Cardiology

Chronic cough took center stage at the European Respiratory Society Congress session titled “Conditions We Are Just Dealing With the Tip of the Iceberg in Primary Care: Frequently Mismanaged Conditions in Primary Health Care.”

“When it comes to chronic cough, general practitioners often feel lost,” Miguel Román Rodríguez, family doctor and an associate professor of family medicine at the University of the Balearic Islands, Palma, Mallorca, Spain, and one of the chairs of the session, said to this news organization.

“GPs are central in diagnosing conditions like chronic cough. We bring something that the specialists don’t bring: the knowledge of the context, of the family, the longitudinal history,” echoed the second chair of the session, Hilary Pinnock, family physician and professor of primary care respiratory medicine at the University of Edinburgh.
 

Understanding the multifaceted nature of chronic cough

Imran Satia, an assistant professor at McMaster University, Hamilton, Ont., guided attendees at the Milan, Italy, meeting through a comprehensive exploration of chronic cough. The first issue he addressed was the definition of the condition, emphasizing that it is defined by its duration, with chronic cough typically lasting for more than 8 weeks. Prof. Satia pointed out common associations of chronic cough, including asthma, nasal disease, and reflux disease.

Delving into epidemiology, he cited a meta-analysis indicating a global prevalence of approximately 10% in the adult population, with significant regional variability: from 18.1% in Australia to 2.3% in Africa. Notably, the Canadian Longitudinal Study on Aging found an overall prevalence of 16% at baseline. “The most common risk factor was smoke, but even in nonsmokers the prevalence reached 10%,” Prof. Satia added, highlighting that it increased with age and changed depending on location. “The most common associated comorbidities were heart failure and hypertension, but also conditions related to chronic pain, mood, and anxiety,” he explained.

Mental health was identified as a crucial factor in chronic cough, with psychological distress and depressive symptoms emerging as risk factors for developing chronic cough over the next 3 years, contributing to a 20% increased risk.
 

Effective management strategies

Prof. Satia proposed the use of algorithms to aid in the management of patients with chronic cough in primary care. He introduced a Canadian algorithm that offers specific recommendations for both primary and secondary care.

The algorithm’s primary care assessment, step 1, includes a comprehensive evaluation of the cough history (duration, severity, triggers, nature, location); cardiorespiratory, gastrointestinal, and nasal symptoms; and use of angiotensin-converting enzyme inhibitors and smoking status. Essential diagnostic tests, such as chest radiography (to check for structural disease), complete blood cell count, and spirometry (with or without bronchodilator reversibility), were emphasized. Urgent referral criteria encompassed symptoms like hemoptysis, weight loss, fever, or abnormal chest radiography findings.

“When checking for cough history, GPs should always consider factors like the presence of dry or productive cough, mental health, presence of chronic pain, stroke, and swallowing,” said Prof. Satia, stressing the importance of documenting the impact of chronic cough on quality of life, work life, social life, and family life. “This is something that doctors sometimes do not ask about. They may think that these are not major problems, but acknowledging their importance can help the patient,” he added.

Step 2 of the algorithm focuses on treatment options tailored to specific diagnoses, such as asthma or chronic obstructive pulmonary disease. Prof. Satia urged caution, emphasizing that treatment should only be initiated when evidence of these conditions is present. Additionally, he encouraged early consideration of cough hypersensitivity syndrome when patients exhibit coughing in response to low levels of mechanical stimulation.
 

Current treatments and future prospects

Prof. Satia presented an overview of existing treatments for chronic cough, outlining their respective advantages and disadvantages. For instance, speech therapy is a patient-led approach with no side effects but entails challenges related to access, costs, and patient motivation. On the other hand, low-dose morphine offers rapid relief but is associated with issues like nausea, stigma, and constipation.

Looking ahead, Prof. Satia shared the results of COUGH-1 and COUGH-2, pivotal phase 3 trials evaluating the oral, peripherally acting P2X3-receptor antagonist gefapixant. This drug, currently approved in Switzerland and Japan, demonstrated a significant reduction in cough frequency, compared with placebo, with rapid and sustained effects. “The estimated relative reduction for 45 mg was 18.45% in COUGH-1 (12 weeks) and 14.64% in COUGH-2 (24 weeks). Of note, cough reduction is very quick and sustained with gefapixant, but a 40% reduction is observed in the placebo arm,” commented Prof. Satia.

Experts unanimously stressed the importance for specialists and GPs of effective communication in managing chronic cough, involving both patients and their families.

“As GPs, we are crucial to manage the common problems, but we are also crucial to spot the needle in the haystack: this is extremely difficult and challenging, and we need support from our colleagues,” Dr. Pinnock concluded.

Prof. Satia reported funding from Merck MSD, AstraZeneca, and GSK; consulting fees from Merck MSD, Genentech, and Respiplus; and speaker fees from AstraZeneca, GSK, and Merck MSD.

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

Chronic cough took center stage at the European Respiratory Society Congress session titled “Conditions We Are Just Dealing With the Tip of the Iceberg in Primary Care: Frequently Mismanaged Conditions in Primary Health Care.”

“When it comes to chronic cough, general practitioners often feel lost,” Miguel Román Rodríguez, family doctor and an associate professor of family medicine at the University of the Balearic Islands, Palma, Mallorca, Spain, and one of the chairs of the session, said to this news organization.

“GPs are central in diagnosing conditions like chronic cough. We bring something that the specialists don’t bring: the knowledge of the context, of the family, the longitudinal history,” echoed the second chair of the session, Hilary Pinnock, family physician and professor of primary care respiratory medicine at the University of Edinburgh.
 

Understanding the multifaceted nature of chronic cough

Imran Satia, an assistant professor at McMaster University, Hamilton, Ont., guided attendees at the Milan, Italy, meeting through a comprehensive exploration of chronic cough. The first issue he addressed was the definition of the condition, emphasizing that it is defined by its duration, with chronic cough typically lasting for more than 8 weeks. Prof. Satia pointed out common associations of chronic cough, including asthma, nasal disease, and reflux disease.

Delving into epidemiology, he cited a meta-analysis indicating a global prevalence of approximately 10% in the adult population, with significant regional variability: from 18.1% in Australia to 2.3% in Africa. Notably, the Canadian Longitudinal Study on Aging found an overall prevalence of 16% at baseline. “The most common risk factor was smoke, but even in nonsmokers the prevalence reached 10%,” Prof. Satia added, highlighting that it increased with age and changed depending on location. “The most common associated comorbidities were heart failure and hypertension, but also conditions related to chronic pain, mood, and anxiety,” he explained.

Mental health was identified as a crucial factor in chronic cough, with psychological distress and depressive symptoms emerging as risk factors for developing chronic cough over the next 3 years, contributing to a 20% increased risk.
 

Effective management strategies

Prof. Satia proposed the use of algorithms to aid in the management of patients with chronic cough in primary care. He introduced a Canadian algorithm that offers specific recommendations for both primary and secondary care.

The algorithm’s primary care assessment, step 1, includes a comprehensive evaluation of the cough history (duration, severity, triggers, nature, location); cardiorespiratory, gastrointestinal, and nasal symptoms; and use of angiotensin-converting enzyme inhibitors and smoking status. Essential diagnostic tests, such as chest radiography (to check for structural disease), complete blood cell count, and spirometry (with or without bronchodilator reversibility), were emphasized. Urgent referral criteria encompassed symptoms like hemoptysis, weight loss, fever, or abnormal chest radiography findings.

“When checking for cough history, GPs should always consider factors like the presence of dry or productive cough, mental health, presence of chronic pain, stroke, and swallowing,” said Prof. Satia, stressing the importance of documenting the impact of chronic cough on quality of life, work life, social life, and family life. “This is something that doctors sometimes do not ask about. They may think that these are not major problems, but acknowledging their importance can help the patient,” he added.

Step 2 of the algorithm focuses on treatment options tailored to specific diagnoses, such as asthma or chronic obstructive pulmonary disease. Prof. Satia urged caution, emphasizing that treatment should only be initiated when evidence of these conditions is present. Additionally, he encouraged early consideration of cough hypersensitivity syndrome when patients exhibit coughing in response to low levels of mechanical stimulation.
 

Current treatments and future prospects

Prof. Satia presented an overview of existing treatments for chronic cough, outlining their respective advantages and disadvantages. For instance, speech therapy is a patient-led approach with no side effects but entails challenges related to access, costs, and patient motivation. On the other hand, low-dose morphine offers rapid relief but is associated with issues like nausea, stigma, and constipation.

Looking ahead, Prof. Satia shared the results of COUGH-1 and COUGH-2, pivotal phase 3 trials evaluating the oral, peripherally acting P2X3-receptor antagonist gefapixant. This drug, currently approved in Switzerland and Japan, demonstrated a significant reduction in cough frequency, compared with placebo, with rapid and sustained effects. “The estimated relative reduction for 45 mg was 18.45% in COUGH-1 (12 weeks) and 14.64% in COUGH-2 (24 weeks). Of note, cough reduction is very quick and sustained with gefapixant, but a 40% reduction is observed in the placebo arm,” commented Prof. Satia.

Experts unanimously stressed the importance for specialists and GPs of effective communication in managing chronic cough, involving both patients and their families.

“As GPs, we are crucial to manage the common problems, but we are also crucial to spot the needle in the haystack: this is extremely difficult and challenging, and we need support from our colleagues,” Dr. Pinnock concluded.

Prof. Satia reported funding from Merck MSD, AstraZeneca, and GSK; consulting fees from Merck MSD, Genentech, and Respiplus; and speaker fees from AstraZeneca, GSK, and Merck MSD.

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

Chronic cough took center stage at the European Respiratory Society Congress session titled “Conditions We Are Just Dealing With the Tip of the Iceberg in Primary Care: Frequently Mismanaged Conditions in Primary Health Care.”

“When it comes to chronic cough, general practitioners often feel lost,” Miguel Román Rodríguez, family doctor and an associate professor of family medicine at the University of the Balearic Islands, Palma, Mallorca, Spain, and one of the chairs of the session, said to this news organization.

“GPs are central in diagnosing conditions like chronic cough. We bring something that the specialists don’t bring: the knowledge of the context, of the family, the longitudinal history,” echoed the second chair of the session, Hilary Pinnock, family physician and professor of primary care respiratory medicine at the University of Edinburgh.
 

Understanding the multifaceted nature of chronic cough

Imran Satia, an assistant professor at McMaster University, Hamilton, Ont., guided attendees at the Milan, Italy, meeting through a comprehensive exploration of chronic cough. The first issue he addressed was the definition of the condition, emphasizing that it is defined by its duration, with chronic cough typically lasting for more than 8 weeks. Prof. Satia pointed out common associations of chronic cough, including asthma, nasal disease, and reflux disease.

Delving into epidemiology, he cited a meta-analysis indicating a global prevalence of approximately 10% in the adult population, with significant regional variability: from 18.1% in Australia to 2.3% in Africa. Notably, the Canadian Longitudinal Study on Aging found an overall prevalence of 16% at baseline. “The most common risk factor was smoke, but even in nonsmokers the prevalence reached 10%,” Prof. Satia added, highlighting that it increased with age and changed depending on location. “The most common associated comorbidities were heart failure and hypertension, but also conditions related to chronic pain, mood, and anxiety,” he explained.

Mental health was identified as a crucial factor in chronic cough, with psychological distress and depressive symptoms emerging as risk factors for developing chronic cough over the next 3 years, contributing to a 20% increased risk.
 

Effective management strategies

Prof. Satia proposed the use of algorithms to aid in the management of patients with chronic cough in primary care. He introduced a Canadian algorithm that offers specific recommendations for both primary and secondary care.

The algorithm’s primary care assessment, step 1, includes a comprehensive evaluation of the cough history (duration, severity, triggers, nature, location); cardiorespiratory, gastrointestinal, and nasal symptoms; and use of angiotensin-converting enzyme inhibitors and smoking status. Essential diagnostic tests, such as chest radiography (to check for structural disease), complete blood cell count, and spirometry (with or without bronchodilator reversibility), were emphasized. Urgent referral criteria encompassed symptoms like hemoptysis, weight loss, fever, or abnormal chest radiography findings.

“When checking for cough history, GPs should always consider factors like the presence of dry or productive cough, mental health, presence of chronic pain, stroke, and swallowing,” said Prof. Satia, stressing the importance of documenting the impact of chronic cough on quality of life, work life, social life, and family life. “This is something that doctors sometimes do not ask about. They may think that these are not major problems, but acknowledging their importance can help the patient,” he added.

Step 2 of the algorithm focuses on treatment options tailored to specific diagnoses, such as asthma or chronic obstructive pulmonary disease. Prof. Satia urged caution, emphasizing that treatment should only be initiated when evidence of these conditions is present. Additionally, he encouraged early consideration of cough hypersensitivity syndrome when patients exhibit coughing in response to low levels of mechanical stimulation.
 

Current treatments and future prospects

Prof. Satia presented an overview of existing treatments for chronic cough, outlining their respective advantages and disadvantages. For instance, speech therapy is a patient-led approach with no side effects but entails challenges related to access, costs, and patient motivation. On the other hand, low-dose morphine offers rapid relief but is associated with issues like nausea, stigma, and constipation.

Looking ahead, Prof. Satia shared the results of COUGH-1 and COUGH-2, pivotal phase 3 trials evaluating the oral, peripherally acting P2X3-receptor antagonist gefapixant. This drug, currently approved in Switzerland and Japan, demonstrated a significant reduction in cough frequency, compared with placebo, with rapid and sustained effects. “The estimated relative reduction for 45 mg was 18.45% in COUGH-1 (12 weeks) and 14.64% in COUGH-2 (24 weeks). Of note, cough reduction is very quick and sustained with gefapixant, but a 40% reduction is observed in the placebo arm,” commented Prof. Satia.

Experts unanimously stressed the importance for specialists and GPs of effective communication in managing chronic cough, involving both patients and their families.

“As GPs, we are crucial to manage the common problems, but we are also crucial to spot the needle in the haystack: this is extremely difficult and challenging, and we need support from our colleagues,” Dr. Pinnock concluded.

Prof. Satia reported funding from Merck MSD, AstraZeneca, and GSK; consulting fees from Merck MSD, Genentech, and Respiplus; and speaker fees from AstraZeneca, GSK, and Merck MSD.

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

Zilebesiran (Alnylam Pharmaceuticals), an investigational, subcutaneously administered small-interfering RNA (siRNA) therapeutic in development for the treatment of hypertension, met the primary and secondary endpoints, with an “encouraging” safety profile in the phase 2 KARDIA-1 study, the company announced.

KARDIA-1 is a phase 2 randomized, double-blind, placebo-controlled, dose-ranging study evaluating the efficacy and safety of zilebesiran as monotherapy in 394 adults with mild to moderate untreated hypertension or on stable therapy with one or more antihypertensive drugs.

Patients were randomly assigned to one of five treatment arms during a 12-month double-blind period and double-blind extension period: 150 mg or 300 mg zilebesiran subcutaneously once every 6 months, 300 mg or 600 mg zilebesiran subcutaneously once every 3 months, or placebo. Patients taking placebo were randomly assigned to one of the four initial zilebesiran dose regimens beginning at month 6.

The primary endpoint was change from baseline in systolic blood pressure (SBP) at 3 months assessed by 24-hour ambulatory blood pressure monitoring.

Topline data show a dose-dependent, clinically significant reduction in 24-hour mean SBP, with a placebo-subtracted reduction greater than 15 mm Hg (P < .0001) with both the 300 mg and 600 mg doses.

The study also met key secondary endpoints, showing “consistent and sustained reductions” in SBP at 6 months, which supports quarterly or biannual dosing, the company said.

There was one death due to cardiopulmonary arrest in a zilebesiran-treated patient that was considered unrelated to the drug. Serious adverse events were reported in 3.6% of zilebesiran-treated patients and 6.7% of placebo-treated patients. None was considered related to the study drug.

