Cardiology News

BASEL, SWITZERLAND — Minor ischemic stroke patients with intracranial occlusion should not be treated with IV thrombolysis, a new trial has concluded.

Results from the randomized controlled trial TEMPO-2 showed no benefit from treatment with tenecteplase following ischemic stroke. In addition, investigators found a small increased risk for symptomatic intracranial hemorrhage (ICH) and more deaths in the tenecteplase group compared with the control group.

The research suggests that although it makes sense to open up vessels in patients with minor stroke, they didn’t do better with thrombolysis.

“This is not the result we were hoping for, but I think the question of whether to treat these minor stroke patients who are not disabled has now been answered,” said lead investigator Shelagh B. Coutts, MD, University of Calgary, Alberta, Canada.

“After these results, I think we should scan these patients, admit them, give them dual antiplatelet therapy and IV fluids, and watch them like a hawk. If they deteriorate, we can intervene at that point.”

The findings were presented at the European Stroke Organization Conference (ESOC) 2024 annual meeting and published online simultaneously in The Lancet.
 

Very Little Data

Up to half of patients with ischemic stroke initially present with minimal symptoms, which are not disabling, investigators noted. Despite having low scores on the National Institutes of Health Stroke Scale (NIHSS) that typically range from 0 to 5, a third of these patients are dead or disabled at 90-day follow-up if thrombolysis is withheld.

Patients with minor deficits and evidence of an intracranial occlusion are a subpopulation at a high risk for early neurological deterioration, which most often occurs within the first 24 hours after presentation.

However, many physicians have concerns about giving thrombolysis to these patients because of the potential harm from bleeding in the absence of major deficits, and most trials of thrombolysis have excluded patients with minor stroke. That leaves very little high-quality data to guide practice for these patients.

Two previous studies have compared alteplase with antiplatelet agents in minor stroke, but no trial has specifically looked at the subset of patients with minor stroke who have intracranial occlusion. The TEMPO-2 trial was conducted to evaluate the use of tenecteplase in this patient population.

The multicenter, parallel group, open-label study was conducted at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the United Kingdom.

The trial included patients with minor acute ischemic stroke (NIHSS score of 0-5) and intracranial occlusion or focal perfusion abnormality who were within 12 hours from stroke onset.

Patients received IV tenecteplase (0.25 mg/kg) or non-thrombolytic standard of care (control). Most patients in the control group were treated with dual antiplatelet therapy with aspirin and clopidogrel (57%) or aspirin monotherapy (23%).

The trial was stopped early for futility after 886 patients had been enrolled. The median NIHSS score was 2.

The primary outcome — a return to baseline functioning on the modified Rankin Scale score at 90 days — occurred in 75% of the control group and in 72% of the tenecteplase group (risk ratio [RR], 0.96; P = .29).

Although there were significantly more patients with early recanalization and an NIHSS score of 0 at day 5 or discharge after tenecteplase treatment, this did not translate into improved functional outcomes at 90 days.

More patients died in the tenecteplase group compared with the control group (5% vs 1%; adjusted hazard ratio, 3.8; P = .0085).

There were eight (2%) symptomatic ICHs in the tenecteplase group versus two (< 1%) in the control group (RR, 4.2; P = .059).

The ICH rate was not different in patients treated after 4.5 hours versus before 4.5 hours. The subgroup of patients treated at 4.5-12.0 hours showed weaker evidence of better outcomes with thrombolysis than those treated before 4.5 hours, suggesting that the 12-hour window for TEMPO-2 did not explain the absence of benefit seen with tenecteplase.

Patients in the control group did better than expected, which may have been the result of chance, patient selection, or greater use of dual antiplatelet therapy, researchers noted.

Despite higher recanalization rates in the tenecteplase group (48% vs 22%), there was no change in the rate of stroke progression between groups, with an 8% rate of progression seen overall in the study.

Noting that previous studies have shown that patients with minor stroke and intracranial occlusion are at a risk for both progression and disability, the authors suggested that good supportive care may have improved outcomes in both groups.
 

More Trials Needed

Commenting on the study at the ESOC meeting, Urs Fischer, MD, Basel University Hospital, Switzerland, said “What should we do for patients with mild stroke with vessel occlusion has been a huge unanswered question. The TEMPO-2 study did not show a benefit with thrombolysis, and there was a tendency toward an increased risk of ICH. This is an important finding.”

In an accompanying editorial, Simona Sacco, MD, University of L’Aquila, Italy, and Guillaume Turc, MD, Université Paris Cité, France, noted that different minor ischemic stroke populations pose different therapeutic challenges.

Observational data suggest a benefit of endovascular treatment for minor stroke with large vessel occlusion, and dedicated randomized controlled trials in this group are ongoing, they added.

Early dual antiplatelet treatment is now the recommended treatment of minor stroke and should therefore be the active comparator for non-cardioembolic strokes in future trials.

While TEMPO-2 did not prove that tenecteplase is better than the standard of care for the acute treatment of minor stroke, Dr. Sacco and Dr. Turc said the study confirms that tenecteplase is associated with a high rate of recanalization.

“Fast recanalization with intravenous thrombolysis, endovascular treatment, proper patient selection, and combination with dual antiplatelet treatment or early initiation of anticoagulants may translate into tangible clinical benefits for patients with minor ischemic stroke, which should be tested in future studies,” they wrote.

This trial was funded by grants from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the British Heart Foundation. Boehringer Ingelheim provided tenecteplase for the study. Dr. Coutts reported no conflicts of interest. Dr. Sacco reported receiving grants for research from Novartis and Uriach; consulting fees from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; payment for lectures from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; and support for attending conferences from Lilly, Novartis, Teva, Lundbeck, and Pfizer. She is president elect of the European Stroke Organization and editor-in-chief of Cephalalgia. Dr. Turc reported payment for lectures from Guerbet France, is a member of the scientific advisory board of AI-Stroke, and is the Secretary General of the European Stroke Organisation.

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — Minor ischemic stroke patients with intracranial occlusion should not be treated with IV thrombolysis, a new trial has concluded.

Results from the randomized controlled trial TEMPO-2 showed no benefit from treatment with tenecteplase following ischemic stroke. In addition, investigators found a small increased risk for symptomatic intracranial hemorrhage (ICH) and more deaths in the tenecteplase group compared with the control group.

The research suggests that although it makes sense to open up vessels in patients with minor stroke, they didn’t do better with thrombolysis.

“This is not the result we were hoping for, but I think the question of whether to treat these minor stroke patients who are not disabled has now been answered,” said lead investigator Shelagh B. Coutts, MD, University of Calgary, Alberta, Canada.

“After these results, I think we should scan these patients, admit them, give them dual antiplatelet therapy and IV fluids, and watch them like a hawk. If they deteriorate, we can intervene at that point.”

The findings were presented at the European Stroke Organization Conference (ESOC) 2024 annual meeting and published online simultaneously in The Lancet.
 

Very Little Data

Up to half of patients with ischemic stroke initially present with minimal symptoms, which are not disabling, investigators noted. Despite having low scores on the National Institutes of Health Stroke Scale (NIHSS) that typically range from 0 to 5, a third of these patients are dead or disabled at 90-day follow-up if thrombolysis is withheld.

Patients with minor deficits and evidence of an intracranial occlusion are a subpopulation at a high risk for early neurological deterioration, which most often occurs within the first 24 hours after presentation.

However, many physicians have concerns about giving thrombolysis to these patients because of the potential harm from bleeding in the absence of major deficits, and most trials of thrombolysis have excluded patients with minor stroke. That leaves very little high-quality data to guide practice for these patients.

Two previous studies have compared alteplase with antiplatelet agents in minor stroke, but no trial has specifically looked at the subset of patients with minor stroke who have intracranial occlusion. The TEMPO-2 trial was conducted to evaluate the use of tenecteplase in this patient population.

The multicenter, parallel group, open-label study was conducted at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the United Kingdom.

The trial included patients with minor acute ischemic stroke (NIHSS score of 0-5) and intracranial occlusion or focal perfusion abnormality who were within 12 hours from stroke onset.

Patients received IV tenecteplase (0.25 mg/kg) or non-thrombolytic standard of care (control). Most patients in the control group were treated with dual antiplatelet therapy with aspirin and clopidogrel (57%) or aspirin monotherapy (23%).

The trial was stopped early for futility after 886 patients had been enrolled. The median NIHSS score was 2.

The primary outcome — a return to baseline functioning on the modified Rankin Scale score at 90 days — occurred in 75% of the control group and in 72% of the tenecteplase group (risk ratio [RR], 0.96; P = .29).

Although there were significantly more patients with early recanalization and an NIHSS score of 0 at day 5 or discharge after tenecteplase treatment, this did not translate into improved functional outcomes at 90 days.

More patients died in the tenecteplase group compared with the control group (5% vs 1%; adjusted hazard ratio, 3.8; P = .0085).

There were eight (2%) symptomatic ICHs in the tenecteplase group versus two (< 1%) in the control group (RR, 4.2; P = .059).

The ICH rate was not different in patients treated after 4.5 hours versus before 4.5 hours. The subgroup of patients treated at 4.5-12.0 hours showed weaker evidence of better outcomes with thrombolysis than those treated before 4.5 hours, suggesting that the 12-hour window for TEMPO-2 did not explain the absence of benefit seen with tenecteplase.

Patients in the control group did better than expected, which may have been the result of chance, patient selection, or greater use of dual antiplatelet therapy, researchers noted.

Despite higher recanalization rates in the tenecteplase group (48% vs 22%), there was no change in the rate of stroke progression between groups, with an 8% rate of progression seen overall in the study.

Noting that previous studies have shown that patients with minor stroke and intracranial occlusion are at a risk for both progression and disability, the authors suggested that good supportive care may have improved outcomes in both groups.
 

More Trials Needed

Commenting on the study at the ESOC meeting, Urs Fischer, MD, Basel University Hospital, Switzerland, said “What should we do for patients with mild stroke with vessel occlusion has been a huge unanswered question. The TEMPO-2 study did not show a benefit with thrombolysis, and there was a tendency toward an increased risk of ICH. This is an important finding.”

In an accompanying editorial, Simona Sacco, MD, University of L’Aquila, Italy, and Guillaume Turc, MD, Université Paris Cité, France, noted that different minor ischemic stroke populations pose different therapeutic challenges.

Observational data suggest a benefit of endovascular treatment for minor stroke with large vessel occlusion, and dedicated randomized controlled trials in this group are ongoing, they added.

Early dual antiplatelet treatment is now the recommended treatment of minor stroke and should therefore be the active comparator for non-cardioembolic strokes in future trials.

While TEMPO-2 did not prove that tenecteplase is better than the standard of care for the acute treatment of minor stroke, Dr. Sacco and Dr. Turc said the study confirms that tenecteplase is associated with a high rate of recanalization.

“Fast recanalization with intravenous thrombolysis, endovascular treatment, proper patient selection, and combination with dual antiplatelet treatment or early initiation of anticoagulants may translate into tangible clinical benefits for patients with minor ischemic stroke, which should be tested in future studies,” they wrote.

This trial was funded by grants from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the British Heart Foundation. Boehringer Ingelheim provided tenecteplase for the study. Dr. Coutts reported no conflicts of interest. Dr. Sacco reported receiving grants for research from Novartis and Uriach; consulting fees from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; payment for lectures from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; and support for attending conferences from Lilly, Novartis, Teva, Lundbeck, and Pfizer. She is president elect of the European Stroke Organization and editor-in-chief of Cephalalgia. Dr. Turc reported payment for lectures from Guerbet France, is a member of the scientific advisory board of AI-Stroke, and is the Secretary General of the European Stroke Organisation.

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — Minor ischemic stroke patients with intracranial occlusion should not be treated with IV thrombolysis, a new trial has concluded.

Results from the randomized controlled trial TEMPO-2 showed no benefit from treatment with tenecteplase following ischemic stroke. In addition, investigators found a small increased risk for symptomatic intracranial hemorrhage (ICH) and more deaths in the tenecteplase group compared with the control group.

The research suggests that although it makes sense to open up vessels in patients with minor stroke, they didn’t do better with thrombolysis.

“This is not the result we were hoping for, but I think the question of whether to treat these minor stroke patients who are not disabled has now been answered,” said lead investigator Shelagh B. Coutts, MD, University of Calgary, Alberta, Canada.

“After these results, I think we should scan these patients, admit them, give them dual antiplatelet therapy and IV fluids, and watch them like a hawk. If they deteriorate, we can intervene at that point.”

The findings were presented at the European Stroke Organization Conference (ESOC) 2024 annual meeting and published online simultaneously in The Lancet.
 

Very Little Data

Up to half of patients with ischemic stroke initially present with minimal symptoms, which are not disabling, investigators noted. Despite having low scores on the National Institutes of Health Stroke Scale (NIHSS) that typically range from 0 to 5, a third of these patients are dead or disabled at 90-day follow-up if thrombolysis is withheld.

Patients with minor deficits and evidence of an intracranial occlusion are a subpopulation at a high risk for early neurological deterioration, which most often occurs within the first 24 hours after presentation.

However, many physicians have concerns about giving thrombolysis to these patients because of the potential harm from bleeding in the absence of major deficits, and most trials of thrombolysis have excluded patients with minor stroke. That leaves very little high-quality data to guide practice for these patients.

Two previous studies have compared alteplase with antiplatelet agents in minor stroke, but no trial has specifically looked at the subset of patients with minor stroke who have intracranial occlusion. The TEMPO-2 trial was conducted to evaluate the use of tenecteplase in this patient population.

The multicenter, parallel group, open-label study was conducted at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the United Kingdom.

The trial included patients with minor acute ischemic stroke (NIHSS score of 0-5) and intracranial occlusion or focal perfusion abnormality who were within 12 hours from stroke onset.

Patients received IV tenecteplase (0.25 mg/kg) or non-thrombolytic standard of care (control). Most patients in the control group were treated with dual antiplatelet therapy with aspirin and clopidogrel (57%) or aspirin monotherapy (23%).

The trial was stopped early for futility after 886 patients had been enrolled. The median NIHSS score was 2.

The primary outcome — a return to baseline functioning on the modified Rankin Scale score at 90 days — occurred in 75% of the control group and in 72% of the tenecteplase group (risk ratio [RR], 0.96; P = .29).

Although there were significantly more patients with early recanalization and an NIHSS score of 0 at day 5 or discharge after tenecteplase treatment, this did not translate into improved functional outcomes at 90 days.

More patients died in the tenecteplase group compared with the control group (5% vs 1%; adjusted hazard ratio, 3.8; P = .0085).

There were eight (2%) symptomatic ICHs in the tenecteplase group versus two (< 1%) in the control group (RR, 4.2; P = .059).

The ICH rate was not different in patients treated after 4.5 hours versus before 4.5 hours. The subgroup of patients treated at 4.5-12.0 hours showed weaker evidence of better outcomes with thrombolysis than those treated before 4.5 hours, suggesting that the 12-hour window for TEMPO-2 did not explain the absence of benefit seen with tenecteplase.

Patients in the control group did better than expected, which may have been the result of chance, patient selection, or greater use of dual antiplatelet therapy, researchers noted.

Despite higher recanalization rates in the tenecteplase group (48% vs 22%), there was no change in the rate of stroke progression between groups, with an 8% rate of progression seen overall in the study.

Noting that previous studies have shown that patients with minor stroke and intracranial occlusion are at a risk for both progression and disability, the authors suggested that good supportive care may have improved outcomes in both groups.
 

More Trials Needed

Commenting on the study at the ESOC meeting, Urs Fischer, MD, Basel University Hospital, Switzerland, said “What should we do for patients with mild stroke with vessel occlusion has been a huge unanswered question. The TEMPO-2 study did not show a benefit with thrombolysis, and there was a tendency toward an increased risk of ICH. This is an important finding.”

In an accompanying editorial, Simona Sacco, MD, University of L’Aquila, Italy, and Guillaume Turc, MD, Université Paris Cité, France, noted that different minor ischemic stroke populations pose different therapeutic challenges.

Observational data suggest a benefit of endovascular treatment for minor stroke with large vessel occlusion, and dedicated randomized controlled trials in this group are ongoing, they added.

Early dual antiplatelet treatment is now the recommended treatment of minor stroke and should therefore be the active comparator for non-cardioembolic strokes in future trials.

While TEMPO-2 did not prove that tenecteplase is better than the standard of care for the acute treatment of minor stroke, Dr. Sacco and Dr. Turc said the study confirms that tenecteplase is associated with a high rate of recanalization.

“Fast recanalization with intravenous thrombolysis, endovascular treatment, proper patient selection, and combination with dual antiplatelet treatment or early initiation of anticoagulants may translate into tangible clinical benefits for patients with minor ischemic stroke, which should be tested in future studies,” they wrote.

This trial was funded by grants from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the British Heart Foundation. Boehringer Ingelheim provided tenecteplase for the study. Dr. Coutts reported no conflicts of interest. Dr. Sacco reported receiving grants for research from Novartis and Uriach; consulting fees from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; payment for lectures from Novartis, Allergan-AbbVie, Teva, Lilly, Lundbeck, Pfizer, Novo Nordisk, Abbott, and AstraZeneca; and support for attending conferences from Lilly, Novartis, Teva, Lundbeck, and Pfizer. She is president elect of the European Stroke Organization and editor-in-chief of Cephalalgia. Dr. Turc reported payment for lectures from Guerbet France, is a member of the scientific advisory board of AI-Stroke, and is the Secretary General of the European Stroke Organisation.

A version of this article appeared on Medscape.com.

In April, the Federal Trade Commission (FTC), by a vote of 3-2, opened a long-anticipated can of worms by approving its final rule that effectively bans employers’ use of all non-compete agreements (with very limited exceptions). The final rule will not go into effect until 120 days after its publication in the Federal Register, which took place on May 7, and numerous legal challenges appear to be on the horizon.

The principal components of the rule are as follows:

• After the effective date, most non-compete agreements (which prevent departing employees from signing with a new employer for a defined period within a specific geographic area) are banned nationwide.
• The rule exempts certain “senior executives,” ie individuals who earn more than $151,164 annually and serve in policy-making positions.
• There is another major exception for non-competes connected with a sale of a business.
• While not explicitly stated, the rule arguably exempts non-profits, tax-exempt hospitals, and other tax-exempt entities.
• Employers must provide verbal and written notice to employees regarding existing agreements, which would be voided under the rule.

