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Single injection reduces blood pressure for 6 months: KARDIA-1
with what appeared to be an encouraging side-effect profile, in the phase 2 dose-ranging KARDIA-1 study.
“Our study demonstrates that either quarterly or biannual doses of zilebesiran can effectively and safely lower blood pressure in patients with uncontrolled hypertension,” said senior study investigator George Bakris, MD.
“Based on these results, zilebesiran has the potential to improve medication adherence, which will, in turn, reduce cardiovascular risk in people with hypertension,” added Dr. Bakris, who is professor of medicine and director of the Comprehensive Hypertension Center at the University of Chicago Medicine.
The KARDIA-1 study was presented at the American Heart Association scientific sessions.
Dr. Bakris noted that uncontrolled hypertension is a leading cause of morbidity and mortality, and despite availability of effective antihypertensives, many adults with hypertension are untreated, and up to 80% have uncontrolled disease, both globally and in the United States.
Zilebesiran is a subcutaneous RNA interference therapeutic that binds with high affinity to the hepatic asialoglycoprotein receptor, bringing about a reduction in the synthesis of angiotensinogen, the sole precursor of all angiotensin peptides. It is hoped that its hepatocyte-targeted delivery may allow extrahepatic angiotensinogen expression to be preserved, which could limit off-target effects in the kidney and other tissues.
The KARDIA-1 trial investigated the safety and efficacy of different doses of zilebesiran in patients with mild to moderate hypertension (systolic BP of 135-160 mm Hg), who are untreated or on stable therapy with up to two antihypertensive medications.
The study included 394 such patients (average baseline systolic BP was 142 mm Hg) who were randomly assigned to receive one of four different zilebesiran doses (150 mg, 300 mg, or 600 mg once every 6 months or 300 mg once every 2 months) or a placebo. The final analysis included 377 patients (56% men, 25% Black).
Results showed sustained reductions in serum angiotensinogen (between 88% and 98%) over the 6-month follow-up period.
Ambulatory systolic BP measured over 24 hours was significantly decreased with all zilebesiran regimens, with a mean reduction from baseline to month 6 of around 10 mm Hg in the three top doses studied and by around 14 mm Hg compared with placebo.
Patients receiving zilebesiran were more likely to achieve 24-hour average systolic BP measurements of 130 mm Hg or less at 6 months.
In addition, participants in all four zilebesiran groups consistently experienced significantly greater reductions in both daytime and nighttime systolic BP.
There were four nonserious adverse reactions leading to discontinuation in the zilebesiran groups: two instances of orthostatic hypotension, one of BP elevation, and one of injection site reaction.
Most hyperkalemia adverse events, which occurred in 6% of patients, were mild, did not require intervention, and generally resolved with repeat measurement; none were associated with acute kidney injury or led to study drug discontinuation. The incidence of hypotension events was low, and no clinically relevant changes in renal or hepatic function were observed, Dr. Bakris reported.
There was one death caused by cardiopulmonary arrest in a patient receiving zilebesiran 300 mg every 3 months, but this was not classified as drug related.
Zilebesiran is being further evaluated as an add-on therapy for treatment of hypertension in the ongoing KARDIA-2 phase 2 study.
Moderator of an AHA press conference at which the study was discussed, Sandra Taler, MD, professor of medicine at the Mayo Clinic, Rochester, Minn., said that “to have an injectable medicine that gives long-term blood pressure lowering is extremely exciting.”
Dr. Taler raised the point that some patients may not return for subsequent doses, but added that with subcutaneous dosing, administration at home may be a possibility.
Also commenting at the press conference, Keith Ferdinand, MD, professor of clinical medicine at Tulane University, New Orleans, said that this study “suggests we can now target the first step in the renin-angiotensin system – angiotensinogen – which then appears to lead to robust and continued blood pressure lowering for up to 6 months, which should improve adherence.”
Noting that only 50% of patients continue to take antihypertensive drugs after 1 year, Dr. Ferdinand added: “If we can increase adherence, we will increase efficacy and perhaps protect against some of the target organ damage.”
Designated discussant of the KARDIA-1 study at the AHA late-breaking clinical trial session, Anna Dominiczak, MD, University of Glasgow, noted that hypertension affects one in three adults worldwide, but only around 20% of people have it under control.
“An increase in the number of patients effectively treated for hypertension to levels observed in high-performing countries could prevent 76 million deaths, 120 million strokes, 79 million heart attacks, and 17 million cases of heart failure between now and 2050,” she said.
Dr. Bakris has received consulting fees from Alnylam Pharmaceuticals.
A version of this article first appeared on Medscape.com.
with what appeared to be an encouraging side-effect profile, in the phase 2 dose-ranging KARDIA-1 study.
“Our study demonstrates that either quarterly or biannual doses of zilebesiran can effectively and safely lower blood pressure in patients with uncontrolled hypertension,” said senior study investigator George Bakris, MD.
“Based on these results, zilebesiran has the potential to improve medication adherence, which will, in turn, reduce cardiovascular risk in people with hypertension,” added Dr. Bakris, who is professor of medicine and director of the Comprehensive Hypertension Center at the University of Chicago Medicine.
The KARDIA-1 study was presented at the American Heart Association scientific sessions.
Dr. Bakris noted that uncontrolled hypertension is a leading cause of morbidity and mortality, and despite availability of effective antihypertensives, many adults with hypertension are untreated, and up to 80% have uncontrolled disease, both globally and in the United States.
Zilebesiran is a subcutaneous RNA interference therapeutic that binds with high affinity to the hepatic asialoglycoprotein receptor, bringing about a reduction in the synthesis of angiotensinogen, the sole precursor of all angiotensin peptides. It is hoped that its hepatocyte-targeted delivery may allow extrahepatic angiotensinogen expression to be preserved, which could limit off-target effects in the kidney and other tissues.
The KARDIA-1 trial investigated the safety and efficacy of different doses of zilebesiran in patients with mild to moderate hypertension (systolic BP of 135-160 mm Hg), who are untreated or on stable therapy with up to two antihypertensive medications.
The study included 394 such patients (average baseline systolic BP was 142 mm Hg) who were randomly assigned to receive one of four different zilebesiran doses (150 mg, 300 mg, or 600 mg once every 6 months or 300 mg once every 2 months) or a placebo. The final analysis included 377 patients (56% men, 25% Black).
Results showed sustained reductions in serum angiotensinogen (between 88% and 98%) over the 6-month follow-up period.
Ambulatory systolic BP measured over 24 hours was significantly decreased with all zilebesiran regimens, with a mean reduction from baseline to month 6 of around 10 mm Hg in the three top doses studied and by around 14 mm Hg compared with placebo.
Patients receiving zilebesiran were more likely to achieve 24-hour average systolic BP measurements of 130 mm Hg or less at 6 months.
In addition, participants in all four zilebesiran groups consistently experienced significantly greater reductions in both daytime and nighttime systolic BP.
There were four nonserious adverse reactions leading to discontinuation in the zilebesiran groups: two instances of orthostatic hypotension, one of BP elevation, and one of injection site reaction.
Most hyperkalemia adverse events, which occurred in 6% of patients, were mild, did not require intervention, and generally resolved with repeat measurement; none were associated with acute kidney injury or led to study drug discontinuation. The incidence of hypotension events was low, and no clinically relevant changes in renal or hepatic function were observed, Dr. Bakris reported.
There was one death caused by cardiopulmonary arrest in a patient receiving zilebesiran 300 mg every 3 months, but this was not classified as drug related.
Zilebesiran is being further evaluated as an add-on therapy for treatment of hypertension in the ongoing KARDIA-2 phase 2 study.
Moderator of an AHA press conference at which the study was discussed, Sandra Taler, MD, professor of medicine at the Mayo Clinic, Rochester, Minn., said that “to have an injectable medicine that gives long-term blood pressure lowering is extremely exciting.”
Dr. Taler raised the point that some patients may not return for subsequent doses, but added that with subcutaneous dosing, administration at home may be a possibility.
Also commenting at the press conference, Keith Ferdinand, MD, professor of clinical medicine at Tulane University, New Orleans, said that this study “suggests we can now target the first step in the renin-angiotensin system – angiotensinogen – which then appears to lead to robust and continued blood pressure lowering for up to 6 months, which should improve adherence.”
Noting that only 50% of patients continue to take antihypertensive drugs after 1 year, Dr. Ferdinand added: “If we can increase adherence, we will increase efficacy and perhaps protect against some of the target organ damage.”
Designated discussant of the KARDIA-1 study at the AHA late-breaking clinical trial session, Anna Dominiczak, MD, University of Glasgow, noted that hypertension affects one in three adults worldwide, but only around 20% of people have it under control.
“An increase in the number of patients effectively treated for hypertension to levels observed in high-performing countries could prevent 76 million deaths, 120 million strokes, 79 million heart attacks, and 17 million cases of heart failure between now and 2050,” she said.
Dr. Bakris has received consulting fees from Alnylam Pharmaceuticals.
A version of this article first appeared on Medscape.com.
with what appeared to be an encouraging side-effect profile, in the phase 2 dose-ranging KARDIA-1 study.
“Our study demonstrates that either quarterly or biannual doses of zilebesiran can effectively and safely lower blood pressure in patients with uncontrolled hypertension,” said senior study investigator George Bakris, MD.
“Based on these results, zilebesiran has the potential to improve medication adherence, which will, in turn, reduce cardiovascular risk in people with hypertension,” added Dr. Bakris, who is professor of medicine and director of the Comprehensive Hypertension Center at the University of Chicago Medicine.
The KARDIA-1 study was presented at the American Heart Association scientific sessions.
Dr. Bakris noted that uncontrolled hypertension is a leading cause of morbidity and mortality, and despite availability of effective antihypertensives, many adults with hypertension are untreated, and up to 80% have uncontrolled disease, both globally and in the United States.
Zilebesiran is a subcutaneous RNA interference therapeutic that binds with high affinity to the hepatic asialoglycoprotein receptor, bringing about a reduction in the synthesis of angiotensinogen, the sole precursor of all angiotensin peptides. It is hoped that its hepatocyte-targeted delivery may allow extrahepatic angiotensinogen expression to be preserved, which could limit off-target effects in the kidney and other tissues.
The KARDIA-1 trial investigated the safety and efficacy of different doses of zilebesiran in patients with mild to moderate hypertension (systolic BP of 135-160 mm Hg), who are untreated or on stable therapy with up to two antihypertensive medications.
The study included 394 such patients (average baseline systolic BP was 142 mm Hg) who were randomly assigned to receive one of four different zilebesiran doses (150 mg, 300 mg, or 600 mg once every 6 months or 300 mg once every 2 months) or a placebo. The final analysis included 377 patients (56% men, 25% Black).
Results showed sustained reductions in serum angiotensinogen (between 88% and 98%) over the 6-month follow-up period.
Ambulatory systolic BP measured over 24 hours was significantly decreased with all zilebesiran regimens, with a mean reduction from baseline to month 6 of around 10 mm Hg in the three top doses studied and by around 14 mm Hg compared with placebo.
Patients receiving zilebesiran were more likely to achieve 24-hour average systolic BP measurements of 130 mm Hg or less at 6 months.
In addition, participants in all four zilebesiran groups consistently experienced significantly greater reductions in both daytime and nighttime systolic BP.
There were four nonserious adverse reactions leading to discontinuation in the zilebesiran groups: two instances of orthostatic hypotension, one of BP elevation, and one of injection site reaction.
Most hyperkalemia adverse events, which occurred in 6% of patients, were mild, did not require intervention, and generally resolved with repeat measurement; none were associated with acute kidney injury or led to study drug discontinuation. The incidence of hypotension events was low, and no clinically relevant changes in renal or hepatic function were observed, Dr. Bakris reported.
There was one death caused by cardiopulmonary arrest in a patient receiving zilebesiran 300 mg every 3 months, but this was not classified as drug related.
Zilebesiran is being further evaluated as an add-on therapy for treatment of hypertension in the ongoing KARDIA-2 phase 2 study.
Moderator of an AHA press conference at which the study was discussed, Sandra Taler, MD, professor of medicine at the Mayo Clinic, Rochester, Minn., said that “to have an injectable medicine that gives long-term blood pressure lowering is extremely exciting.”
Dr. Taler raised the point that some patients may not return for subsequent doses, but added that with subcutaneous dosing, administration at home may be a possibility.
Also commenting at the press conference, Keith Ferdinand, MD, professor of clinical medicine at Tulane University, New Orleans, said that this study “suggests we can now target the first step in the renin-angiotensin system – angiotensinogen – which then appears to lead to robust and continued blood pressure lowering for up to 6 months, which should improve adherence.”
Noting that only 50% of patients continue to take antihypertensive drugs after 1 year, Dr. Ferdinand added: “If we can increase adherence, we will increase efficacy and perhaps protect against some of the target organ damage.”
Designated discussant of the KARDIA-1 study at the AHA late-breaking clinical trial session, Anna Dominiczak, MD, University of Glasgow, noted that hypertension affects one in three adults worldwide, but only around 20% of people have it under control.
“An increase in the number of patients effectively treated for hypertension to levels observed in high-performing countries could prevent 76 million deaths, 120 million strokes, 79 million heart attacks, and 17 million cases of heart failure between now and 2050,” she said.
Dr. Bakris has received consulting fees from Alnylam Pharmaceuticals.
A version of this article first appeared on Medscape.com.
FROM AHA 2023
PREVENT: AHA’s new risk calculator incorporates CKM health
.
The new Predicting Risk of CVD Events (PREVENT) calculator is the first risk calculator that combines measures of cardiovascular, kidney, and metabolic health to estimate risk for CVD.
It follows an AHA presidential advisory and scientific statement published in October, formally defining cardiovascular-kidney-metabolic (CKM) syndrome.
The PREVENT calculator also “starts earlier and goes longer” than the pooled cohort equations (PCE), Sadiya Khan, MD, MSc, chair of the statement writing committee, told this news organization.