Adverse events occurring in 5% or more of zilebesiran-treated patients in any dose arm included COVID-19, injection-site reaction, hyperkalemia, hypertension, upper respiratory tract infection, arthralgia, and headache.

“As a physician, I believe these KARDIA-1 results, which demonstrate clinically significant reductions in systolic blood pressure of greater than 15 mm Hg, along with the ability to achieve durable tonic blood pressure control, provide hope that we may one day have access to a novel therapy with the potential to address the significant unmet needs of patients with uncontrolled hypertension who are at high risk of future cardiovascular events,” study investigator George L. Bakris, MD, director, American Heart Association Comprehensive Hypertension Center, University of Chicago Medicine, said in a statement.

The phase 2 results “further validate” the phase 1 results, published in the New England Journal of Medicine, Simon Fox, PhD, vice president, zilebesiran program lead at Alnylam, said in the statement.

The full KARDIA-1 results will be reported at an upcoming scientific conference, the statement notes. Topline results from the KARDIA-2 phase 2 study of zilebesiran in combination with one of three standard classes of antihypertensive medications in patients with mild to moderate hypertension are expected in early 2024.

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

Zilebesiran (Alnylam Pharmaceuticals), an investigational, subcutaneously administered small-interfering RNA (siRNA) therapeutic in development for the treatment of hypertension, met the primary and secondary endpoints, with an “encouraging” safety profile in the phase 2 KARDIA-1 study, the company announced.

KARDIA-1 is a phase 2 randomized, double-blind, placebo-controlled, dose-ranging study evaluating the efficacy and safety of zilebesiran as monotherapy in 394 adults with mild to moderate untreated hypertension or on stable therapy with one or more antihypertensive drugs.

Patients were randomly assigned to one of five treatment arms during a 12-month double-blind period and double-blind extension period: 150 mg or 300 mg zilebesiran subcutaneously once every 6 months, 300 mg or 600 mg zilebesiran subcutaneously once every 3 months, or placebo. Patients taking placebo were randomly assigned to one of the four initial zilebesiran dose regimens beginning at month 6.

The primary endpoint was change from baseline in systolic blood pressure (SBP) at 3 months assessed by 24-hour ambulatory blood pressure monitoring.

Topline data show a dose-dependent, clinically significant reduction in 24-hour mean SBP, with a placebo-subtracted reduction greater than 15 mm Hg (P < .0001) with both the 300 mg and 600 mg doses.

The study also met key secondary endpoints, showing “consistent and sustained reductions” in SBP at 6 months, which supports quarterly or biannual dosing, the company said.

There was one death due to cardiopulmonary arrest in a zilebesiran-treated patient that was considered unrelated to the drug. Serious adverse events were reported in 3.6% of zilebesiran-treated patients and 6.7% of placebo-treated patients. None was considered related to the study drug.

Adverse events occurring in 5% or more of zilebesiran-treated patients in any dose arm included COVID-19, injection-site reaction, hyperkalemia, hypertension, upper respiratory tract infection, arthralgia, and headache.

“As a physician, I believe these KARDIA-1 results, which demonstrate clinically significant reductions in systolic blood pressure of greater than 15 mm Hg, along with the ability to achieve durable tonic blood pressure control, provide hope that we may one day have access to a novel therapy with the potential to address the significant unmet needs of patients with uncontrolled hypertension who are at high risk of future cardiovascular events,” study investigator George L. Bakris, MD, director, American Heart Association Comprehensive Hypertension Center, University of Chicago Medicine, said in a statement.

The phase 2 results “further validate” the phase 1 results, published in the New England Journal of Medicine, Simon Fox, PhD, vice president, zilebesiran program lead at Alnylam, said in the statement.

The full KARDIA-1 results will be reported at an upcoming scientific conference, the statement notes. Topline results from the KARDIA-2 phase 2 study of zilebesiran in combination with one of three standard classes of antihypertensive medications in patients with mild to moderate hypertension are expected in early 2024.

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

Zilebesiran (Alnylam Pharmaceuticals), an investigational, subcutaneously administered small-interfering RNA (siRNA) therapeutic in development for the treatment of hypertension, met the primary and secondary endpoints, with an “encouraging” safety profile in the phase 2 KARDIA-1 study, the company announced.

KARDIA-1 is a phase 2 randomized, double-blind, placebo-controlled, dose-ranging study evaluating the efficacy and safety of zilebesiran as monotherapy in 394 adults with mild to moderate untreated hypertension or on stable therapy with one or more antihypertensive drugs.

Patients were randomly assigned to one of five treatment arms during a 12-month double-blind period and double-blind extension period: 150 mg or 300 mg zilebesiran subcutaneously once every 6 months, 300 mg or 600 mg zilebesiran subcutaneously once every 3 months, or placebo. Patients taking placebo were randomly assigned to one of the four initial zilebesiran dose regimens beginning at month 6.

The primary endpoint was change from baseline in systolic blood pressure (SBP) at 3 months assessed by 24-hour ambulatory blood pressure monitoring.

Topline data show a dose-dependent, clinically significant reduction in 24-hour mean SBP, with a placebo-subtracted reduction greater than 15 mm Hg (P < .0001) with both the 300 mg and 600 mg doses.

The study also met key secondary endpoints, showing “consistent and sustained reductions” in SBP at 6 months, which supports quarterly or biannual dosing, the company said.

There was one death due to cardiopulmonary arrest in a zilebesiran-treated patient that was considered unrelated to the drug. Serious adverse events were reported in 3.6% of zilebesiran-treated patients and 6.7% of placebo-treated patients. None was considered related to the study drug.

Adverse events occurring in 5% or more of zilebesiran-treated patients in any dose arm included COVID-19, injection-site reaction, hyperkalemia, hypertension, upper respiratory tract infection, arthralgia, and headache.

“As a physician, I believe these KARDIA-1 results, which demonstrate clinically significant reductions in systolic blood pressure of greater than 15 mm Hg, along with the ability to achieve durable tonic blood pressure control, provide hope that we may one day have access to a novel therapy with the potential to address the significant unmet needs of patients with uncontrolled hypertension who are at high risk of future cardiovascular events,” study investigator George L. Bakris, MD, director, American Heart Association Comprehensive Hypertension Center, University of Chicago Medicine, said in a statement.

The phase 2 results “further validate” the phase 1 results, published in the New England Journal of Medicine, Simon Fox, PhD, vice president, zilebesiran program lead at Alnylam, said in the statement.

The full KARDIA-1 results will be reported at an upcoming scientific conference, the statement notes. Topline results from the KARDIA-2 phase 2 study of zilebesiran in combination with one of three standard classes of antihypertensive medications in patients with mild to moderate hypertension are expected in early 2024.

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

BACKGROUND

There are 5 germline mutations that lead to hypercoagulability in the general population including: Factor V Leiden (FVL), Prothrombin G20210A (F2A), Protein C Deficiency (PCD), Protein S Deficiency (PSD), and Antithrombin Deficiency (ATD). Typical guidance is to defer testing, as it is thought not to change management.

CASE REPORT

We present a case of a patient who was found to be compound heterozygous mutations for FVL and F2A, who presented with two episodes of arterial thromboembolism resulting in cerebrovascular accident (CVA). A 63-year-old male with past medical history of hypertension, a CVA four years prior, and medication non-compliance presents with new onset left sided hemiparesis after an episode of convulsions. MRI and CT imaging of the head revealed ischemic CVA secondary to thromboembolism in the right posterior cerebral artery’s (PCA), P1 branch. Following administration of tissue plasminogen activator (tPA) he had rapid symptom improvement. This second ischemic CVA prompted a workup which was notable for: negative echocardiogram, negative 30-day cardiac monitor, CT chest negative for malignancy, no significant vascular findings, negative for antiphospholipid syndrome, but genetic testing revealed the patient to be heterozygous for FVL and F2A mutations. He was started on apixaban 5 mg twice daily for ongoing secondary prevention. Though medication compliance continues to be difficult, after being placed on direct anticoagulant (DOAC), he has not had recurrent venous or arterial thrombotic events. A small case series found double heterozygosity for FVL and F2A further increases the risk of venous thromboembolism up to 17% or more in a lifetime.

CONCLUSIONS

Although current recommendations advocate against testing for specific mutations in most cases as it is likely not to change management1, this case suggests that it may be of some benefit in patients that have a workup that does not yield a clear etiology, especially in cryptogenic stroke which is typically managed with aspirin rather than direct oral anticoagulant.

BACKGROUND

There are 5 germline mutations that lead to hypercoagulability in the general population including: Factor V Leiden (FVL), Prothrombin G20210A (F2A), Protein C Deficiency (PCD), Protein S Deficiency (PSD), and Antithrombin Deficiency (ATD). Typical guidance is to defer testing, as it is thought not to change management.

CASE REPORT

We present a case of a patient who was found to be compound heterozygous mutations for FVL and F2A, who presented with two episodes of arterial thromboembolism resulting in cerebrovascular accident (CVA). A 63-year-old male with past medical history of hypertension, a CVA four years prior, and medication non-compliance presents with new onset left sided hemiparesis after an episode of convulsions. MRI and CT imaging of the head revealed ischemic CVA secondary to thromboembolism in the right posterior cerebral artery’s (PCA), P1 branch. Following administration of tissue plasminogen activator (tPA) he had rapid symptom improvement. This second ischemic CVA prompted a workup which was notable for: negative echocardiogram, negative 30-day cardiac monitor, CT chest negative for malignancy, no significant vascular findings, negative for antiphospholipid syndrome, but genetic testing revealed the patient to be heterozygous for FVL and F2A mutations. He was started on apixaban 5 mg twice daily for ongoing secondary prevention. Though medication compliance continues to be difficult, after being placed on direct anticoagulant (DOAC), he has not had recurrent venous or arterial thrombotic events. A small case series found double heterozygosity for FVL and F2A further increases the risk of venous thromboembolism up to 17% or more in a lifetime.

CONCLUSIONS

Although current recommendations advocate against testing for specific mutations in most cases as it is likely not to change management1, this case suggests that it may be of some benefit in patients that have a workup that does not yield a clear etiology, especially in cryptogenic stroke which is typically managed with aspirin rather than direct oral anticoagulant.

BACKGROUND

There are 5 germline mutations that lead to hypercoagulability in the general population including: Factor V Leiden (FVL), Prothrombin G20210A (F2A), Protein C Deficiency (PCD), Protein S Deficiency (PSD), and Antithrombin Deficiency (ATD). Typical guidance is to defer testing, as it is thought not to change management.

CASE REPORT

We present a case of a patient who was found to be compound heterozygous mutations for FVL and F2A, who presented with two episodes of arterial thromboembolism resulting in cerebrovascular accident (CVA). A 63-year-old male with past medical history of hypertension, a CVA four years prior, and medication non-compliance presents with new onset left sided hemiparesis after an episode of convulsions. MRI and CT imaging of the head revealed ischemic CVA secondary to thromboembolism in the right posterior cerebral artery’s (PCA), P1 branch. Following administration of tissue plasminogen activator (tPA) he had rapid symptom improvement. This second ischemic CVA prompted a workup which was notable for: negative echocardiogram, negative 30-day cardiac monitor, CT chest negative for malignancy, no significant vascular findings, negative for antiphospholipid syndrome, but genetic testing revealed the patient to be heterozygous for FVL and F2A mutations. He was started on apixaban 5 mg twice daily for ongoing secondary prevention. Though medication compliance continues to be difficult, after being placed on direct anticoagulant (DOAC), he has not had recurrent venous or arterial thrombotic events. A small case series found double heterozygosity for FVL and F2A further increases the risk of venous thromboembolism up to 17% or more in a lifetime.

CONCLUSIONS

Although current recommendations advocate against testing for specific mutations in most cases as it is likely not to change management1, this case suggests that it may be of some benefit in patients that have a workup that does not yield a clear etiology, especially in cryptogenic stroke which is typically managed with aspirin rather than direct oral anticoagulant.

PURPOSE

To improve the time to release of blood products for patients with severe or life-threatening bleeding.

BACKGROUND

Exsanguination, and the resultant coagulopathy, is the number one cause of trauma-related death. Massive transfusion protocols (MTP) improve mortality by shortening the time to transfusion and correcting coagulopathy. Many patients do not meet criteria for massive transfusion (> 10 units RBCs in 24 hours), yet present with clinical instability and require rapid release (RR) of uncrossmatched blood. A quality improvement initiative was performed to identify barriers to the MTP/RR protocol at a single institution.

METHODS/DATA

A multidisciplinary subcommittee was formed to evaluate the safety and efficacy of the current MTP/RR process. Timed mock-MTP/RR trials were conducted to identify areas of delay with a goal to achieve a blood to bedside (B2B) time of under 10 minutes.

RESULTS

Timed mock-MTP/RR trials were conducted, which revealed a baseline B2B time of approximately 30 minutes. We identified problems and categorized them in terms of ordering (phase 1) and processing (phase 2). We found significant delays in phase 1. Reasons for delay were varied and included difficulty logging into the computer, staff unavailable to place orders (involved in resuscitation efforts), orders entered incorrectly, etc. Once orders were received, the blood bank could process them quickly in phase 2. Using root cause analysis, we discovered a critical step was to remove the barrier of electronic ordering. For this, a new process was developed in which the blood bank could accept verbal orders to release uncrossmatched blood during a medical emergency. Over the course of one year, a new policy for MTP/RR was drafted, an education training video was recorded, informational flyers were printed, and training drills were conducted. A repeat mock-MTP/RR scenario was performed after the change showing the B2B time was reduced by 90% from pre-intervention values to under 3 minutes. Since implementation, no new safety signals have been received, and the staff have reported improved satisfaction with the MTP/RR process.

IMPLICATIONS

A critical piece of any MTP/RR is the immediate availability of blood. Allowing verbal orders for blood products reduced time to transfusion by 90%. Through multidisciplinary effort, safe and efficient release of uncrossmatched blood products for nontraumatic massive transfusion can be achieved.

PURPOSE

To improve the time to release of blood products for patients with severe or life-threatening bleeding.

BACKGROUND

Exsanguination, and the resultant coagulopathy, is the number one cause of trauma-related death. Massive transfusion protocols (MTP) improve mortality by shortening the time to transfusion and correcting coagulopathy. Many patients do not meet criteria for massive transfusion (> 10 units RBCs in 24 hours), yet present with clinical instability and require rapid release (RR) of uncrossmatched blood. A quality improvement initiative was performed to identify barriers to the MTP/RR protocol at a single institution.

METHODS/DATA

A multidisciplinary subcommittee was formed to evaluate the safety and efficacy of the current MTP/RR process. Timed mock-MTP/RR trials were conducted to identify areas of delay with a goal to achieve a blood to bedside (B2B) time of under 10 minutes.

RESULTS

Timed mock-MTP/RR trials were conducted, which revealed a baseline B2B time of approximately 30 minutes. We identified problems and categorized them in terms of ordering (phase 1) and processing (phase 2). We found significant delays in phase 1. Reasons for delay were varied and included difficulty logging into the computer, staff unavailable to place orders (involved in resuscitation efforts), orders entered incorrectly, etc. Once orders were received, the blood bank could process them quickly in phase 2. Using root cause analysis, we discovered a critical step was to remove the barrier of electronic ordering. For this, a new process was developed in which the blood bank could accept verbal orders to release uncrossmatched blood during a medical emergency. Over the course of one year, a new policy for MTP/RR was drafted, an education training video was recorded, informational flyers were printed, and training drills were conducted. A repeat mock-MTP/RR scenario was performed after the change showing the B2B time was reduced by 90% from pre-intervention values to under 3 minutes. Since implementation, no new safety signals have been received, and the staff have reported improved satisfaction with the MTP/RR process.

IMPLICATIONS

A critical piece of any MTP/RR is the immediate availability of blood. Allowing verbal orders for blood products reduced time to transfusion by 90%. Through multidisciplinary effort, safe and efficient release of uncrossmatched blood products for nontraumatic massive transfusion can be achieved.

