inhibitor measurement at enrollment, and no or minimal exposure (less than 5 exposure days) to blood products.

The patients were randomized to either a single plasma-derived FVIII product containing von Willebrand factor (n=125) or a single rFVIII product (n=126). The treatment was at the discretion of the local physician.

Confounders—such as family history, previous exposure, and surgery—were equally distributed between the treatment arms. The same was true for the treatment type—on-demand, standard prophylaxis, etc.

Patients were treated for 50 exposure days, 3 years, or until inhibitor development. They were assessed every 3 to 5 exposure days in the first 20 exposure days, then every 10 exposure days or every 3 months and every 2 weeks during prophylaxis.

Results

The primary outcome was any FVIII inhibitor at titers ≥ 0.4 BU/mL. High-titer inhibitors (≥ 5 BU/mL) were a secondary outcome. Transient inhibitors were defined as those that spontaneously disappeared within 6 months.

Overall, 76 patients developed inhibitors, for a cumulative incidence of 35.4%. Fifty patients had high-titer inhibitors, for a cumulative incidence of 23.3%.

The cumulative incidence of all inhibitors was 44.5% (n=47) in the rFVIII arm and 26.8% (n=29) in the plasma-derived FVIII arm. The cumulative incidence of high-titer inhibitors was 28.4% (n=30) and 18.6% (n=20), respectively.

More than 73% of all inhibitors were non-transient in both arms.

By univariate Cox regression analysis, rFVIII was associated with an 87% higher incidence of inhibitors than plasma-derived FVIII (hazard ratio [HR]=1.87). And rFVIII was associated with a 69% higher incidence of high-titer inhibitors (HR=1.69).

A previous study published in NEJM in 2013 suggested that second-generation, full-length FVIII products are associated with an increased risk of inhibitor development when compared to third-generation FVIII products.

So Dr Peyvandi and her colleagues stopped using second-generation FVIII products during the course of the SIPPET study. And they adjusted their analysis to ensure their observations were not due to any confounding effects of the products.

After excluding second-generation, full-length rFVIII from their analysis, the researchers still observed an increased risk of inhibitor development with rFVIII. The HRs were 1.98 for all inhibitors and 2.59 for high-titer inhibitors.

PRACTICE CHANGER
Consider treating nondiabetic patients ages 50 and older to a systolic blood pressure (SBP) target < 120 mm Hg (as compared to < 140 mm Hg) when the benefits—lower rates of fatal and nonfatal cardiovascular (CV) events and death from any cause—are likely to outweigh the risks from possible additional medication.¹

Strength of Recommendation
B: Based on a single, good-quality randomized controlled trial (RCT). ¹

A 55-year-old man with hypertension and stage 3 chronic kidney disease (CKD) presents for routine care. His blood pressure is 135/85 mm Hg, and he is currently taking lisinopril 40 mg/d. Should you increase his antihypertensive ­regimen?

Hypertension is common and leads to significant morbidity and mortality, but pharmacologic treatment reduces incidence of stroke by 35% to 40%, myocardial infarction (MI) by 15% to 25%, and heart failure by up to ­64%.­^2-4 Specific blood pressure targets for defined populations continue to be studied.

The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial found that more intensive BP targets did not reduce the rate of major CV events in patients with diabetes, but the study may have been underpowered.⁵ The members of the Eighth Joint National Committee (JNC 8) recommended treating patients older than 60 to BP goals < 150/90 mm Hg.⁶ This was based on evidence from six RCTs, but there remains debate—even among the JNC 8 committee members—as to appropriate BP goals in patients of any age without CV disease who have BP measurements of 140-159/90-99 mm Hg. ^7-13

Continue for the study summary >>

STUDY SUMMARY
Treating to SBP < 120 mm Hg lowers mortality
The Systolic Blood Pressure Intervention Trial (SPRINT) was a multicenter RCT designed to determine if treating to lower SBP targets in nondiabetic patients at high risk for CV events improves outcomes, compared with standard care. Patients were at least 50, had an SBP of 130 to 180 mm Hg, and were at increased CV risk; the last was defined as clinical or subclinical CV disease other than stroke; CKD with a glomerular filtration rate (GFR) of 20 to 60 mL/min/1.73 m²; 10-year risk for CV disease > 15% on Framingham risk score; or age 75 or older. Patients with diabetes, prior stroke, polycystic kidney disease, significant proteinuria or symptomatic heart failure within the past six months, or left ventricular ejection fraction < 35% were excluded.¹

Patients (N = 9,361) were randomly assigned to an SBP target < 120 mm Hg in the intensive group or < 140 mm Hg in the standard treatment group, in an open-label design. Allocation was concealed. The study protocol encouraged, but did not require, the use of thiazide-type diuretics, loop diuretics (for those with advanced renal disease), ACE inhibitors or angiotensin receptor blockers, calcium channel blockers, and ß-blockers. Clinicians could add other agents as needed. All major classes of antihypertensives were used.

Medication dosing adjustments were based on the average of three BP measurements taken with an automated measurement system with the patient seated after 5 minutes of quiet rest. Target SBP in the standard therapy group was 135 to 139 mm Hg. Medication dosages were lowered if SBP was < 130 mm Hg at a single visit or < 135 mm Hg at two consecutive visits.¹

The primary composite outcome included the first occurrence of MI, acute coronary syndrome, stroke, heart failure, or death from CV causes. Secondary outcomes were the individual components of the primary composite outcome; death from any cause; and the composite of the primary outcome or death from any cause.¹

Study halted early. The study was stopped early due to significantly lower rates of the primary outcome in the intensive therapy group versus the standard therapy group (1.65% vs 2.19% per year, respectively; hazard ratio [HR], 0.75 with intensive treatment). The resulting median follow-up time was 3.26 years.¹ This corresponds to a 25% lower relative risk for the primary outcome, with a decrease in event rates from 6.8% to 5.2% over the trial period. All-cause mortality was also lower in the intensive therapy group: 3.4% vs 4.5% (HR, 0.73).

The number needed to treat (NNT) over 3.26 years to prevent a primary outcome event, death from any cause, and death from CV causes was 61, 90, and 172, respectively. Serious adverse events occurred more frequently in the intensive therapy group than in the standard therapy group (38.3% vs 37.1%; HR, 1.04), with a number needed to harm (NNH) of 46 over the study period.¹ 

Rates of serious adverse events that were identified as likely associated with the intervention were 4.7% vs 2.5%, respectively. Hypotension, syncope, electrolyte abnormalities, and acute kidney injury/acute renal failure reached statistical significance. The incidence of bradycardia and injurious falls, although higher in the intensive treatment group, did not reach statistical significance. In the subgroup of patients 75 or older, 48% in each study group experienced a serious adverse event.¹

Throughout the study, mean SBP was 121.5 mm Hg in the intensive therapy group and 134.6 mm Hg in the standard treatment group. Patients in the intensive therapy group required, on average, one additional BP medication, compared to those in the standard treatment group (2.8 vs 1.8, respectively).¹

Continue for what's new >>

WHAT’S NEW
Lower SBP produces mortality benefits in those younger, and older, than 75
This trial builds on a body of evidence that shows the advantages of lowering SBP to < 150 mm Hg^7,11,12 by demonstrating benefits, including reduced all-cause mortality, for lower SBP targets in nondiabetic patients at high risk for CV disease. The SPRINT trial also showed that the benefits of intensive therapy remained true in a subgroup of patients 75 or older.

The incidence of the primary outcome in the cohort 75 or older receiving intensive therapy was 7.7%, compared with 10.9% for those receiving standard therapy (HR, 0.67; NNT, 31). All-cause mortality was also lower in the intensive therapy group than in the standard therapy group among patients 75 or older: 5.5% vs 8.04% (HR, 0.68; NNT, 38).¹

CAVEATS
Many do not benefit from—or are harmed by—increased medication
The absolute risk reduction for the primary outcome is 1.6%, meaning 98.4% of patients receiving more intensive treatment will not benefit. In a group of 1,000 patients, an estimated 16 patients will benefit, 22 patients will be seriously harmed, and 962 patients will experience neither benefit nor harm.¹⁴ The difference between how BP was measured in this trial (an average of three readings after the patient had rested for 5 minutes) and what occurs typically in clinical practice could potentially lead to overtreatment in a “real world” setting.

Also, reducing antihypertensive therapies when the SBP was about 130 to 135 mm Hg in the standard therapy group likely exaggerated the difference in outcomes between the intensive and standard therapy groups; this is neither routine nor recommended in clinical practice.⁶ Finally, the trial specifically studied nondiabetic patients at high risk for CV disease who were 50 or older, limiting generalizability to other populations.

CHALLENGES TO IMPLEMENTATION
Who will benefit/who can achieve intensive SBP goals?
Identifying patients most likely to benefit from more intensive BP targets remains challenging. The SPRINT trial showed a mortality benefit, but at a cost of increased morbidity.^1,14 Caution should be exercised particularly in the subgroup of patients 75 or older. Despite a lower NNT than the rest of the study population, this group experienced serious adverse events more frequently. Also, this particular cohort of volunteers may not be representative of those 75 or older in the general population.

Additionally, achieving intensive SBP goals can be challenging. In the SPRINT trial, only half of the intensive target group achieved an SBP < 120 mm Hg.¹ And in a 2011-2012 National Health and Nutrition Examination Survey, only 52% of patients in the general population achieved a BP target < 140/90 mm Hg.¹⁵ Lower mor­bidity and mortality should remain the ultimate goals in the management of hypertension, requiring clinicians to carefully assess an individual patient’s likelihood of benefit versus harm.

REFERENCES
1. Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103-2116.
2. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.
3. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials.Lancet. 2000;356:1955-1964.
4. Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA. 1997;277:739-745.
5. Margolis KL, O’Connor PJ, Morgan TM, et al. Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: the ACCORD randomized trial. Diabetes Care. 2014;37:1721-1728.
6. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).JAMA. 2014;311:507-520.
7. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older.N Engl J Med. 2008;358:1887-1898.
8. Verdecchia P, Staessen JA, Angeli F, et al. Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial. Lancet. 2009;374:525-533.
9. JATOS Study Group. Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertens Res. 2008;31:2115-2127.
10. Ogihara T, Saruta T, Rakugi H, et al. Target blood pressure for treatment of isolated systolic hypertension in the elderly: valsartan in elderly isolated systolic hypertension study. Hypertension. 2010;56:196-202.
11. Staessen JA, Fagard R, Thijs L, et al; the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension.Lancet. 1997;350:757-764.
12. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255-3264.
13. Cundiff DK, Gueyffier F, Wright JM. Guidelines for managing high blood pressure. JAMA. 2014;312:294.
14. Ortiz E, James PA. Let’s not SPRINT to judgment about new blood pressure goals. Ann Intern Med. 2016 Feb 23. [Epub ahead of print]
15. Nwankwo T, Yoon SS, Burt V, et al. Hypertension among adults in the United States: National Health and Nutrition Examination Survey, 2011-2012. NCHS Data Brief. 2013;1-8.

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

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(5):342-344.

PRACTICE CHANGER
Consider treating nondiabetic patients ages 50 and older to a systolic blood pressure (SBP) target < 120 mm Hg (as compared to < 140 mm Hg) when the benefits—lower rates of fatal and nonfatal cardiovascular (CV) events and death from any cause—are likely to outweigh the risks from possible additional medication.¹

Strength of Recommendation
B: Based on a single, good-quality randomized controlled trial (RCT). ¹

A 55-year-old man with hypertension and stage 3 chronic kidney disease (CKD) presents for routine care. His blood pressure is 135/85 mm Hg, and he is currently taking lisinopril 40 mg/d. Should you increase his antihypertensive ­regimen?

Hypertension is common and leads to significant morbidity and mortality, but pharmacologic treatment reduces incidence of stroke by 35% to 40%, myocardial infarction (MI) by 15% to 25%, and heart failure by up to ­64%.­^2-4 Specific blood pressure targets for defined populations continue to be studied.

The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial found that more intensive BP targets did not reduce the rate of major CV events in patients with diabetes, but the study may have been underpowered.⁵ The members of the Eighth Joint National Committee (JNC 8) recommended treating patients older than 60 to BP goals < 150/90 mm Hg.⁶ This was based on evidence from six RCTs, but there remains debate—even among the JNC 8 committee members—as to appropriate BP goals in patients of any age without CV disease who have BP measurements of 140-159/90-99 mm Hg. ^7-13

Continue for the study summary >>

STUDY SUMMARY
Treating to SBP < 120 mm Hg lowers mortality
The Systolic Blood Pressure Intervention Trial (SPRINT) was a multicenter RCT designed to determine if treating to lower SBP targets in nondiabetic patients at high risk for CV events improves outcomes, compared with standard care. Patients were at least 50, had an SBP of 130 to 180 mm Hg, and were at increased CV risk; the last was defined as clinical or subclinical CV disease other than stroke; CKD with a glomerular filtration rate (GFR) of 20 to 60 mL/min/1.73 m²; 10-year risk for CV disease > 15% on Framingham risk score; or age 75 or older. Patients with diabetes, prior stroke, polycystic kidney disease, significant proteinuria or symptomatic heart failure within the past six months, or left ventricular ejection fraction < 35% were excluded.¹

Patients (N = 9,361) were randomly assigned to an SBP target < 120 mm Hg in the intensive group or < 140 mm Hg in the standard treatment group, in an open-label design. Allocation was concealed. The study protocol encouraged, but did not require, the use of thiazide-type diuretics, loop diuretics (for those with advanced renal disease), ACE inhibitors or angiotensin receptor blockers, calcium channel blockers, and ß-blockers. Clinicians could add other agents as needed. All major classes of antihypertensives were used.