PREVENT is for use in adults aged 30-79 years and estimates the 10- and 30-year risk of total CVD including, for the first time, heart failure. The PCE were designed to assess 10-year risk of only myocardial infarction and stroke and only in adults aged 40-79 years.
“The new PREVENT equations are important for doctors because they allow us to start conversations earlier and more comprehensively and accurately calculate risk for our patients,” said Dr. Khan, preventive cardiologist at Northwestern Medicine and associate professor at Northwestern University in Chicago.
“We want to support clinicians in starting these conversations around optimizing CKM health earlier and begin to engage in discussions on ways to optimize health,” Dr. Khan added.
The AHA scientific statement on the PREVENT calculator, with Dr. Khan as lead author, was published online in Circulation, with an accompanying article that describes development and validation of the tool.
Going beyond the PCE
The new calculator was developed using health information from more than 6 million adults from diverse racial and ethnic, socioeconomic, and geographic backgrounds.
In addition to blood pressure and cholesterol levels, the PREVENT equations allow for inclusion of hemoglobin A1c, if necessary, to monitor metabolic health.
It also includes estimated glomerular filtration rate (eGFR), a measure of kidney function, and allows for use of albumin excretion to monitor kidney disease to further individualize risk assessment and help inform personalized treatment options.
The new calculator also asks about tobacco use and use of medications for CVD risk factors and factors in age and sex, and it removes race from the risk calculations.
“The inclusion of race in risk prediction may imply that differences by race are not modifiable and may reify race as a biological construct, which may worsen health disparities. Therefore, it was decided a priori not to include race as a predictor in the development of PREVENT,” the writing group said.
They emphasized that the PREVENT calculator has similar accuracy among varied racial and ethnic groups.
The equations include an option to use the Social Deprivation Index, which incorporates measures of adverse social determinants of health such as education, poverty, unemployment, and factors based on a person’s environment.
The PREVENT equations are a “critical first step” toward including CKM health and social factors in risk prediction for CVD, Dr. Khan said in a news release.
“We are working on finalizing the online tool and it should be available soon – hopefully in a few weeks,” Dr. Khan told this news organization.
Knowledge gaps
The scientific statement lists several knowledge gaps and areas for more research. These include:
- Incorporating “net benefit” to identify the expected benefit of treatment recommendations based on an individual’s level of risk.
- Collecting more data from people of diverse race and ethnic backgrounds to better represent the increasing diversity in the United States. The number of Hispanic and Asian people included in the PREVENT datasets is lower than national estimates in the general U.S. population, so risk estimations in these populations may be less precise.
- Expanding the collection, reporting, and standardization of social determinants of health data, such as individual information rather than neighborhood information.
- Expanding risk assessment and prevention to earlier in life (childhood and/or adolescence) and in key life periods, such as during the peripartum period, since adverse pregnancy outcomes are associated with increased CVD risk.
- Investigating whether predicting adverse kidney outcomes, particularly among people with and without type 2 diabetes, may further optimize cardiovascular risk prediction.
The scientific statement was prepared by the volunteer writing group on behalf of the AHA. Dr. Khan reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
.
The new Predicting Risk of CVD Events (PREVENT) calculator is the first risk calculator that combines measures of cardiovascular, kidney, and metabolic health to estimate risk for CVD.
It follows an AHA presidential advisory and scientific statement published in October, formally defining cardiovascular-kidney-metabolic (CKM) syndrome.
The PREVENT calculator also “starts earlier and goes longer” than the pooled cohort equations (PCE), Sadiya Khan, MD, MSc, chair of the statement writing committee, told this news organization.
PREVENT is for use in adults aged 30-79 years and estimates the 10- and 30-year risk of total CVD including, for the first time, heart failure. The PCE were designed to assess 10-year risk of only myocardial infarction and stroke and only in adults aged 40-79 years.
“The new PREVENT equations are important for doctors because they allow us to start conversations earlier and more comprehensively and accurately calculate risk for our patients,” said Dr. Khan, preventive cardiologist at Northwestern Medicine and associate professor at Northwestern University in Chicago.
“We want to support clinicians in starting these conversations around optimizing CKM health earlier and begin to engage in discussions on ways to optimize health,” Dr. Khan added.
The AHA scientific statement on the PREVENT calculator, with Dr. Khan as lead author, was published online in Circulation, with an accompanying article that describes development and validation of the tool.
Going beyond the PCE
The new calculator was developed using health information from more than 6 million adults from diverse racial and ethnic, socioeconomic, and geographic backgrounds.
In addition to blood pressure and cholesterol levels, the PREVENT equations allow for inclusion of hemoglobin A1c, if necessary, to monitor metabolic health.
It also includes estimated glomerular filtration rate (eGFR), a measure of kidney function, and allows for use of albumin excretion to monitor kidney disease to further individualize risk assessment and help inform personalized treatment options.
The new calculator also asks about tobacco use and use of medications for CVD risk factors and factors in age and sex, and it removes race from the risk calculations.
“The inclusion of race in risk prediction may imply that differences by race are not modifiable and may reify race as a biological construct, which may worsen health disparities. Therefore, it was decided a priori not to include race as a predictor in the development of PREVENT,” the writing group said.
They emphasized that the PREVENT calculator has similar accuracy among varied racial and ethnic groups.
The equations include an option to use the Social Deprivation Index, which incorporates measures of adverse social determinants of health such as education, poverty, unemployment, and factors based on a person’s environment.
The PREVENT equations are a “critical first step” toward including CKM health and social factors in risk prediction for CVD, Dr. Khan said in a news release.
“We are working on finalizing the online tool and it should be available soon – hopefully in a few weeks,” Dr. Khan told this news organization.
Knowledge gaps
The scientific statement lists several knowledge gaps and areas for more research. These include:
- Incorporating “net benefit” to identify the expected benefit of treatment recommendations based on an individual’s level of risk.
- Collecting more data from people of diverse race and ethnic backgrounds to better represent the increasing diversity in the United States. The number of Hispanic and Asian people included in the PREVENT datasets is lower than national estimates in the general U.S. population, so risk estimations in these populations may be less precise.
- Expanding the collection, reporting, and standardization of social determinants of health data, such as individual information rather than neighborhood information.
- Expanding risk assessment and prevention to earlier in life (childhood and/or adolescence) and in key life periods, such as during the peripartum period, since adverse pregnancy outcomes are associated with increased CVD risk.
- Investigating whether predicting adverse kidney outcomes, particularly among people with and without type 2 diabetes, may further optimize cardiovascular risk prediction.
The scientific statement was prepared by the volunteer writing group on behalf of the AHA. Dr. Khan reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
.
The new Predicting Risk of CVD Events (PREVENT) calculator is the first risk calculator that combines measures of cardiovascular, kidney, and metabolic health to estimate risk for CVD.
It follows an AHA presidential advisory and scientific statement published in October, formally defining cardiovascular-kidney-metabolic (CKM) syndrome.
The PREVENT calculator also “starts earlier and goes longer” than the pooled cohort equations (PCE), Sadiya Khan, MD, MSc, chair of the statement writing committee, told this news organization.
PREVENT is for use in adults aged 30-79 years and estimates the 10- and 30-year risk of total CVD including, for the first time, heart failure. The PCE were designed to assess 10-year risk of only myocardial infarction and stroke and only in adults aged 40-79 years.
“The new PREVENT equations are important for doctors because they allow us to start conversations earlier and more comprehensively and accurately calculate risk for our patients,” said Dr. Khan, preventive cardiologist at Northwestern Medicine and associate professor at Northwestern University in Chicago.
“We want to support clinicians in starting these conversations around optimizing CKM health earlier and begin to engage in discussions on ways to optimize health,” Dr. Khan added.
The AHA scientific statement on the PREVENT calculator, with Dr. Khan as lead author, was published online in Circulation, with an accompanying article that describes development and validation of the tool.
Going beyond the PCE
The new calculator was developed using health information from more than 6 million adults from diverse racial and ethnic, socioeconomic, and geographic backgrounds.
In addition to blood pressure and cholesterol levels, the PREVENT equations allow for inclusion of hemoglobin A1c, if necessary, to monitor metabolic health.
It also includes estimated glomerular filtration rate (eGFR), a measure of kidney function, and allows for use of albumin excretion to monitor kidney disease to further individualize risk assessment and help inform personalized treatment options.
The new calculator also asks about tobacco use and use of medications for CVD risk factors and factors in age and sex, and it removes race from the risk calculations.
“The inclusion of race in risk prediction may imply that differences by race are not modifiable and may reify race as a biological construct, which may worsen health disparities. Therefore, it was decided a priori not to include race as a predictor in the development of PREVENT,” the writing group said.
They emphasized that the PREVENT calculator has similar accuracy among varied racial and ethnic groups.
The equations include an option to use the Social Deprivation Index, which incorporates measures of adverse social determinants of health such as education, poverty, unemployment, and factors based on a person’s environment.
The PREVENT equations are a “critical first step” toward including CKM health and social factors in risk prediction for CVD, Dr. Khan said in a news release.
“We are working on finalizing the online tool and it should be available soon – hopefully in a few weeks,” Dr. Khan told this news organization.
Knowledge gaps
The scientific statement lists several knowledge gaps and areas for more research. These include:
- Incorporating “net benefit” to identify the expected benefit of treatment recommendations based on an individual’s level of risk.
- Collecting more data from people of diverse race and ethnic backgrounds to better represent the increasing diversity in the United States. The number of Hispanic and Asian people included in the PREVENT datasets is lower than national estimates in the general U.S. population, so risk estimations in these populations may be less precise.
- Expanding the collection, reporting, and standardization of social determinants of health data, such as individual information rather than neighborhood information.
- Expanding risk assessment and prevention to earlier in life (childhood and/or adolescence) and in key life periods, such as during the peripartum period, since adverse pregnancy outcomes are associated with increased CVD risk.
- Investigating whether predicting adverse kidney outcomes, particularly among people with and without type 2 diabetes, may further optimize cardiovascular risk prediction.
The scientific statement was prepared by the volunteer writing group on behalf of the AHA. Dr. Khan reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM CIRCULATION
Already-available drug could help treat type 1 diabetes
“I think we have lots of potential to improve people’s quality of life who are living with type 1 diabetes if we can increase their endogenous insulin secretion. ... I think long-term combination therapy is going to be the answer,” study author Emily K. Sims, MD, a pediatric endocrinologist at Indiana University, Indianapolis, said in an interview.
DFMO inhibits the polyamine biosynthesis pathway, which plays a role in the inflammatory responses in autoimmune diseases, including type 1 diabetes. It’s sold under the name eflornithine as an intravenous treatment for African sleeping sickness (trypanosomiasis) and as a cream for unwanted hair growth in women. It also has orphan designations for treating various cancers, including neuroblastoma.
In type 1 diabetes, the immune system destroys insulin-producing pancreatic beta cells. Insulin treatment is required. Recently, the monoclonal antibody teplizumab (Tzield, Sanofi) was approved as a treatment for delaying the onset of type 1 diabetes in people with autoantibodies that signify a preclinical stage of the condition. As yet, no agent has been approved for preserving beta-cell function after the onset of type 1 diabetes, but many are under investigation.
The new safety study by Dr. Sims and colleagues, which was published in Cell Medicine Reports, enrolled 41 people with type 1 diabetes who had been diagnosed within the previous 8 months, including 31 children. Participants were randomly assigned to undergo oral treatment with DFMO at one of five doses or placebo for 3 months, with 3 additional months of follow-up.
Following a mixed-meal tolerance test at 6 months, the C-peptide area under the curve – a measure of beta-cell function – was significantly higher with the three highest DFMO doses compared to placebo (P = .02, .03, and .02 for 125 mg/m2, 750 mg/m2, and 1,000 mg/m2, respectively).
Two individuals dropped out, one because of anaphylaxis. There were no dose-limiting toxicities or serious adverse events, while mild gastrointestinal events, anemia, and headache were common. “Although there’s no [Food and Drug Administration] approval for the oral form right now, there’s a lot of safety data, including in kids from the neuroblastoma studies,” Dr. Sims explained.
There were no differences in C-peptide at 3 months or in hemoglobin A1c at any time point. Glucose areas under the curve were significantly lower for DFMO, compared with placebo in the 125-mg/m2 and 750-mg/m2 treatment groups at the 6-month time point (P = .03 and .04, respectively).
In their article, Dr. Sims and colleagues also reported confirmatory analyses in mice, as well as testing in the humans showing that there didn’t appear to be significant immune system modulation. “So, we can envision giving DFMO in addition to something that targets the immune system, as a combination therapy,” said Dr. Sims, who also worked on the pivotal study of teplizumab.
“I’m excited. The sample size is small, so I was kind of expecting no efficacy signals. ... It’s definitely worth following up,” she said.
However, she noted, “it wasn’t a slam-dunk huge effect. It was subtle. It seemed that things were kind of more stable compared to placebo over time versus ... a big increase in C-peptide over time.”
But, she added, “I believe that even teplizumab will need to be used in combination. It delays the onset of type 1 diabetes and improves C-peptide, but it didn’t get everyone off insulin. I don’t think we’ve seen any drug that won’t need to be used in combination.”
Dr. Sims pointed to other investigational agents, such as verapamil and various Janus kinase inhibitors, that may also serve in combination to forestall or reduce insulin dependency for people with either new-onset type 1 diabetes or those who have been identified via screening as having type 1 diabetes–related autoantibodies. “I think there are a lot of potential different interventions.”
Dr. Sims and colleagues are now conducting a larger six-center JDRF-funded study of DFMO in early-onset type 1 diabetes that will be fully powered and that will use the highest tolerated doses from the preliminary study.
She believes there will likely be benefit even if the agent doesn’t completely reverse the disease. “The people who are making more insulin are just easier to manage, with more time in range and less hypoglycemia.” Even if the drugs only delay but don’t prevent type 1 diabetes entirely in those at risk, “the improvement in quality of life of being able to delay insulin for a few years is really palpable. ... I’m really optimistic.”
Dr. Sims disclosed no relevant financial relationships. Three other authors are coauthors on a patent application for the use of DFMO for the treatment of beta-cell dysfunction in type 1 diabetes; one of those three authors is an employee of Cancer Prevention Pharmaceuticals.