PURPOSE

To improve the time to release of blood products for patients with severe or life-threatening bleeding.

BACKGROUND

Exsanguination, and the resultant coagulopathy, is the number one cause of trauma-related death. Massive transfusion protocols (MTP) improve mortality by shortening the time to transfusion and correcting coagulopathy. Many patients do not meet criteria for massive transfusion (> 10 units RBCs in 24 hours), yet present with clinical instability and require rapid release (RR) of uncrossmatched blood. A quality improvement initiative was performed to identify barriers to the MTP/RR protocol at a single institution.

METHODS/DATA

A multidisciplinary subcommittee was formed to evaluate the safety and efficacy of the current MTP/RR process. Timed mock-MTP/RR trials were conducted to identify areas of delay with a goal to achieve a blood to bedside (B2B) time of under 10 minutes.

RESULTS

Timed mock-MTP/RR trials were conducted, which revealed a baseline B2B time of approximately 30 minutes. We identified problems and categorized them in terms of ordering (phase 1) and processing (phase 2). We found significant delays in phase 1. Reasons for delay were varied and included difficulty logging into the computer, staff unavailable to place orders (involved in resuscitation efforts), orders entered incorrectly, etc. Once orders were received, the blood bank could process them quickly in phase 2. Using root cause analysis, we discovered a critical step was to remove the barrier of electronic ordering. For this, a new process was developed in which the blood bank could accept verbal orders to release uncrossmatched blood during a medical emergency. Over the course of one year, a new policy for MTP/RR was drafted, an education training video was recorded, informational flyers were printed, and training drills were conducted. A repeat mock-MTP/RR scenario was performed after the change showing the B2B time was reduced by 90% from pre-intervention values to under 3 minutes. Since implementation, no new safety signals have been received, and the staff have reported improved satisfaction with the MTP/RR process.

IMPLICATIONS

A critical piece of any MTP/RR is the immediate availability of blood. Allowing verbal orders for blood products reduced time to transfusion by 90%. Through multidisciplinary effort, safe and efficient release of uncrossmatched blood products for nontraumatic massive transfusion can be achieved.

To avoid cardiovascular disease, the American Heart Association (AHA) recommends performing at least 150 minutes of moderate-intensity aerobic activity every week, 75 minutes of intense aerobic activity every week, or a combination of both, preferably spread out throughout the week. But how knowledgeable are physicians when it comes to prescribing exercise, and how should patients be assessed so that appropriate physical activity can be recommended?

In a presentation titled, “Patient Evaluation and Exercise Prescription in Primary Prevention,” Thelma Sánchez Grillo, MD, a cardiologist at the Clínica Bíblica Hospital in San José, Costa Rica, explained the benefits and risks of exercise and gave recommendations for proper patient assessment before prescribing physical activity.

“Exercise has cardioprotective, emotional, antiarrhythmic, and antithrombotic benefits, and it reduces stress,” she explained.

She also noted that the risk regarding cardiopulmonary and musculoskeletal components must be evaluated, because exercise can itself trigger coronary events, and the last thing intended when prescribing exercise is to cause complications. “We must recommend exercise progressively. We can’t suggest a high-intensity regimen to a patient if they haven’t had any preconditioning where collateral circulation could be developed and lung and cardiac capacity could be improved.”

Dr. Sánchez went on to say that, according to the AHA, patients should be classified as follows: those who exercise and those who don’t, those with a history of cardiovascular, metabolic, or renal disease, and those with symptomatic and asymptomatic diseases, in order to consider the parameters when recommending exercise.

“If the patient has symptoms and is doing light physical activity, like walking, they can keep doing this exercise and don’t need further assessments. But if they have a symptomatic disease and are not exercising, they need to be evaluated after exercise has been prescribed, and not just clinically, either. Some sort of diagnostic method should be considered. Also, for patients who are physically active and who desire to increase the intensity of their exercise, the recommendation is to perform a detailed clinical examination and, if necessary, perform additional imaging studies.”

Warning signs

• Dizziness.
• Orthopnea.
• Abnormal heart rate.
• Edema in the lower extremities.
• Chest pain, especially when occurring with exercise.
• Intermittent claudication.
• Heart murmurs.
• Dyspnea.
• Reduced output.
• Fatigue.

Calibrating exercise parameters

The parameters of frequency (number of sessions per week), intensity (perceived exertion measured by heart rate reached), time, and type (aerobic exercise vs. strength training) should be considered when forming an appropriate prescription for exercise, explained Dr. Sánchez.

“The big problem is that most physicians don’t know how to prescribe it properly. And beyond knowing how, the important thing is that, when we’re with the patient during the consultation, we ought to be doing more than just establishing a routine. We need to be motivators and we need to be identifying obstacles and the patient’s interest in exercise, because it’s clear that incorporating physical activity into our daily lives helps improve the quality and length of life,” the specialist added.

The recommendations are straightforward: for individuals aged 18-64 years, 150 minutes of moderate-intensity activity per week, whether aerobic, strength training, or mixed, should be prescribed. “We need to encourage moving more and sitting less, and recommend comprehensive programs that include coordination, balance, and muscle strengthening. If a sedentary lifestyle is a risk factor, we need to encourage patients to start performing physical activity for 1-2 minutes every hour, because any exercise must be gradual and progressive to avoid complications,” she noted.
 

Evaluate, then recommend

The specialist emphasized the importance of making personalized prescriptions, exercising caution, and performing adequate assessments to know which exercise routine to recommend. “The patient should also be involved in their self-care and must have an adequate diet and hydration, and we need to remind them that they shouldn’t be exercising if they have an infection, due to the risk of myocarditis and sudden death,” she added.

Rafaelina Concepción, MD, cardiologist from the Dominican Republic and vice president of the Inter-American Society of Cardiology for Central America and the Caribbean, agreed with the importance of assessing risk and risk factors for patients who request an exercise routine. “For example, in patients with prediabetes, it has been shown that exercising can slow the progression to diabetes. The essential thing is to use stratification and know what kind of exercise to recommend, whether aerobic, strength training, or a combination of the two, to improve functional capacity without reaching the threshold heart rate while reducing the risk of other comorbidities like hypertension, obesity, and high lipids, and achieving lifestyle changes.”

Carlos Franco, MD, a cardiologist in El Salvador, emphasized that there is no such thing as zero risk when evaluating a patient. “Of course, there’s a difference between an athlete and someone who isn’t physically active, but we need to profile all patients correctly, evaluate risk factors in detail, not overlook subclinical cardiovascular disease, and check whether they need stress testing or additional imaging to assess cardiac functional capacity. Also, exercise must be prescribed gradually, and the patient’s nutritional status must be assessed.”

Dr. Franco ended by explaining that physicians must understand how to prescribe the basics of exercise and make small interventions of reasonable intensity, provide practical advice, and, to the extent possible, rely on specialists such as physiatrists, sports specialists, and physical therapists.

This article was translated from the Medscape Spanish Edition. A version of this article appeared on Medscape.com.

To avoid cardiovascular disease, the American Heart Association (AHA) recommends performing at least 150 minutes of moderate-intensity aerobic activity every week, 75 minutes of intense aerobic activity every week, or a combination of both, preferably spread out throughout the week. But how knowledgeable are physicians when it comes to prescribing exercise, and how should patients be assessed so that appropriate physical activity can be recommended?

In a presentation titled, “Patient Evaluation and Exercise Prescription in Primary Prevention,” Thelma Sánchez Grillo, MD, a cardiologist at the Clínica Bíblica Hospital in San José, Costa Rica, explained the benefits and risks of exercise and gave recommendations for proper patient assessment before prescribing physical activity.

“Exercise has cardioprotective, emotional, antiarrhythmic, and antithrombotic benefits, and it reduces stress,” she explained.

She also noted that the risk regarding cardiopulmonary and musculoskeletal components must be evaluated, because exercise can itself trigger coronary events, and the last thing intended when prescribing exercise is to cause complications. “We must recommend exercise progressively. We can’t suggest a high-intensity regimen to a patient if they haven’t had any preconditioning where collateral circulation could be developed and lung and cardiac capacity could be improved.”

Dr. Sánchez went on to say that, according to the AHA, patients should be classified as follows: those who exercise and those who don’t, those with a history of cardiovascular, metabolic, or renal disease, and those with symptomatic and asymptomatic diseases, in order to consider the parameters when recommending exercise.

“If the patient has symptoms and is doing light physical activity, like walking, they can keep doing this exercise and don’t need further assessments. But if they have a symptomatic disease and are not exercising, they need to be evaluated after exercise has been prescribed, and not just clinically, either. Some sort of diagnostic method should be considered. Also, for patients who are physically active and who desire to increase the intensity of their exercise, the recommendation is to perform a detailed clinical examination and, if necessary, perform additional imaging studies.”

Warning signs

• Dizziness.
• Orthopnea.
• Abnormal heart rate.
• Edema in the lower extremities.
• Chest pain, especially when occurring with exercise.
• Intermittent claudication.
• Heart murmurs.
• Dyspnea.
• Reduced output.
• Fatigue.

Calibrating exercise parameters

The parameters of frequency (number of sessions per week), intensity (perceived exertion measured by heart rate reached), time, and type (aerobic exercise vs. strength training) should be considered when forming an appropriate prescription for exercise, explained Dr. Sánchez.

“The big problem is that most physicians don’t know how to prescribe it properly. And beyond knowing how, the important thing is that, when we’re with the patient during the consultation, we ought to be doing more than just establishing a routine. We need to be motivators and we need to be identifying obstacles and the patient’s interest in exercise, because it’s clear that incorporating physical activity into our daily lives helps improve the quality and length of life,” the specialist added.

The recommendations are straightforward: for individuals aged 18-64 years, 150 minutes of moderate-intensity activity per week, whether aerobic, strength training, or mixed, should be prescribed. “We need to encourage moving more and sitting less, and recommend comprehensive programs that include coordination, balance, and muscle strengthening. If a sedentary lifestyle is a risk factor, we need to encourage patients to start performing physical activity for 1-2 minutes every hour, because any exercise must be gradual and progressive to avoid complications,” she noted.
 

Evaluate, then recommend

The specialist emphasized the importance of making personalized prescriptions, exercising caution, and performing adequate assessments to know which exercise routine to recommend. “The patient should also be involved in their self-care and must have an adequate diet and hydration, and we need to remind them that they shouldn’t be exercising if they have an infection, due to the risk of myocarditis and sudden death,” she added.

Rafaelina Concepción, MD, cardiologist from the Dominican Republic and vice president of the Inter-American Society of Cardiology for Central America and the Caribbean, agreed with the importance of assessing risk and risk factors for patients who request an exercise routine. “For example, in patients with prediabetes, it has been shown that exercising can slow the progression to diabetes. The essential thing is to use stratification and know what kind of exercise to recommend, whether aerobic, strength training, or a combination of the two, to improve functional capacity without reaching the threshold heart rate while reducing the risk of other comorbidities like hypertension, obesity, and high lipids, and achieving lifestyle changes.”

Carlos Franco, MD, a cardiologist in El Salvador, emphasized that there is no such thing as zero risk when evaluating a patient. “Of course, there’s a difference between an athlete and someone who isn’t physically active, but we need to profile all patients correctly, evaluate risk factors in detail, not overlook subclinical cardiovascular disease, and check whether they need stress testing or additional imaging to assess cardiac functional capacity. Also, exercise must be prescribed gradually, and the patient’s nutritional status must be assessed.”

Dr. Franco ended by explaining that physicians must understand how to prescribe the basics of exercise and make small interventions of reasonable intensity, provide practical advice, and, to the extent possible, rely on specialists such as physiatrists, sports specialists, and physical therapists.

This article was translated from the Medscape Spanish Edition. A version of this article appeared on Medscape.com.

To avoid cardiovascular disease, the American Heart Association (AHA) recommends performing at least 150 minutes of moderate-intensity aerobic activity every week, 75 minutes of intense aerobic activity every week, or a combination of both, preferably spread out throughout the week. But how knowledgeable are physicians when it comes to prescribing exercise, and how should patients be assessed so that appropriate physical activity can be recommended?

In a presentation titled, “Patient Evaluation and Exercise Prescription in Primary Prevention,” Thelma Sánchez Grillo, MD, a cardiologist at the Clínica Bíblica Hospital in San José, Costa Rica, explained the benefits and risks of exercise and gave recommendations for proper patient assessment before prescribing physical activity.

“Exercise has cardioprotective, emotional, antiarrhythmic, and antithrombotic benefits, and it reduces stress,” she explained.

She also noted that the risk regarding cardiopulmonary and musculoskeletal components must be evaluated, because exercise can itself trigger coronary events, and the last thing intended when prescribing exercise is to cause complications. “We must recommend exercise progressively. We can’t suggest a high-intensity regimen to a patient if they haven’t had any preconditioning where collateral circulation could be developed and lung and cardiac capacity could be improved.”

Dr. Sánchez went on to say that, according to the AHA, patients should be classified as follows: those who exercise and those who don’t, those with a history of cardiovascular, metabolic, or renal disease, and those with symptomatic and asymptomatic diseases, in order to consider the parameters when recommending exercise.

“If the patient has symptoms and is doing light physical activity, like walking, they can keep doing this exercise and don’t need further assessments. But if they have a symptomatic disease and are not exercising, they need to be evaluated after exercise has been prescribed, and not just clinically, either. Some sort of diagnostic method should be considered. Also, for patients who are physically active and who desire to increase the intensity of their exercise, the recommendation is to perform a detailed clinical examination and, if necessary, perform additional imaging studies.”

Warning signs

• Dizziness.
• Orthopnea.
• Abnormal heart rate.
• Edema in the lower extremities.
• Chest pain, especially when occurring with exercise.
• Intermittent claudication.
• Heart murmurs.
• Dyspnea.
• Reduced output.
• Fatigue.

Calibrating exercise parameters

The parameters of frequency (number of sessions per week), intensity (perceived exertion measured by heart rate reached), time, and type (aerobic exercise vs. strength training) should be considered when forming an appropriate prescription for exercise, explained Dr. Sánchez.

“The big problem is that most physicians don’t know how to prescribe it properly. And beyond knowing how, the important thing is that, when we’re with the patient during the consultation, we ought to be doing more than just establishing a routine. We need to be motivators and we need to be identifying obstacles and the patient’s interest in exercise, because it’s clear that incorporating physical activity into our daily lives helps improve the quality and length of life,” the specialist added.

The recommendations are straightforward: for individuals aged 18-64 years, 150 minutes of moderate-intensity activity per week, whether aerobic, strength training, or mixed, should be prescribed. “We need to encourage moving more and sitting less, and recommend comprehensive programs that include coordination, balance, and muscle strengthening. If a sedentary lifestyle is a risk factor, we need to encourage patients to start performing physical activity for 1-2 minutes every hour, because any exercise must be gradual and progressive to avoid complications,” she noted.
 

Evaluate, then recommend

The specialist emphasized the importance of making personalized prescriptions, exercising caution, and performing adequate assessments to know which exercise routine to recommend. “The patient should also be involved in their self-care and must have an adequate diet and hydration, and we need to remind them that they shouldn’t be exercising if they have an infection, due to the risk of myocarditis and sudden death,” she added.

Rafaelina Concepción, MD, cardiologist from the Dominican Republic and vice president of the Inter-American Society of Cardiology for Central America and the Caribbean, agreed with the importance of assessing risk and risk factors for patients who request an exercise routine. “For example, in patients with prediabetes, it has been shown that exercising can slow the progression to diabetes. The essential thing is to use stratification and know what kind of exercise to recommend, whether aerobic, strength training, or a combination of the two, to improve functional capacity without reaching the threshold heart rate while reducing the risk of other comorbidities like hypertension, obesity, and high lipids, and achieving lifestyle changes.”