The final rule is the latest skirmish in an ongoing, years-long debate. Twelve states have already put non-compete bans in place, according to a recent paper, and they may serve as a harbinger of things to come should the federal ban go into effect. Each state rule varies in its specifics as states respond to local market conditions. While some states ban all non-compete agreements outright, others limit them based on variables, such as income and employment circumstances. Of course, should the federal ban take effect, it will supersede whatever rules the individual states have in place.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.

In April, the Federal Trade Commission (FTC), by a vote of 3-2, opened a long-anticipated can of worms by approving its final rule that effectively bans employers’ use of all non-compete agreements (with very limited exceptions). The final rule will not go into effect until 120 days after its publication in the Federal Register, which took place on May 7, and numerous legal challenges appear to be on the horizon.

The principal components of the rule are as follows:

• After the effective date, most non-compete agreements (which prevent departing employees from signing with a new employer for a defined period within a specific geographic area) are banned nationwide.
• The rule exempts certain “senior executives,” ie individuals who earn more than $151,164 annually and serve in policy-making positions.
• There is another major exception for non-competes connected with a sale of a business.
• While not explicitly stated, the rule arguably exempts non-profits, tax-exempt hospitals, and other tax-exempt entities.
• Employers must provide verbal and written notice to employees regarding existing agreements, which would be voided under the rule.

The final rule is the latest skirmish in an ongoing, years-long debate. Twelve states have already put non-compete bans in place, according to a recent paper, and they may serve as a harbinger of things to come should the federal ban go into effect. Each state rule varies in its specifics as states respond to local market conditions. While some states ban all non-compete agreements outright, others limit them based on variables, such as income and employment circumstances. Of course, should the federal ban take effect, it will supersede whatever rules the individual states have in place.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.

In April, the Federal Trade Commission (FTC), by a vote of 3-2, opened a long-anticipated can of worms by approving its final rule that effectively bans employers’ use of all non-compete agreements (with very limited exceptions). The final rule will not go into effect until 120 days after its publication in the Federal Register, which took place on May 7, and numerous legal challenges appear to be on the horizon.

The principal components of the rule are as follows:

• After the effective date, most non-compete agreements (which prevent departing employees from signing with a new employer for a defined period within a specific geographic area) are banned nationwide.
• The rule exempts certain “senior executives,” ie individuals who earn more than $151,164 annually and serve in policy-making positions.
• There is another major exception for non-competes connected with a sale of a business.
• While not explicitly stated, the rule arguably exempts non-profits, tax-exempt hospitals, and other tax-exempt entities.
• Employers must provide verbal and written notice to employees regarding existing agreements, which would be voided under the rule.

The final rule is the latest skirmish in an ongoing, years-long debate. Twelve states have already put non-compete bans in place, according to a recent paper, and they may serve as a harbinger of things to come should the federal ban go into effect. Each state rule varies in its specifics as states respond to local market conditions. While some states ban all non-compete agreements outright, others limit them based on variables, such as income and employment circumstances. Of course, should the federal ban take effect, it will supersede whatever rules the individual states have in place.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.

Presentation

A 24-year-old man with no significant past medical history presents to urgent care with a 1-week history of sudden-onset dark urine, leg swelling, and unusually high blood pressure readings, with recent values around 160/100 mm Hg. Physical examination reveals pitting edema up to the mid-shins and mild periorbital edema, with an elevated blood pressure of 158/98 mm Hg. Past medical history was significant for frequent upper respiratory tract infections over the past year. Laboratory findings include hematuria, proteinuria, and a raised serum creatinine level at 1.8 mg/dL, indicating a reduced estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m². Other tests such as a complete blood count and comprehensive metabolic panel (except for creatinine and albumin) are within normal limits. Given these findings, the patient is referred to nephrology for further evaluation to determine the underlying cause of his renal symptoms.

Differential Diagnosis

A glomerular disease can be assumed to be present if the patient manifests glomerular hematuria, glomerular proteinuria, or both, such as in this patient.

Glomerulonephritis occurs due to inflammation in the glomeruli, which leads to blood in urine, variable degrees of protein in urine (sometimes in the nephrotic range), and white blood cells in urine without any urinary tract infection. Patients may also experience hypertension and kidney function impairment. Diagnoses to consider include:

• Postinfectious glomerulonephritis
• Crescentic glomerulonephritis
• Diffuse proliferative glomerulonephritis
• Glomerulonephritis associated with nonstreptococcal infection
• Membranoproliferative glomerulonephritis
• Membranous glomerulonephritis
• Poststreptococcal glomerulonephritis
• Rapidly Progressive glomerulonephritis

All patients presenting with proteinuria and hematuria should undergo a thorough evaluation for glomerular disease, which generally involves laboratory testing and, in most patients, a kidney biopsy to obtain a definitive diagnosis.
 

Diagnosis

This patient underwent a renal biopsy, which showed C3-dominant deposition by immunofluorescence; electron microscopy (EM) showed discontinuous, ill-defined intramembranous deposits; and mass spectrometry showed terminal complement components in C3 deposits. The patient was diagnosed with C3 glomerulonephritis (C3G).

The diagnosis of C3G is established by kidney biopsy demonstrating the characteristic findings on immunofluorescence microscopy or EM in a patient with suspected glomerulonephritis. In patients with biopsy-confirmed C3G, additional testing should be performed to help identify the underlying etiology of the glomerulopathy to help determine therapy.

For all patients diagnosed with C3G, especially those who are older than 50 years, it is important to rule out monoclonal gammopathy which can be done through various tests such as serum protein electrophoresis and immunofixation, serum free light chains, and urine protein electrophoresis and immunofixation. The presence of a paraprotein, including a monoclonal light chain, can activate the alternative complement cascade and may be responsible for the condition.

Expert opinion recommends a comprehensive complement evaluation for all C3 glomerulopathy patients, including overall complement activity assessment, serum levels measurement of complement proteins and their split products, and autoantibodies screening.

Complement evaluation may include:

• Serum C3 and C4
• Soluble C5b-9 (soluble membrane attack complex)
• Serum factor H
• Serum factor B, factor I, and membrane cofactor protein (MCP; CD46)

All patients with C3G should also undergo screening for autoantibodies:

• C3 nephritic factor (C3NeF)
• C5 nephritic factor (C5NeF)
• C4 nephritic factor (C4NeF)
• Other autoantibodies against factor H, factor B, and/or C3b

It is recommended that genetic testing be considered for patients with C3 glomerulopathy to screen for complement genes including C3, CFB, CFH, CFHR5, and CFI and copy number variations and rearrangements of the CFH-CFHR gene cluster. The value of genetic testing in the clinical setting is still being defined; however, it has been observed that patients with mutations in complement genes generally respond less favorably to mycophenolate mofetil (MMF) compared with those who are positive for nephritic factors.
 

Management

The patient was managed with an angiotensin-converting enzyme (ACE) inhibitor to treat proteinuria and hypertension and MMF for immunosuppression. Enrollment in a clinical trial of an investigational complement inhibitor was discussed with the patient.

Currently, there are no therapeutic agents specifically designed to target the underlying complement dysregulation that occurs in individuals with C3G, and an optimal treatment for C3 glomerulopathy has not been established.

Various nonspecific therapies have been used to treat C3G, including plasmapheresis, steroids, rituximab, cyclophosphamide, and MMF and have shown positive results. For patients with C3G who have a known genetic variant (eg, CFH mutation) or who have acute kidney injury, plasmapheresis and plasma exchange may be helpful. Using these agents judiciously and in conjunction with optimal blood pressure control is important for maximum benefit in treating C3G. When someone with end-stage renal disease (ESRD) caused by C3G chooses to have a kidney transplant, it is important to know that C3G is likely to return in almost all cases and is the leading cause of transplant failure in 50%-90% of recipients.
 

Prognosis

The prognosis of C3G varies and is affected by various clinical and histological factors. While some patients may have consistently low levels of protein in their urine and maintain stable kidney function over time, others may experience severe nephrotic syndrome or rapidly progressive glomerulonephritis, which often leads to a poor prognosis.

Progression to ESRD is a major complication of C3G, with approximately 70% of affected children and 30%-50% of adults reaching this stage. In addition, disease recurrence is common after kidney transplantation, with about 50% of patients experiencing allograft loss within 10 years. Predictive factors for disease progression, although not robustly established, include initial eGFR at diagnosis, percentage of tubular atrophy, and extent of interstitial fibrosis in the cortical area as observed on kidney biopsies.
 

Clinical Takeaways

For patients exhibiting symptoms like proteinuria and hematuria indicative of glomerulonephritis, a comprehensive evaluation including laboratory tests and a kidney biopsy is essential to confirm a C3G diagnosis through characteristic findings on immunofluorescence microscopy or electron microscopy.

Additional tests to rule out associated conditions like monoclonal gammopathy and comprehensive complement evaluation are also recommended to understand the underlying etiology and guide therapy.

Though there are no treatments specifically targeting the underlying complement dysregulation unique to C3G, nonspecific therapies like ACE inhibitors, immunosuppressants (eg, MMF), and plasmapheresis are commonly used.

Some anticomplement therapies are available or under investigation, which might offer more targeted intervention options.

The prognosis for patients with C3G can vary widely and factors such as initial eGFR, the extent of tubular atrophy, and interstitial fibrosis are important predictors of disease progression.

Dr. Alper is an associate professor, Nephrology, Tulane University School of Medicine, New Orleans, Louisiana. He has disclosed no relevant financial relationships.

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

Presentation

A 24-year-old man with no significant past medical history presents to urgent care with a 1-week history of sudden-onset dark urine, leg swelling, and unusually high blood pressure readings, with recent values around 160/100 mm Hg. Physical examination reveals pitting edema up to the mid-shins and mild periorbital edema, with an elevated blood pressure of 158/98 mm Hg. Past medical history was significant for frequent upper respiratory tract infections over the past year. Laboratory findings include hematuria, proteinuria, and a raised serum creatinine level at 1.8 mg/dL, indicating a reduced estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m². Other tests such as a complete blood count and comprehensive metabolic panel (except for creatinine and albumin) are within normal limits. Given these findings, the patient is referred to nephrology for further evaluation to determine the underlying cause of his renal symptoms.

Differential Diagnosis

A glomerular disease can be assumed to be present if the patient manifests glomerular hematuria, glomerular proteinuria, or both, such as in this patient.

Glomerulonephritis occurs due to inflammation in the glomeruli, which leads to blood in urine, variable degrees of protein in urine (sometimes in the nephrotic range), and white blood cells in urine without any urinary tract infection. Patients may also experience hypertension and kidney function impairment. Diagnoses to consider include:

• Postinfectious glomerulonephritis
• Crescentic glomerulonephritis
• Diffuse proliferative glomerulonephritis
• Glomerulonephritis associated with nonstreptococcal infection
• Membranoproliferative glomerulonephritis
• Membranous glomerulonephritis
• Poststreptococcal glomerulonephritis
• Rapidly Progressive glomerulonephritis

All patients presenting with proteinuria and hematuria should undergo a thorough evaluation for glomerular disease, which generally involves laboratory testing and, in most patients, a kidney biopsy to obtain a definitive diagnosis.
 

Diagnosis

This patient underwent a renal biopsy, which showed C3-dominant deposition by immunofluorescence; electron microscopy (EM) showed discontinuous, ill-defined intramembranous deposits; and mass spectrometry showed terminal complement components in C3 deposits. The patient was diagnosed with C3 glomerulonephritis (C3G).

The diagnosis of C3G is established by kidney biopsy demonstrating the characteristic findings on immunofluorescence microscopy or EM in a patient with suspected glomerulonephritis. In patients with biopsy-confirmed C3G, additional testing should be performed to help identify the underlying etiology of the glomerulopathy to help determine therapy.

For all patients diagnosed with C3G, especially those who are older than 50 years, it is important to rule out monoclonal gammopathy which can be done through various tests such as serum protein electrophoresis and immunofixation, serum free light chains, and urine protein electrophoresis and immunofixation. The presence of a paraprotein, including a monoclonal light chain, can activate the alternative complement cascade and may be responsible for the condition.

Expert opinion recommends a comprehensive complement evaluation for all C3 glomerulopathy patients, including overall complement activity assessment, serum levels measurement of complement proteins and their split products, and autoantibodies screening.

Complement evaluation may include:

• Serum C3 and C4
• Soluble C5b-9 (soluble membrane attack complex)
• Serum factor H
• Serum factor B, factor I, and membrane cofactor protein (MCP; CD46)

All patients with C3G should also undergo screening for autoantibodies:

• C3 nephritic factor (C3NeF)
• C5 nephritic factor (C5NeF)
• C4 nephritic factor (C4NeF)
• Other autoantibodies against factor H, factor B, and/or C3b

It is recommended that genetic testing be considered for patients with C3 glomerulopathy to screen for complement genes including C3, CFB, CFH, CFHR5, and CFI and copy number variations and rearrangements of the CFH-CFHR gene cluster. The value of genetic testing in the clinical setting is still being defined; however, it has been observed that patients with mutations in complement genes generally respond less favorably to mycophenolate mofetil (MMF) compared with those who are positive for nephritic factors.
 

Management

The patient was managed with an angiotensin-converting enzyme (ACE) inhibitor to treat proteinuria and hypertension and MMF for immunosuppression. Enrollment in a clinical trial of an investigational complement inhibitor was discussed with the patient.

Currently, there are no therapeutic agents specifically designed to target the underlying complement dysregulation that occurs in individuals with C3G, and an optimal treatment for C3 glomerulopathy has not been established.

Various nonspecific therapies have been used to treat C3G, including plasmapheresis, steroids, rituximab, cyclophosphamide, and MMF and have shown positive results. For patients with C3G who have a known genetic variant (eg, CFH mutation) or who have acute kidney injury, plasmapheresis and plasma exchange may be helpful. Using these agents judiciously and in conjunction with optimal blood pressure control is important for maximum benefit in treating C3G. When someone with end-stage renal disease (ESRD) caused by C3G chooses to have a kidney transplant, it is important to know that C3G is likely to return in almost all cases and is the leading cause of transplant failure in 50%-90% of recipients.
 

Prognosis

The prognosis of C3G varies and is affected by various clinical and histological factors. While some patients may have consistently low levels of protein in their urine and maintain stable kidney function over time, others may experience severe nephrotic syndrome or rapidly progressive glomerulonephritis, which often leads to a poor prognosis.

Progression to ESRD is a major complication of C3G, with approximately 70% of affected children and 30%-50% of adults reaching this stage. In addition, disease recurrence is common after kidney transplantation, with about 50% of patients experiencing allograft loss within 10 years. Predictive factors for disease progression, although not robustly established, include initial eGFR at diagnosis, percentage of tubular atrophy, and extent of interstitial fibrosis in the cortical area as observed on kidney biopsies.
 

Clinical Takeaways

For patients exhibiting symptoms like proteinuria and hematuria indicative of glomerulonephritis, a comprehensive evaluation including laboratory tests and a kidney biopsy is essential to confirm a C3G diagnosis through characteristic findings on immunofluorescence microscopy or electron microscopy.

Additional tests to rule out associated conditions like monoclonal gammopathy and comprehensive complement evaluation are also recommended to understand the underlying etiology and guide therapy.

Though there are no treatments specifically targeting the underlying complement dysregulation unique to C3G, nonspecific therapies like ACE inhibitors, immunosuppressants (eg, MMF), and plasmapheresis are commonly used.

Some anticomplement therapies are available or under investigation, which might offer more targeted intervention options.

The prognosis for patients with C3G can vary widely and factors such as initial eGFR, the extent of tubular atrophy, and interstitial fibrosis are important predictors of disease progression.

Dr. Alper is an associate professor, Nephrology, Tulane University School of Medicine, New Orleans, Louisiana. He has disclosed no relevant financial relationships.

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

Presentation

A 24-year-old man with no significant past medical history presents to urgent care with a 1-week history of sudden-onset dark urine, leg swelling, and unusually high blood pressure readings, with recent values around 160/100 mm Hg. Physical examination reveals pitting edema up to the mid-shins and mild periorbital edema, with an elevated blood pressure of 158/98 mm Hg. Past medical history was significant for frequent upper respiratory tract infections over the past year. Laboratory findings include hematuria, proteinuria, and a raised serum creatinine level at 1.8 mg/dL, indicating a reduced estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m². Other tests such as a complete blood count and comprehensive metabolic panel (except for creatinine and albumin) are within normal limits. Given these findings, the patient is referred to nephrology for further evaluation to determine the underlying cause of his renal symptoms.

Differential Diagnosis

A glomerular disease can be assumed to be present if the patient manifests glomerular hematuria, glomerular proteinuria, or both, such as in this patient.

Glomerulonephritis occurs due to inflammation in the glomeruli, which leads to blood in urine, variable degrees of protein in urine (sometimes in the nephrotic range), and white blood cells in urine without any urinary tract infection. Patients may also experience hypertension and kidney function impairment. Diagnoses to consider include:

• Postinfectious glomerulonephritis
• Crescentic glomerulonephritis
• Diffuse proliferative glomerulonephritis
• Glomerulonephritis associated with nonstreptococcal infection
• Membranoproliferative glomerulonephritis
• Membranous glomerulonephritis
• Poststreptococcal glomerulonephritis
• Rapidly Progressive glomerulonephritis

All patients presenting with proteinuria and hematuria should undergo a thorough evaluation for glomerular disease, which generally involves laboratory testing and, in most patients, a kidney biopsy to obtain a definitive diagnosis.
 

Diagnosis

This patient underwent a renal biopsy, which showed C3-dominant deposition by immunofluorescence; electron microscopy (EM) showed discontinuous, ill-defined intramembranous deposits; and mass spectrometry showed terminal complement components in C3 deposits. The patient was diagnosed with C3 glomerulonephritis (C3G).

The diagnosis of C3G is established by kidney biopsy demonstrating the characteristic findings on immunofluorescence microscopy or EM in a patient with suspected glomerulonephritis. In patients with biopsy-confirmed C3G, additional testing should be performed to help identify the underlying etiology of the glomerulopathy to help determine therapy.