A version of this article first appeared on Medscape.com.
“I think we have lots of potential to improve people’s quality of life who are living with type 1 diabetes if we can increase their endogenous insulin secretion. ... I think long-term combination therapy is going to be the answer,” study author Emily K. Sims, MD, a pediatric endocrinologist at Indiana University, Indianapolis, said in an interview.
DFMO inhibits the polyamine biosynthesis pathway, which plays a role in the inflammatory responses in autoimmune diseases, including type 1 diabetes. It’s sold under the name eflornithine as an intravenous treatment for African sleeping sickness (trypanosomiasis) and as a cream for unwanted hair growth in women. It also has orphan designations for treating various cancers, including neuroblastoma.
In type 1 diabetes, the immune system destroys insulin-producing pancreatic beta cells. Insulin treatment is required. Recently, the monoclonal antibody teplizumab (Tzield, Sanofi) was approved as a treatment for delaying the onset of type 1 diabetes in people with autoantibodies that signify a preclinical stage of the condition. As yet, no agent has been approved for preserving beta-cell function after the onset of type 1 diabetes, but many are under investigation.
The new safety study by Dr. Sims and colleagues, which was published in Cell Medicine Reports, enrolled 41 people with type 1 diabetes who had been diagnosed within the previous 8 months, including 31 children. Participants were randomly assigned to undergo oral treatment with DFMO at one of five doses or placebo for 3 months, with 3 additional months of follow-up.
Following a mixed-meal tolerance test at 6 months, the C-peptide area under the curve – a measure of beta-cell function – was significantly higher with the three highest DFMO doses compared to placebo (P = .02, .03, and .02 for 125 mg/m2, 750 mg/m2, and 1,000 mg/m2, respectively).
Two individuals dropped out, one because of anaphylaxis. There were no dose-limiting toxicities or serious adverse events, while mild gastrointestinal events, anemia, and headache were common. “Although there’s no [Food and Drug Administration] approval for the oral form right now, there’s a lot of safety data, including in kids from the neuroblastoma studies,” Dr. Sims explained.
There were no differences in C-peptide at 3 months or in hemoglobin A1c at any time point. Glucose areas under the curve were significantly lower for DFMO, compared with placebo in the 125-mg/m2 and 750-mg/m2 treatment groups at the 6-month time point (P = .03 and .04, respectively).
In their article, Dr. Sims and colleagues also reported confirmatory analyses in mice, as well as testing in the humans showing that there didn’t appear to be significant immune system modulation. “So, we can envision giving DFMO in addition to something that targets the immune system, as a combination therapy,” said Dr. Sims, who also worked on the pivotal study of teplizumab.
“I’m excited. The sample size is small, so I was kind of expecting no efficacy signals. ... It’s definitely worth following up,” she said.
However, she noted, “it wasn’t a slam-dunk huge effect. It was subtle. It seemed that things were kind of more stable compared to placebo over time versus ... a big increase in C-peptide over time.”
But, she added, “I believe that even teplizumab will need to be used in combination. It delays the onset of type 1 diabetes and improves C-peptide, but it didn’t get everyone off insulin. I don’t think we’ve seen any drug that won’t need to be used in combination.”
Dr. Sims pointed to other investigational agents, such as verapamil and various Janus kinase inhibitors, that may also serve in combination to forestall or reduce insulin dependency for people with either new-onset type 1 diabetes or those who have been identified via screening as having type 1 diabetes–related autoantibodies. “I think there are a lot of potential different interventions.”
Dr. Sims and colleagues are now conducting a larger six-center JDRF-funded study of DFMO in early-onset type 1 diabetes that will be fully powered and that will use the highest tolerated doses from the preliminary study.
She believes there will likely be benefit even if the agent doesn’t completely reverse the disease. “The people who are making more insulin are just easier to manage, with more time in range and less hypoglycemia.” Even if the drugs only delay but don’t prevent type 1 diabetes entirely in those at risk, “the improvement in quality of life of being able to delay insulin for a few years is really palpable. ... I’m really optimistic.”
Dr. Sims disclosed no relevant financial relationships. Three other authors are coauthors on a patent application for the use of DFMO for the treatment of beta-cell dysfunction in type 1 diabetes; one of those three authors is an employee of Cancer Prevention Pharmaceuticals.
A version of this article first appeared on Medscape.com.
“I think we have lots of potential to improve people’s quality of life who are living with type 1 diabetes if we can increase their endogenous insulin secretion. ... I think long-term combination therapy is going to be the answer,” study author Emily K. Sims, MD, a pediatric endocrinologist at Indiana University, Indianapolis, said in an interview.
DFMO inhibits the polyamine biosynthesis pathway, which plays a role in the inflammatory responses in autoimmune diseases, including type 1 diabetes. It’s sold under the name eflornithine as an intravenous treatment for African sleeping sickness (trypanosomiasis) and as a cream for unwanted hair growth in women. It also has orphan designations for treating various cancers, including neuroblastoma.
In type 1 diabetes, the immune system destroys insulin-producing pancreatic beta cells. Insulin treatment is required. Recently, the monoclonal antibody teplizumab (Tzield, Sanofi) was approved as a treatment for delaying the onset of type 1 diabetes in people with autoantibodies that signify a preclinical stage of the condition. As yet, no agent has been approved for preserving beta-cell function after the onset of type 1 diabetes, but many are under investigation.
The new safety study by Dr. Sims and colleagues, which was published in Cell Medicine Reports, enrolled 41 people with type 1 diabetes who had been diagnosed within the previous 8 months, including 31 children. Participants were randomly assigned to undergo oral treatment with DFMO at one of five doses or placebo for 3 months, with 3 additional months of follow-up.
Following a mixed-meal tolerance test at 6 months, the C-peptide area under the curve – a measure of beta-cell function – was significantly higher with the three highest DFMO doses compared to placebo (P = .02, .03, and .02 for 125 mg/m2, 750 mg/m2, and 1,000 mg/m2, respectively).
Two individuals dropped out, one because of anaphylaxis. There were no dose-limiting toxicities or serious adverse events, while mild gastrointestinal events, anemia, and headache were common. “Although there’s no [Food and Drug Administration] approval for the oral form right now, there’s a lot of safety data, including in kids from the neuroblastoma studies,” Dr. Sims explained.
There were no differences in C-peptide at 3 months or in hemoglobin A1c at any time point. Glucose areas under the curve were significantly lower for DFMO, compared with placebo in the 125-mg/m2 and 750-mg/m2 treatment groups at the 6-month time point (P = .03 and .04, respectively).
In their article, Dr. Sims and colleagues also reported confirmatory analyses in mice, as well as testing in the humans showing that there didn’t appear to be significant immune system modulation. “So, we can envision giving DFMO in addition to something that targets the immune system, as a combination therapy,” said Dr. Sims, who also worked on the pivotal study of teplizumab.
“I’m excited. The sample size is small, so I was kind of expecting no efficacy signals. ... It’s definitely worth following up,” she said.
However, she noted, “it wasn’t a slam-dunk huge effect. It was subtle. It seemed that things were kind of more stable compared to placebo over time versus ... a big increase in C-peptide over time.”
But, she added, “I believe that even teplizumab will need to be used in combination. It delays the onset of type 1 diabetes and improves C-peptide, but it didn’t get everyone off insulin. I don’t think we’ve seen any drug that won’t need to be used in combination.”
Dr. Sims pointed to other investigational agents, such as verapamil and various Janus kinase inhibitors, that may also serve in combination to forestall or reduce insulin dependency for people with either new-onset type 1 diabetes or those who have been identified via screening as having type 1 diabetes–related autoantibodies. “I think there are a lot of potential different interventions.”
Dr. Sims and colleagues are now conducting a larger six-center JDRF-funded study of DFMO in early-onset type 1 diabetes that will be fully powered and that will use the highest tolerated doses from the preliminary study.
She believes there will likely be benefit even if the agent doesn’t completely reverse the disease. “The people who are making more insulin are just easier to manage, with more time in range and less hypoglycemia.” Even if the drugs only delay but don’t prevent type 1 diabetes entirely in those at risk, “the improvement in quality of life of being able to delay insulin for a few years is really palpable. ... I’m really optimistic.”
Dr. Sims disclosed no relevant financial relationships. Three other authors are coauthors on a patent application for the use of DFMO for the treatment of beta-cell dysfunction in type 1 diabetes; one of those three authors is an employee of Cancer Prevention Pharmaceuticals.
A version of this article first appeared on Medscape.com.
FROM CELL MEDICINE REPORTS
Revisiting the role of hydrocortisone, fludrocortisone in septic shock
Earlier this year, I stumbled across a podcast in a content update email from the Journal of the American Medical Association. The moderator was interviewing the first author of a study comparing hydrocortisone and fludrocortisone (hydro/fludro) to hydrocortisone alone for treatment of septic shock. In the introduction,
I thought this issue had been settled with publication of the COIITSS trial in 2010. This study randomly assigned 509 patients with septic shock to hydro/fludro versus hydrocortisone alone. There was a nonsignificant reduction in mortality with hydro/fludro and everyone I knew stopped adding fludrocortisone for septic shock. It wasn’t included in guidelines (and still isn›t). I figured the only docs still using it were also prescribing ivermectin and vitamin C – another treatment touted to work in an apocryphal podcast.
It wasn’t just COIITSS that killed fludrocortisone for me. Back in 2002, I was a loyal adherent. That year, a randomized controlled trial (RCT) published by “the lord of corticosteroids for critical illness” doctor, Djillali Annane, found benefit to hydro/fludro in septic shock . Everyone in that study had a cosyntropin stim test and only certain subgroups had better outcomes. As a medical resident paying obeisance to all things evidence-based medicine, I rigidly adopted their protocol for all septic patients. I also kept their insulin between 80 and 110 mg/dL, prescribed drotrecogin alfa, and made sure they were floating in crystalloid. But those are topics for another time.
Subsequent trials and meta-analyses cast doubt on the need for the stim test, and a consensus around hydrocortisone at moderate doses for patients with septic shock emerged. Because one part of the Annane protocol was already deemed unnecessary (the cosyntropin stim test), it was easy to dismiss fludrocortisone after COIITTS was published. Yes, I read Annane’s 2018 APROCCHSS trial, and I’m aware that it found that hydro/fludro reduced 90-day mortality. Like others, I rationalized this finding by framing it as a function of baseline mortality. The two Annane RCTs that found that hydro/fludro reduced mortality in enrolled patients who were considerably more likely to die than those enrolled in RCTs of hydrocortisone alone were negative. It was the target population mortality rate and not the addition of fludrocortisone that made the difference, right?
Rethinking hydro/fludro
The author interviewed for the recent JAMA podcast forced me to rethink my blithe dismissal of fludrocortisone. He contended that the COIITTS trial was underpowered and the two Annane RCTs that used fludrocortisone supply the evidence that shows corticosteroids reduce septic shock mortality. As discussed earlier, he found clinical equipoise among his colleagues. Last, he invoked pleiotropic mineralocorticoid effects, such as activation of innate immunity and clearance of alveolar fluid, to support the need to reexamine hydro/fludro.
In his study, he used Big Data to compare hospital records from 2016 to 2020. He analyzed a total of 88,275 patients with septic shock. Most were prescribed hydrocortisone alone (85,995 [97.4%] vs. only 2.6% hydro/fludro). After a number of statistical adjustments and sensitivity analyses, the authors concluded that the addition of fludrocortisone to hydrocortisone for patients with septic shock provides a 3.7% absolute risk reduction in mortality (or discharge to hospice) when compared with hydrocortisone alone. That’s a number needed to treat of 28 to prevent one death (or discharge to hospice).
Key takeaways
The study isn’t perfect. In their methods section they use terms like “ensemble machine learner (super learner)” and “immortal time bias.” The first is a fancy way of saying they did a form of propensity scoring, which in turn is a fancy way of saying they tried to control for confounding. The second is a way to adjust for time delays between drug administration. Both are attempts to compensate for the observational design, as is their argument for biologic plausibility. Here they’re on particularly thin ice when trying to prove causal inference. Biologic plausibility is never hard to find; after all, what compound doesn’t have pleiotropic effects? Furthermore, the analysis lacks any data to support their biologic plausibility hypothesis that fludrocortisone’s effect on mortality is mediated via activation of innate immunity and/or clearance of alveolar fluid.
The editorial accompanying this Big Data study endorsed adding fludrocortisone. We have very little that reduces ICU mortality so the low number needed to treat is enticing, especially in light of the low risk from adverse events, so I’m going to start using it. Do I think I’ll save one life for every 28 patients with septic shock to whom I give hydro/fludro instead of hydrocortisone alone? I sure don’t. No way an oral mineralocorticoid at that dose has that type of impact on top of hydrocortisone alone. I still believe that the Annane studies are positive because of the mortality rate in the population enrolled and not because fludrocortisone was added. It all comes full circle, though – 20 years after I abandoned hydro/fludro, I’m going back to it.
Aaron B. Holley, MD, is a professor of medicine at Uniformed Services University in Bethesda, Md., and a pulmonary/critical care and sleep medicine physician at MedStar Washington Hospital Center in Washington, D.C.
A version of this article first appeared on Medscape.com.
Earlier this year, I stumbled across a podcast in a content update email from the Journal of the American Medical Association. The moderator was interviewing the first author of a study comparing hydrocortisone and fludrocortisone (hydro/fludro) to hydrocortisone alone for treatment of septic shock. In the introduction,
I thought this issue had been settled with publication of the COIITSS trial in 2010. This study randomly assigned 509 patients with septic shock to hydro/fludro versus hydrocortisone alone. There was a nonsignificant reduction in mortality with hydro/fludro and everyone I knew stopped adding fludrocortisone for septic shock. It wasn’t included in guidelines (and still isn›t). I figured the only docs still using it were also prescribing ivermectin and vitamin C – another treatment touted to work in an apocryphal podcast.
