TBD Meeting (3134-22)

BARCELONA – Increased frailty of patients with heart failure with preserved ejection fraction (HFpEF) should have no bearing on whether those patients receive sacubitril/valsartan (Entresto), according to results of a post hoc analysis of data from a pivotal trial.

Plus, a recently reported prespecified analysis of data from a different pivotal trial shows that the same rule applies to patients with HFpEF who receive treatment with dapagliflozin (Farxiga). A pair of earlier reports showed similar findings for dapagliflozin and sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF).

“There appears to be a greater reduction in the primary outcome and in hospitalizations for heart failure with sacubitril/valsartan compared with valsartan with increasing frailty, and sacubitril/valsartan was safe and well tolerated regardless of frailty status” in post hoc analysis of data from the PARAGON-HF trial, Jawad H. Butt, MD, reported at the annual congress of the European Society of Cardiology.

Analysis of the treatment effect by sacubitril/valsartan compared with valsartan in patients with HFpEF in PARAGON-HF showed that sacubitril/valsartan actually benefited patients more as their frailty increased when researchers applied frailty severity as a continuous variable. When they analyzed frailty’s effect by dividing the study cohort into three subgroups based on frailty severity – not frail, more frail, and most frail – the statistical analysis showed no significant heterogeneity of effect, although the point estimates for each subgroup showed by far the biggest benefit among the most frail patients. A safety analysis showed consistent safety of sacubitril/valsartan compared with valsartan across all three frailty subgroups, Dr. Butt reported.

Simultaneously with his report at the congress the results appeared online in the Journal of the American College of Cardiology.
 

Don’t withhold sacubitril/valsartan because of frailty

“We should not withhold [sacubitril/valsartan] treatment in patients perceived to be frail,” Dr. Butt declared in an interview. “There are no safety concerns, and no efficacy concerns,” although he cautioned that sacubitril/valsartan is not indicated for all patients with HFpEF. “If you believe that sacubitril/valsartan is indicated for a patient with HFpEF, do not withhold it just because of frailty,” said Dr. Butt, a cardiologist at Copenhagen University Hospital.

Dr. Butt went a step further and stressed, “I don’t think we should measure frailty” when considering patients with heart failure for treatment with sacubitril/valsartan, or with dapagliflozin, which had shown safety and maintained efficacy in a prespecified analysis he recently reported for patients with HFpEF, and in a separate recent report on a post hoc analysis of dapagliflozin use in patients with HFrEF in the DAPA-HF trial.

A published report also showed no evidence for an interaction between frailty and efficacy for sacubitril/valsartan compared with valsartan in the PARADIGM-HF pivotal trial, which enrolled people with HFrEF.

The issue of treatment safety and efficacy for patients considered frail is especially notable because “clinicians may be more reluctant to initiate new therapies due to doubt about the benefit of treatments in frail patients and apprehensions about predisposing them to potential new adverse effects,” said Dr. Butt.

“We should not defer these treatments on account of patient frailty,” said Maja Cikes, MD, a cardiologist at the University Hospital Center Zagreb, Croatia. The report by Dr. Butt “shows the safety” of using sacubitril/valsartan in most patients with HFpEF regardless of their frailty status, Dr. Cikes added in an interview.

Mitchel L. Zoler/MDedge News

‘Benefits without increasing the risk of frailty’

The data reported by Dr. Butt “suggest that although frail older persons with HFpEF are at greater risk for adverse outcomes overall, the prescription of sacubitril/valsartan seems to confer benefits without increasing the risk of frailty-related adverse events,” George A. Heckman, MD, a geriatrician at the University of Waterloo (Canada), and Kenneth Rockwood, MD, professor of geriatric medicine at Dalhousie University in Halifax, N.S., wrote in an editorial that accompanied the published version of Dr. Butt’s report.

The PARADIGM-HF trial enrolled 4,822 patients with heart failure and a left ventricular ejection fraction of at least 45% at 848 centers in 43 countries during 2014-2016, and followed them for a median of 35 months, with a primary endpoint of the combined rate of hospitalization for heart failure or cardiovascular death. Treatment with sacubitril/valsartan reduced the incidence of the primary endpoint by 13% compared with the control patients who received valsartan, a difference that missed narrowly missed significance (P = .06).

Despite this statistically neutral result, the Food and Drug Administration subsequently, based on these results, modified the indication for using sacubitril/valsartan from exclusively patients with HFrEF to patients with higher left ventricular ejection fractions, including at least some patients diagnosed with HFpEF.

To run the frailty analysis, Dr. Butt and his associates devised a 41-item frailty index, which identified 45% of the study cohort as not frail, 44% as more frail, and 11% as most frail. Their analyses also showed that frailty severity had no significant relationship to the effect of treatment with sacubitril valsartan on improving quality of life, or on improving functional status. Frailty also played no apparent role in the impact of sacubitril/valsartan compared with valsartan on treatment discontinuations or adverse effects.

PARAGON-HF and PARADIGM-HF were sponsored by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. Butt has been an adviser to Bayer. Dr. Cikes has received travel support or honoraria from Novartis as well as from Amicus, AstraZeneca, Bayer, Boehringer Ingelheim, GE Healthcare, Krka, LivaNova, Pfizer, Sanofi, and Teva, and research support or contracts from Novartis as well as from Abbott, Corvia, and Pfizer. Dr. Heckman had no disclosures. Dr. Rockwood is a cofounder of Ardea Outcomes, an adviser to Nutricia, and he holds a copyright through Dalhousie University on the Clinical Frailty Scale (which allows free use for educational, research, and not-for-profit health care purposes).

BARCELONA – Increased frailty of patients with heart failure with preserved ejection fraction (HFpEF) should have no bearing on whether those patients receive sacubitril/valsartan (Entresto), according to results of a post hoc analysis of data from a pivotal trial.

Plus, a recently reported prespecified analysis of data from a different pivotal trial shows that the same rule applies to patients with HFpEF who receive treatment with dapagliflozin (Farxiga). A pair of earlier reports showed similar findings for dapagliflozin and sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF).

“There appears to be a greater reduction in the primary outcome and in hospitalizations for heart failure with sacubitril/valsartan compared with valsartan with increasing frailty, and sacubitril/valsartan was safe and well tolerated regardless of frailty status” in post hoc analysis of data from the PARAGON-HF trial, Jawad H. Butt, MD, reported at the annual congress of the European Society of Cardiology.

Analysis of the treatment effect by sacubitril/valsartan compared with valsartan in patients with HFpEF in PARAGON-HF showed that sacubitril/valsartan actually benefited patients more as their frailty increased when researchers applied frailty severity as a continuous variable. When they analyzed frailty’s effect by dividing the study cohort into three subgroups based on frailty severity – not frail, more frail, and most frail – the statistical analysis showed no significant heterogeneity of effect, although the point estimates for each subgroup showed by far the biggest benefit among the most frail patients. A safety analysis showed consistent safety of sacubitril/valsartan compared with valsartan across all three frailty subgroups, Dr. Butt reported.

Simultaneously with his report at the congress the results appeared online in the Journal of the American College of Cardiology.
 

Don’t withhold sacubitril/valsartan because of frailty

“We should not withhold [sacubitril/valsartan] treatment in patients perceived to be frail,” Dr. Butt declared in an interview. “There are no safety concerns, and no efficacy concerns,” although he cautioned that sacubitril/valsartan is not indicated for all patients with HFpEF. “If you believe that sacubitril/valsartan is indicated for a patient with HFpEF, do not withhold it just because of frailty,” said Dr. Butt, a cardiologist at Copenhagen University Hospital.

Dr. Butt went a step further and stressed, “I don’t think we should measure frailty” when considering patients with heart failure for treatment with sacubitril/valsartan, or with dapagliflozin, which had shown safety and maintained efficacy in a prespecified analysis he recently reported for patients with HFpEF, and in a separate recent report on a post hoc analysis of dapagliflozin use in patients with HFrEF in the DAPA-HF trial.

A published report also showed no evidence for an interaction between frailty and efficacy for sacubitril/valsartan compared with valsartan in the PARADIGM-HF pivotal trial, which enrolled people with HFrEF.

The issue of treatment safety and efficacy for patients considered frail is especially notable because “clinicians may be more reluctant to initiate new therapies due to doubt about the benefit of treatments in frail patients and apprehensions about predisposing them to potential new adverse effects,” said Dr. Butt.

“We should not defer these treatments on account of patient frailty,” said Maja Cikes, MD, a cardiologist at the University Hospital Center Zagreb, Croatia. The report by Dr. Butt “shows the safety” of using sacubitril/valsartan in most patients with HFpEF regardless of their frailty status, Dr. Cikes added in an interview.

Mitchel L. Zoler/MDedge News

‘Benefits without increasing the risk of frailty’

The data reported by Dr. Butt “suggest that although frail older persons with HFpEF are at greater risk for adverse outcomes overall, the prescription of sacubitril/valsartan seems to confer benefits without increasing the risk of frailty-related adverse events,” George A. Heckman, MD, a geriatrician at the University of Waterloo (Canada), and Kenneth Rockwood, MD, professor of geriatric medicine at Dalhousie University in Halifax, N.S., wrote in an editorial that accompanied the published version of Dr. Butt’s report.