Medication dosing adjustments were based on the average of three BP measurements taken with an automated measurement system with the patient seated after 5 minutes of quiet rest. Target SBP in the standard therapy group was 135 to 139 mm Hg. Medication dosages were lowered if SBP was < 130 mm Hg at a single visit or < 135 mm Hg at two consecutive visits.¹

The primary composite outcome included the first occurrence of MI, acute coronary syndrome, stroke, heart failure, or death from CV causes. Secondary outcomes were the individual components of the primary composite outcome; death from any cause; and the composite of the primary outcome or death from any cause.¹

Study halted early. The study was stopped early due to significantly lower rates of the primary outcome in the intensive therapy group versus the standard therapy group (1.65% vs 2.19% per year, respectively; hazard ratio [HR], 0.75 with intensive treatment). The resulting median follow-up time was 3.26 years.¹ This corresponds to a 25% lower relative risk for the primary outcome, with a decrease in event rates from 6.8% to 5.2% over the trial period. All-cause mortality was also lower in the intensive therapy group: 3.4% vs 4.5% (HR, 0.73).

The number needed to treat (NNT) over 3.26 years to prevent a primary outcome event, death from any cause, and death from CV causes was 61, 90, and 172, respectively. Serious adverse events occurred more frequently in the intensive therapy group than in the standard therapy group (38.3% vs 37.1%; HR, 1.04), with a number needed to harm (NNH) of 46 over the study period.¹ 

Rates of serious adverse events that were identified as likely associated with the intervention were 4.7% vs 2.5%, respectively. Hypotension, syncope, electrolyte abnormalities, and acute kidney injury/acute renal failure reached statistical significance. The incidence of bradycardia and injurious falls, although higher in the intensive treatment group, did not reach statistical significance. In the subgroup of patients 75 or older, 48% in each study group experienced a serious adverse event.¹

Throughout the study, mean SBP was 121.5 mm Hg in the intensive therapy group and 134.6 mm Hg in the standard treatment group. Patients in the intensive therapy group required, on average, one additional BP medication, compared to those in the standard treatment group (2.8 vs 1.8, respectively).¹

Continue for what's new >>

WHAT’S NEW
Lower SBP produces mortality benefits in those younger, and older, than 75
This trial builds on a body of evidence that shows the advantages of lowering SBP to < 150 mm Hg^7,11,12 by demonstrating benefits, including reduced all-cause mortality, for lower SBP targets in nondiabetic patients at high risk for CV disease. The SPRINT trial also showed that the benefits of intensive therapy remained true in a subgroup of patients 75 or older.

The incidence of the primary outcome in the cohort 75 or older receiving intensive therapy was 7.7%, compared with 10.9% for those receiving standard therapy (HR, 0.67; NNT, 31). All-cause mortality was also lower in the intensive therapy group than in the standard therapy group among patients 75 or older: 5.5% vs 8.04% (HR, 0.68; NNT, 38).¹

CAVEATS
Many do not benefit from—or are harmed by—increased medication
The absolute risk reduction for the primary outcome is 1.6%, meaning 98.4% of patients receiving more intensive treatment will not benefit. In a group of 1,000 patients, an estimated 16 patients will benefit, 22 patients will be seriously harmed, and 962 patients will experience neither benefit nor harm.¹⁴ The difference between how BP was measured in this trial (an average of three readings after the patient had rested for 5 minutes) and what occurs typically in clinical practice could potentially lead to overtreatment in a “real world” setting.

Also, reducing antihypertensive therapies when the SBP was about 130 to 135 mm Hg in the standard therapy group likely exaggerated the difference in outcomes between the intensive and standard therapy groups; this is neither routine nor recommended in clinical practice.⁶ Finally, the trial specifically studied nondiabetic patients at high risk for CV disease who were 50 or older, limiting generalizability to other populations.

CHALLENGES TO IMPLEMENTATION
Who will benefit/who can achieve intensive SBP goals?
Identifying patients most likely to benefit from more intensive BP targets remains challenging. The SPRINT trial showed a mortality benefit, but at a cost of increased morbidity.^1,14 Caution should be exercised particularly in the subgroup of patients 75 or older. Despite a lower NNT than the rest of the study population, this group experienced serious adverse events more frequently. Also, this particular cohort of volunteers may not be representative of those 75 or older in the general population.

Additionally, achieving intensive SBP goals can be challenging. In the SPRINT trial, only half of the intensive target group achieved an SBP < 120 mm Hg.¹ And in a 2011-2012 National Health and Nutrition Examination Survey, only 52% of patients in the general population achieved a BP target < 140/90 mm Hg.¹⁵ Lower mor­bidity and mortality should remain the ultimate goals in the management of hypertension, requiring clinicians to carefully assess an individual patient’s likelihood of benefit versus harm.

REFERENCES
1. Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103-2116.
2. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.
3. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials.Lancet. 2000;356:1955-1964.
4. Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA. 1997;277:739-745.
5. Margolis KL, O’Connor PJ, Morgan TM, et al. Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: the ACCORD randomized trial. Diabetes Care. 2014;37:1721-1728.
6. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).JAMA. 2014;311:507-520.
7. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older.N Engl J Med. 2008;358:1887-1898.
8. Verdecchia P, Staessen JA, Angeli F, et al. Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial. Lancet. 2009;374:525-533.
9. JATOS Study Group. Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertens Res. 2008;31:2115-2127.
10. Ogihara T, Saruta T, Rakugi H, et al. Target blood pressure for treatment of isolated systolic hypertension in the elderly: valsartan in elderly isolated systolic hypertension study. Hypertension. 2010;56:196-202.
11. Staessen JA, Fagard R, Thijs L, et al; the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension.Lancet. 1997;350:757-764.
12. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255-3264.
13. Cundiff DK, Gueyffier F, Wright JM. Guidelines for managing high blood pressure. JAMA. 2014;312:294.
14. Ortiz E, James PA. Let’s not SPRINT to judgment about new blood pressure goals. Ann Intern Med. 2016 Feb 23. [Epub ahead of print]
15. Nwankwo T, Yoon SS, Burt V, et al. Hypertension among adults in the United States: National Health and Nutrition Examination Survey, 2011-2012. NCHS Data Brief. 2013;1-8.

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

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(5):342-344.

PRACTICE CHANGER
Consider treating nondiabetic patients ages 50 and older to a systolic blood pressure (SBP) target < 120 mm Hg (as compared to < 140 mm Hg) when the benefits—lower rates of fatal and nonfatal cardiovascular (CV) events and death from any cause—are likely to outweigh the risks from possible additional medication.¹

Strength of Recommendation
B: Based on a single, good-quality randomized controlled trial (RCT). ¹

A 55-year-old man with hypertension and stage 3 chronic kidney disease (CKD) presents for routine care. His blood pressure is 135/85 mm Hg, and he is currently taking lisinopril 40 mg/d. Should you increase his antihypertensive ­regimen?

Hypertension is common and leads to significant morbidity and mortality, but pharmacologic treatment reduces incidence of stroke by 35% to 40%, myocardial infarction (MI) by 15% to 25%, and heart failure by up to ­64%.­^2-4 Specific blood pressure targets for defined populations continue to be studied.

The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial found that more intensive BP targets did not reduce the rate of major CV events in patients with diabetes, but the study may have been underpowered.⁵ The members of the Eighth Joint National Committee (JNC 8) recommended treating patients older than 60 to BP goals < 150/90 mm Hg.⁶ This was based on evidence from six RCTs, but there remains debate—even among the JNC 8 committee members—as to appropriate BP goals in patients of any age without CV disease who have BP measurements of 140-159/90-99 mm Hg. ^7-13

Continue for the study summary >>

STUDY SUMMARY
Treating to SBP < 120 mm Hg lowers mortality
The Systolic Blood Pressure Intervention Trial (SPRINT) was a multicenter RCT designed to determine if treating to lower SBP targets in nondiabetic patients at high risk for CV events improves outcomes, compared with standard care. Patients were at least 50, had an SBP of 130 to 180 mm Hg, and were at increased CV risk; the last was defined as clinical or subclinical CV disease other than stroke; CKD with a glomerular filtration rate (GFR) of 20 to 60 mL/min/1.73 m²; 10-year risk for CV disease > 15% on Framingham risk score; or age 75 or older. Patients with diabetes, prior stroke, polycystic kidney disease, significant proteinuria or symptomatic heart failure within the past six months, or left ventricular ejection fraction < 35% were excluded.¹

Patients (N = 9,361) were randomly assigned to an SBP target < 120 mm Hg in the intensive group or < 140 mm Hg in the standard treatment group, in an open-label design. Allocation was concealed. The study protocol encouraged, but did not require, the use of thiazide-type diuretics, loop diuretics (for those with advanced renal disease), ACE inhibitors or angiotensin receptor blockers, calcium channel blockers, and ß-blockers. Clinicians could add other agents as needed. All major classes of antihypertensives were used.

Medication dosing adjustments were based on the average of three BP measurements taken with an automated measurement system with the patient seated after 5 minutes of quiet rest. Target SBP in the standard therapy group was 135 to 139 mm Hg. Medication dosages were lowered if SBP was < 130 mm Hg at a single visit or < 135 mm Hg at two consecutive visits.¹

The primary composite outcome included the first occurrence of MI, acute coronary syndrome, stroke, heart failure, or death from CV causes. Secondary outcomes were the individual components of the primary composite outcome; death from any cause; and the composite of the primary outcome or death from any cause.¹

Study halted early. The study was stopped early due to significantly lower rates of the primary outcome in the intensive therapy group versus the standard therapy group (1.65% vs 2.19% per year, respectively; hazard ratio [HR], 0.75 with intensive treatment). The resulting median follow-up time was 3.26 years.¹ This corresponds to a 25% lower relative risk for the primary outcome, with a decrease in event rates from 6.8% to 5.2% over the trial period. All-cause mortality was also lower in the intensive therapy group: 3.4% vs 4.5% (HR, 0.73).

The number needed to treat (NNT) over 3.26 years to prevent a primary outcome event, death from any cause, and death from CV causes was 61, 90, and 172, respectively. Serious adverse events occurred more frequently in the intensive therapy group than in the standard therapy group (38.3% vs 37.1%; HR, 1.04), with a number needed to harm (NNH) of 46 over the study period.¹ 

Rates of serious adverse events that were identified as likely associated with the intervention were 4.7% vs 2.5%, respectively. Hypotension, syncope, electrolyte abnormalities, and acute kidney injury/acute renal failure reached statistical significance. The incidence of bradycardia and injurious falls, although higher in the intensive treatment group, did not reach statistical significance. In the subgroup of patients 75 or older, 48% in each study group experienced a serious adverse event.¹

Throughout the study, mean SBP was 121.5 mm Hg in the intensive therapy group and 134.6 mm Hg in the standard treatment group. Patients in the intensive therapy group required, on average, one additional BP medication, compared to those in the standard treatment group (2.8 vs 1.8, respectively).¹

Continue for what's new >>

WHAT’S NEW
Lower SBP produces mortality benefits in those younger, and older, than 75
This trial builds on a body of evidence that shows the advantages of lowering SBP to < 150 mm Hg^7,11,12 by demonstrating benefits, including reduced all-cause mortality, for lower SBP targets in nondiabetic patients at high risk for CV disease. The SPRINT trial also showed that the benefits of intensive therapy remained true in a subgroup of patients 75 or older.

The incidence of the primary outcome in the cohort 75 or older receiving intensive therapy was 7.7%, compared with 10.9% for those receiving standard therapy (HR, 0.67; NNT, 31). All-cause mortality was also lower in the intensive therapy group than in the standard therapy group among patients 75 or older: 5.5% vs 8.04% (HR, 0.68; NNT, 38).¹

CAVEATS
Many do not benefit from—or are harmed by—increased medication
The absolute risk reduction for the primary outcome is 1.6%, meaning 98.4% of patients receiving more intensive treatment will not benefit. In a group of 1,000 patients, an estimated 16 patients will benefit, 22 patients will be seriously harmed, and 962 patients will experience neither benefit nor harm.¹⁴ The difference between how BP was measured in this trial (an average of three readings after the patient had rested for 5 minutes) and what occurs typically in clinical practice could potentially lead to overtreatment in a “real world” setting.

Also, reducing antihypertensive therapies when the SBP was about 130 to 135 mm Hg in the standard therapy group likely exaggerated the difference in outcomes between the intensive and standard therapy groups; this is neither routine nor recommended in clinical practice.⁶ Finally, the trial specifically studied nondiabetic patients at high risk for CV disease who were 50 or older, limiting generalizability to other populations.

CHALLENGES TO IMPLEMENTATION
Who will benefit/who can achieve intensive SBP goals?
Identifying patients most likely to benefit from more intensive BP targets remains challenging. The SPRINT trial showed a mortality benefit, but at a cost of increased morbidity.^1,14 Caution should be exercised particularly in the subgroup of patients 75 or older. Despite a lower NNT than the rest of the study population, this group experienced serious adverse events more frequently. Also, this particular cohort of volunteers may not be representative of those 75 or older in the general population.

Additionally, achieving intensive SBP goals can be challenging. In the SPRINT trial, only half of the intensive target group achieved an SBP < 120 mm Hg.¹ And in a 2011-2012 National Health and Nutrition Examination Survey, only 52% of patients in the general population achieved a BP target < 140/90 mm Hg.¹⁵ Lower mor­bidity and mortality should remain the ultimate goals in the management of hypertension, requiring clinicians to carefully assess an individual patient’s likelihood of benefit versus harm.