It wasn’t just COIITSS that killed fludrocortisone for me. Back in 2002, I was a loyal adherent. That year, a randomized controlled trial (RCT) published by “the lord of corticosteroids for critical illness” doctor, Djillali Annane, found benefit to hydro/fludro in septic shock . Everyone in that study had a cosyntropin stim test and only certain subgroups had better outcomes. As a medical resident paying obeisance to all things evidence-based medicine, I rigidly adopted their protocol for all septic patients. I also kept their insulin between 80 and 110 mg/dL, prescribed drotrecogin alfa, and made sure they were floating in crystalloid. But those are topics for another time.
Subsequent trials and meta-analyses cast doubt on the need for the stim test, and a consensus around hydrocortisone at moderate doses for patients with septic shock emerged. Because one part of the Annane protocol was already deemed unnecessary (the cosyntropin stim test), it was easy to dismiss fludrocortisone after COIITTS was published. Yes, I read Annane’s 2018 APROCCHSS trial, and I’m aware that it found that hydro/fludro reduced 90-day mortality. Like others, I rationalized this finding by framing it as a function of baseline mortality. The two Annane RCTs that found that hydro/fludro reduced mortality in enrolled patients who were considerably more likely to die than those enrolled in RCTs of hydrocortisone alone were negative. It was the target population mortality rate and not the addition of fludrocortisone that made the difference, right?
Rethinking hydro/fludro
The author interviewed for the recent JAMA podcast forced me to rethink my blithe dismissal of fludrocortisone. He contended that the COIITTS trial was underpowered and the two Annane RCTs that used fludrocortisone supply the evidence that shows corticosteroids reduce septic shock mortality. As discussed earlier, he found clinical equipoise among his colleagues. Last, he invoked pleiotropic mineralocorticoid effects, such as activation of innate immunity and clearance of alveolar fluid, to support the need to reexamine hydro/fludro.
In his study, he used Big Data to compare hospital records from 2016 to 2020. He analyzed a total of 88,275 patients with septic shock. Most were prescribed hydrocortisone alone (85,995 [97.4%] vs. only 2.6% hydro/fludro). After a number of statistical adjustments and sensitivity analyses, the authors concluded that the addition of fludrocortisone to hydrocortisone for patients with septic shock provides a 3.7% absolute risk reduction in mortality (or discharge to hospice) when compared with hydrocortisone alone. That’s a number needed to treat of 28 to prevent one death (or discharge to hospice).
Key takeaways
The study isn’t perfect. In their methods section they use terms like “ensemble machine learner (super learner)” and “immortal time bias.” The first is a fancy way of saying they did a form of propensity scoring, which in turn is a fancy way of saying they tried to control for confounding. The second is a way to adjust for time delays between drug administration. Both are attempts to compensate for the observational design, as is their argument for biologic plausibility. Here they’re on particularly thin ice when trying to prove causal inference. Biologic plausibility is never hard to find; after all, what compound doesn’t have pleiotropic effects? Furthermore, the analysis lacks any data to support their biologic plausibility hypothesis that fludrocortisone’s effect on mortality is mediated via activation of innate immunity and/or clearance of alveolar fluid.
The editorial accompanying this Big Data study endorsed adding fludrocortisone. We have very little that reduces ICU mortality so the low number needed to treat is enticing, especially in light of the low risk from adverse events, so I’m going to start using it. Do I think I’ll save one life for every 28 patients with septic shock to whom I give hydro/fludro instead of hydrocortisone alone? I sure don’t. No way an oral mineralocorticoid at that dose has that type of impact on top of hydrocortisone alone. I still believe that the Annane studies are positive because of the mortality rate in the population enrolled and not because fludrocortisone was added. It all comes full circle, though – 20 years after I abandoned hydro/fludro, I’m going back to it.
Aaron B. Holley, MD, is a professor of medicine at Uniformed Services University in Bethesda, Md., and a pulmonary/critical care and sleep medicine physician at MedStar Washington Hospital Center in Washington, D.C.
A version of this article first appeared on Medscape.com.
Earlier this year, I stumbled across a podcast in a content update email from the Journal of the American Medical Association. The moderator was interviewing the first author of a study comparing hydrocortisone and fludrocortisone (hydro/fludro) to hydrocortisone alone for treatment of septic shock. In the introduction,
I thought this issue had been settled with publication of the COIITSS trial in 2010. This study randomly assigned 509 patients with septic shock to hydro/fludro versus hydrocortisone alone. There was a nonsignificant reduction in mortality with hydro/fludro and everyone I knew stopped adding fludrocortisone for septic shock. It wasn’t included in guidelines (and still isn›t). I figured the only docs still using it were also prescribing ivermectin and vitamin C – another treatment touted to work in an apocryphal podcast.
It wasn’t just COIITSS that killed fludrocortisone for me. Back in 2002, I was a loyal adherent. That year, a randomized controlled trial (RCT) published by “the lord of corticosteroids for critical illness” doctor, Djillali Annane, found benefit to hydro/fludro in septic shock . Everyone in that study had a cosyntropin stim test and only certain subgroups had better outcomes. As a medical resident paying obeisance to all things evidence-based medicine, I rigidly adopted their protocol for all septic patients. I also kept their insulin between 80 and 110 mg/dL, prescribed drotrecogin alfa, and made sure they were floating in crystalloid. But those are topics for another time.
Subsequent trials and meta-analyses cast doubt on the need for the stim test, and a consensus around hydrocortisone at moderate doses for patients with septic shock emerged. Because one part of the Annane protocol was already deemed unnecessary (the cosyntropin stim test), it was easy to dismiss fludrocortisone after COIITTS was published. Yes, I read Annane’s 2018 APROCCHSS trial, and I’m aware that it found that hydro/fludro reduced 90-day mortality. Like others, I rationalized this finding by framing it as a function of baseline mortality. The two Annane RCTs that found that hydro/fludro reduced mortality in enrolled patients who were considerably more likely to die than those enrolled in RCTs of hydrocortisone alone were negative. It was the target population mortality rate and not the addition of fludrocortisone that made the difference, right?
Rethinking hydro/fludro
The author interviewed for the recent JAMA podcast forced me to rethink my blithe dismissal of fludrocortisone. He contended that the COIITTS trial was underpowered and the two Annane RCTs that used fludrocortisone supply the evidence that shows corticosteroids reduce septic shock mortality. As discussed earlier, he found clinical equipoise among his colleagues. Last, he invoked pleiotropic mineralocorticoid effects, such as activation of innate immunity and clearance of alveolar fluid, to support the need to reexamine hydro/fludro.
In his study, he used Big Data to compare hospital records from 2016 to 2020. He analyzed a total of 88,275 patients with septic shock. Most were prescribed hydrocortisone alone (85,995 [97.4%] vs. only 2.6% hydro/fludro). After a number of statistical adjustments and sensitivity analyses, the authors concluded that the addition of fludrocortisone to hydrocortisone for patients with septic shock provides a 3.7% absolute risk reduction in mortality (or discharge to hospice) when compared with hydrocortisone alone. That’s a number needed to treat of 28 to prevent one death (or discharge to hospice).
Key takeaways
The study isn’t perfect. In their methods section they use terms like “ensemble machine learner (super learner)” and “immortal time bias.” The first is a fancy way of saying they did a form of propensity scoring, which in turn is a fancy way of saying they tried to control for confounding. The second is a way to adjust for time delays between drug administration. Both are attempts to compensate for the observational design, as is their argument for biologic plausibility. Here they’re on particularly thin ice when trying to prove causal inference. Biologic plausibility is never hard to find; after all, what compound doesn’t have pleiotropic effects? Furthermore, the analysis lacks any data to support their biologic plausibility hypothesis that fludrocortisone’s effect on mortality is mediated via activation of innate immunity and/or clearance of alveolar fluid.
The editorial accompanying this Big Data study endorsed adding fludrocortisone. We have very little that reduces ICU mortality so the low number needed to treat is enticing, especially in light of the low risk from adverse events, so I’m going to start using it. Do I think I’ll save one life for every 28 patients with septic shock to whom I give hydro/fludro instead of hydrocortisone alone? I sure don’t. No way an oral mineralocorticoid at that dose has that type of impact on top of hydrocortisone alone. I still believe that the Annane studies are positive because of the mortality rate in the population enrolled and not because fludrocortisone was added. It all comes full circle, though – 20 years after I abandoned hydro/fludro, I’m going back to it.
Aaron B. Holley, MD, is a professor of medicine at Uniformed Services University in Bethesda, Md., and a pulmonary/critical care and sleep medicine physician at MedStar Washington Hospital Center in Washington, D.C.
A version of this article first appeared on Medscape.com.
A better way to control blood pressure
My Bing AI engine, when prompted, tells me that there are about 87 journals, 45 conferences, and 53 workshops presently dedicated exclusively to hypertension. All of that attention, and yet ...
What is going on?
The top killers of Americans remain coronary artery heart disease (26%), cancer (22%), and stroke (6%). The precursors and attributable risk factors for coronary artery heart disease include hypertension (40%), obesity (20%), diabetes (15%), and combustible tobacco use (15%). The key precursors and attributable risk factors for stroke are hypertension (53%), obesity (37%), diabetes (9%), and combustible tobacco use (11%). Obviously, these are estimates, with substantial overlap.
It’s pretty obvious that
We have addressed improving tobacco control and preventing obesity and diabetes on these pages many times, and lamented the medical, public health, and societal failings. Today we turn our attention to the control of hypertension. That is much easier and far less expensive.
All physicians and medical organizations know that hypertension is a major attributable cause of many serious, expensive, and fatal illnesses. As many as 119 million (48%) of American adults have hypertension. The American Heart Association (AHA), American Medical Association (AMA), American College of Cardiology (ACC), and hundreds of other organizations have set a new target of 130/80 (revised from 140/90) for blood pressure control and have launched a major initiative, Target: BP, to reach it.
That is just great. We all wish this massive effort to succeed where few others have. But do AHA, AMA, ACC, and others understand why most efforts to this point have failed? The blame is typically aimed at patients failing to adhere to their instructions. Maybe, but why? And how does Target: BP intend to convert chronic failure into success if it just continues to do everything they have been trying to do that doesn’t work?
At this point, the Centers for Disease Control and Prevention reports that fewer than 48% of American patients with hypertension meet even the less stringent historical 140/90 goal.
A group practice in Ohio, PriMed Physicians, has consistently exceeded 90% or even 95% blood pressure control for its patients with hypertension for more than 10 years. Exemplary. How do they do it? This video of the 13th annual Lundberg Institute lecture describes this unique and successful program.
PriMed’s clinicians use the MedsEngine AI tool from MediSync and the NICaS (noninvasive cardiac system with impedance cardiography) to determine each patient’s unique blood pressure pathophysiology. Clinicians and patients understand that the simplest explanation of this pathophysiology encompasses three factors: (1) the volume of “water” (blood) in the system; (2) the strength of the pumping (pulsatile) process; and (3) the tightness (resistance) of the tubes that carry the blood. Patients “get it” when it is explained this way, and they cooperate.
At the first patient encounter, the Food and Drug Administration–approved PhysioFlow is employed to assess those three vital hemodynamic factors. The individual patient’s data are loaded into a tightly programed EHR-based algorithm with 37 clinical factors and five classes of drugs, providing multiple ways to influence the three key pathophysiologic processes. In this way, they arrive at the precise drug(s) and dosages for that patient. During the second visit, most patients are already showing improvement. By the third visit, the blood pressures of most patients have reached target control. After that, it is maintenance and tweaking.
These factors summarize why it works:
- Senior management belief, commitment, and leadership
- Informed buy-in from clinicians and patients
- A test that determines root causes of too much fluid, too strong pump action, or too tight pipes, and their proportionality
- An AI tool that matches those three pathophysiologic factors and 35 other clinical factors with the best drug or drugs (of many, not just a few) and dosages
- Persistent clinician-patient follow-up
- Refusal to accept failure
Since this approach is so successful, why is its use not everywhere?
It is not as if nobody noticed, even if you and many organizations have not. The American Medical Group Association recognized the program’s success by giving its top award to PriMed in 2015.
Klepper and Rodis wrote about this approach for managing multiple chronic conditions in 2021. Here’s a background article and an explainer, Clinical use of impedance cardiography for hemodynamic assessment of early cardiovascular disease and management of hypertension.
I found one pragmatic controlled clinical trial of impedance cardiography with a decision-support system from Beijing that did demonstrate clinical and statistical significance.
Frankly, we do need more rigorous, unbiased, large, controlled clinical trials assessing the MedsEngine and NICaS approach to managing blood pressure to facilitate a massive switch from the old and established (but failing) approach to a starkly better way.
Almost no one ever “completes a database.” All decision makers must act based upon the best data to which they have access. Data are often incomplete. The difference between success and mediocrity is often the ability of an individual or system to decide when enough information is enough and act accordingly.
Cost-effectiveness studies in three countries (United Kingdom, United States, and China) confirm sharply lower lifelong costs when blood pressure is well controlled. Of course.
For the American medical-industrial complex, lowered costs for managing common serious diseases may be an undesired rather than a good thing. In money-driven medicine, lower costs to the payer and purchaser translate to less revenue for the providers. Imagine all of those invasive and noninvasive diagnostic and therapeutic procedures forgone by prevention of hypertension. Is it possible that such an underlying truth is the real reason why American medicine is habitually unsuccessful at controlling blood pressure?
Right now, if my blood pressure were not well controlled (it is), I would find my way to Cincinnati, to give PriMed physicians, MediSync, and MedsEngine a crack at prolonging my useful life.
Dr. Lundberg is editor in chief of Cancer Commons. He disclosed no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
My Bing AI engine, when prompted, tells me that there are about 87 journals, 45 conferences, and 53 workshops presently dedicated exclusively to hypertension. All of that attention, and yet ...
What is going on?
The top killers of Americans remain coronary artery heart disease (26%), cancer (22%), and stroke (6%). The precursors and attributable risk factors for coronary artery heart disease include hypertension (40%), obesity (20%), diabetes (15%), and combustible tobacco use (15%). The key precursors and attributable risk factors for stroke are hypertension (53%), obesity (37%), diabetes (9%), and combustible tobacco use (11%). Obviously, these are estimates, with substantial overlap.