Carlos Franco, MD, a cardiologist in El Salvador, emphasized that there is no such thing as zero risk when evaluating a patient. “Of course, there’s a difference between an athlete and someone who isn’t physically active, but we need to profile all patients correctly, evaluate risk factors in detail, not overlook subclinical cardiovascular disease, and check whether they need stress testing or additional imaging to assess cardiac functional capacity. Also, exercise must be prescribed gradually, and the patient’s nutritional status must be assessed.”

Dr. Franco ended by explaining that physicians must understand how to prescribe the basics of exercise and make small interventions of reasonable intensity, provide practical advice, and, to the extent possible, rely on specialists such as physiatrists, sports specialists, and physical therapists.

This article was translated from the Medscape Spanish Edition. A version of this article appeared on Medscape.com.

AMSTERDAM – A short course of the interleukin-1 receptor antagonist, anakinra, appeared safe but did not reduce complications of acute myocarditis in the ARAMIS trial.

The trial was presented at the annual congress of the European Society of Cardiology.

Lead investigator, Mathieu Kerneis, MD, Pitie Salpetriere APHP University Hospital, Paris, said this was the largest randomized controlled trial of patients with acute myocarditis and probably the first ever study in the acute setting of myocarditis patients diagnosed with cardiac magnetic resonance (CMR) imaging, not on biopsy, who are mostly at low risk for events.

He suggested that one of the reasons for the neutral result could have been the low-risk population involved and the low complication rate. “We enrolled an all-comer acute myocarditis population diagnosed with CMR, who were mostly at a low risk of complications,” he noted.

“I don’t think the story of anti-inflammatory drugs in acute myocarditis is over. This is just the beginning. This was the first trial, and it was just a phase 2 trial. We need further randomized trials to explore the potential benefit of an anti-inflammatory strategy in acute myocarditis patients at higher risk of complications. In addition, larger studies are needed to evaluate prolonged anti-inflammatory strategies in acute myocarditis patients at low-to-moderate risk of complications,” Dr. Kerneis concluded.

“It is very challenging to do a trial in high-risk patients with myocarditis as these patients are quite rare,” he added.
 

Inflammation of the myocardium

Dr. Kerneis explained that acute myocarditis is an inflammation of the myocardium that can cause permanent damage to the heart muscle and lead to myocardial infarction, stroke, heart failure, arrhythmias, and death. The condition can occur in individuals of all ages but is most frequent in young people. There is no specific treatment, but patients are generally treated with beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and sometimes steroids.

Anakinra is an interleukin-1 receptor antagonist that works by targeting the interleukin-1β innate immune pathway. Anakinra is used for the treatment of rheumatoid arthritis and has shown efficacy in pericarditis. Dr. Kerneis noted that there have been several case reports of successful treatment with anakinra in acute myocarditis.

The ARAMIS trial – conducted at six academic centers in France – was the first randomized study to evaluate inhibition of the interleukin-1β innate immune pathway in myocarditis patients. The trial enrolled 120 hospitalized, symptomatic patients with chest pain, increased cardiac troponin, and acute myocarditis diagnosed using CMR. More than half had had a recent bacterial or viral infection.

Patients were randomized within 72 hours of hospital admission to a daily subcutaneous dose of anakinra 100 mg or placebo until hospital discharge. Patients in both groups received standard-of-care treatments, including an ACE inhibitor, for at least 1 month. Consistent with prior data, the median age of participants was 28 years and 90% were men.

The primary endpoint was the number of days free of myocarditis complications (heart failure requiring hospitalization, chest pain requiring medication, left ventricular ejection fraction less than 50%, and ventricular arrhythmias) within 28 days postdischarge.

There was no significant difference in this endpoint between the two arms, with a median of 30 days for anakinra versus 31 days for placebo.

Overall, the rate of the composite endpoint of myocarditis complications occurred in 13.7% of patients, and there was a numerical reduction in the number of patients with these myocarditis complications with anakinra – 6 patients (10.5%) in the anakinra group versus 10 patients (16.5%) in the placebo group (odds ratio, 0.59; 95% confidence interval, 0.19-1.78). This was driven by fewer patients with chest pain requiring new medication (two patients versus six patients).

The safety endpoint was the number of serious adverse events within 28 days postdischarge. This endpoint occurred in seven patients (12.1%) in the anakinra arm and six patients (10.2%) in the placebo arm, with no significant difference between groups. Cases of severe infection within 28 days postdischarge were reported in both arms.
 

Low-risk population

Designated discussant of the study at the ESC Hotline session, Enrico Ammirati, MD, PhD, University of Milano-Bicocca, Monza, Italy, said that patients involved in ARAMIS fit the profile of acute myocarditis and that the CMR diagnosis was positive in all the patients enrolled.

Dr. Ammirati agreed with Dr. Kerneis that the neutral results of the study were probably caused by the low-risk population. “If we look at retrospective registries, at 30 days there are zero cardiac deaths or heart transplants at 30 days in patients with a low-risk presentation.

“The ARAMIS trial has shown the feasibility of conducting studies in the setting of acute myocarditis, and even if the primary endpoint was neutral, some important data are still missing, such as change in ejection fraction and troponin levels,” he noted.

“In terms of future perspective, we are moving to assessing efficacy of anakinra or other immunosuppressive drugs from acute low risk patients to higher risk patients with heart failure and severe dysfunction,” he said.  

Dr. Ammirati is the lead investigator of another ongoing study in such a higher-risk population; the MYTHS trial is investigating the use of intravenous steroids in patients with suspected acute myocarditis complicated by acute heart failure or cardiogenic shock, and an ejection fraction below 41%.

“So, we will have more results on the best treatment in this higher risk group of patients,” he concluded.

The ARAMIS trial was an academic study funded by the French Health Ministry and coordinated by the ACTION Group. Dr. Kerneis reports having received consulting fees from Kiniksa, Sanofi, and Bayer, and holds a patent for use of abatacept in immune checkpoint inhibitor (ICI)–induced myocarditis.

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

AMSTERDAM – A short course of the interleukin-1 receptor antagonist, anakinra, appeared safe but did not reduce complications of acute myocarditis in the ARAMIS trial.

The trial was presented at the annual congress of the European Society of Cardiology.

Lead investigator, Mathieu Kerneis, MD, Pitie Salpetriere APHP University Hospital, Paris, said this was the largest randomized controlled trial of patients with acute myocarditis and probably the first ever study in the acute setting of myocarditis patients diagnosed with cardiac magnetic resonance (CMR) imaging, not on biopsy, who are mostly at low risk for events.

He suggested that one of the reasons for the neutral result could have been the low-risk population involved and the low complication rate. “We enrolled an all-comer acute myocarditis population diagnosed with CMR, who were mostly at a low risk of complications,” he noted.

“I don’t think the story of anti-inflammatory drugs in acute myocarditis is over. This is just the beginning. This was the first trial, and it was just a phase 2 trial. We need further randomized trials to explore the potential benefit of an anti-inflammatory strategy in acute myocarditis patients at higher risk of complications. In addition, larger studies are needed to evaluate prolonged anti-inflammatory strategies in acute myocarditis patients at low-to-moderate risk of complications,” Dr. Kerneis concluded.

“It is very challenging to do a trial in high-risk patients with myocarditis as these patients are quite rare,” he added.
 

Inflammation of the myocardium

Dr. Kerneis explained that acute myocarditis is an inflammation of the myocardium that can cause permanent damage to the heart muscle and lead to myocardial infarction, stroke, heart failure, arrhythmias, and death. The condition can occur in individuals of all ages but is most frequent in young people. There is no specific treatment, but patients are generally treated with beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and sometimes steroids.

Anakinra is an interleukin-1 receptor antagonist that works by targeting the interleukin-1β innate immune pathway. Anakinra is used for the treatment of rheumatoid arthritis and has shown efficacy in pericarditis. Dr. Kerneis noted that there have been several case reports of successful treatment with anakinra in acute myocarditis.

The ARAMIS trial – conducted at six academic centers in France – was the first randomized study to evaluate inhibition of the interleukin-1β innate immune pathway in myocarditis patients. The trial enrolled 120 hospitalized, symptomatic patients with chest pain, increased cardiac troponin, and acute myocarditis diagnosed using CMR. More than half had had a recent bacterial or viral infection.

Patients were randomized within 72 hours of hospital admission to a daily subcutaneous dose of anakinra 100 mg or placebo until hospital discharge. Patients in both groups received standard-of-care treatments, including an ACE inhibitor, for at least 1 month. Consistent with prior data, the median age of participants was 28 years and 90% were men.

The primary endpoint was the number of days free of myocarditis complications (heart failure requiring hospitalization, chest pain requiring medication, left ventricular ejection fraction less than 50%, and ventricular arrhythmias) within 28 days postdischarge.

There was no significant difference in this endpoint between the two arms, with a median of 30 days for anakinra versus 31 days for placebo.

Overall, the rate of the composite endpoint of myocarditis complications occurred in 13.7% of patients, and there was a numerical reduction in the number of patients with these myocarditis complications with anakinra – 6 patients (10.5%) in the anakinra group versus 10 patients (16.5%) in the placebo group (odds ratio, 0.59; 95% confidence interval, 0.19-1.78). This was driven by fewer patients with chest pain requiring new medication (two patients versus six patients).

The safety endpoint was the number of serious adverse events within 28 days postdischarge. This endpoint occurred in seven patients (12.1%) in the anakinra arm and six patients (10.2%) in the placebo arm, with no significant difference between groups. Cases of severe infection within 28 days postdischarge were reported in both arms.
 

Low-risk population

Designated discussant of the study at the ESC Hotline session, Enrico Ammirati, MD, PhD, University of Milano-Bicocca, Monza, Italy, said that patients involved in ARAMIS fit the profile of acute myocarditis and that the CMR diagnosis was positive in all the patients enrolled.

Dr. Ammirati agreed with Dr. Kerneis that the neutral results of the study were probably caused by the low-risk population. “If we look at retrospective registries, at 30 days there are zero cardiac deaths or heart transplants at 30 days in patients with a low-risk presentation.

“The ARAMIS trial has shown the feasibility of conducting studies in the setting of acute myocarditis, and even if the primary endpoint was neutral, some important data are still missing, such as change in ejection fraction and troponin levels,” he noted.

“In terms of future perspective, we are moving to assessing efficacy of anakinra or other immunosuppressive drugs from acute low risk patients to higher risk patients with heart failure and severe dysfunction,” he said.  

Dr. Ammirati is the lead investigator of another ongoing study in such a higher-risk population; the MYTHS trial is investigating the use of intravenous steroids in patients with suspected acute myocarditis complicated by acute heart failure or cardiogenic shock, and an ejection fraction below 41%.

“So, we will have more results on the best treatment in this higher risk group of patients,” he concluded.

The ARAMIS trial was an academic study funded by the French Health Ministry and coordinated by the ACTION Group. Dr. Kerneis reports having received consulting fees from Kiniksa, Sanofi, and Bayer, and holds a patent for use of abatacept in immune checkpoint inhibitor (ICI)–induced myocarditis.

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

AMSTERDAM – A short course of the interleukin-1 receptor antagonist, anakinra, appeared safe but did not reduce complications of acute myocarditis in the ARAMIS trial.

The trial was presented at the annual congress of the European Society of Cardiology.

Lead investigator, Mathieu Kerneis, MD, Pitie Salpetriere APHP University Hospital, Paris, said this was the largest randomized controlled trial of patients with acute myocarditis and probably the first ever study in the acute setting of myocarditis patients diagnosed with cardiac magnetic resonance (CMR) imaging, not on biopsy, who are mostly at low risk for events.

He suggested that one of the reasons for the neutral result could have been the low-risk population involved and the low complication rate. “We enrolled an all-comer acute myocarditis population diagnosed with CMR, who were mostly at a low risk of complications,” he noted.

“I don’t think the story of anti-inflammatory drugs in acute myocarditis is over. This is just the beginning. This was the first trial, and it was just a phase 2 trial. We need further randomized trials to explore the potential benefit of an anti-inflammatory strategy in acute myocarditis patients at higher risk of complications. In addition, larger studies are needed to evaluate prolonged anti-inflammatory strategies in acute myocarditis patients at low-to-moderate risk of complications,” Dr. Kerneis concluded.

“It is very challenging to do a trial in high-risk patients with myocarditis as these patients are quite rare,” he added.
 

Inflammation of the myocardium

Dr. Kerneis explained that acute myocarditis is an inflammation of the myocardium that can cause permanent damage to the heart muscle and lead to myocardial infarction, stroke, heart failure, arrhythmias, and death. The condition can occur in individuals of all ages but is most frequent in young people. There is no specific treatment, but patients are generally treated with beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and sometimes steroids.

Anakinra is an interleukin-1 receptor antagonist that works by targeting the interleukin-1β innate immune pathway. Anakinra is used for the treatment of rheumatoid arthritis and has shown efficacy in pericarditis. Dr. Kerneis noted that there have been several case reports of successful treatment with anakinra in acute myocarditis.

The ARAMIS trial – conducted at six academic centers in France – was the first randomized study to evaluate inhibition of the interleukin-1β innate immune pathway in myocarditis patients. The trial enrolled 120 hospitalized, symptomatic patients with chest pain, increased cardiac troponin, and acute myocarditis diagnosed using CMR. More than half had had a recent bacterial or viral infection.

Patients were randomized within 72 hours of hospital admission to a daily subcutaneous dose of anakinra 100 mg or placebo until hospital discharge. Patients in both groups received standard-of-care treatments, including an ACE inhibitor, for at least 1 month. Consistent with prior data, the median age of participants was 28 years and 90% were men.

The primary endpoint was the number of days free of myocarditis complications (heart failure requiring hospitalization, chest pain requiring medication, left ventricular ejection fraction less than 50%, and ventricular arrhythmias) within 28 days postdischarge.

There was no significant difference in this endpoint between the two arms, with a median of 30 days for anakinra versus 31 days for placebo.

Overall, the rate of the composite endpoint of myocarditis complications occurred in 13.7% of patients, and there was a numerical reduction in the number of patients with these myocarditis complications with anakinra – 6 patients (10.5%) in the anakinra group versus 10 patients (16.5%) in the placebo group (odds ratio, 0.59; 95% confidence interval, 0.19-1.78). This was driven by fewer patients with chest pain requiring new medication (two patients versus six patients).

The safety endpoint was the number of serious adverse events within 28 days postdischarge. This endpoint occurred in seven patients (12.1%) in the anakinra arm and six patients (10.2%) in the placebo arm, with no significant difference between groups. Cases of severe infection within 28 days postdischarge were reported in both arms.
 

Low-risk population

Designated discussant of the study at the ESC Hotline session, Enrico Ammirati, MD, PhD, University of Milano-Bicocca, Monza, Italy, said that patients involved in ARAMIS fit the profile of acute myocarditis and that the CMR diagnosis was positive in all the patients enrolled.

Dr. Ammirati agreed with Dr. Kerneis that the neutral results of the study were probably caused by the low-risk population. “If we look at retrospective registries, at 30 days there are zero cardiac deaths or heart transplants at 30 days in patients with a low-risk presentation.

“The ARAMIS trial has shown the feasibility of conducting studies in the setting of acute myocarditis, and even if the primary endpoint was neutral, some important data are still missing, such as change in ejection fraction and troponin levels,” he noted.

“In terms of future perspective, we are moving to assessing efficacy of anakinra or other immunosuppressive drugs from acute low risk patients to higher risk patients with heart failure and severe dysfunction,” he said.  

Dr. Ammirati is the lead investigator of another ongoing study in such a higher-risk population; the MYTHS trial is investigating the use of intravenous steroids in patients with suspected acute myocarditis complicated by acute heart failure or cardiogenic shock, and an ejection fraction below 41%.

“So, we will have more results on the best treatment in this higher risk group of patients,” he concluded.

The ARAMIS trial was an academic study funded by the French Health Ministry and coordinated by the ACTION Group. Dr. Kerneis reports having received consulting fees from Kiniksa, Sanofi, and Bayer, and holds a patent for use of abatacept in immune checkpoint inhibitor (ICI)–induced myocarditis.

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

TOPLINE:

In contrast to an overall decline in cardiovascular mortality, obesity-related cardiovascular deaths have risen substantially in the past 2 decades, most prominently among Black women. “We observed a threefold increase in obesity-related cardiovascular age-adjusted mortality rates between 1999 and 2020,” wrote the authors.

METHODOLOGY:

Data from the U.S. population-level Multiple Cause of Death database were analyzed, including 281,135 deaths in 1999-2020 for which obesity was listed as a contributing factor.

TAKEAWAY:

• Overall, the crude rate of all cardiovascular deaths dropped by 17.6% across all races.
• However, age-adjusted obesity-related cardiovascular mortality tripled from 2.2/100,000 to 6.6/100,000 from 1999 to 2020, consistent across all racial groups.
• Blacks had the highest age-adjusted obesity-related cardiovascular mortality (rising from 4.2/100,000 in 1999 to 11.6/100,000 in 2000).
• Ischemic heart disease was the most common cardiovascular cause of death across all races, and hypertensive disease was second.
• Age-adjusted obesity-related cardiovascular mortality was higher among Blacks (6.7/100,000) than any other racial group, followed by American Indians or Alaskan Natives (3.8/100,000), and lowest among Asian or Pacific Islanders (0.9/100,000).
• The risk of obesity-related cardiovascular disease death rose most rapidly among American Indians and Alaskan Natives.
• Among Blacks, age-adjusted mortality was slightly higher among women than men (6.7/100,000 vs. 6.6/100,000), whereas the reverse was true for all other races (0.6-3.0/100,000 vs. 1.2-6.0/100,000).
• Blacks living in urban settings experienced higher rates of age-adjusted cardiovascular mortality than those living in rural areas (6.8/100,000 vs. 5.9/100,000), whereas the opposite was true for all other racial groups (0.9-3.5/100,000 vs. 2.2-5.4/100,000).

IN PRACTICE:

“There is need for dedicated health strategies aimed at individual communities to better understand and tackle the social determinants of obesity and to design interventions that may alleviate the population burden of both obesity and cardiovascular disease,” the authors wrote.

SOURCE:

The study, by Zahra Raisi-Estabragh, MD, PhD, Queen Mary University, London, and colleagues, was published online Sept. 6 in the Journal of the American Heart Association.

LIMITATIONS:

• Database limited to U.S. residents.
• Possible miscoding or diagnostic errors.
• Potential for residual confounding.
• No data on underlying drivers of observed trends.

DISCLOSURES:

Dr. Raisi-Estabragh has reported receiving funding from the Integrated Academic Training program of the National Institute for Health Research and a Clinical Research Training Fellowship from the British Heart Foundation. Another author has reported receiving research support from the National Heart, Lung, and Blood Institute.

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

TOPLINE:

In contrast to an overall decline in cardiovascular mortality, obesity-related cardiovascular deaths have risen substantially in the past 2 decades, most prominently among Black women. “We observed a threefold increase in obesity-related cardiovascular age-adjusted mortality rates between 1999 and 2020,” wrote the authors.

METHODOLOGY:

Data from the U.S. population-level Multiple Cause of Death database were analyzed, including 281,135 deaths in 1999-2020 for which obesity was listed as a contributing factor.

TAKEAWAY:

• Overall, the crude rate of all cardiovascular deaths dropped by 17.6% across all races.
• However, age-adjusted obesity-related cardiovascular mortality tripled from 2.2/100,000 to 6.6/100,000 from 1999 to 2020, consistent across all racial groups.
• Blacks had the highest age-adjusted obesity-related cardiovascular mortality (rising from 4.2/100,000 in 1999 to 11.6/100,000 in 2000).
• Ischemic heart disease was the most common cardiovascular cause of death across all races, and hypertensive disease was second.
• Age-adjusted obesity-related cardiovascular mortality was higher among Blacks (6.7/100,000) than any other racial group, followed by American Indians or Alaskan Natives (3.8/100,000), and lowest among Asian or Pacific Islanders (0.9/100,000).
• The risk of obesity-related cardiovascular disease death rose most rapidly among American Indians and Alaskan Natives.
• Among Blacks, age-adjusted mortality was slightly higher among women than men (6.7/100,000 vs. 6.6/100,000), whereas the reverse was true for all other races (0.6-3.0/100,000 vs. 1.2-6.0/100,000).
• Blacks living in urban settings experienced higher rates of age-adjusted cardiovascular mortality than those living in rural areas (6.8/100,000 vs. 5.9/100,000), whereas the opposite was true for all other racial groups (0.9-3.5/100,000 vs. 2.2-5.4/100,000).

IN PRACTICE:

“There is need for dedicated health strategies aimed at individual communities to better understand and tackle the social determinants of obesity and to design interventions that may alleviate the population burden of both obesity and cardiovascular disease,” the authors wrote.

SOURCE:

The study, by Zahra Raisi-Estabragh, MD, PhD, Queen Mary University, London, and colleagues, was published online Sept. 6 in the Journal of the American Heart Association.

LIMITATIONS:

• Database limited to U.S. residents.
• Possible miscoding or diagnostic errors.
• Potential for residual confounding.
• No data on underlying drivers of observed trends.

DISCLOSURES:

Dr. Raisi-Estabragh has reported receiving funding from the Integrated Academic Training program of the National Institute for Health Research and a Clinical Research Training Fellowship from the British Heart Foundation. Another author has reported receiving research support from the National Heart, Lung, and Blood Institute.

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

TOPLINE:

In contrast to an overall decline in cardiovascular mortality, obesity-related cardiovascular deaths have risen substantially in the past 2 decades, most prominently among Black women. “We observed a threefold increase in obesity-related cardiovascular age-adjusted mortality rates between 1999 and 2020,” wrote the authors.

METHODOLOGY:

Data from the U.S. population-level Multiple Cause of Death database were analyzed, including 281,135 deaths in 1999-2020 for which obesity was listed as a contributing factor.

TAKEAWAY:

• Overall, the crude rate of all cardiovascular deaths dropped by 17.6% across all races.
• However, age-adjusted obesity-related cardiovascular mortality tripled from 2.2/100,000 to 6.6/100,000 from 1999 to 2020, consistent across all racial groups.
• Blacks had the highest age-adjusted obesity-related cardiovascular mortality (rising from 4.2/100,000 in 1999 to 11.6/100,000 in 2000).
• Ischemic heart disease was the most common cardiovascular cause of death across all races, and hypertensive disease was second.
• Age-adjusted obesity-related cardiovascular mortality was higher among Blacks (6.7/100,000) than any other racial group, followed by American Indians or Alaskan Natives (3.8/100,000), and lowest among Asian or Pacific Islanders (0.9/100,000).
• The risk of obesity-related cardiovascular disease death rose most rapidly among American Indians and Alaskan Natives.
• Among Blacks, age-adjusted mortality was slightly higher among women than men (6.7/100,000 vs. 6.6/100,000), whereas the reverse was true for all other races (0.6-3.0/100,000 vs. 1.2-6.0/100,000).
• Blacks living in urban settings experienced higher rates of age-adjusted cardiovascular mortality than those living in rural areas (6.8/100,000 vs. 5.9/100,000), whereas the opposite was true for all other racial groups (0.9-3.5/100,000 vs. 2.2-5.4/100,000).

IN PRACTICE:

“There is need for dedicated health strategies aimed at individual communities to better understand and tackle the social determinants of obesity and to design interventions that may alleviate the population burden of both obesity and cardiovascular disease,” the authors wrote.

SOURCE:

The study, by Zahra Raisi-Estabragh, MD, PhD, Queen Mary University, London, and colleagues, was published online Sept. 6 in the Journal of the American Heart Association.

LIMITATIONS:

• Database limited to U.S. residents.
• Possible miscoding or diagnostic errors.
• Potential for residual confounding.
• No data on underlying drivers of observed trends.

DISCLOSURES:

Dr. Raisi-Estabragh has reported receiving funding from the Integrated Academic Training program of the National Institute for Health Research and a Clinical Research Training Fellowship from the British Heart Foundation. Another author has reported receiving research support from the National Heart, Lung, and Blood Institute.

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

One of the hardest tasks of a clinician is applying evidence from trials to the person in your office. At the annual congress of the European Society of Cardiology, the surprising and unexpected results of the FRAIL-AF trial confirm the massive challenge of evidence translation.

FRAIL-AF investigators set out to study the question of whether frail, elderly patients with atrial fibrillation who were doing well with vitamin K antagonists (VKA) should be switched to direct-acting oral anticoagulants (DOAC).

Senior author Geert-Jan Geersing, MD, PhD, from the University Medical Center Utrecht (the Netherlands), told me that frustration led him to design this study. He was frustrated that colleagues assumed that evidence in nonfrail patients can always be translated to frail patients. 

Dr. Geersing offered two reasons why common wisdom may be wrong. First was that the large DOAC versus warfarin trials included few elderly patients with frailty. Second, first author Linda Joosten, MD, made it clear in her presentation that frailty is a lot more than aging. It is a clinical syndrome, which entails a “high burden of comorbidities, dependency on others, and a reduced ability to resist stressors.”
 

The FRAIL-AF trial

The investigators recruited elderly, frail patients with fibrillation who were treated with VKAs and had stable international normalized ratios from outpatient clinics throughout the Netherlands. They screened about 2,600 patients and enrolled nearly 1,400. Most were excluded for not being frail.

Half the group was randomized to switching to a DOAC – drug choice was left to the treating clinician – and the other half remained on VKAs. Patients were 83 years of age on average with a mean CHA2DS2-VASc score of 4. All four classes of DOAC were used in the switching arm.

The primary endpoint was major or clinically relevant nonmajor bleeding, whichever came first, accounting for death as a competing risk. Follow-up was 1 year.
 

The results for switching to DOAC vs. VKA

Dr. Joosten started her presentation with this: “The results turned out to be different than we expected.” The authors designed the trial with the idea that switching to DOACs would be superior in safety to remaining on VKAs.

But the trial was halted after an interim analysis found a rate of major bleeding in the switching arm of 15.3% versus 9.4% in the arm staying on VKA (hazard ratio, 1.69; 95% confidence interval, 1.23-2.32; P = .0012).

The Kaplan-Meier event curves reveal that the excess risk of bleeding occurred after 100 days and increased with time. This argued against an early effect from transitioning the drugs.

An analysis looking at specific DOAC drugs revealed similar hazards for the two most common ones used – apixaban and rivaroxaban.

Thrombotic events were a secondary endpoint and were low in absolute numbers, 2.4% versus 2.0%, for remaining on VKA and switching to DOAC, respectively (HR, 1.26; 95% CI, 0.60-2.61).

The time in therapeutic range in FRAIL-AF was similar to that in the seminal DOAC trials.
 

Comments

Three reasons lead me to choose FRAIL-AF as the most important study from the 2023 ESC congress.

First is the specific lesson about switching drugs. Note that FRAIL-AF did not address the question of starting anticoagulation. The trial results show that if you have a frail older patient who is doing well on VKA, don’t change to a DOAC. That is important to know, but it is not what gives this study its heft.

The second reason centers on the investigators choice to do this trial. Dr. Geersing had a feeling that common wisdom was wrong. He did not try to persuade colleagues with anecdote or plausibility or meta-analyses of observational studies. He set out to answer a question in the correct way – with a randomized trial.

This is the path forward in medicine. I’ve often heard proponents of observational research declare that many topics in medicine cannot be studied with trials. I could hear people arguing that it’s not feasible to study mostly home-bound, elderly frail patients. And the fact that there exist so few trials in this space would support that argument.

But the FRAIL-AF authors showed that it is possible. This is the kind of science that medicine should celebrate. There were no soft endpoints, financial conflicts, or spin. If medical science had science as its incentive, rather than attention, FRAIL-AF easily wins top honors.

The third reason FRAIL-AF is so important is that it teaches us the humility required in translating evidence in our clinics. I like to say evidence is what separates doctors from palm readers. But using this evidence requires thinking hard about how average effects in trial environments apply to our patient.

Yes, of course, there is clear evidence from tens of thousands of patients in the DOAC versus warfarin trials, that, for those patients, on average, DOACs compare favorably with VKA. The average age of patients in these trials was 70-73 years; the average age in FRAIL-AF was 83 years. And that is just age. A substudy of the ENGAGE AF-TIMI 48 trial found that only 360 of more than 20,000 patients in the trial had severe frailty.

FRAIL-AF clearly shows how cautious we should be in applying evidence gathered in younger, healthier patients to older, more vulnerable patients. That lesson extends to nearly every common therapy in medicine today. It also casts great doubt on the soft-thinking idea of using evidence from trials to derive quality metrics. As if the nuance of evidence translation can be captured in an electronic health record.

The skillful use of evidence will be one of the main challenges of the next generation of clinicians. Thanks to advances in medical science, more patients will live long enough to become frail. And the so-called “guideline-directed” therapies may not apply to them.

Dr. Joosten, Dr. Geersing, and the FRAIL-AF team have taught us specific lessons about anticoagulation, but their greatest contribution has been to demonstrate the value of humility in science and the practice of evidence-based medicine.

If you treat patients, no trial at this meeting is more important.

Dr. Mandrola is a clinical electrophysiologist at Baptist Medical Associates, Louisville, Ky. He reported no relevant conflicts of interest.
 

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

One of the hardest tasks of a clinician is applying evidence from trials to the person in your office. At the annual congress of the European Society of Cardiology, the surprising and unexpected results of the FRAIL-AF trial confirm the massive challenge of evidence translation.

FRAIL-AF investigators set out to study the question of whether frail, elderly patients with atrial fibrillation who were doing well with vitamin K antagonists (VKA) should be switched to direct-acting oral anticoagulants (DOAC).

Senior author Geert-Jan Geersing, MD, PhD, from the University Medical Center Utrecht (the Netherlands), told me that frustration led him to design this study. He was frustrated that colleagues assumed that evidence in nonfrail patients can always be translated to frail patients. 

Dr. Geersing offered two reasons why common wisdom may be wrong. First was that the large DOAC versus warfarin trials included few elderly patients with frailty. Second, first author Linda Joosten, MD, made it clear in her presentation that frailty is a lot more than aging. It is a clinical syndrome, which entails a “high burden of comorbidities, dependency on others, and a reduced ability to resist stressors.”
 

The FRAIL-AF trial

The investigators recruited elderly, frail patients with fibrillation who were treated with VKAs and had stable international normalized ratios from outpatient clinics throughout the Netherlands. They screened about 2,600 patients and enrolled nearly 1,400. Most were excluded for not being frail.

Half the group was randomized to switching to a DOAC – drug choice was left to the treating clinician – and the other half remained on VKAs. Patients were 83 years of age on average with a mean CHA2DS2-VASc score of 4. All four classes of DOAC were used in the switching arm.

The primary endpoint was major or clinically relevant nonmajor bleeding, whichever came first, accounting for death as a competing risk. Follow-up was 1 year.
 

The results for switching to DOAC vs. VKA

Dr. Joosten started her presentation with this: “The results turned out to be different than we expected.” The authors designed the trial with the idea that switching to DOACs would be superior in safety to remaining on VKAs.

But the trial was halted after an interim analysis found a rate of major bleeding in the switching arm of 15.3% versus 9.4% in the arm staying on VKA (hazard ratio, 1.69; 95% confidence interval, 1.23-2.32; P = .0012).

The Kaplan-Meier event curves reveal that the excess risk of bleeding occurred after 100 days and increased with time. This argued against an early effect from transitioning the drugs.

An analysis looking at specific DOAC drugs revealed similar hazards for the two most common ones used – apixaban and rivaroxaban.

Thrombotic events were a secondary endpoint and were low in absolute numbers, 2.4% versus 2.0%, for remaining on VKA and switching to DOAC, respectively (HR, 1.26; 95% CI, 0.60-2.61).