REFERENCES
1. Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103-2116.
2. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.
3. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials.Lancet. 2000;356:1955-1964.
4. Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA. 1997;277:739-745.
5. Margolis KL, O’Connor PJ, Morgan TM, et al. Outcomes of combined cardiovascular risk factor management strategies in type 2 diabetes: the ACCORD randomized trial. Diabetes Care. 2014;37:1721-1728.
6. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).JAMA. 2014;311:507-520.
7. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older.N Engl J Med. 2008;358:1887-1898.
8. Verdecchia P, Staessen JA, Angeli F, et al. Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial. Lancet. 2009;374:525-533.
9. JATOS Study Group. Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertens Res. 2008;31:2115-2127.
10. Ogihara T, Saruta T, Rakugi H, et al. Target blood pressure for treatment of isolated systolic hypertension in the elderly: valsartan in elderly isolated systolic hypertension study. Hypertension. 2010;56:196-202.
11. Staessen JA, Fagard R, Thijs L, et al; the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension.Lancet. 1997;350:757-764.
12. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255-3264.
13. Cundiff DK, Gueyffier F, Wright JM. Guidelines for managing high blood pressure. JAMA. 2014;312:294.
14. Ortiz E, James PA. Let’s not SPRINT to judgment about new blood pressure goals. Ann Intern Med. 2016 Feb 23. [Epub ahead of print]
15. Nwankwo T, Yoon SS, Burt V, et al. Hypertension among adults in the United States: National Health and Nutrition Examination Survey, 2011-2012. NCHS Data Brief. 2013;1-8.

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

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(5):342-344.

Cardiovascular disease (CVD) is the leading cause of death in the United States. CVD-related diseases affect 83.6 million people in the US and are responsible for almost 800,000 deaths annually.¹ The myriad underlying causes for these disorders range from inadequate lifestyle management to genetic abnormalities. One genetically determined abnormality is lipoprotein(a), or Lp(a).^2-4

It is estimated that 25% of the US population has elevated Lp(a) levels (> 30 mg/dL) that are clinically significant.⁵ Lp(a) is recognized as an independent risk factor for CVD, stroke, retinal artery occlusions, and restenosis of vein grafts.^2-5

Regardless of practice type, clinicians at some point in their career will see a “vasculopath.” Many of these patients have undiagnosed familial hypercholesterolemia, which affects 1 in 200 to 300 patients in the US and manifests with LDL cholesterol (LDL-C) levels ≥ 190 mg/dL.^6-8 Other patients may have CVD with relatively “normal” traditional lipids, more aggressive premature disease, and/or progressive disease despite “usual therapy.”

As clinical lipid specialists working both in cardiology and endocrinology, the authors find the lack of evaluation for additional abnormalities in high-risk patients to be quite disturbing. The patient most commonly seen with the Lp(a) abnormality is one with CVD onset approximately one decade earlier than expected, along with a family history of premature CVD or closure of recently placed stents. Unfortunately, this may result in disease in the second or third decade for men and third or fourth decade for women.

Of course, CVD can leave patients with less productive lives and increase the burden to the health care system and to society. A positive outcome of identification of this apolipoprotein abnormality is that it may prompt evaluation of other family members prior to the inception of vascular disease. When it is identified in the asymptomatic, disease-free patient, aggressive risk reduction—in the form of lifestyle management and medication—may delay or prevent disease onset.

Continue for identification of the problem >>

Identification of the problem
Office visits seldom include a thorough and complete patient history. A “good” family history should include first-degree relatives. Time-constrained practi­tioners may take a rudimentary family history of immediate relatives when a pedigree of the patient would be more appropriate.

Pedigree assessment offers a more specific picture of disease in families and identifies prevalence and incidence. Busy clinicians could have patients use an online resource to generate their own family pedigree. Or, as in most practices, a medical assistant or other appropriate office staff could initiate the process in the chart.

Patients with premature or advanced disease and significant family history need further investigation. A suspect history would include multiple family members with disease earlier in life than expected and perhaps early cardiovascular death. The personal history of the patient may include multiple cardiovascular incidents despite therapeutic intervention; despite taking lipid-lowering and/or antiplatelet therapy, the patient will present with progressive disease. Often, disease manifests in multiple areas of the vasculature or as restenosis of previous interventions.

Genetics
Lp(a) results from a genetic variation of the apolipoprotein(a) (LPA) locus on chromosome 6q27. Lp(a) is comprised of an apolipoprotein(b) (apoB)–containing LDL molecule that is bonded to LPA. LPA is structurally similar to plasminogen, the precursor for plasmin that degrades fibrin in blood clots. Due to this similarity, LPA can competitively inhibit plasmin activity and thereby increase risk for thrombosis.^4,9

Continue for physical examination >>

Physical Examination
Patients with very elevated LDL-C levels in whom Lp(a) is also high may present with other outward stigmata of dyslipidemia. Visualization of the eye may reveal evidence of severe dyslipidemia with arcus cornea. This arcus can present as unilateral, bilateral, inferior, superior, or mixed and is representative of the buildup of cholesterol that cannot be removed from the body by normal means. Further examination may reveal tendon xanthomas, which are also representative of a genetic cholesterol disorder—in most cases, familial hypercholesterolemia.⁷

Laboratory Workup
In patients who are known or suspected to be at high risk for CVD, the laboratory workup should include a fasting lipid panel, with Lp(a) and apoB; a comprehensive metabolic profile to establish renal and liver function (as therapeutic interventions utilize these organs for metabolism); and a fasting glucose measurement to rule out occult diabetes, which enhances risk factors. Thyroid function is also assessed, secondary to its deleterious effects on lipid metabolism.

Lp(a) results must be interpreted in the context of ethnicity; significance will vary. For example, both the African-American and Asian populations have been found to have high levels of Lp(a), but these are generally felt to be less atherogenic in African Americans. No major differences have been identified for other populations. It is, however, important to note that those patients with nephropathies and elevated Lp(a) carry a higher risk for coronary artery disease.

Lp(a) levels will remain relatively steady throughout life, negating the need for routine monitoring once a patient’s levels have been established. The exception is postmenopausal women, in whom Lp(a) levels may increase due to changes in estrogen. It is prudent to assess Lp(a) in women both pre- and postmenopause, based on data from the Women’s Health Study.¹⁰

Continue for diagnosis and treatment >>

Diagnosis and Treatment
Elevated Lp(a), which is found in 25% to 35% of the population, is diagnosed at a level > 30 mg/dL, regardless of sex.^4,9 In conjunction with known disease, elevated Lp(a) is sufficient to warrant consideration of very aggressive treatment. In these circumstan­ces, the provider may consider a target LDL-C level ≤ 70 mg/dL.^6,7,11 In primary prevention, clinicians should consider lowering this threshold. Levels that may have been considered appropriate in a low- or moderate-risk patient (≤ 160 mg/dL and ≤ 130 mg/dL, respectively) may be reduced to ≤ 130 mg/dL and ≤ 100 mg/dL, respectively.^6,11

There is no peer-reviewed evidence with regard to lifestyle management (exercise and diet) for reduction of Lp(a). However, it is reasonable to recommend that high-risk patients adopt healthier regimens.

Management of elevated Lp(a) includes consideration of pharmacologic intervention. Since Lp(a) is prothrombotic, all patients without contraindications should at least be taking low-dose (81-mg) aspirin. Those with evidence of thrombotic events may need lifetime antiplatelet therapy.¹² Statin therapy has mixed and minimal effects on Lp(a), although it remains the mainstay of treatment due to its effects on LDL-C and other lipoproteins.¹³ Although long-term data are lacking, there is some anecdotal evidence of improvement with fibrate therapy. However, it is not recommended for treatment of elevated Lp(a).¹⁴

Nicotinic acid has had the longest and most robust history for reduction of Lp(a).^9,12 However, recent studies examining combination therapy with statins and nicotinic acid have yielded discouraging results—and in some cases have suggested negative outcomes with this combination.^15,16 High doses (4-5 g for immediate release and 2-3 g for sustained release) of nicotinic acid are necessary to produce beneficial results on Lp(a) or other lipid abnormalities (eg, elevated triglycerides, low HDL cholesterol).¹⁷ Use of OTC nicotinic acid is not recommended, since these products are considered dietary supplements and regulated as such, raising the potential for untoward adverse effects and/or the possibility that little to no active ingredient is present.^18-20

Results from the Women’s Health Study and the Heart and Estrogen/progestin Replacement Study suggested that estrogen might be an effective therapy. In one analysis, women with elevated Lp(a) derived greater potential cardioprotective effects from hormone replacement therapy (HRT) than those with lower Lp(a), and the researchers noted a “significant interaction” between baseline Lp(a), HRT treatment, and CVD risk. However, use of HRT is not approved for treatment of vascular risk today, due to the potential for adverse effects.^10,21

A novel therapy, in the form of PCSK9 inhibition, has been shown to reduce LDL-C significantly; reduction in Lp(a) was also observed. The FDA recently approved two PCSK9 inhibitors (alirocumab and evolocumab) for use, although the primary indication is for further reduction in LDL-C on top of the maximally tolerated dose of statin therapy, not for reduction of Lp(a).^22,23

Apheresis has been shown to have positive effects in reducing ongoing vascular events in select patient populations. It is approved by the FDA for treatment of refractory LDL-C, mostly in patients with familial hypercholesterolemia, but it is not indicated for treatment of elevated Lp(a). However, since Lp(a) tracks with LDL-C, it is also removed during the process; about a 50% reduction in Lp(a) levels has been noted, although levels rebound posttreatment. To date, reimbursement issues remain in the absence of an FDA indication and due to the paucity of treatment centers in the US.^24,25

Follow-up. The therapies mentioned require routine evaluation to assess tolerability and safety, as recommended in the prescribing information. Patients with known CVD should undergo an appropriate cardiac workup annually to evaluate for occult progression of disease. Patients require further evaluation of related cardiovascular risk factors and adherence with medication regimens. For primary prevention patients, annual follow-up is also recommended to assess for any changes in health status, lifestyle, or medication adherence.

Continue for conclusion >>

Conclusion
The average health care provider frequently performs the standard evaluation of a patient at risk for, or with, CVD. However, a subset of this population may be at increased cardiovascular risk due to Lp(a), a common genetic risk factor that can be responsible for premature or progressive CVD. Because of the aggressive nature of this disorder and the young age at which it influences the development of vascular disease, health care providers must be more vigilant about looking beyond the obvious in patients with familial hypercholesterolemia or family history of premature CVD.

Patients with progressive disease must be more thoroughly evaluated; there are already more than 63 million persons with elevated Lp(a) in the US—and many more undiagnosed—who may benefit from aggressive care. Underdiagnosis has been associated with decreased quality and productivity in the work environment, decreased quality of life, increased use of health dollars, and possibly early loss of life.

While the test for Lp(a) is readily available, the cost may not be covered by insurance and therefore may be passed on to the patient. It would behoove health care professionals to lobby for coverage as a means to reduce the prevalence of CVD, the number one cause of mortality in the US.

References
1. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Executive Summary: heart disease and stroke statistics—2014 Update: a report from the American Heart Association. Circulation. 2014;129:399-410.
2. Bennet A, Di Angelantonio E, Erqou S, et al. Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data [published corrections appear in Arch Intern Med. 2008;168(10):1089 and Arch Intern Med. 2008;168(10):1096]. Arch Intern Med. 2008;168(6):598-608.
3. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301(22):2331-2339.
4. Suk DJ, Rifai N, Buring JE, Ridker PM. Lipo­protein(a), hormone replacement therapy, and risk of future cardiovascular events. J Am Coll Cardiol. 2008;52(2):124-131.
5. Scanu AM. Lipoprotein(a). A genetic risk factor for premature coronary heart disease. JAMA. 1992;267(24):3326-3329.
6. Goldberg AC, Hopkins PN, Toth PP; National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipid. 2011;5(3 suppl):S1-S8.
7. Ito M, McGowan MP, Moriarty PM; National Lipid Association Expert Panel on Familial Hypercholesterolemia. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipid. 2011;5(3 suppl):S38-S45.
8. Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J. 2014 Feb 28. [Epub ahead of print]
9. Nordestgaard BG, Chapman MJ, Ray K, et al; European Atherosclerosis Society Consensus Panel. Lipoprotein (a) as a cardiovascular risk factor: current status. Eur Heart J. 2010; 31(23):2844-2853.
10. Suk DJ, Rifai N, Buring JE, Ridker PM. Lipo­protein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women. JAMA. 2006;296 (11):1363-1370.
11. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227-239.
12. Jacobson TA. Lipoprotein (a), cardiovascular disease, and contemporary management. Mayo Clin Proc. 2013;88(11):1294-1311.
13. Hunninghake DB, Stein EA, Mellies MJ. Effects of one year of treatment with pravastatin, an HMG-CoA reductase inhibitor, on lipoprotein a. J Clin Pharmacol. 1993;33 (6):574-580.
14. Jones PH, Pownall HJ, Patsch W, et al. Effect of gemfibrozil on levels of lipoprotein[a] in type 2 hyperlipoproteinemic subjects. J Lipid Res. 1996;37(6):1298-1308.
15. Boden WE, Probstfield JL, Anderson T, et al; AIM-HIGH investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011; 365(24):2255-2267.
16. Landray MJ, Haynes R, Hopewell JC, et al; HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371 (3):203-212.
17. Morgan JM, Capuzzi DM, Guyton JR. A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients. Am J Cardiol. 1998;82 (12A): 29U-34U.
18. Piepho RW. The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol. Am J Cardiol. 2000;86(12A):35L-40L.
19. Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol. 2007; 99(6A):22C-31C.
20. McKenney JM, Proctor JD, Harris S, Chinchili VM. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA. 1994;271(9):672-677.
21. Shlipak MG, Simon JA, Vittinghoff E, et al. Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause. JAMA. 2000;283 (14):1845-1852.
22. Marbach JA, McKeon JL, Ross JL, Duffy D. Novel treatments for familial hypercholesterolemia: pharmacogenetics at work. Pharmacotherapy. 2014;34(9):961-972.
23. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366(12): 1108-1118.
24. Sachais BS, Katz J, Ross J, Rader DJ. Long-term effects of LDL apheresis in patients with severe hypercholesterolemia. J Clin Apher. 2005;20:252-255.
25. Waldmann E, Parhofer K. Lipoprotein apheresis to treat elevated lipoprotein(a). J Lipid Res. 2016 Feb 17. [Epub ahead of print]

Cardiovascular disease (CVD) is the leading cause of death in the United States. CVD-related diseases affect 83.6 million people in the US and are responsible for almost 800,000 deaths annually.¹ The myriad underlying causes for these disorders range from inadequate lifestyle management to genetic abnormalities. One genetically determined abnormality is lipoprotein(a), or Lp(a).^2-4

It is estimated that 25% of the US population has elevated Lp(a) levels (> 30 mg/dL) that are clinically significant.⁵ Lp(a) is recognized as an independent risk factor for CVD, stroke, retinal artery occlusions, and restenosis of vein grafts.^2-5

Regardless of practice type, clinicians at some point in their career will see a “vasculopath.” Many of these patients have undiagnosed familial hypercholesterolemia, which affects 1 in 200 to 300 patients in the US and manifests with LDL cholesterol (LDL-C) levels ≥ 190 mg/dL.^6-8 Other patients may have CVD with relatively “normal” traditional lipids, more aggressive premature disease, and/or progressive disease despite “usual therapy.”