It’s pretty obvious that
We have addressed improving tobacco control and preventing obesity and diabetes on these pages many times, and lamented the medical, public health, and societal failings. Today we turn our attention to the control of hypertension. That is much easier and far less expensive.
All physicians and medical organizations know that hypertension is a major attributable cause of many serious, expensive, and fatal illnesses. As many as 119 million (48%) of American adults have hypertension. The American Heart Association (AHA), American Medical Association (AMA), American College of Cardiology (ACC), and hundreds of other organizations have set a new target of 130/80 (revised from 140/90) for blood pressure control and have launched a major initiative, Target: BP, to reach it.
That is just great. We all wish this massive effort to succeed where few others have. But do AHA, AMA, ACC, and others understand why most efforts to this point have failed? The blame is typically aimed at patients failing to adhere to their instructions. Maybe, but why? And how does Target: BP intend to convert chronic failure into success if it just continues to do everything they have been trying to do that doesn’t work?
At this point, the Centers for Disease Control and Prevention reports that fewer than 48% of American patients with hypertension meet even the less stringent historical 140/90 goal.
A group practice in Ohio, PriMed Physicians, has consistently exceeded 90% or even 95% blood pressure control for its patients with hypertension for more than 10 years. Exemplary. How do they do it? This video of the 13th annual Lundberg Institute lecture describes this unique and successful program.
PriMed’s clinicians use the MedsEngine AI tool from MediSync and the NICaS (noninvasive cardiac system with impedance cardiography) to determine each patient’s unique blood pressure pathophysiology. Clinicians and patients understand that the simplest explanation of this pathophysiology encompasses three factors: (1) the volume of “water” (blood) in the system; (2) the strength of the pumping (pulsatile) process; and (3) the tightness (resistance) of the tubes that carry the blood. Patients “get it” when it is explained this way, and they cooperate.
At the first patient encounter, the Food and Drug Administration–approved PhysioFlow is employed to assess those three vital hemodynamic factors. The individual patient’s data are loaded into a tightly programed EHR-based algorithm with 37 clinical factors and five classes of drugs, providing multiple ways to influence the three key pathophysiologic processes. In this way, they arrive at the precise drug(s) and dosages for that patient. During the second visit, most patients are already showing improvement. By the third visit, the blood pressures of most patients have reached target control. After that, it is maintenance and tweaking.
These factors summarize why it works:
- Senior management belief, commitment, and leadership
- Informed buy-in from clinicians and patients
- A test that determines root causes of too much fluid, too strong pump action, or too tight pipes, and their proportionality
- An AI tool that matches those three pathophysiologic factors and 35 other clinical factors with the best drug or drugs (of many, not just a few) and dosages
- Persistent clinician-patient follow-up
- Refusal to accept failure
Since this approach is so successful, why is its use not everywhere?
It is not as if nobody noticed, even if you and many organizations have not. The American Medical Group Association recognized the program’s success by giving its top award to PriMed in 2015.
Klepper and Rodis wrote about this approach for managing multiple chronic conditions in 2021. Here’s a background article and an explainer, Clinical use of impedance cardiography for hemodynamic assessment of early cardiovascular disease and management of hypertension.
I found one pragmatic controlled clinical trial of impedance cardiography with a decision-support system from Beijing that did demonstrate clinical and statistical significance.
Frankly, we do need more rigorous, unbiased, large, controlled clinical trials assessing the MedsEngine and NICaS approach to managing blood pressure to facilitate a massive switch from the old and established (but failing) approach to a starkly better way.
Almost no one ever “completes a database.” All decision makers must act based upon the best data to which they have access. Data are often incomplete. The difference between success and mediocrity is often the ability of an individual or system to decide when enough information is enough and act accordingly.
Cost-effectiveness studies in three countries (United Kingdom, United States, and China) confirm sharply lower lifelong costs when blood pressure is well controlled. Of course.
For the American medical-industrial complex, lowered costs for managing common serious diseases may be an undesired rather than a good thing. In money-driven medicine, lower costs to the payer and purchaser translate to less revenue for the providers. Imagine all of those invasive and noninvasive diagnostic and therapeutic procedures forgone by prevention of hypertension. Is it possible that such an underlying truth is the real reason why American medicine is habitually unsuccessful at controlling blood pressure?
Right now, if my blood pressure were not well controlled (it is), I would find my way to Cincinnati, to give PriMed physicians, MediSync, and MedsEngine a crack at prolonging my useful life.
Dr. Lundberg is editor in chief of Cancer Commons. He disclosed no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
My Bing AI engine, when prompted, tells me that there are about 87 journals, 45 conferences, and 53 workshops presently dedicated exclusively to hypertension. All of that attention, and yet ...
What is going on?
The top killers of Americans remain coronary artery heart disease (26%), cancer (22%), and stroke (6%). The precursors and attributable risk factors for coronary artery heart disease include hypertension (40%), obesity (20%), diabetes (15%), and combustible tobacco use (15%). The key precursors and attributable risk factors for stroke are hypertension (53%), obesity (37%), diabetes (9%), and combustible tobacco use (11%). Obviously, these are estimates, with substantial overlap.
It’s pretty obvious that
We have addressed improving tobacco control and preventing obesity and diabetes on these pages many times, and lamented the medical, public health, and societal failings. Today we turn our attention to the control of hypertension. That is much easier and far less expensive.
All physicians and medical organizations know that hypertension is a major attributable cause of many serious, expensive, and fatal illnesses. As many as 119 million (48%) of American adults have hypertension. The American Heart Association (AHA), American Medical Association (AMA), American College of Cardiology (ACC), and hundreds of other organizations have set a new target of 130/80 (revised from 140/90) for blood pressure control and have launched a major initiative, Target: BP, to reach it.
That is just great. We all wish this massive effort to succeed where few others have. But do AHA, AMA, ACC, and others understand why most efforts to this point have failed? The blame is typically aimed at patients failing to adhere to their instructions. Maybe, but why? And how does Target: BP intend to convert chronic failure into success if it just continues to do everything they have been trying to do that doesn’t work?
At this point, the Centers for Disease Control and Prevention reports that fewer than 48% of American patients with hypertension meet even the less stringent historical 140/90 goal.
A group practice in Ohio, PriMed Physicians, has consistently exceeded 90% or even 95% blood pressure control for its patients with hypertension for more than 10 years. Exemplary. How do they do it? This video of the 13th annual Lundberg Institute lecture describes this unique and successful program.
PriMed’s clinicians use the MedsEngine AI tool from MediSync and the NICaS (noninvasive cardiac system with impedance cardiography) to determine each patient’s unique blood pressure pathophysiology. Clinicians and patients understand that the simplest explanation of this pathophysiology encompasses three factors: (1) the volume of “water” (blood) in the system; (2) the strength of the pumping (pulsatile) process; and (3) the tightness (resistance) of the tubes that carry the blood. Patients “get it” when it is explained this way, and they cooperate.
At the first patient encounter, the Food and Drug Administration–approved PhysioFlow is employed to assess those three vital hemodynamic factors. The individual patient’s data are loaded into a tightly programed EHR-based algorithm with 37 clinical factors and five classes of drugs, providing multiple ways to influence the three key pathophysiologic processes. In this way, they arrive at the precise drug(s) and dosages for that patient. During the second visit, most patients are already showing improvement. By the third visit, the blood pressures of most patients have reached target control. After that, it is maintenance and tweaking.
These factors summarize why it works:
- Senior management belief, commitment, and leadership
- Informed buy-in from clinicians and patients
- A test that determines root causes of too much fluid, too strong pump action, or too tight pipes, and their proportionality
- An AI tool that matches those three pathophysiologic factors and 35 other clinical factors with the best drug or drugs (of many, not just a few) and dosages
- Persistent clinician-patient follow-up
- Refusal to accept failure
Since this approach is so successful, why is its use not everywhere?
It is not as if nobody noticed, even if you and many organizations have not. The American Medical Group Association recognized the program’s success by giving its top award to PriMed in 2015.
Klepper and Rodis wrote about this approach for managing multiple chronic conditions in 2021. Here’s a background article and an explainer, Clinical use of impedance cardiography for hemodynamic assessment of early cardiovascular disease and management of hypertension.
I found one pragmatic controlled clinical trial of impedance cardiography with a decision-support system from Beijing that did demonstrate clinical and statistical significance.
Frankly, we do need more rigorous, unbiased, large, controlled clinical trials assessing the MedsEngine and NICaS approach to managing blood pressure to facilitate a massive switch from the old and established (but failing) approach to a starkly better way.
Almost no one ever “completes a database.” All decision makers must act based upon the best data to which they have access. Data are often incomplete. The difference between success and mediocrity is often the ability of an individual or system to decide when enough information is enough and act accordingly.
Cost-effectiveness studies in three countries (United Kingdom, United States, and China) confirm sharply lower lifelong costs when blood pressure is well controlled. Of course.
For the American medical-industrial complex, lowered costs for managing common serious diseases may be an undesired rather than a good thing. In money-driven medicine, lower costs to the payer and purchaser translate to less revenue for the providers. Imagine all of those invasive and noninvasive diagnostic and therapeutic procedures forgone by prevention of hypertension. Is it possible that such an underlying truth is the real reason why American medicine is habitually unsuccessful at controlling blood pressure?
Right now, if my blood pressure were not well controlled (it is), I would find my way to Cincinnati, to give PriMed physicians, MediSync, and MedsEngine a crack at prolonging my useful life.
Dr. Lundberg is editor in chief of Cancer Commons. He disclosed no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Promising first results with DNA editing to lower LDL
PHILADELPHIA –
While one of four patients in the highest-dose groups had a myocardial infarction the day after getting the treatment, investigators have enough confidence to go forward with the next phase of study.
“The HEART-1trial demonstrated the first human proof of concept for in vivo DNA-based editing,” said Andrew Bellinger, MD, PhD, chief scientific officer of Verve Therapeutics, the company developing the treatment. “We saw dose-dependent–based reductions in LDL and the PCSK9 protein.”
The HEART-1 study was a phase 1b trial of VERVE-101, a CRISPR-based gene editing mechanism designed to inactivate the liver gene PCSK9, which contributes to raising cholesterol. “Human genetics suggest that turning off the cholesterol-raising gene PCSK9 in the liver will durably reduce LDL cholesterol,” Dr. Bellinger said in presenting the results at the annual scientific sessions of the American Heart Association.
Lipid nanoparticle
VERVE-101 is designed to be a single-course treatment to specifically treat HeFH, Dr. Bellinger said. He explained how the therapy, given by intravenous infusion, differs from adeno-associated virus vectors that have dominated gene therapy platforms.
“It’s a lipid nanoparticle encapsulating two RNA nanoparticles that are taken up by hepatocytes in the liver from the blood by the LDL receptor,” he explained. “Then the A-to-G–based editor protein and the guide mRNA protein together find the PCSK9 gene in the liver.” That single DNA-base change in one position of the PCSK9 gene is able to turn off PCSK9 production in those liver cells.
Dr. Bellinger presented interim results of the first 10 patients treated in the open-label, single ascending dose study. The patients were male and female, ages 18-75, with HeFH, established atherosclerotic cardiovascular disease and uncontrolled hypercholesterolemia despite being on maximally tolerated lipid-lowering therapy.
They received four different doses: Three patients each received 0.1, 0.3, and 0.45 mg/kg; and one patient received 0.6 mg/kg.
Reductions in blood PCSK9 levels were measured across all dosing groups at 4 weeks, but they were most pronounced in the two highest groups, Dr. Bellinger said. Two patients in the 0.45-mg/kg group had reductions of 59% and 84%. The sole patient in the 0.6-mg/kg arm had a reduction of 47%.
Regarding the 84% reduction in one individual, Dr. Bellinger said, “Roughly 85% of PCSK9 comes from the liver. These data suggest that we have successfully made a single base pair change in both copies of the PCSK9 gene in nearly every hepatocyte in the liver of this individual.”
Those benefits carried over to LDL cholesterol measures, with the highest-dose patients registering 39%, 48% and 55% reductions.
Safety outcomes
Two patients had serious cardiovascular (CV) events. One in the 0.3-mg/kg arm died from cardiac arrest 5 weeks after receiving the infusion. A patient in the 0.45-mg/kg arm had a myocardial infarction a day after getting the infusion and then nonsustained ventricular tachycardia (NSVT) 4 weeks later. Dr. Bellinger said an independent review panel determined that the CV events were in line with outcomes for high-risk patients and weren’t directly related to treatment.
He added, “Increased liver transaminases were seen in patients treated in the higher-dose cohorts. It’s transient, asymptomatic, and it resolved quickly.”
The next step involves pursuing only the 0.45- and 0.6-mg/kg doses in the next dose-escalation phase and enrolling an expansion cohort in 2024, Dr. Bellinger said, with a plan to initiate a randomized, placebo-controlled phase 2 trial in 2025.
First, do no harm
Karol Watson, MD, PhD, a women’s cardiovascular disease specialist at UCLA, said the promise of gene therapy was “revolutionary,” but that proving safety was critical going forward.
“You’re changing the genome forever,” she said. “Safety is going to be of the utmost importance especially because there are currently safe and efficacious strategies available for lipid lowering. This is a strategy that could be revolutionary, but we have to make sure that it’s safe.”
She pointed to a multinational study from earlier this year that warned about pathogenic consequences from CRISPR-based gene editing. “There are concerns about gene editing,” Dr. Watson said. “This was a whole-genome analysis showing atypical nonhomologous on-target effects of genome editing. Of course this is a very different strategy from what we heard today, but, again, we have to know that this is safe.”
Despite the small sample size from the two highest-dose groups in the study, Dr. Watson said the investigators have reason for going forward. “I think the preclinical data supports moving forward, but the next studies will have to be scrutinized carefully,” she said. “This is a preventive therapy; the first tenet is to do no harm.”
