Video

PARIS – In rural Peru, a comprehensive community-wide strategy to replace conventional table salt with a formulation that was 25% potassium chloride halved incident hypertension, also dropping blood pressure in participants with baseline hypertension.

The multifaceted intervention targeted six villages at the far north of Peru, replacing table salt with the lower-sodium substitute, J. Jaime Miranda, MD, PhD, said at a prevention-focused, late-breaking research session at the annual congress of the European Society of Cardiology. The 75/25 mixture had a palatable proportion of potassium, and was easily produced by combining table salt with potassium chloride crystals.

Dr. Miranda, director of the CRONICAS Center of Excellence at the Cayetano Heredia Peruvian University, Lima, and colleagues enrolled virtually all adult residents of the six villages in the study; patients who reported heart disease or chronic kidney disease were excluded.

“We wanted to achieve and shape a pragmatic study – and a pragmatic study that incorporates day-to-day behavior. We eat every day, but we think very little of our salt habits,” said Dr. Miranda in a video interview.

In all, 2,376 of 2,605 potential participants enrolled in the study, which used a stepped-wedge, cluster-randomized, controlled trial design. To track the primary outcome measures of systolic and diastolic BP, measurements were obtained every 5 months for a total of seven rounds of measurement, said Dr. Miranda.

Dr. Miranda said that the investigators borrowed principles from social marketing to ensure community-wide replacement of table salt with the low-sodium substitute. This meant that they branded and packaged the low-sodium salt and gave it to participants at no cost – but with a catch. To receive the low-sodium salt, participants had to turn in their table salt.

The effort was supported by promotional events and a trained “sales force” who brought messaging to families, restaurants, and key voices in the community. The attractively packaged replacement salt was distributed with a similarly branded shaker. “We wanted to guarantee the full replacement of salt in the entire village,” explained Dr. Miranda.

At the end of the study, individuals with hypertension saw a decrease in systolic BP of 1.92 mm Hg (95% confidence interval, –3.29 to –0.54).

New hypertension diagnoses, a secondary outcome measure, fell by 55% in participating villages; the hazard ratio for hypertension incidence was 0.45 (95% CI, 0.31-0.66) in a fully adjusted statistical model that accounted for clustering at the village level, as well as age, sex, education, wealth index, and body mass index, said Dr. Miranda.

Older village residents with hypertension saw greater BP reduction; for those aged at least 60 years, the mean reduction was 2.17 mm Hg (95% CI, –3.67 to –0.68).

The positive findings were met with broad applause during his presentation, a response that made his 15-hour trip from Lima to Paris worthwhile, said Dr. Miranda.

Adherence was assessed by obtaining 24-hour urine samples from a random sample of 100 participants before and after the study. “This was my biggest fear – that as soon as we left the door, people would go and throw it away,” said Dr. Miranda. Among these participants, excreted potassium rose, indicating adherence, but sodium stayed basically the same. Possible explanations included that individuals were adding table salt to their diets, or that other prepared foods or condiments contained high amounts of sodium.

The study shows the feasibility of a community-wide intervention that achieved the dual aims of population-wide reductions in BP and reduction in incident BP, and of achieving clinically meaningful benefits for the high-risk population, said Dr. Miranda. He remarked that the population was young overall, with a mean age of 43 years and a low mean baseline systolic BP of 113, making the modest population-wide reduction more notable.

“We wanted to shift the entire distribution of blood pressure in the village. And with that, we see gains not only in public health, but also effective improvements in blood pressure in those at high risk, particularly those who tend to have high blood pressure,” said Dr. Miranda.

Discussant Bruce Neal, MD, professor of medicine at the University of Sydney and senior director of the George Institute for Global Health in Newtown, Australia, congratulated Dr. Miranda and colleagues on accomplishing “a truly enormous project.” He began by noting that, though the reductions were modest, “the low starting blood pressures were almost certainly responsible for the magnitude of effect seen in this study.” He added that “this is nonetheless a worthwhile blood pressure reduction, particularly if it was sustained throughout life.”

Addressing the lack of decrease in excreted urine sodium, Dr. Neal noted that participants may have supplemented their diet with additional sodium by one means or another, “which might also have attenuated the blood pressure difference – but it could also reflect the challenges of measuring sodium and potassium effectively with 24-hour urine samples, which are difficult to collect.”

The lack of adverse effects was notable, said Dr. Neal. “When considering the use of salt substitute at the population level, the first question that arises is: ‘What about the risks of hyperkalemia?’

“I think those risks are probably greatly overstated,” he said, noting that only individuals with severe chronic kidney disease would likely be affected, and those individuals are already well versed on the importance of avoiding excess dietary potassium.

The study was funded by the National Institutes of Health through the Global Alliance for Chronic Disease program. Dr. Miranda reported that he had no conflicts of interest. Dr. Neal reported that he has financial relationships with Nu-Tec Salt and a Beijing-based salt manufacturer, related to research into salt substitutes.

PARIS – In rural Peru, a comprehensive community-wide strategy to replace conventional table salt with a formulation that was 25% potassium chloride halved incident hypertension, also dropping blood pressure in participants with baseline hypertension.

The multifaceted intervention targeted six villages at the far north of Peru, replacing table salt with the lower-sodium substitute, J. Jaime Miranda, MD, PhD, said at a prevention-focused, late-breaking research session at the annual congress of the European Society of Cardiology. The 75/25 mixture had a palatable proportion of potassium, and was easily produced by combining table salt with potassium chloride crystals.

Dr. Miranda, director of the CRONICAS Center of Excellence at the Cayetano Heredia Peruvian University, Lima, and colleagues enrolled virtually all adult residents of the six villages in the study; patients who reported heart disease or chronic kidney disease were excluded.

“We wanted to achieve and shape a pragmatic study – and a pragmatic study that incorporates day-to-day behavior. We eat every day, but we think very little of our salt habits,” said Dr. Miranda in a video interview.

In all, 2,376 of 2,605 potential participants enrolled in the study, which used a stepped-wedge, cluster-randomized, controlled trial design. To track the primary outcome measures of systolic and diastolic BP, measurements were obtained every 5 months for a total of seven rounds of measurement, said Dr. Miranda.

Dr. Miranda said that the investigators borrowed principles from social marketing to ensure community-wide replacement of table salt with the low-sodium substitute. This meant that they branded and packaged the low-sodium salt and gave it to participants at no cost – but with a catch. To receive the low-sodium salt, participants had to turn in their table salt.

The effort was supported by promotional events and a trained “sales force” who brought messaging to families, restaurants, and key voices in the community. The attractively packaged replacement salt was distributed with a similarly branded shaker. “We wanted to guarantee the full replacement of salt in the entire village,” explained Dr. Miranda.

At the end of the study, individuals with hypertension saw a decrease in systolic BP of 1.92 mm Hg (95% confidence interval, –3.29 to –0.54).

New hypertension diagnoses, a secondary outcome measure, fell by 55% in participating villages; the hazard ratio for hypertension incidence was 0.45 (95% CI, 0.31-0.66) in a fully adjusted statistical model that accounted for clustering at the village level, as well as age, sex, education, wealth index, and body mass index, said Dr. Miranda.

Older village residents with hypertension saw greater BP reduction; for those aged at least 60 years, the mean reduction was 2.17 mm Hg (95% CI, –3.67 to –0.68).

The positive findings were met with broad applause during his presentation, a response that made his 15-hour trip from Lima to Paris worthwhile, said Dr. Miranda.

Adherence was assessed by obtaining 24-hour urine samples from a random sample of 100 participants before and after the study. “This was my biggest fear – that as soon as we left the door, people would go and throw it away,” said Dr. Miranda. Among these participants, excreted potassium rose, indicating adherence, but sodium stayed basically the same. Possible explanations included that individuals were adding table salt to their diets, or that other prepared foods or condiments contained high amounts of sodium.

The study shows the feasibility of a community-wide intervention that achieved the dual aims of population-wide reductions in BP and reduction in incident BP, and of achieving clinically meaningful benefits for the high-risk population, said Dr. Miranda. He remarked that the population was young overall, with a mean age of 43 years and a low mean baseline systolic BP of 113, making the modest population-wide reduction more notable.

“We wanted to shift the entire distribution of blood pressure in the village. And with that, we see gains not only in public health, but also effective improvements in blood pressure in those at high risk, particularly those who tend to have high blood pressure,” said Dr. Miranda.

Discussant Bruce Neal, MD, professor of medicine at the University of Sydney and senior director of the George Institute for Global Health in Newtown, Australia, congratulated Dr. Miranda and colleagues on accomplishing “a truly enormous project.” He began by noting that, though the reductions were modest, “the low starting blood pressures were almost certainly responsible for the magnitude of effect seen in this study.” He added that “this is nonetheless a worthwhile blood pressure reduction, particularly if it was sustained throughout life.”

Addressing the lack of decrease in excreted urine sodium, Dr. Neal noted that participants may have supplemented their diet with additional sodium by one means or another, “which might also have attenuated the blood pressure difference – but it could also reflect the challenges of measuring sodium and potassium effectively with 24-hour urine samples, which are difficult to collect.”

The lack of adverse effects was notable, said Dr. Neal. “When considering the use of salt substitute at the population level, the first question that arises is: ‘What about the risks of hyperkalemia?’

“I think those risks are probably greatly overstated,” he said, noting that only individuals with severe chronic kidney disease would likely be affected, and those individuals are already well versed on the importance of avoiding excess dietary potassium.

The study was funded by the National Institutes of Health through the Global Alliance for Chronic Disease program. Dr. Miranda reported that he had no conflicts of interest. Dr. Neal reported that he has financial relationships with Nu-Tec Salt and a Beijing-based salt manufacturer, related to research into salt substitutes.

PARIS – In rural Peru, a comprehensive community-wide strategy to replace conventional table salt with a formulation that was 25% potassium chloride halved incident hypertension, also dropping blood pressure in participants with baseline hypertension.

The multifaceted intervention targeted six villages at the far north of Peru, replacing table salt with the lower-sodium substitute, J. Jaime Miranda, MD, PhD, said at a prevention-focused, late-breaking research session at the annual congress of the European Society of Cardiology. The 75/25 mixture had a palatable proportion of potassium, and was easily produced by combining table salt with potassium chloride crystals.

Dr. Miranda, director of the CRONICAS Center of Excellence at the Cayetano Heredia Peruvian University, Lima, and colleagues enrolled virtually all adult residents of the six villages in the study; patients who reported heart disease or chronic kidney disease were excluded.

“We wanted to achieve and shape a pragmatic study – and a pragmatic study that incorporates day-to-day behavior. We eat every day, but we think very little of our salt habits,” said Dr. Miranda in a video interview.

In all, 2,376 of 2,605 potential participants enrolled in the study, which used a stepped-wedge, cluster-randomized, controlled trial design. To track the primary outcome measures of systolic and diastolic BP, measurements were obtained every 5 months for a total of seven rounds of measurement, said Dr. Miranda.

Dr. Miranda said that the investigators borrowed principles from social marketing to ensure community-wide replacement of table salt with the low-sodium substitute. This meant that they branded and packaged the low-sodium salt and gave it to participants at no cost – but with a catch. To receive the low-sodium salt, participants had to turn in their table salt.

The effort was supported by promotional events and a trained “sales force” who brought messaging to families, restaurants, and key voices in the community. The attractively packaged replacement salt was distributed with a similarly branded shaker. “We wanted to guarantee the full replacement of salt in the entire village,” explained Dr. Miranda.

At the end of the study, individuals with hypertension saw a decrease in systolic BP of 1.92 mm Hg (95% confidence interval, –3.29 to –0.54).

New hypertension diagnoses, a secondary outcome measure, fell by 55% in participating villages; the hazard ratio for hypertension incidence was 0.45 (95% CI, 0.31-0.66) in a fully adjusted statistical model that accounted for clustering at the village level, as well as age, sex, education, wealth index, and body mass index, said Dr. Miranda.

Older village residents with hypertension saw greater BP reduction; for those aged at least 60 years, the mean reduction was 2.17 mm Hg (95% CI, –3.67 to –0.68).

The positive findings were met with broad applause during his presentation, a response that made his 15-hour trip from Lima to Paris worthwhile, said Dr. Miranda.

Adherence was assessed by obtaining 24-hour urine samples from a random sample of 100 participants before and after the study. “This was my biggest fear – that as soon as we left the door, people would go and throw it away,” said Dr. Miranda. Among these participants, excreted potassium rose, indicating adherence, but sodium stayed basically the same. Possible explanations included that individuals were adding table salt to their diets, or that other prepared foods or condiments contained high amounts of sodium.

The study shows the feasibility of a community-wide intervention that achieved the dual aims of population-wide reductions in BP and reduction in incident BP, and of achieving clinically meaningful benefits for the high-risk population, said Dr. Miranda. He remarked that the population was young overall, with a mean age of 43 years and a low mean baseline systolic BP of 113, making the modest population-wide reduction more notable.

“We wanted to shift the entire distribution of blood pressure in the village. And with that, we see gains not only in public health, but also effective improvements in blood pressure in those at high risk, particularly those who tend to have high blood pressure,” said Dr. Miranda.

Discussant Bruce Neal, MD, professor of medicine at the University of Sydney and senior director of the George Institute for Global Health in Newtown, Australia, congratulated Dr. Miranda and colleagues on accomplishing “a truly enormous project.” He began by noting that, though the reductions were modest, “the low starting blood pressures were almost certainly responsible for the magnitude of effect seen in this study.” He added that “this is nonetheless a worthwhile blood pressure reduction, particularly if it was sustained throughout life.”

Addressing the lack of decrease in excreted urine sodium, Dr. Neal noted that participants may have supplemented their diet with additional sodium by one means or another, “which might also have attenuated the blood pressure difference – but it could also reflect the challenges of measuring sodium and potassium effectively with 24-hour urine samples, which are difficult to collect.”

The lack of adverse effects was notable, said Dr. Neal. “When considering the use of salt substitute at the population level, the first question that arises is: ‘What about the risks of hyperkalemia?’

“I think those risks are probably greatly overstated,” he said, noting that only individuals with severe chronic kidney disease would likely be affected, and those individuals are already well versed on the importance of avoiding excess dietary potassium.

The study was funded by the National Institutes of Health through the Global Alliance for Chronic Disease program. Dr. Miranda reported that he had no conflicts of interest. Dr. Neal reported that he has financial relationships with Nu-Tec Salt and a Beijing-based salt manufacturer, related to research into salt substitutes.

PARIS – Treatment with the SGLT2 inhibitor dapagliflozin produced a statistically significant 27% drop in cardiovascular death or heart failure events in patients with existing heart failure with reduced ejection fraction and no diabetes, results that in a stroke changed the status of dapagliflozin from fundamentally a drug that treats diabetes to a drug that treats heart failure.

Mitchel L. Zoler/MDedge News

“Dapagliflozin offers a new approach to the treatment of heart failure with reduced ejection fraction” (HFrEF), John McMurray, MD, said at the annual congress of the European Society of Cardiology.

The results he reported from the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial showed statistically significant benefits when adding dapagliflozin to guideline-directed therapy for a list of outcomes that include a 17% drop in all-cause death compared with placebo, an 18% fall in cardiovascular death, and a 25% relative reduction in total heart failure hospitalizations plus cardiovascular deaths during a median follow-up of just over 18 months. The primary endpoint of the reduction in cardiovascular death, first heart failure hospitalization, or an urgent heart failure visit fell by 25% in the enrolled patients with diabetes (45% of the study population, all with type 2 diabetes), and by 27% in the remaining patients who had no diabetes, showing that the presence of diabetes had no impact on the heart failure benefit from dapagliflozin (Farxiga). The absolute reduction in the primary endpoint was about 5%, with a number needed to treat of 21 to prevent one primary endpoint during 18 months of treatment.

Dr. McMurray’s report of the primary endpoint as well as the finding that the drug was as effective in patients without diabetes as in those with diabetes were both met with loud applause by the packed congress audience.

The efficacy results also showed that 58% of patients on dapagliflozin had a clinically meaningful (5 point or greater) increase in their quality of life score on the Kansas City Cardiomyopathy Questionnaire after 8 months on treatment compared with a 51% rate in the placebo patients, a statistically significant difference.

The safety results showed no new signals for a drug that already has regulatory approval but was being used in a novel population. The rate of major hypoglycemia was virtually nonexistent, 0.2%, and identical in both treatment arms. All adverse events occurred at roughly equal rates in the dapagliflozin and placebo groups, with a 5% rate of adverse events leading to study discontinuation in both arms, and a serious adverse event rate of 38% in the dapaglifolzin patients and 42% in the placebo patients. The rate of worsening renal function was less than 2% in both arms and not statistically different.

“This is as close to a home run as you see in heart failure treatment,” commented Douglas L. Mann, MD, professor of medicine at Washington University, St. Louis, and a heart failure clinician and researcher.

DAPA-HF “is a landmark trial. It took a diabetes drug and used it in patients without diabetes, a concept that would have been considered outlandish 5 years ago. Scientifically it’s huge,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston.

The DAPA-HF results were another step in the remarkable journey toward heart failure intervention taken by the SGLT2 (sodium glucose cotransport 2) inhibitor class of drugs that includes dapagliflozin as well as canagliflozin (Invokana) and empagliflozin(Jardiance), a path that began 4 years ago with the report of empagliflozin’s unexpected efficacy for reducing cardiovascular death and heart failure hospitalizations in a large cardiovascular-safety study, EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28). Subsequent reports showed similar effects benefiting heart failure and survival for canagliflozin and dapagliflozin, and now with DAPA-HF the evidence extended the benefit to heart failure patients regardless of whether they have diabetes. Additional studies now in progress are exploring the same question for empagliflozin and canagliflozin.

The results from DAPA-HF are likely a class effect for all these SGLT2 inhibitors, suggested Dr. McMurray in a video interview, a view shared by several other experts. He cautioned clinicians against using dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) but without diabetes until this indication receives regulatory approval, and even then using dapagliflozin or other SGLT2 inhibitors this way may take some getting used to on the part of cardiologists and other clinicians.

“The results put dapagliflozin in the same league as [standard HFrEF drugs], but using it will require a shift in thinking. Most physicians will initially say “aren’t SGLT2 inhibitors used for treating diabetes?” Dr. Bhatt said.

“I’m sure most cardiologists are not familiar with the SGLT2 inhibitors; we’ll have to educate them,” conceded Dr. McMurray, professor of medical cardiology at the University of Glasgow. However, other aspects of dapagliflozin and this drug class in general may make the SGLT2 inhibitors particularly attractive and spur their use once labeling changes.

[email protected]

PARIS – Treatment with the SGLT2 inhibitor dapagliflozin produced a statistically significant 27% drop in cardiovascular death or heart failure events in patients with existing heart failure with reduced ejection fraction and no diabetes, results that in a stroke changed the status of dapagliflozin from fundamentally a drug that treats diabetes to a drug that treats heart failure.

Mitchel L. Zoler/MDedge News

“Dapagliflozin offers a new approach to the treatment of heart failure with reduced ejection fraction” (HFrEF), John McMurray, MD, said at the annual congress of the European Society of Cardiology.

The results he reported from the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial showed statistically significant benefits when adding dapagliflozin to guideline-directed therapy for a list of outcomes that include a 17% drop in all-cause death compared with placebo, an 18% fall in cardiovascular death, and a 25% relative reduction in total heart failure hospitalizations plus cardiovascular deaths during a median follow-up of just over 18 months. The primary endpoint of the reduction in cardiovascular death, first heart failure hospitalization, or an urgent heart failure visit fell by 25% in the enrolled patients with diabetes (45% of the study population, all with type 2 diabetes), and by 27% in the remaining patients who had no diabetes, showing that the presence of diabetes had no impact on the heart failure benefit from dapagliflozin (Farxiga). The absolute reduction in the primary endpoint was about 5%, with a number needed to treat of 21 to prevent one primary endpoint during 18 months of treatment.

Dr. McMurray’s report of the primary endpoint as well as the finding that the drug was as effective in patients without diabetes as in those with diabetes were both met with loud applause by the packed congress audience.

The efficacy results also showed that 58% of patients on dapagliflozin had a clinically meaningful (5 point or greater) increase in their quality of life score on the Kansas City Cardiomyopathy Questionnaire after 8 months on treatment compared with a 51% rate in the placebo patients, a statistically significant difference.

The safety results showed no new signals for a drug that already has regulatory approval but was being used in a novel population. The rate of major hypoglycemia was virtually nonexistent, 0.2%, and identical in both treatment arms. All adverse events occurred at roughly equal rates in the dapagliflozin and placebo groups, with a 5% rate of adverse events leading to study discontinuation in both arms, and a serious adverse event rate of 38% in the dapaglifolzin patients and 42% in the placebo patients. The rate of worsening renal function was less than 2% in both arms and not statistically different.

“This is as close to a home run as you see in heart failure treatment,” commented Douglas L. Mann, MD, professor of medicine at Washington University, St. Louis, and a heart failure clinician and researcher.

DAPA-HF “is a landmark trial. It took a diabetes drug and used it in patients without diabetes, a concept that would have been considered outlandish 5 years ago. Scientifically it’s huge,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston.

The DAPA-HF results were another step in the remarkable journey toward heart failure intervention taken by the SGLT2 (sodium glucose cotransport 2) inhibitor class of drugs that includes dapagliflozin as well as canagliflozin (Invokana) and empagliflozin(Jardiance), a path that began 4 years ago with the report of empagliflozin’s unexpected efficacy for reducing cardiovascular death and heart failure hospitalizations in a large cardiovascular-safety study, EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28). Subsequent reports showed similar effects benefiting heart failure and survival for canagliflozin and dapagliflozin, and now with DAPA-HF the evidence extended the benefit to heart failure patients regardless of whether they have diabetes. Additional studies now in progress are exploring the same question for empagliflozin and canagliflozin.

The results from DAPA-HF are likely a class effect for all these SGLT2 inhibitors, suggested Dr. McMurray in a video interview, a view shared by several other experts. He cautioned clinicians against using dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) but without diabetes until this indication receives regulatory approval, and even then using dapagliflozin or other SGLT2 inhibitors this way may take some getting used to on the part of cardiologists and other clinicians.

“The results put dapagliflozin in the same league as [standard HFrEF drugs], but using it will require a shift in thinking. Most physicians will initially say “aren’t SGLT2 inhibitors used for treating diabetes?” Dr. Bhatt said.

“I’m sure most cardiologists are not familiar with the SGLT2 inhibitors; we’ll have to educate them,” conceded Dr. McMurray, professor of medical cardiology at the University of Glasgow. However, other aspects of dapagliflozin and this drug class in general may make the SGLT2 inhibitors particularly attractive and spur their use once labeling changes.

[email protected]

PARIS – Treatment with the SGLT2 inhibitor dapagliflozin produced a statistically significant 27% drop in cardiovascular death or heart failure events in patients with existing heart failure with reduced ejection fraction and no diabetes, results that in a stroke changed the status of dapagliflozin from fundamentally a drug that treats diabetes to a drug that treats heart failure.

Mitchel L. Zoler/MDedge News

“Dapagliflozin offers a new approach to the treatment of heart failure with reduced ejection fraction” (HFrEF), John McMurray, MD, said at the annual congress of the European Society of Cardiology.

The results he reported from the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial showed statistically significant benefits when adding dapagliflozin to guideline-directed therapy for a list of outcomes that include a 17% drop in all-cause death compared with placebo, an 18% fall in cardiovascular death, and a 25% relative reduction in total heart failure hospitalizations plus cardiovascular deaths during a median follow-up of just over 18 months. The primary endpoint of the reduction in cardiovascular death, first heart failure hospitalization, or an urgent heart failure visit fell by 25% in the enrolled patients with diabetes (45% of the study population, all with type 2 diabetes), and by 27% in the remaining patients who had no diabetes, showing that the presence of diabetes had no impact on the heart failure benefit from dapagliflozin (Farxiga). The absolute reduction in the primary endpoint was about 5%, with a number needed to treat of 21 to prevent one primary endpoint during 18 months of treatment.

Dr. McMurray’s report of the primary endpoint as well as the finding that the drug was as effective in patients without diabetes as in those with diabetes were both met with loud applause by the packed congress audience.

The efficacy results also showed that 58% of patients on dapagliflozin had a clinically meaningful (5 point or greater) increase in their quality of life score on the Kansas City Cardiomyopathy Questionnaire after 8 months on treatment compared with a 51% rate in the placebo patients, a statistically significant difference.

The safety results showed no new signals for a drug that already has regulatory approval but was being used in a novel population. The rate of major hypoglycemia was virtually nonexistent, 0.2%, and identical in both treatment arms. All adverse events occurred at roughly equal rates in the dapagliflozin and placebo groups, with a 5% rate of adverse events leading to study discontinuation in both arms, and a serious adverse event rate of 38% in the dapaglifolzin patients and 42% in the placebo patients. The rate of worsening renal function was less than 2% in both arms and not statistically different.

“This is as close to a home run as you see in heart failure treatment,” commented Douglas L. Mann, MD, professor of medicine at Washington University, St. Louis, and a heart failure clinician and researcher.

DAPA-HF “is a landmark trial. It took a diabetes drug and used it in patients without diabetes, a concept that would have been considered outlandish 5 years ago. Scientifically it’s huge,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston.

The DAPA-HF results were another step in the remarkable journey toward heart failure intervention taken by the SGLT2 (sodium glucose cotransport 2) inhibitor class of drugs that includes dapagliflozin as well as canagliflozin (Invokana) and empagliflozin(Jardiance), a path that began 4 years ago with the report of empagliflozin’s unexpected efficacy for reducing cardiovascular death and heart failure hospitalizations in a large cardiovascular-safety study, EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28). Subsequent reports showed similar effects benefiting heart failure and survival for canagliflozin and dapagliflozin, and now with DAPA-HF the evidence extended the benefit to heart failure patients regardless of whether they have diabetes. Additional studies now in progress are exploring the same question for empagliflozin and canagliflozin.

The results from DAPA-HF are likely a class effect for all these SGLT2 inhibitors, suggested Dr. McMurray in a video interview, a view shared by several other experts. He cautioned clinicians against using dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) but without diabetes until this indication receives regulatory approval, and even then using dapagliflozin or other SGLT2 inhibitors this way may take some getting used to on the part of cardiologists and other clinicians.

“The results put dapagliflozin in the same league as [standard HFrEF drugs], but using it will require a shift in thinking. Most physicians will initially say “aren’t SGLT2 inhibitors used for treating diabetes?” Dr. Bhatt said.

“I’m sure most cardiologists are not familiar with the SGLT2 inhibitors; we’ll have to educate them,” conceded Dr. McMurray, professor of medical cardiology at the University of Glasgow. However, other aspects of dapagliflozin and this drug class in general may make the SGLT2 inhibitors particularly attractive and spur their use once labeling changes.

[email protected]

A community-based care model to control hypertension led by nonphysician health care workers significantly reduced cardiovascular disease risk over 12 months, data from a cluster-controlled randomized study has shown.

Hypertension remains the most common risk factor for cardiovascular disease, but fewer than 20% of individuals with hypertension have their blood pressure controlled, wrote Jon-David Schwalm, MD, of McMaster University in Hamilton, Ont., and colleagues. To help control hypertension in underserved populations, the researchers tested a care model involving nonphysician health workers (NPHWs), primary care physicians, and family members.

The HOPE4 study, presented at the annual congress of the European Society of Cardiology and published simultaneously in the Lancet, included 1,371 adults aged 50 years and older with new or poorly controlled hypertension from 30 communities in Colombia and Malaysia. Sixteen communities were randomized to usual care and 14 to an intervention. The intervention included community screening and treatment of cardiovascular disease risk factors by NPHWs, free medications recommended by NPHWs under physician supervision, and family support for treatment adherence.

After 12 months, the Framingham Risk Scores for 10-year cardiovascular disease risk were significantly lower in the intervention group, compared with the control group (–11.17% vs. –6.40%). In addition, the intervention group showed a significant 11.45 mm Hg greater reduction in systolic blood pressure and a significant 0.41 mmol/L reduction in LDL cholesterol, compared with controls (P less than .0001 for both measures).

Baseline characteristics were similar between the two groups. Approximately 74% of the participants had a history of poorly controlled hypertension, while the remaining patients had new hypertension diagnoses.

“NPHWs were found to be consistently accurate in their ability to identify cardiovascular risk (patient identified by NPHWs as having poorly controlled blood pressure and medication was indicated) and recommend appropriate therapies (antihypertensives and statin as per the study algorithm) when compared with the assessment by local primary care physicians,” the researchers wrote. The study shows how effectively NPHWs can help reduce cardiovascular disease risk at the community level with proper training, effective community outreach, and task sharing with physicians and family members, they noted.

The findings were limited by the inability to assess the safety of specific medications, but no differences in adverse events were reported between the intervention and control groups. Other limitations included the screening of controls for cardiovascular disease risk at baseline, which meant that controls may have modified their behavior as a result, the researchers noted. In addition, the study was not blinded and surrogate outcomes were used because of the short study duration and relatively small sample size, they said.

However, the results support the use of a comprehensive, NPHW-led model, and “the HOPE 4 strategy could help to attain the UN General Assembly Action Plan for a one-third reduction in premature mortality from cardiovascular disease” by 2030, the researchers concluded.

The study was supported by the Canadian Institutes of Health Research; Grand Challenges Canada; Ontario SPOR Support Unit and the Ontario Ministry of Health and Long-Term Care; Boehringer Ingelheim; Department of Management of Non-Communicable Diseases, World Health Organization; and the Population Health Research Institute. Lead author Dr. Schwalm and several coauthors disclosed grants to their institutions for this study from the Canadian Institutes of Health Research, Ontario Ministry of Health and Long-Term Care, Boehringer Ingelheim, and the Department of Management of Non-Communicable Diseases, WHO.

SOURCE: Schwalm J-D et al. Lancet. 2019 Sept 2. doi: http://dx.doi.org/10.1016/ S0140-6736(19)31949-X.

A community-based care model to control hypertension led by nonphysician health care workers significantly reduced cardiovascular disease risk over 12 months, data from a cluster-controlled randomized study has shown.

Hypertension remains the most common risk factor for cardiovascular disease, but fewer than 20% of individuals with hypertension have their blood pressure controlled, wrote Jon-David Schwalm, MD, of McMaster University in Hamilton, Ont., and colleagues. To help control hypertension in underserved populations, the researchers tested a care model involving nonphysician health workers (NPHWs), primary care physicians, and family members.

The HOPE4 study, presented at the annual congress of the European Society of Cardiology and published simultaneously in the Lancet, included 1,371 adults aged 50 years and older with new or poorly controlled hypertension from 30 communities in Colombia and Malaysia. Sixteen communities were randomized to usual care and 14 to an intervention. The intervention included community screening and treatment of cardiovascular disease risk factors by NPHWs, free medications recommended by NPHWs under physician supervision, and family support for treatment adherence.

After 12 months, the Framingham Risk Scores for 10-year cardiovascular disease risk were significantly lower in the intervention group, compared with the control group (–11.17% vs. –6.40%). In addition, the intervention group showed a significant 11.45 mm Hg greater reduction in systolic blood pressure and a significant 0.41 mmol/L reduction in LDL cholesterol, compared with controls (P less than .0001 for both measures).

Baseline characteristics were similar between the two groups. Approximately 74% of the participants had a history of poorly controlled hypertension, while the remaining patients had new hypertension diagnoses.

“NPHWs were found to be consistently accurate in their ability to identify cardiovascular risk (patient identified by NPHWs as having poorly controlled blood pressure and medication was indicated) and recommend appropriate therapies (antihypertensives and statin as per the study algorithm) when compared with the assessment by local primary care physicians,” the researchers wrote. The study shows how effectively NPHWs can help reduce cardiovascular disease risk at the community level with proper training, effective community outreach, and task sharing with physicians and family members, they noted.

The findings were limited by the inability to assess the safety of specific medications, but no differences in adverse events were reported between the intervention and control groups. Other limitations included the screening of controls for cardiovascular disease risk at baseline, which meant that controls may have modified their behavior as a result, the researchers noted. In addition, the study was not blinded and surrogate outcomes were used because of the short study duration and relatively small sample size, they said.

However, the results support the use of a comprehensive, NPHW-led model, and “the HOPE 4 strategy could help to attain the UN General Assembly Action Plan for a one-third reduction in premature mortality from cardiovascular disease” by 2030, the researchers concluded.

The study was supported by the Canadian Institutes of Health Research; Grand Challenges Canada; Ontario SPOR Support Unit and the Ontario Ministry of Health and Long-Term Care; Boehringer Ingelheim; Department of Management of Non-Communicable Diseases, World Health Organization; and the Population Health Research Institute. Lead author Dr. Schwalm and several coauthors disclosed grants to their institutions for this study from the Canadian Institutes of Health Research, Ontario Ministry of Health and Long-Term Care, Boehringer Ingelheim, and the Department of Management of Non-Communicable Diseases, WHO.

SOURCE: Schwalm J-D et al. Lancet. 2019 Sept 2. doi: http://dx.doi.org/10.1016/ S0140-6736(19)31949-X.

A community-based care model to control hypertension led by nonphysician health care workers significantly reduced cardiovascular disease risk over 12 months, data from a cluster-controlled randomized study has shown.

Hypertension remains the most common risk factor for cardiovascular disease, but fewer than 20% of individuals with hypertension have their blood pressure controlled, wrote Jon-David Schwalm, MD, of McMaster University in Hamilton, Ont., and colleagues. To help control hypertension in underserved populations, the researchers tested a care model involving nonphysician health workers (NPHWs), primary care physicians, and family members.

The HOPE4 study, presented at the annual congress of the European Society of Cardiology and published simultaneously in the Lancet, included 1,371 adults aged 50 years and older with new or poorly controlled hypertension from 30 communities in Colombia and Malaysia. Sixteen communities were randomized to usual care and 14 to an intervention. The intervention included community screening and treatment of cardiovascular disease risk factors by NPHWs, free medications recommended by NPHWs under physician supervision, and family support for treatment adherence.

After 12 months, the Framingham Risk Scores for 10-year cardiovascular disease risk were significantly lower in the intervention group, compared with the control group (–11.17% vs. –6.40%). In addition, the intervention group showed a significant 11.45 mm Hg greater reduction in systolic blood pressure and a significant 0.41 mmol/L reduction in LDL cholesterol, compared with controls (P less than .0001 for both measures).

Baseline characteristics were similar between the two groups. Approximately 74% of the participants had a history of poorly controlled hypertension, while the remaining patients had new hypertension diagnoses.

“NPHWs were found to be consistently accurate in their ability to identify cardiovascular risk (patient identified by NPHWs as having poorly controlled blood pressure and medication was indicated) and recommend appropriate therapies (antihypertensives and statin as per the study algorithm) when compared with the assessment by local primary care physicians,” the researchers wrote. The study shows how effectively NPHWs can help reduce cardiovascular disease risk at the community level with proper training, effective community outreach, and task sharing with physicians and family members, they noted.

The findings were limited by the inability to assess the safety of specific medications, but no differences in adverse events were reported between the intervention and control groups. Other limitations included the screening of controls for cardiovascular disease risk at baseline, which meant that controls may have modified their behavior as a result, the researchers noted. In addition, the study was not blinded and surrogate outcomes were used because of the short study duration and relatively small sample size, they said.

However, the results support the use of a comprehensive, NPHW-led model, and “the HOPE 4 strategy could help to attain the UN General Assembly Action Plan for a one-third reduction in premature mortality from cardiovascular disease” by 2030, the researchers concluded.

The study was supported by the Canadian Institutes of Health Research; Grand Challenges Canada; Ontario SPOR Support Unit and the Ontario Ministry of Health and Long-Term Care; Boehringer Ingelheim; Department of Management of Non-Communicable Diseases, World Health Organization; and the Population Health Research Institute. Lead author Dr. Schwalm and several coauthors disclosed grants to their institutions for this study from the Canadian Institutes of Health Research, Ontario Ministry of Health and Long-Term Care, Boehringer Ingelheim, and the Department of Management of Non-Communicable Diseases, WHO.

SOURCE: Schwalm J-D et al. Lancet. 2019 Sept 2. doi: http://dx.doi.org/10.1016/ S0140-6736(19)31949-X.

PARIS – Lower levels of physical activity over time were linked to a significantly increased risk of both cardiovascular and all-cause mortality, according to results from a prospective cohort study that followed more than 23,000 adults for over 2 decades.

“Individuals who remained physically inactive, or who decreased their physical activity over 22 years, had substantially increased risk of dying from all causes, and from cardiovascular disease,” Trine Moholdt, PhD, said at a press conference at the annual congress of the European Society of Cardiology.

“The bad news is that sustained inactivity was associated with a 99% increase in all-cause mortality and 168% increase in cardiovascular deaths” compared with sustained physical activity, she said.

The news was similarly bad for individuals who had been highly active and then became inactive; this cohort had an increase in all-cause mortality of 116% and sustained a 173% increase in cardiovascular deaths. “Previous activity levels – they don’t count. You have to keep it up,” said Dr. Moholdt, speaking in a video interview.

However, the risk associated with inactivity was attenuated for those patients who became more active over the course of the study period; their risk was still higher than that of those who had sustained activity, but lower than those who remained inactive. “It’s never too late to start being physically active,” said Dr. Moholdt.

All groups were compared with individuals who remained highly active over the study period; this reference group had the lowest risk of both cardiovascular and all-cause death.

Dr. Moholdt noted a limitation of most previous research into how physical activity relates to cardiovascular and all-cause mortality: Data are obtained just at baseline, and then associated with a downstream outcome. “But people change!” she said, so it’s important to track how activity levels change over time.

To that end, the Nord-Trøndelag Health Study (HUNT study) measured activity levels for 23,156 participants at two points, and then assessed cardiovascular and all-cause mortality, over a period of 22 years.

[email protected]

SOURCE: Moholdt T. et al. ESC Congress 2019, Abstract P627.

PARIS – Lower levels of physical activity over time were linked to a significantly increased risk of both cardiovascular and all-cause mortality, according to results from a prospective cohort study that followed more than 23,000 adults for over 2 decades.

“Individuals who remained physically inactive, or who decreased their physical activity over 22 years, had substantially increased risk of dying from all causes, and from cardiovascular disease,” Trine Moholdt, PhD, said at a press conference at the annual congress of the European Society of Cardiology.

“The bad news is that sustained inactivity was associated with a 99% increase in all-cause mortality and 168% increase in cardiovascular deaths” compared with sustained physical activity, she said.

The news was similarly bad for individuals who had been highly active and then became inactive; this cohort had an increase in all-cause mortality of 116% and sustained a 173% increase in cardiovascular deaths. “Previous activity levels – they don’t count. You have to keep it up,” said Dr. Moholdt, speaking in a video interview.

However, the risk associated with inactivity was attenuated for those patients who became more active over the course of the study period; their risk was still higher than that of those who had sustained activity, but lower than those who remained inactive. “It’s never too late to start being physically active,” said Dr. Moholdt.

All groups were compared with individuals who remained highly active over the study period; this reference group had the lowest risk of both cardiovascular and all-cause death.

Dr. Moholdt noted a limitation of most previous research into how physical activity relates to cardiovascular and all-cause mortality: Data are obtained just at baseline, and then associated with a downstream outcome. “But people change!” she said, so it’s important to track how activity levels change over time.

To that end, the Nord-Trøndelag Health Study (HUNT study) measured activity levels for 23,156 participants at two points, and then assessed cardiovascular and all-cause mortality, over a period of 22 years.

[email protected]

SOURCE: Moholdt T. et al. ESC Congress 2019, Abstract P627.

PARIS – Lower levels of physical activity over time were linked to a significantly increased risk of both cardiovascular and all-cause mortality, according to results from a prospective cohort study that followed more than 23,000 adults for over 2 decades.

“Individuals who remained physically inactive, or who decreased their physical activity over 22 years, had substantially increased risk of dying from all causes, and from cardiovascular disease,” Trine Moholdt, PhD, said at a press conference at the annual congress of the European Society of Cardiology.

“The bad news is that sustained inactivity was associated with a 99% increase in all-cause mortality and 168% increase in cardiovascular deaths” compared with sustained physical activity, she said.

The news was similarly bad for individuals who had been highly active and then became inactive; this cohort had an increase in all-cause mortality of 116% and sustained a 173% increase in cardiovascular deaths. “Previous activity levels – they don’t count. You have to keep it up,” said Dr. Moholdt, speaking in a video interview.

However, the risk associated with inactivity was attenuated for those patients who became more active over the course of the study period; their risk was still higher than that of those who had sustained activity, but lower than those who remained inactive. “It’s never too late to start being physically active,” said Dr. Moholdt.

All groups were compared with individuals who remained highly active over the study period; this reference group had the lowest risk of both cardiovascular and all-cause death.

Dr. Moholdt noted a limitation of most previous research into how physical activity relates to cardiovascular and all-cause mortality: Data are obtained just at baseline, and then associated with a downstream outcome. “But people change!” she said, so it’s important to track how activity levels change over time.

To that end, the Nord-Trøndelag Health Study (HUNT study) measured activity levels for 23,156 participants at two points, and then assessed cardiovascular and all-cause mortality, over a period of 22 years.

[email protected]

SOURCE: Moholdt T. et al. ESC Congress 2019, Abstract P627.

When the summons arrived, Nataly Minkina, MD, took one look at the lawsuit and fainted.

Leonid Weinstein

The Boston-area internist had treated the plaintiff just once while covering for the patient’s primary care physician. During a visit for an upper respiratory infection, the patient mentioned a lump in her breast, and Dr. Minkina confirmed a small thickening in the woman’s right breast. She sent the patient for a mammogram and ultrasound, the results of which the radiologist reported were normal, according to court documents.

Five years later, the patient claimed Dr. Minkina was one of several providers responsible for a missed breast cancer diagnosis.

Even worse than the lawsuit, however, was how her former insurer resolved the case, said Dr. Minkina, now an internist at Brigham and Women’s Hospital in Chestnut Hill, Mass. The claim was settled against the defendants for $500,000, and Dr. Minkina was alloted 30% of the liability. No fault was assigned to the other physicians named, while a nurse practitioner was alloted 10%, and the medical practice was alloted 60% liability, according to court documents.

“I was very upset,” Dr. Minkina said. “First of all, I was kept in the dark. Nobody ever talked to me. I did not get a single report or any document from my attorney in 12 months. When I asked why was I assigned the [30%] liability, they said the experts gave me bad evaluations, but they would not show reports to me. I was literally scapegoated.”

When the insurer refused to reconsider the allocation, Dr. Minkina took her complaint to court. The internist now has been embroiled in a legal challenge against Medical Professional Mutual Insurance Company (ProMutual) for 7 years. Dr. Minkina’s lawsuit alleges the insurer engaged in a bad faith allocation to serve its own economic interests by shifting fault for the claim from its insureds to its former client, Dr. Minkina. The insurance company contends the allocation was a careful and rational decision based on case evidence. In late July, the case went to trial in Dedham, Mass.

ProMutual declined comment on the case; the insurer also would not address general questions about its allocation policies.

“I started this fight because I felt violated and betrayed, not to make money,” Dr. Minkina said. “I am not rich by a long shot, and I wanted to clear my name because [a] good name is all I have. Additionally, having [a] record about malpractice payment in my physician profile makes me vulnerable.”

Liability experts say the case highlights the conflicts that can arise between physicians and insurers during malpractice lawsuits. The legal challenge also raises questions about allocations of liability by insurers, how the determinations are made, and what impact they have on doctors going forward.

The proportion of liability assigned after a settlement matters, said Jeffrey Segal, MD, JD, a neurosurgeon and founder of Medical Justice, a medicolegal consulting firm for physicians.

Vidyard Video

“There’s a subtext that your piece of the pie – the part that is allocated to you – is your liability, your culpability, your guilt,” Dr. Segal said in an interview. “This has impact going down the road in terms of reputation, in terms of credibility, and potentially of your premiums going forward. There are some real-world economic consequences.”

 

 

Bad care or bad faith?

In Dr. Minkina’s case, some facts are undisputed. In 2002, Dr. Minkina, then a physician at Blue Hills Medical Associates in Braintree, Mass., referred a 55-year-old patient for a mammogram and an ultrasound after confirming some nodularity in the women’s breast. A radiologist twice reported no abnormalities which Dr. Minkina relayed to the patient, advising her to follow-up with her primary care physician and to schedule yearly mammograms. The patient did neither, according to court records. Dr. Minkina left the practice shortly after the visit.

In early 2006, the patient visited the practice, and a nurse practitioner sent her for another mammogram and an ultrasound. The mammogram report included some signs of malignancy, but the nurse misread, misunderstood, or overlooked the signs and recorded that “the benign breast condition had no changes,” according to court transcripts. Later that year, the patient visited the practice complaining of headaches and a droopy eye at which time her primary care physician diagnosed sinusitis and prescribed antibiotics. In 2007, the patient underwent a brain MRI and a breast MRI, which revealed widespread metastatic carcinoma. She and her family sued Dr. Minkina and several others in June 2007. The patient died in 2008.

The agreement between parties ends there. Dr. Minkina believes she followed the standard of care and was not responsible for the delayed breast cancer diagnosis. Given the radiologist’s negative report and the patient’s lack of visual abnormalities, she contends she adequately referred the patient to her primary care physician for further consultation and evaluation. Dr. Minkina argues the insurer allocated an unjustifiably high percentage of liability to her because she was no longer an insured and because the company had an economic incentive to allocate a disproportionate percentage of responsibility and damages.

ProMutual contends Dr. Minkina bore more responsibility than the other health care professionals named for the delayed diagnosis because of violations of standards of care and because of causation factors. The insurer’s experts asserted that when treating an older woman with a palpable lump, the standard of care is to obtain a biopsy, according to opening arguments by ProMutual defense counsel Tamara Wolfson.

The experts also concluded that, when the nurse practitioner and primary care physician saw the patient in 2006, the patient would have already had metastatic disease, and a cancer diagnosis at that time would not have saved her, according to court transcripts. Had the cancer been diagnosed in 2002 when Dr. Minkina saw the patient, the disease would have been “very treatable,” the experts further concluded.

“So, faced with negative opinions on both the standard of care and causation, [the claim representative] was very concerned that Dr. Minkina not only faced a very substantial risk of an adverse verdict in the ... suit, but a verdict that would exceed Dr. Minkina’s policy limits,” Ms. Wolfson said during opening arguments.

The evidence led to the settlement and the allocation decision, Ms. Wolfson said, adding that the majority – 60% – fell on Blue Hills Medical Associates because it lacked a good system to track and follow up with patients. There was zero benefit to ProMutual as to how the $500,000 settlement was parsed, she said during trial.

A lower court initially dismissed Dr. Minkina’s suit, but the Commonwealth of Massachusetts Appeals Court in 2015 overturned that decision, ruling the case could move forward. In 2018, the superior court agreed Dr. Minkina had a valid bad faith claim, stating that she had provided information about ProMutual’s conduct from which “a reasonable juror could infer the defendant’s bad faith in connection with its settling the underlying malpractice suit, including the allocation of liability.”

Dr. Minkina had been a plaintiff in unrelated litigation in the past. In 2005, she sued her former employer for alleged discrimination and retaliation after claiming she was mistreated and terminated for complaining about fumes. She prevailed and was awarded an arbitration award of about $266,000. In 2009, Dr. Minkina sued the original law firm that represented her in the discrimination suit for malpractice, alleging the firm’s negligence cost her the chance to go to trial. A judge dismissed the claim as frivolous and ordered Dr. Minkina to pay the firm’s legal fees. The doctor twice has been jailed for failing to fully resolve that legal payment. The case remains outstanding, and Dr. Minkina is now in bankruptcy.
 

 

 

What’s in an allocation?

Liability allocations are an integral part of multiparty medical malpractice claims, said Brian Atchinson, president and CEO for the Medical Professional Liability Association, a trade association for medical liability insurers.

“In any case involving more than one party, there is a potential allocation issue,” Mr. Atchinson said in an interview. “[Insurers] generally look to the liability and damages incurred with regard to their respective insureds in a case and work to establish an allocation that reflects actual liability.”

If the case goes to a jury and jurors find for the plaintiff, depending on the nature of the damages awarded, the jury may be called on to allocate liability among multiple defendants, he said.

Because settlements are reported to the National Practitioner Data Bank (NPDB), the proportion of liability assigned to each defendant has significance, said J. Richard Moore, a medical liability defense attorney based in Indianapolis and chair for the Defense Research Institute’s Medical Liability and Health Care Law Committee.

Vidyard Video

“The allocation matters because the amount of settlement matters,” Mr. Moore said. “A lower settlement amount suggests the physician’s insurance company made a cost-benefit business decision to end litigation without more expense, while an extremely high settlement suggests actual malpractice.”

State medical boards have varying reporting requirements. Some state boards require both the amount paid by the individual provider and the global settlement amount – if known – while other state boards require only the amount paid on behalf of the provider.

Conflicts over allocations are not common, Dr. Segal said. More frequent are disputes among physicians and insurers over the potential settling of a claim. Such conflicts underscore the importance of paying close attention to contract language when signing with an insurer, Dr. Segal said.

Whether the contract includes a consent to settle clause, for example, can markedly change the case outcome. The clause means the insurer must have the doctor’s approval to settle the case. Absent the clause, insurers generally have authority to settle all claims arising under the policy.

Other contracts may include a “hammer clause,” Dr. Segal notes. This gives doctors the ultimate vote on settling, but it stipulates that if the physician refuses a settlement offer and opts for trial, the doctor is responsible for any surplus award, should the doctor lose.

In Dr. Minkina’s case, the doctor’s contract allowed ProMutual to settle without her consent, but the contract was silent on allocations.

Dr. Segal and Mr. Moore both said the odds of Dr. Minkina prevailing are fairly low. In another case, a South Carolina doctor similarly sued the South Carolina Medical Malpractice Liability Joint Underwriting Association over an allocation of liability following a settlement. The doctor claimed he should not be assigned any portion of the $500,000 settlement, and he sued after his insurer assigned him one-seventh liability.

A trial court found in his favor, ruling the insurer breached the covenant of good faith and fair dealing by failing to treat each physician equally when determining liability. The Supreme Court of South Carolina in 2001 overturned that decision, finding the evidence did not support a bad faith finding and that the insurer’s allocation decision was reasonable.

If the Massachusetts case ends in Dr. Minkina’s favor, it will be as a result of strong evidence that the insurer placed its interests ahead of the physician’s financial and other interests, Mr. Moore said.

“If that happens, I anticipate that insurers may revise their standard policy provisions to clarify and limit the extent to which physicians have the right to be involved in allocation decisions,” he said.

[email protected]

When the summons arrived, Nataly Minkina, MD, took one look at the lawsuit and fainted.

Leonid Weinstein

The Boston-area internist had treated the plaintiff just once while covering for the patient’s primary care physician. During a visit for an upper respiratory infection, the patient mentioned a lump in her breast, and Dr. Minkina confirmed a small thickening in the woman’s right breast. She sent the patient for a mammogram and ultrasound, the results of which the radiologist reported were normal, according to court documents.

Five years later, the patient claimed Dr. Minkina was one of several providers responsible for a missed breast cancer diagnosis.

Even worse than the lawsuit, however, was how her former insurer resolved the case, said Dr. Minkina, now an internist at Brigham and Women’s Hospital in Chestnut Hill, Mass. The claim was settled against the defendants for $500,000, and Dr. Minkina was alloted 30% of the liability. No fault was assigned to the other physicians named, while a nurse practitioner was alloted 10%, and the medical practice was alloted 60% liability, according to court documents.

“I was very upset,” Dr. Minkina said. “First of all, I was kept in the dark. Nobody ever talked to me. I did not get a single report or any document from my attorney in 12 months. When I asked why was I assigned the [30%] liability, they said the experts gave me bad evaluations, but they would not show reports to me. I was literally scapegoated.”

When the insurer refused to reconsider the allocation, Dr. Minkina took her complaint to court. The internist now has been embroiled in a legal challenge against Medical Professional Mutual Insurance Company (ProMutual) for 7 years. Dr. Minkina’s lawsuit alleges the insurer engaged in a bad faith allocation to serve its own economic interests by shifting fault for the claim from its insureds to its former client, Dr. Minkina. The insurance company contends the allocation was a careful and rational decision based on case evidence. In late July, the case went to trial in Dedham, Mass.

ProMutual declined comment on the case; the insurer also would not address general questions about its allocation policies.

“I started this fight because I felt violated and betrayed, not to make money,” Dr. Minkina said. “I am not rich by a long shot, and I wanted to clear my name because [a] good name is all I have. Additionally, having [a] record about malpractice payment in my physician profile makes me vulnerable.”

Liability experts say the case highlights the conflicts that can arise between physicians and insurers during malpractice lawsuits. The legal challenge also raises questions about allocations of liability by insurers, how the determinations are made, and what impact they have on doctors going forward.

The proportion of liability assigned after a settlement matters, said Jeffrey Segal, MD, JD, a neurosurgeon and founder of Medical Justice, a medicolegal consulting firm for physicians.

Vidyard Video

“There’s a subtext that your piece of the pie – the part that is allocated to you – is your liability, your culpability, your guilt,” Dr. Segal said in an interview. “This has impact going down the road in terms of reputation, in terms of credibility, and potentially of your premiums going forward. There are some real-world economic consequences.”

 

 

Bad care or bad faith?

In Dr. Minkina’s case, some facts are undisputed. In 2002, Dr. Minkina, then a physician at Blue Hills Medical Associates in Braintree, Mass., referred a 55-year-old patient for a mammogram and an ultrasound after confirming some nodularity in the women’s breast. A radiologist twice reported no abnormalities which Dr. Minkina relayed to the patient, advising her to follow-up with her primary care physician and to schedule yearly mammograms. The patient did neither, according to court records. Dr. Minkina left the practice shortly after the visit.

In early 2006, the patient visited the practice, and a nurse practitioner sent her for another mammogram and an ultrasound. The mammogram report included some signs of malignancy, but the nurse misread, misunderstood, or overlooked the signs and recorded that “the benign breast condition had no changes,” according to court transcripts. Later that year, the patient visited the practice complaining of headaches and a droopy eye at which time her primary care physician diagnosed sinusitis and prescribed antibiotics. In 2007, the patient underwent a brain MRI and a breast MRI, which revealed widespread metastatic carcinoma. She and her family sued Dr. Minkina and several others in June 2007. The patient died in 2008.

The agreement between parties ends there. Dr. Minkina believes she followed the standard of care and was not responsible for the delayed breast cancer diagnosis. Given the radiologist’s negative report and the patient’s lack of visual abnormalities, she contends she adequately referred the patient to her primary care physician for further consultation and evaluation. Dr. Minkina argues the insurer allocated an unjustifiably high percentage of liability to her because she was no longer an insured and because the company had an economic incentive to allocate a disproportionate percentage of responsibility and damages.

ProMutual contends Dr. Minkina bore more responsibility than the other health care professionals named for the delayed diagnosis because of violations of standards of care and because of causation factors. The insurer’s experts asserted that when treating an older woman with a palpable lump, the standard of care is to obtain a biopsy, according to opening arguments by ProMutual defense counsel Tamara Wolfson.

The experts also concluded that, when the nurse practitioner and primary care physician saw the patient in 2006, the patient would have already had metastatic disease, and a cancer diagnosis at that time would not have saved her, according to court transcripts. Had the cancer been diagnosed in 2002 when Dr. Minkina saw the patient, the disease would have been “very treatable,” the experts further concluded.

“So, faced with negative opinions on both the standard of care and causation, [the claim representative] was very concerned that Dr. Minkina not only faced a very substantial risk of an adverse verdict in the ... suit, but a verdict that would exceed Dr. Minkina’s policy limits,” Ms. Wolfson said during opening arguments.

The evidence led to the settlement and the allocation decision, Ms. Wolfson said, adding that the majority – 60% – fell on Blue Hills Medical Associates because it lacked a good system to track and follow up with patients. There was zero benefit to ProMutual as to how the $500,000 settlement was parsed, she said during trial.

A lower court initially dismissed Dr. Minkina’s suit, but the Commonwealth of Massachusetts Appeals Court in 2015 overturned that decision, ruling the case could move forward. In 2018, the superior court agreed Dr. Minkina had a valid bad faith claim, stating that she had provided information about ProMutual’s conduct from which “a reasonable juror could infer the defendant’s bad faith in connection with its settling the underlying malpractice suit, including the allocation of liability.”

Dr. Minkina had been a plaintiff in unrelated litigation in the past. In 2005, she sued her former employer for alleged discrimination and retaliation after claiming she was mistreated and terminated for complaining about fumes. She prevailed and was awarded an arbitration award of about $266,000. In 2009, Dr. Minkina sued the original law firm that represented her in the discrimination suit for malpractice, alleging the firm’s negligence cost her the chance to go to trial. A judge dismissed the claim as frivolous and ordered Dr. Minkina to pay the firm’s legal fees. The doctor twice has been jailed for failing to fully resolve that legal payment. The case remains outstanding, and Dr. Minkina is now in bankruptcy.
 

 

 

What’s in an allocation?

Liability allocations are an integral part of multiparty medical malpractice claims, said Brian Atchinson, president and CEO for the Medical Professional Liability Association, a trade association for medical liability insurers.

“In any case involving more than one party, there is a potential allocation issue,” Mr. Atchinson said in an interview. “[Insurers] generally look to the liability and damages incurred with regard to their respective insureds in a case and work to establish an allocation that reflects actual liability.”

If the case goes to a jury and jurors find for the plaintiff, depending on the nature of the damages awarded, the jury may be called on to allocate liability among multiple defendants, he said.

Because settlements are reported to the National Practitioner Data Bank (NPDB), the proportion of liability assigned to each defendant has significance, said J. Richard Moore, a medical liability defense attorney based in Indianapolis and chair for the Defense Research Institute’s Medical Liability and Health Care Law Committee.

Vidyard Video

“The allocation matters because the amount of settlement matters,” Mr. Moore said. “A lower settlement amount suggests the physician’s insurance company made a cost-benefit business decision to end litigation without more expense, while an extremely high settlement suggests actual malpractice.”

State medical boards have varying reporting requirements. Some state boards require both the amount paid by the individual provider and the global settlement amount – if known – while other state boards require only the amount paid on behalf of the provider.

Conflicts over allocations are not common, Dr. Segal said. More frequent are disputes among physicians and insurers over the potential settling of a claim. Such conflicts underscore the importance of paying close attention to contract language when signing with an insurer, Dr. Segal said.

Whether the contract includes a consent to settle clause, for example, can markedly change the case outcome. The clause means the insurer must have the doctor’s approval to settle the case. Absent the clause, insurers generally have authority to settle all claims arising under the policy.

Other contracts may include a “hammer clause,” Dr. Segal notes. This gives doctors the ultimate vote on settling, but it stipulates that if the physician refuses a settlement offer and opts for trial, the doctor is responsible for any surplus award, should the doctor lose.

In Dr. Minkina’s case, the doctor’s contract allowed ProMutual to settle without her consent, but the contract was silent on allocations.

Dr. Segal and Mr. Moore both said the odds of Dr. Minkina prevailing are fairly low. In another case, a South Carolina doctor similarly sued the South Carolina Medical Malpractice Liability Joint Underwriting Association over an allocation of liability following a settlement. The doctor claimed he should not be assigned any portion of the $500,000 settlement, and he sued after his insurer assigned him one-seventh liability.

A trial court found in his favor, ruling the insurer breached the covenant of good faith and fair dealing by failing to treat each physician equally when determining liability. The Supreme Court of South Carolina in 2001 overturned that decision, finding the evidence did not support a bad faith finding and that the insurer’s allocation decision was reasonable.

If the Massachusetts case ends in Dr. Minkina’s favor, it will be as a result of strong evidence that the insurer placed its interests ahead of the physician’s financial and other interests, Mr. Moore said.

“If that happens, I anticipate that insurers may revise their standard policy provisions to clarify and limit the extent to which physicians have the right to be involved in allocation decisions,” he said.

[email protected]

When the summons arrived, Nataly Minkina, MD, took one look at the lawsuit and fainted.

Leonid Weinstein

The Boston-area internist had treated the plaintiff just once while covering for the patient’s primary care physician. During a visit for an upper respiratory infection, the patient mentioned a lump in her breast, and Dr. Minkina confirmed a small thickening in the woman’s right breast. She sent the patient for a mammogram and ultrasound, the results of which the radiologist reported were normal, according to court documents.

Five years later, the patient claimed Dr. Minkina was one of several providers responsible for a missed breast cancer diagnosis.

Even worse than the lawsuit, however, was how her former insurer resolved the case, said Dr. Minkina, now an internist at Brigham and Women’s Hospital in Chestnut Hill, Mass. The claim was settled against the defendants for $500,000, and Dr. Minkina was alloted 30% of the liability. No fault was assigned to the other physicians named, while a nurse practitioner was alloted 10%, and the medical practice was alloted 60% liability, according to court documents.

“I was very upset,” Dr. Minkina said. “First of all, I was kept in the dark. Nobody ever talked to me. I did not get a single report or any document from my attorney in 12 months. When I asked why was I assigned the [30%] liability, they said the experts gave me bad evaluations, but they would not show reports to me. I was literally scapegoated.”

When the insurer refused to reconsider the allocation, Dr. Minkina took her complaint to court. The internist now has been embroiled in a legal challenge against Medical Professional Mutual Insurance Company (ProMutual) for 7 years. Dr. Minkina’s lawsuit alleges the insurer engaged in a bad faith allocation to serve its own economic interests by shifting fault for the claim from its insureds to its former client, Dr. Minkina. The insurance company contends the allocation was a careful and rational decision based on case evidence. In late July, the case went to trial in Dedham, Mass.

ProMutual declined comment on the case; the insurer also would not address general questions about its allocation policies.

“I started this fight because I felt violated and betrayed, not to make money,” Dr. Minkina said. “I am not rich by a long shot, and I wanted to clear my name because [a] good name is all I have. Additionally, having [a] record about malpractice payment in my physician profile makes me vulnerable.”

Liability experts say the case highlights the conflicts that can arise between physicians and insurers during malpractice lawsuits. The legal challenge also raises questions about allocations of liability by insurers, how the determinations are made, and what impact they have on doctors going forward.

The proportion of liability assigned after a settlement matters, said Jeffrey Segal, MD, JD, a neurosurgeon and founder of Medical Justice, a medicolegal consulting firm for physicians.

Vidyard Video

“There’s a subtext that your piece of the pie – the part that is allocated to you – is your liability, your culpability, your guilt,” Dr. Segal said in an interview. “This has impact going down the road in terms of reputation, in terms of credibility, and potentially of your premiums going forward. There are some real-world economic consequences.”

 

 

Bad care or bad faith?

In Dr. Minkina’s case, some facts are undisputed. In 2002, Dr. Minkina, then a physician at Blue Hills Medical Associates in Braintree, Mass., referred a 55-year-old patient for a mammogram and an ultrasound after confirming some nodularity in the women’s breast. A radiologist twice reported no abnormalities which Dr. Minkina relayed to the patient, advising her to follow-up with her primary care physician and to schedule yearly mammograms. The patient did neither, according to court records. Dr. Minkina left the practice shortly after the visit.

In early 2006, the patient visited the practice, and a nurse practitioner sent her for another mammogram and an ultrasound. The mammogram report included some signs of malignancy, but the nurse misread, misunderstood, or overlooked the signs and recorded that “the benign breast condition had no changes,” according to court transcripts. Later that year, the patient visited the practice complaining of headaches and a droopy eye at which time her primary care physician diagnosed sinusitis and prescribed antibiotics. In 2007, the patient underwent a brain MRI and a breast MRI, which revealed widespread metastatic carcinoma. She and her family sued Dr. Minkina and several others in June 2007. The patient died in 2008.

The agreement between parties ends there. Dr. Minkina believes she followed the standard of care and was not responsible for the delayed breast cancer diagnosis. Given the radiologist’s negative report and the patient’s lack of visual abnormalities, she contends she adequately referred the patient to her primary care physician for further consultation and evaluation. Dr. Minkina argues the insurer allocated an unjustifiably high percentage of liability to her because she was no longer an insured and because the company had an economic incentive to allocate a disproportionate percentage of responsibility and damages.

ProMutual contends Dr. Minkina bore more responsibility than the other health care professionals named for the delayed diagnosis because of violations of standards of care and because of causation factors. The insurer’s experts asserted that when treating an older woman with a palpable lump, the standard of care is to obtain a biopsy, according to opening arguments by ProMutual defense counsel Tamara Wolfson.

The experts also concluded that, when the nurse practitioner and primary care physician saw the patient in 2006, the patient would have already had metastatic disease, and a cancer diagnosis at that time would not have saved her, according to court transcripts. Had the cancer been diagnosed in 2002 when Dr. Minkina saw the patient, the disease would have been “very treatable,” the experts further concluded.

“So, faced with negative opinions on both the standard of care and causation, [the claim representative] was very concerned that Dr. Minkina not only faced a very substantial risk of an adverse verdict in the ... suit, but a verdict that would exceed Dr. Minkina’s policy limits,” Ms. Wolfson said during opening arguments.

The evidence led to the settlement and the allocation decision, Ms. Wolfson said, adding that the majority – 60% – fell on Blue Hills Medical Associates because it lacked a good system to track and follow up with patients. There was zero benefit to ProMutual as to how the $500,000 settlement was parsed, she said during trial.

A lower court initially dismissed Dr. Minkina’s suit, but the Commonwealth of Massachusetts Appeals Court in 2015 overturned that decision, ruling the case could move forward. In 2018, the superior court agreed Dr. Minkina had a valid bad faith claim, stating that she had provided information about ProMutual’s conduct from which “a reasonable juror could infer the defendant’s bad faith in connection with its settling the underlying malpractice suit, including the allocation of liability.”

Dr. Minkina had been a plaintiff in unrelated litigation in the past. In 2005, she sued her former employer for alleged discrimination and retaliation after claiming she was mistreated and terminated for complaining about fumes. She prevailed and was awarded an arbitration award of about $266,000. In 2009, Dr. Minkina sued the original law firm that represented her in the discrimination suit for malpractice, alleging the firm’s negligence cost her the chance to go to trial. A judge dismissed the claim as frivolous and ordered Dr. Minkina to pay the firm’s legal fees. The doctor twice has been jailed for failing to fully resolve that legal payment. The case remains outstanding, and Dr. Minkina is now in bankruptcy.
 

 

 

What’s in an allocation?

Liability allocations are an integral part of multiparty medical malpractice claims, said Brian Atchinson, president and CEO for the Medical Professional Liability Association, a trade association for medical liability insurers.

“In any case involving more than one party, there is a potential allocation issue,” Mr. Atchinson said in an interview. “[Insurers] generally look to the liability and damages incurred with regard to their respective insureds in a case and work to establish an allocation that reflects actual liability.”

If the case goes to a jury and jurors find for the plaintiff, depending on the nature of the damages awarded, the jury may be called on to allocate liability among multiple defendants, he said.

Because settlements are reported to the National Practitioner Data Bank (NPDB), the proportion of liability assigned to each defendant has significance, said J. Richard Moore, a medical liability defense attorney based in Indianapolis and chair for the Defense Research Institute’s Medical Liability and Health Care Law Committee.

Vidyard Video

“The allocation matters because the amount of settlement matters,” Mr. Moore said. “A lower settlement amount suggests the physician’s insurance company made a cost-benefit business decision to end litigation without more expense, while an extremely high settlement suggests actual malpractice.”

State medical boards have varying reporting requirements. Some state boards require both the amount paid by the individual provider and the global settlement amount – if known – while other state boards require only the amount paid on behalf of the provider.

Conflicts over allocations are not common, Dr. Segal said. More frequent are disputes among physicians and insurers over the potential settling of a claim. Such conflicts underscore the importance of paying close attention to contract language when signing with an insurer, Dr. Segal said.

Whether the contract includes a consent to settle clause, for example, can markedly change the case outcome. The clause means the insurer must have the doctor’s approval to settle the case. Absent the clause, insurers generally have authority to settle all claims arising under the policy.

Other contracts may include a “hammer clause,” Dr. Segal notes. This gives doctors the ultimate vote on settling, but it stipulates that if the physician refuses a settlement offer and opts for trial, the doctor is responsible for any surplus award, should the doctor lose.

In Dr. Minkina’s case, the doctor’s contract allowed ProMutual to settle without her consent, but the contract was silent on allocations.

Dr. Segal and Mr. Moore both said the odds of Dr. Minkina prevailing are fairly low. In another case, a South Carolina doctor similarly sued the South Carolina Medical Malpractice Liability Joint Underwriting Association over an allocation of liability following a settlement. The doctor claimed he should not be assigned any portion of the $500,000 settlement, and he sued after his insurer assigned him one-seventh liability.

A trial court found in his favor, ruling the insurer breached the covenant of good faith and fair dealing by failing to treat each physician equally when determining liability. The Supreme Court of South Carolina in 2001 overturned that decision, finding the evidence did not support a bad faith finding and that the insurer’s allocation decision was reasonable.

If the Massachusetts case ends in Dr. Minkina’s favor, it will be as a result of strong evidence that the insurer placed its interests ahead of the physician’s financial and other interests, Mr. Moore said.

“If that happens, I anticipate that insurers may revise their standard policy provisions to clarify and limit the extent to which physicians have the right to be involved in allocation decisions,” he said.

[email protected]

PHILADELPHIA – An intravenous formulation of a calcitonin gene–related peptide inhibitor monoclonal antibody showed efficacy for preventing chronic migraine headaches for 3 months in a dose-ranging, phase 3 trial with 1,072 patients.

In a separate study with 669 patients, a single IV dose of the antibody, eptinezumab, also significantly reduced the incidence of episodic migraine headaches during 3 months of follow-up, compared with placebo. And in both the chronic and episodic migraine studies a similar 3-month effect resulted from a second IV dose of the humanized antibody that binds the calcitonin gene–related peptide (CGRP) ligand, thereby blocking the pathway, Laszlo L. Mechtler, MD, and his associates reported in a poster at the annual meeting of the American Headache Society.

Eptinezumab follows the therapeutic approach already used by three Food and Drug Administration–approved monoclonal antibody drugs that cut migraine headache recurrences by blocking the CGRP pathway by binding either the peptide ligand or its receptor: erenumab-aooe (Aimovig), fremanezumab-vfrm (Ajovy), and galcanezumab-gnlm (Emgality). Eptinezumab differs from the three approved CGRP antibodies by using an IV route of administration – the other three are delivered by subcutaneous injection – and by a 3-month dosing interval. Both erenumab-aooe and galcanezumab-gnlm are labeled for monthly administration only, while fremanezumab-vfrm is labeled for both monthly and once every 3 months dosing schedules.

The PROMISE-1 (A Multicenter Assessment of ALD403 in Frequent Episodic Migraine) trial randomized 669 patients with episodic migraine (defined as 4-14 headache days/month with at least 4 classifiable as migraine headache days) at 87 centers mostly in the United States and with some in Georgia. The PROMISE-2 (Evaluation of ALD403 (Eptinezumab) in the Prevention of Chronic Migraine) trial randomized 1,072 patients with chronic migraine (defined as a history of 15-26 headache days/month and with at least 8 of the days involving a migraine headache) at any of 145 study sites, many in the United States, in several countries.

In PROMISE-1, patients could receive as many as four serial infusions every 3 months, and up to two serial infusions in PROMISE-2, but the primary endpoint in both studies was the change in monthly migraine count from baseline during the 3 months following the first dosage.

Among patients with chronic migraine in PROMISE-2, the average monthly migraine number fell by 8.2 migraine days/month, compared with an average 5.6 monthly migraine days drop from baseline among placebo patients, which was a statistically significant difference for the higher dosage of eptinezumab tested, 300 mg. A 100-mg dose linked with an average 7.7 migraine days/month reduction, also a statistically significant difference from the placebo patients, reported Dr. Mechtler, professor of neurology at the State University of New York at Buffalo and medical director of the Dent Neurologic Institute in Buffalo, and his associates.

Among patients with episodic migraine in PROMISE-1, the 300-mg dosage cut monthly migraines by an average 4.3 migraine headache days/month, compared with 3.2 in the placebo group, a statistically significant difference. Among patients who received the 100-mg dosage, the average cut was 3.9 migraine headache days/month, also a statistically significant difference from the placebo controls.

The researchers included no safety findings in their report, but in an interview Dr. Mechtler said that eptinezumab showed an excellent safety profile that was consistent with what’s been previously reported for the approved agents from this class. He cited the safety of the drugs in the class as a major feature of their clinical utility.

PROMISE-1 and PROMISE-2 were sponsored by Alder BioPharmaceuticals, the company developing eptinezumab. Dr. Mechtler has been a speaker on behalf of Allergan, Amgen/Novartis, Boston Biomedical, Promius, Avanir, and Teva, and he has received research funding from Allergan, Autonomic Technologies, Boston Biomedical, and Teva.

[email protected]

SOURCE: Mechtler LL et al. Headache. 2019 June;59[S1]:34, Abstract P12

PHILADELPHIA – An intravenous formulation of a calcitonin gene–related peptide inhibitor monoclonal antibody showed efficacy for preventing chronic migraine headaches for 3 months in a dose-ranging, phase 3 trial with 1,072 patients.

In a separate study with 669 patients, a single IV dose of the antibody, eptinezumab, also significantly reduced the incidence of episodic migraine headaches during 3 months of follow-up, compared with placebo. And in both the chronic and episodic migraine studies a similar 3-month effect resulted from a second IV dose of the humanized antibody that binds the calcitonin gene–related peptide (CGRP) ligand, thereby blocking the pathway, Laszlo L. Mechtler, MD, and his associates reported in a poster at the annual meeting of the American Headache Society.

Eptinezumab follows the therapeutic approach already used by three Food and Drug Administration–approved monoclonal antibody drugs that cut migraine headache recurrences by blocking the CGRP pathway by binding either the peptide ligand or its receptor: erenumab-aooe (Aimovig), fremanezumab-vfrm (Ajovy), and galcanezumab-gnlm (Emgality). Eptinezumab differs from the three approved CGRP antibodies by using an IV route of administration – the other three are delivered by subcutaneous injection – and by a 3-month dosing interval. Both erenumab-aooe and galcanezumab-gnlm are labeled for monthly administration only, while fremanezumab-vfrm is labeled for both monthly and once every 3 months dosing schedules.

The PROMISE-1 (A Multicenter Assessment of ALD403 in Frequent Episodic Migraine) trial randomized 669 patients with episodic migraine (defined as 4-14 headache days/month with at least 4 classifiable as migraine headache days) at 87 centers mostly in the United States and with some in Georgia. The PROMISE-2 (Evaluation of ALD403 (Eptinezumab) in the Prevention of Chronic Migraine) trial randomized 1,072 patients with chronic migraine (defined as a history of 15-26 headache days/month and with at least 8 of the days involving a migraine headache) at any of 145 study sites, many in the United States, in several countries.

In PROMISE-1, patients could receive as many as four serial infusions every 3 months, and up to two serial infusions in PROMISE-2, but the primary endpoint in both studies was the change in monthly migraine count from baseline during the 3 months following the first dosage.

Among patients with chronic migraine in PROMISE-2, the average monthly migraine number fell by 8.2 migraine days/month, compared with an average 5.6 monthly migraine days drop from baseline among placebo patients, which was a statistically significant difference for the higher dosage of eptinezumab tested, 300 mg. A 100-mg dose linked with an average 7.7 migraine days/month reduction, also a statistically significant difference from the placebo patients, reported Dr. Mechtler, professor of neurology at the State University of New York at Buffalo and medical director of the Dent Neurologic Institute in Buffalo, and his associates.

Among patients with episodic migraine in PROMISE-1, the 300-mg dosage cut monthly migraines by an average 4.3 migraine headache days/month, compared with 3.2 in the placebo group, a statistically significant difference. Among patients who received the 100-mg dosage, the average cut was 3.9 migraine headache days/month, also a statistically significant difference from the placebo controls.

The researchers included no safety findings in their report, but in an interview Dr. Mechtler said that eptinezumab showed an excellent safety profile that was consistent with what’s been previously reported for the approved agents from this class. He cited the safety of the drugs in the class as a major feature of their clinical utility.

PROMISE-1 and PROMISE-2 were sponsored by Alder BioPharmaceuticals, the company developing eptinezumab. Dr. Mechtler has been a speaker on behalf of Allergan, Amgen/Novartis, Boston Biomedical, Promius, Avanir, and Teva, and he has received research funding from Allergan, Autonomic Technologies, Boston Biomedical, and Teva.

[email protected]

SOURCE: Mechtler LL et al. Headache. 2019 June;59[S1]:34, Abstract P12

PHILADELPHIA – An intravenous formulation of a calcitonin gene–related peptide inhibitor monoclonal antibody showed efficacy for preventing chronic migraine headaches for 3 months in a dose-ranging, phase 3 trial with 1,072 patients.

In a separate study with 669 patients, a single IV dose of the antibody, eptinezumab, also significantly reduced the incidence of episodic migraine headaches during 3 months of follow-up, compared with placebo. And in both the chronic and episodic migraine studies a similar 3-month effect resulted from a second IV dose of the humanized antibody that binds the calcitonin gene–related peptide (CGRP) ligand, thereby blocking the pathway, Laszlo L. Mechtler, MD, and his associates reported in a poster at the annual meeting of the American Headache Society.

Eptinezumab follows the therapeutic approach already used by three Food and Drug Administration–approved monoclonal antibody drugs that cut migraine headache recurrences by blocking the CGRP pathway by binding either the peptide ligand or its receptor: erenumab-aooe (Aimovig), fremanezumab-vfrm (Ajovy), and galcanezumab-gnlm (Emgality). Eptinezumab differs from the three approved CGRP antibodies by using an IV route of administration – the other three are delivered by subcutaneous injection – and by a 3-month dosing interval. Both erenumab-aooe and galcanezumab-gnlm are labeled for monthly administration only, while fremanezumab-vfrm is labeled for both monthly and once every 3 months dosing schedules.

The PROMISE-1 (A Multicenter Assessment of ALD403 in Frequent Episodic Migraine) trial randomized 669 patients with episodic migraine (defined as 4-14 headache days/month with at least 4 classifiable as migraine headache days) at 87 centers mostly in the United States and with some in Georgia. The PROMISE-2 (Evaluation of ALD403 (Eptinezumab) in the Prevention of Chronic Migraine) trial randomized 1,072 patients with chronic migraine (defined as a history of 15-26 headache days/month and with at least 8 of the days involving a migraine headache) at any of 145 study sites, many in the United States, in several countries.

In PROMISE-1, patients could receive as many as four serial infusions every 3 months, and up to two serial infusions in PROMISE-2, but the primary endpoint in both studies was the change in monthly migraine count from baseline during the 3 months following the first dosage.

Among patients with chronic migraine in PROMISE-2, the average monthly migraine number fell by 8.2 migraine days/month, compared with an average 5.6 monthly migraine days drop from baseline among placebo patients, which was a statistically significant difference for the higher dosage of eptinezumab tested, 300 mg. A 100-mg dose linked with an average 7.7 migraine days/month reduction, also a statistically significant difference from the placebo patients, reported Dr. Mechtler, professor of neurology at the State University of New York at Buffalo and medical director of the Dent Neurologic Institute in Buffalo, and his associates.

Among patients with episodic migraine in PROMISE-1, the 300-mg dosage cut monthly migraines by an average 4.3 migraine headache days/month, compared with 3.2 in the placebo group, a statistically significant difference. Among patients who received the 100-mg dosage, the average cut was 3.9 migraine headache days/month, also a statistically significant difference from the placebo controls.

The researchers included no safety findings in their report, but in an interview Dr. Mechtler said that eptinezumab showed an excellent safety profile that was consistent with what’s been previously reported for the approved agents from this class. He cited the safety of the drugs in the class as a major feature of their clinical utility.

PROMISE-1 and PROMISE-2 were sponsored by Alder BioPharmaceuticals, the company developing eptinezumab. Dr. Mechtler has been a speaker on behalf of Allergan, Amgen/Novartis, Boston Biomedical, Promius, Avanir, and Teva, and he has received research funding from Allergan, Autonomic Technologies, Boston Biomedical, and Teva.

[email protected]

SOURCE: Mechtler LL et al. Headache. 2019 June;59[S1]:34, Abstract P12