The PARADIGM-HF trial enrolled 4,822 patients with heart failure and a left ventricular ejection fraction of at least 45% at 848 centers in 43 countries during 2014-2016, and followed them for a median of 35 months, with a primary endpoint of the combined rate of hospitalization for heart failure or cardiovascular death. Treatment with sacubitril/valsartan reduced the incidence of the primary endpoint by 13% compared with the control patients who received valsartan, a difference that missed narrowly missed significance (P = .06).

Despite this statistically neutral result, the Food and Drug Administration subsequently, based on these results, modified the indication for using sacubitril/valsartan from exclusively patients with HFrEF to patients with higher left ventricular ejection fractions, including at least some patients diagnosed with HFpEF.

To run the frailty analysis, Dr. Butt and his associates devised a 41-item frailty index, which identified 45% of the study cohort as not frail, 44% as more frail, and 11% as most frail. Their analyses also showed that frailty severity had no significant relationship to the effect of treatment with sacubitril valsartan on improving quality of life, or on improving functional status. Frailty also played no apparent role in the impact of sacubitril/valsartan compared with valsartan on treatment discontinuations or adverse effects.

PARAGON-HF and PARADIGM-HF were sponsored by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. Butt has been an adviser to Bayer. Dr. Cikes has received travel support or honoraria from Novartis as well as from Amicus, AstraZeneca, Bayer, Boehringer Ingelheim, GE Healthcare, Krka, LivaNova, Pfizer, Sanofi, and Teva, and research support or contracts from Novartis as well as from Abbott, Corvia, and Pfizer. Dr. Heckman had no disclosures. Dr. Rockwood is a cofounder of Ardea Outcomes, an adviser to Nutricia, and he holds a copyright through Dalhousie University on the Clinical Frailty Scale (which allows free use for educational, research, and not-for-profit health care purposes).

BARCELONA – Increased frailty of patients with heart failure with preserved ejection fraction (HFpEF) should have no bearing on whether those patients receive sacubitril/valsartan (Entresto), according to results of a post hoc analysis of data from a pivotal trial.

Plus, a recently reported prespecified analysis of data from a different pivotal trial shows that the same rule applies to patients with HFpEF who receive treatment with dapagliflozin (Farxiga). A pair of earlier reports showed similar findings for dapagliflozin and sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF).

“There appears to be a greater reduction in the primary outcome and in hospitalizations for heart failure with sacubitril/valsartan compared with valsartan with increasing frailty, and sacubitril/valsartan was safe and well tolerated regardless of frailty status” in post hoc analysis of data from the PARAGON-HF trial, Jawad H. Butt, MD, reported at the annual congress of the European Society of Cardiology.

Analysis of the treatment effect by sacubitril/valsartan compared with valsartan in patients with HFpEF in PARAGON-HF showed that sacubitril/valsartan actually benefited patients more as their frailty increased when researchers applied frailty severity as a continuous variable. When they analyzed frailty’s effect by dividing the study cohort into three subgroups based on frailty severity – not frail, more frail, and most frail – the statistical analysis showed no significant heterogeneity of effect, although the point estimates for each subgroup showed by far the biggest benefit among the most frail patients. A safety analysis showed consistent safety of sacubitril/valsartan compared with valsartan across all three frailty subgroups, Dr. Butt reported.

Simultaneously with his report at the congress the results appeared online in the Journal of the American College of Cardiology.
 

Don’t withhold sacubitril/valsartan because of frailty

“We should not withhold [sacubitril/valsartan] treatment in patients perceived to be frail,” Dr. Butt declared in an interview. “There are no safety concerns, and no efficacy concerns,” although he cautioned that sacubitril/valsartan is not indicated for all patients with HFpEF. “If you believe that sacubitril/valsartan is indicated for a patient with HFpEF, do not withhold it just because of frailty,” said Dr. Butt, a cardiologist at Copenhagen University Hospital.

Dr. Butt went a step further and stressed, “I don’t think we should measure frailty” when considering patients with heart failure for treatment with sacubitril/valsartan, or with dapagliflozin, which had shown safety and maintained efficacy in a prespecified analysis he recently reported for patients with HFpEF, and in a separate recent report on a post hoc analysis of dapagliflozin use in patients with HFrEF in the DAPA-HF trial.

A published report also showed no evidence for an interaction between frailty and efficacy for sacubitril/valsartan compared with valsartan in the PARADIGM-HF pivotal trial, which enrolled people with HFrEF.

The issue of treatment safety and efficacy for patients considered frail is especially notable because “clinicians may be more reluctant to initiate new therapies due to doubt about the benefit of treatments in frail patients and apprehensions about predisposing them to potential new adverse effects,” said Dr. Butt.

“We should not defer these treatments on account of patient frailty,” said Maja Cikes, MD, a cardiologist at the University Hospital Center Zagreb, Croatia. The report by Dr. Butt “shows the safety” of using sacubitril/valsartan in most patients with HFpEF regardless of their frailty status, Dr. Cikes added in an interview.

Mitchel L. Zoler/MDedge News

‘Benefits without increasing the risk of frailty’

The data reported by Dr. Butt “suggest that although frail older persons with HFpEF are at greater risk for adverse outcomes overall, the prescription of sacubitril/valsartan seems to confer benefits without increasing the risk of frailty-related adverse events,” George A. Heckman, MD, a geriatrician at the University of Waterloo (Canada), and Kenneth Rockwood, MD, professor of geriatric medicine at Dalhousie University in Halifax, N.S., wrote in an editorial that accompanied the published version of Dr. Butt’s report.

The PARADIGM-HF trial enrolled 4,822 patients with heart failure and a left ventricular ejection fraction of at least 45% at 848 centers in 43 countries during 2014-2016, and followed them for a median of 35 months, with a primary endpoint of the combined rate of hospitalization for heart failure or cardiovascular death. Treatment with sacubitril/valsartan reduced the incidence of the primary endpoint by 13% compared with the control patients who received valsartan, a difference that missed narrowly missed significance (P = .06).

Despite this statistically neutral result, the Food and Drug Administration subsequently, based on these results, modified the indication for using sacubitril/valsartan from exclusively patients with HFrEF to patients with higher left ventricular ejection fractions, including at least some patients diagnosed with HFpEF.

To run the frailty analysis, Dr. Butt and his associates devised a 41-item frailty index, which identified 45% of the study cohort as not frail, 44% as more frail, and 11% as most frail. Their analyses also showed that frailty severity had no significant relationship to the effect of treatment with sacubitril valsartan on improving quality of life, or on improving functional status. Frailty also played no apparent role in the impact of sacubitril/valsartan compared with valsartan on treatment discontinuations or adverse effects.

PARAGON-HF and PARADIGM-HF were sponsored by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. Butt has been an adviser to Bayer. Dr. Cikes has received travel support or honoraria from Novartis as well as from Amicus, AstraZeneca, Bayer, Boehringer Ingelheim, GE Healthcare, Krka, LivaNova, Pfizer, Sanofi, and Teva, and research support or contracts from Novartis as well as from Abbott, Corvia, and Pfizer. Dr. Heckman had no disclosures. Dr. Rockwood is a cofounder of Ardea Outcomes, an adviser to Nutricia, and he holds a copyright through Dalhousie University on the Clinical Frailty Scale (which allows free use for educational, research, and not-for-profit health care purposes).

The European Society of Cardiology guidelines on cardiovascular assessment and management of patients undergoing noncardiac surgery have seen extensive revision since the 2014 version.

They still have the same aim – to prevent surgery-related bleeding complications, perioperative myocardial infarction/injury (PMI), stent thrombosis, acute heart failure, arrhythmias, pulmonary embolism, ischemic stroke, and cardiovascular (CV) death.

lyosha_nazarenko/Thinkstock

Cochairpersons Sigrun Halvorsen, MD, PhD, and Julinda Mehilli, MD, presented highlights from the guidelines at the annual congress of the European Society of Cardiology and the document was simultaneously published online in the European Heart Journal.

The document classifies noncardiac surgery into three levels of 30-day risk of CV death, MI, or stroke. Low (< 1%) risk includes eye or thyroid surgery; intermediate (1%-5%) risk includes knee or hip replacement or renal transplant; and high (> 5%) risk includes aortic aneurysm, lung transplant, or pancreatic or bladder cancer surgery (see more examples below).

It classifies patients as low risk if they are younger than 65 without CV disease or CV risk factors (smoking, hypertension, diabetes, dyslipidemia, family history); intermediate risk if they are 65 or older or have CV risk factors; and high risk if they have CVD.  

In an interview, Dr. Halvorsen, professor in cardiology, University of Oslo, zeroed in on three important revisions:

First, recommendations for preoperative ECG and biomarkers are more specific, he noted.