Dr. Bellinger is an employee of Verve Therapeutics, which sponsored the trial. Dr. Watson disclosed relationships with Boehringer-Ingelheim, Amgen, Lilly and Novartis.
PHILADELPHIA –
While one of four patients in the highest-dose groups had a myocardial infarction the day after getting the treatment, investigators have enough confidence to go forward with the next phase of study.
“The HEART-1trial demonstrated the first human proof of concept for in vivo DNA-based editing,” said Andrew Bellinger, MD, PhD, chief scientific officer of Verve Therapeutics, the company developing the treatment. “We saw dose-dependent–based reductions in LDL and the PCSK9 protein.”
The HEART-1 study was a phase 1b trial of VERVE-101, a CRISPR-based gene editing mechanism designed to inactivate the liver gene PCSK9, which contributes to raising cholesterol. “Human genetics suggest that turning off the cholesterol-raising gene PCSK9 in the liver will durably reduce LDL cholesterol,” Dr. Bellinger said in presenting the results at the annual scientific sessions of the American Heart Association.
Lipid nanoparticle
VERVE-101 is designed to be a single-course treatment to specifically treat HeFH, Dr. Bellinger said. He explained how the therapy, given by intravenous infusion, differs from adeno-associated virus vectors that have dominated gene therapy platforms.
“It’s a lipid nanoparticle encapsulating two RNA nanoparticles that are taken up by hepatocytes in the liver from the blood by the LDL receptor,” he explained. “Then the A-to-G–based editor protein and the guide mRNA protein together find the PCSK9 gene in the liver.” That single DNA-base change in one position of the PCSK9 gene is able to turn off PCSK9 production in those liver cells.
Dr. Bellinger presented interim results of the first 10 patients treated in the open-label, single ascending dose study. The patients were male and female, ages 18-75, with HeFH, established atherosclerotic cardiovascular disease and uncontrolled hypercholesterolemia despite being on maximally tolerated lipid-lowering therapy.
They received four different doses: Three patients each received 0.1, 0.3, and 0.45 mg/kg; and one patient received 0.6 mg/kg.
Reductions in blood PCSK9 levels were measured across all dosing groups at 4 weeks, but they were most pronounced in the two highest groups, Dr. Bellinger said. Two patients in the 0.45-mg/kg group had reductions of 59% and 84%. The sole patient in the 0.6-mg/kg arm had a reduction of 47%.
Regarding the 84% reduction in one individual, Dr. Bellinger said, “Roughly 85% of PCSK9 comes from the liver. These data suggest that we have successfully made a single base pair change in both copies of the PCSK9 gene in nearly every hepatocyte in the liver of this individual.”
Those benefits carried over to LDL cholesterol measures, with the highest-dose patients registering 39%, 48% and 55% reductions.
Safety outcomes
Two patients had serious cardiovascular (CV) events. One in the 0.3-mg/kg arm died from cardiac arrest 5 weeks after receiving the infusion. A patient in the 0.45-mg/kg arm had a myocardial infarction a day after getting the infusion and then nonsustained ventricular tachycardia (NSVT) 4 weeks later. Dr. Bellinger said an independent review panel determined that the CV events were in line with outcomes for high-risk patients and weren’t directly related to treatment.
He added, “Increased liver transaminases were seen in patients treated in the higher-dose cohorts. It’s transient, asymptomatic, and it resolved quickly.”
The next step involves pursuing only the 0.45- and 0.6-mg/kg doses in the next dose-escalation phase and enrolling an expansion cohort in 2024, Dr. Bellinger said, with a plan to initiate a randomized, placebo-controlled phase 2 trial in 2025.
First, do no harm
Karol Watson, MD, PhD, a women’s cardiovascular disease specialist at UCLA, said the promise of gene therapy was “revolutionary,” but that proving safety was critical going forward.
“You’re changing the genome forever,” she said. “Safety is going to be of the utmost importance especially because there are currently safe and efficacious strategies available for lipid lowering. This is a strategy that could be revolutionary, but we have to make sure that it’s safe.”
She pointed to a multinational study from earlier this year that warned about pathogenic consequences from CRISPR-based gene editing. “There are concerns about gene editing,” Dr. Watson said. “This was a whole-genome analysis showing atypical nonhomologous on-target effects of genome editing. Of course this is a very different strategy from what we heard today, but, again, we have to know that this is safe.”
Despite the small sample size from the two highest-dose groups in the study, Dr. Watson said the investigators have reason for going forward. “I think the preclinical data supports moving forward, but the next studies will have to be scrutinized carefully,” she said. “This is a preventive therapy; the first tenet is to do no harm.”
Dr. Bellinger is an employee of Verve Therapeutics, which sponsored the trial. Dr. Watson disclosed relationships with Boehringer-Ingelheim, Amgen, Lilly and Novartis.
PHILADELPHIA –
While one of four patients in the highest-dose groups had a myocardial infarction the day after getting the treatment, investigators have enough confidence to go forward with the next phase of study.
“The HEART-1trial demonstrated the first human proof of concept for in vivo DNA-based editing,” said Andrew Bellinger, MD, PhD, chief scientific officer of Verve Therapeutics, the company developing the treatment. “We saw dose-dependent–based reductions in LDL and the PCSK9 protein.”
The HEART-1 study was a phase 1b trial of VERVE-101, a CRISPR-based gene editing mechanism designed to inactivate the liver gene PCSK9, which contributes to raising cholesterol. “Human genetics suggest that turning off the cholesterol-raising gene PCSK9 in the liver will durably reduce LDL cholesterol,” Dr. Bellinger said in presenting the results at the annual scientific sessions of the American Heart Association.
Lipid nanoparticle
VERVE-101 is designed to be a single-course treatment to specifically treat HeFH, Dr. Bellinger said. He explained how the therapy, given by intravenous infusion, differs from adeno-associated virus vectors that have dominated gene therapy platforms.
“It’s a lipid nanoparticle encapsulating two RNA nanoparticles that are taken up by hepatocytes in the liver from the blood by the LDL receptor,” he explained. “Then the A-to-G–based editor protein and the guide mRNA protein together find the PCSK9 gene in the liver.” That single DNA-base change in one position of the PCSK9 gene is able to turn off PCSK9 production in those liver cells.
Dr. Bellinger presented interim results of the first 10 patients treated in the open-label, single ascending dose study. The patients were male and female, ages 18-75, with HeFH, established atherosclerotic cardiovascular disease and uncontrolled hypercholesterolemia despite being on maximally tolerated lipid-lowering therapy.
They received four different doses: Three patients each received 0.1, 0.3, and 0.45 mg/kg; and one patient received 0.6 mg/kg.
Reductions in blood PCSK9 levels were measured across all dosing groups at 4 weeks, but they were most pronounced in the two highest groups, Dr. Bellinger said. Two patients in the 0.45-mg/kg group had reductions of 59% and 84%. The sole patient in the 0.6-mg/kg arm had a reduction of 47%.
Regarding the 84% reduction in one individual, Dr. Bellinger said, “Roughly 85% of PCSK9 comes from the liver. These data suggest that we have successfully made a single base pair change in both copies of the PCSK9 gene in nearly every hepatocyte in the liver of this individual.”
Those benefits carried over to LDL cholesterol measures, with the highest-dose patients registering 39%, 48% and 55% reductions.
Safety outcomes
Two patients had serious cardiovascular (CV) events. One in the 0.3-mg/kg arm died from cardiac arrest 5 weeks after receiving the infusion. A patient in the 0.45-mg/kg arm had a myocardial infarction a day after getting the infusion and then nonsustained ventricular tachycardia (NSVT) 4 weeks later. Dr. Bellinger said an independent review panel determined that the CV events were in line with outcomes for high-risk patients and weren’t directly related to treatment.
He added, “Increased liver transaminases were seen in patients treated in the higher-dose cohorts. It’s transient, asymptomatic, and it resolved quickly.”
The next step involves pursuing only the 0.45- and 0.6-mg/kg doses in the next dose-escalation phase and enrolling an expansion cohort in 2024, Dr. Bellinger said, with a plan to initiate a randomized, placebo-controlled phase 2 trial in 2025.
First, do no harm
Karol Watson, MD, PhD, a women’s cardiovascular disease specialist at UCLA, said the promise of gene therapy was “revolutionary,” but that proving safety was critical going forward.
“You’re changing the genome forever,” she said. “Safety is going to be of the utmost importance especially because there are currently safe and efficacious strategies available for lipid lowering. This is a strategy that could be revolutionary, but we have to make sure that it’s safe.”
She pointed to a multinational study from earlier this year that warned about pathogenic consequences from CRISPR-based gene editing. “There are concerns about gene editing,” Dr. Watson said. “This was a whole-genome analysis showing atypical nonhomologous on-target effects of genome editing. Of course this is a very different strategy from what we heard today, but, again, we have to know that this is safe.”
Despite the small sample size from the two highest-dose groups in the study, Dr. Watson said the investigators have reason for going forward. “I think the preclinical data supports moving forward, but the next studies will have to be scrutinized carefully,” she said. “This is a preventive therapy; the first tenet is to do no harm.”
Dr. Bellinger is an employee of Verve Therapeutics, which sponsored the trial. Dr. Watson disclosed relationships with Boehringer-Ingelheim, Amgen, Lilly and Novartis.
AT AHA 2023
Diagnosing patients with sarcoidosis
A 40-year-old women is evaluated for liver abnormalities. She had elevated transaminases and alkaline phosphatase. A liver ultrasound showed multiple lesions. She underwent liver biopsy, which showed granulomas. What test results, if abnormal, would be most suggestive of sarcoidosis?
A. Erythrocyte sedimentation rate
B. C-reactive protein
C. Lymphocyte count
D. Antinuclear antibodies
The correct answer here is lymphocyte count. Sarcoidosis is in just about every differential diagnosis, as it can involve every organ system. I will share with you a few pearls I have learned over 30 years of taking care of patients with sarcoidosis. Lymphocyte counts drop with active sarcoidosis. Sarcoidosis should always be part of the differential when you see lymphopenia. El Jammal et al. studied 90 patients referred for possible granulomatous hepatitis.1 Seventy-three patients had a final diagnosis of granulomatous hepatitis, and 38 of those patients had sarcoidosis. Lymphopenia had a high specificity (85.7%) for the diagnosis of sarcoidosis, with a specificity of 100% in the patients under 50 years old.
Morell and colleagues looked at whether low lymphocyte counts and low lymphocyte percentage were markers of active sarcoidosis.2 Forty patients with biopsy-proven sarcoidosis were prospectively evaluated every 6 months. A low lymphocyte count and a low lymphocyte percentage (< 20%) were detected more frequently in patients with active sarcoidosis than in the patients with asymptomatic sarcoidosis (P < .02 and P < .0001).
Jones et al. looked at lymphopenia as a marker of sarcoidosis in patients presenting with uveitis.3 The study was a retrospective case-control study (112 patients with sarcoidosis-associated uveitis and 398 controls with other forms of uveitis). The mean lymphocyte count for patients with sarcoidosis was 1.43 vs. 2.04 for other causes of uveitis (P ≤ .0001).
Patients with sarcoidosis are at risk of hypercalciuria, hypercalcemia, and kidney stones. These are common in patients with sarcoidosis, with up to 50% of such patients having hypercalciuria. This is because in sarcoidosis patients 25(OH) vitamin D is converted in granulomas by activated macrophages to 1,25(OH)2 vitamin D, which is the active form of vitamin D.
Several studies have looked at the diagnostic utility of 1,25(OH)2 vitamin D levels in patients with suspected sarcoidosis. Rohmer and colleagues looked at whether 1,25(OH)2 vitamin D levels could help with the diagnosis of sarcoidosis as the cause of uveitis.4 They found that the level of 25(OH) vitamin D in sarcoidosis patients with uveitis was lower than in patients with uveitis without sarcoidosis, 34 vs. 43 nmol/mL (P < .02), whereas the 1,25(OH)2 vitamin D level was higher in patients with sarcoidosis than in those with uveitis without sarcoidosis, 132 vs. 108 pmol/L (P = .02). They looked at the 1,25(OH)2D/25(OH)D ratio; a ratio > 3.5 was strongly associated with an abnormal chest CT-scan (OR = 5.7, P = .003) and granulomas on bronchial biopsy (OR = 14.7, P = .007).
Kavathia et al. looked at whether elevated 1,25(OH)2 vitamin D levels predicted chronicity of sarcoidosis.5 A total of 59 sarcoidosis patients were recruited for the study. Higher serum 1,25(OH)2 vitamin D levels were associated with patients requiring repeated systemic immunosuppressive therapy or > 1 year of therapy. Increasing quartiles of serum 1,25(OH)2 vitamin D level were associated with increased odds of patients having chronic sarcoidosis (OR = 1.82; 95% CI, 1.11-2.99, P = .019).
Because of the higher activated vitamin D levels in sarcoidosis patients, they are at risk for problems with vitamin D supplementation. I have seen two patients develop large numbers of kidney stones after receiving high-dose vitamin D. Sodhi and Aldrich reported on a cohort of 196 sarcoidosis patients who had received vitamin D and compared them with 196 control patients with sarcoidosis who were not receiving vitamin D.6 Hypercalcemia was more frequent in the group that received vitamin D (42.3%) than in the group that did not (18.3%, P < .0001). In this study, only a minority (23%) of patients receiving vitamin D had their 1,25(OH)2 vitamin D level checked.
Pearl: Lymphocyte count and 1,25(OH)2 vitamin D levels can be helpful tests in assessing sarcoidosis activity. Patients with sarcoidosis who receive vitamin D should have their 1.25(OH)2 vitamin D levels monitored.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. El Jammal et al. Sarcoidosis Vasc Diffuse Lung Dis. 2023 Sep 13;40(3):e2023031.
2. Morell F et al. Chest. 2002 Apr;121(4):1239-44.
3. Jones NP et al. Br J Ophthalmol. 2016 Oct;100(10):1393-6.
4. Rohmer J et al. Ocul Immunol Inflamm. 2020 Apr 2;28(3):341-7.
5. Kavathia D et al. Respir Med. 2010 Apr;104(4):564–70.
6. Sodhi A and Aldrich T. Am J Med Sci. 2016 Sep;352(3):252-7.
A 40-year-old women is evaluated for liver abnormalities. She had elevated transaminases and alkaline phosphatase. A liver ultrasound showed multiple lesions. She underwent liver biopsy, which showed granulomas. What test results, if abnormal, would be most suggestive of sarcoidosis?