For all patients diagnosed with C3G, especially those who are older than 50 years, it is important to rule out monoclonal gammopathy which can be done through various tests such as serum protein electrophoresis and immunofixation, serum free light chains, and urine protein electrophoresis and immunofixation. The presence of a paraprotein, including a monoclonal light chain, can activate the alternative complement cascade and may be responsible for the condition.

Expert opinion recommends a comprehensive complement evaluation for all C3 glomerulopathy patients, including overall complement activity assessment, serum levels measurement of complement proteins and their split products, and autoantibodies screening.

Complement evaluation may include:

• Serum C3 and C4
• Soluble C5b-9 (soluble membrane attack complex)
• Serum factor H
• Serum factor B, factor I, and membrane cofactor protein (MCP; CD46)

All patients with C3G should also undergo screening for autoantibodies:

• C3 nephritic factor (C3NeF)
• C5 nephritic factor (C5NeF)
• C4 nephritic factor (C4NeF)
• Other autoantibodies against factor H, factor B, and/or C3b

It is recommended that genetic testing be considered for patients with C3 glomerulopathy to screen for complement genes including C3, CFB, CFH, CFHR5, and CFI and copy number variations and rearrangements of the CFH-CFHR gene cluster. The value of genetic testing in the clinical setting is still being defined; however, it has been observed that patients with mutations in complement genes generally respond less favorably to mycophenolate mofetil (MMF) compared with those who are positive for nephritic factors.
 

Management

The patient was managed with an angiotensin-converting enzyme (ACE) inhibitor to treat proteinuria and hypertension and MMF for immunosuppression. Enrollment in a clinical trial of an investigational complement inhibitor was discussed with the patient.

Currently, there are no therapeutic agents specifically designed to target the underlying complement dysregulation that occurs in individuals with C3G, and an optimal treatment for C3 glomerulopathy has not been established.

Various nonspecific therapies have been used to treat C3G, including plasmapheresis, steroids, rituximab, cyclophosphamide, and MMF and have shown positive results. For patients with C3G who have a known genetic variant (eg, CFH mutation) or who have acute kidney injury, plasmapheresis and plasma exchange may be helpful. Using these agents judiciously and in conjunction with optimal blood pressure control is important for maximum benefit in treating C3G. When someone with end-stage renal disease (ESRD) caused by C3G chooses to have a kidney transplant, it is important to know that C3G is likely to return in almost all cases and is the leading cause of transplant failure in 50%-90% of recipients.
 

Prognosis

The prognosis of C3G varies and is affected by various clinical and histological factors. While some patients may have consistently low levels of protein in their urine and maintain stable kidney function over time, others may experience severe nephrotic syndrome or rapidly progressive glomerulonephritis, which often leads to a poor prognosis.

Progression to ESRD is a major complication of C3G, with approximately 70% of affected children and 30%-50% of adults reaching this stage. In addition, disease recurrence is common after kidney transplantation, with about 50% of patients experiencing allograft loss within 10 years. Predictive factors for disease progression, although not robustly established, include initial eGFR at diagnosis, percentage of tubular atrophy, and extent of interstitial fibrosis in the cortical area as observed on kidney biopsies.
 

Clinical Takeaways

For patients exhibiting symptoms like proteinuria and hematuria indicative of glomerulonephritis, a comprehensive evaluation including laboratory tests and a kidney biopsy is essential to confirm a C3G diagnosis through characteristic findings on immunofluorescence microscopy or electron microscopy.

Additional tests to rule out associated conditions like monoclonal gammopathy and comprehensive complement evaluation are also recommended to understand the underlying etiology and guide therapy.

Though there are no treatments specifically targeting the underlying complement dysregulation unique to C3G, nonspecific therapies like ACE inhibitors, immunosuppressants (eg, MMF), and plasmapheresis are commonly used.

Some anticomplement therapies are available or under investigation, which might offer more targeted intervention options.

The prognosis for patients with C3G can vary widely and factors such as initial eGFR, the extent of tubular atrophy, and interstitial fibrosis are important predictors of disease progression.

Dr. Alper is an associate professor, Nephrology, Tulane University School of Medicine, New Orleans, Louisiana. He has disclosed no relevant financial relationships.

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

Breast cancer mortality was significantly lower among patients who used statins than in those who did not use these cholesterol-lowering drugs, a new study finds.

Previous research examining the association between cholesterol and breast cancer metabolism suggests that cholesterol-lowering medications such as statins may improve outcomes in breast cancer patients, Sixten Harborg, a medical student and PhD student at Aarhus University, Denmark, said in a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

In addition, cardiovascular-related death is the second most common cause of death for breast cancer survivors, and given the survival rates in early breast cancer, there is a demand for cardioprotective initiatives and maintenance of cardioprotective drugs after diagnosis, he said in an interview.
 

What Is Known About Statins and Breast Cancer?

Statins are the most common drugs used to lower cholesterol and may deprive tumor cells of the cholesterol needed for cell membrane synthesis, Mr. Harborg said in his presentation.

Data from a randomized trial published in the Journal of Clinical Oncology in 2017 showed significantly improved disease-free survival, breast cancer–free interval, and distant recurrence–free interval in early stage breast cancer patients randomized to cholesterol-lowering medication vs. those who did not receive cholesterol-lowering medication.

The 2017 study prompted the creation of the MASTER study, a randomized, multicenter, double-blind, placebo-controlled trial comparing standard adjuvant therapy plus placebo to standard adjuvant therapy plus atorvastatin in patients with early breast cancer (NCT04601116), Mr. Harborg said. The MASTER trial is currently recruiting patients in Denmark.
 

How Was the Current Study Designed?

To provide preliminary analysis, Mr. Harborg and colleagues used an emulation trial design based on electronic health care data from 110,160 females with a diagnosis of stage I, II, or III breast cancer who were part of the Danish Breast Cancer Group, a national clinical registry in Denmark, between 2000 and 2020.

As defined in the European Journal of Epidemiology in 2017, target trial emulation involves application of randomized trial designs to observational data with the goal of improving the quality of observational epidemiology when a comparator trial is not yet available.

The researchers created a cohort of patients based on electronic health care data to simulate a target trial of the use of atorvastatin after breast cancer diagnosis. Patients were randomized to one of two treatment strategies: starting to use statins within 36 months of diagnosis, or not using statins. The primary outcome was death from breast cancer. The follow-up for the MASTER study starts with inclusion and ends with death, emigration from Denmark, end of clinical follow-up, or 10 years of follow-up (whichever comes first); the follow-up was the same in the current study.

The researchers calculated hazard ratios (HR) of breast cancer mortality in statin users vs. non–statin users and used a technique known as inverse-probability of censoring-weighting (IPCW) to estimate the effects of statin use based on prognostic factors.
 

What Did the Results Show?

The results favored statin use for improved survival in early breast cancer patients, Mr. Harborg said. Overall, the hazard ratio for breast cancer mortality was 0.96 in statin users compared with non–statin users, and was similar in both a Cox regression analysis (HR 0.81), and in a 10-year landmark analysis (HR 0.86).

The difference in mortality between statin and non–statin users was even stronger in patients who were receiving adjuvant chemotherapy (HR 0.94, 0.64, and 0.76 on the IPCW, Cox, and landmark analyses, respectively).

The results were in line with previous reports of statins’ effect on breast cancer survival, Mr. Harborg said in an interview.

“We believe the results encourage the continuous effort of the currently enrolling MASTER trial,” he said.

The results also suggest that deprescribing statins at the time of breast cancer diagnosis is not recommended, and that statin treatment can safely be prescribed to breast cancer patients with increased cardiovascular disease risk and/or dyslipidemia, Mr. Harborg said in the interview.
 

What Is the Takeaway Message for Clinical Practice?

“The clinical takeaway from our study is that statin use is associated with reduced risk of dying from breast cancer, but that it is not possible to determine the true effect of statins on breast cancer survival without a randomized, placebo-controlled trial,” Mr. Harborg told this publication. “Statins are inexpensive and well-tolerated drugs and may have a beneficial effect in terms of survival for breast cancer patients. However, with the current level of evidence [because the MASTER study is ongoing], we still cannot recommend that oncologists prescribe statins to prevent mortality from breast cancer,” he said.

What Are the Next Steps for Research?

The findings were limited by the study design, and real-world data are needed, Dr. Harborg said. Other limitations include the presence of residual bias, and the use of data based on prescription codes, but these were not considered to have an effect on the main conclusion of the study, Mr. Harborg said in the interview.

However, the results suggest that the addition of statins may improve outcomes for early breast cancer patients, especially when used with chemotherapy, and support the value of the ongoing MASTER study, he concluded.

Ultimately, the MASTER study will provide a more definitive answer to the question of whether statins should be added to the adjuvant treatment regimen of breast cancer to improve breast cancer outcomes, he said.
 

What Do Clinicians Think of the Study?

The current study is timely and highlights the need for phase 3 trials to examine the potential of statin use for breast cancer outcomes, Malinda T. West, MD, a medical oncologist and breast oncologist at the University of Wisconsin Carbone Cancer Center, Madison, said in an interview.

Questions for future research include whether statins can be used in combination with adjuvant abemaciclib if indicated, or how to best sequence these agents, said Dr. West, who was not involved in the study. Other questions raised by the current study include whether other cholesterol-lowering agents have a potential adjuvant benefit in reducing breast cancer recurrent and/or mortality, and whether the addition of statins would benefit subgroups such as HER2+ and triple negative breast cancer, she said.

“I was not surprised to see another study reporting benefit with statins and reduced risk of breast cancer recurrence and/or mortality, but I think the larger question is defining the subgroups who benefit the most, and identifying predictors for benefit or resistance,” Dr. West said in an interview.

Previous studies have shown that cholesterol elevation, specifically LDL levels, can be linked to increased tumor growth in breast cancer, so the lower mortality risk associated with lipid-lowering therapies in the current study was consistent, Peyton L. Reves, MD, a hematology/oncology fellow, also at the University of Wisconsin, said in an interview. In practice, data from the current study and previous research could be especially useful for patients with elevated LDL levels, said Dr. Reves, who was not involved in the study.

“These results could impact clinical practice in many ways, including leading to routine cholesterol monitoring in breast cancer patients on adjuvant therapy as well as the addition of lipid-lowering therapy with statins in these patients,” Dr. Reves said.

The findings showing particular benefit for patients on adjuvant chemotherapy highlight the need for more research on this specific population and the effect of statins on overall breast cancer mortality, to explore the extent to which the results of the current study were driven by the benefit seen in patients receiving adjuvant chemotherapy, Dr. Reves said.

The study was supported by Director Michael Hermann Nielsen’s Memorial Grant, Manufacturer Einar Willumsen’s Memorial Grant, Astrid Thaysen’s Grant for Medical Basic Research, Eva and Henry Fraenkel’s Memorial Fund, and the Novo Nordisk Foundation.

The researchers had no financial conflicts to disclose. Dr. West and Dr. Reves had no financial conflicts to disclose.

Breast cancer mortality was significantly lower among patients who used statins than in those who did not use these cholesterol-lowering drugs, a new study finds.

Previous research examining the association between cholesterol and breast cancer metabolism suggests that cholesterol-lowering medications such as statins may improve outcomes in breast cancer patients, Sixten Harborg, a medical student and PhD student at Aarhus University, Denmark, said in a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

In addition, cardiovascular-related death is the second most common cause of death for breast cancer survivors, and given the survival rates in early breast cancer, there is a demand for cardioprotective initiatives and maintenance of cardioprotective drugs after diagnosis, he said in an interview.
 

What Is Known About Statins and Breast Cancer?

Statins are the most common drugs used to lower cholesterol and may deprive tumor cells of the cholesterol needed for cell membrane synthesis, Mr. Harborg said in his presentation.

Data from a randomized trial published in the Journal of Clinical Oncology in 2017 showed significantly improved disease-free survival, breast cancer–free interval, and distant recurrence–free interval in early stage breast cancer patients randomized to cholesterol-lowering medication vs. those who did not receive cholesterol-lowering medication.

The 2017 study prompted the creation of the MASTER study, a randomized, multicenter, double-blind, placebo-controlled trial comparing standard adjuvant therapy plus placebo to standard adjuvant therapy plus atorvastatin in patients with early breast cancer (NCT04601116), Mr. Harborg said. The MASTER trial is currently recruiting patients in Denmark.
 

How Was the Current Study Designed?

To provide preliminary analysis, Mr. Harborg and colleagues used an emulation trial design based on electronic health care data from 110,160 females with a diagnosis of stage I, II, or III breast cancer who were part of the Danish Breast Cancer Group, a national clinical registry in Denmark, between 2000 and 2020.

As defined in the European Journal of Epidemiology in 2017, target trial emulation involves application of randomized trial designs to observational data with the goal of improving the quality of observational epidemiology when a comparator trial is not yet available.

The researchers created a cohort of patients based on electronic health care data to simulate a target trial of the use of atorvastatin after breast cancer diagnosis. Patients were randomized to one of two treatment strategies: starting to use statins within 36 months of diagnosis, or not using statins. The primary outcome was death from breast cancer. The follow-up for the MASTER study starts with inclusion and ends with death, emigration from Denmark, end of clinical follow-up, or 10 years of follow-up (whichever comes first); the follow-up was the same in the current study.

The researchers calculated hazard ratios (HR) of breast cancer mortality in statin users vs. non–statin users and used a technique known as inverse-probability of censoring-weighting (IPCW) to estimate the effects of statin use based on prognostic factors.
 

What Did the Results Show?

The results favored statin use for improved survival in early breast cancer patients, Mr. Harborg said. Overall, the hazard ratio for breast cancer mortality was 0.96 in statin users compared with non–statin users, and was similar in both a Cox regression analysis (HR 0.81), and in a 10-year landmark analysis (HR 0.86).

The difference in mortality between statin and non–statin users was even stronger in patients who were receiving adjuvant chemotherapy (HR 0.94, 0.64, and 0.76 on the IPCW, Cox, and landmark analyses, respectively).

The results were in line with previous reports of statins’ effect on breast cancer survival, Mr. Harborg said in an interview.

“We believe the results encourage the continuous effort of the currently enrolling MASTER trial,” he said.

The results also suggest that deprescribing statins at the time of breast cancer diagnosis is not recommended, and that statin treatment can safely be prescribed to breast cancer patients with increased cardiovascular disease risk and/or dyslipidemia, Mr. Harborg said in the interview.
 

What Is the Takeaway Message for Clinical Practice?

“The clinical takeaway from our study is that statin use is associated with reduced risk of dying from breast cancer, but that it is not possible to determine the true effect of statins on breast cancer survival without a randomized, placebo-controlled trial,” Mr. Harborg told this publication. “Statins are inexpensive and well-tolerated drugs and may have a beneficial effect in terms of survival for breast cancer patients. However, with the current level of evidence [because the MASTER study is ongoing], we still cannot recommend that oncologists prescribe statins to prevent mortality from breast cancer,” he said.

What Are the Next Steps for Research?

The findings were limited by the study design, and real-world data are needed, Dr. Harborg said. Other limitations include the presence of residual bias, and the use of data based on prescription codes, but these were not considered to have an effect on the main conclusion of the study, Mr. Harborg said in the interview.

However, the results suggest that the addition of statins may improve outcomes for early breast cancer patients, especially when used with chemotherapy, and support the value of the ongoing MASTER study, he concluded.

Ultimately, the MASTER study will provide a more definitive answer to the question of whether statins should be added to the adjuvant treatment regimen of breast cancer to improve breast cancer outcomes, he said.
 

What Do Clinicians Think of the Study?

The current study is timely and highlights the need for phase 3 trials to examine the potential of statin use for breast cancer outcomes, Malinda T. West, MD, a medical oncologist and breast oncologist at the University of Wisconsin Carbone Cancer Center, Madison, said in an interview.

Questions for future research include whether statins can be used in combination with adjuvant abemaciclib if indicated, or how to best sequence these agents, said Dr. West, who was not involved in the study. Other questions raised by the current study include whether other cholesterol-lowering agents have a potential adjuvant benefit in reducing breast cancer recurrent and/or mortality, and whether the addition of statins would benefit subgroups such as HER2+ and triple negative breast cancer, she said.

“I was not surprised to see another study reporting benefit with statins and reduced risk of breast cancer recurrence and/or mortality, but I think the larger question is defining the subgroups who benefit the most, and identifying predictors for benefit or resistance,” Dr. West said in an interview.

Previous studies have shown that cholesterol elevation, specifically LDL levels, can be linked to increased tumor growth in breast cancer, so the lower mortality risk associated with lipid-lowering therapies in the current study was consistent, Peyton L. Reves, MD, a hematology/oncology fellow, also at the University of Wisconsin, said in an interview. In practice, data from the current study and previous research could be especially useful for patients with elevated LDL levels, said Dr. Reves, who was not involved in the study.

“These results could impact clinical practice in many ways, including leading to routine cholesterol monitoring in breast cancer patients on adjuvant therapy as well as the addition of lipid-lowering therapy with statins in these patients,” Dr. Reves said.

The findings showing particular benefit for patients on adjuvant chemotherapy highlight the need for more research on this specific population and the effect of statins on overall breast cancer mortality, to explore the extent to which the results of the current study were driven by the benefit seen in patients receiving adjuvant chemotherapy, Dr. Reves said.

The study was supported by Director Michael Hermann Nielsen’s Memorial Grant, Manufacturer Einar Willumsen’s Memorial Grant, Astrid Thaysen’s Grant for Medical Basic Research, Eva and Henry Fraenkel’s Memorial Fund, and the Novo Nordisk Foundation.

The researchers had no financial conflicts to disclose. Dr. West and Dr. Reves had no financial conflicts to disclose.

Breast cancer mortality was significantly lower among patients who used statins than in those who did not use these cholesterol-lowering drugs, a new study finds.

Previous research examining the association between cholesterol and breast cancer metabolism suggests that cholesterol-lowering medications such as statins may improve outcomes in breast cancer patients, Sixten Harborg, a medical student and PhD student at Aarhus University, Denmark, said in a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

In addition, cardiovascular-related death is the second most common cause of death for breast cancer survivors, and given the survival rates in early breast cancer, there is a demand for cardioprotective initiatives and maintenance of cardioprotective drugs after diagnosis, he said in an interview.
 

What Is Known About Statins and Breast Cancer?

Statins are the most common drugs used to lower cholesterol and may deprive tumor cells of the cholesterol needed for cell membrane synthesis, Mr. Harborg said in his presentation.

Data from a randomized trial published in the Journal of Clinical Oncology in 2017 showed significantly improved disease-free survival, breast cancer–free interval, and distant recurrence–free interval in early stage breast cancer patients randomized to cholesterol-lowering medication vs. those who did not receive cholesterol-lowering medication.

The 2017 study prompted the creation of the MASTER study, a randomized, multicenter, double-blind, placebo-controlled trial comparing standard adjuvant therapy plus placebo to standard adjuvant therapy plus atorvastatin in patients with early breast cancer (NCT04601116), Mr. Harborg said. The MASTER trial is currently recruiting patients in Denmark.
 

How Was the Current Study Designed?

To provide preliminary analysis, Mr. Harborg and colleagues used an emulation trial design based on electronic health care data from 110,160 females with a diagnosis of stage I, II, or III breast cancer who were part of the Danish Breast Cancer Group, a national clinical registry in Denmark, between 2000 and 2020.

As defined in the European Journal of Epidemiology in 2017, target trial emulation involves application of randomized trial designs to observational data with the goal of improving the quality of observational epidemiology when a comparator trial is not yet available.

The researchers created a cohort of patients based on electronic health care data to simulate a target trial of the use of atorvastatin after breast cancer diagnosis. Patients were randomized to one of two treatment strategies: starting to use statins within 36 months of diagnosis, or not using statins. The primary outcome was death from breast cancer. The follow-up for the MASTER study starts with inclusion and ends with death, emigration from Denmark, end of clinical follow-up, or 10 years of follow-up (whichever comes first); the follow-up was the same in the current study.

The researchers calculated hazard ratios (HR) of breast cancer mortality in statin users vs. non–statin users and used a technique known as inverse-probability of censoring-weighting (IPCW) to estimate the effects of statin use based on prognostic factors.
 

What Did the Results Show?

The results favored statin use for improved survival in early breast cancer patients, Mr. Harborg said. Overall, the hazard ratio for breast cancer mortality was 0.96 in statin users compared with non–statin users, and was similar in both a Cox regression analysis (HR 0.81), and in a 10-year landmark analysis (HR 0.86).

The difference in mortality between statin and non–statin users was even stronger in patients who were receiving adjuvant chemotherapy (HR 0.94, 0.64, and 0.76 on the IPCW, Cox, and landmark analyses, respectively).

The results were in line with previous reports of statins’ effect on breast cancer survival, Mr. Harborg said in an interview.

“We believe the results encourage the continuous effort of the currently enrolling MASTER trial,” he said.

The results also suggest that deprescribing statins at the time of breast cancer diagnosis is not recommended, and that statin treatment can safely be prescribed to breast cancer patients with increased cardiovascular disease risk and/or dyslipidemia, Mr. Harborg said in the interview.
 

What Is the Takeaway Message for Clinical Practice?

“The clinical takeaway from our study is that statin use is associated with reduced risk of dying from breast cancer, but that it is not possible to determine the true effect of statins on breast cancer survival without a randomized, placebo-controlled trial,” Mr. Harborg told this publication. “Statins are inexpensive and well-tolerated drugs and may have a beneficial effect in terms of survival for breast cancer patients. However, with the current level of evidence [because the MASTER study is ongoing], we still cannot recommend that oncologists prescribe statins to prevent mortality from breast cancer,” he said.

What Are the Next Steps for Research?

The findings were limited by the study design, and real-world data are needed, Dr. Harborg said. Other limitations include the presence of residual bias, and the use of data based on prescription codes, but these were not considered to have an effect on the main conclusion of the study, Mr. Harborg said in the interview.

However, the results suggest that the addition of statins may improve outcomes for early breast cancer patients, especially when used with chemotherapy, and support the value of the ongoing MASTER study, he concluded.

Ultimately, the MASTER study will provide a more definitive answer to the question of whether statins should be added to the adjuvant treatment regimen of breast cancer to improve breast cancer outcomes, he said.
 

What Do Clinicians Think of the Study?

The current study is timely and highlights the need for phase 3 trials to examine the potential of statin use for breast cancer outcomes, Malinda T. West, MD, a medical oncologist and breast oncologist at the University of Wisconsin Carbone Cancer Center, Madison, said in an interview.

Questions for future research include whether statins can be used in combination with adjuvant abemaciclib if indicated, or how to best sequence these agents, said Dr. West, who was not involved in the study. Other questions raised by the current study include whether other cholesterol-lowering agents have a potential adjuvant benefit in reducing breast cancer recurrent and/or mortality, and whether the addition of statins would benefit subgroups such as HER2+ and triple negative breast cancer, she said.

“I was not surprised to see another study reporting benefit with statins and reduced risk of breast cancer recurrence and/or mortality, but I think the larger question is defining the subgroups who benefit the most, and identifying predictors for benefit or resistance,” Dr. West said in an interview.

Previous studies have shown that cholesterol elevation, specifically LDL levels, can be linked to increased tumor growth in breast cancer, so the lower mortality risk associated with lipid-lowering therapies in the current study was consistent, Peyton L. Reves, MD, a hematology/oncology fellow, also at the University of Wisconsin, said in an interview. In practice, data from the current study and previous research could be especially useful for patients with elevated LDL levels, said Dr. Reves, who was not involved in the study.

“These results could impact clinical practice in many ways, including leading to routine cholesterol monitoring in breast cancer patients on adjuvant therapy as well as the addition of lipid-lowering therapy with statins in these patients,” Dr. Reves said.

The findings showing particular benefit for patients on adjuvant chemotherapy highlight the need for more research on this specific population and the effect of statins on overall breast cancer mortality, to explore the extent to which the results of the current study were driven by the benefit seen in patients receiving adjuvant chemotherapy, Dr. Reves said.

The study was supported by Director Michael Hermann Nielsen’s Memorial Grant, Manufacturer Einar Willumsen’s Memorial Grant, Astrid Thaysen’s Grant for Medical Basic Research, Eva and Henry Fraenkel’s Memorial Fund, and the Novo Nordisk Foundation.

The researchers had no financial conflicts to disclose. Dr. West and Dr. Reves had no financial conflicts to disclose.

A California jury has awarded $14 million to a former University of California, Los Angeles (UCLA) oncologist who claimed she was paid thousands less than her male colleagues and wrongfully terminated after her complaints of gender-based harassment and intimidation were ignored by program leadership.

The decision comes after a lengthy 8-year legal battle in which an appellate judge reversed a previous jury decision in her favor.

Lauren Pinter-Brown, MD, a hematologic oncologist, was hired in 2005 by the University of California, Los Angeles School of Medicine — now called UCLA’s David Geffen School of Medicine. As the school’s lymphoma program director, she conducted clinical research alongside other oncology doctors, including Sven de Vos, MD.

She claimed that her professional relationship with Dr. de Vos became contentious after he demonstrated “oppositional” and “disrespectful” behavior at team meetings, such as talking over her and turning his chair so Dr. Pinter-Brown faced his back. Court documents indicated that Dr. de Vos refused to use Dr. Pinter-Brown’s title in front of colleagues despite doing so for male counterparts.

Dr. Pinter-Brown argued that she was treated as the “butt of a joke” by Dr. de Vos and other male colleagues. In 2016, she sued Dr. de Vos, the university, and its governing body, the Board of Regents, for wrongful termination.

She was awarded a $13 million verdict in 2018. However, the California Court of Appeals overturned it in 2020 after concluding that several mistakes during the court proceedings impeded the school’s right to a fair and impartial trial. The case was retried, culminating in the even higher award of $14 million issued on May 9.

“Two juries have come to virtually identical findings showing multiple problems at UCLA involving gender discrimination,” Dr. Pinter-Brown’s attorney, Carney R. Shegerian, JD, told this news organization.

A spokesperson from UCLA’s David Geffen School of Medicine said administrators are carefully reviewing the new decision.

The spokesperson told this news organization that the medical school and its health system remain “deeply committed to maintaining a workplace free from discrimination, intimidation, retaliation, or harassment of any kind” and fostering a “respectful and inclusive environment ... in research, medical education, and patient care.”
 

Gender Pay Disparities Persist in Medicine

The gender pay gap in medicine is well documented. The 2024 Medscape Physician Compensation Report found that male doctors earn about 29% more than their female counterparts, with the disparity growing larger among specialists. In addition, a recent JAMA Health Forum study found that male physicians earned 21%-24% more per hour than female physicians.

Dr. Pinter-Brown, who now works at the University of California, Irvine, alleged that she was paid $200,000 less annually, on average, than her male colleagues.

That’s not surprising, says Martha Gulati, MD, professor and director of preventive cardiology at Cedars-Sinai Smidt Heart Institute, Los Angeles. She coauthored a commentary about gender disparities in JAMA Network Open. Dr. Gulati told this news organization that even a “small” pay disparity of $100,000 annually adds up.

“Let’s say the [male physician] invests it at 3% and adds to it yearly. Even without a raise, in 20 years, that is approximately $3 million,” Dr. Gulati explained. “Once you find out you are paid less than your male colleagues, you are upset. Your sense of value and self-worth disappears.”

Eileen Barrett, MD, MPH, president-elect of the American Medical Women’s Association, said that gender discrimination is likely more prevalent than research indicates. She told this news organization that self-doubt and fear of retaliation keep many from exposing the mistreatment.

Although more women are entering medicine, too few rise to the highest positions, Dr. Barrett said.

“Unfortunately, many are pulled and pushed into specialties and subspecialties that have lower compensation and are not promoted to leadership, so just having numbers isn’t enough to achieve equity,” Dr. Barrett said.

Dr. Pinter-Brown claimed she was repeatedly harassed and intimidated by Dr. de Vos from 2008 to 2015. Despite voicing concerns multiple times about the discriminatory behavior, the only resolutions offered by the male-dominated program leadership were for her to separate from the group and conduct lymphoma research independently or to avoid interacting with Dr. de Vos, court records said.

Even the school’s male Title IX officer, Jan Tillisch, MD, who handled gender-based discrimination complaints, reportedly made sexist comments. When Dr. Pinter-Brown sought his help, he allegedly told her that she had a reputation as an “angry woman” and “diva,” court records showed.

According to court documents, Dr. Pinter-Brown endured nitpicking and research audits as retaliation for speaking out, temporarily suspending her research privileges. She said she was subsequently removed from the director position and replaced by Dr. de Vos.

Female physicians who report discriminatory behavior often have unfavorable outcomes and risk future career prospects, Dr. Gulati said.

To shift this dynamic, she said institutions must increase transparency and practices that support female doctors receiving “equal pay for equal work.”
 

A version of this article appeared on Medscape.com.

A California jury has awarded $14 million to a former University of California, Los Angeles (UCLA) oncologist who claimed she was paid thousands less than her male colleagues and wrongfully terminated after her complaints of gender-based harassment and intimidation were ignored by program leadership.

The decision comes after a lengthy 8-year legal battle in which an appellate judge reversed a previous jury decision in her favor.

Lauren Pinter-Brown, MD, a hematologic oncologist, was hired in 2005 by the University of California, Los Angeles School of Medicine — now called UCLA’s David Geffen School of Medicine. As the school’s lymphoma program director, she conducted clinical research alongside other oncology doctors, including Sven de Vos, MD.

She claimed that her professional relationship with Dr. de Vos became contentious after he demonstrated “oppositional” and “disrespectful” behavior at team meetings, such as talking over her and turning his chair so Dr. Pinter-Brown faced his back. Court documents indicated that Dr. de Vos refused to use Dr. Pinter-Brown’s title in front of colleagues despite doing so for male counterparts.

Dr. Pinter-Brown argued that she was treated as the “butt of a joke” by Dr. de Vos and other male colleagues. In 2016, she sued Dr. de Vos, the university, and its governing body, the Board of Regents, for wrongful termination.

She was awarded a $13 million verdict in 2018. However, the California Court of Appeals overturned it in 2020 after concluding that several mistakes during the court proceedings impeded the school’s right to a fair and impartial trial. The case was retried, culminating in the even higher award of $14 million issued on May 9.

“Two juries have come to virtually identical findings showing multiple problems at UCLA involving gender discrimination,” Dr. Pinter-Brown’s attorney, Carney R. Shegerian, JD, told this news organization.

A spokesperson from UCLA’s David Geffen School of Medicine said administrators are carefully reviewing the new decision.

The spokesperson told this news organization that the medical school and its health system remain “deeply committed to maintaining a workplace free from discrimination, intimidation, retaliation, or harassment of any kind” and fostering a “respectful and inclusive environment ... in research, medical education, and patient care.”
 

Gender Pay Disparities Persist in Medicine

The gender pay gap in medicine is well documented. The 2024 Medscape Physician Compensation Report found that male doctors earn about 29% more than their female counterparts, with the disparity growing larger among specialists. In addition, a recent JAMA Health Forum study found that male physicians earned 21%-24% more per hour than female physicians.

Dr. Pinter-Brown, who now works at the University of California, Irvine, alleged that she was paid $200,000 less annually, on average, than her male colleagues.

That’s not surprising, says Martha Gulati, MD, professor and director of preventive cardiology at Cedars-Sinai Smidt Heart Institute, Los Angeles. She coauthored a commentary about gender disparities in JAMA Network Open. Dr. Gulati told this news organization that even a “small” pay disparity of $100,000 annually adds up.

“Let’s say the [male physician] invests it at 3% and adds to it yearly. Even without a raise, in 20 years, that is approximately $3 million,” Dr. Gulati explained. “Once you find out you are paid less than your male colleagues, you are upset. Your sense of value and self-worth disappears.”

Eileen Barrett, MD, MPH, president-elect of the American Medical Women’s Association, said that gender discrimination is likely more prevalent than research indicates. She told this news organization that self-doubt and fear of retaliation keep many from exposing the mistreatment.

Although more women are entering medicine, too few rise to the highest positions, Dr. Barrett said.

“Unfortunately, many are pulled and pushed into specialties and subspecialties that have lower compensation and are not promoted to leadership, so just having numbers isn’t enough to achieve equity,” Dr. Barrett said.

Dr. Pinter-Brown claimed she was repeatedly harassed and intimidated by Dr. de Vos from 2008 to 2015. Despite voicing concerns multiple times about the discriminatory behavior, the only resolutions offered by the male-dominated program leadership were for her to separate from the group and conduct lymphoma research independently or to avoid interacting with Dr. de Vos, court records said.

Even the school’s male Title IX officer, Jan Tillisch, MD, who handled gender-based discrimination complaints, reportedly made sexist comments. When Dr. Pinter-Brown sought his help, he allegedly told her that she had a reputation as an “angry woman” and “diva,” court records showed.

According to court documents, Dr. Pinter-Brown endured nitpicking and research audits as retaliation for speaking out, temporarily suspending her research privileges. She said she was subsequently removed from the director position and replaced by Dr. de Vos.

Female physicians who report discriminatory behavior often have unfavorable outcomes and risk future career prospects, Dr. Gulati said.

To shift this dynamic, she said institutions must increase transparency and practices that support female doctors receiving “equal pay for equal work.”
 

A version of this article appeared on Medscape.com.

A California jury has awarded $14 million to a former University of California, Los Angeles (UCLA) oncologist who claimed she was paid thousands less than her male colleagues and wrongfully terminated after her complaints of gender-based harassment and intimidation were ignored by program leadership.

The decision comes after a lengthy 8-year legal battle in which an appellate judge reversed a previous jury decision in her favor.

Lauren Pinter-Brown, MD, a hematologic oncologist, was hired in 2005 by the University of California, Los Angeles School of Medicine — now called UCLA’s David Geffen School of Medicine. As the school’s lymphoma program director, she conducted clinical research alongside other oncology doctors, including Sven de Vos, MD.

She claimed that her professional relationship with Dr. de Vos became contentious after he demonstrated “oppositional” and “disrespectful” behavior at team meetings, such as talking over her and turning his chair so Dr. Pinter-Brown faced his back. Court documents indicated that Dr. de Vos refused to use Dr. Pinter-Brown’s title in front of colleagues despite doing so for male counterparts.

Dr. Pinter-Brown argued that she was treated as the “butt of a joke” by Dr. de Vos and other male colleagues. In 2016, she sued Dr. de Vos, the university, and its governing body, the Board of Regents, for wrongful termination.

She was awarded a $13 million verdict in 2018. However, the California Court of Appeals overturned it in 2020 after concluding that several mistakes during the court proceedings impeded the school’s right to a fair and impartial trial. The case was retried, culminating in the even higher award of $14 million issued on May 9.

“Two juries have come to virtually identical findings showing multiple problems at UCLA involving gender discrimination,” Dr. Pinter-Brown’s attorney, Carney R. Shegerian, JD, told this news organization.

A spokesperson from UCLA’s David Geffen School of Medicine said administrators are carefully reviewing the new decision.

The spokesperson told this news organization that the medical school and its health system remain “deeply committed to maintaining a workplace free from discrimination, intimidation, retaliation, or harassment of any kind” and fostering a “respectful and inclusive environment ... in research, medical education, and patient care.”
 

Gender Pay Disparities Persist in Medicine

The gender pay gap in medicine is well documented. The 2024 Medscape Physician Compensation Report found that male doctors earn about 29% more than their female counterparts, with the disparity growing larger among specialists. In addition, a recent JAMA Health Forum study found that male physicians earned 21%-24% more per hour than female physicians.

Dr. Pinter-Brown, who now works at the University of California, Irvine, alleged that she was paid $200,000 less annually, on average, than her male colleagues.

That’s not surprising, says Martha Gulati, MD, professor and director of preventive cardiology at Cedars-Sinai Smidt Heart Institute, Los Angeles. She coauthored a commentary about gender disparities in JAMA Network Open. Dr. Gulati told this news organization that even a “small” pay disparity of $100,000 annually adds up.

“Let’s say the [male physician] invests it at 3% and adds to it yearly. Even without a raise, in 20 years, that is approximately $3 million,” Dr. Gulati explained. “Once you find out you are paid less than your male colleagues, you are upset. Your sense of value and self-worth disappears.”

Eileen Barrett, MD, MPH, president-elect of the American Medical Women’s Association, said that gender discrimination is likely more prevalent than research indicates. She told this news organization that self-doubt and fear of retaliation keep many from exposing the mistreatment.

Although more women are entering medicine, too few rise to the highest positions, Dr. Barrett said.

“Unfortunately, many are pulled and pushed into specialties and subspecialties that have lower compensation and are not promoted to leadership, so just having numbers isn’t enough to achieve equity,” Dr. Barrett said.

Dr. Pinter-Brown claimed she was repeatedly harassed and intimidated by Dr. de Vos from 2008 to 2015. Despite voicing concerns multiple times about the discriminatory behavior, the only resolutions offered by the male-dominated program leadership were for her to separate from the group and conduct lymphoma research independently or to avoid interacting with Dr. de Vos, court records said.

Even the school’s male Title IX officer, Jan Tillisch, MD, who handled gender-based discrimination complaints, reportedly made sexist comments. When Dr. Pinter-Brown sought his help, he allegedly told her that she had a reputation as an “angry woman” and “diva,” court records showed.

According to court documents, Dr. Pinter-Brown endured nitpicking and research audits as retaliation for speaking out, temporarily suspending her research privileges. She said she was subsequently removed from the director position and replaced by Dr. de Vos.

Female physicians who report discriminatory behavior often have unfavorable outcomes and risk future career prospects, Dr. Gulati said.

To shift this dynamic, she said institutions must increase transparency and practices that support female doctors receiving “equal pay for equal work.”
 

A version of this article appeared on Medscape.com.

Tell someone you’re a doctor, and the reaction is often: “You must be rich.” But physicians who are just finishing medical school or are in their early careers might feel far from it. The average medical school debt is more than $200,000, with total debts including undergrad climbing well north of $250,000.

That leaves house-hunting physicians in a predicament. A key factor for lending institutions is the “debt to income” ratio, a calculation which indicates if you already have too much debt to pay your mortgage. That single equation could eliminate you from lenders’ mortgage requirements.

But young doctors are also in a unique situation. Yes, they carry above-average levels of debt, but they are on a path to substantial income in future years. That’s where the physician mortgage loan (PML) becomes a useful option. 

What Is a Physician Mortgage Loan?

A PML is designed to help physicians access mortgages despite large amounts of debt. They are also sometimes available to dentists, veterinarians, podiatrists, and others, according to Stephen Chang, MD, a radiologist, and a managing director at Acts Financial Advisors in McLean, Virginia.

The key features, according to James M. Dahle, MD, an emergency physician and founder of The White Coat Investor, include:

• No required down payment, which is typically 20% with a conventional loan.
• No private mortgage insurance (PMI). This is often a requirement of traditional loans, designed to protect the lender if the buyer misses payments. PMLs don’t involve PMI even if you don’t put down 20%.
• No pay stubs. With a conventional loan, pay stubs are often required to prove income level and reliability. PMLs will often allow an employment contract in place of those. 
• Different consideration of the student loan burden.

Those are the upsides, of course, but there may be downsides. Dr. Dahle said a PML might involve slightly higher rates and fees than a conventional mortgage does but not always.

Who Is Best Suited for a Physician Mortgage Loan?

Financial advisers caution that everyone should first consider their full financial picture before applying for a mortgage, PML or otherwise. “If you don’t have the money saved for a down payment, one can ask if you are financially prepared to purchase a home,” says Cobin Soelberg, MD, an anesthesiologist and owner of Greeley Wealth Management, a financial planning firm serving physician families in Bend, Oregon. 

If your savings are slim, you might need to build those accounts further before pursuing home ownership and the expenses that come along with it.

Your credit score can contribute to the equation. “With any loan product, we always recommend working to optimize your personal credit score as soon as possible before applying for a loan,” said Mark P. Eid, MD, a dermatologist and co–managing director (with Dr. Chang) at Act Financial Advisors. “Once you get into the high 700s, you’ve typically qualified for the best interest rates, so while that perfect 850 is nice to achieve, it’s by no means necessary.”

Also, assess your reasons for purchasing a home and whether it will fit your lifestyle in the coming years. “The main reason that [my wife and I] wanted to buy a home was for stability,” said Jordan Frey, MD, founder of The Prudent Plastic Surgeon. “After living in apartments for years, we wanted a place that was truly our own. We definitely felt disappointed and frustrated when worrying that our student debt may limit our ability to do this.”

Like many physicians, Dr. Frey had taken on a huge amount of debt, to the tune of half a million dollars in student loans and credit card debt when he finished training in 2020. The question Dr. Frey and his wife wrestled with was: “How much debt should we take on in addition to what we already have?”

What Are the Risks? What’s in the Fine Print?

The eased limitations of PMLs come with potential pitfalls, and physicians should not imagine that they have unlimited buying power.

“Many physicians buy more expensive or bigger houses than they need simply because banks are willing to lend physicians money,” Dr. Soelberg warns. “So, the doctor gets locked into a large mortgage and cannot build wealth, save for retirement, and repay their student loans.” 

As you shop around, beware of omissions and scams. When meeting with lenders, Dr. Frey recalled that some didn’t even present PMLs as an option, and others presented them with unfavorable terms. He was careful to look for disadvantages hidden in the fine print, such as a potential “big hike in the rate a year later.” 

But sometimes, a scam is not outright deception but is more like temptation. So it’s important to have your own best interests in mind without relying on lenders’ advice. 

“When we were shopping around, some mortgage lenders would [offer] $1.5 million, and we thought ‘that makes no sense,’ ” said Dr. Frey. “[Physicians] have big future income, which makes us attractive to these lenders. No one in their right mind would give a mortgage like this to anyone else. They aren’t worried about whether it’s a smart decision for you or not.” 

What Other Red Flags Should You Look Out for?

Dr. Frey recommends medical professionals beware of these red flags when shopping for PMLs:

• A request for any type of collateral, including your medical practice
• A rate that is much higher than others
• A lender is pushing you to borrow a higher amount than you’re comfortable with 
• A lender attempts to influence your decision about the size of your down payment

Remember, if you are choosing an adjustable-rate mortgage (ARM), your rate will recalibrate on the basis of the market’s rates — for better or worse. This means that your payment might be higher or lower, taking current interest rates into account, based on the market.

Looking back, Dr. Frey said he might reconsider his decision to use a 10-year ARM. He and his wife chose it because the rate was low at the time, and they planned to pay off the mortgage quickly or move before it went up. But the uncertainty added an element of pressure. 

How Can PMLs Contribute to Overall Financial Health?

Dr. Frey says his physician mortgage was “a huge advantage,” allowing him and his wife to put 0% down on their home without PMI. But most importantly, it fit within their overall financial plan, which included investing. “The money that we would have potentially used for a down payment, we used to buy a rental property, which then got us more income,” he says. 

Of course, buying a rental property is not the only path to financial health and freedom. Many people approach a home as an investment that will eventually become fully their own. Others might put that down payment toward building a safety net of savings accounts. 

Used strategically and intentionally, PMLs can put you on a more predictable financial path. And with less money stress, buying a home can be an exciting milestone as you plan your future and put down roots in a community.

A version of this article appeared on Medscape.com.

Tell someone you’re a doctor, and the reaction is often: “You must be rich.” But physicians who are just finishing medical school or are in their early careers might feel far from it. The average medical school debt is more than $200,000, with total debts including undergrad climbing well north of $250,000.

That leaves house-hunting physicians in a predicament. A key factor for lending institutions is the “debt to income” ratio, a calculation which indicates if you already have too much debt to pay your mortgage. That single equation could eliminate you from lenders’ mortgage requirements.

But young doctors are also in a unique situation. Yes, they carry above-average levels of debt, but they are on a path to substantial income in future years. That’s where the physician mortgage loan (PML) becomes a useful option. 

What Is a Physician Mortgage Loan?

A PML is designed to help physicians access mortgages despite large amounts of debt. They are also sometimes available to dentists, veterinarians, podiatrists, and others, according to Stephen Chang, MD, a radiologist, and a managing director at Acts Financial Advisors in McLean, Virginia.

The key features, according to James M. Dahle, MD, an emergency physician and founder of The White Coat Investor, include:

• No required down payment, which is typically 20% with a conventional loan.
• No private mortgage insurance (PMI). This is often a requirement of traditional loans, designed to protect the lender if the buyer misses payments. PMLs don’t involve PMI even if you don’t put down 20%.
• No pay stubs. With a conventional loan, pay stubs are often required to prove income level and reliability. PMLs will often allow an employment contract in place of those. 
• Different consideration of the student loan burden.

Those are the upsides, of course, but there may be downsides. Dr. Dahle said a PML might involve slightly higher rates and fees than a conventional mortgage does but not always.

Who Is Best Suited for a Physician Mortgage Loan?

Financial advisers caution that everyone should first consider their full financial picture before applying for a mortgage, PML or otherwise. “If you don’t have the money saved for a down payment, one can ask if you are financially prepared to purchase a home,” says Cobin Soelberg, MD, an anesthesiologist and owner of Greeley Wealth Management, a financial planning firm serving physician families in Bend, Oregon. 

If your savings are slim, you might need to build those accounts further before pursuing home ownership and the expenses that come along with it.

Your credit score can contribute to the equation. “With any loan product, we always recommend working to optimize your personal credit score as soon as possible before applying for a loan,” said Mark P. Eid, MD, a dermatologist and co–managing director (with Dr. Chang) at Act Financial Advisors. “Once you get into the high 700s, you’ve typically qualified for the best interest rates, so while that perfect 850 is nice to achieve, it’s by no means necessary.”

Also, assess your reasons for purchasing a home and whether it will fit your lifestyle in the coming years. “The main reason that [my wife and I] wanted to buy a home was for stability,” said Jordan Frey, MD, founder of The Prudent Plastic Surgeon. “After living in apartments for years, we wanted a place that was truly our own. We definitely felt disappointed and frustrated when worrying that our student debt may limit our ability to do this.”

Like many physicians, Dr. Frey had taken on a huge amount of debt, to the tune of half a million dollars in student loans and credit card debt when he finished training in 2020. The question Dr. Frey and his wife wrestled with was: “How much debt should we take on in addition to what we already have?”

What Are the Risks? What’s in the Fine Print?

The eased limitations of PMLs come with potential pitfalls, and physicians should not imagine that they have unlimited buying power.

“Many physicians buy more expensive or bigger houses than they need simply because banks are willing to lend physicians money,” Dr. Soelberg warns. “So, the doctor gets locked into a large mortgage and cannot build wealth, save for retirement, and repay their student loans.” 

As you shop around, beware of omissions and scams. When meeting with lenders, Dr. Frey recalled that some didn’t even present PMLs as an option, and others presented them with unfavorable terms. He was careful to look for disadvantages hidden in the fine print, such as a potential “big hike in the rate a year later.” 

But sometimes, a scam is not outright deception but is more like temptation. So it’s important to have your own best interests in mind without relying on lenders’ advice. 

“When we were shopping around, some mortgage lenders would [offer] $1.5 million, and we thought ‘that makes no sense,’ ” said Dr. Frey. “[Physicians] have big future income, which makes us attractive to these lenders. No one in their right mind would give a mortgage like this to anyone else. They aren’t worried about whether it’s a smart decision for you or not.” 

What Other Red Flags Should You Look Out for?

Dr. Frey recommends medical professionals beware of these red flags when shopping for PMLs:

• A request for any type of collateral, including your medical practice
• A rate that is much higher than others
• A lender is pushing you to borrow a higher amount than you’re comfortable with 
• A lender attempts to influence your decision about the size of your down payment

Remember, if you are choosing an adjustable-rate mortgage (ARM), your rate will recalibrate on the basis of the market’s rates — for better or worse. This means that your payment might be higher or lower, taking current interest rates into account, based on the market.

Looking back, Dr. Frey said he might reconsider his decision to use a 10-year ARM. He and his wife chose it because the rate was low at the time, and they planned to pay off the mortgage quickly or move before it went up. But the uncertainty added an element of pressure. 

How Can PMLs Contribute to Overall Financial Health?

Dr. Frey says his physician mortgage was “a huge advantage,” allowing him and his wife to put 0% down on their home without PMI. But most importantly, it fit within their overall financial plan, which included investing. “The money that we would have potentially used for a down payment, we used to buy a rental property, which then got us more income,” he says. 

Of course, buying a rental property is not the only path to financial health and freedom. Many people approach a home as an investment that will eventually become fully their own. Others might put that down payment toward building a safety net of savings accounts. 

Used strategically and intentionally, PMLs can put you on a more predictable financial path. And with less money stress, buying a home can be an exciting milestone as you plan your future and put down roots in a community.

A version of this article appeared on Medscape.com.

Tell someone you’re a doctor, and the reaction is often: “You must be rich.” But physicians who are just finishing medical school or are in their early careers might feel far from it. The average medical school debt is more than $200,000, with total debts including undergrad climbing well north of $250,000.

That leaves house-hunting physicians in a predicament. A key factor for lending institutions is the “debt to income” ratio, a calculation which indicates if you already have too much debt to pay your mortgage. That single equation could eliminate you from lenders’ mortgage requirements.

But young doctors are also in a unique situation. Yes, they carry above-average levels of debt, but they are on a path to substantial income in future years. That’s where the physician mortgage loan (PML) becomes a useful option. 

What Is a Physician Mortgage Loan?

A PML is designed to help physicians access mortgages despite large amounts of debt. They are also sometimes available to dentists, veterinarians, podiatrists, and others, according to Stephen Chang, MD, a radiologist, and a managing director at Acts Financial Advisors in McLean, Virginia.

The key features, according to James M. Dahle, MD, an emergency physician and founder of The White Coat Investor, include:

• No required down payment, which is typically 20% with a conventional loan.
• No private mortgage insurance (PMI). This is often a requirement of traditional loans, designed to protect the lender if the buyer misses payments. PMLs don’t involve PMI even if you don’t put down 20%.
• No pay stubs. With a conventional loan, pay stubs are often required to prove income level and reliability. PMLs will often allow an employment contract in place of those. 
• Different consideration of the student loan burden.

Those are the upsides, of course, but there may be downsides. Dr. Dahle said a PML might involve slightly higher rates and fees than a conventional mortgage does but not always.

Who Is Best Suited for a Physician Mortgage Loan?

Financial advisers caution that everyone should first consider their full financial picture before applying for a mortgage, PML or otherwise. “If you don’t have the money saved for a down payment, one can ask if you are financially prepared to purchase a home,” says Cobin Soelberg, MD, an anesthesiologist and owner of Greeley Wealth Management, a financial planning firm serving physician families in Bend, Oregon. 

If your savings are slim, you might need to build those accounts further before pursuing home ownership and the expenses that come along with it.

Your credit score can contribute to the equation. “With any loan product, we always recommend working to optimize your personal credit score as soon as possible before applying for a loan,” said Mark P. Eid, MD, a dermatologist and co–managing director (with Dr. Chang) at Act Financial Advisors. “Once you get into the high 700s, you’ve typically qualified for the best interest rates, so while that perfect 850 is nice to achieve, it’s by no means necessary.”

Also, assess your reasons for purchasing a home and whether it will fit your lifestyle in the coming years. “The main reason that [my wife and I] wanted to buy a home was for stability,” said Jordan Frey, MD, founder of The Prudent Plastic Surgeon. “After living in apartments for years, we wanted a place that was truly our own. We definitely felt disappointed and frustrated when worrying that our student debt may limit our ability to do this.”

Like many physicians, Dr. Frey had taken on a huge amount of debt, to the tune of half a million dollars in student loans and credit card debt when he finished training in 2020. The question Dr. Frey and his wife wrestled with was: “How much debt should we take on in addition to what we already have?”

What Are the Risks? What’s in the Fine Print?

The eased limitations of PMLs come with potential pitfalls, and physicians should not imagine that they have unlimited buying power.

“Many physicians buy more expensive or bigger houses than they need simply because banks are willing to lend physicians money,” Dr. Soelberg warns. “So, the doctor gets locked into a large mortgage and cannot build wealth, save for retirement, and repay their student loans.” 

As you shop around, beware of omissions and scams. When meeting with lenders, Dr. Frey recalled that some didn’t even present PMLs as an option, and others presented them with unfavorable terms. He was careful to look for disadvantages hidden in the fine print, such as a potential “big hike in the rate a year later.” 

But sometimes, a scam is not outright deception but is more like temptation. So it’s important to have your own best interests in mind without relying on lenders’ advice. 

“When we were shopping around, some mortgage lenders would [offer] $1.5 million, and we thought ‘that makes no sense,’ ” said Dr. Frey. “[Physicians] have big future income, which makes us attractive to these lenders. No one in their right mind would give a mortgage like this to anyone else. They aren’t worried about whether it’s a smart decision for you or not.” 

What Other Red Flags Should You Look Out for?

Dr. Frey recommends medical professionals beware of these red flags when shopping for PMLs:

• A request for any type of collateral, including your medical practice
• A rate that is much higher than others
• A lender is pushing you to borrow a higher amount than you’re comfortable with 
• A lender attempts to influence your decision about the size of your down payment

Remember, if you are choosing an adjustable-rate mortgage (ARM), your rate will recalibrate on the basis of the market’s rates — for better or worse. This means that your payment might be higher or lower, taking current interest rates into account, based on the market.

Looking back, Dr. Frey said he might reconsider his decision to use a 10-year ARM. He and his wife chose it because the rate was low at the time, and they planned to pay off the mortgage quickly or move before it went up. But the uncertainty added an element of pressure. 

How Can PMLs Contribute to Overall Financial Health?

Dr. Frey says his physician mortgage was “a huge advantage,” allowing him and his wife to put 0% down on their home without PMI. But most importantly, it fit within their overall financial plan, which included investing. “The money that we would have potentially used for a down payment, we used to buy a rental property, which then got us more income,” he says. 