The guidelines advise that before intermediate- or high-risk noncardiac surgery, in patients who have known CVD, CV risk factors (including age 65 or older), or symptoms suggestive of CVD:

• It is recommended to obtain a preoperative 12-lead ECG (class I).
• It is recommended to measure high-sensitivity cardiac troponin T (hs-cTn T) or high-sensitivity cardiac troponin I (hs-cTn I). It is also recommended to measure these biomarkers at 24 hours and 48 hours post surgery (class I).
• It should be considered to measure B-type natriuretic peptide or N-terminal of the prohormone BNP (NT-proBNP).

However, for low-risk patients undergoing low- and intermediate-risk noncardiac surgery, it is not recommended to routinely obtain preoperative ECG, hs-cTn T/I, or BNP/NT-proBNP concentrations (class III).

Troponins have a stronger class I recommendation, compared with the IIA recommendation for BNP, because they are useful for preoperative risk stratification and for diagnosis of PMI, Dr. Halvorsen explained. “Patients receive painkillers after surgery and may have no pain,” she noted, but they may have PMI, which has a bad prognosis.

Second, the guidelines recommend that “all patients should stop smoking 4 weeks before noncardiac surgery [class I],” she noted. Clinicians should also “measure hemoglobin, and if the patient is anemic, treat the anemia.”

Third, the sections on antithrombotic treatment have been significantly revised. “Bridging – stopping an oral antithrombotic drug and switching to a subcutaneous or IV drug – has been common,” Dr. Halvorsen said, “but recently we have new evidence that in most cases that increases the risk of bleeding.”

“We are [now] much more restrictive with respect to bridging” with unfractionated heparin or low-molecular-weight heparin, she said. “We recommend against bridging in patients with low to moderate thrombotic risk,” and bridging should only be considered in patients with mechanical prosthetic heart valves or with very high thrombotic risk.
 

More preoperative recommendations

In the guideline overview session at the congress, Dr. Halverson highlighted some of the new recommendations for preoperative risk assessment.  

If time allows, it is recommended to optimize guideline-recommended treatment of CVD and control of CV risk factors including blood pressure, dyslipidemia, and diabetes, before noncardiac surgery (class I).

Patients commonly have “murmurs, chest pain, dyspnea, and edema that may suggest severe CVD, but may also be caused by noncardiac disease,” she noted. The guidelines state that “for patients with a newly detected murmur and symptoms or signs of CVD, transthoracic echocardiography is recommended before noncardiac surgery (class I).

“Many studies have been performed to try to find out if initiation of specific drugs before surgery could reduce the risk of complications,” Dr. Halvorsen noted. However, few have shown any benefit and “the question of presurgery initiation of beta-blockers has been greatly debated,” she said. “We have again reviewed the literature and concluded ‘Routine initiation of beta-blockers perioperatively is not recommended (class IIIA).’ “

“We adhere to the guidelines on acute and chronic coronary syndrome recommending 6-12 months of dual antiplatelet treatment as a standard before elective surgery,” she said. “However, in case of time-sensitive surgery, the duration of that treatment can be shortened down to a minimum of 1 month after elective PCI and a minimum of 3 months after PCI and ACS.”
 

Patients with specific types of CVD

Dr. Mehilli, a professor at Landshut-Achdorf (Germany) Hospital, highlighted some new guideline recommendations for patients who have specific types of cardiovascular disease.

Coronary artery disease (CAD). “For chronic coronary syndrome, a cardiac workup is recommended only for patients undergoing intermediate risk or high-risk noncardiac surgery.”

“Stress imaging should be considered before any high risk, noncardiac surgery in asymptomatic patients with poor functional capacity and prior PCI or coronary artery bypass graft (new recommendation, class IIa).”

Mitral valve regurgitation. For patients undergoing scheduled noncardiac surgery, who remain symptomatic despite guideline-directed medical treatment for mitral valve regurgitation (including resynchronization and myocardial revascularization), consider a valve intervention – either transcatheter or surgical – before noncardiac surgery in eligible patients with acceptable procedural risk (new recommendation).

Cardiac implantable electronic devices (CIED). For high-risk patients with CIEDs undergoing noncardiac surgery with high probability of electromagnetic interference, a CIED checkup and necessary reprogramming immediately before the procedure should be considered (new recommendation).

Arrhythmias. “I want only to stress,” Dr. Mehilli said, “in patients with atrial fibrillation with acute or worsening hemodynamic instability undergoing noncardiac surgery, an emergency electrical cardioversion is recommended (class I).”

Peripheral artery disease (PAD) and abdominal aortic aneurysm. For these patients “we do not recommend a routine referral for a cardiac workup. But we recommend it for patients with poor functional capacity or with significant risk factors or symptoms (new recommendations).”

Chronic arterial hypertension. “We have modified the recommendation, recommending avoidance of large perioperative fluctuations in blood pressure, and we do not recommend deferring noncardiac surgery in patients with stage 1 or 2 hypertension,” she said.
 

Postoperative cardiovascular complications

The most frequent postoperative cardiovascular complication is PMI, Dr. Mehilli noted.

“In the BASEL-PMI registry, the incidence of this complication around intermediate or high-risk noncardiac surgery was up to 15% among patients older than 65 years or with a history of CAD or PAD, which makes this kind of complication really important to prevent, to assess, and to know how to treat.”

“It is recommended to have a high awareness for perioperative cardiovascular complications, combined with surveillance for PMI in patients undergoing intermediate- or high-risk noncardiac surgery” based on serial measurements of high-sensitivity cardiac troponin.

The guidelines define PMI as “an increase in the delta of high-sensitivity troponin more than the upper level of normal,” Dr. Mehilli said. “It’s different from the one used in a rule-in algorithm for non-STEMI acute coronary syndrome.”

Postoperative atrial fibrillation (AFib) is observed in 2%-30% of noncardiac surgery patients in different registries, particularly in patients undergoing intermediate or high-risk noncardiac surgery, she noted.

“We propose an algorithm on how to prevent and treat this complication. I want to highlight that in patients with hemodynamic unstable postoperative AF[ib], an emergency cardioversion is indicated. For the others, a rate control with the target heart rate of less than 110 beats per minute is indicated.”

In patients with postoperative AFib, long-term oral anticoagulation therapy should be considered in all patients at risk for stroke, considering the anticipated net clinical benefit of oral anticoagulation therapy as well as informed patient preference (new recommendations).

Routine use of beta-blockers to prevent postoperative AFib in patients undergoing noncardiac surgery is not recommended.

The document also covers the management of patients with kidney disease, diabetes, cancer, obesity, and COVID-19. In general, elective noncardiac surgery should be postponed after a patient has COVID-19, until he or she recovers completely, and coexisting conditions are optimized.

The guidelines are available from the ESC website in several formats: pocket guidelines, pocket guidelines smartphone app, guidelines slide set, essential messages, and the European Heart Journal article.
 

Noncardiac surgery risk categories

The guideline includes a table that classifies noncardiac surgeries into three groups, based on the associated 30-day risk of death, MI, or stroke:

• Low (< 1%): breast, dental, eye, thyroid, and minor gynecologic, orthopedic, and urologic surgery.
• Intermediate (1%-5%): carotid surgery, endovascular aortic aneurysm repair, gallbladder surgery, head or neck surgery, hernia repair, peripheral arterial angioplasty, renal transplant, major gynecologic, orthopedic, or neurologic (hip or spine) surgery, or urologic surgery
• High (> 5%): aortic and major vascular surgery (including aortic aneurysm), bladder removal (usually as a result of cancer), limb amputation, lung or liver transplant, pancreatic surgery, or perforated bowel repair.

The guidelines were endorsed by the European Society of Anaesthesiology and Intensive Care. The guideline authors reported numerous disclosures.

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

The European Society of Cardiology guidelines on cardiovascular assessment and management of patients undergoing noncardiac surgery have seen extensive revision since the 2014 version.

They still have the same aim – to prevent surgery-related bleeding complications, perioperative myocardial infarction/injury (PMI), stent thrombosis, acute heart failure, arrhythmias, pulmonary embolism, ischemic stroke, and cardiovascular (CV) death.

lyosha_nazarenko/Thinkstock

Cochairpersons Sigrun Halvorsen, MD, PhD, and Julinda Mehilli, MD, presented highlights from the guidelines at the annual congress of the European Society of Cardiology and the document was simultaneously published online in the European Heart Journal.

The document classifies noncardiac surgery into three levels of 30-day risk of CV death, MI, or stroke. Low (< 1%) risk includes eye or thyroid surgery; intermediate (1%-5%) risk includes knee or hip replacement or renal transplant; and high (> 5%) risk includes aortic aneurysm, lung transplant, or pancreatic or bladder cancer surgery (see more examples below).

It classifies patients as low risk if they are younger than 65 without CV disease or CV risk factors (smoking, hypertension, diabetes, dyslipidemia, family history); intermediate risk if they are 65 or older or have CV risk factors; and high risk if they have CVD.  

In an interview, Dr. Halvorsen, professor in cardiology, University of Oslo, zeroed in on three important revisions:

First, recommendations for preoperative ECG and biomarkers are more specific, he noted.