A. Erythrocyte sedimentation rate
B. C-reactive protein
C. Lymphocyte count
D. Antinuclear antibodies
The correct answer here is lymphocyte count. Sarcoidosis is in just about every differential diagnosis, as it can involve every organ system. I will share with you a few pearls I have learned over 30 years of taking care of patients with sarcoidosis. Lymphocyte counts drop with active sarcoidosis. Sarcoidosis should always be part of the differential when you see lymphopenia. El Jammal et al. studied 90 patients referred for possible granulomatous hepatitis.1 Seventy-three patients had a final diagnosis of granulomatous hepatitis, and 38 of those patients had sarcoidosis. Lymphopenia had a high specificity (85.7%) for the diagnosis of sarcoidosis, with a specificity of 100% in the patients under 50 years old.
Morell and colleagues looked at whether low lymphocyte counts and low lymphocyte percentage were markers of active sarcoidosis.2 Forty patients with biopsy-proven sarcoidosis were prospectively evaluated every 6 months. A low lymphocyte count and a low lymphocyte percentage (< 20%) were detected more frequently in patients with active sarcoidosis than in the patients with asymptomatic sarcoidosis (P < .02 and P < .0001).
Jones et al. looked at lymphopenia as a marker of sarcoidosis in patients presenting with uveitis.3 The study was a retrospective case-control study (112 patients with sarcoidosis-associated uveitis and 398 controls with other forms of uveitis). The mean lymphocyte count for patients with sarcoidosis was 1.43 vs. 2.04 for other causes of uveitis (P ≤ .0001).
Patients with sarcoidosis are at risk of hypercalciuria, hypercalcemia, and kidney stones. These are common in patients with sarcoidosis, with up to 50% of such patients having hypercalciuria. This is because in sarcoidosis patients 25(OH) vitamin D is converted in granulomas by activated macrophages to 1,25(OH)2 vitamin D, which is the active form of vitamin D.
Several studies have looked at the diagnostic utility of 1,25(OH)2 vitamin D levels in patients with suspected sarcoidosis. Rohmer and colleagues looked at whether 1,25(OH)2 vitamin D levels could help with the diagnosis of sarcoidosis as the cause of uveitis.4 They found that the level of 25(OH) vitamin D in sarcoidosis patients with uveitis was lower than in patients with uveitis without sarcoidosis, 34 vs. 43 nmol/mL (P < .02), whereas the 1,25(OH)2 vitamin D level was higher in patients with sarcoidosis than in those with uveitis without sarcoidosis, 132 vs. 108 pmol/L (P = .02). They looked at the 1,25(OH)2D/25(OH)D ratio; a ratio > 3.5 was strongly associated with an abnormal chest CT-scan (OR = 5.7, P = .003) and granulomas on bronchial biopsy (OR = 14.7, P = .007).
Kavathia et al. looked at whether elevated 1,25(OH)2 vitamin D levels predicted chronicity of sarcoidosis.5 A total of 59 sarcoidosis patients were recruited for the study. Higher serum 1,25(OH)2 vitamin D levels were associated with patients requiring repeated systemic immunosuppressive therapy or > 1 year of therapy. Increasing quartiles of serum 1,25(OH)2 vitamin D level were associated with increased odds of patients having chronic sarcoidosis (OR = 1.82; 95% CI, 1.11-2.99, P = .019).
Because of the higher activated vitamin D levels in sarcoidosis patients, they are at risk for problems with vitamin D supplementation. I have seen two patients develop large numbers of kidney stones after receiving high-dose vitamin D. Sodhi and Aldrich reported on a cohort of 196 sarcoidosis patients who had received vitamin D and compared them with 196 control patients with sarcoidosis who were not receiving vitamin D.6 Hypercalcemia was more frequent in the group that received vitamin D (42.3%) than in the group that did not (18.3%, P < .0001). In this study, only a minority (23%) of patients receiving vitamin D had their 1,25(OH)2 vitamin D level checked.
Pearl: Lymphocyte count and 1,25(OH)2 vitamin D levels can be helpful tests in assessing sarcoidosis activity. Patients with sarcoidosis who receive vitamin D should have their 1.25(OH)2 vitamin D levels monitored.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. El Jammal et al. Sarcoidosis Vasc Diffuse Lung Dis. 2023 Sep 13;40(3):e2023031.
2. Morell F et al. Chest. 2002 Apr;121(4):1239-44.
3. Jones NP et al. Br J Ophthalmol. 2016 Oct;100(10):1393-6.
4. Rohmer J et al. Ocul Immunol Inflamm. 2020 Apr 2;28(3):341-7.
5. Kavathia D et al. Respir Med. 2010 Apr;104(4):564–70.
6. Sodhi A and Aldrich T. Am J Med Sci. 2016 Sep;352(3):252-7.
A 40-year-old women is evaluated for liver abnormalities. She had elevated transaminases and alkaline phosphatase. A liver ultrasound showed multiple lesions. She underwent liver biopsy, which showed granulomas. What test results, if abnormal, would be most suggestive of sarcoidosis?
A. Erythrocyte sedimentation rate
B. C-reactive protein
C. Lymphocyte count
D. Antinuclear antibodies
The correct answer here is lymphocyte count. Sarcoidosis is in just about every differential diagnosis, as it can involve every organ system. I will share with you a few pearls I have learned over 30 years of taking care of patients with sarcoidosis. Lymphocyte counts drop with active sarcoidosis. Sarcoidosis should always be part of the differential when you see lymphopenia. El Jammal et al. studied 90 patients referred for possible granulomatous hepatitis.1 Seventy-three patients had a final diagnosis of granulomatous hepatitis, and 38 of those patients had sarcoidosis. Lymphopenia had a high specificity (85.7%) for the diagnosis of sarcoidosis, with a specificity of 100% in the patients under 50 years old.
Morell and colleagues looked at whether low lymphocyte counts and low lymphocyte percentage were markers of active sarcoidosis.2 Forty patients with biopsy-proven sarcoidosis were prospectively evaluated every 6 months. A low lymphocyte count and a low lymphocyte percentage (< 20%) were detected more frequently in patients with active sarcoidosis than in the patients with asymptomatic sarcoidosis (P < .02 and P < .0001).
Jones et al. looked at lymphopenia as a marker of sarcoidosis in patients presenting with uveitis.3 The study was a retrospective case-control study (112 patients with sarcoidosis-associated uveitis and 398 controls with other forms of uveitis). The mean lymphocyte count for patients with sarcoidosis was 1.43 vs. 2.04 for other causes of uveitis (P ≤ .0001).
Patients with sarcoidosis are at risk of hypercalciuria, hypercalcemia, and kidney stones. These are common in patients with sarcoidosis, with up to 50% of such patients having hypercalciuria. This is because in sarcoidosis patients 25(OH) vitamin D is converted in granulomas by activated macrophages to 1,25(OH)2 vitamin D, which is the active form of vitamin D.
Several studies have looked at the diagnostic utility of 1,25(OH)2 vitamin D levels in patients with suspected sarcoidosis. Rohmer and colleagues looked at whether 1,25(OH)2 vitamin D levels could help with the diagnosis of sarcoidosis as the cause of uveitis.4 They found that the level of 25(OH) vitamin D in sarcoidosis patients with uveitis was lower than in patients with uveitis without sarcoidosis, 34 vs. 43 nmol/mL (P < .02), whereas the 1,25(OH)2 vitamin D level was higher in patients with sarcoidosis than in those with uveitis without sarcoidosis, 132 vs. 108 pmol/L (P = .02). They looked at the 1,25(OH)2D/25(OH)D ratio; a ratio > 3.5 was strongly associated with an abnormal chest CT-scan (OR = 5.7, P = .003) and granulomas on bronchial biopsy (OR = 14.7, P = .007).
Kavathia et al. looked at whether elevated 1,25(OH)2 vitamin D levels predicted chronicity of sarcoidosis.5 A total of 59 sarcoidosis patients were recruited for the study. Higher serum 1,25(OH)2 vitamin D levels were associated with patients requiring repeated systemic immunosuppressive therapy or > 1 year of therapy. Increasing quartiles of serum 1,25(OH)2 vitamin D level were associated with increased odds of patients having chronic sarcoidosis (OR = 1.82; 95% CI, 1.11-2.99, P = .019).
Because of the higher activated vitamin D levels in sarcoidosis patients, they are at risk for problems with vitamin D supplementation. I have seen two patients develop large numbers of kidney stones after receiving high-dose vitamin D. Sodhi and Aldrich reported on a cohort of 196 sarcoidosis patients who had received vitamin D and compared them with 196 control patients with sarcoidosis who were not receiving vitamin D.6 Hypercalcemia was more frequent in the group that received vitamin D (42.3%) than in the group that did not (18.3%, P < .0001). In this study, only a minority (23%) of patients receiving vitamin D had their 1,25(OH)2 vitamin D level checked.
Pearl: Lymphocyte count and 1,25(OH)2 vitamin D levels can be helpful tests in assessing sarcoidosis activity. Patients with sarcoidosis who receive vitamin D should have their 1.25(OH)2 vitamin D levels monitored.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. El Jammal et al. Sarcoidosis Vasc Diffuse Lung Dis. 2023 Sep 13;40(3):e2023031.
2. Morell F et al. Chest. 2002 Apr;121(4):1239-44.
3. Jones NP et al. Br J Ophthalmol. 2016 Oct;100(10):1393-6.
4. Rohmer J et al. Ocul Immunol Inflamm. 2020 Apr 2;28(3):341-7.
5. Kavathia D et al. Respir Med. 2010 Apr;104(4):564–70.
6. Sodhi A and Aldrich T. Am J Med Sci. 2016 Sep;352(3):252-7.
New at-home test approved for chlamydia and gonorrhea
Called Simple 2, it’s the first test approved by the Food and Drug Administration that uses a sample collected at home to test for an STD, other than tests for HIV. The test can be purchased over-the-counter in stores or ordered online and delivered in discreet packaging. A vaginal swab or urine sample is collected and then sent for laboratory testing using a prepaid shipping label.
The FDA issued the final needed approval on Nov. 15, and the product is already for sale on the website of the manufacturer, LetsGetChecked. The listed price is $99 with free shipping for a single test kit, and the site offers a discounted subscription to receive a kit every 3 months for $69.30 per kit.
Gonorrhea cases have surged 28% since 2017, reaching 700,000 cases during 2021, Centers for Disease Control and Prevention data show. Chlamydia has also been on the rise, up 4% from 2020 to 2021, with 1.6 million annual infections.
Previously, tests for the two STDs required that samples be taken at a health care location such as a doctor’s office. The Simple 2 test results can be retrieved online, and a health care provider will reach out to people whose tests are positive or invalid. Results are typically received in 2-5 days, according to a press release from LetsGetChecked, which also offers treatment services.
“This authorization marks an important public health milestone, giving patients more information about their health from the privacy of their own home,” said Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, in a statement. “We are eager to continue supporting greater consumer access to diagnostic tests, which helps further our goal of bringing more health care into the home.”
A version of this article first appeared on WebMD.com.
Called Simple 2, it’s the first test approved by the Food and Drug Administration that uses a sample collected at home to test for an STD, other than tests for HIV. The test can be purchased over-the-counter in stores or ordered online and delivered in discreet packaging. A vaginal swab or urine sample is collected and then sent for laboratory testing using a prepaid shipping label.
The FDA issued the final needed approval on Nov. 15, and the product is already for sale on the website of the manufacturer, LetsGetChecked. The listed price is $99 with free shipping for a single test kit, and the site offers a discounted subscription to receive a kit every 3 months for $69.30 per kit.
Gonorrhea cases have surged 28% since 2017, reaching 700,000 cases during 2021, Centers for Disease Control and Prevention data show. Chlamydia has also been on the rise, up 4% from 2020 to 2021, with 1.6 million annual infections.
Previously, tests for the two STDs required that samples be taken at a health care location such as a doctor’s office. The Simple 2 test results can be retrieved online, and a health care provider will reach out to people whose tests are positive or invalid. Results are typically received in 2-5 days, according to a press release from LetsGetChecked, which also offers treatment services.
“This authorization marks an important public health milestone, giving patients more information about their health from the privacy of their own home,” said Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, in a statement. “We are eager to continue supporting greater consumer access to diagnostic tests, which helps further our goal of bringing more health care into the home.”
A version of this article first appeared on WebMD.com.
Called Simple 2, it’s the first test approved by the Food and Drug Administration that uses a sample collected at home to test for an STD, other than tests for HIV. The test can be purchased over-the-counter in stores or ordered online and delivered in discreet packaging. A vaginal swab or urine sample is collected and then sent for laboratory testing using a prepaid shipping label.
The FDA issued the final needed approval on Nov. 15, and the product is already for sale on the website of the manufacturer, LetsGetChecked. The listed price is $99 with free shipping for a single test kit, and the site offers a discounted subscription to receive a kit every 3 months for $69.30 per kit.
Gonorrhea cases have surged 28% since 2017, reaching 700,000 cases during 2021, Centers for Disease Control and Prevention data show. Chlamydia has also been on the rise, up 4% from 2020 to 2021, with 1.6 million annual infections.
Previously, tests for the two STDs required that samples be taken at a health care location such as a doctor’s office. The Simple 2 test results can be retrieved online, and a health care provider will reach out to people whose tests are positive or invalid. Results are typically received in 2-5 days, according to a press release from LetsGetChecked, which also offers treatment services.
“This authorization marks an important public health milestone, giving patients more information about their health from the privacy of their own home,” said Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological Health, in a statement. “We are eager to continue supporting greater consumer access to diagnostic tests, which helps further our goal of bringing more health care into the home.”
A version of this article first appeared on WebMD.com.