The time in therapeutic range in FRAIL-AF was similar to that in the seminal DOAC trials.
 

Comments

Three reasons lead me to choose FRAIL-AF as the most important study from the 2023 ESC congress.

First is the specific lesson about switching drugs. Note that FRAIL-AF did not address the question of starting anticoagulation. The trial results show that if you have a frail older patient who is doing well on VKA, don’t change to a DOAC. That is important to know, but it is not what gives this study its heft.

The second reason centers on the investigators choice to do this trial. Dr. Geersing had a feeling that common wisdom was wrong. He did not try to persuade colleagues with anecdote or plausibility or meta-analyses of observational studies. He set out to answer a question in the correct way – with a randomized trial.

This is the path forward in medicine. I’ve often heard proponents of observational research declare that many topics in medicine cannot be studied with trials. I could hear people arguing that it’s not feasible to study mostly home-bound, elderly frail patients. And the fact that there exist so few trials in this space would support that argument.

But the FRAIL-AF authors showed that it is possible. This is the kind of science that medicine should celebrate. There were no soft endpoints, financial conflicts, or spin. If medical science had science as its incentive, rather than attention, FRAIL-AF easily wins top honors.

The third reason FRAIL-AF is so important is that it teaches us the humility required in translating evidence in our clinics. I like to say evidence is what separates doctors from palm readers. But using this evidence requires thinking hard about how average effects in trial environments apply to our patient.

Yes, of course, there is clear evidence from tens of thousands of patients in the DOAC versus warfarin trials, that, for those patients, on average, DOACs compare favorably with VKA. The average age of patients in these trials was 70-73 years; the average age in FRAIL-AF was 83 years. And that is just age. A substudy of the ENGAGE AF-TIMI 48 trial found that only 360 of more than 20,000 patients in the trial had severe frailty.

FRAIL-AF clearly shows how cautious we should be in applying evidence gathered in younger, healthier patients to older, more vulnerable patients. That lesson extends to nearly every common therapy in medicine today. It also casts great doubt on the soft-thinking idea of using evidence from trials to derive quality metrics. As if the nuance of evidence translation can be captured in an electronic health record.

The skillful use of evidence will be one of the main challenges of the next generation of clinicians. Thanks to advances in medical science, more patients will live long enough to become frail. And the so-called “guideline-directed” therapies may not apply to them.

Dr. Joosten, Dr. Geersing, and the FRAIL-AF team have taught us specific lessons about anticoagulation, but their greatest contribution has been to demonstrate the value of humility in science and the practice of evidence-based medicine.

If you treat patients, no trial at this meeting is more important.

Dr. Mandrola is a clinical electrophysiologist at Baptist Medical Associates, Louisville, Ky. He reported no relevant conflicts of interest.
 

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

One of the hardest tasks of a clinician is applying evidence from trials to the person in your office. At the annual congress of the European Society of Cardiology, the surprising and unexpected results of the FRAIL-AF trial confirm the massive challenge of evidence translation.

FRAIL-AF investigators set out to study the question of whether frail, elderly patients with atrial fibrillation who were doing well with vitamin K antagonists (VKA) should be switched to direct-acting oral anticoagulants (DOAC).

Senior author Geert-Jan Geersing, MD, PhD, from the University Medical Center Utrecht (the Netherlands), told me that frustration led him to design this study. He was frustrated that colleagues assumed that evidence in nonfrail patients can always be translated to frail patients. 

Dr. Geersing offered two reasons why common wisdom may be wrong. First was that the large DOAC versus warfarin trials included few elderly patients with frailty. Second, first author Linda Joosten, MD, made it clear in her presentation that frailty is a lot more than aging. It is a clinical syndrome, which entails a “high burden of comorbidities, dependency on others, and a reduced ability to resist stressors.”
 

The FRAIL-AF trial

The investigators recruited elderly, frail patients with fibrillation who were treated with VKAs and had stable international normalized ratios from outpatient clinics throughout the Netherlands. They screened about 2,600 patients and enrolled nearly 1,400. Most were excluded for not being frail.

Half the group was randomized to switching to a DOAC – drug choice was left to the treating clinician – and the other half remained on VKAs. Patients were 83 years of age on average with a mean CHA2DS2-VASc score of 4. All four classes of DOAC were used in the switching arm.

The primary endpoint was major or clinically relevant nonmajor bleeding, whichever came first, accounting for death as a competing risk. Follow-up was 1 year.
 

The results for switching to DOAC vs. VKA

Dr. Joosten started her presentation with this: “The results turned out to be different than we expected.” The authors designed the trial with the idea that switching to DOACs would be superior in safety to remaining on VKAs.

But the trial was halted after an interim analysis found a rate of major bleeding in the switching arm of 15.3% versus 9.4% in the arm staying on VKA (hazard ratio, 1.69; 95% confidence interval, 1.23-2.32; P = .0012).

The Kaplan-Meier event curves reveal that the excess risk of bleeding occurred after 100 days and increased with time. This argued against an early effect from transitioning the drugs.

An analysis looking at specific DOAC drugs revealed similar hazards for the two most common ones used – apixaban and rivaroxaban.

Thrombotic events were a secondary endpoint and were low in absolute numbers, 2.4% versus 2.0%, for remaining on VKA and switching to DOAC, respectively (HR, 1.26; 95% CI, 0.60-2.61).

The time in therapeutic range in FRAIL-AF was similar to that in the seminal DOAC trials.
 

Comments

Three reasons lead me to choose FRAIL-AF as the most important study from the 2023 ESC congress.

First is the specific lesson about switching drugs. Note that FRAIL-AF did not address the question of starting anticoagulation. The trial results show that if you have a frail older patient who is doing well on VKA, don’t change to a DOAC. That is important to know, but it is not what gives this study its heft.

The second reason centers on the investigators choice to do this trial. Dr. Geersing had a feeling that common wisdom was wrong. He did not try to persuade colleagues with anecdote or plausibility or meta-analyses of observational studies. He set out to answer a question in the correct way – with a randomized trial.

This is the path forward in medicine. I’ve often heard proponents of observational research declare that many topics in medicine cannot be studied with trials. I could hear people arguing that it’s not feasible to study mostly home-bound, elderly frail patients. And the fact that there exist so few trials in this space would support that argument.

But the FRAIL-AF authors showed that it is possible. This is the kind of science that medicine should celebrate. There were no soft endpoints, financial conflicts, or spin. If medical science had science as its incentive, rather than attention, FRAIL-AF easily wins top honors.

The third reason FRAIL-AF is so important is that it teaches us the humility required in translating evidence in our clinics. I like to say evidence is what separates doctors from palm readers. But using this evidence requires thinking hard about how average effects in trial environments apply to our patient.

Yes, of course, there is clear evidence from tens of thousands of patients in the DOAC versus warfarin trials, that, for those patients, on average, DOACs compare favorably with VKA. The average age of patients in these trials was 70-73 years; the average age in FRAIL-AF was 83 years. And that is just age. A substudy of the ENGAGE AF-TIMI 48 trial found that only 360 of more than 20,000 patients in the trial had severe frailty.

FRAIL-AF clearly shows how cautious we should be in applying evidence gathered in younger, healthier patients to older, more vulnerable patients. That lesson extends to nearly every common therapy in medicine today. It also casts great doubt on the soft-thinking idea of using evidence from trials to derive quality metrics. As if the nuance of evidence translation can be captured in an electronic health record.

The skillful use of evidence will be one of the main challenges of the next generation of clinicians. Thanks to advances in medical science, more patients will live long enough to become frail. And the so-called “guideline-directed” therapies may not apply to them.

Dr. Joosten, Dr. Geersing, and the FRAIL-AF team have taught us specific lessons about anticoagulation, but their greatest contribution has been to demonstrate the value of humility in science and the practice of evidence-based medicine.

If you treat patients, no trial at this meeting is more important.

Dr. Mandrola is a clinical electrophysiologist at Baptist Medical Associates, Louisville, Ky. He reported no relevant conflicts of interest.
 

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

AMSTERDAM – A simple, low-cost 5-day course of dietary inorganic nitrate has shown apparent overwhelming benefit in preventing contrast-induced nephropathy (CIN) and reducing subsequent renal and cardiovascular outcomes.

In the NITRATE-CIN Study, non-ST segment elevation myocardial infarction acute coronary syndrome (ACS) patients at risk of renal injury from coronary angiography who received dietary inorganic nitrates had a 70% reduction in CIN compared with those given placebo.

The nitrate group also showed an impressive reduction in periprocedural myocardial infarction (MI) and improved renal function at 3 months, as well as a halving of major adverse cardiovascular events and major adverse kidney events at 1 year.

The trial was presented by Dan Jones, MD, Barts Health NHS Trust, London, at the annual congress of the European Society of Cardiology.

“Currently, aside from intravenous hydration, there is no proven treatment that reduces contrast-induced nephropathy. We feel that dietary inorganic nitrate shows huge promise in this study, and these findings could have important implications in reducing this serious complication of coronary angiography,” Dr. Jones concluded.

He explained that the product used was a formulation of dietary inorganic nitrates given as potassium nitrate capsules, which the study investigators produced specifically for this trial.

At this point, “the only way to get inorganic nitrate is in the diet – specifically by consuming beetroot juice or green leafy vegetables such as spinach and rocket. From a clinician perspective, while these results suggest this is an effective therapy and has great potential, it is not currently possible to prescribe the medication we used in our study, although we are working on producing a commercial product,” he said in an interview.

However, Dr. Jones noted that it is possible to buy beetroot shots, which contain 7 mmol of potassium nitrate in each shot, from health food shops and websites, and two such shots per day for 5 days would give a dose similar to that used in this study, starting the day before angiography.

“While we need a larger multicenter study to confirm these results, studies so far suggest no signal at all that there is any harm in this approach, and there could be a great deal of benefit in taking a couple of beetroot shots prior to and for a few days after an angiogram,” he said.
 

Dietary nitrates “make sense”

Designated discussant of the NITRATE-CIN trial at the ESC Hotline session, Roxanna Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, said the study was well designed, and the “interesting and plausible” hypothesis to raise nitric oxide levels by dietary nitrates “makes sense.”

On the main findings of a major significant 50% reduction in acute kidney injury, Dr. Mehran said, “It is difficult to imagine such a reduction is possible.”

She pointed out that the large reduction in major adverse cardiac events and major adverse kidney events at 1 year also suggests that there is a sustained benefit in protecting the kidney.

“We’re all going to get on beet juice after this,” she quipped.

Still, Dr. Mehran questioned whether the results were “too good to be true,” adding that a larger trial actually powered for longer term outcome events is needed, as well as a better understanding of whether CIN has a causative role in mortality.

Responding to questions about whether such a large effect could actually be achieved with dietary nitrates, Dr. Jones said he thought there would definitely be some benefits, but maybe not quite as large as those seen in this study.

“From our pilot data we thought nitrate may be effective in preventing CIN,” he said in an interview. “We recruited a higher risk group than we thought, which is why the control event rates were higher than we expected, but the acute kidney injury reduction is roughly what we had estimated, and makes sense biologically.”

Dr. Jones acknowledged that the large reductions in long-term major adverse cardiovascular and kidney events were unexpected.

“The trial was not powered to see reductions in these outcomes, so we need to see if those event reductions can be replicated in larger multicenter trials,” he said. “But this was a double-blind placebo-controlled trial so in this trial the effects are real, and I think the effect size in this trial is too large for there not to be a beneficial effect.

“But I’m not so sure that we would see the same magnitude of effect when we have a larger study with tighter confidence intervals but perhaps a 20%-25% reduction in cardiovascular and kidney may be more realistic, which would still be amazing for such an easy and cost-effective intervention,” Dr. Jones added.

A larger trial is now being planned.

The researchers are also working on the development of a commercial form of dietary inorganic nitrate that would be needed for larger multicenter studies and would then be generally available. “We want this to be a low-cost product that would be available to all,” Dr. Jones said.

He noted that other studies have shown that dietary inorganic nitrates in the form of beetroot juice lower blood pressure; there are suggestions it may also lower cholesterol and prevent stent restenosis, and athletes sometimes take it to increase their aerobic capacity.

“There appears to be many benefits of dietary nitrates, and the one thing we can do at this time is to encourage people to increase their dietary nitrate consumption by eating large quantities of green leafy vegetables and beetroot,” Dr. Jones said.
 

Replacing lost nitric oxide

In his presentation, Dr. Jones noted that CIN is a serious complication after coronary angiography and is associated with longer hospital stays, worse long-term kidney function, and increased risk of MI and death.

The incidence varies depending on patient risk and definitions used, but it can affect up to 50% of high-risk ACS patients – older patients and/or those with heart failure, chronic kidney disease, or diabetes.

“We don’t really understand the mechanisms that cause CIN, but multiple proposed mechanisms exist, and we know from previous studies that a deficiency of nitric oxide is crucial to the development of CIN,” he explained. “We also know that [nitric oxide] is crucial for normal renal hemostasis. Therefore, a potential therapeutic target to prevent CIN would be to replace this lost nitric oxide.”

The inorganic nitrate evaluated in this trial is found in the diet, is produced endogenously, and is different from medicinally synthesized organic nitrates such as isosorbide mononitrate, he said.

“Isosorbide mononitrate/dinitrate tablets contain organic nitrates and while they are good for angina, we know that they do not have the same beneficial effects on the sustained generation of nitric oxide as inorganic nitrates,” Dr. Jones added.
 

NITRATE-CIN study

NITRATE-CIN was a double-blind, randomized, placebo-controlled trial conducted at Queen Mary University of London and St. Bartholomew’s Hospital in London, which tested the effectiveness of inorganic nitrate in preventing contrast-induced nephropathy in 640 patients with non-ST elevation ACS referred for invasive coronary angiography.

To be eligible for the trial, patients had to be at risk of contrast-induced nephropathy with an estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m² or have two of the following significant risk factors: diabetes, liver failure, over 70 years of age, exposure to contrast within 7 days, heart failure, or on concomitant renally acting drugs.

Patients were randomly assigned to a formulation of potassium nitrate (12 mmol/744 mg nitrate) per day given as capsules for a 5-day course with the first dose administered prior to angiography or to a control group that received potassium chloride with a matched potassium concentration.

The patient population had a mean age of 71 years, 73% were male, 75% were White, 46% had diabetes, and 56% had chronic kidney disease. There was a 13% loss to follow-up, which was attributed to the COVID pandemic.

The amount of contrast administration was 180 mL in the placebo and 170 mL in the nitrate arm, with 50% of patients undergoing some sort of revascularization.

The primary endpoint was the incidence of CIN as defined by KDIGO criteria – a series of stages of acute kidney injury defined by changes in serum creatinine within 72 hours and up to 1 week.

Results showed that this primary CIN endpoint was reduced significantly from 30% in the placebo arm to 9.1% in the nitrate group, a 70% relative risk reduction (P < .0001). The majority (90%) of this CIN was stage 1, but 10% was stage 2.

Consistent results were seen when an alternative definition of CIN (Mehran) was used, although the rates in both arms were lower than when the KDIGO definition was used.

The benefit was seen across prespecified subgroups including diabetes status, troponin positivity, and Mehran risk. But the benefit seemed to be attenuated in patients on preexisting organic nitrate therapy, although the numbers in these groups were too small to draw definitive conclusions.

As would be expected, there were significant elevations in both systemic nitrate and nitrite levels both up to 72 hours after the procedure, which was consistent with the 5-day course. This was associated with reductions in systolic and diastolic blood pressure, but not associated with any adverse events, Dr. Jones reported.

Rates of procedural MI, a prespecified secondary endpoint, were reduced from 12.5% to 4.1% in those on inorganic nitrates (P = .003).

Looking at longer term outcomes, kidney function was improved at 3 months as measured by change in eGFR, which showed a 10% relative improvement of 5.2 mL/min per 1.73 m² (10%) in the nitrate group vs. the placebo group. Serum creatinine levels were also significantly increased in the nitrate group.

At 12 months, there was a significant 50% relative reduction in major adverse cardiovascular events – including all-cause mortality, recurrent MI, and recurrent revascularization – which were reduced from 18.1% in the placebo group to 9.1% in the nitrate group, with a reduction in all three of the constituent components of the composite endpoint including all-cause mortality.

Major adverse kidney events (all-cause mortality, renal replacement therapy, or persistent renal dysfunction) were also reduced at 12 months from 28.4% in the placebo group to 10.7% in the nitrate group (P < .0001), a 60% relative reduction. This was driven by lower rates of all-cause mortality and persistent renal dysfunction.

While Dr. Jones said these results on major cardiovascular and kidney outcomes should be viewed as hypothesis-generating at the present time, he said there were biological mechanisms that could explain these benefits.

“We saw a reduction in procedural MI, and we know there is a lot of similar biology in preventing procedural MI and subsequent cardiac events in the acute phase. This, in combination with the large reduction in acute kidney injury, could explain why there’s improved outcomes out to 12 months.”

In her comments, Dr. Mehran congratulated the investigators on having conducted the first study to have shown benefit in the prevention of contrast-associated acute kidney injury as well as major adverse cardiovascular and kidney events associated with the condition.

She used the term “contrast-associated acute kidney injury” rather than “contrast-induced nephropathy” because, she said, it has not been proven that the acute kidney injury seen after angiography is actually caused by the contrast and “so many other things are occurring during procedures when these patients are presenting with different syndromes.”

Dr. Mehran pointed out some weaknesses in the NITRATE-CIN study including the single-center design, the large volume of contrast administered, 13% of patients missing the primary endpoint blood draw, and an imbalance in relevant baseline characteristics despite randomization.

The NITRATE-CIN study was funded by Heart Research UK. Dr. Jones has disclosed no relevant financial relationships.

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

AMSTERDAM – A simple, low-cost 5-day course of dietary inorganic nitrate has shown apparent overwhelming benefit in preventing contrast-induced nephropathy (CIN) and reducing subsequent renal and cardiovascular outcomes.

In the NITRATE-CIN Study, non-ST segment elevation myocardial infarction acute coronary syndrome (ACS) patients at risk of renal injury from coronary angiography who received dietary inorganic nitrates had a 70% reduction in CIN compared with those given placebo.

The nitrate group also showed an impressive reduction in periprocedural myocardial infarction (MI) and improved renal function at 3 months, as well as a halving of major adverse cardiovascular events and major adverse kidney events at 1 year.

The trial was presented by Dan Jones, MD, Barts Health NHS Trust, London, at the annual congress of the European Society of Cardiology.

“Currently, aside from intravenous hydration, there is no proven treatment that reduces contrast-induced nephropathy. We feel that dietary inorganic nitrate shows huge promise in this study, and these findings could have important implications in reducing this serious complication of coronary angiography,” Dr. Jones concluded.

He explained that the product used was a formulation of dietary inorganic nitrates given as potassium nitrate capsules, which the study investigators produced specifically for this trial.

At this point, “the only way to get inorganic nitrate is in the diet – specifically by consuming beetroot juice or green leafy vegetables such as spinach and rocket. From a clinician perspective, while these results suggest this is an effective therapy and has great potential, it is not currently possible to prescribe the medication we used in our study, although we are working on producing a commercial product,” he said in an interview.

However, Dr. Jones noted that it is possible to buy beetroot shots, which contain 7 mmol of potassium nitrate in each shot, from health food shops and websites, and two such shots per day for 5 days would give a dose similar to that used in this study, starting the day before angiography.

“While we need a larger multicenter study to confirm these results, studies so far suggest no signal at all that there is any harm in this approach, and there could be a great deal of benefit in taking a couple of beetroot shots prior to and for a few days after an angiogram,” he said.
 

Dietary nitrates “make sense”

Designated discussant of the NITRATE-CIN trial at the ESC Hotline session, Roxanna Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, said the study was well designed, and the “interesting and plausible” hypothesis to raise nitric oxide levels by dietary nitrates “makes sense.”

On the main findings of a major significant 50% reduction in acute kidney injury, Dr. Mehran said, “It is difficult to imagine such a reduction is possible.”

She pointed out that the large reduction in major adverse cardiac events and major adverse kidney events at 1 year also suggests that there is a sustained benefit in protecting the kidney.

“We’re all going to get on beet juice after this,” she quipped.

Still, Dr. Mehran questioned whether the results were “too good to be true,” adding that a larger trial actually powered for longer term outcome events is needed, as well as a better understanding of whether CIN has a causative role in mortality.

Responding to questions about whether such a large effect could actually be achieved with dietary nitrates, Dr. Jones said he thought there would definitely be some benefits, but maybe not quite as large as those seen in this study.

“From our pilot data we thought nitrate may be effective in preventing CIN,” he said in an interview. “We recruited a higher risk group than we thought, which is why the control event rates were higher than we expected, but the acute kidney injury reduction is roughly what we had estimated, and makes sense biologically.”

Dr. Jones acknowledged that the large reductions in long-term major adverse cardiovascular and kidney events were unexpected.

“The trial was not powered to see reductions in these outcomes, so we need to see if those event reductions can be replicated in larger multicenter trials,” he said. “But this was a double-blind placebo-controlled trial so in this trial the effects are real, and I think the effect size in this trial is too large for there not to be a beneficial effect.

“But I’m not so sure that we would see the same magnitude of effect when we have a larger study with tighter confidence intervals but perhaps a 20%-25% reduction in cardiovascular and kidney may be more realistic, which would still be amazing for such an easy and cost-effective intervention,” Dr. Jones added.

A larger trial is now being planned.

The researchers are also working on the development of a commercial form of dietary inorganic nitrate that would be needed for larger multicenter studies and would then be generally available. “We want this to be a low-cost product that would be available to all,” Dr. Jones said.

He noted that other studies have shown that dietary inorganic nitrates in the form of beetroot juice lower blood pressure; there are suggestions it may also lower cholesterol and prevent stent restenosis, and athletes sometimes take it to increase their aerobic capacity.

“There appears to be many benefits of dietary nitrates, and the one thing we can do at this time is to encourage people to increase their dietary nitrate consumption by eating large quantities of green leafy vegetables and beetroot,” Dr. Jones said.
 

Replacing lost nitric oxide

In his presentation, Dr. Jones noted that CIN is a serious complication after coronary angiography and is associated with longer hospital stays, worse long-term kidney function, and increased risk of MI and death.

The incidence varies depending on patient risk and definitions used, but it can affect up to 50% of high-risk ACS patients – older patients and/or those with heart failure, chronic kidney disease, or diabetes.

“We don’t really understand the mechanisms that cause CIN, but multiple proposed mechanisms exist, and we know from previous studies that a deficiency of nitric oxide is crucial to the development of CIN,” he explained. “We also know that [nitric oxide] is crucial for normal renal hemostasis. Therefore, a potential therapeutic target to prevent CIN would be to replace this lost nitric oxide.”

The inorganic nitrate evaluated in this trial is found in the diet, is produced endogenously, and is different from medicinally synthesized organic nitrates such as isosorbide mononitrate, he said.

“Isosorbide mononitrate/dinitrate tablets contain organic nitrates and while they are good for angina, we know that they do not have the same beneficial effects on the sustained generation of nitric oxide as inorganic nitrates,” Dr. Jones added.
 

NITRATE-CIN study

NITRATE-CIN was a double-blind, randomized, placebo-controlled trial conducted at Queen Mary University of London and St. Bartholomew’s Hospital in London, which tested the effectiveness of inorganic nitrate in preventing contrast-induced nephropathy in 640 patients with non-ST elevation ACS referred for invasive coronary angiography.

To be eligible for the trial, patients had to be at risk of contrast-induced nephropathy with an estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m² or have two of the following significant risk factors: diabetes, liver failure, over 70 years of age, exposure to contrast within 7 days, heart failure, or on concomitant renally acting drugs.

Patients were randomly assigned to a formulation of potassium nitrate (12 mmol/744 mg nitrate) per day given as capsules for a 5-day course with the first dose administered prior to angiography or to a control group that received potassium chloride with a matched potassium concentration.

The patient population had a mean age of 71 years, 73% were male, 75% were White, 46% had diabetes, and 56% had chronic kidney disease. There was a 13% loss to follow-up, which was attributed to the COVID pandemic.

The amount of contrast administration was 180 mL in the placebo and 170 mL in the nitrate arm, with 50% of patients undergoing some sort of revascularization.

The primary endpoint was the incidence of CIN as defined by KDIGO criteria – a series of stages of acute kidney injury defined by changes in serum creatinine within 72 hours and up to 1 week.

Results showed that this primary CIN endpoint was reduced significantly from 30% in the placebo arm to 9.1% in the nitrate group, a 70% relative risk reduction (P < .0001). The majority (90%) of this CIN was stage 1, but 10% was stage 2.

Consistent results were seen when an alternative definition of CIN (Mehran) was used, although the rates in both arms were lower than when the KDIGO definition was used.

The benefit was seen across prespecified subgroups including diabetes status, troponin positivity, and Mehran risk. But the benefit seemed to be attenuated in patients on preexisting organic nitrate therapy, although the numbers in these groups were too small to draw definitive conclusions.

As would be expected, there were significant elevations in both systemic nitrate and nitrite levels both up to 72 hours after the procedure, which was consistent with the 5-day course. This was associated with reductions in systolic and diastolic blood pressure, but not associated with any adverse events, Dr. Jones reported.

Rates of procedural MI, a prespecified secondary endpoint, were reduced from 12.5% to 4.1% in those on inorganic nitrates (P = .003).

Looking at longer term outcomes, kidney function was improved at 3 months as measured by change in eGFR, which showed a 10% relative improvement of 5.2 mL/min per 1.73 m² (10%) in the nitrate group vs. the placebo group. Serum creatinine levels were also significantly increased in the nitrate group.

At 12 months, there was a significant 50% relative reduction in major adverse cardiovascular events – including all-cause mortality, recurrent MI, and recurrent revascularization – which were reduced from 18.1% in the placebo group to 9.1% in the nitrate group, with a reduction in all three of the constituent components of the composite endpoint including all-cause mortality.

Major adverse kidney events (all-cause mortality, renal replacement therapy, or persistent renal dysfunction) were also reduced at 12 months from 28.4% in the placebo group to 10.7% in the nitrate group (P < .0001), a 60% relative reduction. This was driven by lower rates of all-cause mortality and persistent renal dysfunction.

While Dr. Jones said these results on major cardiovascular and kidney outcomes should be viewed as hypothesis-generating at the present time, he said there were biological mechanisms that could explain these benefits.

“We saw a reduction in procedural MI, and we know there is a lot of similar biology in preventing procedural MI and subsequent cardiac events in the acute phase. This, in combination with the large reduction in acute kidney injury, could explain why there’s improved outcomes out to 12 months.”

In her comments, Dr. Mehran congratulated the investigators on having conducted the first study to have shown benefit in the prevention of contrast-associated acute kidney injury as well as major adverse cardiovascular and kidney events associated with the condition.

She used the term “contrast-associated acute kidney injury” rather than “contrast-induced nephropathy” because, she said, it has not been proven that the acute kidney injury seen after angiography is actually caused by the contrast and “so many other things are occurring during procedures when these patients are presenting with different syndromes.”

Dr. Mehran pointed out some weaknesses in the NITRATE-CIN study including the single-center design, the large volume of contrast administered, 13% of patients missing the primary endpoint blood draw, and an imbalance in relevant baseline characteristics despite randomization.

The NITRATE-CIN study was funded by Heart Research UK. Dr. Jones has disclosed no relevant financial relationships.

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

AMSTERDAM – A simple, low-cost 5-day course of dietary inorganic nitrate has shown apparent overwhelming benefit in preventing contrast-induced nephropathy (CIN) and reducing subsequent renal and cardiovascular outcomes.

In the NITRATE-CIN Study, non-ST segment elevation myocardial infarction acute coronary syndrome (ACS) patients at risk of renal injury from coronary angiography who received dietary inorganic nitrates had a 70% reduction in CIN compared with those given placebo.

The nitrate group also showed an impressive reduction in periprocedural myocardial infarction (MI) and improved renal function at 3 months, as well as a halving of major adverse cardiovascular events and major adverse kidney events at 1 year.

The trial was presented by Dan Jones, MD, Barts Health NHS Trust, London, at the annual congress of the European Society of Cardiology.

“Currently, aside from intravenous hydration, there is no proven treatment that reduces contrast-induced nephropathy. We feel that dietary inorganic nitrate shows huge promise in this study, and these findings could have important implications in reducing this serious complication of coronary angiography,” Dr. Jones concluded.

He explained that the product used was a formulation of dietary inorganic nitrates given as potassium nitrate capsules, which the study investigators produced specifically for this trial.

At this point, “the only way to get inorganic nitrate is in the diet – specifically by consuming beetroot juice or green leafy vegetables such as spinach and rocket. From a clinician perspective, while these results suggest this is an effective therapy and has great potential, it is not currently possible to prescribe the medication we used in our study, although we are working on producing a commercial product,” he said in an interview.

However, Dr. Jones noted that it is possible to buy beetroot shots, which contain 7 mmol of potassium nitrate in each shot, from health food shops and websites, and two such shots per day for 5 days would give a dose similar to that used in this study, starting the day before angiography.

“While we need a larger multicenter study to confirm these results, studies so far suggest no signal at all that there is any harm in this approach, and there could be a great deal of benefit in taking a couple of beetroot shots prior to and for a few days after an angiogram,” he said.
 

Dietary nitrates “make sense”

Designated discussant of the NITRATE-CIN trial at the ESC Hotline session, Roxanna Mehran, MD, Icahn School of Medicine at Mount Sinai, New York, said the study was well designed, and the “interesting and plausible” hypothesis to raise nitric oxide levels by dietary nitrates “makes sense.”

On the main findings of a major significant 50% reduction in acute kidney injury, Dr. Mehran said, “It is difficult to imagine such a reduction is possible.”

She pointed out that the large reduction in major adverse cardiac events and major adverse kidney events at 1 year also suggests that there is a sustained benefit in protecting the kidney.

“We’re all going to get on beet juice after this,” she quipped.

Still, Dr. Mehran questioned whether the results were “too good to be true,” adding that a larger trial actually powered for longer term outcome events is needed, as well as a better understanding of whether CIN has a causative role in mortality.

Responding to questions about whether such a large effect could actually be achieved with dietary nitrates, Dr. Jones said he thought there would definitely be some benefits, but maybe not quite as large as those seen in this study.

“From our pilot data we thought nitrate may be effective in preventing CIN,” he said in an interview. “We recruited a higher risk group than we thought, which is why the control event rates were higher than we expected, but the acute kidney injury reduction is roughly what we had estimated, and makes sense biologically.”

Dr. Jones acknowledged that the large reductions in long-term major adverse cardiovascular and kidney events were unexpected.

“The trial was not powered to see reductions in these outcomes, so we need to see if those event reductions can be replicated in larger multicenter trials,” he said. “But this was a double-blind placebo-controlled trial so in this trial the effects are real, and I think the effect size in this trial is too large for there not to be a beneficial effect.

“But I’m not so sure that we would see the same magnitude of effect when we have a larger study with tighter confidence intervals but perhaps a 20%-25% reduction in cardiovascular and kidney may be more realistic, which would still be amazing for such an easy and cost-effective intervention,” Dr. Jones added.

A larger trial is now being planned.

The researchers are also working on the development of a commercial form of dietary inorganic nitrate that would be needed for larger multicenter studies and would then be generally available. “We want this to be a low-cost product that would be available to all,” Dr. Jones said.

He noted that other studies have shown that dietary inorganic nitrates in the form of beetroot juice lower blood pressure; there are suggestions it may also lower cholesterol and prevent stent restenosis, and athletes sometimes take it to increase their aerobic capacity.