The guidelines advise that before intermediate- or high-risk noncardiac surgery, in patients who have known CVD, CV risk factors (including age 65 or older), or symptoms suggestive of CVD:

• It is recommended to obtain a preoperative 12-lead ECG (class I).
• It is recommended to measure high-sensitivity cardiac troponin T (hs-cTn T) or high-sensitivity cardiac troponin I (hs-cTn I). It is also recommended to measure these biomarkers at 24 hours and 48 hours post surgery (class I).
• It should be considered to measure B-type natriuretic peptide or N-terminal of the prohormone BNP (NT-proBNP).

However, for low-risk patients undergoing low- and intermediate-risk noncardiac surgery, it is not recommended to routinely obtain preoperative ECG, hs-cTn T/I, or BNP/NT-proBNP concentrations (class III).

Troponins have a stronger class I recommendation, compared with the IIA recommendation for BNP, because they are useful for preoperative risk stratification and for diagnosis of PMI, Dr. Halvorsen explained. “Patients receive painkillers after surgery and may have no pain,” she noted, but they may have PMI, which has a bad prognosis.

Second, the guidelines recommend that “all patients should stop smoking 4 weeks before noncardiac surgery [class I],” she noted. Clinicians should also “measure hemoglobin, and if the patient is anemic, treat the anemia.”

Third, the sections on antithrombotic treatment have been significantly revised. “Bridging – stopping an oral antithrombotic drug and switching to a subcutaneous or IV drug – has been common,” Dr. Halvorsen said, “but recently we have new evidence that in most cases that increases the risk of bleeding.”

“We are [now] much more restrictive with respect to bridging” with unfractionated heparin or low-molecular-weight heparin, she said. “We recommend against bridging in patients with low to moderate thrombotic risk,” and bridging should only be considered in patients with mechanical prosthetic heart valves or with very high thrombotic risk.
 

More preoperative recommendations

In the guideline overview session at the congress, Dr. Halverson highlighted some of the new recommendations for preoperative risk assessment.  

If time allows, it is recommended to optimize guideline-recommended treatment of CVD and control of CV risk factors including blood pressure, dyslipidemia, and diabetes, before noncardiac surgery (class I).

Patients commonly have “murmurs, chest pain, dyspnea, and edema that may suggest severe CVD, but may also be caused by noncardiac disease,” she noted. The guidelines state that “for patients with a newly detected murmur and symptoms or signs of CVD, transthoracic echocardiography is recommended before noncardiac surgery (class I).

“Many studies have been performed to try to find out if initiation of specific drugs before surgery could reduce the risk of complications,” Dr. Halvorsen noted. However, few have shown any benefit and “the question of presurgery initiation of beta-blockers has been greatly debated,” she said. “We have again reviewed the literature and concluded ‘Routine initiation of beta-blockers perioperatively is not recommended (class IIIA).’ “

“We adhere to the guidelines on acute and chronic coronary syndrome recommending 6-12 months of dual antiplatelet treatment as a standard before elective surgery,” she said. “However, in case of time-sensitive surgery, the duration of that treatment can be shortened down to a minimum of 1 month after elective PCI and a minimum of 3 months after PCI and ACS.”
 

Patients with specific types of CVD

Dr. Mehilli, a professor at Landshut-Achdorf (Germany) Hospital, highlighted some new guideline recommendations for patients who have specific types of cardiovascular disease.

Coronary artery disease (CAD). “For chronic coronary syndrome, a cardiac workup is recommended only for patients undergoing intermediate risk or high-risk noncardiac surgery.”

“Stress imaging should be considered before any high risk, noncardiac surgery in asymptomatic patients with poor functional capacity and prior PCI or coronary artery bypass graft (new recommendation, class IIa).”

Mitral valve regurgitation. For patients undergoing scheduled noncardiac surgery, who remain symptomatic despite guideline-directed medical treatment for mitral valve regurgitation (including resynchronization and myocardial revascularization), consider a valve intervention – either transcatheter or surgical – before noncardiac surgery in eligible patients with acceptable procedural risk (new recommendation).

Cardiac implantable electronic devices (CIED). For high-risk patients with CIEDs undergoing noncardiac surgery with high probability of electromagnetic interference, a CIED checkup and necessary reprogramming immediately before the procedure should be considered (new recommendation).

Arrhythmias. “I want only to stress,” Dr. Mehilli said, “in patients with atrial fibrillation with acute or worsening hemodynamic instability undergoing noncardiac surgery, an emergency electrical cardioversion is recommended (class I).”

Peripheral artery disease (PAD) and abdominal aortic aneurysm. For these patients “we do not recommend a routine referral for a cardiac workup. But we recommend it for patients with poor functional capacity or with significant risk factors or symptoms (new recommendations).”

Chronic arterial hypertension. “We have modified the recommendation, recommending avoidance of large perioperative fluctuations in blood pressure, and we do not recommend deferring noncardiac surgery in patients with stage 1 or 2 hypertension,” she said.
 

Postoperative cardiovascular complications

The most frequent postoperative cardiovascular complication is PMI, Dr. Mehilli noted.

“In the BASEL-PMI registry, the incidence of this complication around intermediate or high-risk noncardiac surgery was up to 15% among patients older than 65 years or with a history of CAD or PAD, which makes this kind of complication really important to prevent, to assess, and to know how to treat.”

“It is recommended to have a high awareness for perioperative cardiovascular complications, combined with surveillance for PMI in patients undergoing intermediate- or high-risk noncardiac surgery” based on serial measurements of high-sensitivity cardiac troponin.

The guidelines define PMI as “an increase in the delta of high-sensitivity troponin more than the upper level of normal,” Dr. Mehilli said. “It’s different from the one used in a rule-in algorithm for non-STEMI acute coronary syndrome.”

Postoperative atrial fibrillation (AFib) is observed in 2%-30% of noncardiac surgery patients in different registries, particularly in patients undergoing intermediate or high-risk noncardiac surgery, she noted.

“We propose an algorithm on how to prevent and treat this complication. I want to highlight that in patients with hemodynamic unstable postoperative AF[ib], an emergency cardioversion is indicated. For the others, a rate control with the target heart rate of less than 110 beats per minute is indicated.”

In patients with postoperative AFib, long-term oral anticoagulation therapy should be considered in all patients at risk for stroke, considering the anticipated net clinical benefit of oral anticoagulation therapy as well as informed patient preference (new recommendations).

Routine use of beta-blockers to prevent postoperative AFib in patients undergoing noncardiac surgery is not recommended.

The document also covers the management of patients with kidney disease, diabetes, cancer, obesity, and COVID-19. In general, elective noncardiac surgery should be postponed after a patient has COVID-19, until he or she recovers completely, and coexisting conditions are optimized.

The guidelines are available from the ESC website in several formats: pocket guidelines, pocket guidelines smartphone app, guidelines slide set, essential messages, and the European Heart Journal article.
 

Noncardiac surgery risk categories

The guideline includes a table that classifies noncardiac surgeries into three groups, based on the associated 30-day risk of death, MI, or stroke:

• Low (< 1%): breast, dental, eye, thyroid, and minor gynecologic, orthopedic, and urologic surgery.
• Intermediate (1%-5%): carotid surgery, endovascular aortic aneurysm repair, gallbladder surgery, head or neck surgery, hernia repair, peripheral arterial angioplasty, renal transplant, major gynecologic, orthopedic, or neurologic (hip or spine) surgery, or urologic surgery
• High (> 5%): aortic and major vascular surgery (including aortic aneurysm), bladder removal (usually as a result of cancer), limb amputation, lung or liver transplant, pancreatic surgery, or perforated bowel repair.

The guidelines were endorsed by the European Society of Anaesthesiology and Intensive Care. The guideline authors reported numerous disclosures.

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

The European Society of Cardiology guidelines on cardiovascular assessment and management of patients undergoing noncardiac surgery have seen extensive revision since the 2014 version.

They still have the same aim – to prevent surgery-related bleeding complications, perioperative myocardial infarction/injury (PMI), stent thrombosis, acute heart failure, arrhythmias, pulmonary embolism, ischemic stroke, and cardiovascular (CV) death.

lyosha_nazarenko/Thinkstock

Cochairpersons Sigrun Halvorsen, MD, PhD, and Julinda Mehilli, MD, presented highlights from the guidelines at the annual congress of the European Society of Cardiology and the document was simultaneously published online in the European Heart Journal.

The document classifies noncardiac surgery into three levels of 30-day risk of CV death, MI, or stroke. Low (< 1%) risk includes eye or thyroid surgery; intermediate (1%-5%) risk includes knee or hip replacement or renal transplant; and high (> 5%) risk includes aortic aneurysm, lung transplant, or pancreatic or bladder cancer surgery (see more examples below).

It classifies patients as low risk if they are younger than 65 without CV disease or CV risk factors (smoking, hypertension, diabetes, dyslipidemia, family history); intermediate risk if they are 65 or older or have CV risk factors; and high risk if they have CVD.  

In an interview, Dr. Halvorsen, professor in cardiology, University of Oslo, zeroed in on three important revisions:

First, recommendations for preoperative ECG and biomarkers are more specific, he noted.

The guidelines advise that before intermediate- or high-risk noncardiac surgery, in patients who have known CVD, CV risk factors (including age 65 or older), or symptoms suggestive of CVD:

• It is recommended to obtain a preoperative 12-lead ECG (class I).
• It is recommended to measure high-sensitivity cardiac troponin T (hs-cTn T) or high-sensitivity cardiac troponin I (hs-cTn I). It is also recommended to measure these biomarkers at 24 hours and 48 hours post surgery (class I).
• It should be considered to measure B-type natriuretic peptide or N-terminal of the prohormone BNP (NT-proBNP).

However, for low-risk patients undergoing low- and intermediate-risk noncardiac surgery, it is not recommended to routinely obtain preoperative ECG, hs-cTn T/I, or BNP/NT-proBNP concentrations (class III).

Troponins have a stronger class I recommendation, compared with the IIA recommendation for BNP, because they are useful for preoperative risk stratification and for diagnosis of PMI, Dr. Halvorsen explained. “Patients receive painkillers after surgery and may have no pain,” she noted, but they may have PMI, which has a bad prognosis.

Second, the guidelines recommend that “all patients should stop smoking 4 weeks before noncardiac surgery [class I],” she noted. Clinicians should also “measure hemoglobin, and if the patient is anemic, treat the anemia.”

Third, the sections on antithrombotic treatment have been significantly revised. “Bridging – stopping an oral antithrombotic drug and switching to a subcutaneous or IV drug – has been common,” Dr. Halvorsen said, “but recently we have new evidence that in most cases that increases the risk of bleeding.”

“We are [now] much more restrictive with respect to bridging” with unfractionated heparin or low-molecular-weight heparin, she said. “We recommend against bridging in patients with low to moderate thrombotic risk,” and bridging should only be considered in patients with mechanical prosthetic heart valves or with very high thrombotic risk.
 

More preoperative recommendations

In the guideline overview session at the congress, Dr. Halverson highlighted some of the new recommendations for preoperative risk assessment.  

If time allows, it is recommended to optimize guideline-recommended treatment of CVD and control of CV risk factors including blood pressure, dyslipidemia, and diabetes, before noncardiac surgery (class I).

Patients commonly have “murmurs, chest pain, dyspnea, and edema that may suggest severe CVD, but may also be caused by noncardiac disease,” she noted. The guidelines state that “for patients with a newly detected murmur and symptoms or signs of CVD, transthoracic echocardiography is recommended before noncardiac surgery (class I).

“Many studies have been performed to try to find out if initiation of specific drugs before surgery could reduce the risk of complications,” Dr. Halvorsen noted. However, few have shown any benefit and “the question of presurgery initiation of beta-blockers has been greatly debated,” she said. “We have again reviewed the literature and concluded ‘Routine initiation of beta-blockers perioperatively is not recommended (class IIIA).’ “

“We adhere to the guidelines on acute and chronic coronary syndrome recommending 6-12 months of dual antiplatelet treatment as a standard before elective surgery,” she said. “However, in case of time-sensitive surgery, the duration of that treatment can be shortened down to a minimum of 1 month after elective PCI and a minimum of 3 months after PCI and ACS.”
 

Patients with specific types of CVD

Dr. Mehilli, a professor at Landshut-Achdorf (Germany) Hospital, highlighted some new guideline recommendations for patients who have specific types of cardiovascular disease.

Coronary artery disease (CAD). “For chronic coronary syndrome, a cardiac workup is recommended only for patients undergoing intermediate risk or high-risk noncardiac surgery.”

“Stress imaging should be considered before any high risk, noncardiac surgery in asymptomatic patients with poor functional capacity and prior PCI or coronary artery bypass graft (new recommendation, class IIa).”

Mitral valve regurgitation. For patients undergoing scheduled noncardiac surgery, who remain symptomatic despite guideline-directed medical treatment for mitral valve regurgitation (including resynchronization and myocardial revascularization), consider a valve intervention – either transcatheter or surgical – before noncardiac surgery in eligible patients with acceptable procedural risk (new recommendation).

Cardiac implantable electronic devices (CIED). For high-risk patients with CIEDs undergoing noncardiac surgery with high probability of electromagnetic interference, a CIED checkup and necessary reprogramming immediately before the procedure should be considered (new recommendation).

Arrhythmias. “I want only to stress,” Dr. Mehilli said, “in patients with atrial fibrillation with acute or worsening hemodynamic instability undergoing noncardiac surgery, an emergency electrical cardioversion is recommended (class I).”

Peripheral artery disease (PAD) and abdominal aortic aneurysm. For these patients “we do not recommend a routine referral for a cardiac workup. But we recommend it for patients with poor functional capacity or with significant risk factors or symptoms (new recommendations).”

Chronic arterial hypertension. “We have modified the recommendation, recommending avoidance of large perioperative fluctuations in blood pressure, and we do not recommend deferring noncardiac surgery in patients with stage 1 or 2 hypertension,” she said.
 

Postoperative cardiovascular complications

The most frequent postoperative cardiovascular complication is PMI, Dr. Mehilli noted.

“In the BASEL-PMI registry, the incidence of this complication around intermediate or high-risk noncardiac surgery was up to 15% among patients older than 65 years or with a history of CAD or PAD, which makes this kind of complication really important to prevent, to assess, and to know how to treat.”

“It is recommended to have a high awareness for perioperative cardiovascular complications, combined with surveillance for PMI in patients undergoing intermediate- or high-risk noncardiac surgery” based on serial measurements of high-sensitivity cardiac troponin.

The guidelines define PMI as “an increase in the delta of high-sensitivity troponin more than the upper level of normal,” Dr. Mehilli said. “It’s different from the one used in a rule-in algorithm for non-STEMI acute coronary syndrome.”

Postoperative atrial fibrillation (AFib) is observed in 2%-30% of noncardiac surgery patients in different registries, particularly in patients undergoing intermediate or high-risk noncardiac surgery, she noted.

“We propose an algorithm on how to prevent and treat this complication. I want to highlight that in patients with hemodynamic unstable postoperative AF[ib], an emergency cardioversion is indicated. For the others, a rate control with the target heart rate of less than 110 beats per minute is indicated.”

In patients with postoperative AFib, long-term oral anticoagulation therapy should be considered in all patients at risk for stroke, considering the anticipated net clinical benefit of oral anticoagulation therapy as well as informed patient preference (new recommendations).

Routine use of beta-blockers to prevent postoperative AFib in patients undergoing noncardiac surgery is not recommended.

The document also covers the management of patients with kidney disease, diabetes, cancer, obesity, and COVID-19. In general, elective noncardiac surgery should be postponed after a patient has COVID-19, until he or she recovers completely, and coexisting conditions are optimized.

The guidelines are available from the ESC website in several formats: pocket guidelines, pocket guidelines smartphone app, guidelines slide set, essential messages, and the European Heart Journal article.
 

Noncardiac surgery risk categories

The guideline includes a table that classifies noncardiac surgeries into three groups, based on the associated 30-day risk of death, MI, or stroke:

• Low (< 1%): breast, dental, eye, thyroid, and minor gynecologic, orthopedic, and urologic surgery.
• Intermediate (1%-5%): carotid surgery, endovascular aortic aneurysm repair, gallbladder surgery, head or neck surgery, hernia repair, peripheral arterial angioplasty, renal transplant, major gynecologic, orthopedic, or neurologic (hip or spine) surgery, or urologic surgery
• High (> 5%): aortic and major vascular surgery (including aortic aneurysm), bladder removal (usually as a result of cancer), limb amputation, lung or liver transplant, pancreatic surgery, or perforated bowel repair.

The guidelines were endorsed by the European Society of Anaesthesiology and Intensive Care. The guideline authors reported numerous disclosures.

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

BARCELONA – A novel “extravascular” implantable cardioverter defibrillator (ICD) that uses substernally placed electrodes surpassed its prespecified efficacy and safety targets in the device’s pivotal trial with 299 patients who received an implant.

The results showed that the extravascular ICD “provides antitachycardia pacing and low energy defibrillation while avoiding the vascular space” for lead placement, Ian Crozier, MD, said at the annual congress of the European Society of Cardiology.

Mitchel L. Zoler/MDedge News

“The results are fantastic; they exceeded our expectations,” said Dr. Crozier in an interview, adding that he expects the new device to receive marketing approval from regulatory agencies based on the findings. “This will be the next generation of ICD going forward,” predicted Dr. Crozier, an electrophysiologist cardiologist at Christchurch (New Zealand) Hospital.
 

Moving beyond transvenous and subcutaneous ICDs

Traditional ICDs use transvenous leads, which can cause vascular injury, are prone to lead fracture over time, and can produce serious infections as well as other potential complications. The U.S. Food and Drug Administration first approved an alternative-design, subcutaneous ICD in 2012 that avoids the need for transvenous leads and the risks they pose. But subcutaneous ICDs have their own limitations: an inability to provide antitachycardia pacing or chronic pacing; a limited ability to provide bradycardia pacing; and an increased device size with shorter battery life, because of the high shock power needed for effective performance. These drawbacks have collectively hindered uptake, Dr. Crozier said.