As clinical lipid specialists working both in cardiology and endocrinology, the authors find the lack of evaluation for additional abnormalities in high-risk patients to be quite disturbing. The patient most commonly seen with the Lp(a) abnormality is one with CVD onset approximately one decade earlier than expected, along with a family history of premature CVD or closure of recently placed stents. Unfortunately, this may result in disease in the second or third decade for men and third or fourth decade for women.

Of course, CVD can leave patients with less productive lives and increase the burden to the health care system and to society. A positive outcome of identification of this apolipoprotein abnormality is that it may prompt evaluation of other family members prior to the inception of vascular disease. When it is identified in the asymptomatic, disease-free patient, aggressive risk reduction—in the form of lifestyle management and medication—may delay or prevent disease onset.

Continue for identification of the problem >>

Identification of the problem
Office visits seldom include a thorough and complete patient history. A “good” family history should include first-degree relatives. Time-constrained practi­tioners may take a rudimentary family history of immediate relatives when a pedigree of the patient would be more appropriate.

Pedigree assessment offers a more specific picture of disease in families and identifies prevalence and incidence. Busy clinicians could have patients use an online resource to generate their own family pedigree. Or, as in most practices, a medical assistant or other appropriate office staff could initiate the process in the chart.

Patients with premature or advanced disease and significant family history need further investigation. A suspect history would include multiple family members with disease earlier in life than expected and perhaps early cardiovascular death. The personal history of the patient may include multiple cardiovascular incidents despite therapeutic intervention; despite taking lipid-lowering and/or antiplatelet therapy, the patient will present with progressive disease. Often, disease manifests in multiple areas of the vasculature or as restenosis of previous interventions.

Genetics
Lp(a) results from a genetic variation of the apolipoprotein(a) (LPA) locus on chromosome 6q27. Lp(a) is comprised of an apolipoprotein(b) (apoB)–containing LDL molecule that is bonded to LPA. LPA is structurally similar to plasminogen, the precursor for plasmin that degrades fibrin in blood clots. Due to this similarity, LPA can competitively inhibit plasmin activity and thereby increase risk for thrombosis.^4,9

Continue for physical examination >>

Physical Examination
Patients with very elevated LDL-C levels in whom Lp(a) is also high may present with other outward stigmata of dyslipidemia. Visualization of the eye may reveal evidence of severe dyslipidemia with arcus cornea. This arcus can present as unilateral, bilateral, inferior, superior, or mixed and is representative of the buildup of cholesterol that cannot be removed from the body by normal means. Further examination may reveal tendon xanthomas, which are also representative of a genetic cholesterol disorder—in most cases, familial hypercholesterolemia.⁷

Laboratory Workup
In patients who are known or suspected to be at high risk for CVD, the laboratory workup should include a fasting lipid panel, with Lp(a) and apoB; a comprehensive metabolic profile to establish renal and liver function (as therapeutic interventions utilize these organs for metabolism); and a fasting glucose measurement to rule out occult diabetes, which enhances risk factors. Thyroid function is also assessed, secondary to its deleterious effects on lipid metabolism.

Lp(a) results must be interpreted in the context of ethnicity; significance will vary. For example, both the African-American and Asian populations have been found to have high levels of Lp(a), but these are generally felt to be less atherogenic in African Americans. No major differences have been identified for other populations. It is, however, important to note that those patients with nephropathies and elevated Lp(a) carry a higher risk for coronary artery disease.

Lp(a) levels will remain relatively steady throughout life, negating the need for routine monitoring once a patient’s levels have been established. The exception is postmenopausal women, in whom Lp(a) levels may increase due to changes in estrogen. It is prudent to assess Lp(a) in women both pre- and postmenopause, based on data from the Women’s Health Study.¹⁰

Continue for diagnosis and treatment >>

Diagnosis and Treatment
Elevated Lp(a), which is found in 25% to 35% of the population, is diagnosed at a level > 30 mg/dL, regardless of sex.^4,9 In conjunction with known disease, elevated Lp(a) is sufficient to warrant consideration of very aggressive treatment. In these circumstan­ces, the provider may consider a target LDL-C level ≤ 70 mg/dL.^6,7,11 In primary prevention, clinicians should consider lowering this threshold. Levels that may have been considered appropriate in a low- or moderate-risk patient (≤ 160 mg/dL and ≤ 130 mg/dL, respectively) may be reduced to ≤ 130 mg/dL and ≤ 100 mg/dL, respectively.^6,11

There is no peer-reviewed evidence with regard to lifestyle management (exercise and diet) for reduction of Lp(a). However, it is reasonable to recommend that high-risk patients adopt healthier regimens.

Management of elevated Lp(a) includes consideration of pharmacologic intervention. Since Lp(a) is prothrombotic, all patients without contraindications should at least be taking low-dose (81-mg) aspirin. Those with evidence of thrombotic events may need lifetime antiplatelet therapy.¹² Statin therapy has mixed and minimal effects on Lp(a), although it remains the mainstay of treatment due to its effects on LDL-C and other lipoproteins.¹³ Although long-term data are lacking, there is some anecdotal evidence of improvement with fibrate therapy. However, it is not recommended for treatment of elevated Lp(a).¹⁴

Nicotinic acid has had the longest and most robust history for reduction of Lp(a).^9,12 However, recent studies examining combination therapy with statins and nicotinic acid have yielded discouraging results—and in some cases have suggested negative outcomes with this combination.^15,16 High doses (4-5 g for immediate release and 2-3 g for sustained release) of nicotinic acid are necessary to produce beneficial results on Lp(a) or other lipid abnormalities (eg, elevated triglycerides, low HDL cholesterol).¹⁷ Use of OTC nicotinic acid is not recommended, since these products are considered dietary supplements and regulated as such, raising the potential for untoward adverse effects and/or the possibility that little to no active ingredient is present.^18-20

Results from the Women’s Health Study and the Heart and Estrogen/progestin Replacement Study suggested that estrogen might be an effective therapy. In one analysis, women with elevated Lp(a) derived greater potential cardioprotective effects from hormone replacement therapy (HRT) than those with lower Lp(a), and the researchers noted a “significant interaction” between baseline Lp(a), HRT treatment, and CVD risk. However, use of HRT is not approved for treatment of vascular risk today, due to the potential for adverse effects.^10,21

A novel therapy, in the form of PCSK9 inhibition, has been shown to reduce LDL-C significantly; reduction in Lp(a) was also observed. The FDA recently approved two PCSK9 inhibitors (alirocumab and evolocumab) for use, although the primary indication is for further reduction in LDL-C on top of the maximally tolerated dose of statin therapy, not for reduction of Lp(a).^22,23

Apheresis has been shown to have positive effects in reducing ongoing vascular events in select patient populations. It is approved by the FDA for treatment of refractory LDL-C, mostly in patients with familial hypercholesterolemia, but it is not indicated for treatment of elevated Lp(a). However, since Lp(a) tracks with LDL-C, it is also removed during the process; about a 50% reduction in Lp(a) levels has been noted, although levels rebound posttreatment. To date, reimbursement issues remain in the absence of an FDA indication and due to the paucity of treatment centers in the US.^24,25

Follow-up. The therapies mentioned require routine evaluation to assess tolerability and safety, as recommended in the prescribing information. Patients with known CVD should undergo an appropriate cardiac workup annually to evaluate for occult progression of disease. Patients require further evaluation of related cardiovascular risk factors and adherence with medication regimens. For primary prevention patients, annual follow-up is also recommended to assess for any changes in health status, lifestyle, or medication adherence.

Continue for conclusion >>

Conclusion
The average health care provider frequently performs the standard evaluation of a patient at risk for, or with, CVD. However, a subset of this population may be at increased cardiovascular risk due to Lp(a), a common genetic risk factor that can be responsible for premature or progressive CVD. Because of the aggressive nature of this disorder and the young age at which it influences the development of vascular disease, health care providers must be more vigilant about looking beyond the obvious in patients with familial hypercholesterolemia or family history of premature CVD.

Patients with progressive disease must be more thoroughly evaluated; there are already more than 63 million persons with elevated Lp(a) in the US—and many more undiagnosed—who may benefit from aggressive care. Underdiagnosis has been associated with decreased quality and productivity in the work environment, decreased quality of life, increased use of health dollars, and possibly early loss of life.

While the test for Lp(a) is readily available, the cost may not be covered by insurance and therefore may be passed on to the patient. It would behoove health care professionals to lobby for coverage as a means to reduce the prevalence of CVD, the number one cause of mortality in the US.

References
1. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Executive Summary: heart disease and stroke statistics—2014 Update: a report from the American Heart Association. Circulation. 2014;129:399-410.
2. Bennet A, Di Angelantonio E, Erqou S, et al. Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data [published corrections appear in Arch Intern Med. 2008;168(10):1089 and Arch Intern Med. 2008;168(10):1096]. Arch Intern Med. 2008;168(6):598-608.
3. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301(22):2331-2339.
4. Suk DJ, Rifai N, Buring JE, Ridker PM. Lipo­protein(a), hormone replacement therapy, and risk of future cardiovascular events. J Am Coll Cardiol. 2008;52(2):124-131.
5. Scanu AM. Lipoprotein(a). A genetic risk factor for premature coronary heart disease. JAMA. 1992;267(24):3326-3329.
6. Goldberg AC, Hopkins PN, Toth PP; National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipid. 2011;5(3 suppl):S1-S8.
7. Ito M, McGowan MP, Moriarty PM; National Lipid Association Expert Panel on Familial Hypercholesterolemia. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipid. 2011;5(3 suppl):S38-S45.
8. Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J. 2014 Feb 28. [Epub ahead of print]
9. Nordestgaard BG, Chapman MJ, Ray K, et al; European Atherosclerosis Society Consensus Panel. Lipoprotein (a) as a cardiovascular risk factor: current status. Eur Heart J. 2010; 31(23):2844-2853.
10. Suk DJ, Rifai N, Buring JE, Ridker PM. Lipo­protein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women. JAMA. 2006;296 (11):1363-1370.
11. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227-239.
12. Jacobson TA. Lipoprotein (a), cardiovascular disease, and contemporary management. Mayo Clin Proc. 2013;88(11):1294-1311.
13. Hunninghake DB, Stein EA, Mellies MJ. Effects of one year of treatment with pravastatin, an HMG-CoA reductase inhibitor, on lipoprotein a. J Clin Pharmacol. 1993;33 (6):574-580.
14. Jones PH, Pownall HJ, Patsch W, et al. Effect of gemfibrozil on levels of lipoprotein[a] in type 2 hyperlipoproteinemic subjects. J Lipid Res. 1996;37(6):1298-1308.
15. Boden WE, Probstfield JL, Anderson T, et al; AIM-HIGH investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011; 365(24):2255-2267.
16. Landray MJ, Haynes R, Hopewell JC, et al; HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371 (3):203-212.
17. Morgan JM, Capuzzi DM, Guyton JR. A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients. Am J Cardiol. 1998;82 (12A): 29U-34U.
18. Piepho RW. The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol. Am J Cardiol. 2000;86(12A):35L-40L.
19. Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol. 2007; 99(6A):22C-31C.
20. McKenney JM, Proctor JD, Harris S, Chinchili VM. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA. 1994;271(9):672-677.
21. Shlipak MG, Simon JA, Vittinghoff E, et al. Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause. JAMA. 2000;283 (14):1845-1852.
22. Marbach JA, McKeon JL, Ross JL, Duffy D. Novel treatments for familial hypercholesterolemia: pharmacogenetics at work. Pharmacotherapy. 2014;34(9):961-972.
23. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366(12): 1108-1118.
24. Sachais BS, Katz J, Ross J, Rader DJ. Long-term effects of LDL apheresis in patients with severe hypercholesterolemia. J Clin Apher. 2005;20:252-255.
25. Waldmann E, Parhofer K. Lipoprotein apheresis to treat elevated lipoprotein(a). J Lipid Res. 2016 Feb 17. [Epub ahead of print]

Cardiovascular disease (CVD) is the leading cause of death in the United States. CVD-related diseases affect 83.6 million people in the US and are responsible for almost 800,000 deaths annually.¹ The myriad underlying causes for these disorders range from inadequate lifestyle management to genetic abnormalities. One genetically determined abnormality is lipoprotein(a), or Lp(a).^2-4

It is estimated that 25% of the US population has elevated Lp(a) levels (> 30 mg/dL) that are clinically significant.⁵ Lp(a) is recognized as an independent risk factor for CVD, stroke, retinal artery occlusions, and restenosis of vein grafts.^2-5

Regardless of practice type, clinicians at some point in their career will see a “vasculopath.” Many of these patients have undiagnosed familial hypercholesterolemia, which affects 1 in 200 to 300 patients in the US and manifests with LDL cholesterol (LDL-C) levels ≥ 190 mg/dL.^6-8 Other patients may have CVD with relatively “normal” traditional lipids, more aggressive premature disease, and/or progressive disease despite “usual therapy.”

As clinical lipid specialists working both in cardiology and endocrinology, the authors find the lack of evaluation for additional abnormalities in high-risk patients to be quite disturbing. The patient most commonly seen with the Lp(a) abnormality is one with CVD onset approximately one decade earlier than expected, along with a family history of premature CVD or closure of recently placed stents. Unfortunately, this may result in disease in the second or third decade for men and third or fourth decade for women.

Of course, CVD can leave patients with less productive lives and increase the burden to the health care system and to society. A positive outcome of identification of this apolipoprotein abnormality is that it may prompt evaluation of other family members prior to the inception of vascular disease. When it is identified in the asymptomatic, disease-free patient, aggressive risk reduction—in the form of lifestyle management and medication—may delay or prevent disease onset.

Continue for identification of the problem >>

Identification of the problem
Office visits seldom include a thorough and complete patient history. A “good” family history should include first-degree relatives. Time-constrained practi­tioners may take a rudimentary family history of immediate relatives when a pedigree of the patient would be more appropriate.

Pedigree assessment offers a more specific picture of disease in families and identifies prevalence and incidence. Busy clinicians could have patients use an online resource to generate their own family pedigree. Or, as in most practices, a medical assistant or other appropriate office staff could initiate the process in the chart.

Patients with premature or advanced disease and significant family history need further investigation. A suspect history would include multiple family members with disease earlier in life than expected and perhaps early cardiovascular death. The personal history of the patient may include multiple cardiovascular incidents despite therapeutic intervention; despite taking lipid-lowering and/or antiplatelet therapy, the patient will present with progressive disease. Often, disease manifests in multiple areas of the vasculature or as restenosis of previous interventions.

Genetics
Lp(a) results from a genetic variation of the apolipoprotein(a) (LPA) locus on chromosome 6q27. Lp(a) is comprised of an apolipoprotein(b) (apoB)–containing LDL molecule that is bonded to LPA. LPA is structurally similar to plasminogen, the precursor for plasmin that degrades fibrin in blood clots. Due to this similarity, LPA can competitively inhibit plasmin activity and thereby increase risk for thrombosis.^4,9

Continue for physical examination >>

Physical Examination
Patients with very elevated LDL-C levels in whom Lp(a) is also high may present with other outward stigmata of dyslipidemia. Visualization of the eye may reveal evidence of severe dyslipidemia with arcus cornea. This arcus can present as unilateral, bilateral, inferior, superior, or mixed and is representative of the buildup of cholesterol that cannot be removed from the body by normal means. Further examination may reveal tendon xanthomas, which are also representative of a genetic cholesterol disorder—in most cases, familial hypercholesterolemia.⁷

Laboratory Workup
In patients who are known or suspected to be at high risk for CVD, the laboratory workup should include a fasting lipid panel, with Lp(a) and apoB; a comprehensive metabolic profile to establish renal and liver function (as therapeutic interventions utilize these organs for metabolism); and a fasting glucose measurement to rule out occult diabetes, which enhances risk factors. Thyroid function is also assessed, secondary to its deleterious effects on lipid metabolism.

Lp(a) results must be interpreted in the context of ethnicity; significance will vary. For example, both the African-American and Asian populations have been found to have high levels of Lp(a), but these are generally felt to be less atherogenic in African Americans. No major differences have been identified for other populations. It is, however, important to note that those patients with nephropathies and elevated Lp(a) carry a higher risk for coronary artery disease.

Lp(a) levels will remain relatively steady throughout life, negating the need for routine monitoring once a patient’s levels have been established. The exception is postmenopausal women, in whom Lp(a) levels may increase due to changes in estrogen. It is prudent to assess Lp(a) in women both pre- and postmenopause, based on data from the Women’s Health Study.¹⁰

Continue for diagnosis and treatment >>

Diagnosis and Treatment
Elevated Lp(a), which is found in 25% to 35% of the population, is diagnosed at a level > 30 mg/dL, regardless of sex.^4,9 In conjunction with known disease, elevated Lp(a) is sufficient to warrant consideration of very aggressive treatment. In these circumstan­ces, the provider may consider a target LDL-C level ≤ 70 mg/dL.^6,7,11 In primary prevention, clinicians should consider lowering this threshold. Levels that may have been considered appropriate in a low- or moderate-risk patient (≤ 160 mg/dL and ≤ 130 mg/dL, respectively) may be reduced to ≤ 130 mg/dL and ≤ 100 mg/dL, respectively.^6,11

There is no peer-reviewed evidence with regard to lifestyle management (exercise and diet) for reduction of Lp(a). However, it is reasonable to recommend that high-risk patients adopt healthier regimens.

Management of elevated Lp(a) includes consideration of pharmacologic intervention. Since Lp(a) is prothrombotic, all patients without contraindications should at least be taking low-dose (81-mg) aspirin. Those with evidence of thrombotic events may need lifetime antiplatelet therapy.¹² Statin therapy has mixed and minimal effects on Lp(a), although it remains the mainstay of treatment due to its effects on LDL-C and other lipoproteins.¹³ Although long-term data are lacking, there is some anecdotal evidence of improvement with fibrate therapy. However, it is not recommended for treatment of elevated Lp(a).¹⁴

Nicotinic acid has had the longest and most robust history for reduction of Lp(a).^9,12 However, recent studies examining combination therapy with statins and nicotinic acid have yielded discouraging results—and in some cases have suggested negative outcomes with this combination.^15,16 High doses (4-5 g for immediate release and 2-3 g for sustained release) of nicotinic acid are necessary to produce beneficial results on Lp(a) or other lipid abnormalities (eg, elevated triglycerides, low HDL cholesterol).¹⁷ Use of OTC nicotinic acid is not recommended, since these products are considered dietary supplements and regulated as such, raising the potential for untoward adverse effects and/or the possibility that little to no active ingredient is present.^18-20

Results from the Women’s Health Study and the Heart and Estrogen/progestin Replacement Study suggested that estrogen might be an effective therapy. In one analysis, women with elevated Lp(a) derived greater potential cardioprotective effects from hormone replacement therapy (HRT) than those with lower Lp(a), and the researchers noted a “significant interaction” between baseline Lp(a), HRT treatment, and CVD risk. However, use of HRT is not approved for treatment of vascular risk today, due to the potential for adverse effects.^10,21

A novel therapy, in the form of PCSK9 inhibition, has been shown to reduce LDL-C significantly; reduction in Lp(a) was also observed. The FDA recently approved two PCSK9 inhibitors (alirocumab and evolocumab) for use, although the primary indication is for further reduction in LDL-C on top of the maximally tolerated dose of statin therapy, not for reduction of Lp(a).^22,23

Apheresis has been shown to have positive effects in reducing ongoing vascular events in select patient populations. It is approved by the FDA for treatment of refractory LDL-C, mostly in patients with familial hypercholesterolemia, but it is not indicated for treatment of elevated Lp(a). However, since Lp(a) tracks with LDL-C, it is also removed during the process; about a 50% reduction in Lp(a) levels has been noted, although levels rebound posttreatment. To date, reimbursement issues remain in the absence of an FDA indication and due to the paucity of treatment centers in the US.^24,25

Follow-up. The therapies mentioned require routine evaluation to assess tolerability and safety, as recommended in the prescribing information. Patients with known CVD should undergo an appropriate cardiac workup annually to evaluate for occult progression of disease. Patients require further evaluation of related cardiovascular risk factors and adherence with medication regimens. For primary prevention patients, annual follow-up is also recommended to assess for any changes in health status, lifestyle, or medication adherence.

Continue for conclusion >>

Conclusion
The average health care provider frequently performs the standard evaluation of a patient at risk for, or with, CVD. However, a subset of this population may be at increased cardiovascular risk due to Lp(a), a common genetic risk factor that can be responsible for premature or progressive CVD. Because of the aggressive nature of this disorder and the young age at which it influences the development of vascular disease, health care providers must be more vigilant about looking beyond the obvious in patients with familial hypercholesterolemia or family history of premature CVD.

Patients with progressive disease must be more thoroughly evaluated; there are already more than 63 million persons with elevated Lp(a) in the US—and many more undiagnosed—who may benefit from aggressive care. Underdiagnosis has been associated with decreased quality and productivity in the work environment, decreased quality of life, increased use of health dollars, and possibly early loss of life.

While the test for Lp(a) is readily available, the cost may not be covered by insurance and therefore may be passed on to the patient. It would behoove health care professionals to lobby for coverage as a means to reduce the prevalence of CVD, the number one cause of mortality in the US.

References
1. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Executive Summary: heart disease and stroke statistics—2014 Update: a report from the American Heart Association. Circulation. 2014;129:399-410.
2. Bennet A, Di Angelantonio E, Erqou S, et al. Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data [published corrections appear in Arch Intern Med. 2008;168(10):1089 and Arch Intern Med. 2008;168(10):1096]. Arch Intern Med. 2008;168(6):598-608.
3. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301(22):2331-2339.
4. Suk DJ, Rifai N, Buring JE, Ridker PM. Lipo­protein(a), hormone replacement therapy, and risk of future cardiovascular events. J Am Coll Cardiol. 2008;52(2):124-131.
5. Scanu AM. Lipoprotein(a). A genetic risk factor for premature coronary heart disease. JAMA. 1992;267(24):3326-3329.
6. Goldberg AC, Hopkins PN, Toth PP; National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipid. 2011;5(3 suppl):S1-S8.
7. Ito M, McGowan MP, Moriarty PM; National Lipid Association Expert Panel on Familial Hypercholesterolemia. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipid. 2011;5(3 suppl):S38-S45.
8. Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J. 2014 Feb 28. [Epub ahead of print]
9. Nordestgaard BG, Chapman MJ, Ray K, et al; European Atherosclerosis Society Consensus Panel. Lipoprotein (a) as a cardiovascular risk factor: current status. Eur Heart J. 2010; 31(23):2844-2853.
10. Suk DJ, Rifai N, Buring JE, Ridker PM. Lipo­protein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women. JAMA. 2006;296 (11):1363-1370.
11. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227-239.
12. Jacobson TA. Lipoprotein (a), cardiovascular disease, and contemporary management. Mayo Clin Proc. 2013;88(11):1294-1311.
13. Hunninghake DB, Stein EA, Mellies MJ. Effects of one year of treatment with pravastatin, an HMG-CoA reductase inhibitor, on lipoprotein a. J Clin Pharmacol. 1993;33 (6):574-580.
14. Jones PH, Pownall HJ, Patsch W, et al. Effect of gemfibrozil on levels of lipoprotein[a] in type 2 hyperlipoproteinemic subjects. J Lipid Res. 1996;37(6):1298-1308.
15. Boden WE, Probstfield JL, Anderson T, et al; AIM-HIGH investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011; 365(24):2255-2267.
16. Landray MJ, Haynes R, Hopewell JC, et al; HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371 (3):203-212.
17. Morgan JM, Capuzzi DM, Guyton JR. A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients. Am J Cardiol. 1998;82 (12A): 29U-34U.
18. Piepho RW. The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol. Am J Cardiol. 2000;86(12A):35L-40L.
19. Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol. 2007; 99(6A):22C-31C.
20. McKenney JM, Proctor JD, Harris S, Chinchili VM. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA. 1994;271(9):672-677.
21. Shlipak MG, Simon JA, Vittinghoff E, et al. Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause. JAMA. 2000;283 (14):1845-1852.
22. Marbach JA, McKeon JL, Ross JL, Duffy D. Novel treatments for familial hypercholesterolemia: pharmacogenetics at work. Pharmacotherapy. 2014;34(9):961-972.
23. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366(12): 1108-1118.
24. Sachais BS, Katz J, Ross J, Rader DJ. Long-term effects of LDL apheresis in patients with severe hypercholesterolemia. J Clin Apher. 2005;20:252-255.
25. Waldmann E, Parhofer K. Lipoprotein apheresis to treat elevated lipoprotein(a). J Lipid Res. 2016 Feb 17. [Epub ahead of print]

Patients with severe hemophilia A treated with plasma-derived factor VIII, as compared with recombinant factor VIII, had a lower risk of developing neutralizing antibodies, based on a recent report from the randomized SIPPET trial published in the New England Journal of Medicine.

In a second study, also published in the journal, prophylactic treatment with the bispecific antibody emicizumab decreased bleeding in patients with or without neutralizing antibodies.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Of 125 patients with severe hemophilia A who were treated with plasma-derived factor VIII with von Willebrand factor, 29 (23.2%) developed inhibitors, compared with 47 of 126 patients (37.3%) treated with recombinant factor VIII. In the plasma-derived group, 20 (16.0%) had high-titer inhibitors compared with 30 (23.8%) in the recombinant group. Cox regression models showed an 87% higher rate of inhibitor development with recombinant factor VIII (hazard ratio, 1.87; 95% confidence interval, 1.17-2.96). For development of high-titer inhibitors, the HR was 1.69 (95% CI, 0.96-2.98).

Previous observational studies have suggested greater immunogenicity of recombinant vs. plasm-derived factor VIII, but the results remained inconclusive. Meta-analyses of studies have been hindered by differences in design, enrollment criteria, definition of hemophilia A, sample size, method of inhibitor detection, and intervals of follow-up testing, according to Dr. Flora Peyvandi of the IRCCS Maggiore Hospital, University of Milan and colleagues. “Our trial was specifically designed to compare the immunogenicity of factor VIII products. As a result of randomization, the main risk factors for inhibitor development were evenly distributed between the two factor VIII classes,” they wrote, adding, “The finding that native factor VIII products from human plasma are less immunogenic than those engineered by recombinant DNA technology in animal cell lines has the potential to affect treatment strategies and open new investigations to better understand the mechanisms of the immunogenicity of various factor VIII preparations.” (N Engl J Med. 2016 May 25. doi: 10.1200/JCO.2015.64.0730).

The Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) clinical trial randomized 251 patients with severe hemophilia A who received infusions of plasma-derived or recombinant factor VIII. The investigators found no association between risk of inhibitor development and race, intensity of treatment, or age at first treatment.

The second study, a 12-week dose-escalation trial of emicizumab, included 18 patients with severe hemophilia A, aged 12-59 years. Patients were assigned to one of three cohorts and received a once-weekly subcutaneous dose of 0.3, 1, or 3 mg per kilogram of body weight. During prophylactic emicizumab treatment, median annualized bleeding rates decreased from 32.5 (range, 8.1-77.1) to 4.4 (0.0-59.5) in cohort 1, from 18.3 (range, 10.1-38.6) to 0.0 (range, 0.0-4.3) in cohort 2, and from 15.2 (range, 0.0-32.5) to 0.0 (range, 0.0-4.2) in cohort 3. The annualized bleeding rate decreased regardless of factor VIII inhibitor status. Of 11 patients with factor VIII inhibitors, 8 (73%) had no bleeding episodes; 5 of 7 patients without factor VIII inhibitors (71%) had no bleeding episodes.

“This study showed that once-weekly subcutaneous administration of emicizumab as prophylaxis is safe and has the potential to reduce or prevent bleeding episodes in patients who have severe hemophilia A with or without factor VIII inhibitors,” wrote Dr. Midori Shima of Nara Medical University, Kashihara, Japan, and colleagues (N. Engl J Med. 2016 May 25. doi: 10.1056/NEJMoa1511769).

Emicizumab had an acceptable safety profile. In total, 43 adverse events were reported in 15 of 18 patients. All were mild, except two moderate events – an upper respiratory tract infection and a headache. Events thought to be treatment related included malaise, injection-site erythema, injection-site rash, diarrhea, increased C-reactive protein level, and increased blood creatine kinase level.

Dr. Peyvandi and coauthors disclosed consulting, advising, research funding and other relationships with several industry sources, including Grifols, Kedrion, and LFB. Dr. Shima and coauthors disclosed consulting, advising, research funding and other relationships with several industry sources, including Chugai Pharmaceuticals, which supported the study.

Patients with severe hemophilia A treated with plasma-derived factor VIII, as compared with recombinant factor VIII, had a lower risk of developing neutralizing antibodies, based on a recent report from the randomized SIPPET trial published in the New England Journal of Medicine.

In a second study, also published in the journal, prophylactic treatment with the bispecific antibody emicizumab decreased bleeding in patients with or without neutralizing antibodies.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Of 125 patients with severe hemophilia A who were treated with plasma-derived factor VIII with von Willebrand factor, 29 (23.2%) developed inhibitors, compared with 47 of 126 patients (37.3%) treated with recombinant factor VIII. In the plasma-derived group, 20 (16.0%) had high-titer inhibitors compared with 30 (23.8%) in the recombinant group. Cox regression models showed an 87% higher rate of inhibitor development with recombinant factor VIII (hazard ratio, 1.87; 95% confidence interval, 1.17-2.96). For development of high-titer inhibitors, the HR was 1.69 (95% CI, 0.96-2.98).

Previous observational studies have suggested greater immunogenicity of recombinant vs. plasm-derived factor VIII, but the results remained inconclusive. Meta-analyses of studies have been hindered by differences in design, enrollment criteria, definition of hemophilia A, sample size, method of inhibitor detection, and intervals of follow-up testing, according to Dr. Flora Peyvandi of the IRCCS Maggiore Hospital, University of Milan and colleagues. “Our trial was specifically designed to compare the immunogenicity of factor VIII products. As a result of randomization, the main risk factors for inhibitor development were evenly distributed between the two factor VIII classes,” they wrote, adding, “The finding that native factor VIII products from human plasma are less immunogenic than those engineered by recombinant DNA technology in animal cell lines has the potential to affect treatment strategies and open new investigations to better understand the mechanisms of the immunogenicity of various factor VIII preparations.” (N Engl J Med. 2016 May 25. doi: 10.1200/JCO.2015.64.0730).

The Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) clinical trial randomized 251 patients with severe hemophilia A who received infusions of plasma-derived or recombinant factor VIII. The investigators found no association between risk of inhibitor development and race, intensity of treatment, or age at first treatment.

The second study, a 12-week dose-escalation trial of emicizumab, included 18 patients with severe hemophilia A, aged 12-59 years. Patients were assigned to one of three cohorts and received a once-weekly subcutaneous dose of 0.3, 1, or 3 mg per kilogram of body weight. During prophylactic emicizumab treatment, median annualized bleeding rates decreased from 32.5 (range, 8.1-77.1) to 4.4 (0.0-59.5) in cohort 1, from 18.3 (range, 10.1-38.6) to 0.0 (range, 0.0-4.3) in cohort 2, and from 15.2 (range, 0.0-32.5) to 0.0 (range, 0.0-4.2) in cohort 3. The annualized bleeding rate decreased regardless of factor VIII inhibitor status. Of 11 patients with factor VIII inhibitors, 8 (73%) had no bleeding episodes; 5 of 7 patients without factor VIII inhibitors (71%) had no bleeding episodes.

“This study showed that once-weekly subcutaneous administration of emicizumab as prophylaxis is safe and has the potential to reduce or prevent bleeding episodes in patients who have severe hemophilia A with or without factor VIII inhibitors,” wrote Dr. Midori Shima of Nara Medical University, Kashihara, Japan, and colleagues (N. Engl J Med. 2016 May 25. doi: 10.1056/NEJMoa1511769).

Emicizumab had an acceptable safety profile. In total, 43 adverse events were reported in 15 of 18 patients. All were mild, except two moderate events – an upper respiratory tract infection and a headache. Events thought to be treatment related included malaise, injection-site erythema, injection-site rash, diarrhea, increased C-reactive protein level, and increased blood creatine kinase level.

Dr. Peyvandi and coauthors disclosed consulting, advising, research funding and other relationships with several industry sources, including Grifols, Kedrion, and LFB. Dr. Shima and coauthors disclosed consulting, advising, research funding and other relationships with several industry sources, including Chugai Pharmaceuticals, which supported the study.

Patients with severe hemophilia A treated with plasma-derived factor VIII, as compared with recombinant factor VIII, had a lower risk of developing neutralizing antibodies, based on a recent report from the randomized SIPPET trial published in the New England Journal of Medicine.

In a second study, also published in the journal, prophylactic treatment with the bispecific antibody emicizumab decreased bleeding in patients with or without neutralizing antibodies.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Of 125 patients with severe hemophilia A who were treated with plasma-derived factor VIII with von Willebrand factor, 29 (23.2%) developed inhibitors, compared with 47 of 126 patients (37.3%) treated with recombinant factor VIII. In the plasma-derived group, 20 (16.0%) had high-titer inhibitors compared with 30 (23.8%) in the recombinant group. Cox regression models showed an 87% higher rate of inhibitor development with recombinant factor VIII (hazard ratio, 1.87; 95% confidence interval, 1.17-2.96). For development of high-titer inhibitors, the HR was 1.69 (95% CI, 0.96-2.98).

Previous observational studies have suggested greater immunogenicity of recombinant vs. plasm-derived factor VIII, but the results remained inconclusive. Meta-analyses of studies have been hindered by differences in design, enrollment criteria, definition of hemophilia A, sample size, method of inhibitor detection, and intervals of follow-up testing, according to Dr. Flora Peyvandi of the IRCCS Maggiore Hospital, University of Milan and colleagues. “Our trial was specifically designed to compare the immunogenicity of factor VIII products. As a result of randomization, the main risk factors for inhibitor development were evenly distributed between the two factor VIII classes,” they wrote, adding, “The finding that native factor VIII products from human plasma are less immunogenic than those engineered by recombinant DNA technology in animal cell lines has the potential to affect treatment strategies and open new investigations to better understand the mechanisms of the immunogenicity of various factor VIII preparations.” (N Engl J Med. 2016 May 25. doi: 10.1200/JCO.2015.64.0730).

The Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) clinical trial randomized 251 patients with severe hemophilia A who received infusions of plasma-derived or recombinant factor VIII. The investigators found no association between risk of inhibitor development and race, intensity of treatment, or age at first treatment.

The second study, a 12-week dose-escalation trial of emicizumab, included 18 patients with severe hemophilia A, aged 12-59 years. Patients were assigned to one of three cohorts and received a once-weekly subcutaneous dose of 0.3, 1, or 3 mg per kilogram of body weight. During prophylactic emicizumab treatment, median annualized bleeding rates decreased from 32.5 (range, 8.1-77.1) to 4.4 (0.0-59.5) in cohort 1, from 18.3 (range, 10.1-38.6) to 0.0 (range, 0.0-4.3) in cohort 2, and from 15.2 (range, 0.0-32.5) to 0.0 (range, 0.0-4.2) in cohort 3. The annualized bleeding rate decreased regardless of factor VIII inhibitor status. Of 11 patients with factor VIII inhibitors, 8 (73%) had no bleeding episodes; 5 of 7 patients without factor VIII inhibitors (71%) had no bleeding episodes.

“This study showed that once-weekly subcutaneous administration of emicizumab as prophylaxis is safe and has the potential to reduce or prevent bleeding episodes in patients who have severe hemophilia A with or without factor VIII inhibitors,” wrote Dr. Midori Shima of Nara Medical University, Kashihara, Japan, and colleagues (N. Engl J Med. 2016 May 25. doi: 10.1056/NEJMoa1511769).

Emicizumab had an acceptable safety profile. In total, 43 adverse events were reported in 15 of 18 patients. All were mild, except two moderate events – an upper respiratory tract infection and a headache. Events thought to be treatment related included malaise, injection-site erythema, injection-site rash, diarrhea, increased C-reactive protein level, and increased blood creatine kinase level.

Dr. Peyvandi and coauthors disclosed consulting, advising, research funding and other relationships with several industry sources, including Grifols, Kedrion, and LFB. Dr. Shima and coauthors disclosed consulting, advising, research funding and other relationships with several industry sources, including Chugai Pharmaceuticals, which supported the study.

VANCOUVER – Ocrelizumab, a B-cell depleting humanized monoclonal antibody being developed by Hoffman–La Roche, consistently outperformed interferon beta-1a (Rebif) for relapsing multiple sclerosis in two phase III trials reported at the annual meeting of the American Academy of Neurology.

The identical trials, dubbed OPERA I and OPERA II, each had about 800 patients. Subjects were randomized one-to-one to intravenous ocrelizumab 600 mg every 24 weeks or to subcutaneous interferon beta-1a 44 micrograms three times weekly over 96 weeks. Patients had early disease; a significant portion were naive to multiple sclerosis (MS) treatments.

At 96 weeks, 47.9% and 47.5% of ocrelizumab patients versus 29.2% and 25.1% of interferon patients had no evidence of disease activity (NEDA) in the two studies. NEDA is a composite score defined as no relapses, no confirmed disability progression, and no new or enlarging T2 or gadolinium-enhancing T1 lesions.

Across both studies, relapses occurred in about 20% of ocrelizumab patients versus about 35% of interferon patients. About 10% of ocrelizumab, but about 15% of interferon patients, had clinical disease progression. Similarly, about 10% of ocrelizumab patients developed new gadolinium-enhancing lesions, compared with about 35% in the interferon groups. New or enlarging T2 lesions were found in about 40% in the ocrelizumab groups but in more than 60% in the interferon arms.

After week 24, 96% percent of ocrelizumab patients, compared with 60%-70% on interferon, were free of new or enlarging T2 lesions.

In short, ocrelizumab “resulted in greater achievement of NEDA versus [interferon] over 96 weeks, with elimination of new/enlarging T2 lesions in nearly all patients after week 24,” the researchers concluded.

“These are very impressive numbers,” especially because ocrelizumab was compared with a standard treatment. “There was a wonderful constancy of results” across the trials; “a very highly effective treatment is emerging for multiple sclerosis,” said investigator and presenter Dr. Anthony Traboulsee, a neurologist at the University of British Columbia, Vancouver, who also noted that in many cases, patients opted to stay on ocrelizumab at the end of the trials.

Dr. Traboulsee did not present safety data. A previous report of 24-week results found that infusion reactions were significantly more common with ocrelizumab than with interferon beta-1a (34% vs. 9.7%). Otherwise, there were similar rates of serious adverse events, including serious infections, and there were no cases of progressive multifocal leukoencephalopathy (PML). The PML and infection findings are especially important; Roche shelved earlier attempts to develop the biologic for lupus and rheumatoid arthritis due to serious and opportunistic infections, some of which were fatal.