Of course, buying a rental property is not the only path to financial health and freedom. Many people approach a home as an investment that will eventually become fully their own. Others might put that down payment toward building a safety net of savings accounts. 

Used strategically and intentionally, PMLs can put you on a more predictable financial path. And with less money stress, buying a home can be an exciting milestone as you plan your future and put down roots in a community.

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — Early reduction of blood pressure has a beneficial effect in hemorrhagic stroke but a detrimental effect in ischemic stroke, new trial data show. The findings could shake up recommendations on control of blood pressure in acute stroke patients. 

“This is the first time that we have randomized evidence of blood pressure control prior to reperfusion in ischemic stroke patients, and our data will challenge the current guidelines that recommend lowering blood pressure to below 180 mm Hg systolic in these patients,” said study coauthor Craig Anderson, MD, George Institute for Global Health, Sydney, Australia. 

“And this study also clearly shows for the first time that getting blood pressure under control in hemorrhagic stroke patients in the first couple of hours has definitive benefits,” he added.

The findings were presented on May 16 at the European Stroke Organization Conference (ESOC) annual meeting and published online simultaneously in The New England Journal of Medicine. 

A Test of Early BP Control

The trial was conducted to test the strategy of very early blood pressure control during patient transport in an ambulance after acute stroke, which investigators suspected could benefit patients with both types of stroke. 

The hypothesis was that this would reduce bleeding in the brain for those with hemorrhagic stroke. For ischemic stroke patients, it was thought this strategy would speed up administration of thrombolysis, because guidelines recommend bringing blood pressure under control before thrombolysis. 

For the INTERACT4 trial, which was conducted in China, 2404 patients with suspected acute stroke and elevated systolic blood pressure (≥ 150 mm Hg) who were assessed in the ambulance within 2 hours after symptom onset were randomized to receive immediate treatment with intravenous urapidil to lower the systolic blood pressure or usual blood pressure management (usual care group).

The median time between symptom onset and randomization was 61 minutes, and the mean blood pressure at randomization was 178/98 mm Hg. 

Stroke was subsequently confirmed by imaging in 2240 patients, of whom 46% had a hemorrhagic stroke and 54% an ischemic stroke. 

At the time of arrival at the hospital, the mean systolic blood pressure in the intervention group was 158 mm Hg, compared with 170 mm Hg in the usual care group. 

The primary efficacy outcome was functional status as assessed by modified Rankin scale score at 90 days. 

Overall, there was no difference between the two groups in terms of functional outcome scores (common odds ratio [OR], 1.00; 95% CI, 0.87-1.15), and the incidence of serious adverse events was similar. 

But the study showed very different results in patients with hemorrhagic stroke vs those with ischemic stroke. 

Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common OR, 0.75; 95% CI, 0.60-0.92) but an increase in poor outcomes among patients with cerebral ischemia (common OR, 1.30; 95% CI, 1.06-1.60).

‘Slam-Dunk’ Effect 

Anderson has led several previous trials of blood pressure control in stroke patients, some of which have suggested benefit of lowering blood pressure in those with hemorrhagic stroke, but he says the results of the current trial are more clear-cut.

“We have never seen such a slam-dunk effect as there was in INTERACT4,” Dr. Anderson said. “Not only did we show that early reduction of blood pressure in hemorrhagic stroke patients improved functional outcome, it also reduced bleeding in the brain, improved survival and quality of life, and reduced surgery and infection complications. That’s quite remarkable.”

The findings offer “clear evidence that for patients with hemorrhagic stroke, we must get the blood pressure under control as soon as possible and introduce systems of care to ensure this happens,” he added.

The reason for the clear findings in the current trial is probably the treatment time, Dr. Anderson said. 

“This is the first trial in which blood pressure has been controlled in the ambulance and occurred much earlier than in the previous trials.” 

Challenging Ischemic Stroke Guidelines

The INTERACT4 results in ischemic stroke patients are likely to be more controversial. 

“Our results are clearly challenging longstanding beliefs around blood pressure control in ischemic stroke prior to thrombolysis,” Dr. Anderson said. 

Current guidelines recommend a blood pressure < 185 mm Hg systolic before initiation of thrombolysis because of concerns about intracerebral hemorrhage, he noted. Often, blood pressure is lowered rapidly down to much lower levels in order give thrombolysis quickly. 

“Our results suggest this may not be a good idea,” Dr. Anderson said. “I think these data will shake us up a bit and make us more cautious about reducing blood pressure in these patients. Personally, I wouldn’t touch the blood pressure at all in ischemic stroke patients after these results.” 

He said the mechanisms behind the different stroke types would explain the results. 

“If a patient is bleeding, it makes sense that higher blood pressure would make that worse,” Dr. Anderson said. “But when a patient has a blocked artery and ischemia in the brain, it seems likely that the extra pressure is needed to keep oxygen delivery to the ischemic tissue.”

Accurate Diagnosis Necessary

Because it is not possible to make an accurate diagnosis between ischemic and hemorrhagic stroke without a CT scan, Dr. Anderson stressed that at the present time, no action on blood pressure can be taken in the ambulance. 

“There is a lot of interest in developing a lightweight brain scanner to be used in ambulances, but this won’t be routinely available for several years,” he said. “So for now, quick diagnosis of the type of stroke that is occurring on the patient’s arrival at the emergency department and, for hemorrhagic stroke patients, swift action to control blood pressure at this point is critical to preserving brain function.”

Commenting on the INTERACT4 results at the ESOC meeting, Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said this was a very important trial that would impact clinical practice. 

“The data really reinforce that hemorrhagic stroke patients must have their blood pressure reduced as soon as possible,” she stated. 

Dr. Sacco said the trial emphasizes the need to be able to distinguish between a hemorrhagic and ischemic stroke in a prehospital setting and supports the introduction of more mobile stroke units carrying CT scanners and calls for the development of biomarkers that can allow rapid differentiation between the two conditions. 

In an accompanying editorial, Jonathan Edlow, MD, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, points out several aspects of the trial that may potentially limit the generalizability of the findings. These include use of urapidil as the antihypertensive agent, which is unavailable in the United States; all patients being of Han Chinese ethnicity; and an unusually high sensitivity of initial CT scans in detecting visible signs of ischemia or infarction in patients in acute ischemic stroke. 

“These findings should be considered hypothesis-generating, and they make the case for validation of the trial results in other settings,” Dr. Edlow wrote. 

The INTERACT4 trial was funded by the National Health and Medical Research Council of Australia, the George Institute for Global Health, several Chinese healthcare institutions, and Takeda Pharmaceuticals China. Disclosures for study and editorial authors are provided in the original articles.

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — Early reduction of blood pressure has a beneficial effect in hemorrhagic stroke but a detrimental effect in ischemic stroke, new trial data show. The findings could shake up recommendations on control of blood pressure in acute stroke patients. 

“This is the first time that we have randomized evidence of blood pressure control prior to reperfusion in ischemic stroke patients, and our data will challenge the current guidelines that recommend lowering blood pressure to below 180 mm Hg systolic in these patients,” said study coauthor Craig Anderson, MD, George Institute for Global Health, Sydney, Australia. 

“And this study also clearly shows for the first time that getting blood pressure under control in hemorrhagic stroke patients in the first couple of hours has definitive benefits,” he added.

The findings were presented on May 16 at the European Stroke Organization Conference (ESOC) annual meeting and published online simultaneously in The New England Journal of Medicine. 

A Test of Early BP Control

The trial was conducted to test the strategy of very early blood pressure control during patient transport in an ambulance after acute stroke, which investigators suspected could benefit patients with both types of stroke. 

The hypothesis was that this would reduce bleeding in the brain for those with hemorrhagic stroke. For ischemic stroke patients, it was thought this strategy would speed up administration of thrombolysis, because guidelines recommend bringing blood pressure under control before thrombolysis. 

For the INTERACT4 trial, which was conducted in China, 2404 patients with suspected acute stroke and elevated systolic blood pressure (≥ 150 mm Hg) who were assessed in the ambulance within 2 hours after symptom onset were randomized to receive immediate treatment with intravenous urapidil to lower the systolic blood pressure or usual blood pressure management (usual care group).

The median time between symptom onset and randomization was 61 minutes, and the mean blood pressure at randomization was 178/98 mm Hg. 

Stroke was subsequently confirmed by imaging in 2240 patients, of whom 46% had a hemorrhagic stroke and 54% an ischemic stroke. 

At the time of arrival at the hospital, the mean systolic blood pressure in the intervention group was 158 mm Hg, compared with 170 mm Hg in the usual care group. 

The primary efficacy outcome was functional status as assessed by modified Rankin scale score at 90 days. 

Overall, there was no difference between the two groups in terms of functional outcome scores (common odds ratio [OR], 1.00; 95% CI, 0.87-1.15), and the incidence of serious adverse events was similar. 

But the study showed very different results in patients with hemorrhagic stroke vs those with ischemic stroke. 

Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common OR, 0.75; 95% CI, 0.60-0.92) but an increase in poor outcomes among patients with cerebral ischemia (common OR, 1.30; 95% CI, 1.06-1.60).

‘Slam-Dunk’ Effect 

Anderson has led several previous trials of blood pressure control in stroke patients, some of which have suggested benefit of lowering blood pressure in those with hemorrhagic stroke, but he says the results of the current trial are more clear-cut.

“We have never seen such a slam-dunk effect as there was in INTERACT4,” Dr. Anderson said. “Not only did we show that early reduction of blood pressure in hemorrhagic stroke patients improved functional outcome, it also reduced bleeding in the brain, improved survival and quality of life, and reduced surgery and infection complications. That’s quite remarkable.”

The findings offer “clear evidence that for patients with hemorrhagic stroke, we must get the blood pressure under control as soon as possible and introduce systems of care to ensure this happens,” he added.

The reason for the clear findings in the current trial is probably the treatment time, Dr. Anderson said. 

“This is the first trial in which blood pressure has been controlled in the ambulance and occurred much earlier than in the previous trials.” 

Challenging Ischemic Stroke Guidelines

The INTERACT4 results in ischemic stroke patients are likely to be more controversial. 

“Our results are clearly challenging longstanding beliefs around blood pressure control in ischemic stroke prior to thrombolysis,” Dr. Anderson said. 

Current guidelines recommend a blood pressure < 185 mm Hg systolic before initiation of thrombolysis because of concerns about intracerebral hemorrhage, he noted. Often, blood pressure is lowered rapidly down to much lower levels in order give thrombolysis quickly. 

“Our results suggest this may not be a good idea,” Dr. Anderson said. “I think these data will shake us up a bit and make us more cautious about reducing blood pressure in these patients. Personally, I wouldn’t touch the blood pressure at all in ischemic stroke patients after these results.” 

He said the mechanisms behind the different stroke types would explain the results. 

“If a patient is bleeding, it makes sense that higher blood pressure would make that worse,” Dr. Anderson said. “But when a patient has a blocked artery and ischemia in the brain, it seems likely that the extra pressure is needed to keep oxygen delivery to the ischemic tissue.”

Accurate Diagnosis Necessary

Because it is not possible to make an accurate diagnosis between ischemic and hemorrhagic stroke without a CT scan, Dr. Anderson stressed that at the present time, no action on blood pressure can be taken in the ambulance. 

“There is a lot of interest in developing a lightweight brain scanner to be used in ambulances, but this won’t be routinely available for several years,” he said. “So for now, quick diagnosis of the type of stroke that is occurring on the patient’s arrival at the emergency department and, for hemorrhagic stroke patients, swift action to control blood pressure at this point is critical to preserving brain function.”

Commenting on the INTERACT4 results at the ESOC meeting, Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said this was a very important trial that would impact clinical practice. 

“The data really reinforce that hemorrhagic stroke patients must have their blood pressure reduced as soon as possible,” she stated. 

Dr. Sacco said the trial emphasizes the need to be able to distinguish between a hemorrhagic and ischemic stroke in a prehospital setting and supports the introduction of more mobile stroke units carrying CT scanners and calls for the development of biomarkers that can allow rapid differentiation between the two conditions. 

In an accompanying editorial, Jonathan Edlow, MD, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, points out several aspects of the trial that may potentially limit the generalizability of the findings. These include use of urapidil as the antihypertensive agent, which is unavailable in the United States; all patients being of Han Chinese ethnicity; and an unusually high sensitivity of initial CT scans in detecting visible signs of ischemia or infarction in patients in acute ischemic stroke. 

“These findings should be considered hypothesis-generating, and they make the case for validation of the trial results in other settings,” Dr. Edlow wrote. 

The INTERACT4 trial was funded by the National Health and Medical Research Council of Australia, the George Institute for Global Health, several Chinese healthcare institutions, and Takeda Pharmaceuticals China. Disclosures for study and editorial authors are provided in the original articles.

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — Early reduction of blood pressure has a beneficial effect in hemorrhagic stroke but a detrimental effect in ischemic stroke, new trial data show. The findings could shake up recommendations on control of blood pressure in acute stroke patients. 

“This is the first time that we have randomized evidence of blood pressure control prior to reperfusion in ischemic stroke patients, and our data will challenge the current guidelines that recommend lowering blood pressure to below 180 mm Hg systolic in these patients,” said study coauthor Craig Anderson, MD, George Institute for Global Health, Sydney, Australia. 

“And this study also clearly shows for the first time that getting blood pressure under control in hemorrhagic stroke patients in the first couple of hours has definitive benefits,” he added.

The findings were presented on May 16 at the European Stroke Organization Conference (ESOC) annual meeting and published online simultaneously in The New England Journal of Medicine. 

A Test of Early BP Control

The trial was conducted to test the strategy of very early blood pressure control during patient transport in an ambulance after acute stroke, which investigators suspected could benefit patients with both types of stroke. 

The hypothesis was that this would reduce bleeding in the brain for those with hemorrhagic stroke. For ischemic stroke patients, it was thought this strategy would speed up administration of thrombolysis, because guidelines recommend bringing blood pressure under control before thrombolysis. 

For the INTERACT4 trial, which was conducted in China, 2404 patients with suspected acute stroke and elevated systolic blood pressure (≥ 150 mm Hg) who were assessed in the ambulance within 2 hours after symptom onset were randomized to receive immediate treatment with intravenous urapidil to lower the systolic blood pressure or usual blood pressure management (usual care group).

The median time between symptom onset and randomization was 61 minutes, and the mean blood pressure at randomization was 178/98 mm Hg. 

Stroke was subsequently confirmed by imaging in 2240 patients, of whom 46% had a hemorrhagic stroke and 54% an ischemic stroke. 

At the time of arrival at the hospital, the mean systolic blood pressure in the intervention group was 158 mm Hg, compared with 170 mm Hg in the usual care group. 

The primary efficacy outcome was functional status as assessed by modified Rankin scale score at 90 days. 

Overall, there was no difference between the two groups in terms of functional outcome scores (common odds ratio [OR], 1.00; 95% CI, 0.87-1.15), and the incidence of serious adverse events was similar. 

But the study showed very different results in patients with hemorrhagic stroke vs those with ischemic stroke. 

Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common OR, 0.75; 95% CI, 0.60-0.92) but an increase in poor outcomes among patients with cerebral ischemia (common OR, 1.30; 95% CI, 1.06-1.60).

‘Slam-Dunk’ Effect 

Anderson has led several previous trials of blood pressure control in stroke patients, some of which have suggested benefit of lowering blood pressure in those with hemorrhagic stroke, but he says the results of the current trial are more clear-cut.

“We have never seen such a slam-dunk effect as there was in INTERACT4,” Dr. Anderson said. “Not only did we show that early reduction of blood pressure in hemorrhagic stroke patients improved functional outcome, it also reduced bleeding in the brain, improved survival and quality of life, and reduced surgery and infection complications. That’s quite remarkable.”

The findings offer “clear evidence that for patients with hemorrhagic stroke, we must get the blood pressure under control as soon as possible and introduce systems of care to ensure this happens,” he added.

The reason for the clear findings in the current trial is probably the treatment time, Dr. Anderson said. 

“This is the first trial in which blood pressure has been controlled in the ambulance and occurred much earlier than in the previous trials.” 

Challenging Ischemic Stroke Guidelines

The INTERACT4 results in ischemic stroke patients are likely to be more controversial. 

“Our results are clearly challenging longstanding beliefs around blood pressure control in ischemic stroke prior to thrombolysis,” Dr. Anderson said. 

Current guidelines recommend a blood pressure < 185 mm Hg systolic before initiation of thrombolysis because of concerns about intracerebral hemorrhage, he noted. Often, blood pressure is lowered rapidly down to much lower levels in order give thrombolysis quickly. 

“Our results suggest this may not be a good idea,” Dr. Anderson said. “I think these data will shake us up a bit and make us more cautious about reducing blood pressure in these patients. Personally, I wouldn’t touch the blood pressure at all in ischemic stroke patients after these results.” 

He said the mechanisms behind the different stroke types would explain the results. 

“If a patient is bleeding, it makes sense that higher blood pressure would make that worse,” Dr. Anderson said. “But when a patient has a blocked artery and ischemia in the brain, it seems likely that the extra pressure is needed to keep oxygen delivery to the ischemic tissue.”

Accurate Diagnosis Necessary

Because it is not possible to make an accurate diagnosis between ischemic and hemorrhagic stroke without a CT scan, Dr. Anderson stressed that at the present time, no action on blood pressure can be taken in the ambulance. 

“There is a lot of interest in developing a lightweight brain scanner to be used in ambulances, but this won’t be routinely available for several years,” he said. “So for now, quick diagnosis of the type of stroke that is occurring on the patient’s arrival at the emergency department and, for hemorrhagic stroke patients, swift action to control blood pressure at this point is critical to preserving brain function.”

Commenting on the INTERACT4 results at the ESOC meeting, Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said this was a very important trial that would impact clinical practice. 

“The data really reinforce that hemorrhagic stroke patients must have their blood pressure reduced as soon as possible,” she stated. 

Dr. Sacco said the trial emphasizes the need to be able to distinguish between a hemorrhagic and ischemic stroke in a prehospital setting and supports the introduction of more mobile stroke units carrying CT scanners and calls for the development of biomarkers that can allow rapid differentiation between the two conditions. 

In an accompanying editorial, Jonathan Edlow, MD, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, points out several aspects of the trial that may potentially limit the generalizability of the findings. These include use of urapidil as the antihypertensive agent, which is unavailable in the United States; all patients being of Han Chinese ethnicity; and an unusually high sensitivity of initial CT scans in detecting visible signs of ischemia or infarction in patients in acute ischemic stroke. 

“These findings should be considered hypothesis-generating, and they make the case for validation of the trial results in other settings,” Dr. Edlow wrote. 

The INTERACT4 trial was funded by the National Health and Medical Research Council of Australia, the George Institute for Global Health, several Chinese healthcare institutions, and Takeda Pharmaceuticals China. Disclosures for study and editorial authors are provided in the original articles.

A version of this article appeared on Medscape.com.

For years, researchers and medical companies have explored low-field MRI systems (those with a magnetic field strength of less than 1 T) — searching for a feasible alternative to the loud, expensive machines requiring special rooms with shielding to block their powerful magnetic field.

Most low-field scanners in development are for brain scans only. In 2022, the US Food and Drug Administration (FDA) cleared the first portable MRI system — Hyperfine’s Swoop, designed for use at a patient’s bedside — for head and brain scans. But the technology has not been applied to whole-body MRI — until now.

In a new study published in Science, researchers from Hong Kong described a whole-body, ultra low–field MRI.

“This is a big breakthrough,” said Kevin Sheth, MD, director of the Yale Center for Brain & Mind Health, who was not involved in the study. “It is one of the first, if not the first, demonstrations of low-field MRI imaging for the entire body.”

The device uses a 0.05 T magnet — one sixtieth the magnetic field strength of the standard 3 T MRI model common in hospitals today, said lead author Ed Wu, PhD, professor of biomedical engineering at The University of Hong Kong.

Because the field strength is so low, no protective shielding is needed. Patients and bystanders can safely use smart phones . And the scanner is safe for patients with implanted devices, like a cochlear implant or pacemaker, or any metal on their body or clothes. No hearing protection is required, either, because the machine is so quiet.

If all goes well, the technology could be commercially available in as little as a few years, Dr. Wu said.

But first, funding and FDA approval would be needed. “A company is going to have to come along and say, ‘This looks fantastic. We’re going to commercialize this, and we’re going to go through this certification process,’ ” said Andrew Webb, PhD, professor of radiology and the founding director of the C.J. Gorter MRI Center at the Leiden University Medical Center, Leiden, the Netherlands. (Dr. Webb was not involved in the study.)
 

Improving Access to MRI

One hope for this technology is to bring MRI to more people worldwide. Africa has less than one MRI scanner per million residents, whereas the United States has about 40.

While a new 3 T machine can cost about $1 million, the low-field version is much cheaper — only about $22,000 in materials cost per scanner, according to Dr. Wu.

A low magnetic field means less electricity, too — the machine can be plugged into a standard wall outlet. And because a fully shielded room isn’t needed, that could save another $100,000 in materials, Dr. Webb said.

Its ease of use could improve accessibility in countries with limited training, Dr. Webb pointed out.

“To be a technician is 2-3 years training for a regular MRI machine, a lot of it to do safety, a lot of it to do very subtle planning,” said Webb. “These [low-field] systems are much simpler.”
 

Challenges and the Future

The prototype weighs about 1.5 tons or 3000 lb. (A 3 T MRI can weigh between 6 and 13 tons or 12,000 and 26,000 lb.) That might sound like a lot, but it’s comparable to a mobile CT scanner, which is designed to be moved from room to room. Plus, “its weight can be substantially reduced if further optimized,” Dr. Wu said.

One challenge with low-field MRIs is image quality, which tends to be not as clear and detailed as those from high-power machines. To address this, the research team used deep learning (artificial intelligence) to enhance the image quality. “Computing power and large-scale data underpin our success, which tackles the physics and math problems that are traditionally considered intractable in existing MRI methodology,” Dr. Wu said.

Dr. Webb said he was impressed by the image quality shown in the study. They “look much higher quality than you would expect from such a low-field system,” he said. Still, only healthy volunteers were scanned. The true test will be using it to view subtle pathologies, Dr. Webb said.

That’s what Dr. Wu and his team are working on now — taking scans to diagnose various medical conditions. His group’s brain-only version of the low-field MRI has been used for diagnosis, he noted.
 

A version of this article appeared on Medscape.com.

For years, researchers and medical companies have explored low-field MRI systems (those with a magnetic field strength of less than 1 T) — searching for a feasible alternative to the loud, expensive machines requiring special rooms with shielding to block their powerful magnetic field.

Most low-field scanners in development are for brain scans only. In 2022, the US Food and Drug Administration (FDA) cleared the first portable MRI system — Hyperfine’s Swoop, designed for use at a patient’s bedside — for head and brain scans. But the technology has not been applied to whole-body MRI — until now.

In a new study published in Science, researchers from Hong Kong described a whole-body, ultra low–field MRI.

“This is a big breakthrough,” said Kevin Sheth, MD, director of the Yale Center for Brain & Mind Health, who was not involved in the study. “It is one of the first, if not the first, demonstrations of low-field MRI imaging for the entire body.”

The device uses a 0.05 T magnet — one sixtieth the magnetic field strength of the standard 3 T MRI model common in hospitals today, said lead author Ed Wu, PhD, professor of biomedical engineering at The University of Hong Kong.

Because the field strength is so low, no protective shielding is needed. Patients and bystanders can safely use smart phones . And the scanner is safe for patients with implanted devices, like a cochlear implant or pacemaker, or any metal on their body or clothes. No hearing protection is required, either, because the machine is so quiet.

If all goes well, the technology could be commercially available in as little as a few years, Dr. Wu said.

But first, funding and FDA approval would be needed. “A company is going to have to come along and say, ‘This looks fantastic. We’re going to commercialize this, and we’re going to go through this certification process,’ ” said Andrew Webb, PhD, professor of radiology and the founding director of the C.J. Gorter MRI Center at the Leiden University Medical Center, Leiden, the Netherlands. (Dr. Webb was not involved in the study.)
 

Improving Access to MRI

One hope for this technology is to bring MRI to more people worldwide. Africa has less than one MRI scanner per million residents, whereas the United States has about 40.

While a new 3 T machine can cost about $1 million, the low-field version is much cheaper — only about $22,000 in materials cost per scanner, according to Dr. Wu.

A low magnetic field means less electricity, too — the machine can be plugged into a standard wall outlet. And because a fully shielded room isn’t needed, that could save another $100,000 in materials, Dr. Webb said.

Its ease of use could improve accessibility in countries with limited training, Dr. Webb pointed out.

“To be a technician is 2-3 years training for a regular MRI machine, a lot of it to do safety, a lot of it to do very subtle planning,” said Webb. “These [low-field] systems are much simpler.”
 

Challenges and the Future

The prototype weighs about 1.5 tons or 3000 lb. (A 3 T MRI can weigh between 6 and 13 tons or 12,000 and 26,000 lb.) That might sound like a lot, but it’s comparable to a mobile CT scanner, which is designed to be moved from room to room. Plus, “its weight can be substantially reduced if further optimized,” Dr. Wu said.

One challenge with low-field MRIs is image quality, which tends to be not as clear and detailed as those from high-power machines. To address this, the research team used deep learning (artificial intelligence) to enhance the image quality. “Computing power and large-scale data underpin our success, which tackles the physics and math problems that are traditionally considered intractable in existing MRI methodology,” Dr. Wu said.

Dr. Webb said he was impressed by the image quality shown in the study. They “look much higher quality than you would expect from such a low-field system,” he said. Still, only healthy volunteers were scanned. The true test will be using it to view subtle pathologies, Dr. Webb said.

That’s what Dr. Wu and his team are working on now — taking scans to diagnose various medical conditions. His group’s brain-only version of the low-field MRI has been used for diagnosis, he noted.
 

A version of this article appeared on Medscape.com.

For years, researchers and medical companies have explored low-field MRI systems (those with a magnetic field strength of less than 1 T) — searching for a feasible alternative to the loud, expensive machines requiring special rooms with shielding to block their powerful magnetic field.

Most low-field scanners in development are for brain scans only. In 2022, the US Food and Drug Administration (FDA) cleared the first portable MRI system — Hyperfine’s Swoop, designed for use at a patient’s bedside — for head and brain scans. But the technology has not been applied to whole-body MRI — until now.

In a new study published in Science, researchers from Hong Kong described a whole-body, ultra low–field MRI.

“This is a big breakthrough,” said Kevin Sheth, MD, director of the Yale Center for Brain & Mind Health, who was not involved in the study. “It is one of the first, if not the first, demonstrations of low-field MRI imaging for the entire body.”

The device uses a 0.05 T magnet — one sixtieth the magnetic field strength of the standard 3 T MRI model common in hospitals today, said lead author Ed Wu, PhD, professor of biomedical engineering at The University of Hong Kong.

Because the field strength is so low, no protective shielding is needed. Patients and bystanders can safely use smart phones . And the scanner is safe for patients with implanted devices, like a cochlear implant or pacemaker, or any metal on their body or clothes. No hearing protection is required, either, because the machine is so quiet.

If all goes well, the technology could be commercially available in as little as a few years, Dr. Wu said.

But first, funding and FDA approval would be needed. “A company is going to have to come along and say, ‘This looks fantastic. We’re going to commercialize this, and we’re going to go through this certification process,’ ” said Andrew Webb, PhD, professor of radiology and the founding director of the C.J. Gorter MRI Center at the Leiden University Medical Center, Leiden, the Netherlands. (Dr. Webb was not involved in the study.)
 

Improving Access to MRI

One hope for this technology is to bring MRI to more people worldwide. Africa has less than one MRI scanner per million residents, whereas the United States has about 40.

While a new 3 T machine can cost about $1 million, the low-field version is much cheaper — only about $22,000 in materials cost per scanner, according to Dr. Wu.

A low magnetic field means less electricity, too — the machine can be plugged into a standard wall outlet. And because a fully shielded room isn’t needed, that could save another $100,000 in materials, Dr. Webb said.

Its ease of use could improve accessibility in countries with limited training, Dr. Webb pointed out.

“To be a technician is 2-3 years training for a regular MRI machine, a lot of it to do safety, a lot of it to do very subtle planning,” said Webb. “These [low-field] systems are much simpler.”
 

Challenges and the Future

The prototype weighs about 1.5 tons or 3000 lb. (A 3 T MRI can weigh between 6 and 13 tons or 12,000 and 26,000 lb.) That might sound like a lot, but it’s comparable to a mobile CT scanner, which is designed to be moved from room to room. Plus, “its weight can be substantially reduced if further optimized,” Dr. Wu said.

One challenge with low-field MRIs is image quality, which tends to be not as clear and detailed as those from high-power machines. To address this, the research team used deep learning (artificial intelligence) to enhance the image quality. “Computing power and large-scale data underpin our success, which tackles the physics and math problems that are traditionally considered intractable in existing MRI methodology,” Dr. Wu said.

Dr. Webb said he was impressed by the image quality shown in the study. They “look much higher quality than you would expect from such a low-field system,” he said. Still, only healthy volunteers were scanned. The true test will be using it to view subtle pathologies, Dr. Webb said.

That’s what Dr. Wu and his team are working on now — taking scans to diagnose various medical conditions. His group’s brain-only version of the low-field MRI has been used for diagnosis, he noted.
 

A version of this article appeared on Medscape.com.

For decades, physicians and nurses who ventured across state lines to practice, particularly in locum tenens roles, have reaped the benefits of medical licensure compacts. Yet, the same courtesy has eluded physician assistants (PAs), until now. The introduction of the PA Licensure Compact (PA Compact) marks a long-awaited and significant step forward for the PA community.

In April, Virginia Governor Glenn Youngkin signed the bill enacting the PA Compact making Virginia the seventh state to join. The legislation opens a cross-state agreement with seven states and finally allows locum tenens PAs to practice across these state’s borders.

How the PA Compact Works

The interstate arrangement recognizes valid, unencumbered PA licenses issued by other states in the compact. PAs working within the seven states won’t need a separate license from any of those states to practice.

The states include Delaware, Nebraska, Utah, Washington, West Virginia, Wisconsin, and Virginia. While the compact has been approved, the American Academy of Physician Associates said it could take an additional 18-24 months for the states to execute it, giving PAs the access they need to work in the compact states.

How the PA Compact Helps

The PA Compact holds the promise of alleviating some of the travel barriers that PAs often encounter, especially when they work locum tenens or in telehealth and must traverse state lines to deliver essential healthcare. This agreement not only enhances healthcare access but also empowers facilities to recruit new PAs, thereby bridging gaps in their healthcare staffing and addressing public health emergencies more effectively.

PAs will also gain increased flexibility and additional opportunities to earn and benefit from the right to practice in more states without requiring a time-consuming and expensive licensure from each state.

One motivating factor behind developing an interstate compact for physician assistants is that the same types of compacts for physicians and nurses are highly successful. The Nurse Licensure Compact and the Interstate Medical Licensure Compact for physicians encompass 37 and 41 states, respectively. While the seven-state PA Compact is in its earliest stages, it will likely be equally beneficial for PAs.

A survey by Barton Associates found that 95% of PAs said they would be more likely to consider working in a different state if the PA Compact made it more accessible.

Other states have begun legislation to enact a PA Compact, including Colorado, New Hampshire, Maine, Michigan New York, Ohio, Oklahoma, Rhode Island, Tennessee, and Vermont. 

If your state still needs to enact a compact or file for compact legislation, let your elected officials know that the PAs in your state want to join a compact. 
 

A version of this article appeared on Medscape.com .

For decades, physicians and nurses who ventured across state lines to practice, particularly in locum tenens roles, have reaped the benefits of medical licensure compacts. Yet, the same courtesy has eluded physician assistants (PAs), until now. The introduction of the PA Licensure Compact (PA Compact) marks a long-awaited and significant step forward for the PA community.

In April, Virginia Governor Glenn Youngkin signed the bill enacting the PA Compact making Virginia the seventh state to join. The legislation opens a cross-state agreement with seven states and finally allows locum tenens PAs to practice across these state’s borders.

How the PA Compact Works

The interstate arrangement recognizes valid, unencumbered PA licenses issued by other states in the compact. PAs working within the seven states won’t need a separate license from any of those states to practice.

The states include Delaware, Nebraska, Utah, Washington, West Virginia, Wisconsin, and Virginia. While the compact has been approved, the American Academy of Physician Associates said it could take an additional 18-24 months for the states to execute it, giving PAs the access they need to work in the compact states.

How the PA Compact Helps

The PA Compact holds the promise of alleviating some of the travel barriers that PAs often encounter, especially when they work locum tenens or in telehealth and must traverse state lines to deliver essential healthcare. This agreement not only enhances healthcare access but also empowers facilities to recruit new PAs, thereby bridging gaps in their healthcare staffing and addressing public health emergencies more effectively.

PAs will also gain increased flexibility and additional opportunities to earn and benefit from the right to practice in more states without requiring a time-consuming and expensive licensure from each state.

One motivating factor behind developing an interstate compact for physician assistants is that the same types of compacts for physicians and nurses are highly successful. The Nurse Licensure Compact and the Interstate Medical Licensure Compact for physicians encompass 37 and 41 states, respectively. While the seven-state PA Compact is in its earliest stages, it will likely be equally beneficial for PAs.

A survey by Barton Associates found that 95% of PAs said they would be more likely to consider working in a different state if the PA Compact made it more accessible.

Other states have begun legislation to enact a PA Compact, including Colorado, New Hampshire, Maine, Michigan New York, Ohio, Oklahoma, Rhode Island, Tennessee, and Vermont. 

If your state still needs to enact a compact or file for compact legislation, let your elected officials know that the PAs in your state want to join a compact. 
 

A version of this article appeared on Medscape.com .

For decades, physicians and nurses who ventured across state lines to practice, particularly in locum tenens roles, have reaped the benefits of medical licensure compacts. Yet, the same courtesy has eluded physician assistants (PAs), until now. The introduction of the PA Licensure Compact (PA Compact) marks a long-awaited and significant step forward for the PA community.

In April, Virginia Governor Glenn Youngkin signed the bill enacting the PA Compact making Virginia the seventh state to join. The legislation opens a cross-state agreement with seven states and finally allows locum tenens PAs to practice across these state’s borders.

How the PA Compact Works

The interstate arrangement recognizes valid, unencumbered PA licenses issued by other states in the compact. PAs working within the seven states won’t need a separate license from any of those states to practice.

The states include Delaware, Nebraska, Utah, Washington, West Virginia, Wisconsin, and Virginia. While the compact has been approved, the American Academy of Physician Associates said it could take an additional 18-24 months for the states to execute it, giving PAs the access they need to work in the compact states.

How the PA Compact Helps

The PA Compact holds the promise of alleviating some of the travel barriers that PAs often encounter, especially when they work locum tenens or in telehealth and must traverse state lines to deliver essential healthcare. This agreement not only enhances healthcare access but also empowers facilities to recruit new PAs, thereby bridging gaps in their healthcare staffing and addressing public health emergencies more effectively.

PAs will also gain increased flexibility and additional opportunities to earn and benefit from the right to practice in more states without requiring a time-consuming and expensive licensure from each state.

One motivating factor behind developing an interstate compact for physician assistants is that the same types of compacts for physicians and nurses are highly successful. The Nurse Licensure Compact and the Interstate Medical Licensure Compact for physicians encompass 37 and 41 states, respectively. While the seven-state PA Compact is in its earliest stages, it will likely be equally beneficial for PAs.

A survey by Barton Associates found that 95% of PAs said they would be more likely to consider working in a different state if the PA Compact made it more accessible.

Other states have begun legislation to enact a PA Compact, including Colorado, New Hampshire, Maine, Michigan New York, Ohio, Oklahoma, Rhode Island, Tennessee, and Vermont. 

If your state still needs to enact a compact or file for compact legislation, let your elected officials know that the PAs in your state want to join a compact. 
 

A version of this article appeared on Medscape.com .

Over the past few decades, the US Food and Drug Administration (FDA) has increasingly relied on surrogate measures such as blood tests instead of clinical outcomes for medication approvals. But critics say the agency lacks consistent standards to ensure the surrogate aligns with clinical outcomes that matter to patients — things like improvements in symptoms and gains in function.