Medtronic

This led to development of the extravascular ICD – 10 years in the making – which uses substernally placed leads that allow antitachycardia pacing and backup pacing in a device with the size of and the anticipated battery longevity of a transvenous ICD device, noted Dr. Crozier.
 

A 98.7% rate of arrhythmia termination at implant

The pivotal trial’s primary efficacy endpoint was successful defibrillation based on terminating an induced, sustained, shockable ventricular arrhythmia at the time of implantation. The rate was 98.7%, compared with a prespecified target of 88%. All patients had a class I or IIa indication for an ICD.

The primary safety endpoint was freedom from major system- or procedure-related complications at 6 months, which occurred at a rate of 92.6%, compared with the study’s prespecified target rate of 79%. Both targets were derived from the historical rates of ICDs with transvenous leads.

Simultaneously with Dr. Crozier’s report at the congress, the results also appeared online in the New England Journal of Medicine.

Although the pivotal study met both prespecified endpoints, the evidence has limitations that make it likely that regulatory bodies will seek additional data, commented Fred Kusumoto, MD, director of heart rhythm services for the Mayo Clinic in Jacksonville, Fla.
 

Short follow-up; questions remain

“Follow-up was relatively short, less than a year,” and “questions remain” about the extravascular ICD’s performance, Dr. Kusumoto said in an interview. “Inappropriate shocks occurred in nearly 10% of patients after 11 month follow-up,” he noted, and also cited the 29 patients who needed revisions including two cases with lead fractures.

“The extravascular lead strategy has an advantage over transvenous systems because of the lower risk for extraction or explant,” and it also provides the antitachycardia pacing that’s not available with subcutaneous ICDs, he granted. But in the new study, antitachycardia termination was delivered to only 10 patients and had “reasonable” effectiveness by resolving 70% of these episodes. “Wide adoption by clinicians will depend on results from larger studies with longer follow-up,” Dr. Kusumoto maintained. He also wanted to see confirmation of the ease of lead removal after longer periods of implantation.

Implantation ‘is not difficult’

The trial ran at 46 sites in 17 countries during September 2019 to October 2021. It enrolled patients with a class I or IIa indication for an ICD, excluding patients with a prior sternotomy or need for chronic pacing, and those unable to undergo defibrillation testing.

Clinicians attempted an implantation in 316 patients and had successful placement in 299 (314 had successful placement of their substernal leads), with 292 having a functional device after 6 months, and 284 completing their planned 6-month follow-up. The median procedure time was 66 minutes, including the time for defibrillation testing.

All of the cardiologists who did the implants had received a full day of training prior to performing the procedure. “This is not a difficult procedure, but it is not a region [the substernal space] that cardiologists are familiar working in,” noted Dr. Crozier, explaining the rationale behind a policy of required implantation training.

Twenty-five adverse events occurred in 23 patients. Eighteen of these events required a system revision, including nine lead dislodgments and five infections. The seven adverse events that did not require a revision included three wound-related episodes and three hospitalizations for inappropriate shock. No patients died, nor were there any cardiac injuries as result of the implant.

During average follow-up of 10.6 months, the implanted devices delivered antitachycardia pacing to 10 patients, successfully terminating 32 of 46 episodes (70%), a rate that Dr. Crozier called “very good, and very comparable to transvenous devices.” The devices also delivered 18 appropriate shocks that successfully converted all 18 episodes.
 

A 10% rate of inappropriate shocks

However, 29 patients (10% of the study cohort) received inappropriate shocks in 81 episodes, with a total of 118 inappropriate shocks delivered, including 34 episodes (42%) triggered by oversensing of a P wave.

“We fully acknowledge that the inappropriate shock rate is higher than what’s seen with transvenous ICDs, but the rate is comparable to what was seen in the early trials with subcutaneous ICDs,” said Dr. Crozier. “We have a number of strategies to reduce the inappropriate shock rate to what we’d expect with conventional devices,” such as making sure that P waves are not detected by the device at the time of implantation, using new algorithms to mitigate P wave sensing, and other programming changes, he added.

Two patients had lead fractures that Dr. Crozier attributed to atypical lead locations and that are likely avoidable in the future. He expressed optimism that the extravascular ICD will avoid the high lead fracture rate over time that remains a problem for ICDs with transvenous leads.

The study also followed a subgroup of 36 patients who underwent a prespecified protocol of chronic defibrillation testing that was successful in all 36.

Dr. Crozier conceded that the extravascular ICD cannot currently deliver chronic pacing, but he expressed optimism that this capability will be available in the future.

“This innovative [extravascular] ICD system would be particularly beneficial for patients with ventricular arrhythmias that can be reliably pace terminated and avoid a transvenous endocardial lead, but more information is required,” concluded Dr. Kusumoto.

The study was sponsored by Medtronic, the company that is developing the extravascular ICD. Dr. Crozier is a consultant to and has received research funding from Medtronic. Dr. Kusumoto had no disclosures.

BARCELONA – A novel “extravascular” implantable cardioverter defibrillator (ICD) that uses substernally placed electrodes surpassed its prespecified efficacy and safety targets in the device’s pivotal trial with 299 patients who received an implant.

The results showed that the extravascular ICD “provides antitachycardia pacing and low energy defibrillation while avoiding the vascular space” for lead placement, Ian Crozier, MD, said at the annual congress of the European Society of Cardiology.

Mitchel L. Zoler/MDedge News

“The results are fantastic; they exceeded our expectations,” said Dr. Crozier in an interview, adding that he expects the new device to receive marketing approval from regulatory agencies based on the findings. “This will be the next generation of ICD going forward,” predicted Dr. Crozier, an electrophysiologist cardiologist at Christchurch (New Zealand) Hospital.
 

Moving beyond transvenous and subcutaneous ICDs

Traditional ICDs use transvenous leads, which can cause vascular injury, are prone to lead fracture over time, and can produce serious infections as well as other potential complications. The U.S. Food and Drug Administration first approved an alternative-design, subcutaneous ICD in 2012 that avoids the need for transvenous leads and the risks they pose. But subcutaneous ICDs have their own limitations: an inability to provide antitachycardia pacing or chronic pacing; a limited ability to provide bradycardia pacing; and an increased device size with shorter battery life, because of the high shock power needed for effective performance. These drawbacks have collectively hindered uptake, Dr. Crozier said.

Medtronic

This led to development of the extravascular ICD – 10 years in the making – which uses substernally placed leads that allow antitachycardia pacing and backup pacing in a device with the size of and the anticipated battery longevity of a transvenous ICD device, noted Dr. Crozier.
 

A 98.7% rate of arrhythmia termination at implant

The pivotal trial’s primary efficacy endpoint was successful defibrillation based on terminating an induced, sustained, shockable ventricular arrhythmia at the time of implantation. The rate was 98.7%, compared with a prespecified target of 88%. All patients had a class I or IIa indication for an ICD.

The primary safety endpoint was freedom from major system- or procedure-related complications at 6 months, which occurred at a rate of 92.6%, compared with the study’s prespecified target rate of 79%. Both targets were derived from the historical rates of ICDs with transvenous leads.

Simultaneously with Dr. Crozier’s report at the congress, the results also appeared online in the New England Journal of Medicine.

Although the pivotal study met both prespecified endpoints, the evidence has limitations that make it likely that regulatory bodies will seek additional data, commented Fred Kusumoto, MD, director of heart rhythm services for the Mayo Clinic in Jacksonville, Fla.
 

Short follow-up; questions remain

“Follow-up was relatively short, less than a year,” and “questions remain” about the extravascular ICD’s performance, Dr. Kusumoto said in an interview. “Inappropriate shocks occurred in nearly 10% of patients after 11 month follow-up,” he noted, and also cited the 29 patients who needed revisions including two cases with lead fractures.

“The extravascular lead strategy has an advantage over transvenous systems because of the lower risk for extraction or explant,” and it also provides the antitachycardia pacing that’s not available with subcutaneous ICDs, he granted. But in the new study, antitachycardia termination was delivered to only 10 patients and had “reasonable” effectiveness by resolving 70% of these episodes. “Wide adoption by clinicians will depend on results from larger studies with longer follow-up,” Dr. Kusumoto maintained. He also wanted to see confirmation of the ease of lead removal after longer periods of implantation.

Implantation ‘is not difficult’

The trial ran at 46 sites in 17 countries during September 2019 to October 2021. It enrolled patients with a class I or IIa indication for an ICD, excluding patients with a prior sternotomy or need for chronic pacing, and those unable to undergo defibrillation testing.

Clinicians attempted an implantation in 316 patients and had successful placement in 299 (314 had successful placement of their substernal leads), with 292 having a functional device after 6 months, and 284 completing their planned 6-month follow-up. The median procedure time was 66 minutes, including the time for defibrillation testing.

All of the cardiologists who did the implants had received a full day of training prior to performing the procedure. “This is not a difficult procedure, but it is not a region [the substernal space] that cardiologists are familiar working in,” noted Dr. Crozier, explaining the rationale behind a policy of required implantation training.

Twenty-five adverse events occurred in 23 patients. Eighteen of these events required a system revision, including nine lead dislodgments and five infections. The seven adverse events that did not require a revision included three wound-related episodes and three hospitalizations for inappropriate shock. No patients died, nor were there any cardiac injuries as result of the implant.

During average follow-up of 10.6 months, the implanted devices delivered antitachycardia pacing to 10 patients, successfully terminating 32 of 46 episodes (70%), a rate that Dr. Crozier called “very good, and very comparable to transvenous devices.” The devices also delivered 18 appropriate shocks that successfully converted all 18 episodes.
 

A 10% rate of inappropriate shocks

However, 29 patients (10% of the study cohort) received inappropriate shocks in 81 episodes, with a total of 118 inappropriate shocks delivered, including 34 episodes (42%) triggered by oversensing of a P wave.

“We fully acknowledge that the inappropriate shock rate is higher than what’s seen with transvenous ICDs, but the rate is comparable to what was seen in the early trials with subcutaneous ICDs,” said Dr. Crozier. “We have a number of strategies to reduce the inappropriate shock rate to what we’d expect with conventional devices,” such as making sure that P waves are not detected by the device at the time of implantation, using new algorithms to mitigate P wave sensing, and other programming changes, he added.

Two patients had lead fractures that Dr. Crozier attributed to atypical lead locations and that are likely avoidable in the future. He expressed optimism that the extravascular ICD will avoid the high lead fracture rate over time that remains a problem for ICDs with transvenous leads.

The study also followed a subgroup of 36 patients who underwent a prespecified protocol of chronic defibrillation testing that was successful in all 36.

Dr. Crozier conceded that the extravascular ICD cannot currently deliver chronic pacing, but he expressed optimism that this capability will be available in the future.

“This innovative [extravascular] ICD system would be particularly beneficial for patients with ventricular arrhythmias that can be reliably pace terminated and avoid a transvenous endocardial lead, but more information is required,” concluded Dr. Kusumoto.

The study was sponsored by Medtronic, the company that is developing the extravascular ICD. Dr. Crozier is a consultant to and has received research funding from Medtronic. Dr. Kusumoto had no disclosures.

BARCELONA – A novel “extravascular” implantable cardioverter defibrillator (ICD) that uses substernally placed electrodes surpassed its prespecified efficacy and safety targets in the device’s pivotal trial with 299 patients who received an implant.

The results showed that the extravascular ICD “provides antitachycardia pacing and low energy defibrillation while avoiding the vascular space” for lead placement, Ian Crozier, MD, said at the annual congress of the European Society of Cardiology.

Mitchel L. Zoler/MDedge News

“The results are fantastic; they exceeded our expectations,” said Dr. Crozier in an interview, adding that he expects the new device to receive marketing approval from regulatory agencies based on the findings. “This will be the next generation of ICD going forward,” predicted Dr. Crozier, an electrophysiologist cardiologist at Christchurch (New Zealand) Hospital.
 

Moving beyond transvenous and subcutaneous ICDs

Traditional ICDs use transvenous leads, which can cause vascular injury, are prone to lead fracture over time, and can produce serious infections as well as other potential complications. The U.S. Food and Drug Administration first approved an alternative-design, subcutaneous ICD in 2012 that avoids the need for transvenous leads and the risks they pose. But subcutaneous ICDs have their own limitations: an inability to provide antitachycardia pacing or chronic pacing; a limited ability to provide bradycardia pacing; and an increased device size with shorter battery life, because of the high shock power needed for effective performance. These drawbacks have collectively hindered uptake, Dr. Crozier said.

Medtronic

This led to development of the extravascular ICD – 10 years in the making – which uses substernally placed leads that allow antitachycardia pacing and backup pacing in a device with the size of and the anticipated battery longevity of a transvenous ICD device, noted Dr. Crozier.
 

A 98.7% rate of arrhythmia termination at implant

The pivotal trial’s primary efficacy endpoint was successful defibrillation based on terminating an induced, sustained, shockable ventricular arrhythmia at the time of implantation. The rate was 98.7%, compared with a prespecified target of 88%. All patients had a class I or IIa indication for an ICD.

The primary safety endpoint was freedom from major system- or procedure-related complications at 6 months, which occurred at a rate of 92.6%, compared with the study’s prespecified target rate of 79%. Both targets were derived from the historical rates of ICDs with transvenous leads.

Simultaneously with Dr. Crozier’s report at the congress, the results also appeared online in the New England Journal of Medicine.

Although the pivotal study met both prespecified endpoints, the evidence has limitations that make it likely that regulatory bodies will seek additional data, commented Fred Kusumoto, MD, director of heart rhythm services for the Mayo Clinic in Jacksonville, Fla.
 

Short follow-up; questions remain

“Follow-up was relatively short, less than a year,” and “questions remain” about the extravascular ICD’s performance, Dr. Kusumoto said in an interview. “Inappropriate shocks occurred in nearly 10% of patients after 11 month follow-up,” he noted, and also cited the 29 patients who needed revisions including two cases with lead fractures.

“The extravascular lead strategy has an advantage over transvenous systems because of the lower risk for extraction or explant,” and it also provides the antitachycardia pacing that’s not available with subcutaneous ICDs, he granted. But in the new study, antitachycardia termination was delivered to only 10 patients and had “reasonable” effectiveness by resolving 70% of these episodes. “Wide adoption by clinicians will depend on results from larger studies with longer follow-up,” Dr. Kusumoto maintained. He also wanted to see confirmation of the ease of lead removal after longer periods of implantation.

Implantation ‘is not difficult’

The trial ran at 46 sites in 17 countries during September 2019 to October 2021. It enrolled patients with a class I or IIa indication for an ICD, excluding patients with a prior sternotomy or need for chronic pacing, and those unable to undergo defibrillation testing.

Clinicians attempted an implantation in 316 patients and had successful placement in 299 (314 had successful placement of their substernal leads), with 292 having a functional device after 6 months, and 284 completing their planned 6-month follow-up. The median procedure time was 66 minutes, including the time for defibrillation testing.

All of the cardiologists who did the implants had received a full day of training prior to performing the procedure. “This is not a difficult procedure, but it is not a region [the substernal space] that cardiologists are familiar working in,” noted Dr. Crozier, explaining the rationale behind a policy of required implantation training.

Twenty-five adverse events occurred in 23 patients. Eighteen of these events required a system revision, including nine lead dislodgments and five infections. The seven adverse events that did not require a revision included three wound-related episodes and three hospitalizations for inappropriate shock. No patients died, nor were there any cardiac injuries as result of the implant.

During average follow-up of 10.6 months, the implanted devices delivered antitachycardia pacing to 10 patients, successfully terminating 32 of 46 episodes (70%), a rate that Dr. Crozier called “very good, and very comparable to transvenous devices.” The devices also delivered 18 appropriate shocks that successfully converted all 18 episodes.
 

A 10% rate of inappropriate shocks

However, 29 patients (10% of the study cohort) received inappropriate shocks in 81 episodes, with a total of 118 inappropriate shocks delivered, including 34 episodes (42%) triggered by oversensing of a P wave.

“We fully acknowledge that the inappropriate shock rate is higher than what’s seen with transvenous ICDs, but the rate is comparable to what was seen in the early trials with subcutaneous ICDs,” said Dr. Crozier. “We have a number of strategies to reduce the inappropriate shock rate to what we’d expect with conventional devices,” such as making sure that P waves are not detected by the device at the time of implantation, using new algorithms to mitigate P wave sensing, and other programming changes, he added.

Two patients had lead fractures that Dr. Crozier attributed to atypical lead locations and that are likely avoidable in the future. He expressed optimism that the extravascular ICD will avoid the high lead fracture rate over time that remains a problem for ICDs with transvenous leads.

The study also followed a subgroup of 36 patients who underwent a prespecified protocol of chronic defibrillation testing that was successful in all 36.

Dr. Crozier conceded that the extravascular ICD cannot currently deliver chronic pacing, but he expressed optimism that this capability will be available in the future.

“This innovative [extravascular] ICD system would be particularly beneficial for patients with ventricular arrhythmias that can be reliably pace terminated and avoid a transvenous endocardial lead, but more information is required,” concluded Dr. Kusumoto.

The study was sponsored by Medtronic, the company that is developing the extravascular ICD. Dr. Crozier is a consultant to and has received research funding from Medtronic. Dr. Kusumoto had no disclosures.

Heparin started in the ambulance or emergency department (ED) makes it more likely a patient with acute ST-segment elevation myocardial infarction (STEMI) will present to the cath lab without a coronary artery occlusion, suggests a large registry study.

An open infarct-related artery (IRA) at angiography on cath-lab arrival presents STEMI patients an opportunity for earlier reperfusion and a chance, in theory at least, for smaller infarcts and maybe improved clinical outcomes.

In the new analysis, which covers more than 40,000 patients with STEMI in Sweden, the 38% who received heparin before cath-lab arrival were 11% less likely to show IRA occlusion at angiography prior to direct percutaneous coronary intervention (PCI). They also showed a 13% lower 30-day mortality compared with patients who were started on heparin in the cath lab. Importantly, their risk of major bleeding in the hospital did not increase.