Roche plans to submit its approval package to the Food and Drug Administration in the first half of 2016; the tentative brand name is Ocrevus. FDA granted the biologic breakthrough, fast-track status for primary progressive MS based on the strength of an earlier phase III trial. At present, there are no MS agents indicated for primary progressive disease.

Patients in OPERA were 37 years old, on average, and two-thirds were women. The mean baseline score on the Extended Disability Status Scale was 2.77, and the mean time since diagnosis was about 4 years. Patients had about 1.5 relapses in the first and second year before entering the studies.

The positive results – and the increasing buzz about ocrelizumab in the MS community – raise the question of how it will fit into the MS armamentarium if it’s approved, which seems likely. A review in Therapeutic Advances in Neurological Disorders tackled the issue in January, before the OPERA results were made public (2016 Jan; 9[1]:44-52).

It’s unclear if ocrelizumab will become the go-to option when patients progress on first-line agents such as interferon and glatiramer acetate. Phase II data suggest ocrelizumab’s “effect on clinical disease activity [seems] to be of the same magnitude compared with that of fingolimod and natalizumab,” and will likely be an alternative to natalizumab and alemtuzumab. “Ocrelizumab seems to have a more favourable risk–benefit profile compared with natalizumab in JC [John Cunningham] virus antibody–positive patients, whereas natalizumab in JC virus antibody–negative patients appears safer. Hence, ocrelizumab could be an attractive option among second-line therapies in patients who are JC virus antibody positive, whereas natalizumab or alternatively oral fingolimod would be the first choice among second-line therapies in JC virus antibody–negative patients,” said authors Dr. Per Soelberg Sorensen and Dr. Morten Blinkenberg, both MS neurologists at the University of Copenhagen.

“It needs to be emphasized that long-term data on the safety of ocrelizumab in the treatment of MS is warranted, and therefore post-marketing safety programs will be needed.” The risk of PML with long-term use is unknown. “Another unsolved question is whether ocrelizumab therapy should be applied at fixed intervals, e.g. every 6 months [as in OPERA], or if re-treatment should be guided by the recovery of CD19-positive B cells,” they said.

In any case, infusion reactions with ocrelizumab should be less than with rituximab (Rituxan), another B-cell depleter used off-label for MS, because ocrelizumab is a more humanized antibody.

OPERA 1 and 2 were funded by Hoffmann–La Roche. Dr. Traboulsee is a paid speaker, consultant, and researcher for the company. Other investigators also reported various ties to Roche; several are employees. The review authors had no disclosures.

[email protected]

VANCOUVER – Ocrelizumab, a B-cell depleting humanized monoclonal antibody being developed by Hoffman–La Roche, consistently outperformed interferon beta-1a (Rebif) for relapsing multiple sclerosis in two phase III trials reported at the annual meeting of the American Academy of Neurology.

The identical trials, dubbed OPERA I and OPERA II, each had about 800 patients. Subjects were randomized one-to-one to intravenous ocrelizumab 600 mg every 24 weeks or to subcutaneous interferon beta-1a 44 micrograms three times weekly over 96 weeks. Patients had early disease; a significant portion were naive to multiple sclerosis (MS) treatments.

At 96 weeks, 47.9% and 47.5% of ocrelizumab patients versus 29.2% and 25.1% of interferon patients had no evidence of disease activity (NEDA) in the two studies. NEDA is a composite score defined as no relapses, no confirmed disability progression, and no new or enlarging T2 or gadolinium-enhancing T1 lesions.

Across both studies, relapses occurred in about 20% of ocrelizumab patients versus about 35% of interferon patients. About 10% of ocrelizumab, but about 15% of interferon patients, had clinical disease progression. Similarly, about 10% of ocrelizumab patients developed new gadolinium-enhancing lesions, compared with about 35% in the interferon groups. New or enlarging T2 lesions were found in about 40% in the ocrelizumab groups but in more than 60% in the interferon arms.

After week 24, 96% percent of ocrelizumab patients, compared with 60%-70% on interferon, were free of new or enlarging T2 lesions.

In short, ocrelizumab “resulted in greater achievement of NEDA versus [interferon] over 96 weeks, with elimination of new/enlarging T2 lesions in nearly all patients after week 24,” the researchers concluded.

“These are very impressive numbers,” especially because ocrelizumab was compared with a standard treatment. “There was a wonderful constancy of results” across the trials; “a very highly effective treatment is emerging for multiple sclerosis,” said investigator and presenter Dr. Anthony Traboulsee, a neurologist at the University of British Columbia, Vancouver, who also noted that in many cases, patients opted to stay on ocrelizumab at the end of the trials.

Dr. Traboulsee did not present safety data. A previous report of 24-week results found that infusion reactions were significantly more common with ocrelizumab than with interferon beta-1a (34% vs. 9.7%). Otherwise, there were similar rates of serious adverse events, including serious infections, and there were no cases of progressive multifocal leukoencephalopathy (PML). The PML and infection findings are especially important; Roche shelved earlier attempts to develop the biologic for lupus and rheumatoid arthritis due to serious and opportunistic infections, some of which were fatal.

Roche plans to submit its approval package to the Food and Drug Administration in the first half of 2016; the tentative brand name is Ocrevus. FDA granted the biologic breakthrough, fast-track status for primary progressive MS based on the strength of an earlier phase III trial. At present, there are no MS agents indicated for primary progressive disease.

Patients in OPERA were 37 years old, on average, and two-thirds were women. The mean baseline score on the Extended Disability Status Scale was 2.77, and the mean time since diagnosis was about 4 years. Patients had about 1.5 relapses in the first and second year before entering the studies.

The positive results – and the increasing buzz about ocrelizumab in the MS community – raise the question of how it will fit into the MS armamentarium if it’s approved, which seems likely. A review in Therapeutic Advances in Neurological Disorders tackled the issue in January, before the OPERA results were made public (2016 Jan; 9[1]:44-52).

It’s unclear if ocrelizumab will become the go-to option when patients progress on first-line agents such as interferon and glatiramer acetate. Phase II data suggest ocrelizumab’s “effect on clinical disease activity [seems] to be of the same magnitude compared with that of fingolimod and natalizumab,” and will likely be an alternative to natalizumab and alemtuzumab. “Ocrelizumab seems to have a more favourable risk–benefit profile compared with natalizumab in JC [John Cunningham] virus antibody–positive patients, whereas natalizumab in JC virus antibody–negative patients appears safer. Hence, ocrelizumab could be an attractive option among second-line therapies in patients who are JC virus antibody positive, whereas natalizumab or alternatively oral fingolimod would be the first choice among second-line therapies in JC virus antibody–negative patients,” said authors Dr. Per Soelberg Sorensen and Dr. Morten Blinkenberg, both MS neurologists at the University of Copenhagen.

“It needs to be emphasized that long-term data on the safety of ocrelizumab in the treatment of MS is warranted, and therefore post-marketing safety programs will be needed.” The risk of PML with long-term use is unknown. “Another unsolved question is whether ocrelizumab therapy should be applied at fixed intervals, e.g. every 6 months [as in OPERA], or if re-treatment should be guided by the recovery of CD19-positive B cells,” they said.

In any case, infusion reactions with ocrelizumab should be less than with rituximab (Rituxan), another B-cell depleter used off-label for MS, because ocrelizumab is a more humanized antibody.

OPERA 1 and 2 were funded by Hoffmann–La Roche. Dr. Traboulsee is a paid speaker, consultant, and researcher for the company. Other investigators also reported various ties to Roche; several are employees. The review authors had no disclosures.

[email protected]

VANCOUVER – Ocrelizumab, a B-cell depleting humanized monoclonal antibody being developed by Hoffman–La Roche, consistently outperformed interferon beta-1a (Rebif) for relapsing multiple sclerosis in two phase III trials reported at the annual meeting of the American Academy of Neurology.

The identical trials, dubbed OPERA I and OPERA II, each had about 800 patients. Subjects were randomized one-to-one to intravenous ocrelizumab 600 mg every 24 weeks or to subcutaneous interferon beta-1a 44 micrograms three times weekly over 96 weeks. Patients had early disease; a significant portion were naive to multiple sclerosis (MS) treatments.

At 96 weeks, 47.9% and 47.5% of ocrelizumab patients versus 29.2% and 25.1% of interferon patients had no evidence of disease activity (NEDA) in the two studies. NEDA is a composite score defined as no relapses, no confirmed disability progression, and no new or enlarging T2 or gadolinium-enhancing T1 lesions.

Across both studies, relapses occurred in about 20% of ocrelizumab patients versus about 35% of interferon patients. About 10% of ocrelizumab, but about 15% of interferon patients, had clinical disease progression. Similarly, about 10% of ocrelizumab patients developed new gadolinium-enhancing lesions, compared with about 35% in the interferon groups. New or enlarging T2 lesions were found in about 40% in the ocrelizumab groups but in more than 60% in the interferon arms.

After week 24, 96% percent of ocrelizumab patients, compared with 60%-70% on interferon, were free of new or enlarging T2 lesions.

In short, ocrelizumab “resulted in greater achievement of NEDA versus [interferon] over 96 weeks, with elimination of new/enlarging T2 lesions in nearly all patients after week 24,” the researchers concluded.

“These are very impressive numbers,” especially because ocrelizumab was compared with a standard treatment. “There was a wonderful constancy of results” across the trials; “a very highly effective treatment is emerging for multiple sclerosis,” said investigator and presenter Dr. Anthony Traboulsee, a neurologist at the University of British Columbia, Vancouver, who also noted that in many cases, patients opted to stay on ocrelizumab at the end of the trials.

Dr. Traboulsee did not present safety data. A previous report of 24-week results found that infusion reactions were significantly more common with ocrelizumab than with interferon beta-1a (34% vs. 9.7%). Otherwise, there were similar rates of serious adverse events, including serious infections, and there were no cases of progressive multifocal leukoencephalopathy (PML). The PML and infection findings are especially important; Roche shelved earlier attempts to develop the biologic for lupus and rheumatoid arthritis due to serious and opportunistic infections, some of which were fatal.

Roche plans to submit its approval package to the Food and Drug Administration in the first half of 2016; the tentative brand name is Ocrevus. FDA granted the biologic breakthrough, fast-track status for primary progressive MS based on the strength of an earlier phase III trial. At present, there are no MS agents indicated for primary progressive disease.

Patients in OPERA were 37 years old, on average, and two-thirds were women. The mean baseline score on the Extended Disability Status Scale was 2.77, and the mean time since diagnosis was about 4 years. Patients had about 1.5 relapses in the first and second year before entering the studies.

The positive results – and the increasing buzz about ocrelizumab in the MS community – raise the question of how it will fit into the MS armamentarium if it’s approved, which seems likely. A review in Therapeutic Advances in Neurological Disorders tackled the issue in January, before the OPERA results were made public (2016 Jan; 9[1]:44-52).

It’s unclear if ocrelizumab will become the go-to option when patients progress on first-line agents such as interferon and glatiramer acetate. Phase II data suggest ocrelizumab’s “effect on clinical disease activity [seems] to be of the same magnitude compared with that of fingolimod and natalizumab,” and will likely be an alternative to natalizumab and alemtuzumab. “Ocrelizumab seems to have a more favourable risk–benefit profile compared with natalizumab in JC [John Cunningham] virus antibody–positive patients, whereas natalizumab in JC virus antibody–negative patients appears safer. Hence, ocrelizumab could be an attractive option among second-line therapies in patients who are JC virus antibody positive, whereas natalizumab or alternatively oral fingolimod would be the first choice among second-line therapies in JC virus antibody–negative patients,” said authors Dr. Per Soelberg Sorensen and Dr. Morten Blinkenberg, both MS neurologists at the University of Copenhagen.

“It needs to be emphasized that long-term data on the safety of ocrelizumab in the treatment of MS is warranted, and therefore post-marketing safety programs will be needed.” The risk of PML with long-term use is unknown. “Another unsolved question is whether ocrelizumab therapy should be applied at fixed intervals, e.g. every 6 months [as in OPERA], or if re-treatment should be guided by the recovery of CD19-positive B cells,” they said.

In any case, infusion reactions with ocrelizumab should be less than with rituximab (Rituxan), another B-cell depleter used off-label for MS, because ocrelizumab is a more humanized antibody.

OPERA 1 and 2 were funded by Hoffmann–La Roche. Dr. Traboulsee is a paid speaker, consultant, and researcher for the company. Other investigators also reported various ties to Roche; several are employees. The review authors had no disclosures.

[email protected]

PARIS – Results of the real-world EWOLUTION registry of recipients of the Watchman device for stroke prevention provide reassuring answers to several key questions which have slowed physician uptake of the left atrial appendage closure device, Dr. Martin W. Bergmann said at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

“EWOLUTION, with more than 1,000 patients, is I think the study that we’ve needed to make this intervention happen in routine practice as a procedure for stroke prevention in atrial fibrillation,” declared Dr. Bergmann of Cardiologicum Hamburg, a large German group practice.

Bruce Jancin/Frontline Medical News

EWOLUTION is a prospective, single-arm, multicenter registry including 1,025 recipients of the first-generation version of the Watchman, a transcatheter device for left atrial appendage closure as a means of stroke prevention in patients with atrial fibrillation (AF). These were high-risk patients: 50% of them had a CHA2DS2-VASc score of 5 or higher, and 72% of participants were deemed unsuitable for warfarin. EWOLUTION was conducted at 47 sites in Europe, the Middle East, and Russia. Dr. Bergmann presented the 3-month outcomes, a key period for device-related complications because protective epithelialization of the device isn’t yet complete. Follow-up will continue at the 1- and 2-year marks.

Among the key findings in the domain of procedural success: The rate of successful device implantation was 98.5%. A complete seal or an echocardiographic color jet of 5 mm or less at the time of implantation was achieved in 99.7% of cases, and this remained the case in 98.9% at 3 months.

With regard to safety, the stroke rate was 0.4%, device embolization occurred in 0.4%, and the pericardial effusion/tamponade rate was 0.7%, all of which are lower rates than in earlier clinical trials.

Just over 4% of patients experienced device-related adverse events with full recovery at the 3-month follow-up. These were mostly bleeding events at the groin access site. More importantly, only 0.5% of patients had device-related serious adverse events that weren’t resolved at 3 months.

“This 0.5% is a major step forward,” Dr. Bergmann said. “This includes all pericardial effusions, all device embolizations, all periprocedural strokes – everything involving the procedure that puts a patient at risk. In fact, that 0.5% risk for left atrial appendage closure with the Watchman is pretty much the same risk as if you refer your patient with AF to an electrophysiologist for pulmonary vein isolation.”

One key question answered by EWOLUTION is, do you need to be an expert in the procedure in order to get excellent results? The answer, Dr. Bergmann said, is emphatically “no.” Interventionalists at the 47 participating sites varied widely in their experience with left atrial appendage occlusion, so investigators divided the sites into quartiles based upon experience and patient volumes contributed to the registry. While cardiologists in the most experienced centers had a significantly higher rate of successful device release on the first try, the most- and least-experienced centers did equally well on the endpoint that really counts: a complete or near-complete seal of the left atrial appendage at follow-up. Complication rates didn’t differ by site experience, either.

Another important practical question that’s been holding up wider adoption of the Watchman concerns how best to handle postimplantation antithrombotic therapy. Here the EWOLUTION registry provides a partial answer: 607 patients were on dual antiplatelet therapy, 113 were on a novel anticoagulant (NOAC), 159 were on warfarin, 67 were on nothing at all, and the rest were on a single antiplatelet agent. And there was no significant difference between any of these groups in the 3-month rates of thrombus on the device, bleeding events, stroke, or other adverse events.

“The main message is there is no difference in serious adverse events between any of the drug regimens. So if you’re in a situation where you can’t give any medication to reduce stroke risk because the bleeding risk is so high, you can go for left atrial appendage closure technology and give them nothing post implant,” according to Dr. Bergmann.

He added that he’d personally try to avoid that strategy: “You want to have some coverage.”

Bruce Jancin/Frontline Medical News

Also noteworthy is that 113 Watchman recipients did well with 3 months of NOAC monotherapy. The appeal of that approach is the short half-life of those agents in the event of a bleeding problem.

Discussant Dr. Farrel Hellig commented that EWOLUTION demonstrates that the Watchman procedure is predictable and safe, with an impressively low complication rate even in inexperienced centers. For that, he added, kudos goes to Boston Scientific, which markets the Watchman, for rolling out an effective physician training program.

“The most important topic to discuss is bleeding, because a bleeding rate of 4.1% at 3 months is certainly not insignificant,” he continued. “It appears, firstly, from EWOLUTION that it’s safe to omit warfarin. I think the most important thing we’d like to know now is could a postprocedure NOAC be the best option, and can aspirin be eliminated in the long term?”

“Is it too early to recommend a NOAC-only for a period of time post procedure? Perhaps. But I think this would be an important next clinical trial: a NOAC-only for a period post procedure with no aspirin to follow. This is the next piece of information we need to complete the puzzle and for left atrial appendage closure to reach its full potential,” according to Dr. Hellig of the University of Cape Town (South Africa).

The EWOLUTION registry is sponsored by Boston Scientific. Dr. Bergmann reported serving as a consultant to Boston Scientific and Biosense Webster and receiving honoraria from more than a half-dozen pharmaceutical and device companies.

[email protected]

PARIS – Results of the real-world EWOLUTION registry of recipients of the Watchman device for stroke prevention provide reassuring answers to several key questions which have slowed physician uptake of the left atrial appendage closure device, Dr. Martin W. Bergmann said at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

“EWOLUTION, with more than 1,000 patients, is I think the study that we’ve needed to make this intervention happen in routine practice as a procedure for stroke prevention in atrial fibrillation,” declared Dr. Bergmann of Cardiologicum Hamburg, a large German group practice.

Bruce Jancin/Frontline Medical News

EWOLUTION is a prospective, single-arm, multicenter registry including 1,025 recipients of the first-generation version of the Watchman, a transcatheter device for left atrial appendage closure as a means of stroke prevention in patients with atrial fibrillation (AF). These were high-risk patients: 50% of them had a CHA2DS2-VASc score of 5 or higher, and 72% of participants were deemed unsuitable for warfarin. EWOLUTION was conducted at 47 sites in Europe, the Middle East, and Russia. Dr. Bergmann presented the 3-month outcomes, a key period for device-related complications because protective epithelialization of the device isn’t yet complete. Follow-up will continue at the 1- and 2-year marks.

Among the key findings in the domain of procedural success: The rate of successful device implantation was 98.5%. A complete seal or an echocardiographic color jet of 5 mm or less at the time of implantation was achieved in 99.7% of cases, and this remained the case in 98.9% at 3 months.

With regard to safety, the stroke rate was 0.4%, device embolization occurred in 0.4%, and the pericardial effusion/tamponade rate was 0.7%, all of which are lower rates than in earlier clinical trials.

Just over 4% of patients experienced device-related adverse events with full recovery at the 3-month follow-up. These were mostly bleeding events at the groin access site. More importantly, only 0.5% of patients had device-related serious adverse events that weren’t resolved at 3 months.

“This 0.5% is a major step forward,” Dr. Bergmann said. “This includes all pericardial effusions, all device embolizations, all periprocedural strokes – everything involving the procedure that puts a patient at risk. In fact, that 0.5% risk for left atrial appendage closure with the Watchman is pretty much the same risk as if you refer your patient with AF to an electrophysiologist for pulmonary vein isolation.”

One key question answered by EWOLUTION is, do you need to be an expert in the procedure in order to get excellent results? The answer, Dr. Bergmann said, is emphatically “no.” Interventionalists at the 47 participating sites varied widely in their experience with left atrial appendage occlusion, so investigators divided the sites into quartiles based upon experience and patient volumes contributed to the registry. While cardiologists in the most experienced centers had a significantly higher rate of successful device release on the first try, the most- and least-experienced centers did equally well on the endpoint that really counts: a complete or near-complete seal of the left atrial appendage at follow-up. Complication rates didn’t differ by site experience, either.

Another important practical question that’s been holding up wider adoption of the Watchman concerns how best to handle postimplantation antithrombotic therapy. Here the EWOLUTION registry provides a partial answer: 607 patients were on dual antiplatelet therapy, 113 were on a novel anticoagulant (NOAC), 159 were on warfarin, 67 were on nothing at all, and the rest were on a single antiplatelet agent. And there was no significant difference between any of these groups in the 3-month rates of thrombus on the device, bleeding events, stroke, or other adverse events.

“The main message is there is no difference in serious adverse events between any of the drug regimens. So if you’re in a situation where you can’t give any medication to reduce stroke risk because the bleeding risk is so high, you can go for left atrial appendage closure technology and give them nothing post implant,” according to Dr. Bergmann.

He added that he’d personally try to avoid that strategy: “You want to have some coverage.”

Bruce Jancin/Frontline Medical News

Also noteworthy is that 113 Watchman recipients did well with 3 months of NOAC monotherapy. The appeal of that approach is the short half-life of those agents in the event of a bleeding problem.

Discussant Dr. Farrel Hellig commented that EWOLUTION demonstrates that the Watchman procedure is predictable and safe, with an impressively low complication rate even in inexperienced centers. For that, he added, kudos goes to Boston Scientific, which markets the Watchman, for rolling out an effective physician training program.

“The most important topic to discuss is bleeding, because a bleeding rate of 4.1% at 3 months is certainly not insignificant,” he continued. “It appears, firstly, from EWOLUTION that it’s safe to omit warfarin. I think the most important thing we’d like to know now is could a postprocedure NOAC be the best option, and can aspirin be eliminated in the long term?”

“Is it too early to recommend a NOAC-only for a period of time post procedure? Perhaps. But I think this would be an important next clinical trial: a NOAC-only for a period post procedure with no aspirin to follow. This is the next piece of information we need to complete the puzzle and for left atrial appendage closure to reach its full potential,” according to Dr. Hellig of the University of Cape Town (South Africa).

The EWOLUTION registry is sponsored by Boston Scientific. Dr. Bergmann reported serving as a consultant to Boston Scientific and Biosense Webster and receiving honoraria from more than a half-dozen pharmaceutical and device companies.

[email protected]

PARIS – Results of the real-world EWOLUTION registry of recipients of the Watchman device for stroke prevention provide reassuring answers to several key questions which have slowed physician uptake of the left atrial appendage closure device, Dr. Martin W. Bergmann said at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

“EWOLUTION, with more than 1,000 patients, is I think the study that we’ve needed to make this intervention happen in routine practice as a procedure for stroke prevention in atrial fibrillation,” declared Dr. Bergmann of Cardiologicum Hamburg, a large German group practice.

Bruce Jancin/Frontline Medical News

EWOLUTION is a prospective, single-arm, multicenter registry including 1,025 recipients of the first-generation version of the Watchman, a transcatheter device for left atrial appendage closure as a means of stroke prevention in patients with atrial fibrillation (AF). These were high-risk patients: 50% of them had a CHA2DS2-VASc score of 5 or higher, and 72% of participants were deemed unsuitable for warfarin. EWOLUTION was conducted at 47 sites in Europe, the Middle East, and Russia. Dr. Bergmann presented the 3-month outcomes, a key period for device-related complications because protective epithelialization of the device isn’t yet complete. Follow-up will continue at the 1- and 2-year marks.

Among the key findings in the domain of procedural success: The rate of successful device implantation was 98.5%. A complete seal or an echocardiographic color jet of 5 mm or less at the time of implantation was achieved in 99.7% of cases, and this remained the case in 98.9% at 3 months.

With regard to safety, the stroke rate was 0.4%, device embolization occurred in 0.4%, and the pericardial effusion/tamponade rate was 0.7%, all of which are lower rates than in earlier clinical trials.

Just over 4% of patients experienced device-related adverse events with full recovery at the 3-month follow-up. These were mostly bleeding events at the groin access site. More importantly, only 0.5% of patients had device-related serious adverse events that weren’t resolved at 3 months.

“This 0.5% is a major step forward,” Dr. Bergmann said. “This includes all pericardial effusions, all device embolizations, all periprocedural strokes – everything involving the procedure that puts a patient at risk. In fact, that 0.5% risk for left atrial appendage closure with the Watchman is pretty much the same risk as if you refer your patient with AF to an electrophysiologist for pulmonary vein isolation.”

One key question answered by EWOLUTION is, do you need to be an expert in the procedure in order to get excellent results? The answer, Dr. Bergmann said, is emphatically “no.” Interventionalists at the 47 participating sites varied widely in their experience with left atrial appendage occlusion, so investigators divided the sites into quartiles based upon experience and patient volumes contributed to the registry. While cardiologists in the most experienced centers had a significantly higher rate of successful device release on the first try, the most- and least-experienced centers did equally well on the endpoint that really counts: a complete or near-complete seal of the left atrial appendage at follow-up. Complication rates didn’t differ by site experience, either.

Another important practical question that’s been holding up wider adoption of the Watchman concerns how best to handle postimplantation antithrombotic therapy. Here the EWOLUTION registry provides a partial answer: 607 patients were on dual antiplatelet therapy, 113 were on a novel anticoagulant (NOAC), 159 were on warfarin, 67 were on nothing at all, and the rest were on a single antiplatelet agent. And there was no significant difference between any of these groups in the 3-month rates of thrombus on the device, bleeding events, stroke, or other adverse events.

“The main message is there is no difference in serious adverse events between any of the drug regimens. So if you’re in a situation where you can’t give any medication to reduce stroke risk because the bleeding risk is so high, you can go for left atrial appendage closure technology and give them nothing post implant,” according to Dr. Bergmann.

He added that he’d personally try to avoid that strategy: “You want to have some coverage.”

Bruce Jancin/Frontline Medical News

Also noteworthy is that 113 Watchman recipients did well with 3 months of NOAC monotherapy. The appeal of that approach is the short half-life of those agents in the event of a bleeding problem.

Discussant Dr. Farrel Hellig commented that EWOLUTION demonstrates that the Watchman procedure is predictable and safe, with an impressively low complication rate even in inexperienced centers. For that, he added, kudos goes to Boston Scientific, which markets the Watchman, for rolling out an effective physician training program.

“The most important topic to discuss is bleeding, because a bleeding rate of 4.1% at 3 months is certainly not insignificant,” he continued. “It appears, firstly, from EWOLUTION that it’s safe to omit warfarin. I think the most important thing we’d like to know now is could a postprocedure NOAC be the best option, and can aspirin be eliminated in the long term?”

“Is it too early to recommend a NOAC-only for a period of time post procedure? Perhaps. But I think this would be an important next clinical trial: a NOAC-only for a period post procedure with no aspirin to follow. This is the next piece of information we need to complete the puzzle and for left atrial appendage closure to reach its full potential,” according to Dr. Hellig of the University of Cape Town (South Africa).

The EWOLUTION registry is sponsored by Boston Scientific. Dr. Bergmann reported serving as a consultant to Boston Scientific and Biosense Webster and receiving honoraria from more than a half-dozen pharmaceutical and device companies.

[email protected]