Hourly air pollution exposure: A risk factor for stroke
TOPLINE:
METHODOLOGY:
- Limited studies have investigated the association between hourly exposure to air pollutants and specific stroke subtypes, especially in regions with moderate to high levels of air pollution.
- The multicenter case-crossover study evaluated the association between hourly exposure to air pollution and stroke among 86,635 emergency admissions for stroke across 10 hospitals in 3 cities.
- Of 86,635 admissions, 79,478 were admitted for ischemic stroke, 3,122 for hemorrhagic stroke, and 4,035 for undetermined type of stroke.
- Hourly levels of fine particulate matter (PM2.5), respirable PM (PM10), nitrogen dioxide (NO2), and sulfur dioxide (SO2) were collected from the China National Environmental Monitoring Center.
TAKEAWAY:
- Exposure to NO2 and SO2 increased the risk for emergency admission for stroke shortly after exposure by 3.34% (95% confidence interval, 1.41%-5.31%) and 2.81% (95% CI, 1.15%-4.51%), respectively.
- Among men, exposure to PM2.5 and PM10 increased the risk for emergency admission for stroke by 3.40% (95% CI, 1.21%-5.64%) and 4.33% (95% CI, 2.18%-6.53%), respectively.
- Among patients aged less than 65 years, exposure to PM10 and NO2 increased the risk for emergency admissions for stroke shortly after exposure by 4.88% (95% CI, 2.29%-7.54%) and 5.59% (95% CI, 2.34%-8.93%), respectively.
IN PRACTICE:
“These variations in susceptibility highlight the importance of implementing effective health protection measures to reduce exposure to air pollution and mitigate the risk of stroke in younger and male populations,” wrote the authors.
SOURCE:
The study was led by Xin Lv, MD, department of epidemiology and biostatistics, School of Public Health, Capital Medical University, Beijing. It was published online in the journal Stroke.
LIMITATIONS:
- Using data from the nearest monitoring site to the hospital address may lead to localized variations in pollution concentrations when assessing exposure.
- There may be a possibility of residual confounding resulting from time-varying lifestyle-related factors.
DISCLOSURES:
This study was supported by the Zhejiang Provincial Project for Medical Research and Health Sciences. No disclosures were reported.
A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Limited studies have investigated the association between hourly exposure to air pollutants and specific stroke subtypes, especially in regions with moderate to high levels of air pollution.
- The multicenter case-crossover study evaluated the association between hourly exposure to air pollution and stroke among 86,635 emergency admissions for stroke across 10 hospitals in 3 cities.
- Of 86,635 admissions, 79,478 were admitted for ischemic stroke, 3,122 for hemorrhagic stroke, and 4,035 for undetermined type of stroke.
- Hourly levels of fine particulate matter (PM2.5), respirable PM (PM10), nitrogen dioxide (NO2), and sulfur dioxide (SO2) were collected from the China National Environmental Monitoring Center.
TAKEAWAY:
- Exposure to NO2 and SO2 increased the risk for emergency admission for stroke shortly after exposure by 3.34% (95% confidence interval, 1.41%-5.31%) and 2.81% (95% CI, 1.15%-4.51%), respectively.
- Among men, exposure to PM2.5 and PM10 increased the risk for emergency admission for stroke by 3.40% (95% CI, 1.21%-5.64%) and 4.33% (95% CI, 2.18%-6.53%), respectively.
- Among patients aged less than 65 years, exposure to PM10 and NO2 increased the risk for emergency admissions for stroke shortly after exposure by 4.88% (95% CI, 2.29%-7.54%) and 5.59% (95% CI, 2.34%-8.93%), respectively.
IN PRACTICE:
“These variations in susceptibility highlight the importance of implementing effective health protection measures to reduce exposure to air pollution and mitigate the risk of stroke in younger and male populations,” wrote the authors.
SOURCE:
The study was led by Xin Lv, MD, department of epidemiology and biostatistics, School of Public Health, Capital Medical University, Beijing. It was published online in the journal Stroke.
LIMITATIONS:
- Using data from the nearest monitoring site to the hospital address may lead to localized variations in pollution concentrations when assessing exposure.
- There may be a possibility of residual confounding resulting from time-varying lifestyle-related factors.
DISCLOSURES:
This study was supported by the Zhejiang Provincial Project for Medical Research and Health Sciences. No disclosures were reported.
A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Limited studies have investigated the association between hourly exposure to air pollutants and specific stroke subtypes, especially in regions with moderate to high levels of air pollution.
- The multicenter case-crossover study evaluated the association between hourly exposure to air pollution and stroke among 86,635 emergency admissions for stroke across 10 hospitals in 3 cities.
- Of 86,635 admissions, 79,478 were admitted for ischemic stroke, 3,122 for hemorrhagic stroke, and 4,035 for undetermined type of stroke.
- Hourly levels of fine particulate matter (PM2.5), respirable PM (PM10), nitrogen dioxide (NO2), and sulfur dioxide (SO2) were collected from the China National Environmental Monitoring Center.
TAKEAWAY:
- Exposure to NO2 and SO2 increased the risk for emergency admission for stroke shortly after exposure by 3.34% (95% confidence interval, 1.41%-5.31%) and 2.81% (95% CI, 1.15%-4.51%), respectively.
- Among men, exposure to PM2.5 and PM10 increased the risk for emergency admission for stroke by 3.40% (95% CI, 1.21%-5.64%) and 4.33% (95% CI, 2.18%-6.53%), respectively.
- Among patients aged less than 65 years, exposure to PM10 and NO2 increased the risk for emergency admissions for stroke shortly after exposure by 4.88% (95% CI, 2.29%-7.54%) and 5.59% (95% CI, 2.34%-8.93%), respectively.
IN PRACTICE:
“These variations in susceptibility highlight the importance of implementing effective health protection measures to reduce exposure to air pollution and mitigate the risk of stroke in younger and male populations,” wrote the authors.
SOURCE:
The study was led by Xin Lv, MD, department of epidemiology and biostatistics, School of Public Health, Capital Medical University, Beijing. It was published online in the journal Stroke.
LIMITATIONS:
- Using data from the nearest monitoring site to the hospital address may lead to localized variations in pollution concentrations when assessing exposure.
- There may be a possibility of residual confounding resulting from time-varying lifestyle-related factors.
DISCLOSURES:
This study was supported by the Zhejiang Provincial Project for Medical Research and Health Sciences. No disclosures were reported.
A version of this article first appeared on Medscape.com.
Unexplained collapse unveils rare blood disorder
This case report was published in the New England Journal of Medicine.
Noting the patient’s confusion and aphasia, emergency medical services were alerted, and she was taken to the emergency department of Massachusetts General Hospital. Initial examination revealed aphasia and coordination difficulties. However, imaging studies, including CT angiography, showed no signs of stroke or other neurological abnormalities.
The patient’s coworkers had observed that she appeared “unwell.” Her medical history included hypertension, which was managed with amlodipine, and there was no known family history of neurologic disorders.
During the examination, her vital signs were within normal ranges.
The patient’s potassium level of 2.5 mmol/L was noteworthy, indicating hypokalemia. Additionally, the patient presented with anemia and thrombocytopenia. Additional laboratory results unveiled thrombotic thrombocytopenic purpura (TTP), a rare blood disorder characterized by microangiopathic hemolytic anemia. The microscopic examination of a peripheral blood smear confirmed the extent of thrombocytopenia and was particularly notable for the increased number of schistocytes. The patient’s peripheral blood smear revealed five or six schistocytes per high-power field, constituting approximately 5% of the red cells. This significant number of schistocytes aligned with the severity of anemia and thrombocytopenia, confirming the diagnosis of microangiopathic hemolytic anemia.
Acquired TTP is an autoimmune condition driven by antibody-mediated clearance of the plasma enzyme ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motif 13). Confirmatory laboratory testing for ADAMTS13 takes 1-3 days; therefore, therapeutic plasma exchange with glucocorticoid therapy and rituximab was initiated, which promptly improved her condition.
In this patient, the ADAMTS13 activity level was severely reduced (< 5%; reference value > 67%), and the inhibitor was present (1.4 inhibitor units; reference value ≤ 0.4).
Rectal cancer was diagnosed in this patient 2 months after the diagnosis of acquired TTP.
After undergoing four weekly infusions of rituximab and a 2-month tapering course of glucocorticoids, the patient experienced a relapse, approximately 6 months following the acquired TTP diagnosis. In response, therapeutic plasma exchange and glucocorticoid therapy were administered. There is a possibility that the underlying cancer played a role in the relapse. To minimize the risk for recurrence, the patient also received a second round of rituximab.
While establishing a clear cause is difficult, acquired TTP often appears to arise in connection with either an immune trigger, such as a viral infection, or immune dysregulation associated with another autoimmune disease or ongoing cancer. In this case, 4 weeks before the acquired TTP diagnosis, the patient had experienced COVID-19, which was likely to be the most probable trigger. However, rectal cancer was also identified in the patient, and whether these conditions are directly linked remains unclear.
A version of this article first appeared on Medscape.com.
This case report was published in the New England Journal of Medicine.
Noting the patient’s confusion and aphasia, emergency medical services were alerted, and she was taken to the emergency department of Massachusetts General Hospital. Initial examination revealed aphasia and coordination difficulties. However, imaging studies, including CT angiography, showed no signs of stroke or other neurological abnormalities.
The patient’s coworkers had observed that she appeared “unwell.” Her medical history included hypertension, which was managed with amlodipine, and there was no known family history of neurologic disorders.
During the examination, her vital signs were within normal ranges.
The patient’s potassium level of 2.5 mmol/L was noteworthy, indicating hypokalemia. Additionally, the patient presented with anemia and thrombocytopenia. Additional laboratory results unveiled thrombotic thrombocytopenic purpura (TTP), a rare blood disorder characterized by microangiopathic hemolytic anemia. The microscopic examination of a peripheral blood smear confirmed the extent of thrombocytopenia and was particularly notable for the increased number of schistocytes. The patient’s peripheral blood smear revealed five or six schistocytes per high-power field, constituting approximately 5% of the red cells. This significant number of schistocytes aligned with the severity of anemia and thrombocytopenia, confirming the diagnosis of microangiopathic hemolytic anemia.
Acquired TTP is an autoimmune condition driven by antibody-mediated clearance of the plasma enzyme ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motif 13). Confirmatory laboratory testing for ADAMTS13 takes 1-3 days; therefore, therapeutic plasma exchange with glucocorticoid therapy and rituximab was initiated, which promptly improved her condition.
In this patient, the ADAMTS13 activity level was severely reduced (< 5%; reference value > 67%), and the inhibitor was present (1.4 inhibitor units; reference value ≤ 0.4).
Rectal cancer was diagnosed in this patient 2 months after the diagnosis of acquired TTP.
After undergoing four weekly infusions of rituximab and a 2-month tapering course of glucocorticoids, the patient experienced a relapse, approximately 6 months following the acquired TTP diagnosis. In response, therapeutic plasma exchange and glucocorticoid therapy were administered. There is a possibility that the underlying cancer played a role in the relapse. To minimize the risk for recurrence, the patient also received a second round of rituximab.
While establishing a clear cause is difficult, acquired TTP often appears to arise in connection with either an immune trigger, such as a viral infection, or immune dysregulation associated with another autoimmune disease or ongoing cancer. In this case, 4 weeks before the acquired TTP diagnosis, the patient had experienced COVID-19, which was likely to be the most probable trigger. However, rectal cancer was also identified in the patient, and whether these conditions are directly linked remains unclear.
A version of this article first appeared on Medscape.com.
This case report was published in the New England Journal of Medicine.
Noting the patient’s confusion and aphasia, emergency medical services were alerted, and she was taken to the emergency department of Massachusetts General Hospital. Initial examination revealed aphasia and coordination difficulties. However, imaging studies, including CT angiography, showed no signs of stroke or other neurological abnormalities.
The patient’s coworkers had observed that she appeared “unwell.” Her medical history included hypertension, which was managed with amlodipine, and there was no known family history of neurologic disorders.
During the examination, her vital signs were within normal ranges.
The patient’s potassium level of 2.5 mmol/L was noteworthy, indicating hypokalemia. Additionally, the patient presented with anemia and thrombocytopenia. Additional laboratory results unveiled thrombotic thrombocytopenic purpura (TTP), a rare blood disorder characterized by microangiopathic hemolytic anemia. The microscopic examination of a peripheral blood smear confirmed the extent of thrombocytopenia and was particularly notable for the increased number of schistocytes. The patient’s peripheral blood smear revealed five or six schistocytes per high-power field, constituting approximately 5% of the red cells. This significant number of schistocytes aligned with the severity of anemia and thrombocytopenia, confirming the diagnosis of microangiopathic hemolytic anemia.
Acquired TTP is an autoimmune condition driven by antibody-mediated clearance of the plasma enzyme ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motif 13). Confirmatory laboratory testing for ADAMTS13 takes 1-3 days; therefore, therapeutic plasma exchange with glucocorticoid therapy and rituximab was initiated, which promptly improved her condition.
In this patient, the ADAMTS13 activity level was severely reduced (< 5%; reference value > 67%), and the inhibitor was present (1.4 inhibitor units; reference value ≤ 0.4).
Rectal cancer was diagnosed in this patient 2 months after the diagnosis of acquired TTP.
After undergoing four weekly infusions of rituximab and a 2-month tapering course of glucocorticoids, the patient experienced a relapse, approximately 6 months following the acquired TTP diagnosis. In response, therapeutic plasma exchange and glucocorticoid therapy were administered. There is a possibility that the underlying cancer played a role in the relapse. To minimize the risk for recurrence, the patient also received a second round of rituximab.
While establishing a clear cause is difficult, acquired TTP often appears to arise in connection with either an immune trigger, such as a viral infection, or immune dysregulation associated with another autoimmune disease or ongoing cancer. In this case, 4 weeks before the acquired TTP diagnosis, the patient had experienced COVID-19, which was likely to be the most probable trigger. However, rectal cancer was also identified in the patient, and whether these conditions are directly linked remains unclear.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE