PHOENIX – Post hoc analysis of the randomized TWILIGHT trial comparing ticagrelor alone with ticagrelor plus aspirin in high-risk patients after percutaneous coronary intervention (PCI) shows both regimens were similarly effective in preventing repeat revascularization after 1 year.

In TWILIGHT, the main findings of which were previously published in the New England Journal of Medicine, 7,119 high-risk PCI patients on standard dual antiplatelet therapy (DAPT) of ticagrelor plus aspirin for 3 months were randomized to continuation of DAPT or to ticagrelor plus placebo for 12 months.

University of Oklahoma

The new post hoc analysis included 6,759 patients and shows the rates of clinically driven revascularization were similar between the two groups: 7.1% and 6.6% for the ticagrelor monotherapy and ticagrelor-based DAPT groups, respectively (P = .363).

The findings were presented at the Society for Cardiovascular Angiography & Interventions annual scientific sessions. 

Three key findings come from the post hoc analysis, Usman Baber, MD, director of the cardiac catheterization lab and associate professor at the University of Oklahoma Health Sciences Center, Oklahoma City, who presented the findings, said in an interview.

“The first is that, over the 1-year follow-up of our trial, we found that a repeat revascularization event occurred in 6.7% of patients,” he said. “We found that a slight majority of these repeat revascularization events were due to events at the target lesion or target vessel; and we found that most of the repeat revascularization events actually occurred in patients without a concomitant acute coronary syndrome. In other words, these were essentially stable patients when they were getting their repeat revascularization.”

The second major finding was that these high-risk patients who had repeat revascularization were at three times greater risk for major adverse cardiac and cerebrovascular events (MACCE), based on a multivariable adjusted model, Dr. Baber said.

“And then third is that ticagrelor on its own as compared with ticagrelor plus aspirin was equally effective in preventing repeat revascularization events,” he said.
 

Repeat revascularization

The goal of the analysis was to focus on clinically driven repeat revascularization as an outcome, Dr. Baber said. The analysis also aimed to understand the association between repeat revascularization and subsequent risk.

Secondary endpoints included target lesion revascularization (TLR); target vessel revascularization (TVR); MACCE, including clinically driven revascularization; and net adverse clinical events (NACE), a composite of MACCE or Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding.

The outcomes of all those endpoints, except for NACE, were similar, Dr. Baber said. “Overall, ticagrelor monotherapy, as expected, reduced rates of bleeding as compared with ticagrelor plus aspirin,” he said. The rates of NACE were 12.2% versus 14.6%, respectively (P = .004). For BARC 2,3, or 5 bleeding, the rates were 3.4% versus 7.1% (P < .001).

The findings validated repeat revascularization as a meaningful endpoint, Dr. Baber said. “Certainly, we don’t elevate repeat revascularization as an endpoint to the same level as death or stroke, but certainly this analysis and some others prior to it highlight the fact that when these patients come back for repeat revascularization, even if they’re stable, they clearly are at elevated risk for future ischemic events,” he said.

One limitation of the analysis is that the data are from a clinical trial, “which renders the findings not as generalizable to the broader patients in a clinical practice,” he said. However, the TWILIGHT data are validated and adjusted for multiple risk factors.

“When patients come in and they have a repeat revascularization, should there be a consideration to placing them on more intensive antithrombotic therapy?” he asked. “Right now, if patients have a repeat revascularization event and they’re stable, guidelines and clinical practice usually calls for continuing clopidogrel, but again our study and others like it indicate these patients are at a higher thrombotic risk, so maybe there’s a rationale for at least a short course of a more potent antiplatelet agent in such patients.”

University of Washington

The post hoc findings confirm those of the primary TWILIGHT trial, Lorenzo Azzalini, MD, PhD, MSc, director of interventional cardiology research at the University of Washington Medical Center, Seattle, said in an interview.

“It’s not surprising to find no difference between the two therapies with regard to unplanned revascularization,” he said. “It’s considered that only stent thrombosis can only actually be mitigated by the drugs being investigated in the trial; all the other ischemic endpoints reflect more chronic ischemia—TLR or known TVR—upon which ticagrelor and aspirin do not play any role.”

However, he added, “I still think this study provides useful information to the community in a period of intense scrutiny on the relative benefits and merits of PCI versus CABG [coronary artery bypass graft], and this study confirms that shortening DAPT to 3 months and then continuing with just ticagrelor does not bring any penalty in terms of ischemic events or repeat revascularization.”

TWILIGHT enrolled high-risk patients, but not “very-high-risk” patients, Dr. Azzalini noted. The enrollment criteria excluded patients on chronic anticoagulation, who had a prior stroke or liver sclerosis, or were on dialysis.

“Future trials should focus more on very-high-risk patients because these are the patients that we deal with on a daily basis in our clinical practice and we need data to inform our decisions,” he said. “I’m not sure I could use the science contained in this study and extrapolate them to patients on dialysis because these patients really have a high risk of restenosis on follow-up.”

Dr. Baber disclosed relationships with Amgen and Abbott. Dr. Azzalini had no relevant disclosures.

PHOENIX – Post hoc analysis of the randomized TWILIGHT trial comparing ticagrelor alone with ticagrelor plus aspirin in high-risk patients after percutaneous coronary intervention (PCI) shows both regimens were similarly effective in preventing repeat revascularization after 1 year.

In TWILIGHT, the main findings of which were previously published in the New England Journal of Medicine, 7,119 high-risk PCI patients on standard dual antiplatelet therapy (DAPT) of ticagrelor plus aspirin for 3 months were randomized to continuation of DAPT or to ticagrelor plus placebo for 12 months.

University of Oklahoma

The new post hoc analysis included 6,759 patients and shows the rates of clinically driven revascularization were similar between the two groups: 7.1% and 6.6% for the ticagrelor monotherapy and ticagrelor-based DAPT groups, respectively (P = .363).

The findings were presented at the Society for Cardiovascular Angiography & Interventions annual scientific sessions. 

Three key findings come from the post hoc analysis, Usman Baber, MD, director of the cardiac catheterization lab and associate professor at the University of Oklahoma Health Sciences Center, Oklahoma City, who presented the findings, said in an interview.

“The first is that, over the 1-year follow-up of our trial, we found that a repeat revascularization event occurred in 6.7% of patients,” he said. “We found that a slight majority of these repeat revascularization events were due to events at the target lesion or target vessel; and we found that most of the repeat revascularization events actually occurred in patients without a concomitant acute coronary syndrome. In other words, these were essentially stable patients when they were getting their repeat revascularization.”

The second major finding was that these high-risk patients who had repeat revascularization were at three times greater risk for major adverse cardiac and cerebrovascular events (MACCE), based on a multivariable adjusted model, Dr. Baber said.

“And then third is that ticagrelor on its own as compared with ticagrelor plus aspirin was equally effective in preventing repeat revascularization events,” he said.
 

Repeat revascularization

The goal of the analysis was to focus on clinically driven repeat revascularization as an outcome, Dr. Baber said. The analysis also aimed to understand the association between repeat revascularization and subsequent risk.

Secondary endpoints included target lesion revascularization (TLR); target vessel revascularization (TVR); MACCE, including clinically driven revascularization; and net adverse clinical events (NACE), a composite of MACCE or Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding.

The outcomes of all those endpoints, except for NACE, were similar, Dr. Baber said. “Overall, ticagrelor monotherapy, as expected, reduced rates of bleeding as compared with ticagrelor plus aspirin,” he said. The rates of NACE were 12.2% versus 14.6%, respectively (P = .004). For BARC 2,3, or 5 bleeding, the rates were 3.4% versus 7.1% (P < .001).

The findings validated repeat revascularization as a meaningful endpoint, Dr. Baber said. “Certainly, we don’t elevate repeat revascularization as an endpoint to the same level as death or stroke, but certainly this analysis and some others prior to it highlight the fact that when these patients come back for repeat revascularization, even if they’re stable, they clearly are at elevated risk for future ischemic events,” he said.

One limitation of the analysis is that the data are from a clinical trial, “which renders the findings not as generalizable to the broader patients in a clinical practice,” he said. However, the TWILIGHT data are validated and adjusted for multiple risk factors.

“When patients come in and they have a repeat revascularization, should there be a consideration to placing them on more intensive antithrombotic therapy?” he asked. “Right now, if patients have a repeat revascularization event and they’re stable, guidelines and clinical practice usually calls for continuing clopidogrel, but again our study and others like it indicate these patients are at a higher thrombotic risk, so maybe there’s a rationale for at least a short course of a more potent antiplatelet agent in such patients.”

University of Washington

The post hoc findings confirm those of the primary TWILIGHT trial, Lorenzo Azzalini, MD, PhD, MSc, director of interventional cardiology research at the University of Washington Medical Center, Seattle, said in an interview.

“It’s not surprising to find no difference between the two therapies with regard to unplanned revascularization,” he said. “It’s considered that only stent thrombosis can only actually be mitigated by the drugs being investigated in the trial; all the other ischemic endpoints reflect more chronic ischemia—TLR or known TVR—upon which ticagrelor and aspirin do not play any role.”

However, he added, “I still think this study provides useful information to the community in a period of intense scrutiny on the relative benefits and merits of PCI versus CABG [coronary artery bypass graft], and this study confirms that shortening DAPT to 3 months and then continuing with just ticagrelor does not bring any penalty in terms of ischemic events or repeat revascularization.”

TWILIGHT enrolled high-risk patients, but not “very-high-risk” patients, Dr. Azzalini noted. The enrollment criteria excluded patients on chronic anticoagulation, who had a prior stroke or liver sclerosis, or were on dialysis.

“Future trials should focus more on very-high-risk patients because these are the patients that we deal with on a daily basis in our clinical practice and we need data to inform our decisions,” he said. “I’m not sure I could use the science contained in this study and extrapolate them to patients on dialysis because these patients really have a high risk of restenosis on follow-up.”

Dr. Baber disclosed relationships with Amgen and Abbott. Dr. Azzalini had no relevant disclosures.

PHOENIX – Post hoc analysis of the randomized TWILIGHT trial comparing ticagrelor alone with ticagrelor plus aspirin in high-risk patients after percutaneous coronary intervention (PCI) shows both regimens were similarly effective in preventing repeat revascularization after 1 year.

In TWILIGHT, the main findings of which were previously published in the New England Journal of Medicine, 7,119 high-risk PCI patients on standard dual antiplatelet therapy (DAPT) of ticagrelor plus aspirin for 3 months were randomized to continuation of DAPT or to ticagrelor plus placebo for 12 months.

University of Oklahoma

The new post hoc analysis included 6,759 patients and shows the rates of clinically driven revascularization were similar between the two groups: 7.1% and 6.6% for the ticagrelor monotherapy and ticagrelor-based DAPT groups, respectively (P = .363).

The findings were presented at the Society for Cardiovascular Angiography & Interventions annual scientific sessions. 

Three key findings come from the post hoc analysis, Usman Baber, MD, director of the cardiac catheterization lab and associate professor at the University of Oklahoma Health Sciences Center, Oklahoma City, who presented the findings, said in an interview.

“The first is that, over the 1-year follow-up of our trial, we found that a repeat revascularization event occurred in 6.7% of patients,” he said. “We found that a slight majority of these repeat revascularization events were due to events at the target lesion or target vessel; and we found that most of the repeat revascularization events actually occurred in patients without a concomitant acute coronary syndrome. In other words, these were essentially stable patients when they were getting their repeat revascularization.”

The second major finding was that these high-risk patients who had repeat revascularization were at three times greater risk for major adverse cardiac and cerebrovascular events (MACCE), based on a multivariable adjusted model, Dr. Baber said.

“And then third is that ticagrelor on its own as compared with ticagrelor plus aspirin was equally effective in preventing repeat revascularization events,” he said.
 

Repeat revascularization

The goal of the analysis was to focus on clinically driven repeat revascularization as an outcome, Dr. Baber said. The analysis also aimed to understand the association between repeat revascularization and subsequent risk.

Secondary endpoints included target lesion revascularization (TLR); target vessel revascularization (TVR); MACCE, including clinically driven revascularization; and net adverse clinical events (NACE), a composite of MACCE or Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding.

The outcomes of all those endpoints, except for NACE, were similar, Dr. Baber said. “Overall, ticagrelor monotherapy, as expected, reduced rates of bleeding as compared with ticagrelor plus aspirin,” he said. The rates of NACE were 12.2% versus 14.6%, respectively (P = .004). For BARC 2,3, or 5 bleeding, the rates were 3.4% versus 7.1% (P < .001).

The findings validated repeat revascularization as a meaningful endpoint, Dr. Baber said. “Certainly, we don’t elevate repeat revascularization as an endpoint to the same level as death or stroke, but certainly this analysis and some others prior to it highlight the fact that when these patients come back for repeat revascularization, even if they’re stable, they clearly are at elevated risk for future ischemic events,” he said.

One limitation of the analysis is that the data are from a clinical trial, “which renders the findings not as generalizable to the broader patients in a clinical practice,” he said. However, the TWILIGHT data are validated and adjusted for multiple risk factors.

“When patients come in and they have a repeat revascularization, should there be a consideration to placing them on more intensive antithrombotic therapy?” he asked. “Right now, if patients have a repeat revascularization event and they’re stable, guidelines and clinical practice usually calls for continuing clopidogrel, but again our study and others like it indicate these patients are at a higher thrombotic risk, so maybe there’s a rationale for at least a short course of a more potent antiplatelet agent in such patients.”

University of Washington

The post hoc findings confirm those of the primary TWILIGHT trial, Lorenzo Azzalini, MD, PhD, MSc, director of interventional cardiology research at the University of Washington Medical Center, Seattle, said in an interview.

“It’s not surprising to find no difference between the two therapies with regard to unplanned revascularization,” he said. “It’s considered that only stent thrombosis can only actually be mitigated by the drugs being investigated in the trial; all the other ischemic endpoints reflect more chronic ischemia—TLR or known TVR—upon which ticagrelor and aspirin do not play any role.”

However, he added, “I still think this study provides useful information to the community in a period of intense scrutiny on the relative benefits and merits of PCI versus CABG [coronary artery bypass graft], and this study confirms that shortening DAPT to 3 months and then continuing with just ticagrelor does not bring any penalty in terms of ischemic events or repeat revascularization.”

TWILIGHT enrolled high-risk patients, but not “very-high-risk” patients, Dr. Azzalini noted. The enrollment criteria excluded patients on chronic anticoagulation, who had a prior stroke or liver sclerosis, or were on dialysis.

“Future trials should focus more on very-high-risk patients because these are the patients that we deal with on a daily basis in our clinical practice and we need data to inform our decisions,” he said. “I’m not sure I could use the science contained in this study and extrapolate them to patients on dialysis because these patients really have a high risk of restenosis on follow-up.”

Dr. Baber disclosed relationships with Amgen and Abbott. Dr. Azzalini had no relevant disclosures.

At the time that it was halted, a multicenter randomized trial was associating venoarterial extracorporeal membrane oxygenation (VA-ECMO) with an intriguing signal of benefit for patients in cardiogenic shock undergoing percutaneous intervention (PCI) for acute myocardial infarction.

Stopped early because of the pandemic, the EURO SHOCK trial has data on only 35 patients, but all-cause mortality at 30 days was nearly 30% lower in the VA-ECMO arm than in the standard-therapy arm, reported Manel Sabate, MD, PhD, chief of the interventional cardiology unit, Clinic University Hospital, Barcelona.

When patients were followed out to 12 months, the numerical survival advantage appeared to persist.

Yet, because of the early trial termination, “there really are no definite conclusions to be drawn from these results,” acknowledged Dr. Sabate, who noted that less than 10% of the planned enrollment had been reached. In addition, the survival benefit in the VA-ECMO arm was achieved at the cost of a higher rate of complications.

Despite the small numbers, results from the halted trial were presented as a late-breaker at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions. They were also simultaneously published in EuroIntervention.

The interest is based on an important unmet need, said Dr. Sabate. Cardiogenic shock occurs in about 10% of acute MI patients. Of those that continue on to revascularization, the 30-day mortality can approach 50%.

Meanwhile, the potential of mechanical circulatory support to maintain perfusion during cardiogenic shock makes it one of the most attractive, if unproven, approaches for improving outcomes.
 

Major multicenter trial terminated

The EURO SHOCK trial had a planned enrollment of 428 patients when it was initiated; 15 centers in six European countries participated. Recruitment and the trial were brought to a halt by the COVID-19 pandemic.

When trial recruitment was stopped, 18 patients had been assigned to standard supportive care and 17 patients to VA-ECMO. The primary endpoint of the trial was all-cause mortality at 30 days. Mortality at 12 months along with bleeding complications, cerebrovascular events, and readmission for heart failure, were among secondary endpoints.

At 30 days, the mortality rate was 61.1% among patients randomized to standard care, versus 43.8% among patients randomized to VA ECMO (hazard ratio, 0.56; 95% confidence interval, 0.21-01.45; P = 0.22).

At 12 months, the numerical advantage of VA-ECMO persisted (81.5% vs. 51.8%) with a similar nonsignificant signal for potential benefit despite the small sample size (HR, 0.52; 95% CI, 0.21-1.26; P = 0.14).

There were also numerically lower rates of cardiovascular death, ischemic stroke, recurrent MI, and acute kidney injury among patients in the VA-ECMO group relative to those in the standard-care group, Dr. Sabate reported.

However, VA-ECMO was associated with more vascular complications (21.4% vs. 0%) and bleeding events (35.7% vs. 5.6%).

Furthermore, although quality of life data were limited, Dr. Sabate noted that about half of patients in the VA-ECMO group reported problems with mobility, self-care, or usual activities on the basis of the EQ-5D-3L questionnaire at 30 days. None of the patients in the standard-care group reported any such difficulties.

When standard care was compared with VA-ECMO, rates of readmission for heart failure over 12 months (8.0% vs. 6.9%) were not different.

To be enrolled in this study, patients being treated for MI had to be in cardiogenic shock for at least 30 minutes following primary PCI. The median time from onset of cardiogenic shock to VA-ECMO in the active treatment arm was 4.8 hours.
 

Patient enrollment was challenging

Even independent of the COVID-19 pandemic, enrolling patients proved to be difficult. The 35 patients enrolled represented about 10% of the 333 patients screened at the participating centers. Unwitnessed out-of-hospital cardiac arrest, cardiogenic shock from a cause other than MI, and recovery from cardiogenic shock after the PCI was performed were among reasons for the high rate of exclusions.

The difficulty of identifying and engaging appropriate candidates for VA-ECMO, along with a substantial crossover rate, should be among lessons for investigators planning the next trial, said Dr. Sabate, who pointed out that 5 of the 17 patients assigned to VA-ECMO were never treated due to complications or patient refusal.

“We cannot associate VA-ECMO with a favorable benefit-to-risk ratio on the basis of this study, but it sets the state for a larger randomized controlled trial to address this question,” Dr. Sabate said.

Davide Capodanno, MD, PhD, a professor of cardiology and interventional cardiologist at the University of Catania (Italy), agreed.

“It was a good decision to publish these results,” he said. Noting that there were challenges in conducting the trial unrelated to COVID-19, Dr. Capodanno acknowledged the promise of mechanical ventilatory support for a relatively common and life-threatening complication.

“This study must be read for the lessons it will provide for future trials,” he said.

Dr. Sabate reported he has no potential conflicts of interest. Dr. Capodanno reported financial relationships with Amgen, Daiichi Sankyo, and Sanofi.

At the time that it was halted, a multicenter randomized trial was associating venoarterial extracorporeal membrane oxygenation (VA-ECMO) with an intriguing signal of benefit for patients in cardiogenic shock undergoing percutaneous intervention (PCI) for acute myocardial infarction.

Stopped early because of the pandemic, the EURO SHOCK trial has data on only 35 patients, but all-cause mortality at 30 days was nearly 30% lower in the VA-ECMO arm than in the standard-therapy arm, reported Manel Sabate, MD, PhD, chief of the interventional cardiology unit, Clinic University Hospital, Barcelona.

When patients were followed out to 12 months, the numerical survival advantage appeared to persist.

Yet, because of the early trial termination, “there really are no definite conclusions to be drawn from these results,” acknowledged Dr. Sabate, who noted that less than 10% of the planned enrollment had been reached. In addition, the survival benefit in the VA-ECMO arm was achieved at the cost of a higher rate of complications.

Despite the small numbers, results from the halted trial were presented as a late-breaker at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions. They were also simultaneously published in EuroIntervention.