“There appears to be many benefits of dietary nitrates, and the one thing we can do at this time is to encourage people to increase their dietary nitrate consumption by eating large quantities of green leafy vegetables and beetroot,” Dr. Jones said.
 

Replacing lost nitric oxide

In his presentation, Dr. Jones noted that CIN is a serious complication after coronary angiography and is associated with longer hospital stays, worse long-term kidney function, and increased risk of MI and death.

The incidence varies depending on patient risk and definitions used, but it can affect up to 50% of high-risk ACS patients – older patients and/or those with heart failure, chronic kidney disease, or diabetes.

“We don’t really understand the mechanisms that cause CIN, but multiple proposed mechanisms exist, and we know from previous studies that a deficiency of nitric oxide is crucial to the development of CIN,” he explained. “We also know that [nitric oxide] is crucial for normal renal hemostasis. Therefore, a potential therapeutic target to prevent CIN would be to replace this lost nitric oxide.”

The inorganic nitrate evaluated in this trial is found in the diet, is produced endogenously, and is different from medicinally synthesized organic nitrates such as isosorbide mononitrate, he said.

“Isosorbide mononitrate/dinitrate tablets contain organic nitrates and while they are good for angina, we know that they do not have the same beneficial effects on the sustained generation of nitric oxide as inorganic nitrates,” Dr. Jones added.
 

NITRATE-CIN study

NITRATE-CIN was a double-blind, randomized, placebo-controlled trial conducted at Queen Mary University of London and St. Bartholomew’s Hospital in London, which tested the effectiveness of inorganic nitrate in preventing contrast-induced nephropathy in 640 patients with non-ST elevation ACS referred for invasive coronary angiography.

To be eligible for the trial, patients had to be at risk of contrast-induced nephropathy with an estimated glomerular filtration rate (eGFR) less than 60 mL/min per 1.73 m² or have two of the following significant risk factors: diabetes, liver failure, over 70 years of age, exposure to contrast within 7 days, heart failure, or on concomitant renally acting drugs.

Patients were randomly assigned to a formulation of potassium nitrate (12 mmol/744 mg nitrate) per day given as capsules for a 5-day course with the first dose administered prior to angiography or to a control group that received potassium chloride with a matched potassium concentration.

The patient population had a mean age of 71 years, 73% were male, 75% were White, 46% had diabetes, and 56% had chronic kidney disease. There was a 13% loss to follow-up, which was attributed to the COVID pandemic.

The amount of contrast administration was 180 mL in the placebo and 170 mL in the nitrate arm, with 50% of patients undergoing some sort of revascularization.

The primary endpoint was the incidence of CIN as defined by KDIGO criteria – a series of stages of acute kidney injury defined by changes in serum creatinine within 72 hours and up to 1 week.

Results showed that this primary CIN endpoint was reduced significantly from 30% in the placebo arm to 9.1% in the nitrate group, a 70% relative risk reduction (P < .0001). The majority (90%) of this CIN was stage 1, but 10% was stage 2.

Consistent results were seen when an alternative definition of CIN (Mehran) was used, although the rates in both arms were lower than when the KDIGO definition was used.

The benefit was seen across prespecified subgroups including diabetes status, troponin positivity, and Mehran risk. But the benefit seemed to be attenuated in patients on preexisting organic nitrate therapy, although the numbers in these groups were too small to draw definitive conclusions.

As would be expected, there were significant elevations in both systemic nitrate and nitrite levels both up to 72 hours after the procedure, which was consistent with the 5-day course. This was associated with reductions in systolic and diastolic blood pressure, but not associated with any adverse events, Dr. Jones reported.

Rates of procedural MI, a prespecified secondary endpoint, were reduced from 12.5% to 4.1% in those on inorganic nitrates (P = .003).

Looking at longer term outcomes, kidney function was improved at 3 months as measured by change in eGFR, which showed a 10% relative improvement of 5.2 mL/min per 1.73 m² (10%) in the nitrate group vs. the placebo group. Serum creatinine levels were also significantly increased in the nitrate group.

At 12 months, there was a significant 50% relative reduction in major adverse cardiovascular events – including all-cause mortality, recurrent MI, and recurrent revascularization – which were reduced from 18.1% in the placebo group to 9.1% in the nitrate group, with a reduction in all three of the constituent components of the composite endpoint including all-cause mortality.

Major adverse kidney events (all-cause mortality, renal replacement therapy, or persistent renal dysfunction) were also reduced at 12 months from 28.4% in the placebo group to 10.7% in the nitrate group (P < .0001), a 60% relative reduction. This was driven by lower rates of all-cause mortality and persistent renal dysfunction.

While Dr. Jones said these results on major cardiovascular and kidney outcomes should be viewed as hypothesis-generating at the present time, he said there were biological mechanisms that could explain these benefits.

“We saw a reduction in procedural MI, and we know there is a lot of similar biology in preventing procedural MI and subsequent cardiac events in the acute phase. This, in combination with the large reduction in acute kidney injury, could explain why there’s improved outcomes out to 12 months.”

In her comments, Dr. Mehran congratulated the investigators on having conducted the first study to have shown benefit in the prevention of contrast-associated acute kidney injury as well as major adverse cardiovascular and kidney events associated with the condition.

She used the term “contrast-associated acute kidney injury” rather than “contrast-induced nephropathy” because, she said, it has not been proven that the acute kidney injury seen after angiography is actually caused by the contrast and “so many other things are occurring during procedures when these patients are presenting with different syndromes.”

Dr. Mehran pointed out some weaknesses in the NITRATE-CIN study including the single-center design, the large volume of contrast administered, 13% of patients missing the primary endpoint blood draw, and an imbalance in relevant baseline characteristics despite randomization.

The NITRATE-CIN study was funded by Heart Research UK. Dr. Jones has disclosed no relevant financial relationships.

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

AMSTERDAM – Systematic screening by primary care physicians for cardiovascular disease (CVD) in high-risk adults – those with type 2 diabetes, chronic obstructive pulmonary disease (COPD), or both – more than doubled the rate of incident CVD diagnosed, compared with usual care, in a Dutch study involving more than 1,200 people and 25 primary care practices.

Scaling up this program to larger populations could potentially uncover huge numbers of currently unrecognized people with CVD given the large number of adults with type 2 diabetes plus those with COPD, Amy Groenewegen, MD, said at the annual congress of the European Society of Cardiology.

“I think this screening is ready for routine use, but it could be followed by prospective studies that investigate whether it produces more benefits in patient-centered outcomes,” Dr. Groenewegen said in a press briefing. She stressed that it has not yet been clearly proven that patients with these chronic diseases are better off long term when their CVD is detected sooner using the tested approach.

“We need simple ways to identify relevant patients for additional screening and potential treatment” of CVD, commented Lars Kober, MD, designated discussant at the Congress and a cardiologist and professor at Rigshospitalet, Copenhagen University Hospital.
 

A ‘very simple’ symptom questionnaire

The study is important because it tested a “very simple” symptom questionnaire as the initial screening phase, yet resulted in a CVD diagnostic rate that was two- to threefold higher than in the control patients managed with usual care, Dr. Kober noted.

The Reviving the Early Diagnosis of CVD (RED-CVD) trial randomized 14 primary care practices in the Netherlands to apply a structured screening protocol to adults with type 2 diabetes or COPD, and another 11 practices that served as controls and provided their patients with usual care.

The study included 624 people in the screening arm and 592 in the usual-care arm. Their average age was about 68 years. In the screening arm, 87% had type 2 diabetes and 20% had COPD, including 6.3% with both. In the usual-care arm, 86% had type 2 diabetes, 21% had COPD, with 7.4% having both.

About a quarter of the study cohort had a history of a CVD diagnosis, but they were included for their potential for developing another form of CVD. The study considered three types of CVD: coronary artery disease, heart failure, and atrial fibrillation.

The CVD screening protocol began with an 11-question survey, completed by patients, that asked about their symptoms. The survey was devised by a research team at the University Medical Center Groningen, the Netherlands, who collaborated on the study.

The second phase for people who had suggestive symptoms was a physical examination, measurement of serum N-terminal pro-brain natriuretic peptide (elevated levels signal incident heart failure), and an ECG. People who continued to show findings consistent with CVD in this phase were then referred on a discretionary basis by the attending physician to a specialist.
 

More than doubling the CVD diagnosis rate

The screening program produced a total of 50 new CVD diagnoses in the screening cohort (8%) and 18 in the control, usual-care arm (3%), for the study’s primary endpoint. The greatest number of events involved heart failure, followed by coronary disease.

The screening questionnaire identified 70% of the people who completed it with suggestive symptoms, such as shortness of breath, claudication, or palpitations. The follow-up assessments of phase two narrowed the group with possible new CVD down to 44% of the people in this arm, and the participating physicians referred 39% to a specialist.

An analysis that adjusted for several demographic and clinical variables and excluded nonobstructive coronary disease as a new CVD diagnosis showed that the systematic screening approach resulted in 2.4-fold more new diagnoses than usual care, reported Dr. Groenewegen, an epidemiologist at University Medical Center Utrecht, the Netherlands.

RED-CVD received no commercial funding. Dr. Groenewegen disclosed no relevant financial relationships. Dr. Kober has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk.

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

AMSTERDAM – Systematic screening by primary care physicians for cardiovascular disease (CVD) in high-risk adults – those with type 2 diabetes, chronic obstructive pulmonary disease (COPD), or both – more than doubled the rate of incident CVD diagnosed, compared with usual care, in a Dutch study involving more than 1,200 people and 25 primary care practices.

Scaling up this program to larger populations could potentially uncover huge numbers of currently unrecognized people with CVD given the large number of adults with type 2 diabetes plus those with COPD, Amy Groenewegen, MD, said at the annual congress of the European Society of Cardiology.

“I think this screening is ready for routine use, but it could be followed by prospective studies that investigate whether it produces more benefits in patient-centered outcomes,” Dr. Groenewegen said in a press briefing. She stressed that it has not yet been clearly proven that patients with these chronic diseases are better off long term when their CVD is detected sooner using the tested approach.

“We need simple ways to identify relevant patients for additional screening and potential treatment” of CVD, commented Lars Kober, MD, designated discussant at the Congress and a cardiologist and professor at Rigshospitalet, Copenhagen University Hospital.
 

A ‘very simple’ symptom questionnaire

The study is important because it tested a “very simple” symptom questionnaire as the initial screening phase, yet resulted in a CVD diagnostic rate that was two- to threefold higher than in the control patients managed with usual care, Dr. Kober noted.

The Reviving the Early Diagnosis of CVD (RED-CVD) trial randomized 14 primary care practices in the Netherlands to apply a structured screening protocol to adults with type 2 diabetes or COPD, and another 11 practices that served as controls and provided their patients with usual care.

The study included 624 people in the screening arm and 592 in the usual-care arm. Their average age was about 68 years. In the screening arm, 87% had type 2 diabetes and 20% had COPD, including 6.3% with both. In the usual-care arm, 86% had type 2 diabetes, 21% had COPD, with 7.4% having both.

About a quarter of the study cohort had a history of a CVD diagnosis, but they were included for their potential for developing another form of CVD. The study considered three types of CVD: coronary artery disease, heart failure, and atrial fibrillation.

The CVD screening protocol began with an 11-question survey, completed by patients, that asked about their symptoms. The survey was devised by a research team at the University Medical Center Groningen, the Netherlands, who collaborated on the study.

The second phase for people who had suggestive symptoms was a physical examination, measurement of serum N-terminal pro-brain natriuretic peptide (elevated levels signal incident heart failure), and an ECG. People who continued to show findings consistent with CVD in this phase were then referred on a discretionary basis by the attending physician to a specialist.
 

More than doubling the CVD diagnosis rate

The screening program produced a total of 50 new CVD diagnoses in the screening cohort (8%) and 18 in the control, usual-care arm (3%), for the study’s primary endpoint. The greatest number of events involved heart failure, followed by coronary disease.

The screening questionnaire identified 70% of the people who completed it with suggestive symptoms, such as shortness of breath, claudication, or palpitations. The follow-up assessments of phase two narrowed the group with possible new CVD down to 44% of the people in this arm, and the participating physicians referred 39% to a specialist.

An analysis that adjusted for several demographic and clinical variables and excluded nonobstructive coronary disease as a new CVD diagnosis showed that the systematic screening approach resulted in 2.4-fold more new diagnoses than usual care, reported Dr. Groenewegen, an epidemiologist at University Medical Center Utrecht, the Netherlands.

RED-CVD received no commercial funding. Dr. Groenewegen disclosed no relevant financial relationships. Dr. Kober has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk.

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

AMSTERDAM – Systematic screening by primary care physicians for cardiovascular disease (CVD) in high-risk adults – those with type 2 diabetes, chronic obstructive pulmonary disease (COPD), or both – more than doubled the rate of incident CVD diagnosed, compared with usual care, in a Dutch study involving more than 1,200 people and 25 primary care practices.

Scaling up this program to larger populations could potentially uncover huge numbers of currently unrecognized people with CVD given the large number of adults with type 2 diabetes plus those with COPD, Amy Groenewegen, MD, said at the annual congress of the European Society of Cardiology.

“I think this screening is ready for routine use, but it could be followed by prospective studies that investigate whether it produces more benefits in patient-centered outcomes,” Dr. Groenewegen said in a press briefing. She stressed that it has not yet been clearly proven that patients with these chronic diseases are better off long term when their CVD is detected sooner using the tested approach.

“We need simple ways to identify relevant patients for additional screening and potential treatment” of CVD, commented Lars Kober, MD, designated discussant at the Congress and a cardiologist and professor at Rigshospitalet, Copenhagen University Hospital.
 

A ‘very simple’ symptom questionnaire

The study is important because it tested a “very simple” symptom questionnaire as the initial screening phase, yet resulted in a CVD diagnostic rate that was two- to threefold higher than in the control patients managed with usual care, Dr. Kober noted.

The Reviving the Early Diagnosis of CVD (RED-CVD) trial randomized 14 primary care practices in the Netherlands to apply a structured screening protocol to adults with type 2 diabetes or COPD, and another 11 practices that served as controls and provided their patients with usual care.

The study included 624 people in the screening arm and 592 in the usual-care arm. Their average age was about 68 years. In the screening arm, 87% had type 2 diabetes and 20% had COPD, including 6.3% with both. In the usual-care arm, 86% had type 2 diabetes, 21% had COPD, with 7.4% having both.

About a quarter of the study cohort had a history of a CVD diagnosis, but they were included for their potential for developing another form of CVD. The study considered three types of CVD: coronary artery disease, heart failure, and atrial fibrillation.

The CVD screening protocol began with an 11-question survey, completed by patients, that asked about their symptoms. The survey was devised by a research team at the University Medical Center Groningen, the Netherlands, who collaborated on the study.

The second phase for people who had suggestive symptoms was a physical examination, measurement of serum N-terminal pro-brain natriuretic peptide (elevated levels signal incident heart failure), and an ECG. People who continued to show findings consistent with CVD in this phase were then referred on a discretionary basis by the attending physician to a specialist.
 

More than doubling the CVD diagnosis rate

The screening program produced a total of 50 new CVD diagnoses in the screening cohort (8%) and 18 in the control, usual-care arm (3%), for the study’s primary endpoint. The greatest number of events involved heart failure, followed by coronary disease.

The screening questionnaire identified 70% of the people who completed it with suggestive symptoms, such as shortness of breath, claudication, or palpitations. The follow-up assessments of phase two narrowed the group with possible new CVD down to 44% of the people in this arm, and the participating physicians referred 39% to a specialist.

An analysis that adjusted for several demographic and clinical variables and excluded nonobstructive coronary disease as a new CVD diagnosis showed that the systematic screening approach resulted in 2.4-fold more new diagnoses than usual care, reported Dr. Groenewegen, an epidemiologist at University Medical Center Utrecht, the Netherlands.

RED-CVD received no commercial funding. Dr. Groenewegen disclosed no relevant financial relationships. Dr. Kober has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, and Novo Nordisk.

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