Sometimes those decisions backfire. Consider: In July 2021, the FDA approved aducanumab for the treatment of Alzheimer’s disease, bucking the advice of an advisory panel for the agency that questioned the effectiveness of the medication. Regulators relied on data from the drugmaker, Biogen, showing the monoclonal antibody could reduce levels of amyloid beta plaques in blood — a surrogate marker officials hoped would translate to clinical benefit.

The FDA’s decision triggered significant controversy, and Biogen in January announced it is pulling it from the market this year, citing disappointing sales.

Although the case of aducanumab might seem extreme, given the stakes — Alzheimer’s remains a disease without an effective treatment — it’s far from unusual.

“When we prescribe a drug, there is an underlying assumption that the FDA has done its due diligence to confirm the drug is safe and of benefit,” said Reshma Ramachandran, MD, MPP, MHS, a researcher at Yale School of Medicine, New Haven, Connecticut, and a coauthor of a recent review of surrogate outcomes. “In fact, we found either no evidence or low-quality evidence.” Such markers are associated with clinical outcomes. “We just don’t know if they work meaningfully to treat the patient’s condition. The results were pretty shocking for us,” she said.

The FDA in 2018 released an Adult Surrogate Endpoint Table listing markers that can be used as substitutes for clinical outcomes to more quickly test, review, and approve new therapies. The analysis found the majority of these endpoints lacked subsequent confirmations, defined as published meta-analyses of clinical studies to validate the association between the marker and a clinical outcome important to patients.

In a paper published in JAMA, Dr. Ramachandran and her colleagues looked at 37 surrogate endpoints for nearly 3 dozen nononcologic diseases in the table.

Approval with surrogate markers implies responsibility for postapproval or validation studies — not just lab measures or imaging findings but mortality, morbidity, or improved quality of life, said Joshua D. Wallach, PhD, MS, assistant professor in the department of epidemiology at the Emory Rollins School of Public Health in Atlanta and lead author of the JAMA review.

Dr. Wallach said surrogate markers are easier to measure and do not require large and long trials. But the FDA has not provided clear rules for what makes a surrogate marker valid in clinical trials.

“They’ve said that at a minimum, it requires meta-analytical evidence from studies that have looked at the correlation or the association between the surrogate and the clinical outcome,” Dr. Wallach said. “Our understanding was that if that’s a minimum expectation, we should be able to find those studies in the literature. And the reality is that we were unable to find evidence from those types of studies supporting the association between the surrogate and the clinical outcome.”

Physicians generally do not receive training about the FDA approval process and the difference between biomarkers, surrogate markers, and clinical endpoints, Dr. Ramachandran said. “Our study shows that things are much more uncertain than we thought when it comes to the prescribing of new drugs,” she said.
 

Surrogate Markers on the Rise

Dr. Wallach’s group looked for published meta-analyses compiling randomized controlled trials reporting surrogate endpoints for more than 3 dozen chronic nononcologic conditions, including type 2 diabetes, Alzheimer’s, kidney disease, HIV, gout, and lupus. They found no meta-analyses at all for 59% of the surrogate markers, while for those that were studied, few reported high-strength evidence of an association with clinical outcomes.

The findings echo previous research. In a 2020 study in JAMA Network Open, researchers tallied primary endpoints for all FDA approvals of new drugs and therapies during three 3-year periods: 1995-1997, 2005-2007, and 2015-2017. The proportion of products whose approvals were based on the use of clinical endpoints decreased from 43.8% in 1995-1997 to 28.4% in 2005-2007 to 23.3% in 2015-2017. The share based on surrogate endpoints rose from 43.3% to roughly 60% over the same interval.

A 2017 study in the Journal of Health Economics found the use of “imperfect” surrogate endpoints helped support the approval of an average of 16 new drugs per year between 2010 and 2014 compared with six per year from 1998 to 2008.

Similar concerns about weak associations between surrogate markers and drugs used to treat cancer have been documented before, including in a 2020 study published in eClinicalMedicine. The researchers found the surrogate endpoints in the FDA table either were not tested or were tested but proven to be weak surrogates.

“And yet the FDA considered these as good enough not only for accelerated approval but also for regular approval,” said Bishal Gyawali, MD, PhD, associate professor in the department of oncology at Queen’s University, Kingston, Ontario, Canada, who led the group.

The use of surrogate endpoints is also increasing in Europe, said Huseyin Naci, MHS, PhD, associate professor of health policy at the London School of Economics and Political Science in England. He cited a cohort study of 298 randomized clinical trials (RCTs) in JAMA Oncology suggesting “contemporary oncology RCTs now largely measure putative surrogate endpoints.” Dr. Wallach called the FDA’s surrogate table “a great first step toward transparency. But a key column is missing from that table, telling us what is the basis for which the FDA allows drug companies to use the recognized surrogate markers. What is the evidence they are considering?”

If the agency allows companies the flexibility to validate surrogate endpoints, postmarketing studies designed to confirm the clinical utility of those endpoints should follow.

“We obviously want physicians to be guided by evidence when they’re selecting treatments, and they need to be able to interpret the clinical benefits of the drug that they’re prescribing,” he said. “This is really about having the research consumer, patients, and physicians, as well as industry, understand why certain markers are considered and not considered.”

Dr. Wallach reported receiving grants from the FDA (through the Yale University — Mayo Clinic Center of Excellence in Regulatory Science and Innovation), National Institute on Alcohol Abuse and Alcoholism (1K01AA028258), and Johnson & Johnson (through the Yale University Open Data Access Project); and consulting fees from Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC outside the submitted work. Dr. Ramachandran reported receiving grants from the Stavros Niarchos Foundation and FDA; receiving consulting fees from ReAct Action on Antibiotic Resistance strategy policy program outside the submitted work; and serving in an unpaid capacity as chair of the FDA task force for the nonprofit organization Doctors for America and in an unpaid capacity as board president for Universities Allied for Essential Medicines North America.
 

A version of this article appeared on Medscape.com.

Over the past few decades, the US Food and Drug Administration (FDA) has increasingly relied on surrogate measures such as blood tests instead of clinical outcomes for medication approvals. But critics say the agency lacks consistent standards to ensure the surrogate aligns with clinical outcomes that matter to patients — things like improvements in symptoms and gains in function.

Sometimes those decisions backfire. Consider: In July 2021, the FDA approved aducanumab for the treatment of Alzheimer’s disease, bucking the advice of an advisory panel for the agency that questioned the effectiveness of the medication. Regulators relied on data from the drugmaker, Biogen, showing the monoclonal antibody could reduce levels of amyloid beta plaques in blood — a surrogate marker officials hoped would translate to clinical benefit.

The FDA’s decision triggered significant controversy, and Biogen in January announced it is pulling it from the market this year, citing disappointing sales.

Although the case of aducanumab might seem extreme, given the stakes — Alzheimer’s remains a disease without an effective treatment — it’s far from unusual.

“When we prescribe a drug, there is an underlying assumption that the FDA has done its due diligence to confirm the drug is safe and of benefit,” said Reshma Ramachandran, MD, MPP, MHS, a researcher at Yale School of Medicine, New Haven, Connecticut, and a coauthor of a recent review of surrogate outcomes. “In fact, we found either no evidence or low-quality evidence.” Such markers are associated with clinical outcomes. “We just don’t know if they work meaningfully to treat the patient’s condition. The results were pretty shocking for us,” she said.

The FDA in 2018 released an Adult Surrogate Endpoint Table listing markers that can be used as substitutes for clinical outcomes to more quickly test, review, and approve new therapies. The analysis found the majority of these endpoints lacked subsequent confirmations, defined as published meta-analyses of clinical studies to validate the association between the marker and a clinical outcome important to patients.

In a paper published in JAMA, Dr. Ramachandran and her colleagues looked at 37 surrogate endpoints for nearly 3 dozen nononcologic diseases in the table.

Approval with surrogate markers implies responsibility for postapproval or validation studies — not just lab measures or imaging findings but mortality, morbidity, or improved quality of life, said Joshua D. Wallach, PhD, MS, assistant professor in the department of epidemiology at the Emory Rollins School of Public Health in Atlanta and lead author of the JAMA review.

Dr. Wallach said surrogate markers are easier to measure and do not require large and long trials. But the FDA has not provided clear rules for what makes a surrogate marker valid in clinical trials.

“They’ve said that at a minimum, it requires meta-analytical evidence from studies that have looked at the correlation or the association between the surrogate and the clinical outcome,” Dr. Wallach said. “Our understanding was that if that’s a minimum expectation, we should be able to find those studies in the literature. And the reality is that we were unable to find evidence from those types of studies supporting the association between the surrogate and the clinical outcome.”

Physicians generally do not receive training about the FDA approval process and the difference between biomarkers, surrogate markers, and clinical endpoints, Dr. Ramachandran said. “Our study shows that things are much more uncertain than we thought when it comes to the prescribing of new drugs,” she said.
 

Surrogate Markers on the Rise

Dr. Wallach’s group looked for published meta-analyses compiling randomized controlled trials reporting surrogate endpoints for more than 3 dozen chronic nononcologic conditions, including type 2 diabetes, Alzheimer’s, kidney disease, HIV, gout, and lupus. They found no meta-analyses at all for 59% of the surrogate markers, while for those that were studied, few reported high-strength evidence of an association with clinical outcomes.

The findings echo previous research. In a 2020 study in JAMA Network Open, researchers tallied primary endpoints for all FDA approvals of new drugs and therapies during three 3-year periods: 1995-1997, 2005-2007, and 2015-2017. The proportion of products whose approvals were based on the use of clinical endpoints decreased from 43.8% in 1995-1997 to 28.4% in 2005-2007 to 23.3% in 2015-2017. The share based on surrogate endpoints rose from 43.3% to roughly 60% over the same interval.

A 2017 study in the Journal of Health Economics found the use of “imperfect” surrogate endpoints helped support the approval of an average of 16 new drugs per year between 2010 and 2014 compared with six per year from 1998 to 2008.

Similar concerns about weak associations between surrogate markers and drugs used to treat cancer have been documented before, including in a 2020 study published in eClinicalMedicine. The researchers found the surrogate endpoints in the FDA table either were not tested or were tested but proven to be weak surrogates.

“And yet the FDA considered these as good enough not only for accelerated approval but also for regular approval,” said Bishal Gyawali, MD, PhD, associate professor in the department of oncology at Queen’s University, Kingston, Ontario, Canada, who led the group.

The use of surrogate endpoints is also increasing in Europe, said Huseyin Naci, MHS, PhD, associate professor of health policy at the London School of Economics and Political Science in England. He cited a cohort study of 298 randomized clinical trials (RCTs) in JAMA Oncology suggesting “contemporary oncology RCTs now largely measure putative surrogate endpoints.” Dr. Wallach called the FDA’s surrogate table “a great first step toward transparency. But a key column is missing from that table, telling us what is the basis for which the FDA allows drug companies to use the recognized surrogate markers. What is the evidence they are considering?”

If the agency allows companies the flexibility to validate surrogate endpoints, postmarketing studies designed to confirm the clinical utility of those endpoints should follow.

“We obviously want physicians to be guided by evidence when they’re selecting treatments, and they need to be able to interpret the clinical benefits of the drug that they’re prescribing,” he said. “This is really about having the research consumer, patients, and physicians, as well as industry, understand why certain markers are considered and not considered.”

Dr. Wallach reported receiving grants from the FDA (through the Yale University — Mayo Clinic Center of Excellence in Regulatory Science and Innovation), National Institute on Alcohol Abuse and Alcoholism (1K01AA028258), and Johnson & Johnson (through the Yale University Open Data Access Project); and consulting fees from Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC outside the submitted work. Dr. Ramachandran reported receiving grants from the Stavros Niarchos Foundation and FDA; receiving consulting fees from ReAct Action on Antibiotic Resistance strategy policy program outside the submitted work; and serving in an unpaid capacity as chair of the FDA task force for the nonprofit organization Doctors for America and in an unpaid capacity as board president for Universities Allied for Essential Medicines North America.
 

A version of this article appeared on Medscape.com.

Over the past few decades, the US Food and Drug Administration (FDA) has increasingly relied on surrogate measures such as blood tests instead of clinical outcomes for medication approvals. But critics say the agency lacks consistent standards to ensure the surrogate aligns with clinical outcomes that matter to patients — things like improvements in symptoms and gains in function.

Sometimes those decisions backfire. Consider: In July 2021, the FDA approved aducanumab for the treatment of Alzheimer’s disease, bucking the advice of an advisory panel for the agency that questioned the effectiveness of the medication. Regulators relied on data from the drugmaker, Biogen, showing the monoclonal antibody could reduce levels of amyloid beta plaques in blood — a surrogate marker officials hoped would translate to clinical benefit.

The FDA’s decision triggered significant controversy, and Biogen in January announced it is pulling it from the market this year, citing disappointing sales.

Although the case of aducanumab might seem extreme, given the stakes — Alzheimer’s remains a disease without an effective treatment — it’s far from unusual.

“When we prescribe a drug, there is an underlying assumption that the FDA has done its due diligence to confirm the drug is safe and of benefit,” said Reshma Ramachandran, MD, MPP, MHS, a researcher at Yale School of Medicine, New Haven, Connecticut, and a coauthor of a recent review of surrogate outcomes. “In fact, we found either no evidence or low-quality evidence.” Such markers are associated with clinical outcomes. “We just don’t know if they work meaningfully to treat the patient’s condition. The results were pretty shocking for us,” she said.

The FDA in 2018 released an Adult Surrogate Endpoint Table listing markers that can be used as substitutes for clinical outcomes to more quickly test, review, and approve new therapies. The analysis found the majority of these endpoints lacked subsequent confirmations, defined as published meta-analyses of clinical studies to validate the association between the marker and a clinical outcome important to patients.

In a paper published in JAMA, Dr. Ramachandran and her colleagues looked at 37 surrogate endpoints for nearly 3 dozen nononcologic diseases in the table.

Approval with surrogate markers implies responsibility for postapproval or validation studies — not just lab measures or imaging findings but mortality, morbidity, or improved quality of life, said Joshua D. Wallach, PhD, MS, assistant professor in the department of epidemiology at the Emory Rollins School of Public Health in Atlanta and lead author of the JAMA review.

Dr. Wallach said surrogate markers are easier to measure and do not require large and long trials. But the FDA has not provided clear rules for what makes a surrogate marker valid in clinical trials.

“They’ve said that at a minimum, it requires meta-analytical evidence from studies that have looked at the correlation or the association between the surrogate and the clinical outcome,” Dr. Wallach said. “Our understanding was that if that’s a minimum expectation, we should be able to find those studies in the literature. And the reality is that we were unable to find evidence from those types of studies supporting the association between the surrogate and the clinical outcome.”

Physicians generally do not receive training about the FDA approval process and the difference between biomarkers, surrogate markers, and clinical endpoints, Dr. Ramachandran said. “Our study shows that things are much more uncertain than we thought when it comes to the prescribing of new drugs,” she said.
 

Surrogate Markers on the Rise

Dr. Wallach’s group looked for published meta-analyses compiling randomized controlled trials reporting surrogate endpoints for more than 3 dozen chronic nononcologic conditions, including type 2 diabetes, Alzheimer’s, kidney disease, HIV, gout, and lupus. They found no meta-analyses at all for 59% of the surrogate markers, while for those that were studied, few reported high-strength evidence of an association with clinical outcomes.

The findings echo previous research. In a 2020 study in JAMA Network Open, researchers tallied primary endpoints for all FDA approvals of new drugs and therapies during three 3-year periods: 1995-1997, 2005-2007, and 2015-2017. The proportion of products whose approvals were based on the use of clinical endpoints decreased from 43.8% in 1995-1997 to 28.4% in 2005-2007 to 23.3% in 2015-2017. The share based on surrogate endpoints rose from 43.3% to roughly 60% over the same interval.

A 2017 study in the Journal of Health Economics found the use of “imperfect” surrogate endpoints helped support the approval of an average of 16 new drugs per year between 2010 and 2014 compared with six per year from 1998 to 2008.

Similar concerns about weak associations between surrogate markers and drugs used to treat cancer have been documented before, including in a 2020 study published in eClinicalMedicine. The researchers found the surrogate endpoints in the FDA table either were not tested or were tested but proven to be weak surrogates.

“And yet the FDA considered these as good enough not only for accelerated approval but also for regular approval,” said Bishal Gyawali, MD, PhD, associate professor in the department of oncology at Queen’s University, Kingston, Ontario, Canada, who led the group.

The use of surrogate endpoints is also increasing in Europe, said Huseyin Naci, MHS, PhD, associate professor of health policy at the London School of Economics and Political Science in England. He cited a cohort study of 298 randomized clinical trials (RCTs) in JAMA Oncology suggesting “contemporary oncology RCTs now largely measure putative surrogate endpoints.” Dr. Wallach called the FDA’s surrogate table “a great first step toward transparency. But a key column is missing from that table, telling us what is the basis for which the FDA allows drug companies to use the recognized surrogate markers. What is the evidence they are considering?”

If the agency allows companies the flexibility to validate surrogate endpoints, postmarketing studies designed to confirm the clinical utility of those endpoints should follow.

“We obviously want physicians to be guided by evidence when they’re selecting treatments, and they need to be able to interpret the clinical benefits of the drug that they’re prescribing,” he said. “This is really about having the research consumer, patients, and physicians, as well as industry, understand why certain markers are considered and not considered.”

Dr. Wallach reported receiving grants from the FDA (through the Yale University — Mayo Clinic Center of Excellence in Regulatory Science and Innovation), National Institute on Alcohol Abuse and Alcoholism (1K01AA028258), and Johnson & Johnson (through the Yale University Open Data Access Project); and consulting fees from Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC outside the submitted work. Dr. Ramachandran reported receiving grants from the Stavros Niarchos Foundation and FDA; receiving consulting fees from ReAct Action on Antibiotic Resistance strategy policy program outside the submitted work; and serving in an unpaid capacity as chair of the FDA task force for the nonprofit organization Doctors for America and in an unpaid capacity as board president for Universities Allied for Essential Medicines North America.
 

A version of this article appeared on Medscape.com.