The interest is based on an important unmet need, said Dr. Sabate. Cardiogenic shock occurs in about 10% of acute MI patients. Of those that continue on to revascularization, the 30-day mortality can approach 50%.

Meanwhile, the potential of mechanical circulatory support to maintain perfusion during cardiogenic shock makes it one of the most attractive, if unproven, approaches for improving outcomes.
 

Major multicenter trial terminated

The EURO SHOCK trial had a planned enrollment of 428 patients when it was initiated; 15 centers in six European countries participated. Recruitment and the trial were brought to a halt by the COVID-19 pandemic.

When trial recruitment was stopped, 18 patients had been assigned to standard supportive care and 17 patients to VA-ECMO. The primary endpoint of the trial was all-cause mortality at 30 days. Mortality at 12 months along with bleeding complications, cerebrovascular events, and readmission for heart failure, were among secondary endpoints.

At 30 days, the mortality rate was 61.1% among patients randomized to standard care, versus 43.8% among patients randomized to VA ECMO (hazard ratio, 0.56; 95% confidence interval, 0.21-01.45; P = 0.22).

At 12 months, the numerical advantage of VA-ECMO persisted (81.5% vs. 51.8%) with a similar nonsignificant signal for potential benefit despite the small sample size (HR, 0.52; 95% CI, 0.21-1.26; P = 0.14).

There were also numerically lower rates of cardiovascular death, ischemic stroke, recurrent MI, and acute kidney injury among patients in the VA-ECMO group relative to those in the standard-care group, Dr. Sabate reported.

However, VA-ECMO was associated with more vascular complications (21.4% vs. 0%) and bleeding events (35.7% vs. 5.6%).

Furthermore, although quality of life data were limited, Dr. Sabate noted that about half of patients in the VA-ECMO group reported problems with mobility, self-care, or usual activities on the basis of the EQ-5D-3L questionnaire at 30 days. None of the patients in the standard-care group reported any such difficulties.

When standard care was compared with VA-ECMO, rates of readmission for heart failure over 12 months (8.0% vs. 6.9%) were not different.

To be enrolled in this study, patients being treated for MI had to be in cardiogenic shock for at least 30 minutes following primary PCI. The median time from onset of cardiogenic shock to VA-ECMO in the active treatment arm was 4.8 hours.
 

Patient enrollment was challenging

Even independent of the COVID-19 pandemic, enrolling patients proved to be difficult. The 35 patients enrolled represented about 10% of the 333 patients screened at the participating centers. Unwitnessed out-of-hospital cardiac arrest, cardiogenic shock from a cause other than MI, and recovery from cardiogenic shock after the PCI was performed were among reasons for the high rate of exclusions.

The difficulty of identifying and engaging appropriate candidates for VA-ECMO, along with a substantial crossover rate, should be among lessons for investigators planning the next trial, said Dr. Sabate, who pointed out that 5 of the 17 patients assigned to VA-ECMO were never treated due to complications or patient refusal.

“We cannot associate VA-ECMO with a favorable benefit-to-risk ratio on the basis of this study, but it sets the state for a larger randomized controlled trial to address this question,” Dr. Sabate said.

Davide Capodanno, MD, PhD, a professor of cardiology and interventional cardiologist at the University of Catania (Italy), agreed.

“It was a good decision to publish these results,” he said. Noting that there were challenges in conducting the trial unrelated to COVID-19, Dr. Capodanno acknowledged the promise of mechanical ventilatory support for a relatively common and life-threatening complication.

“This study must be read for the lessons it will provide for future trials,” he said.

Dr. Sabate reported he has no potential conflicts of interest. Dr. Capodanno reported financial relationships with Amgen, Daiichi Sankyo, and Sanofi.

At the time that it was halted, a multicenter randomized trial was associating venoarterial extracorporeal membrane oxygenation (VA-ECMO) with an intriguing signal of benefit for patients in cardiogenic shock undergoing percutaneous intervention (PCI) for acute myocardial infarction.

Stopped early because of the pandemic, the EURO SHOCK trial has data on only 35 patients, but all-cause mortality at 30 days was nearly 30% lower in the VA-ECMO arm than in the standard-therapy arm, reported Manel Sabate, MD, PhD, chief of the interventional cardiology unit, Clinic University Hospital, Barcelona.

When patients were followed out to 12 months, the numerical survival advantage appeared to persist.

Yet, because of the early trial termination, “there really are no definite conclusions to be drawn from these results,” acknowledged Dr. Sabate, who noted that less than 10% of the planned enrollment had been reached. In addition, the survival benefit in the VA-ECMO arm was achieved at the cost of a higher rate of complications.

Despite the small numbers, results from the halted trial were presented as a late-breaker at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions. They were also simultaneously published in EuroIntervention.

The interest is based on an important unmet need, said Dr. Sabate. Cardiogenic shock occurs in about 10% of acute MI patients. Of those that continue on to revascularization, the 30-day mortality can approach 50%.

Meanwhile, the potential of mechanical circulatory support to maintain perfusion during cardiogenic shock makes it one of the most attractive, if unproven, approaches for improving outcomes.
 

Major multicenter trial terminated

The EURO SHOCK trial had a planned enrollment of 428 patients when it was initiated; 15 centers in six European countries participated. Recruitment and the trial were brought to a halt by the COVID-19 pandemic.

When trial recruitment was stopped, 18 patients had been assigned to standard supportive care and 17 patients to VA-ECMO. The primary endpoint of the trial was all-cause mortality at 30 days. Mortality at 12 months along with bleeding complications, cerebrovascular events, and readmission for heart failure, were among secondary endpoints.

At 30 days, the mortality rate was 61.1% among patients randomized to standard care, versus 43.8% among patients randomized to VA ECMO (hazard ratio, 0.56; 95% confidence interval, 0.21-01.45; P = 0.22).

At 12 months, the numerical advantage of VA-ECMO persisted (81.5% vs. 51.8%) with a similar nonsignificant signal for potential benefit despite the small sample size (HR, 0.52; 95% CI, 0.21-1.26; P = 0.14).

There were also numerically lower rates of cardiovascular death, ischemic stroke, recurrent MI, and acute kidney injury among patients in the VA-ECMO group relative to those in the standard-care group, Dr. Sabate reported.

However, VA-ECMO was associated with more vascular complications (21.4% vs. 0%) and bleeding events (35.7% vs. 5.6%).

Furthermore, although quality of life data were limited, Dr. Sabate noted that about half of patients in the VA-ECMO group reported problems with mobility, self-care, or usual activities on the basis of the EQ-5D-3L questionnaire at 30 days. None of the patients in the standard-care group reported any such difficulties.

When standard care was compared with VA-ECMO, rates of readmission for heart failure over 12 months (8.0% vs. 6.9%) were not different.

To be enrolled in this study, patients being treated for MI had to be in cardiogenic shock for at least 30 minutes following primary PCI. The median time from onset of cardiogenic shock to VA-ECMO in the active treatment arm was 4.8 hours.
 

Patient enrollment was challenging

Even independent of the COVID-19 pandemic, enrolling patients proved to be difficult. The 35 patients enrolled represented about 10% of the 333 patients screened at the participating centers. Unwitnessed out-of-hospital cardiac arrest, cardiogenic shock from a cause other than MI, and recovery from cardiogenic shock after the PCI was performed were among reasons for the high rate of exclusions.

The difficulty of identifying and engaging appropriate candidates for VA-ECMO, along with a substantial crossover rate, should be among lessons for investigators planning the next trial, said Dr. Sabate, who pointed out that 5 of the 17 patients assigned to VA-ECMO were never treated due to complications or patient refusal.

“We cannot associate VA-ECMO with a favorable benefit-to-risk ratio on the basis of this study, but it sets the state for a larger randomized controlled trial to address this question,” Dr. Sabate said.

Davide Capodanno, MD, PhD, a professor of cardiology and interventional cardiologist at the University of Catania (Italy), agreed.

“It was a good decision to publish these results,” he said. Noting that there were challenges in conducting the trial unrelated to COVID-19, Dr. Capodanno acknowledged the promise of mechanical ventilatory support for a relatively common and life-threatening complication.

“This study must be read for the lessons it will provide for future trials,” he said.

Dr. Sabate reported he has no potential conflicts of interest. Dr. Capodanno reported financial relationships with Amgen, Daiichi Sankyo, and Sanofi.

Among the patients treated with trastuzumab deruxtecan, median progression-free survival was significantly prolonged compared with the physician's choice treatment group (17.8 vs 6.9 months; hazard ratio 0.36; P < .0001). There were no new safety signals reported for trastuzumab deruxtecan. Of interest, drug-related interstitial lung disease occurred in 10% of patients treated with trastuzumab deruxtecan (including two grade 5 death events) compared with < 1% in the physician's-choice treatment group.

Overall, trastuzumab deruxtecan demonstrated a favorable benefit-risk profile in patients with HER2+ BC previously treated with trastuzumab emtansine. This is the first randomized study to show efficacy with an antibody-drug conjugate after a previous antibody-drug conjugate.

Breast density is a known independent risk factor for BC, furthermore, dense breast tissue can make identifying BC on screening mammograms more challenging. The nested case-control cohort study by Jiang and colleagues observed women with no history of any cancer for 10 years, with screening mammograms every 1-2 years. Subsequently, 289 women who developed BC were identified and analyzed along with 658 matched control individuals. BC risk factors were also collected via questionnaires at the time of enrollment. Of note, the BC cases cohort had an overall higher mean body mass index, a higher percentage of Black women, and of women with a family history of BC. The results showed that though women's breast density decreased over time in both cases and controls, the rate of change in breast density was significantly slower in the breast that later developed cancer compared with the cancer-free breast in control individuals (estimate 0.027; P = .04). Enhancing screening modalities to enable assessing for longitudinal changes in breast density may provide an additional tool for evaluating the risk for BC.

Reducing the late BC recurrence risk beyond 5 years is a significant issue in patients with hormone receptor–positive (HR+) BC. This prospective, randomized, phase 3, AERAS trial included 1593 postmenopausal women with HR+ early-stage invasive BC who were disease-free at 5 years after postoperative endocrine therapy. Patients were randomly assigned 1:1 to stop or continue receiving anastrozole for an additional 5 years. Results showed that continuation of anastrozole treatment for an additional 5 years significantly improved 5-year disease-free survival (DFS) (hazard ratio 0.61; 95% CI 0.46-0.82; P < .0010). Furthermore, extended anastrozole treatment reduced the incidence of local recurrence and second primary cancers. However, there was no significant difference in distant DFS. The incidence of grade 3 or higher adverse events was < 1% in both groups, although menopausal or bone-related all-grade adverse events were more frequent among patients in the group that continued with anastrozole, as expected. Results from this study help inform the risks and benefits of extending hormone therapy beyond 5 years.

The RxPONDER trial comparing endocrine therapy (ET) alone to chemotherapy plus endocrine therapy (CET) in patients with one to three positive axillary lymph nodes and recurrence score (RS) ≤ 25 showed that CET did not improve survival outcomes compared with ET alone in postmenopausal women with HR+/HER2- BC. This retrospective cohort study of real-world data from the National Cancer Database included 28,427 women with stage I-III HR+/HER2- BC and one to three positive axillary lymph nodes, of which 26.3% and 73.7% of patients received CET and ET, respectively. Results showed that in patients with RS of 20-25, CET was associated with a significant improvement in overall survival compared with ET alone, in both premenopausal (age ≤ 50 years: hazard ratio 0.334, P = .002) and postmenopausal patients (age > 50 years: hazard ratio 0.521, P = .019). Though these results are inconsistent with the RxPONDER trial results regarding the postmenopausal cohort, they do raise an important finding that is supported by prior published data.¹ More studies are needed to validate these findings. At this time, guidelines recommend omitting chemotherapy in patients with HR+/HER2- BC, one to three positive axillary lymph nodes, and an RS of 20-25 per RxPONDER.

Additional Reference

1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379:432-444. doi: 10.1016/S0140-6736(11)61625-5

Among the patients treated with trastuzumab deruxtecan, median progression-free survival was significantly prolonged compared with the physician's choice treatment group (17.8 vs 6.9 months; hazard ratio 0.36; P < .0001). There were no new safety signals reported for trastuzumab deruxtecan. Of interest, drug-related interstitial lung disease occurred in 10% of patients treated with trastuzumab deruxtecan (including two grade 5 death events) compared with < 1% in the physician's-choice treatment group.

Overall, trastuzumab deruxtecan demonstrated a favorable benefit-risk profile in patients with HER2+ BC previously treated with trastuzumab emtansine. This is the first randomized study to show efficacy with an antibody-drug conjugate after a previous antibody-drug conjugate.

Breast density is a known independent risk factor for BC, furthermore, dense breast tissue can make identifying BC on screening mammograms more challenging. The nested case-control cohort study by Jiang and colleagues observed women with no history of any cancer for 10 years, with screening mammograms every 1-2 years. Subsequently, 289 women who developed BC were identified and analyzed along with 658 matched control individuals. BC risk factors were also collected via questionnaires at the time of enrollment. Of note, the BC cases cohort had an overall higher mean body mass index, a higher percentage of Black women, and of women with a family history of BC. The results showed that though women's breast density decreased over time in both cases and controls, the rate of change in breast density was significantly slower in the breast that later developed cancer compared with the cancer-free breast in control individuals (estimate 0.027; P = .04). Enhancing screening modalities to enable assessing for longitudinal changes in breast density may provide an additional tool for evaluating the risk for BC.

Reducing the late BC recurrence risk beyond 5 years is a significant issue in patients with hormone receptor–positive (HR+) BC. This prospective, randomized, phase 3, AERAS trial included 1593 postmenopausal women with HR+ early-stage invasive BC who were disease-free at 5 years after postoperative endocrine therapy. Patients were randomly assigned 1:1 to stop or continue receiving anastrozole for an additional 5 years. Results showed that continuation of anastrozole treatment for an additional 5 years significantly improved 5-year disease-free survival (DFS) (hazard ratio 0.61; 95% CI 0.46-0.82; P < .0010). Furthermore, extended anastrozole treatment reduced the incidence of local recurrence and second primary cancers. However, there was no significant difference in distant DFS. The incidence of grade 3 or higher adverse events was < 1% in both groups, although menopausal or bone-related all-grade adverse events were more frequent among patients in the group that continued with anastrozole, as expected. Results from this study help inform the risks and benefits of extending hormone therapy beyond 5 years.

The RxPONDER trial comparing endocrine therapy (ET) alone to chemotherapy plus endocrine therapy (CET) in patients with one to three positive axillary lymph nodes and recurrence score (RS) ≤ 25 showed that CET did not improve survival outcomes compared with ET alone in postmenopausal women with HR+/HER2- BC. This retrospective cohort study of real-world data from the National Cancer Database included 28,427 women with stage I-III HR+/HER2- BC and one to three positive axillary lymph nodes, of which 26.3% and 73.7% of patients received CET and ET, respectively. Results showed that in patients with RS of 20-25, CET was associated with a significant improvement in overall survival compared with ET alone, in both premenopausal (age ≤ 50 years: hazard ratio 0.334, P = .002) and postmenopausal patients (age > 50 years: hazard ratio 0.521, P = .019). Though these results are inconsistent with the RxPONDER trial results regarding the postmenopausal cohort, they do raise an important finding that is supported by prior published data.¹ More studies are needed to validate these findings. At this time, guidelines recommend omitting chemotherapy in patients with HR+/HER2- BC, one to three positive axillary lymph nodes, and an RS of 20-25 per RxPONDER.

Additional Reference

1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379:432-444. doi: 10.1016/S0140-6736(11)61625-5

Among the patients treated with trastuzumab deruxtecan, median progression-free survival was significantly prolonged compared with the physician's choice treatment group (17.8 vs 6.9 months; hazard ratio 0.36; P < .0001). There were no new safety signals reported for trastuzumab deruxtecan. Of interest, drug-related interstitial lung disease occurred in 10% of patients treated with trastuzumab deruxtecan (including two grade 5 death events) compared with < 1% in the physician's-choice treatment group.

Overall, trastuzumab deruxtecan demonstrated a favorable benefit-risk profile in patients with HER2+ BC previously treated with trastuzumab emtansine. This is the first randomized study to show efficacy with an antibody-drug conjugate after a previous antibody-drug conjugate.

Breast density is a known independent risk factor for BC, furthermore, dense breast tissue can make identifying BC on screening mammograms more challenging. The nested case-control cohort study by Jiang and colleagues observed women with no history of any cancer for 10 years, with screening mammograms every 1-2 years. Subsequently, 289 women who developed BC were identified and analyzed along with 658 matched control individuals. BC risk factors were also collected via questionnaires at the time of enrollment. Of note, the BC cases cohort had an overall higher mean body mass index, a higher percentage of Black women, and of women with a family history of BC. The results showed that though women's breast density decreased over time in both cases and controls, the rate of change in breast density was significantly slower in the breast that later developed cancer compared with the cancer-free breast in control individuals (estimate 0.027; P = .04). Enhancing screening modalities to enable assessing for longitudinal changes in breast density may provide an additional tool for evaluating the risk for BC.

Reducing the late BC recurrence risk beyond 5 years is a significant issue in patients with hormone receptor–positive (HR+) BC. This prospective, randomized, phase 3, AERAS trial included 1593 postmenopausal women with HR+ early-stage invasive BC who were disease-free at 5 years after postoperative endocrine therapy. Patients were randomly assigned 1:1 to stop or continue receiving anastrozole for an additional 5 years. Results showed that continuation of anastrozole treatment for an additional 5 years significantly improved 5-year disease-free survival (DFS) (hazard ratio 0.61; 95% CI 0.46-0.82; P < .0010). Furthermore, extended anastrozole treatment reduced the incidence of local recurrence and second primary cancers. However, there was no significant difference in distant DFS. The incidence of grade 3 or higher adverse events was < 1% in both groups, although menopausal or bone-related all-grade adverse events were more frequent among patients in the group that continued with anastrozole, as expected. Results from this study help inform the risks and benefits of extending hormone therapy beyond 5 years.

The RxPONDER trial comparing endocrine therapy (ET) alone to chemotherapy plus endocrine therapy (CET) in patients with one to three positive axillary lymph nodes and recurrence score (RS) ≤ 25 showed that CET did not improve survival outcomes compared with ET alone in postmenopausal women with HR+/HER2- BC. This retrospective cohort study of real-world data from the National Cancer Database included 28,427 women with stage I-III HR+/HER2- BC and one to three positive axillary lymph nodes, of which 26.3% and 73.7% of patients received CET and ET, respectively. Results showed that in patients with RS of 20-25, CET was associated with a significant improvement in overall survival compared with ET alone, in both premenopausal (age ≤ 50 years: hazard ratio 0.334, P = .002) and postmenopausal patients (age > 50 years: hazard ratio 0.521, P = .019). Though these results are inconsistent with the RxPONDER trial results regarding the postmenopausal cohort, they do raise an important finding that is supported by prior published data.¹ More studies are needed to validate these findings. At this time, guidelines recommend omitting chemotherapy in patients with HR+/HER2- BC, one to three positive axillary lymph nodes, and an RS of 20-25 per RxPONDER.

Additional Reference

1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379:432-444. doi: 10.1016/S0140-6736(11)61625-5

WASHINGTON – Abrocitinib demonstrated an acceptable long-term safety profile in adolescents with moderate to severe atopic dermatitis (AD) in an integrated safety analysis of 635 adolescents and over 1,000 patient-years of exposure, Lawrence F. Eichenfield, MD, reported at the annual Revolutionizing Atopic Dermatitis conference.

In March 2023, the oral Janus kinase 1 (JAK1) inhibitor was approved by the Food and Drug Administration for treating adolescents aged 12-17 with refractory moderate to severe AD – an expanded indication from the approval in adults in 2022.

University of California, San Diego

The new analysis evaluated data from patients who participated in the phase 3 JADE clinical trials – MONO-1, MONO-2, TEEN, and REGIMEN – and were subsequently enrolled in the ongoing phase 3 extension trial JADE EXTEND. Compared with a previous post hoc analysis in which adolescent patients had approximately 1 year of exposure, this updated analysis includes a sizable portion of patients with more than 96 weeks of exposure.

“We’re starting to get good numbers of [adolescents] who’ve had about 2 years of exposure,” said Dr. Eichenfield, professor of dermatology and pediatrics and vice chair of the department of dermatology at the University of California, San Diego, during a late-breaking research session.

With a data cut for this analysis of September 2021, “we haven’t seen additive long-term [adverse] effects” with longer exposures, he said. In addition, “there were no unique safety concerns related to adolescents compared to the findings observed [in an] integrated safety analysis using the same data cut in which most patients were adults.”

(The analysis in adults covered 3,802 patients with over 5,000 patient-years of exposure, and was presented at the annual American Academy of Dermatology meeting in March 2023.)

Also presented in the late-breaking abstract session at RAD 2023 was a long-term safety study of upadacitinib (Rinvoq), the other JAK1 inhibitor approved for adolescents with AD – approved by the FDA for both adolescents and adults with moderate to severe AD in 2022. The new analysis captures exposure of up to 4 years and shows no “worsening or accumulation of events,” compared with 1-year data, reported Christopher G. Bunick, MD, PhD, of the department of dermatology and the program in translational biomedicine at Yale University, New Haven, Conn.
 

Abrocitinib in adolescents

For the safety analysis of abrocitinib (Cibinqo), data were pooled into two cohorts: A consistent-dose cohort of 490 adolescents who received the same dose (200 mg or 100 mg) during the entire duration of the qualifying JADE trials, and a variable-dose cohort of 145 adolescents who received different doses (200 mg or 100 mg) during the JADE REGIMEN qualifying trial.

Duration of exposure was 96 weeks or more in 37%-38% of the consistent-dose cohort and 68% of the variable-dose cohort.

In the consistent-dose cohort, adverse events occurred in 243 (84%) and 153 (76%) of patients receiving 200-mg doses and 100-mg doses, respectively. Incidence rates for severe adverse events were 5.87 per 100 patient-years at both doses, and rates for adverse events leading to study discontinuation were 6.96/100 patient-years at 200 mg and 5.13/100 patient-years at 100 mg.

“No meaningful dose-response relationship was observed for serious adverse events, or adverse events leading to discontinuation, or adverse events of special interest,” said Dr. Eichenfield, also chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego.

The IRs of adverse events of special interest were 1.84/100 patient-years and 1.28/100 patient-years for serious infection; 2.11/100 patient-years, and 1.62/100 patient-years for all herpes zoster infections; and 0.69/100 patient-years and 0.32/100 patient-years for opportunistic herpes zoster infections in the 200-mg and 100-mg arms, respectively.

“Other than herpes zoster, there were no opportunistic infections observed and no tuberculosis cases,” he said. “There was one nonfatal venous thromboembolism in an adolescent who had a very strong family history of [pulmonary embolism], one retinal detachment [with a concurrent diagnosis of cataracts and of left eyebrow folliculitis], and no events of nonmelanoma skin cancer or other malignancies, major adverse cardiovascular events, or deaths.” The thromboembolism case was reported in the previous post hoc analysis.

In the variable-dose cohort, data were similar, Dr. Eichenfield said. The IRs for severe adverse events, adverse events leading to study withdrawal, and adverse events of special interest were consistent with those in the other cohort. And similarly, there were no reports of tuberculosis or other opportunistic infections (excluding herpes zoster), and no reports of nonmelanoma skin cancer (NMSC) or other malignancies, major adverse cardiovascular events (MACE), or death. In this cohort, there were no venous thromboembolism (VTE) reports.

Upadacitinib in adolescents, adults

The new analysis looked at up to 4 years of upadacitinib treatment in almost 2,700 adolescents and adults– and over 6,200 patient-years – using integrated data from three ongoing pivotal phase 3 studies: Measure Up 1, Measure Up 2, and AD Up. (Of these patients, 539 were adolescents, Dr. Bunick said after the meeting.)

In the Measure Up studies, patients were randomized 1:1:1 to receive a 15-mg dose, a 30-mg dose, or placebo once daily. In AD Up, patients in each arm received concomitant topical corticosteroids. At week 16, patients receiving the drug continued their assigned treatment during the ongoing blinded extension period, and those receiving placebo were rerandomized to upadacitinib 15 mg or 30 mg.

The exposure-adjusted event rates for any adverse event leading to discontinuation were 4.1/100 patient-years and 4.7/100 patient-years in patients receiving 15 mg and 30 mg, respectively, and the rates of any serious adverse event were 6.5/100 patient-years and 7.5/100 patient-years, Dr. Bunick reported. Three deaths occurred in the 30-mg group; all deaths were related to COVID infection and occurred in adults with cardiovascular risk factors.

Incidence rates of adverse events of special interest were similar to those in a previous 1-year analysis. The rate of serious infections per 100 patient years, for instance, was 2.3 and 2.8 in the 15-mg and 30-mg groups, respectively, compared with 2.2 and 2.8 in the 1-year analysis.

The rate of opportunistic infections, including eczema herpeticum (and excluding TB and herpes zoster), saw a slight bump in the new analysis to 2.4/100 patient-years with the 30-mg dose. Other event rates, across both dosages and durations, were less than 0.1/100 patient-years for active TB; 0.3-0.4/100 patient-years for NMSC, and 0.1/100 patient-years or below for other malignancies, MACE, and VTE. Herpes zoster had the highest event rate in both the 1- and 4-year analyses of between 3.1/100 patient-years and 5.8/100 patient-years, Dr. Bunick reported.

The adverse event rates for adolescents and adults “show consistency and are very low,” Dr. Bunick said. At 4 years, no new safety risks were identified.
 

‘The more data ... the better’

Data on the safety of new medications in children and adolescents is always important, and with systemic JAK inhibitors in particular, “the more data we can accumulate in [younger] patients with AD ... the better,” said Robert Sidbury, MD, MPH, professor in the department of pediatrics at the University of Washington, Seattle, and chief of the division of dermatology at Seattle Children’s Hospital, who was asked to comment on the two studies.

Dermatologists have taken comfort in the fact that the “daunting” boxed warning on JAK inhibitors “was generated in a very different population than we generally propose to treat, certainly when talking about children and adolescents,” said Dr. Sidbury, who was not involved in either of the new safety analyses.

The JAK inhibitor boxed warning “reflects a study of tofacitinib – a different JAK inhibitor with arguably more risk of adverse effects – in adults over the age of 50 with rheumatoid arthritis and multiple risk factors for comorbidities included in the boxed warning,” he said.

“This allows dermatologists to reasonably conclude that the boxed warning – while critical to discuss and consider in every patient – is likely less concerning than might otherwise by implied.”

With more patient experience, “the more our assessment of risk, and of the ‘legitimacy’ of the boxed warning in our patient population, becomes evidence-based as opposed to extrapolation,” Dr. Sidbury said.

The two studies reported, he said, “detail an experience that is not adverse effect free –I have yet to find that medication – but is a reasonable profile considering the robust efficacy results they accompany.”

The abrocitinib safety analysis was sponsored by Pfizer. Regarding the study of upadacitinib, AbbVie contributed to the design of the safety analysis and participated in data collection. No honoria or payments were made to the authors, according to the study abstract. Dr. Eichenfield is a consultant/advisory board member for Pfizer and other companies, and has served on the speakers bureau/received honoria for Pfizer and other companies. Dr. Bunick is a consultant for AbbVie and other companies, and has served as an speaker/received honoraria or served as an investigator for several companies. Dr. Sidbury disclosed being a consultant/advisory board member for Lilly and Leo and serving on the speakers bureau/honoraria for Beiersdorf. All reported receiving grant/research support from various companies.
 

WASHINGTON – Abrocitinib demonstrated an acceptable long-term safety profile in adolescents with moderate to severe atopic dermatitis (AD) in an integrated safety analysis of 635 adolescents and over 1,000 patient-years of exposure, Lawrence F. Eichenfield, MD, reported at the annual Revolutionizing Atopic Dermatitis conference.

In March 2023, the oral Janus kinase 1 (JAK1) inhibitor was approved by the Food and Drug Administration for treating adolescents aged 12-17 with refractory moderate to severe AD – an expanded indication from the approval in adults in 2022.

University of California, San Diego

The new analysis evaluated data from patients who participated in the phase 3 JADE clinical trials – MONO-1, MONO-2, TEEN, and REGIMEN – and were subsequently enrolled in the ongoing phase 3 extension trial JADE EXTEND. Compared with a previous post hoc analysis in which adolescent patients had approximately 1 year of exposure, this updated analysis includes a sizable portion of patients with more than 96 weeks of exposure.

“We’re starting to get good numbers of [adolescents] who’ve had about 2 years of exposure,” said Dr. Eichenfield, professor of dermatology and pediatrics and vice chair of the department of dermatology at the University of California, San Diego, during a late-breaking research session.

With a data cut for this analysis of September 2021, “we haven’t seen additive long-term [adverse] effects” with longer exposures, he said. In addition, “there were no unique safety concerns related to adolescents compared to the findings observed [in an] integrated safety analysis using the same data cut in which most patients were adults.”

(The analysis in adults covered 3,802 patients with over 5,000 patient-years of exposure, and was presented at the annual American Academy of Dermatology meeting in March 2023.)

Also presented in the late-breaking abstract session at RAD 2023 was a long-term safety study of upadacitinib (Rinvoq), the other JAK1 inhibitor approved for adolescents with AD – approved by the FDA for both adolescents and adults with moderate to severe AD in 2022. The new analysis captures exposure of up to 4 years and shows no “worsening or accumulation of events,” compared with 1-year data, reported Christopher G. Bunick, MD, PhD, of the department of dermatology and the program in translational biomedicine at Yale University, New Haven, Conn.
 

Abrocitinib in adolescents

For the safety analysis of abrocitinib (Cibinqo), data were pooled into two cohorts: A consistent-dose cohort of 490 adolescents who received the same dose (200 mg or 100 mg) during the entire duration of the qualifying JADE trials, and a variable-dose cohort of 145 adolescents who received different doses (200 mg or 100 mg) during the JADE REGIMEN qualifying trial.

Duration of exposure was 96 weeks or more in 37%-38% of the consistent-dose cohort and 68% of the variable-dose cohort.

In the consistent-dose cohort, adverse events occurred in 243 (84%) and 153 (76%) of patients receiving 200-mg doses and 100-mg doses, respectively. Incidence rates for severe adverse events were 5.87 per 100 patient-years at both doses, and rates for adverse events leading to study discontinuation were 6.96/100 patient-years at 200 mg and 5.13/100 patient-years at 100 mg.

“No meaningful dose-response relationship was observed for serious adverse events, or adverse events leading to discontinuation, or adverse events of special interest,” said Dr. Eichenfield, also chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego.

The IRs of adverse events of special interest were 1.84/100 patient-years and 1.28/100 patient-years for serious infection; 2.11/100 patient-years, and 1.62/100 patient-years for all herpes zoster infections; and 0.69/100 patient-years and 0.32/100 patient-years for opportunistic herpes zoster infections in the 200-mg and 100-mg arms, respectively.

“Other than herpes zoster, there were no opportunistic infections observed and no tuberculosis cases,” he said. “There was one nonfatal venous thromboembolism in an adolescent who had a very strong family history of [pulmonary embolism], one retinal detachment [with a concurrent diagnosis of cataracts and of left eyebrow folliculitis], and no events of nonmelanoma skin cancer or other malignancies, major adverse cardiovascular events, or deaths.” The thromboembolism case was reported in the previous post hoc analysis.

In the variable-dose cohort, data were similar, Dr. Eichenfield said. The IRs for severe adverse events, adverse events leading to study withdrawal, and adverse events of special interest were consistent with those in the other cohort. And similarly, there were no reports of tuberculosis or other opportunistic infections (excluding herpes zoster), and no reports of nonmelanoma skin cancer (NMSC) or other malignancies, major adverse cardiovascular events (MACE), or death. In this cohort, there were no venous thromboembolism (VTE) reports.

Upadacitinib in adolescents, adults

The new analysis looked at up to 4 years of upadacitinib treatment in almost 2,700 adolescents and adults– and over 6,200 patient-years – using integrated data from three ongoing pivotal phase 3 studies: Measure Up 1, Measure Up 2, and AD Up. (Of these patients, 539 were adolescents, Dr. Bunick said after the meeting.)

In the Measure Up studies, patients were randomized 1:1:1 to receive a 15-mg dose, a 30-mg dose, or placebo once daily. In AD Up, patients in each arm received concomitant topical corticosteroids. At week 16, patients receiving the drug continued their assigned treatment during the ongoing blinded extension period, and those receiving placebo were rerandomized to upadacitinib 15 mg or 30 mg.

The exposure-adjusted event rates for any adverse event leading to discontinuation were 4.1/100 patient-years and 4.7/100 patient-years in patients receiving 15 mg and 30 mg, respectively, and the rates of any serious adverse event were 6.5/100 patient-years and 7.5/100 patient-years, Dr. Bunick reported. Three deaths occurred in the 30-mg group; all deaths were related to COVID infection and occurred in adults with cardiovascular risk factors.

Incidence rates of adverse events of special interest were similar to those in a previous 1-year analysis. The rate of serious infections per 100 patient years, for instance, was 2.3 and 2.8 in the 15-mg and 30-mg groups, respectively, compared with 2.2 and 2.8 in the 1-year analysis.

The rate of opportunistic infections, including eczema herpeticum (and excluding TB and herpes zoster), saw a slight bump in the new analysis to 2.4/100 patient-years with the 30-mg dose. Other event rates, across both dosages and durations, were less than 0.1/100 patient-years for active TB; 0.3-0.4/100 patient-years for NMSC, and 0.1/100 patient-years or below for other malignancies, MACE, and VTE. Herpes zoster had the highest event rate in both the 1- and 4-year analyses of between 3.1/100 patient-years and 5.8/100 patient-years, Dr. Bunick reported.

The adverse event rates for adolescents and adults “show consistency and are very low,” Dr. Bunick said. At 4 years, no new safety risks were identified.
 

‘The more data ... the better’

Data on the safety of new medications in children and adolescents is always important, and with systemic JAK inhibitors in particular, “the more data we can accumulate in [younger] patients with AD ... the better,” said Robert Sidbury, MD, MPH, professor in the department of pediatrics at the University of Washington, Seattle, and chief of the division of dermatology at Seattle Children’s Hospital, who was asked to comment on the two studies.

Dermatologists have taken comfort in the fact that the “daunting” boxed warning on JAK inhibitors “was generated in a very different population than we generally propose to treat, certainly when talking about children and adolescents,” said Dr. Sidbury, who was not involved in either of the new safety analyses.

The JAK inhibitor boxed warning “reflects a study of tofacitinib – a different JAK inhibitor with arguably more risk of adverse effects – in adults over the age of 50 with rheumatoid arthritis and multiple risk factors for comorbidities included in the boxed warning,” he said.

“This allows dermatologists to reasonably conclude that the boxed warning – while critical to discuss and consider in every patient – is likely less concerning than might otherwise by implied.”

With more patient experience, “the more our assessment of risk, and of the ‘legitimacy’ of the boxed warning in our patient population, becomes evidence-based as opposed to extrapolation,” Dr. Sidbury said.

The two studies reported, he said, “detail an experience that is not adverse effect free –I have yet to find that medication – but is a reasonable profile considering the robust efficacy results they accompany.”

The abrocitinib safety analysis was sponsored by Pfizer. Regarding the study of upadacitinib, AbbVie contributed to the design of the safety analysis and participated in data collection. No honoria or payments were made to the authors, according to the study abstract. Dr. Eichenfield is a consultant/advisory board member for Pfizer and other companies, and has served on the speakers bureau/received honoria for Pfizer and other companies. Dr. Bunick is a consultant for AbbVie and other companies, and has served as an speaker/received honoraria or served as an investigator for several companies. Dr. Sidbury disclosed being a consultant/advisory board member for Lilly and Leo and serving on the speakers bureau/honoraria for Beiersdorf. All reported receiving grant/research support from various companies.
 

WASHINGTON – Abrocitinib demonstrated an acceptable long-term safety profile in adolescents with moderate to severe atopic dermatitis (AD) in an integrated safety analysis of 635 adolescents and over 1,000 patient-years of exposure, Lawrence F. Eichenfield, MD, reported at the annual Revolutionizing Atopic Dermatitis conference.

In March 2023, the oral Janus kinase 1 (JAK1) inhibitor was approved by the Food and Drug Administration for treating adolescents aged 12-17 with refractory moderate to severe AD – an expanded indication from the approval in adults in 2022.

University of California, San Diego

The new analysis evaluated data from patients who participated in the phase 3 JADE clinical trials – MONO-1, MONO-2, TEEN, and REGIMEN – and were subsequently enrolled in the ongoing phase 3 extension trial JADE EXTEND. Compared with a previous post hoc analysis in which adolescent patients had approximately 1 year of exposure, this updated analysis includes a sizable portion of patients with more than 96 weeks of exposure.

“We’re starting to get good numbers of [adolescents] who’ve had about 2 years of exposure,” said Dr. Eichenfield, professor of dermatology and pediatrics and vice chair of the department of dermatology at the University of California, San Diego, during a late-breaking research session.

With a data cut for this analysis of September 2021, “we haven’t seen additive long-term [adverse] effects” with longer exposures, he said. In addition, “there were no unique safety concerns related to adolescents compared to the findings observed [in an] integrated safety analysis using the same data cut in which most patients were adults.”

(The analysis in adults covered 3,802 patients with over 5,000 patient-years of exposure, and was presented at the annual American Academy of Dermatology meeting in March 2023.)

Also presented in the late-breaking abstract session at RAD 2023 was a long-term safety study of upadacitinib (Rinvoq), the other JAK1 inhibitor approved for adolescents with AD – approved by the FDA for both adolescents and adults with moderate to severe AD in 2022. The new analysis captures exposure of up to 4 years and shows no “worsening or accumulation of events,” compared with 1-year data, reported Christopher G. Bunick, MD, PhD, of the department of dermatology and the program in translational biomedicine at Yale University, New Haven, Conn.
 

Abrocitinib in adolescents

For the safety analysis of abrocitinib (Cibinqo), data were pooled into two cohorts: A consistent-dose cohort of 490 adolescents who received the same dose (200 mg or 100 mg) during the entire duration of the qualifying JADE trials, and a variable-dose cohort of 145 adolescents who received different doses (200 mg or 100 mg) during the JADE REGIMEN qualifying trial.

Duration of exposure was 96 weeks or more in 37%-38% of the consistent-dose cohort and 68% of the variable-dose cohort.

In the consistent-dose cohort, adverse events occurred in 243 (84%) and 153 (76%) of patients receiving 200-mg doses and 100-mg doses, respectively. Incidence rates for severe adverse events were 5.87 per 100 patient-years at both doses, and rates for adverse events leading to study discontinuation were 6.96/100 patient-years at 200 mg and 5.13/100 patient-years at 100 mg.

“No meaningful dose-response relationship was observed for serious adverse events, or adverse events leading to discontinuation, or adverse events of special interest,” said Dr. Eichenfield, also chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego.

The IRs of adverse events of special interest were 1.84/100 patient-years and 1.28/100 patient-years for serious infection; 2.11/100 patient-years, and 1.62/100 patient-years for all herpes zoster infections; and 0.69/100 patient-years and 0.32/100 patient-years for opportunistic herpes zoster infections in the 200-mg and 100-mg arms, respectively.

“Other than herpes zoster, there were no opportunistic infections observed and no tuberculosis cases,” he said. “There was one nonfatal venous thromboembolism in an adolescent who had a very strong family history of [pulmonary embolism], one retinal detachment [with a concurrent diagnosis of cataracts and of left eyebrow folliculitis], and no events of nonmelanoma skin cancer or other malignancies, major adverse cardiovascular events, or deaths.” The thromboembolism case was reported in the previous post hoc analysis.

In the variable-dose cohort, data were similar, Dr. Eichenfield said. The IRs for severe adverse events, adverse events leading to study withdrawal, and adverse events of special interest were consistent with those in the other cohort. And similarly, there were no reports of tuberculosis or other opportunistic infections (excluding herpes zoster), and no reports of nonmelanoma skin cancer (NMSC) or other malignancies, major adverse cardiovascular events (MACE), or death. In this cohort, there were no venous thromboembolism (VTE) reports.

Upadacitinib in adolescents, adults

The new analysis looked at up to 4 years of upadacitinib treatment in almost 2,700 adolescents and adults– and over 6,200 patient-years – using integrated data from three ongoing pivotal phase 3 studies: Measure Up 1, Measure Up 2, and AD Up. (Of these patients, 539 were adolescents, Dr. Bunick said after the meeting.)

In the Measure Up studies, patients were randomized 1:1:1 to receive a 15-mg dose, a 30-mg dose, or placebo once daily. In AD Up, patients in each arm received concomitant topical corticosteroids. At week 16, patients receiving the drug continued their assigned treatment during the ongoing blinded extension period, and those receiving placebo were rerandomized to upadacitinib 15 mg or 30 mg.

The exposure-adjusted event rates for any adverse event leading to discontinuation were 4.1/100 patient-years and 4.7/100 patient-years in patients receiving 15 mg and 30 mg, respectively, and the rates of any serious adverse event were 6.5/100 patient-years and 7.5/100 patient-years, Dr. Bunick reported. Three deaths occurred in the 30-mg group; all deaths were related to COVID infection and occurred in adults with cardiovascular risk factors.

Incidence rates of adverse events of special interest were similar to those in a previous 1-year analysis. The rate of serious infections per 100 patient years, for instance, was 2.3 and 2.8 in the 15-mg and 30-mg groups, respectively, compared with 2.2 and 2.8 in the 1-year analysis.

The rate of opportunistic infections, including eczema herpeticum (and excluding TB and herpes zoster), saw a slight bump in the new analysis to 2.4/100 patient-years with the 30-mg dose. Other event rates, across both dosages and durations, were less than 0.1/100 patient-years for active TB; 0.3-0.4/100 patient-years for NMSC, and 0.1/100 patient-years or below for other malignancies, MACE, and VTE. Herpes zoster had the highest event rate in both the 1- and 4-year analyses of between 3.1/100 patient-years and 5.8/100 patient-years, Dr. Bunick reported.

The adverse event rates for adolescents and adults “show consistency and are very low,” Dr. Bunick said. At 4 years, no new safety risks were identified.
 

‘The more data ... the better’

Data on the safety of new medications in children and adolescents is always important, and with systemic JAK inhibitors in particular, “the more data we can accumulate in [younger] patients with AD ... the better,” said Robert Sidbury, MD, MPH, professor in the department of pediatrics at the University of Washington, Seattle, and chief of the division of dermatology at Seattle Children’s Hospital, who was asked to comment on the two studies.

Dermatologists have taken comfort in the fact that the “daunting” boxed warning on JAK inhibitors “was generated in a very different population than we generally propose to treat, certainly when talking about children and adolescents,” said Dr. Sidbury, who was not involved in either of the new safety analyses.

The JAK inhibitor boxed warning “reflects a study of tofacitinib – a different JAK inhibitor with arguably more risk of adverse effects – in adults over the age of 50 with rheumatoid arthritis and multiple risk factors for comorbidities included in the boxed warning,” he said.

“This allows dermatologists to reasonably conclude that the boxed warning – while critical to discuss and consider in every patient – is likely less concerning than might otherwise by implied.”

With more patient experience, “the more our assessment of risk, and of the ‘legitimacy’ of the boxed warning in our patient population, becomes evidence-based as opposed to extrapolation,” Dr. Sidbury said.

The two studies reported, he said, “detail an experience that is not adverse effect free –I have yet to find that medication – but is a reasonable profile considering the robust efficacy results they accompany.”

The abrocitinib safety analysis was sponsored by Pfizer. Regarding the study of upadacitinib, AbbVie contributed to the design of the safety analysis and participated in data collection. No honoria or payments were made to the authors, according to the study abstract. Dr. Eichenfield is a consultant/advisory board member for Pfizer and other companies, and has served on the speakers bureau/received honoria for Pfizer and other companies. Dr. Bunick is a consultant for AbbVie and other companies, and has served as an speaker/received honoraria or served as an investigator for several companies. Dr. Sidbury disclosed being a consultant/advisory board member for Lilly and Leo and serving on the speakers bureau/honoraria for Beiersdorf. All reported receiving grant/research support from various companies.
 

There is good news and bad news regarding the use of tobacco products by young people in the United States, according to the recently released findings from the 2021 Youth Risk Behavior Survey (YRBS).¹ The use of cigarettes among high school students declined from 36.4% in 1997 to 6.0% in 2019.² However, young people have replaced cigarettes with other tobacco products, including electronic vapor products (EVPs). So we need to ask specifically about these products.

Known by many names. EVPs are referred to as e-cigarettes, vapes, hookah pens, and mods. They usually contain nicotine, which is highly addictive, can affect brain development, and may lead to smoking of cigarettes.³ The most common reasons young people say they use EVPs are feelings of anxiety, stress, and depression, as well as the “high” associated with nicotine use.⁴

Use of EVPs among youth. The YRBS, which includes a representative sample of public and private school students in grades 9 to 12 in the 50 states, categorizes the use of EVPs as

• ever use
• current use (≥ 1 use during the 30 days before the survey), and
• daily use (during the 30 days before the survey).

In 2021, 36.2% of young people reported ever use of EVPs (40.9% of females; 32.1% of males), 18% reported current use (21.4% of females; 14.9% of males), and 5% reported daily use (5.6% of females; 4.5% of males). Differences between racial and ethnic groups were minor, except for markedly lower rates in Asian youth (19.5% ever use, 5.5% current use, and 1.2% daily use).⁵

Current recommendations. The US Preventive Services Task Force (USPSTF) recommends education and brief counseling for school-age children and adolescents to prevent them from starting to use tobacco (including use of EVPs).⁶ The USPSTF also recommends tobacco cessation using behavioral interventions and/or pharmacotherapy for those ages 18 years and older.⁷

The USPSTF makes no recommendation on cessation for those younger than 18 years, citing weak evidence. However, it would be reasonable to offer behavioral interventions to younger current users. (Pharmacotherapy is not approved for use in children and adolescents.)

The take-home message. When we ask children and adolescents about use of tobacco products, we need to specifically mention EVPs and advise against their use.

There is good news and bad news regarding the use of tobacco products by young people in the United States, according to the recently released findings from the 2021 Youth Risk Behavior Survey (YRBS).¹ The use of cigarettes among high school students declined from 36.4% in 1997 to 6.0% in 2019.² However, young people have replaced cigarettes with other tobacco products, including electronic vapor products (EVPs). So we need to ask specifically about these products.

Known by many names. EVPs are referred to as e-cigarettes, vapes, hookah pens, and mods. They usually contain nicotine, which is highly addictive, can affect brain development, and may lead to smoking of cigarettes.³ The most common reasons young people say they use EVPs are feelings of anxiety, stress, and depression, as well as the “high” associated with nicotine use.⁴

Use of EVPs among youth. The YRBS, which includes a representative sample of public and private school students in grades 9 to 12 in the 50 states, categorizes the use of EVPs as

• ever use
• current use (≥ 1 use during the 30 days before the survey), and
• daily use (during the 30 days before the survey).

In 2021, 36.2% of young people reported ever use of EVPs (40.9% of females; 32.1% of males), 18% reported current use (21.4% of females; 14.9% of males), and 5% reported daily use (5.6% of females; 4.5% of males). Differences between racial and ethnic groups were minor, except for markedly lower rates in Asian youth (19.5% ever use, 5.5% current use, and 1.2% daily use).⁵

Current recommendations. The US Preventive Services Task Force (USPSTF) recommends education and brief counseling for school-age children and adolescents to prevent them from starting to use tobacco (including use of EVPs).⁶ The USPSTF also recommends tobacco cessation using behavioral interventions and/or pharmacotherapy for those ages 18 years and older.⁷

The USPSTF makes no recommendation on cessation for those younger than 18 years, citing weak evidence. However, it would be reasonable to offer behavioral interventions to younger current users. (Pharmacotherapy is not approved for use in children and adolescents.)

The take-home message. When we ask children and adolescents about use of tobacco products, we need to specifically mention EVPs and advise against their use.

There is good news and bad news regarding the use of tobacco products by young people in the United States, according to the recently released findings from the 2021 Youth Risk Behavior Survey (YRBS).¹ The use of cigarettes among high school students declined from 36.4% in 1997 to 6.0% in 2019.² However, young people have replaced cigarettes with other tobacco products, including electronic vapor products (EVPs). So we need to ask specifically about these products.

Known by many names. EVPs are referred to as e-cigarettes, vapes, hookah pens, and mods. They usually contain nicotine, which is highly addictive, can affect brain development, and may lead to smoking of cigarettes.³ The most common reasons young people say they use EVPs are feelings of anxiety, stress, and depression, as well as the “high” associated with nicotine use.⁴

Use of EVPs among youth. The YRBS, which includes a representative sample of public and private school students in grades 9 to 12 in the 50 states, categorizes the use of EVPs as

• ever use
• current use (≥ 1 use during the 30 days before the survey), and
• daily use (during the 30 days before the survey).

In 2021, 36.2% of young people reported ever use of EVPs (40.9% of females; 32.1% of males), 18% reported current use (21.4% of females; 14.9% of males), and 5% reported daily use (5.6% of females; 4.5% of males). Differences between racial and ethnic groups were minor, except for markedly lower rates in Asian youth (19.5% ever use, 5.5% current use, and 1.2% daily use).⁵

Current recommendations. The US Preventive Services Task Force (USPSTF) recommends education and brief counseling for school-age children and adolescents to prevent them from starting to use tobacco (including use of EVPs).⁶ The USPSTF also recommends tobacco cessation using behavioral interventions and/or pharmacotherapy for those ages 18 years and older.⁷

The USPSTF makes no recommendation on cessation for those younger than 18 years, citing weak evidence. However, it would be reasonable to offer behavioral interventions to younger current users. (Pharmacotherapy is not approved for use in children and adolescents.)

The take-home message. When we ask children and adolescents about use of tobacco products, we need to specifically mention EVPs and advise against their use.

An elevated serum level of cholesterol has been recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD) since the publication of the Framingham Study in 1961.¹ Although clinical outcomes related to ASCVD have improved in recent decades, ASCVD remains the leading cause of morbidity and mortality across the globe and remains, in the United States, the leading cause of death among most racial and ethnic groups. Much of this persistent disease burden can be attributed to inadequate control of ASCVD risk factors and suboptimal implementation of prevention strategies in the general population.²

The most recent (2019) iteration of the American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease emphasizes a comprehensive, patient-centered, team-based approach to the management of ASCVD risk factors.² In this article, I review how, first, medication to reduce ASCVD risk should be considered only when a patient’s risk is sufficiently high and, second, shared decision-making and social determinants of health should, in all cases, guide and inform optimal implementation of treatment.²

Estimating risk for ASCVD by ascertaining LDL-C

• The Friedewald equation. Traditionally, low-density lipoprotein cholesterol (LDL-C) is estimated using the Friedewald equation^a applied to a fasting lipid profile. In patients who have a low level of LDL-C (< 70 mg/dL), however, the Friedewald equation becomes less accurate; in patients with hypertriglyceridemia (TG ≥ 400 mg/dL),estimation of LDL-C is invalid.
• The Martin–Hopkins equation offers a validated estimation of LDL-C when the LDL-C value is < 70 mg/dL.³ This equation—in which the fixed factor of 5 used in the Friedewald equation to estimate very low-density lipoprotein cholesterol is replaced by an adjustable factor that is based on the patient’s non-HDL-C (ie, TC–HDL-C) and TG values—is preferred by the ACC/AHA Task Force on Clinical Practice Guidelines in this clinical circumstance.⁴
• National Institutes of Health equation. This newer equation provides an accurate estimate of the LDL-C level in patients whose TG value is ≤ 800 mg/dL. The equation has not been fully validated for clinical use, however.⁵
• Direct measurement obviates the need for an equation to estimate LDL-C, but the test is not available in all health care settings.

For adults ≥ 20 years of age who are not receiving lipid-lowering therapy, a nonfasting lipid profile can be used to estimate ASCVD risk and document the baseline LDL-C level. If the TG level is ≥ 400 mg/dL, the test should be administered in the fasting state.⁴

• Apolipoprotein B. Alternatively, apolipoprotein B (apoB) can be measured. Because each LDL-C particle contains 1 apoB molecule, the apoB level describes the LDL-C level more accurately than a calculation of LDL-C. Many patients with type 2 diabetes and metabolic syndrome have a relatively low calculated LDL-C (thereby falsely reassuring the testing clinician) but have an elevated apoB level. An apoB level ≥ 130 mg/dL corresponds to an LDL-C level >160 mg/dL.⁴
• Calculation of non-HDL-C. Because the nonfasting state does not have a significant impact on a patient’s TC and HDL-C levels, the non-HDL-C level also can be calculated from the results of a nonfasting lipid profile.

Non-HDL-C and apoB are equivalent predictors of ASCVD risk. These 2 assessments might offer better risk estimation than other available tools in patients who have type 2 diabetes and metabolic syndrome.⁶

Continue to: Applying the estimate of 10-year ASCVD risk...

Your recommendation for preventive intervention, such as lipid-lowering therapy, should be based on the estimated 10-year risk for ASCVD. Although multiple validated risk assessment tools are available, ACC/AHA recommends the pooled cohort risk equations (PCE), introduced in the 2013 ACC/AHA cholesterol treatment guidelines. The Framingham Heart Study now recommends the ACC/AHA PCE for risk assessment as well.⁷

The PCE, developed from 5 large cohorts, is based on hard atherosclerotic events: nonfatal myocardial infarction, death from coronary artery disease, and stroke. The ACC/AHA PCE is the only risk assessment tool developed using a significant percentage of patients who self-identify as Black.⁸ Alternatives to the ACC/AHA PCE include:

• Multi-ethnic Study of Atherosclerosis (MESA) 10-year ASCVD risk calculator, which incorporates the coronary artery calcium (CAC) score.
• Reynolds Risk Score, which incorporates high-sensitivity C-reactive protein measurement and a family history of premature ASCVD.⁹

How much does lifestyle modification actually matter?

The absolute impact of diet and exercise on lipid parameters is relatively modest. No studies have demonstrated a reduction in adverse cardiovascular outcomes with specific interventions regarding diet or activity.

• Diet. Nevertheless, ACC/AHA recommends that at-risk patients follow a dietary pattern that (1) emphasizes vegetables, fruits, and whole grains and (2) limits sweets, sugar-sweetened beverages, and red meat.

Saturated fat should constitute no more than 5% or 6% of total calories. In controlled-feeding trials,¹⁰ for every 1% of calories from saturated fat that are replaced with carbohydrate or monounsaturated or polyunsaturated fat, the LDL-C level was found to decline by as much as 1.8 mg/dL. Evidence is insufficient to assert that lowering dietary cholesterol reduces LDL-C.¹¹

• Activity. Trials of aerobic physical activity, compared with a more sedentary activity pattern, have demonstrated a reduction in the LDL-C level of as much as 6 mg/dL. All adult patients should be counseled to engage in aerobic physical activity of moderate or vigorous intensity—averaging ≥ 40 minutes per session, 3 or 4 sessions per week.¹¹

Primary prevention: Stratification by age

• 40 to 75 years. ACC/AHA recommends that you routinely assess traditional cardiovascular risk factors for these patients and calculate their 10-year risk for ASCVD using the PCE. Statin therapy as primary prevention is indicated for 3 major groups (TABLE 1).⁴ The US Preventive Services Task Force (USPSTF) recommends a 10-year ASCVD risk ≥ 10%, in conjunction with 1 or more additional CVD risk factors (dyslipidemia, diabetes, hypertension, smoking), as the threshold for initiating low- or moderate-intensity statin therapy in this age group.¹²

In adults at borderline risk (5% to < 7.5% 10-year ASCVD risk) or intermediate risk (≥ 7.5% to < 20% 10-year ASCVD risk), consider risk-enhancing factors to better inform your recommendation for preventive interventions. In these 2 groups, the presence of risk-enhancing factors might justify moderate-intensity statin therapy (TABLE 2⁴).

If your decision regarding preventive intervention remains uncertain, measuring CAC might further guide your discussion with the patient.⁴ When the CAC score is:

• 0 Agatston units and higher-risk conditions (eg, diabetes, family history of premature coronary artery disease, smoking) are absent, statin therapy can be withheld; reassess ASCVD risk in 5 to 10 years.
• 1-99 Agatston units, statin therapy can be started, especially for patients ≥ 55 years of age.
• ≥ 100 Agatston units or ≥ 75th percentile, statin therapy is indicated for all patients, regardless of additional risk factors.⁴

Because statins promote progression from unstable, inflammatory atherosclerotic plaque to more stable, calcified plaque, CAC scoring is not valid in patients already on statin therapy.¹³

In primary prevention, patients who have been classified as having low or intermediate risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have an annual all-cause mortality < 1%, regardless of age and gender. Patients classified as being at high risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have a significantly lower annual mortality than low- or intermediate-risk patients with a CAC score > 0 Agatston units.¹⁴

• 20 to 39 years. Focus on evaluation of lifetime ASCVD risk, rather than short-term (10-year) risk. Lifestyle modification is the primary intervention for younger patients; for those with moderate hypercholesterolemia (LDL-C, 160-189 mg/dL) and a family history of premature ASCVD, however, consider statin therapy. For patients with LDL-C ≥ 190 mg/dL, lifetime ASCVD risk is markedly increased, and high-intensity statin therapy is recommended, regardless of age. In this group, reassess ASCVD risk factors every 4 to 6 years.⁴
• > 75 years, without ASCVD. In this group, the benefit of statin therapy is less clear and might be lessened by an increased potential for adverse effects. A meta-analysis of 28 trials demonstrated that people ages > 75 years had a 24% relative reduction in major coronary events for every 38.7mg/dL (1.0 mmol/L) reduction in LDL-C, which is comparable to the risk reduction seen in people ages 40 to 75 years.¹⁵

With increasing age, however, the relative reduction in major coronary events with statin therapy decreased,¹⁵ although other trials have not demonstrated age heterogeneity.¹⁶ Because people > 75 years of age have a significantly higher ASCVD event rate, a comparable relative rate reduction with statin therapy results in a larger absolute rate reduction (ARR) and, therefore, a smaller number needed to treat (NNT) to prevent an event, compared to the NNT in younger people.

Secondary prevention

ACC/AHA guidelines define clinical ASCVD as a history of:

• acute coronary syndrome
• myocardial infarction
• coronary or other arterial revascularization
• cerebrovascular event
• symptomatic peripheral artery disease, including aortic aneurysm.

High-intensity statin therapy is indicated for all patients ≤ 75 years who have clinical ASCVD. In patients > 75 years, consider a taper to moderate-intensity statin therapy. An upper age limit for seeing benefit from statin therapy in secondary prevention has not been identified.⁴

In high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy, ezetimibe (discussed in the next section) can be added. In very-high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy plus ezetimibe, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (also discussed next) can be added. Always precede initiation of a PCSK9 inhibitor with a discussion of the net benefit, safety, and cost with the patient.⁴

Continue to: Options for lipid-lowering pharmacotherapy...

• Statins (formally, hydroxymethylglutaryl-coenzyme A reductase inhibitors) offer the most predictable reduction in ASCVD risk of any lipid-lowering therapy. The evidence report that accompanied the 2016 USPSTF guidelines on statins for the prevention of cardiovascular disease (CVD) stated that low- or moderate-dosage statin therapy is associated with approximately a 30% relative risk reduction (RRR) in CVD events and CVD deaths and a 10% to 15% RRR in all-cause mortality.¹⁷

High-intensity statin therapy reduces LDL-C by ≥ 50%. Moderate-intensity statin therapy reduces LDL-C by 30% to 49% (TABLE 3).⁴

Statins are not without risk: A 2016 report¹⁸ estimated that treating 10,000 patients with a statin for 5 years would cause 1 case of rhabdomyolysis, 5 cases of myopathy, 75 new cases of diabetes, and 7 cases of hemorrhagic stroke. The same treatment would, however, avert approximately 1000 CVD events among patients with preexisting disease and approximately 500 CVD events among patients at elevated risk but without preexisting disease.¹⁸

• Ezetimibe, a selective cholesterol-absorption inhibitor, lowers LDL-C by 13% to 20% and typically is well tolerated. The use of ezetimibe in ASCVD risk reduction is supported by a single randomized controlled trial of more than 18,000 patients with recent acute coronary syndrome. Adding ezetimibe to simvastatin 40 mg resulted in a 2% absolute reduction in major adverse cardiovascular events over a median follow-up of 6 years (NNT = 50), compared to simvastatin alone.¹⁹ ACC/AHA guidelines recommend adding ezetimibe to maximally tolerated statin therapy in patients with clinical ASCVD who do not reach their goal LDL reduction with a statin alone. Ezetimibe also can be considered a statin alternative in patients who are statin intolerant.⁴
• PCSK9 inhibitors. When added to statin therapy, evolocumab and alirocumab—monoclonal antibodies that inhibit PCSK9—offer an incremental decrease in LDL-C of approximately 60%.^20-22 In a meta-analysis of 35 trials evaluating the incremental benefit of PCSK9 inhibitor therapy, a significant reduction in cardiovascular events, including myocardial infarction (ARR = 1.3%; NNT = 77), stroke (ARR = 0.4%; NNT = 250), and coronary revascularization (ARR = 1.6%; NNT = 63) was reported. No significant difference was observed in all-cause or cardiovascular mortality.^21,23
• Inclisiran, an injectable small-interfering RNA that inhibits PCSK9 synthesis, provides an incremental decrease in LDL-C of > 50% in patients already receiving statin therapy. Meta-analysis of 3 small cardiovascular outcomes trials revealed no significant difference in the rate of myocardial infarction, stroke, or cardiovascular mortality with inclisiran compared to placebo. Larger outcomes trials are underway and might offer additional insight into this agent’s role in ASCVD risk management.²⁴
• Omega-3 fatty acids. Multiple trials have demonstrated that adding omega-3 fatty acids to usual lipid-lowering therapy does not offer a consistent reduction in adverse cardiovascular outcomes, despite providing a significant reduction in TG levels. In a high-risk population with persistently elevated TG despite statin therapy, icosapent ethyl, a purified eicosapentaenoic acid ethyl ester, reduced major ASCVD outcomes by 25% over a median 4.9 years (ARR = 4.8%; NNT = 21), and cardiovascular death by 20% (ARR = 0.9%; NNT = 111), compared with a mineral oil placebo.²⁵ Subsequent trials, using a corn oil placebo, failed to duplicate these data²⁶—raising concern that the mineral oil comparator might have altered results of the eicosapentaenoic acid ethyl ester study.^27,28
• Bempedoic acid is a small-molecule inhibitor of ATP citrate lyase that increases LDL uptake by the liver. Pooled data from studies of bempedoic acid show, on average, a 15% reduction in TC, a 23% reduction in LDL-C, and a 6% increase in HDL-C, without a significant change in TG.²⁹ In statin-intolerant patients, bempedoicacid reduced major ASCVD outcomes by 13% over a median 40 months (ARR = 1.6%; NNT = 63), with no significant reduction in cardiovascular death.³⁰
• Niacin. Two large trials failed to demonstrate improvement in major cardiovascular events or other clinical benefit when niacin is added to moderate-intensity statin therapy, despite a significant increase in the HDL-C level (on average, 6 mg/dL) and a decrease in the LDL-C level (10-12 mg/dL)and TG (42 mg/dL).^31,32
• Fenofibrate lowers TG and increases HDL-C but does not consistently improve cardiovascular outcomes.³³ In a trial of patients with type 2 diabetes and persistent dyslipidemia (serum TG > 204 mg/dL; HDL-C< 34 mg/dL) despite statin therapy, adding fenofibrate reduced CVD outcomes by 4.9%—although this absolute difference did not reach statistical significance.³⁴

Neither niacin nor fenofibrate is considered useful for reducing ASCVD risk across broad populations.⁴

Follow-up to assess progress toward goals

Recheck the lipid profile 4 to 12 weeks after starting lipid-lowering therapy to verify adherence to medication and assess response. The primary goal is the percentage reduction in LDL-C based on ASCVD risk. An additional goal for very-high-risk patients is an LDL-C value ≤ 70 mg/dL. If the reduction in LDL-C is less than desired and adherence is assured, consider titrating the statin dosage or augmenting statin therapy with a nonstatin drug (eg, ezetimibe), or both.⁴ ●

CORRESPONDENCE

Jonathon M. Firnhaber, MD, MAEd, MBA, East Carolina University, Family Medicine Center, 101 Heart Drive, Greenville, NC 27834; [email protected]

An elevated serum level of cholesterol has been recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD) since the publication of the Framingham Study in 1961.¹ Although clinical outcomes related to ASCVD have improved in recent decades, ASCVD remains the leading cause of morbidity and mortality across the globe and remains, in the United States, the leading cause of death among most racial and ethnic groups. Much of this persistent disease burden can be attributed to inadequate control of ASCVD risk factors and suboptimal implementation of prevention strategies in the general population.²

The most recent (2019) iteration of the American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease emphasizes a comprehensive, patient-centered, team-based approach to the management of ASCVD risk factors.² In this article, I review how, first, medication to reduce ASCVD risk should be considered only when a patient’s risk is sufficiently high and, second, shared decision-making and social determinants of health should, in all cases, guide and inform optimal implementation of treatment.²

Estimating risk for ASCVD by ascertaining LDL-C

• The Friedewald equation. Traditionally, low-density lipoprotein cholesterol (LDL-C) is estimated using the Friedewald equation^a applied to a fasting lipid profile. In patients who have a low level of LDL-C (< 70 mg/dL), however, the Friedewald equation becomes less accurate; in patients with hypertriglyceridemia (TG ≥ 400 mg/dL),estimation of LDL-C is invalid.
• The Martin–Hopkins equation offers a validated estimation of LDL-C when the LDL-C value is < 70 mg/dL.³ This equation—in which the fixed factor of 5 used in the Friedewald equation to estimate very low-density lipoprotein cholesterol is replaced by an adjustable factor that is based on the patient’s non-HDL-C (ie, TC–HDL-C) and TG values—is preferred by the ACC/AHA Task Force on Clinical Practice Guidelines in this clinical circumstance.⁴
• National Institutes of Health equation. This newer equation provides an accurate estimate of the LDL-C level in patients whose TG value is ≤ 800 mg/dL. The equation has not been fully validated for clinical use, however.⁵
• Direct measurement obviates the need for an equation to estimate LDL-C, but the test is not available in all health care settings.

For adults ≥ 20 years of age who are not receiving lipid-lowering therapy, a nonfasting lipid profile can be used to estimate ASCVD risk and document the baseline LDL-C level. If the TG level is ≥ 400 mg/dL, the test should be administered in the fasting state.⁴

• Apolipoprotein B. Alternatively, apolipoprotein B (apoB) can be measured. Because each LDL-C particle contains 1 apoB molecule, the apoB level describes the LDL-C level more accurately than a calculation of LDL-C. Many patients with type 2 diabetes and metabolic syndrome have a relatively low calculated LDL-C (thereby falsely reassuring the testing clinician) but have an elevated apoB level. An apoB level ≥ 130 mg/dL corresponds to an LDL-C level >160 mg/dL.⁴
• Calculation of non-HDL-C. Because the nonfasting state does not have a significant impact on a patient’s TC and HDL-C levels, the non-HDL-C level also can be calculated from the results of a nonfasting lipid profile.

Non-HDL-C and apoB are equivalent predictors of ASCVD risk. These 2 assessments might offer better risk estimation than other available tools in patients who have type 2 diabetes and metabolic syndrome.⁶

Continue to: Applying the estimate of 10-year ASCVD risk...

Your recommendation for preventive intervention, such as lipid-lowering therapy, should be based on the estimated 10-year risk for ASCVD. Although multiple validated risk assessment tools are available, ACC/AHA recommends the pooled cohort risk equations (PCE), introduced in the 2013 ACC/AHA cholesterol treatment guidelines. The Framingham Heart Study now recommends the ACC/AHA PCE for risk assessment as well.⁷

The PCE, developed from 5 large cohorts, is based on hard atherosclerotic events: nonfatal myocardial infarction, death from coronary artery disease, and stroke. The ACC/AHA PCE is the only risk assessment tool developed using a significant percentage of patients who self-identify as Black.⁸ Alternatives to the ACC/AHA PCE include:

• Multi-ethnic Study of Atherosclerosis (MESA) 10-year ASCVD risk calculator, which incorporates the coronary artery calcium (CAC) score.
• Reynolds Risk Score, which incorporates high-sensitivity C-reactive protein measurement and a family history of premature ASCVD.⁹

How much does lifestyle modification actually matter?

The absolute impact of diet and exercise on lipid parameters is relatively modest. No studies have demonstrated a reduction in adverse cardiovascular outcomes with specific interventions regarding diet or activity.

• Diet. Nevertheless, ACC/AHA recommends that at-risk patients follow a dietary pattern that (1) emphasizes vegetables, fruits, and whole grains and (2) limits sweets, sugar-sweetened beverages, and red meat.

Saturated fat should constitute no more than 5% or 6% of total calories. In controlled-feeding trials,¹⁰ for every 1% of calories from saturated fat that are replaced with carbohydrate or monounsaturated or polyunsaturated fat, the LDL-C level was found to decline by as much as 1.8 mg/dL. Evidence is insufficient to assert that lowering dietary cholesterol reduces LDL-C.¹¹

• Activity. Trials of aerobic physical activity, compared with a more sedentary activity pattern, have demonstrated a reduction in the LDL-C level of as much as 6 mg/dL. All adult patients should be counseled to engage in aerobic physical activity of moderate or vigorous intensity—averaging ≥ 40 minutes per session, 3 or 4 sessions per week.¹¹

Primary prevention: Stratification by age

• 40 to 75 years. ACC/AHA recommends that you routinely assess traditional cardiovascular risk factors for these patients and calculate their 10-year risk for ASCVD using the PCE. Statin therapy as primary prevention is indicated for 3 major groups (TABLE 1).⁴ The US Preventive Services Task Force (USPSTF) recommends a 10-year ASCVD risk ≥ 10%, in conjunction with 1 or more additional CVD risk factors (dyslipidemia, diabetes, hypertension, smoking), as the threshold for initiating low- or moderate-intensity statin therapy in this age group.¹²

In adults at borderline risk (5% to < 7.5% 10-year ASCVD risk) or intermediate risk (≥ 7.5% to < 20% 10-year ASCVD risk), consider risk-enhancing factors to better inform your recommendation for preventive interventions. In these 2 groups, the presence of risk-enhancing factors might justify moderate-intensity statin therapy (TABLE 2⁴).

If your decision regarding preventive intervention remains uncertain, measuring CAC might further guide your discussion with the patient.⁴ When the CAC score is:

• 0 Agatston units and higher-risk conditions (eg, diabetes, family history of premature coronary artery disease, smoking) are absent, statin therapy can be withheld; reassess ASCVD risk in 5 to 10 years.
• 1-99 Agatston units, statin therapy can be started, especially for patients ≥ 55 years of age.
• ≥ 100 Agatston units or ≥ 75th percentile, statin therapy is indicated for all patients, regardless of additional risk factors.⁴

Because statins promote progression from unstable, inflammatory atherosclerotic plaque to more stable, calcified plaque, CAC scoring is not valid in patients already on statin therapy.¹³

In primary prevention, patients who have been classified as having low or intermediate risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have an annual all-cause mortality < 1%, regardless of age and gender. Patients classified as being at high risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have a significantly lower annual mortality than low- or intermediate-risk patients with a CAC score > 0 Agatston units.¹⁴

• 20 to 39 years. Focus on evaluation of lifetime ASCVD risk, rather than short-term (10-year) risk. Lifestyle modification is the primary intervention for younger patients; for those with moderate hypercholesterolemia (LDL-C, 160-189 mg/dL) and a family history of premature ASCVD, however, consider statin therapy. For patients with LDL-C ≥ 190 mg/dL, lifetime ASCVD risk is markedly increased, and high-intensity statin therapy is recommended, regardless of age. In this group, reassess ASCVD risk factors every 4 to 6 years.⁴
• > 75 years, without ASCVD. In this group, the benefit of statin therapy is less clear and might be lessened by an increased potential for adverse effects. A meta-analysis of 28 trials demonstrated that people ages > 75 years had a 24% relative reduction in major coronary events for every 38.7mg/dL (1.0 mmol/L) reduction in LDL-C, which is comparable to the risk reduction seen in people ages 40 to 75 years.¹⁵

With increasing age, however, the relative reduction in major coronary events with statin therapy decreased,¹⁵ although other trials have not demonstrated age heterogeneity.¹⁶ Because people > 75 years of age have a significantly higher ASCVD event rate, a comparable relative rate reduction with statin therapy results in a larger absolute rate reduction (ARR) and, therefore, a smaller number needed to treat (NNT) to prevent an event, compared to the NNT in younger people.

Secondary prevention

ACC/AHA guidelines define clinical ASCVD as a history of:

• acute coronary syndrome
• myocardial infarction
• coronary or other arterial revascularization
• cerebrovascular event
• symptomatic peripheral artery disease, including aortic aneurysm.

High-intensity statin therapy is indicated for all patients ≤ 75 years who have clinical ASCVD. In patients > 75 years, consider a taper to moderate-intensity statin therapy. An upper age limit for seeing benefit from statin therapy in secondary prevention has not been identified.⁴

In high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy, ezetimibe (discussed in the next section) can be added. In very-high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy plus ezetimibe, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (also discussed next) can be added. Always precede initiation of a PCSK9 inhibitor with a discussion of the net benefit, safety, and cost with the patient.⁴

Continue to: Options for lipid-lowering pharmacotherapy...

• Statins (formally, hydroxymethylglutaryl-coenzyme A reductase inhibitors) offer the most predictable reduction in ASCVD risk of any lipid-lowering therapy. The evidence report that accompanied the 2016 USPSTF guidelines on statins for the prevention of cardiovascular disease (CVD) stated that low- or moderate-dosage statin therapy is associated with approximately a 30% relative risk reduction (RRR) in CVD events and CVD deaths and a 10% to 15% RRR in all-cause mortality.¹⁷

High-intensity statin therapy reduces LDL-C by ≥ 50%. Moderate-intensity statin therapy reduces LDL-C by 30% to 49% (TABLE 3).⁴

Statins are not without risk: A 2016 report¹⁸ estimated that treating 10,000 patients with a statin for 5 years would cause 1 case of rhabdomyolysis, 5 cases of myopathy, 75 new cases of diabetes, and 7 cases of hemorrhagic stroke. The same treatment would, however, avert approximately 1000 CVD events among patients with preexisting disease and approximately 500 CVD events among patients at elevated risk but without preexisting disease.¹⁸

• Ezetimibe, a selective cholesterol-absorption inhibitor, lowers LDL-C by 13% to 20% and typically is well tolerated. The use of ezetimibe in ASCVD risk reduction is supported by a single randomized controlled trial of more than 18,000 patients with recent acute coronary syndrome. Adding ezetimibe to simvastatin 40 mg resulted in a 2% absolute reduction in major adverse cardiovascular events over a median follow-up of 6 years (NNT = 50), compared to simvastatin alone.¹⁹ ACC/AHA guidelines recommend adding ezetimibe to maximally tolerated statin therapy in patients with clinical ASCVD who do not reach their goal LDL reduction with a statin alone. Ezetimibe also can be considered a statin alternative in patients who are statin intolerant.⁴
• PCSK9 inhibitors. When added to statin therapy, evolocumab and alirocumab—monoclonal antibodies that inhibit PCSK9—offer an incremental decrease in LDL-C of approximately 60%.^20-22 In a meta-analysis of 35 trials evaluating the incremental benefit of PCSK9 inhibitor therapy, a significant reduction in cardiovascular events, including myocardial infarction (ARR = 1.3%; NNT = 77), stroke (ARR = 0.4%; NNT = 250), and coronary revascularization (ARR = 1.6%; NNT = 63) was reported. No significant difference was observed in all-cause or cardiovascular mortality.^21,23
• Inclisiran, an injectable small-interfering RNA that inhibits PCSK9 synthesis, provides an incremental decrease in LDL-C of > 50% in patients already receiving statin therapy. Meta-analysis of 3 small cardiovascular outcomes trials revealed no significant difference in the rate of myocardial infarction, stroke, or cardiovascular mortality with inclisiran compared to placebo. Larger outcomes trials are underway and might offer additional insight into this agent’s role in ASCVD risk management.²⁴
• Omega-3 fatty acids. Multiple trials have demonstrated that adding omega-3 fatty acids to usual lipid-lowering therapy does not offer a consistent reduction in adverse cardiovascular outcomes, despite providing a significant reduction in TG levels. In a high-risk population with persistently elevated TG despite statin therapy, icosapent ethyl, a purified eicosapentaenoic acid ethyl ester, reduced major ASCVD outcomes by 25% over a median 4.9 years (ARR = 4.8%; NNT = 21), and cardiovascular death by 20% (ARR = 0.9%; NNT = 111), compared with a mineral oil placebo.²⁵ Subsequent trials, using a corn oil placebo, failed to duplicate these data²⁶—raising concern that the mineral oil comparator might have altered results of the eicosapentaenoic acid ethyl ester study.^27,28
• Bempedoic acid is a small-molecule inhibitor of ATP citrate lyase that increases LDL uptake by the liver. Pooled data from studies of bempedoic acid show, on average, a 15% reduction in TC, a 23% reduction in LDL-C, and a 6% increase in HDL-C, without a significant change in TG.²⁹ In statin-intolerant patients, bempedoicacid reduced major ASCVD outcomes by 13% over a median 40 months (ARR = 1.6%; NNT = 63), with no significant reduction in cardiovascular death.³⁰
• Niacin. Two large trials failed to demonstrate improvement in major cardiovascular events or other clinical benefit when niacin is added to moderate-intensity statin therapy, despite a significant increase in the HDL-C level (on average, 6 mg/dL) and a decrease in the LDL-C level (10-12 mg/dL)and TG (42 mg/dL).^31,32
• Fenofibrate lowers TG and increases HDL-C but does not consistently improve cardiovascular outcomes.³³ In a trial of patients with type 2 diabetes and persistent dyslipidemia (serum TG > 204 mg/dL; HDL-C< 34 mg/dL) despite statin therapy, adding fenofibrate reduced CVD outcomes by 4.9%—although this absolute difference did not reach statistical significance.³⁴

Neither niacin nor fenofibrate is considered useful for reducing ASCVD risk across broad populations.⁴

Follow-up to assess progress toward goals

Recheck the lipid profile 4 to 12 weeks after starting lipid-lowering therapy to verify adherence to medication and assess response. The primary goal is the percentage reduction in LDL-C based on ASCVD risk. An additional goal for very-high-risk patients is an LDL-C value ≤ 70 mg/dL. If the reduction in LDL-C is less than desired and adherence is assured, consider titrating the statin dosage or augmenting statin therapy with a nonstatin drug (eg, ezetimibe), or both.⁴ ●

CORRESPONDENCE

Jonathon M. Firnhaber, MD, MAEd, MBA, East Carolina University, Family Medicine Center, 101 Heart Drive, Greenville, NC 27834; [email protected]

An elevated serum level of cholesterol has been recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD) since the publication of the Framingham Study in 1961.¹ Although clinical outcomes related to ASCVD have improved in recent decades, ASCVD remains the leading cause of morbidity and mortality across the globe and remains, in the United States, the leading cause of death among most racial and ethnic groups. Much of this persistent disease burden can be attributed to inadequate control of ASCVD risk factors and suboptimal implementation of prevention strategies in the general population.²

The most recent (2019) iteration of the American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease emphasizes a comprehensive, patient-centered, team-based approach to the management of ASCVD risk factors.² In this article, I review how, first, medication to reduce ASCVD risk should be considered only when a patient’s risk is sufficiently high and, second, shared decision-making and social determinants of health should, in all cases, guide and inform optimal implementation of treatment.²

Estimating risk for ASCVD by ascertaining LDL-C

• The Friedewald equation. Traditionally, low-density lipoprotein cholesterol (LDL-C) is estimated using the Friedewald equation^a applied to a fasting lipid profile. In patients who have a low level of LDL-C (< 70 mg/dL), however, the Friedewald equation becomes less accurate; in patients with hypertriglyceridemia (TG ≥ 400 mg/dL),estimation of LDL-C is invalid.
• The Martin–Hopkins equation offers a validated estimation of LDL-C when the LDL-C value is < 70 mg/dL.³ This equation—in which the fixed factor of 5 used in the Friedewald equation to estimate very low-density lipoprotein cholesterol is replaced by an adjustable factor that is based on the patient’s non-HDL-C (ie, TC–HDL-C) and TG values—is preferred by the ACC/AHA Task Force on Clinical Practice Guidelines in this clinical circumstance.⁴
• National Institutes of Health equation. This newer equation provides an accurate estimate of the LDL-C level in patients whose TG value is ≤ 800 mg/dL. The equation has not been fully validated for clinical use, however.⁵
• Direct measurement obviates the need for an equation to estimate LDL-C, but the test is not available in all health care settings.

For adults ≥ 20 years of age who are not receiving lipid-lowering therapy, a nonfasting lipid profile can be used to estimate ASCVD risk and document the baseline LDL-C level. If the TG level is ≥ 400 mg/dL, the test should be administered in the fasting state.⁴

• Apolipoprotein B. Alternatively, apolipoprotein B (apoB) can be measured. Because each LDL-C particle contains 1 apoB molecule, the apoB level describes the LDL-C level more accurately than a calculation of LDL-C. Many patients with type 2 diabetes and metabolic syndrome have a relatively low calculated LDL-C (thereby falsely reassuring the testing clinician) but have an elevated apoB level. An apoB level ≥ 130 mg/dL corresponds to an LDL-C level >160 mg/dL.⁴
• Calculation of non-HDL-C. Because the nonfasting state does not have a significant impact on a patient’s TC and HDL-C levels, the non-HDL-C level also can be calculated from the results of a nonfasting lipid profile.

Non-HDL-C and apoB are equivalent predictors of ASCVD risk. These 2 assessments might offer better risk estimation than other available tools in patients who have type 2 diabetes and metabolic syndrome.⁶

Continue to: Applying the estimate of 10-year ASCVD risk...

Your recommendation for preventive intervention, such as lipid-lowering therapy, should be based on the estimated 10-year risk for ASCVD. Although multiple validated risk assessment tools are available, ACC/AHA recommends the pooled cohort risk equations (PCE), introduced in the 2013 ACC/AHA cholesterol treatment guidelines. The Framingham Heart Study now recommends the ACC/AHA PCE for risk assessment as well.⁷

The PCE, developed from 5 large cohorts, is based on hard atherosclerotic events: nonfatal myocardial infarction, death from coronary artery disease, and stroke. The ACC/AHA PCE is the only risk assessment tool developed using a significant percentage of patients who self-identify as Black.⁸ Alternatives to the ACC/AHA PCE include:

• Multi-ethnic Study of Atherosclerosis (MESA) 10-year ASCVD risk calculator, which incorporates the coronary artery calcium (CAC) score.
• Reynolds Risk Score, which incorporates high-sensitivity C-reactive protein measurement and a family history of premature ASCVD.⁹

How much does lifestyle modification actually matter?

The absolute impact of diet and exercise on lipid parameters is relatively modest. No studies have demonstrated a reduction in adverse cardiovascular outcomes with specific interventions regarding diet or activity.

• Diet. Nevertheless, ACC/AHA recommends that at-risk patients follow a dietary pattern that (1) emphasizes vegetables, fruits, and whole grains and (2) limits sweets, sugar-sweetened beverages, and red meat.

Saturated fat should constitute no more than 5% or 6% of total calories. In controlled-feeding trials,¹⁰ for every 1% of calories from saturated fat that are replaced with carbohydrate or monounsaturated or polyunsaturated fat, the LDL-C level was found to decline by as much as 1.8 mg/dL. Evidence is insufficient to assert that lowering dietary cholesterol reduces LDL-C.¹¹

• Activity. Trials of aerobic physical activity, compared with a more sedentary activity pattern, have demonstrated a reduction in the LDL-C level of as much as 6 mg/dL. All adult patients should be counseled to engage in aerobic physical activity of moderate or vigorous intensity—averaging ≥ 40 minutes per session, 3 or 4 sessions per week.¹¹

Primary prevention: Stratification by age

• 40 to 75 years. ACC/AHA recommends that you routinely assess traditional cardiovascular risk factors for these patients and calculate their 10-year risk for ASCVD using the PCE. Statin therapy as primary prevention is indicated for 3 major groups (TABLE 1).⁴ The US Preventive Services Task Force (USPSTF) recommends a 10-year ASCVD risk ≥ 10%, in conjunction with 1 or more additional CVD risk factors (dyslipidemia, diabetes, hypertension, smoking), as the threshold for initiating low- or moderate-intensity statin therapy in this age group.¹²

In adults at borderline risk (5% to < 7.5% 10-year ASCVD risk) or intermediate risk (≥ 7.5% to < 20% 10-year ASCVD risk), consider risk-enhancing factors to better inform your recommendation for preventive interventions. In these 2 groups, the presence of risk-enhancing factors might justify moderate-intensity statin therapy (TABLE 2⁴).

If your decision regarding preventive intervention remains uncertain, measuring CAC might further guide your discussion with the patient.⁴ When the CAC score is:

• 0 Agatston units and higher-risk conditions (eg, diabetes, family history of premature coronary artery disease, smoking) are absent, statin therapy can be withheld; reassess ASCVD risk in 5 to 10 years.
• 1-99 Agatston units, statin therapy can be started, especially for patients ≥ 55 years of age.
• ≥ 100 Agatston units or ≥ 75th percentile, statin therapy is indicated for all patients, regardless of additional risk factors.⁴

Because statins promote progression from unstable, inflammatory atherosclerotic plaque to more stable, calcified plaque, CAC scoring is not valid in patients already on statin therapy.¹³

In primary prevention, patients who have been classified as having low or intermediate risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have an annual all-cause mortality < 1%, regardless of age and gender. Patients classified as being at high risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have a significantly lower annual mortality than low- or intermediate-risk patients with a CAC score > 0 Agatston units.¹⁴

• 20 to 39 years. Focus on evaluation of lifetime ASCVD risk, rather than short-term (10-year) risk. Lifestyle modification is the primary intervention for younger patients; for those with moderate hypercholesterolemia (LDL-C, 160-189 mg/dL) and a family history of premature ASCVD, however, consider statin therapy. For patients with LDL-C ≥ 190 mg/dL, lifetime ASCVD risk is markedly increased, and high-intensity statin therapy is recommended, regardless of age. In this group, reassess ASCVD risk factors every 4 to 6 years.⁴
• > 75 years, without ASCVD. In this group, the benefit of statin therapy is less clear and might be lessened by an increased potential for adverse effects. A meta-analysis of 28 trials demonstrated that people ages > 75 years had a 24% relative reduction in major coronary events for every 38.7mg/dL (1.0 mmol/L) reduction in LDL-C, which is comparable to the risk reduction seen in people ages 40 to 75 years.¹⁵

With increasing age, however, the relative reduction in major coronary events with statin therapy decreased,¹⁵ although other trials have not demonstrated age heterogeneity.¹⁶ Because people > 75 years of age have a significantly higher ASCVD event rate, a comparable relative rate reduction with statin therapy results in a larger absolute rate reduction (ARR) and, therefore, a smaller number needed to treat (NNT) to prevent an event, compared to the NNT in younger people.

Secondary prevention

ACC/AHA guidelines define clinical ASCVD as a history of:

• acute coronary syndrome
• myocardial infarction
• coronary or other arterial revascularization
• cerebrovascular event
• symptomatic peripheral artery disease, including aortic aneurysm.

High-intensity statin therapy is indicated for all patients ≤ 75 years who have clinical ASCVD. In patients > 75 years, consider a taper to moderate-intensity statin therapy. An upper age limit for seeing benefit from statin therapy in secondary prevention has not been identified.⁴

In high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy, ezetimibe (discussed in the next section) can be added. In very-high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy plus ezetimibe, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (also discussed next) can be added. Always precede initiation of a PCSK9 inhibitor with a discussion of the net benefit, safety, and cost with the patient.⁴

Continue to: Options for lipid-lowering pharmacotherapy...

• Statins (formally, hydroxymethylglutaryl-coenzyme A reductase inhibitors) offer the most predictable reduction in ASCVD risk of any lipid-lowering therapy. The evidence report that accompanied the 2016 USPSTF guidelines on statins for the prevention of cardiovascular disease (CVD) stated that low- or moderate-dosage statin therapy is associated with approximately a 30% relative risk reduction (RRR) in CVD events and CVD deaths and a 10% to 15% RRR in all-cause mortality.¹⁷

High-intensity statin therapy reduces LDL-C by ≥ 50%. Moderate-intensity statin therapy reduces LDL-C by 30% to 49% (TABLE 3).⁴

Statins are not without risk: A 2016 report¹⁸ estimated that treating 10,000 patients with a statin for 5 years would cause 1 case of rhabdomyolysis, 5 cases of myopathy, 75 new cases of diabetes, and 7 cases of hemorrhagic stroke. The same treatment would, however, avert approximately 1000 CVD events among patients with preexisting disease and approximately 500 CVD events among patients at elevated risk but without preexisting disease.¹⁸

• Ezetimibe, a selective cholesterol-absorption inhibitor, lowers LDL-C by 13% to 20% and typically is well tolerated. The use of ezetimibe in ASCVD risk reduction is supported by a single randomized controlled trial of more than 18,000 patients with recent acute coronary syndrome. Adding ezetimibe to simvastatin 40 mg resulted in a 2% absolute reduction in major adverse cardiovascular events over a median follow-up of 6 years (NNT = 50), compared to simvastatin alone.¹⁹ ACC/AHA guidelines recommend adding ezetimibe to maximally tolerated statin therapy in patients with clinical ASCVD who do not reach their goal LDL reduction with a statin alone. Ezetimibe also can be considered a statin alternative in patients who are statin intolerant.⁴
• PCSK9 inhibitors. When added to statin therapy, evolocumab and alirocumab—monoclonal antibodies that inhibit PCSK9—offer an incremental decrease in LDL-C of approximately 60%.^20-22 In a meta-analysis of 35 trials evaluating the incremental benefit of PCSK9 inhibitor therapy, a significant reduction in cardiovascular events, including myocardial infarction (ARR = 1.3%; NNT = 77), stroke (ARR = 0.4%; NNT = 250), and coronary revascularization (ARR = 1.6%; NNT = 63) was reported. No significant difference was observed in all-cause or cardiovascular mortality.^21,23
• Inclisiran, an injectable small-interfering RNA that inhibits PCSK9 synthesis, provides an incremental decrease in LDL-C of > 50% in patients already receiving statin therapy. Meta-analysis of 3 small cardiovascular outcomes trials revealed no significant difference in the rate of myocardial infarction, stroke, or cardiovascular mortality with inclisiran compared to placebo. Larger outcomes trials are underway and might offer additional insight into this agent’s role in ASCVD risk management.²⁴
• Omega-3 fatty acids. Multiple trials have demonstrated that adding omega-3 fatty acids to usual lipid-lowering therapy does not offer a consistent reduction in adverse cardiovascular outcomes, despite providing a significant reduction in TG levels. In a high-risk population with persistently elevated TG despite statin therapy, icosapent ethyl, a purified eicosapentaenoic acid ethyl ester, reduced major ASCVD outcomes by 25% over a median 4.9 years (ARR = 4.8%; NNT = 21), and cardiovascular death by 20% (ARR = 0.9%; NNT = 111), compared with a mineral oil placebo.²⁵ Subsequent trials, using a corn oil placebo, failed to duplicate these data²⁶—raising concern that the mineral oil comparator might have altered results of the eicosapentaenoic acid ethyl ester study.^27,28
• Bempedoic acid is a small-molecule inhibitor of ATP citrate lyase that increases LDL uptake by the liver. Pooled data from studies of bempedoic acid show, on average, a 15% reduction in TC, a 23% reduction in LDL-C, and a 6% increase in HDL-C, without a significant change in TG.²⁹ In statin-intolerant patients, bempedoicacid reduced major ASCVD outcomes by 13% over a median 40 months (ARR = 1.6%; NNT = 63), with no significant reduction in cardiovascular death.³⁰
• Niacin. Two large trials failed to demonstrate improvement in major cardiovascular events or other clinical benefit when niacin is added to moderate-intensity statin therapy, despite a significant increase in the HDL-C level (on average, 6 mg/dL) and a decrease in the LDL-C level (10-12 mg/dL)and TG (42 mg/dL).^31,32
• Fenofibrate lowers TG and increases HDL-C but does not consistently improve cardiovascular outcomes.³³ In a trial of patients with type 2 diabetes and persistent dyslipidemia (serum TG > 204 mg/dL; HDL-C< 34 mg/dL) despite statin therapy, adding fenofibrate reduced CVD outcomes by 4.9%—although this absolute difference did not reach statistical significance.³⁴

Neither niacin nor fenofibrate is considered useful for reducing ASCVD risk across broad populations.⁴

Follow-up to assess progress toward goals

Recheck the lipid profile 4 to 12 weeks after starting lipid-lowering therapy to verify adherence to medication and assess response. The primary goal is the percentage reduction in LDL-C based on ASCVD risk. An additional goal for very-high-risk patients is an LDL-C value ≤ 70 mg/dL. If the reduction in LDL-C is less than desired and adherence is assured, consider titrating the statin dosage or augmenting statin therapy with a nonstatin drug (eg, ezetimibe), or both.⁴ ●

CORRESPONDENCE

Jonathon M. Firnhaber, MD, MAEd, MBA, East Carolina University, Family Medicine Center, 101 Heart Drive, Greenville, NC 27834; [email protected]

Women with Sjögren’s syndrome have pregnancy outcomes similar to those of the general population, according to the first study to prospectively track pregnancy outcomes among people with the autoimmune condition.

“Most early studies of pregnancy in rheumatic disease patients were retrospective and included only small numbers, making it difficult to know how generalizable the reported results were,” said Lisa Sammaritano, MD, a rheumatologist at Hospital for Special Surgery in New York, in an email interview with this news organization. She was not involved with the research.

Most of these previous studies suggested an increased risk of adverse outcomes, such as miscarriages, preterm deliveries, and small-for-gestational-age birth weight. But in addition to small patient numbers, retrospective studies “are subject to greater reporting bias, which may predispose patients with negative outcomes being more likely to be included because they were followed more closely,” Dr. Sammaritano said.

“This prospective study has several advantages over the earlier retrospective reports: The same data were collected in the same way for all the patients, the patients were recruited at similar time points, and – due to the multicenter nature of the cohort – numbers are larger than in prior studies. All these factors make the results stronger and more generalizable to the Sjögren’s patients we see in our practices,” she added.

In the study, published May 8 in The Lancet Rheumatology, first author Grégoire Martin de Frémont, MD, of the rheumatology service at Bicêtre Hospital, Paris-Saclay University and colleagues used the GR2 registry, an observational database of pregnancies of women with systemic autoimmune diseases managed at 76 participating centers in France, to identify pregnant women with primary Sjögren’s syndrome. To avoid bias, only women who entered the database before 18 weeks’ gestation were included. The final cohort included 106 pregnancies in 96 women with primary Sjögren’s syndrome and 420 control pregnancies that were matched from the general population.

Adverse pregnancy outcomes, including preterm delivery (< 37 weeks of gestation), intrauterine growth retardation, and low birth weight occurred in nine pregnancies (9%) in the Sjögren’s syndrome group and in 28 pregnancies in the control group (7%). Adverse pregnancy outcomes were not significantly associated with Sjögren’s syndrome (P = .52). Researchers found that there were more adverse pregnancy outcomes among women with Sjögren’s syndrome with antiphospholipid (aPL) antibodies. Negative outcomes also increased among those with anti-RNP antibodies, but this association was not statistically significant.

“The main message – based on strong data from a well-designed study – is that patients with Sjögren’s overall do as well as the general population in terms of standard adverse pregnancy outcomes. The rate of flare of Sjögren’s disease was relatively low during the second and third trimesters, also reassuring,” Dr. Sammaritano said. She noted that the association between adverse pregnancy outcomes and aPL antibodies was not unexpected, given that they are a known risk factor.

The study authors recommend that patients with Sjögren’s syndrome be screened for aPL and anti-RNP antibodies prior to conception because of the potential increased risk for complications and that patients with positive screens be closely monitored during their pregnancy.

Dr. Sammaritano noted that there are other health problems to keep in mind. “It is important to remember that Sjögren’s patients – more than any other rheumatic disease patients – have the additional risk for neonatal lupus and complete heart block in their infant, since about two-thirds of Sjögren’s patients are positive for anti-Ro/SSA antibody,” she said. “This is a distinct issue related to the presence of this antibody alone and not specifically related to the underlying diagnosis. In clinical practice, positive anti-Ro/SSA antibody is often the main reason for counseling, monitoring, and even recommending therapy (hydroxychloroquine) in these patients.”

The study received funding from Lupus France, the France Association of Scleroderma, and the Association Gougerot Sjögren, among others. Dr. Sammaritano reports no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Women with Sjögren’s syndrome have pregnancy outcomes similar to those of the general population, according to the first study to prospectively track pregnancy outcomes among people with the autoimmune condition.

“Most early studies of pregnancy in rheumatic disease patients were retrospective and included only small numbers, making it difficult to know how generalizable the reported results were,” said Lisa Sammaritano, MD, a rheumatologist at Hospital for Special Surgery in New York, in an email interview with this news organization. She was not involved with the research.

Most of these previous studies suggested an increased risk of adverse outcomes, such as miscarriages, preterm deliveries, and small-for-gestational-age birth weight. But in addition to small patient numbers, retrospective studies “are subject to greater reporting bias, which may predispose patients with negative outcomes being more likely to be included because they were followed more closely,” Dr. Sammaritano said.

“This prospective study has several advantages over the earlier retrospective reports: The same data were collected in the same way for all the patients, the patients were recruited at similar time points, and – due to the multicenter nature of the cohort – numbers are larger than in prior studies. All these factors make the results stronger and more generalizable to the Sjögren’s patients we see in our practices,” she added.

In the study, published May 8 in The Lancet Rheumatology, first author Grégoire Martin de Frémont, MD, of the rheumatology service at Bicêtre Hospital, Paris-Saclay University and colleagues used the GR2 registry, an observational database of pregnancies of women with systemic autoimmune diseases managed at 76 participating centers in France, to identify pregnant women with primary Sjögren’s syndrome. To avoid bias, only women who entered the database before 18 weeks’ gestation were included. The final cohort included 106 pregnancies in 96 women with primary Sjögren’s syndrome and 420 control pregnancies that were matched from the general population.

Adverse pregnancy outcomes, including preterm delivery (< 37 weeks of gestation), intrauterine growth retardation, and low birth weight occurred in nine pregnancies (9%) in the Sjögren’s syndrome group and in 28 pregnancies in the control group (7%). Adverse pregnancy outcomes were not significantly associated with Sjögren’s syndrome (P = .52). Researchers found that there were more adverse pregnancy outcomes among women with Sjögren’s syndrome with antiphospholipid (aPL) antibodies. Negative outcomes also increased among those with anti-RNP antibodies, but this association was not statistically significant.

“The main message – based on strong data from a well-designed study – is that patients with Sjögren’s overall do as well as the general population in terms of standard adverse pregnancy outcomes. The rate of flare of Sjögren’s disease was relatively low during the second and third trimesters, also reassuring,” Dr. Sammaritano said. She noted that the association between adverse pregnancy outcomes and aPL antibodies was not unexpected, given that they are a known risk factor.

The study authors recommend that patients with Sjögren’s syndrome be screened for aPL and anti-RNP antibodies prior to conception because of the potential increased risk for complications and that patients with positive screens be closely monitored during their pregnancy.

Dr. Sammaritano noted that there are other health problems to keep in mind. “It is important to remember that Sjögren’s patients – more than any other rheumatic disease patients – have the additional risk for neonatal lupus and complete heart block in their infant, since about two-thirds of Sjögren’s patients are positive for anti-Ro/SSA antibody,” she said. “This is a distinct issue related to the presence of this antibody alone and not specifically related to the underlying diagnosis. In clinical practice, positive anti-Ro/SSA antibody is often the main reason for counseling, monitoring, and even recommending therapy (hydroxychloroquine) in these patients.”

The study received funding from Lupus France, the France Association of Scleroderma, and the Association Gougerot Sjögren, among others. Dr. Sammaritano reports no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Women with Sjögren’s syndrome have pregnancy outcomes similar to those of the general population, according to the first study to prospectively track pregnancy outcomes among people with the autoimmune condition.

“Most early studies of pregnancy in rheumatic disease patients were retrospective and included only small numbers, making it difficult to know how generalizable the reported results were,” said Lisa Sammaritano, MD, a rheumatologist at Hospital for Special Surgery in New York, in an email interview with this news organization. She was not involved with the research.

Most of these previous studies suggested an increased risk of adverse outcomes, such as miscarriages, preterm deliveries, and small-for-gestational-age birth weight. But in addition to small patient numbers, retrospective studies “are subject to greater reporting bias, which may predispose patients with negative outcomes being more likely to be included because they were followed more closely,” Dr. Sammaritano said.

“This prospective study has several advantages over the earlier retrospective reports: The same data were collected in the same way for all the patients, the patients were recruited at similar time points, and – due to the multicenter nature of the cohort – numbers are larger than in prior studies. All these factors make the results stronger and more generalizable to the Sjögren’s patients we see in our practices,” she added.

In the study, published May 8 in The Lancet Rheumatology, first author Grégoire Martin de Frémont, MD, of the rheumatology service at Bicêtre Hospital, Paris-Saclay University and colleagues used the GR2 registry, an observational database of pregnancies of women with systemic autoimmune diseases managed at 76 participating centers in France, to identify pregnant women with primary Sjögren’s syndrome. To avoid bias, only women who entered the database before 18 weeks’ gestation were included. The final cohort included 106 pregnancies in 96 women with primary Sjögren’s syndrome and 420 control pregnancies that were matched from the general population.

Adverse pregnancy outcomes, including preterm delivery (< 37 weeks of gestation), intrauterine growth retardation, and low birth weight occurred in nine pregnancies (9%) in the Sjögren’s syndrome group and in 28 pregnancies in the control group (7%). Adverse pregnancy outcomes were not significantly associated with Sjögren’s syndrome (P = .52). Researchers found that there were more adverse pregnancy outcomes among women with Sjögren’s syndrome with antiphospholipid (aPL) antibodies. Negative outcomes also increased among those with anti-RNP antibodies, but this association was not statistically significant.

“The main message – based on strong data from a well-designed study – is that patients with Sjögren’s overall do as well as the general population in terms of standard adverse pregnancy outcomes. The rate of flare of Sjögren’s disease was relatively low during the second and third trimesters, also reassuring,” Dr. Sammaritano said. She noted that the association between adverse pregnancy outcomes and aPL antibodies was not unexpected, given that they are a known risk factor.

The study authors recommend that patients with Sjögren’s syndrome be screened for aPL and anti-RNP antibodies prior to conception because of the potential increased risk for complications and that patients with positive screens be closely monitored during their pregnancy.

Dr. Sammaritano noted that there are other health problems to keep in mind. “It is important to remember that Sjögren’s patients – more than any other rheumatic disease patients – have the additional risk for neonatal lupus and complete heart block in their infant, since about two-thirds of Sjögren’s patients are positive for anti-Ro/SSA antibody,” she said. “This is a distinct issue related to the presence of this antibody alone and not specifically related to the underlying diagnosis. In clinical practice, positive anti-Ro/SSA antibody is often the main reason for counseling, monitoring, and even recommending therapy (hydroxychloroquine) in these patients.”

The study received funding from Lupus France, the France Association of Scleroderma, and the Association Gougerot Sjögren, among others. Dr. Sammaritano reports no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

WASHINGTON – Patients with emphysema treated with one-way endobronchial values showed consistent improvement in lung function after 5 years compared with controls, based on data from 174 individuals.

One-way endobronchial valves demonstrated benefits for patients with severe emphysema over a 12-month period in the EMPROVE trial, according to Gerard J. Criner, MD, of Temple University, Philadelphia, and colleagues.

Five-year results from the EMPROVE study were presented in a poster session at the American Thoracic Society’s international conference.

The initial EMPROVE trial demonstrated safety and efficacy of the Spiration Valve System (SVS) over 12 months. However, data on the long-term benefits of one-way endobronchial values are limited, the researchers wrote.

The valve was designed for use in selected areas of the bronchial airways and features a flexible umbrella that allows air and mucus to clear from treated airways while blocking inspired air flow to areas of the lungs affected by disease, the researchers explained in the poster.

Dr. Criner and colleagues assessed 172 patients who were randomly assigned to treatment with a one-way valve system (113 patients) or a control group (59 patients).

Participants were evaluated at 1, 3, 6, and 12 months, then annually for 5 years.

The primary efficacy outcome was lung function, measured by forced expiratory volume per second (FEV₁). At five years, the FEV₁ values improved by 0.1098 liters in the treatment group (P < .001). Treated patients and controls experienced decreased FEV₁ at a rate of 0.0440 liters per year from baseline, a significant difference (P < .001). Assuming a steady rate of disease progression, “the treatment group gained approximately 2.5 years of FEV₁ improvement immediately following SVS treatment, which was maintained, compared to controls,” the researchers noted in their abstract.

Serious adverse events were assessed from 6 months to 5 years (352.7 patient-years) for treated patients and from 6 months to 2 years (72.9 patient-years) for controls.

Overall, 210 SAEs occurred in the treatment group and 35 occurred in controls, for rates of 0.60 and 0.48, respectively (P = .201). The most common SAEs in the treatment and control groups were COPD exacerbations, pneumothorax, and death.

The results suggest that the FEV₁ improvements seen in patients with severe emphysema after one-way endobronchial value placement compared with usual care are enduring after 5 years, with no significant changes in safety, the researchers concluded.

The original EMPROVE study was supported by Olympus Respiratory America, a part of Olympus Corporation and the developer of the Spiration Valve System. Results of the original study were published in the American Journal of Respiratory and Critical Care Medicine. Dr. Criner is associate editor of the American Journal of Respiratory and Critical Care Medicine. His participation complies with American Thoracic Society requirements for recusal from review and decisions for authored works.
 

A version of this article first appeared on Medscape.com.

WASHINGTON – Patients with emphysema treated with one-way endobronchial values showed consistent improvement in lung function after 5 years compared with controls, based on data from 174 individuals.

One-way endobronchial valves demonstrated benefits for patients with severe emphysema over a 12-month period in the EMPROVE trial, according to Gerard J. Criner, MD, of Temple University, Philadelphia, and colleagues.

Five-year results from the EMPROVE study were presented in a poster session at the American Thoracic Society’s international conference.

The initial EMPROVE trial demonstrated safety and efficacy of the Spiration Valve System (SVS) over 12 months. However, data on the long-term benefits of one-way endobronchial values are limited, the researchers wrote.

The valve was designed for use in selected areas of the bronchial airways and features a flexible umbrella that allows air and mucus to clear from treated airways while blocking inspired air flow to areas of the lungs affected by disease, the researchers explained in the poster.

Dr. Criner and colleagues assessed 172 patients who were randomly assigned to treatment with a one-way valve system (113 patients) or a control group (59 patients).

Participants were evaluated at 1, 3, 6, and 12 months, then annually for 5 years.

The primary efficacy outcome was lung function, measured by forced expiratory volume per second (FEV₁). At five years, the FEV₁ values improved by 0.1098 liters in the treatment group (P < .001). Treated patients and controls experienced decreased FEV₁ at a rate of 0.0440 liters per year from baseline, a significant difference (P < .001). Assuming a steady rate of disease progression, “the treatment group gained approximately 2.5 years of FEV₁ improvement immediately following SVS treatment, which was maintained, compared to controls,” the researchers noted in their abstract.

Serious adverse events were assessed from 6 months to 5 years (352.7 patient-years) for treated patients and from 6 months to 2 years (72.9 patient-years) for controls.

Overall, 210 SAEs occurred in the treatment group and 35 occurred in controls, for rates of 0.60 and 0.48, respectively (P = .201). The most common SAEs in the treatment and control groups were COPD exacerbations, pneumothorax, and death.

The results suggest that the FEV₁ improvements seen in patients with severe emphysema after one-way endobronchial value placement compared with usual care are enduring after 5 years, with no significant changes in safety, the researchers concluded.

The original EMPROVE study was supported by Olympus Respiratory America, a part of Olympus Corporation and the developer of the Spiration Valve System. Results of the original study were published in the American Journal of Respiratory and Critical Care Medicine. Dr. Criner is associate editor of the American Journal of Respiratory and Critical Care Medicine. His participation complies with American Thoracic Society requirements for recusal from review and decisions for authored works.
 

A version of this article first appeared on Medscape.com.

WASHINGTON – Patients with emphysema treated with one-way endobronchial values showed consistent improvement in lung function after 5 years compared with controls, based on data from 174 individuals.

One-way endobronchial valves demonstrated benefits for patients with severe emphysema over a 12-month period in the EMPROVE trial, according to Gerard J. Criner, MD, of Temple University, Philadelphia, and colleagues.

Five-year results from the EMPROVE study were presented in a poster session at the American Thoracic Society’s international conference.

The initial EMPROVE trial demonstrated safety and efficacy of the Spiration Valve System (SVS) over 12 months. However, data on the long-term benefits of one-way endobronchial values are limited, the researchers wrote.

The valve was designed for use in selected areas of the bronchial airways and features a flexible umbrella that allows air and mucus to clear from treated airways while blocking inspired air flow to areas of the lungs affected by disease, the researchers explained in the poster.

Dr. Criner and colleagues assessed 172 patients who were randomly assigned to treatment with a one-way valve system (113 patients) or a control group (59 patients).

Participants were evaluated at 1, 3, 6, and 12 months, then annually for 5 years.

The primary efficacy outcome was lung function, measured by forced expiratory volume per second (FEV₁). At five years, the FEV₁ values improved by 0.1098 liters in the treatment group (P < .001). Treated patients and controls experienced decreased FEV₁ at a rate of 0.0440 liters per year from baseline, a significant difference (P < .001). Assuming a steady rate of disease progression, “the treatment group gained approximately 2.5 years of FEV₁ improvement immediately following SVS treatment, which was maintained, compared to controls,” the researchers noted in their abstract.

Serious adverse events were assessed from 6 months to 5 years (352.7 patient-years) for treated patients and from 6 months to 2 years (72.9 patient-years) for controls.

Overall, 210 SAEs occurred in the treatment group and 35 occurred in controls, for rates of 0.60 and 0.48, respectively (P = .201). The most common SAEs in the treatment and control groups were COPD exacerbations, pneumothorax, and death.

The results suggest that the FEV₁ improvements seen in patients with severe emphysema after one-way endobronchial value placement compared with usual care are enduring after 5 years, with no significant changes in safety, the researchers concluded.

The original EMPROVE study was supported by Olympus Respiratory America, a part of Olympus Corporation and the developer of the Spiration Valve System. Results of the original study were published in the American Journal of Respiratory and Critical Care Medicine. Dr. Criner is associate editor of the American Journal of Respiratory and Critical Care Medicine. His participation complies with American Thoracic Society requirements for recusal from review and decisions for authored works.
 

A version of this article first appeared on Medscape.com.

Measurement error may be the culprit in underdiagnosing obstructive sleep apnea in Black patients, compared with White patients, based on data from nearly 2,000 individuals.

Data collected from ICU patients during the COVID-19 pandemic suggested that pulse oximetry devices used to measure oxygen saturation may be less accurate for patients with darker skin, according to Ali Azarbarzin, PhD, of Harvard Medical School, Boston.

“We wanted to examine the implications for obstructive sleep apnea,” which is often caused by a reduction in air flow, Dr. Azarbarzin said in an interview.

In a study presented at the American Thoracic Society’s international conference, Dr. Azarbarzin and colleagues examined data from 1,955 adults who were enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 5. The study participants underwent unattended 15-channel polysomnography that included a finger pulse oximeter. The mean age of the participants was 68.3 years, and 53.7% were women. A total of 12.1%, 23.7%, 27.7%, and 36.5% of the participants were Asian, Hispanic, Black, and White, respectively.

Apnea hypopnea index (AHI3P) was similar between Black and White patients, at approximately 19 events per hour. Black participants had higher wake SpO2, higher current smoking rates, and higher body mass index, compared with White participants, but these differences were not significant.

Severity of obstructive sleep apnea (OSA) was based on the hypoxic burden, which was defined as the total area under the respiratory curve. The total ventilatory burden was defined as the event-specific area under the ventilation signal and identified by amplitude changes in the nasal pressure signal. The researchers then calculated desaturation sensitivity (the primary outcome) as hypoxic burden divided by ventilatory burden.

In an unadjusted analysis, desaturation sensitivity was significantly lower in Black patients and Asian patients, compared with White patients (P < .001 and P < .02, respectively). After adjusting for age, sex, body mass index, and time spent in a supine position, desaturation sensitivity was lower only in Black patients, compared with White patients, and this difference persisted in both men and women.

The difference in desaturation sensitivity by race could be caused by differences in physiology or in measurement error, Dr. Azarbarzin told this news organization. If measurement error is the culprit, “we may be underestimating OSA severity in [Black people],” especially in Black women, he said.

However, more research is needed to understand the potential impact of both physiology and device accuracy on differences in oxygen saturation across ethnicities and to effectively identify and treat OSA in all patients, Dr. Azarbarzin said.

The MESA Study was supported by the National Institutes of Health and the National Institute on Aging. Data from MESA were obtained through support from the National Heart, Lung, and Blood Institute and the National Center for Advancing Translational Sciences. Dr. Azarbarzin disclosed funding from the National Institutes of Health, the American Health Association, and the American Academy of Sleep Medicine.

A version of this article first appeared on Medscape.com.

Measurement error may be the culprit in underdiagnosing obstructive sleep apnea in Black patients, compared with White patients, based on data from nearly 2,000 individuals.

Data collected from ICU patients during the COVID-19 pandemic suggested that pulse oximetry devices used to measure oxygen saturation may be less accurate for patients with darker skin, according to Ali Azarbarzin, PhD, of Harvard Medical School, Boston.

“We wanted to examine the implications for obstructive sleep apnea,” which is often caused by a reduction in air flow, Dr. Azarbarzin said in an interview.

In a study presented at the American Thoracic Society’s international conference, Dr. Azarbarzin and colleagues examined data from 1,955 adults who were enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 5. The study participants underwent unattended 15-channel polysomnography that included a finger pulse oximeter. The mean age of the participants was 68.3 years, and 53.7% were women. A total of 12.1%, 23.7%, 27.7%, and 36.5% of the participants were Asian, Hispanic, Black, and White, respectively.

Apnea hypopnea index (AHI3P) was similar between Black and White patients, at approximately 19 events per hour. Black participants had higher wake SpO2, higher current smoking rates, and higher body mass index, compared with White participants, but these differences were not significant.

Severity of obstructive sleep apnea (OSA) was based on the hypoxic burden, which was defined as the total area under the respiratory curve. The total ventilatory burden was defined as the event-specific area under the ventilation signal and identified by amplitude changes in the nasal pressure signal. The researchers then calculated desaturation sensitivity (the primary outcome) as hypoxic burden divided by ventilatory burden.

In an unadjusted analysis, desaturation sensitivity was significantly lower in Black patients and Asian patients, compared with White patients (P < .001 and P < .02, respectively). After adjusting for age, sex, body mass index, and time spent in a supine position, desaturation sensitivity was lower only in Black patients, compared with White patients, and this difference persisted in both men and women.

The difference in desaturation sensitivity by race could be caused by differences in physiology or in measurement error, Dr. Azarbarzin told this news organization. If measurement error is the culprit, “we may be underestimating OSA severity in [Black people],” especially in Black women, he said.

However, more research is needed to understand the potential impact of both physiology and device accuracy on differences in oxygen saturation across ethnicities and to effectively identify and treat OSA in all patients, Dr. Azarbarzin said.

The MESA Study was supported by the National Institutes of Health and the National Institute on Aging. Data from MESA were obtained through support from the National Heart, Lung, and Blood Institute and the National Center for Advancing Translational Sciences. Dr. Azarbarzin disclosed funding from the National Institutes of Health, the American Health Association, and the American Academy of Sleep Medicine.

A version of this article first appeared on Medscape.com.

Measurement error may be the culprit in underdiagnosing obstructive sleep apnea in Black patients, compared with White patients, based on data from nearly 2,000 individuals.

Data collected from ICU patients during the COVID-19 pandemic suggested that pulse oximetry devices used to measure oxygen saturation may be less accurate for patients with darker skin, according to Ali Azarbarzin, PhD, of Harvard Medical School, Boston.

“We wanted to examine the implications for obstructive sleep apnea,” which is often caused by a reduction in air flow, Dr. Azarbarzin said in an interview.

In a study presented at the American Thoracic Society’s international conference, Dr. Azarbarzin and colleagues examined data from 1,955 adults who were enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 5. The study participants underwent unattended 15-channel polysomnography that included a finger pulse oximeter. The mean age of the participants was 68.3 years, and 53.7% were women. A total of 12.1%, 23.7%, 27.7%, and 36.5% of the participants were Asian, Hispanic, Black, and White, respectively.

Apnea hypopnea index (AHI3P) was similar between Black and White patients, at approximately 19 events per hour. Black participants had higher wake SpO2, higher current smoking rates, and higher body mass index, compared with White participants, but these differences were not significant.

Severity of obstructive sleep apnea (OSA) was based on the hypoxic burden, which was defined as the total area under the respiratory curve. The total ventilatory burden was defined as the event-specific area under the ventilation signal and identified by amplitude changes in the nasal pressure signal. The researchers then calculated desaturation sensitivity (the primary outcome) as hypoxic burden divided by ventilatory burden.

In an unadjusted analysis, desaturation sensitivity was significantly lower in Black patients and Asian patients, compared with White patients (P < .001 and P < .02, respectively). After adjusting for age, sex, body mass index, and time spent in a supine position, desaturation sensitivity was lower only in Black patients, compared with White patients, and this difference persisted in both men and women.

The difference in desaturation sensitivity by race could be caused by differences in physiology or in measurement error, Dr. Azarbarzin told this news organization. If measurement error is the culprit, “we may be underestimating OSA severity in [Black people],” especially in Black women, he said.

However, more research is needed to understand the potential impact of both physiology and device accuracy on differences in oxygen saturation across ethnicities and to effectively identify and treat OSA in all patients, Dr. Azarbarzin said.

The MESA Study was supported by the National Institutes of Health and the National Institute on Aging. Data from MESA were obtained through support from the National Heart, Lung, and Blood Institute and the National Center for Advancing Translational Sciences. Dr. Azarbarzin disclosed funding from the National Institutes of Health, the American Health Association, and the American Academy of Sleep Medicine.

A version of this article first appeared on Medscape.com.

Amid growing criticism of health insurers’ onerous prior authorization practices, lawmakers in 30 states have introduced bills this year that aim to rein in insurer gatekeeping and improve patient care.

“This is something that goes on in every doctor’s office every day; the frustrations, the delays, and the use of office staff time are just unbelievable,” said Steven Orland, MD, a board-certified urologist and president of the Medical Society of New Jersey.

The bills, which cover private health plans and insurers that states regulate, may provide some relief for physicians as federal efforts to streamline prior authorization for some Medicare patients have lagged.

Last year, Congress failed to pass the Improving Seniors’ Timely Access to Care Act of 2021, despite 326 co-sponsors. The bill would have compelled insurers covering Medicare Advantage enrollees to speed up prior authorizations, make the process more transparent, and remove obstacles such as requiring fax machine submissions.

Last month, however, the Centers for Medicare & Medicaid Services issued a final rule that will improve some aspects of prior authorizations in Medicare Advantage insurance plans and ensure that enrollees have the same access to necessary care as traditional Medicare enrollees.

The insurance industry has long defended prior authorization requirements and opposed legislation that would limit them.

America’s Health Insurance Plans (AHIP) and the Blue Cross Blue Shield Association said in a 2019 letter to a congressional committee when the federal legislation was first introduced, “Prior authorizations enforce best practices and guidelines for care management and help physicians identify and avoid care techniques that would harm patient outcomes, such as designating prescriptions that could feed into an opioid addiction.” AHIP didn’t respond to repeated requests for comment.

But some major insurers now appear willing to compromise and voluntarily reduce the volume of prior authorizations they require. Days before the federal final rule was released, three major insurers – United HealthCare, Cigna, and Aetna CVS Health – announced they plan to drop some prior authorization requirements and automate processes.

United HealthCare said it will eliminate almost 20% of its prior authorizations for some nonurgent surgeries and procedures starting this summer. It also will create a national Gold Card program in 2024 for physicians who meet its eligibility requirements, which would eliminate prior authorization requirements for most procedures. Both initiatives will apply to commercial, Medicare Advantage, and Medicaid businesses, said the insurer in a statement.

However, United HealthCare also announced that in June it will start requiring prior authorization for diagnostic (not screening) gastrointestinal endoscopies for its nearly 27 million privately insured patients, citing data it says shows potentially harmful overuse of scopes. Physician groups have publicly criticized the move, saying it could delay lifesaving treatment, and have asked the insurer to reconsider.

Cigna and Aetna also have moved to pare back prior authorization processes. Scott Josephs, national medical officer for Cigna, told Healthcare Dive that Cigna has removed prior authorization reviews from nearly 500 services since 2020.

An Aetna spokesperson told Healthcare Dive that the CVS-owned payer has implemented a gold card program and rolled back prior authorization requirements on cataract surgeries, video EEGs, and home infusion for some drugs, according to Healthcare Dive.

Cigna has faced increased scrutiny from some state regulators since a ProPublica/The Capitol Forum article revealed in March that its doctors were denying claims without opening patients’ files, contrary to what insurance laws and regulations require in many states.

Over a period of 2 months last year, Cigna doctors denied over 300,000 requests for payments using this method, spending an average of 1.2 seconds on each case, the investigation found. In a written response, Cigna said the reporting by ProPublica and The Capitol Forum was “biased and incomplete.”
 

States aim to reduce prior authorization volume

The American Medical Association said it has been tracking nearly 90 prior authorization reform bills in 30 states. More than a dozen bills are still being considered in this legislative session, including in Arkansas, California, New Jersey, North Carolina, Maryland, and Washington, D.C.

“The groundswell of activity in the states reflects how big a problem this is,” said an AMA legislative expert. “The issue used to be ‘how can we automate and streamline processes’; now the issue is focused on reducing the volume of prior authorizations and the harm that can cause patients.”

The state bills use different strategies to reduce excessive prior authorization requirements. Maryland’s proposed bill, for example, would require just one prior authorization to stay on a prescription drug, if the insurer has previously approved the drug and the patient continues to successfully be treated by the drug.

Washington, D.C. and New Jersey have introduced comprehensive reform bills that include a “grace period” of 60 days, to ensure continuity of care when a patient switches health plans. They also would eliminate repeat authorizations for chronic and long-term conditions, set explicit timelines for insurers to respond to prior authorization requests and appeals, and require that practicing physicians review denials that are appealed.

Many state bills also would require insurers to be more transparent by posting information on their websites about which services and drugs require prior authorization and what their approval rates are for them, said AMA’s legislative expert.

“There’s a black hole of information that insurers have access to. We would really like to know how many prior authorization requests are denied, the time it takes to deny them, and the reasons for denial,” said Josh Bengal, JD, the director of government relations for the Medical Society of New Jersey.

The legislation in New Jersey and other states faces stiff opposition from the insurance lobby, especially state associations of health plans affiliated with AHIP. The California Association of Health Plans, for example, opposes a “gold card” bill (SB 598), introduced in February, that would allow a select group of high-performing doctors to skip prior authorizations for 1 year.

The CAHP states, “Californians deserve safe, high quality, high-value health care. Yet SB 598 will derail the progress we have made in our health care system by lowering the value and safety that Californians should expect from their health care providers,” according to a fact sheet.

The fact-sheet defines “low-value care” as medical services for which there is little to no benefit and poses potential physical or financial harm to patients, such as unnecessary CT scans or MRIs for uncomplicated conditions.

California is one of about a dozen states that have introduced gold card legislation this year. If enacted, they would join five states with gold card laws: West Virginia, Texas, Vermont, Michigan, and Louisiana.
 

How do gold cards work?

Physicians who achieve a high approval rate of prior authorizations from insurers for 1 year are eligible to be exempted from obtaining prior authorizations the following year.

The approval rate is at least 90% for a certain number of eligible health services, but the number of prior authorizations required to qualify can range from 5 to 30, depending on the state law.

Gold card legislation typically also gives the treating physician the right to have an appeal of a prior authorization denial by a physician peer of the same or similar specialty.

California’s bill would also apply to all covered health services, which is broader than what United HealthCare has proposed for its gold card exemption. The bill would also require a plan or insurer to annually monitor rates of prior authorization approval, modification, appeal, and denial, and to discontinue services, items, and supplies that are approved 95% of the time.

“These are important reforms that will help ensure that patients can receive the care they need, when they need it,” said CMA president Donaldo Hernandez, MD.

However, it’s not clear how many physicians will meet “gold card” status based on Texas’ recent experience with its own “gold card” law.

The Texas Department of Insurance estimated that only 3.3% of licensed physicians in the state have met “gold card” status since the bill became law in 2021, said Zeke Silva, MD, an interventional radiologist who serves on the Council of Legislation for the Texas Medical Association.

He noted that the legislation has had a limited effect for several reasons. Commercial health plans only make up only about 20% of all health plans in Texas. Also, the final regulations didn’t go into effect until last May and physicians are evaluated by health plans for “gold card” status every 6 months, said Dr. Silva.

In addition, physicians must have at least five prior authorizations approved for the same health service, which the law left up to the health plans to define, said Dr. Silva.

Now, the Texas Medical Association is lobbying for legislative improvements. “We want to reduce the number of eligible services that health plans require for prior authorizations and have more oversight of prior authorization denials by the Texas Department of Insurance and the Texas Medical Board,” said Dr. Silva.

He’s optimistic that if the bill becomes law, the number of physicians eligible for gold cards may increase.

Meanwhile, the AMA’s legislative expert, who declined to be identified because of organization policy, acknowledged the possibility that some prior authorization bills will die in state legislatures this year.

“We remain hopeful, but it’s an uphill battle. The state medical associations face a lot of opposition from health plans who don’t want to see these reforms become law.”

A version of this article originally appeared on Medscape.com.

Amid growing criticism of health insurers’ onerous prior authorization practices, lawmakers in 30 states have introduced bills this year that aim to rein in insurer gatekeeping and improve patient care.

“This is something that goes on in every doctor’s office every day; the frustrations, the delays, and the use of office staff time are just unbelievable,” said Steven Orland, MD, a board-certified urologist and president of the Medical Society of New Jersey.

The bills, which cover private health plans and insurers that states regulate, may provide some relief for physicians as federal efforts to streamline prior authorization for some Medicare patients have lagged.

Last year, Congress failed to pass the Improving Seniors’ Timely Access to Care Act of 2021, despite 326 co-sponsors. The bill would have compelled insurers covering Medicare Advantage enrollees to speed up prior authorizations, make the process more transparent, and remove obstacles such as requiring fax machine submissions.

Last month, however, the Centers for Medicare & Medicaid Services issued a final rule that will improve some aspects of prior authorizations in Medicare Advantage insurance plans and ensure that enrollees have the same access to necessary care as traditional Medicare enrollees.

The insurance industry has long defended prior authorization requirements and opposed legislation that would limit them.

America’s Health Insurance Plans (AHIP) and the Blue Cross Blue Shield Association said in a 2019 letter to a congressional committee when the federal legislation was first introduced, “Prior authorizations enforce best practices and guidelines for care management and help physicians identify and avoid care techniques that would harm patient outcomes, such as designating prescriptions that could feed into an opioid addiction.” AHIP didn’t respond to repeated requests for comment.

But some major insurers now appear willing to compromise and voluntarily reduce the volume of prior authorizations they require. Days before the federal final rule was released, three major insurers – United HealthCare, Cigna, and Aetna CVS Health – announced they plan to drop some prior authorization requirements and automate processes.

United HealthCare said it will eliminate almost 20% of its prior authorizations for some nonurgent surgeries and procedures starting this summer. It also will create a national Gold Card program in 2024 for physicians who meet its eligibility requirements, which would eliminate prior authorization requirements for most procedures. Both initiatives will apply to commercial, Medicare Advantage, and Medicaid businesses, said the insurer in a statement.

However, United HealthCare also announced that in June it will start requiring prior authorization for diagnostic (not screening) gastrointestinal endoscopies for its nearly 27 million privately insured patients, citing data it says shows potentially harmful overuse of scopes. Physician groups have publicly criticized the move, saying it could delay lifesaving treatment, and have asked the insurer to reconsider.

Cigna and Aetna also have moved to pare back prior authorization processes. Scott Josephs, national medical officer for Cigna, told Healthcare Dive that Cigna has removed prior authorization reviews from nearly 500 services since 2020.

An Aetna spokesperson told Healthcare Dive that the CVS-owned payer has implemented a gold card program and rolled back prior authorization requirements on cataract surgeries, video EEGs, and home infusion for some drugs, according to Healthcare Dive.

Cigna has faced increased scrutiny from some state regulators since a ProPublica/The Capitol Forum article revealed in March that its doctors were denying claims without opening patients’ files, contrary to what insurance laws and regulations require in many states.

Over a period of 2 months last year, Cigna doctors denied over 300,000 requests for payments using this method, spending an average of 1.2 seconds on each case, the investigation found. In a written response, Cigna said the reporting by ProPublica and The Capitol Forum was “biased and incomplete.”
 

States aim to reduce prior authorization volume

The American Medical Association said it has been tracking nearly 90 prior authorization reform bills in 30 states. More than a dozen bills are still being considered in this legislative session, including in Arkansas, California, New Jersey, North Carolina, Maryland, and Washington, D.C.

“The groundswell of activity in the states reflects how big a problem this is,” said an AMA legislative expert. “The issue used to be ‘how can we automate and streamline processes’; now the issue is focused on reducing the volume of prior authorizations and the harm that can cause patients.”

The state bills use different strategies to reduce excessive prior authorization requirements. Maryland’s proposed bill, for example, would require just one prior authorization to stay on a prescription drug, if the insurer has previously approved the drug and the patient continues to successfully be treated by the drug.

Washington, D.C. and New Jersey have introduced comprehensive reform bills that include a “grace period” of 60 days, to ensure continuity of care when a patient switches health plans. They also would eliminate repeat authorizations for chronic and long-term conditions, set explicit timelines for insurers to respond to prior authorization requests and appeals, and require that practicing physicians review denials that are appealed.

Many state bills also would require insurers to be more transparent by posting information on their websites about which services and drugs require prior authorization and what their approval rates are for them, said AMA’s legislative expert.

“There’s a black hole of information that insurers have access to. We would really like to know how many prior authorization requests are denied, the time it takes to deny them, and the reasons for denial,” said Josh Bengal, JD, the director of government relations for the Medical Society of New Jersey.

The legislation in New Jersey and other states faces stiff opposition from the insurance lobby, especially state associations of health plans affiliated with AHIP. The California Association of Health Plans, for example, opposes a “gold card” bill (SB 598), introduced in February, that would allow a select group of high-performing doctors to skip prior authorizations for 1 year.

The CAHP states, “Californians deserve safe, high quality, high-value health care. Yet SB 598 will derail the progress we have made in our health care system by lowering the value and safety that Californians should expect from their health care providers,” according to a fact sheet.

The fact-sheet defines “low-value care” as medical services for which there is little to no benefit and poses potential physical or financial harm to patients, such as unnecessary CT scans or MRIs for uncomplicated conditions.

California is one of about a dozen states that have introduced gold card legislation this year. If enacted, they would join five states with gold card laws: West Virginia, Texas, Vermont, Michigan, and Louisiana.
 

How do gold cards work?

Physicians who achieve a high approval rate of prior authorizations from insurers for 1 year are eligible to be exempted from obtaining prior authorizations the following year.

The approval rate is at least 90% for a certain number of eligible health services, but the number of prior authorizations required to qualify can range from 5 to 30, depending on the state law.

Gold card legislation typically also gives the treating physician the right to have an appeal of a prior authorization denial by a physician peer of the same or similar specialty.

California’s bill would also apply to all covered health services, which is broader than what United HealthCare has proposed for its gold card exemption. The bill would also require a plan or insurer to annually monitor rates of prior authorization approval, modification, appeal, and denial, and to discontinue services, items, and supplies that are approved 95% of the time.

“These are important reforms that will help ensure that patients can receive the care they need, when they need it,” said CMA president Donaldo Hernandez, MD.

However, it’s not clear how many physicians will meet “gold card” status based on Texas’ recent experience with its own “gold card” law.

The Texas Department of Insurance estimated that only 3.3% of licensed physicians in the state have met “gold card” status since the bill became law in 2021, said Zeke Silva, MD, an interventional radiologist who serves on the Council of Legislation for the Texas Medical Association.

He noted that the legislation has had a limited effect for several reasons. Commercial health plans only make up only about 20% of all health plans in Texas. Also, the final regulations didn’t go into effect until last May and physicians are evaluated by health plans for “gold card” status every 6 months, said Dr. Silva.

In addition, physicians must have at least five prior authorizations approved for the same health service, which the law left up to the health plans to define, said Dr. Silva.

Now, the Texas Medical Association is lobbying for legislative improvements. “We want to reduce the number of eligible services that health plans require for prior authorizations and have more oversight of prior authorization denials by the Texas Department of Insurance and the Texas Medical Board,” said Dr. Silva.

He’s optimistic that if the bill becomes law, the number of physicians eligible for gold cards may increase.

Meanwhile, the AMA’s legislative expert, who declined to be identified because of organization policy, acknowledged the possibility that some prior authorization bills will die in state legislatures this year.

“We remain hopeful, but it’s an uphill battle. The state medical associations face a lot of opposition from health plans who don’t want to see these reforms become law.”

A version of this article originally appeared on Medscape.com.

Amid growing criticism of health insurers’ onerous prior authorization practices, lawmakers in 30 states have introduced bills this year that aim to rein in insurer gatekeeping and improve patient care.

“This is something that goes on in every doctor’s office every day; the frustrations, the delays, and the use of office staff time are just unbelievable,” said Steven Orland, MD, a board-certified urologist and president of the Medical Society of New Jersey.

The bills, which cover private health plans and insurers that states regulate, may provide some relief for physicians as federal efforts to streamline prior authorization for some Medicare patients have lagged.

Last year, Congress failed to pass the Improving Seniors’ Timely Access to Care Act of 2021, despite 326 co-sponsors. The bill would have compelled insurers covering Medicare Advantage enrollees to speed up prior authorizations, make the process more transparent, and remove obstacles such as requiring fax machine submissions.

Last month, however, the Centers for Medicare & Medicaid Services issued a final rule that will improve some aspects of prior authorizations in Medicare Advantage insurance plans and ensure that enrollees have the same access to necessary care as traditional Medicare enrollees.

The insurance industry has long defended prior authorization requirements and opposed legislation that would limit them.

America’s Health Insurance Plans (AHIP) and the Blue Cross Blue Shield Association said in a 2019 letter to a congressional committee when the federal legislation was first introduced, “Prior authorizations enforce best practices and guidelines for care management and help physicians identify and avoid care techniques that would harm patient outcomes, such as designating prescriptions that could feed into an opioid addiction.” AHIP didn’t respond to repeated requests for comment.

But some major insurers now appear willing to compromise and voluntarily reduce the volume of prior authorizations they require. Days before the federal final rule was released, three major insurers – United HealthCare, Cigna, and Aetna CVS Health – announced they plan to drop some prior authorization requirements and automate processes.

United HealthCare said it will eliminate almost 20% of its prior authorizations for some nonurgent surgeries and procedures starting this summer. It also will create a national Gold Card program in 2024 for physicians who meet its eligibility requirements, which would eliminate prior authorization requirements for most procedures. Both initiatives will apply to commercial, Medicare Advantage, and Medicaid businesses, said the insurer in a statement.

However, United HealthCare also announced that in June it will start requiring prior authorization for diagnostic (not screening) gastrointestinal endoscopies for its nearly 27 million privately insured patients, citing data it says shows potentially harmful overuse of scopes. Physician groups have publicly criticized the move, saying it could delay lifesaving treatment, and have asked the insurer to reconsider.

Cigna and Aetna also have moved to pare back prior authorization processes. Scott Josephs, national medical officer for Cigna, told Healthcare Dive that Cigna has removed prior authorization reviews from nearly 500 services since 2020.

An Aetna spokesperson told Healthcare Dive that the CVS-owned payer has implemented a gold card program and rolled back prior authorization requirements on cataract surgeries, video EEGs, and home infusion for some drugs, according to Healthcare Dive.

Cigna has faced increased scrutiny from some state regulators since a ProPublica/The Capitol Forum article revealed in March that its doctors were denying claims without opening patients’ files, contrary to what insurance laws and regulations require in many states.

Over a period of 2 months last year, Cigna doctors denied over 300,000 requests for payments using this method, spending an average of 1.2 seconds on each case, the investigation found. In a written response, Cigna said the reporting by ProPublica and The Capitol Forum was “biased and incomplete.”
 

States aim to reduce prior authorization volume

The American Medical Association said it has been tracking nearly 90 prior authorization reform bills in 30 states. More than a dozen bills are still being considered in this legislative session, including in Arkansas, California, New Jersey, North Carolina, Maryland, and Washington, D.C.

“The groundswell of activity in the states reflects how big a problem this is,” said an AMA legislative expert. “The issue used to be ‘how can we automate and streamline processes’; now the issue is focused on reducing the volume of prior authorizations and the harm that can cause patients.”

The state bills use different strategies to reduce excessive prior authorization requirements. Maryland’s proposed bill, for example, would require just one prior authorization to stay on a prescription drug, if the insurer has previously approved the drug and the patient continues to successfully be treated by the drug.

Washington, D.C. and New Jersey have introduced comprehensive reform bills that include a “grace period” of 60 days, to ensure continuity of care when a patient switches health plans. They also would eliminate repeat authorizations for chronic and long-term conditions, set explicit timelines for insurers to respond to prior authorization requests and appeals, and require that practicing physicians review denials that are appealed.

Many state bills also would require insurers to be more transparent by posting information on their websites about which services and drugs require prior authorization and what their approval rates are for them, said AMA’s legislative expert.

“There’s a black hole of information that insurers have access to. We would really like to know how many prior authorization requests are denied, the time it takes to deny them, and the reasons for denial,” said Josh Bengal, JD, the director of government relations for the Medical Society of New Jersey.

The legislation in New Jersey and other states faces stiff opposition from the insurance lobby, especially state associations of health plans affiliated with AHIP. The California Association of Health Plans, for example, opposes a “gold card” bill (SB 598), introduced in February, that would allow a select group of high-performing doctors to skip prior authorizations for 1 year.

The CAHP states, “Californians deserve safe, high quality, high-value health care. Yet SB 598 will derail the progress we have made in our health care system by lowering the value and safety that Californians should expect from their health care providers,” according to a fact sheet.

The fact-sheet defines “low-value care” as medical services for which there is little to no benefit and poses potential physical or financial harm to patients, such as unnecessary CT scans or MRIs for uncomplicated conditions.

California is one of about a dozen states that have introduced gold card legislation this year. If enacted, they would join five states with gold card laws: West Virginia, Texas, Vermont, Michigan, and Louisiana.
 

How do gold cards work?

Physicians who achieve a high approval rate of prior authorizations from insurers for 1 year are eligible to be exempted from obtaining prior authorizations the following year.

The approval rate is at least 90% for a certain number of eligible health services, but the number of prior authorizations required to qualify can range from 5 to 30, depending on the state law.

Gold card legislation typically also gives the treating physician the right to have an appeal of a prior authorization denial by a physician peer of the same or similar specialty.

California’s bill would also apply to all covered health services, which is broader than what United HealthCare has proposed for its gold card exemption. The bill would also require a plan or insurer to annually monitor rates of prior authorization approval, modification, appeal, and denial, and to discontinue services, items, and supplies that are approved 95% of the time.

“These are important reforms that will help ensure that patients can receive the care they need, when they need it,” said CMA president Donaldo Hernandez, MD.

However, it’s not clear how many physicians will meet “gold card” status based on Texas’ recent experience with its own “gold card” law.

The Texas Department of Insurance estimated that only 3.3% of licensed physicians in the state have met “gold card” status since the bill became law in 2021, said Zeke Silva, MD, an interventional radiologist who serves on the Council of Legislation for the Texas Medical Association.

He noted that the legislation has had a limited effect for several reasons. Commercial health plans only make up only about 20% of all health plans in Texas. Also, the final regulations didn’t go into effect until last May and physicians are evaluated by health plans for “gold card” status every 6 months, said Dr. Silva.

In addition, physicians must have at least five prior authorizations approved for the same health service, which the law left up to the health plans to define, said Dr. Silva.

Now, the Texas Medical Association is lobbying for legislative improvements. “We want to reduce the number of eligible services that health plans require for prior authorizations and have more oversight of prior authorization denials by the Texas Department of Insurance and the Texas Medical Board,” said Dr. Silva.

He’s optimistic that if the bill becomes law, the number of physicians eligible for gold cards may increase.

Meanwhile, the AMA’s legislative expert, who declined to be identified because of organization policy, acknowledged the possibility that some prior authorization bills will die in state legislatures this year.

“We remain hopeful, but it’s an uphill battle. The state medical associations face a lot of opposition from health plans who don’t want to see these reforms become law.”

A version of this article originally appeared on Medscape.com.