The “early reperfusion” associated with IRA patency at angiography “could have long-term benefit due to smaller infarct size,” potentially explaining the observed 30-day survival gain in the pretreatment group, Oskar Love Emilsson, Lund (Sweden) University, said in an interview.

Mr. Emilsson, a third-year medical student, reported the analysis at the annual congress of the European Society of Cardiology, and is lead author on its same-day publication in the journal EuroIntervention.

He mentioned a few cautions in interpreting the study, which is based primarily on data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). It included several sensitivity analyses that continued to back pretreatment heparin as a significant predictor of an unoccluded IRA but didn’t consistently support the 30-day mortality benefit seen in the primary analysis.

And, although the pretreatment group overall didn’t have more major bleeds, the risk did go up significantly for those older than 75 or those who weighed less than 60 kg (132 pounds) or underwent catheterization with an access route other than the radial artery. Extra caution should be exercised in such patients who receive heparin before cath-lab arrival for PCI, Mr. Emilsson observed.

“Our results suggest that heparin pretreatment might be a good option to improve patency of infarct related arteries in STEMI,” and potentially clinical outcomes, he said. “However, a definite answer would require a randomized controlled trial.”

Meanwhile, the current study may be the largest yet to look at clinical outcomes after pretreatment with unfractionated heparin before PCI for acute STEMI, the report states. There have been some observational studies, subanalyses of STEMI trials, and even a few limited randomized trials – including the HEAP trial published in 2000 – to weigh in on the subject. Some have supported the strategy, others have not.

“With rapid door-to-balloon times in STEMI, it can be challenging to show a significant difference between a prehospital heparin approach and heparin given in the lab,” observed Sunil V. Rao, MD, NYU Langone Health System, New York, who is not connected with the current study.

Many EDs in the United States have “a STEMI protocol that calls for an IV bolus of heparin. It would be tougher in the U.S. to give it in the ambulance but again, it’s not clear how much advantage that would really provide,” he told this news organization.

Support from randomized trials would be needed before the practice could be formally recommended. “The SCAAR registries have set the standard for how registries should be conducted,” Dr. Rao said. “This is a very well done observational study, but it is observational.”

The priority for STEMI patients, he added, “really should be to get them to the lab as fast as possible. If the ED protocol includes heparin before the cath lab, that’s great, but I don’t think we should delay getting these patients to the lab to accommodate pre–cath-lab heparin.”

The current analysis covered 41,631 patients with STEMI from 2008 through to 2016, of whom 38% were pretreated with heparin in an ambulance or the ED. The remaining 62% initiated heparin in the cath lab.

About one-third of the group had an open IRA at angiography. The adjusted risk ratio (RR) for IRA occlusion at angiography for patients pretreated vs. not pretreated with heparin was 0.89 (95% confidence interval [CI], 0.87-0.90).

The corresponding RR for death within 30 days was 0.87 (95% CI, 0.77-0.99), and for major in-hospital bleeding it was 1.01 (95% CI, 0.86-1.18).

The analysis was adjusted for other medications received before cath-lab arrival, especially a long list of antiplatelets and non-heparin antithrombins. That strengthens the case for heparin pretreatment as an independent predictor of an open IRA at initial angiography, Mr. Emilsson said.

Comparisons of propensity-score–matched subgroups of the total cohort, conducted separately for the IRA-occlusion endpoint and the endpoints of 30-day mortality and major bleeding, produced similar results.

Some observational data suggest that antiplatelet pretreatment with a P2Y12 inhibitor may promote IRA patency on angiography after cath lab arrival, Dr. Rao observed. “This indicates that there probably is a role of earlier antithrombotic therapy in STEMI patients, but the randomized trials have not shown a consistent benefit,” he said, referring in particular to the ATLANTIC trial.

Mr. Emilsson and Dr. Rao disclosed no relevant financial relationships.

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

Heparin started in the ambulance or emergency department (ED) makes it more likely a patient with acute ST-segment elevation myocardial infarction (STEMI) will present to the cath lab without a coronary artery occlusion, suggests a large registry study.

An open infarct-related artery (IRA) at angiography on cath-lab arrival presents STEMI patients an opportunity for earlier reperfusion and a chance, in theory at least, for smaller infarcts and maybe improved clinical outcomes.

In the new analysis, which covers more than 40,000 patients with STEMI in Sweden, the 38% who received heparin before cath-lab arrival were 11% less likely to show IRA occlusion at angiography prior to direct percutaneous coronary intervention (PCI). They also showed a 13% lower 30-day mortality compared with patients who were started on heparin in the cath lab. Importantly, their risk of major bleeding in the hospital did not increase.

The “early reperfusion” associated with IRA patency at angiography “could have long-term benefit due to smaller infarct size,” potentially explaining the observed 30-day survival gain in the pretreatment group, Oskar Love Emilsson, Lund (Sweden) University, said in an interview.

Mr. Emilsson, a third-year medical student, reported the analysis at the annual congress of the European Society of Cardiology, and is lead author on its same-day publication in the journal EuroIntervention.

He mentioned a few cautions in interpreting the study, which is based primarily on data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). It included several sensitivity analyses that continued to back pretreatment heparin as a significant predictor of an unoccluded IRA but didn’t consistently support the 30-day mortality benefit seen in the primary analysis.

And, although the pretreatment group overall didn’t have more major bleeds, the risk did go up significantly for those older than 75 or those who weighed less than 60 kg (132 pounds) or underwent catheterization with an access route other than the radial artery. Extra caution should be exercised in such patients who receive heparin before cath-lab arrival for PCI, Mr. Emilsson observed.

“Our results suggest that heparin pretreatment might be a good option to improve patency of infarct related arteries in STEMI,” and potentially clinical outcomes, he said. “However, a definite answer would require a randomized controlled trial.”

Meanwhile, the current study may be the largest yet to look at clinical outcomes after pretreatment with unfractionated heparin before PCI for acute STEMI, the report states. There have been some observational studies, subanalyses of STEMI trials, and even a few limited randomized trials – including the HEAP trial published in 2000 – to weigh in on the subject. Some have supported the strategy, others have not.

“With rapid door-to-balloon times in STEMI, it can be challenging to show a significant difference between a prehospital heparin approach and heparin given in the lab,” observed Sunil V. Rao, MD, NYU Langone Health System, New York, who is not connected with the current study.

Many EDs in the United States have “a STEMI protocol that calls for an IV bolus of heparin. It would be tougher in the U.S. to give it in the ambulance but again, it’s not clear how much advantage that would really provide,” he told this news organization.

Support from randomized trials would be needed before the practice could be formally recommended. “The SCAAR registries have set the standard for how registries should be conducted,” Dr. Rao said. “This is a very well done observational study, but it is observational.”

The priority for STEMI patients, he added, “really should be to get them to the lab as fast as possible. If the ED protocol includes heparin before the cath lab, that’s great, but I don’t think we should delay getting these patients to the lab to accommodate pre–cath-lab heparin.”

The current analysis covered 41,631 patients with STEMI from 2008 through to 2016, of whom 38% were pretreated with heparin in an ambulance or the ED. The remaining 62% initiated heparin in the cath lab.

About one-third of the group had an open IRA at angiography. The adjusted risk ratio (RR) for IRA occlusion at angiography for patients pretreated vs. not pretreated with heparin was 0.89 (95% confidence interval [CI], 0.87-0.90).

The corresponding RR for death within 30 days was 0.87 (95% CI, 0.77-0.99), and for major in-hospital bleeding it was 1.01 (95% CI, 0.86-1.18).

The analysis was adjusted for other medications received before cath-lab arrival, especially a long list of antiplatelets and non-heparin antithrombins. That strengthens the case for heparin pretreatment as an independent predictor of an open IRA at initial angiography, Mr. Emilsson said.

Comparisons of propensity-score–matched subgroups of the total cohort, conducted separately for the IRA-occlusion endpoint and the endpoints of 30-day mortality and major bleeding, produced similar results.

Some observational data suggest that antiplatelet pretreatment with a P2Y12 inhibitor may promote IRA patency on angiography after cath lab arrival, Dr. Rao observed. “This indicates that there probably is a role of earlier antithrombotic therapy in STEMI patients, but the randomized trials have not shown a consistent benefit,” he said, referring in particular to the ATLANTIC trial.

Mr. Emilsson and Dr. Rao disclosed no relevant financial relationships.

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

Heparin started in the ambulance or emergency department (ED) makes it more likely a patient with acute ST-segment elevation myocardial infarction (STEMI) will present to the cath lab without a coronary artery occlusion, suggests a large registry study.

An open infarct-related artery (IRA) at angiography on cath-lab arrival presents STEMI patients an opportunity for earlier reperfusion and a chance, in theory at least, for smaller infarcts and maybe improved clinical outcomes.

In the new analysis, which covers more than 40,000 patients with STEMI in Sweden, the 38% who received heparin before cath-lab arrival were 11% less likely to show IRA occlusion at angiography prior to direct percutaneous coronary intervention (PCI). They also showed a 13% lower 30-day mortality compared with patients who were started on heparin in the cath lab. Importantly, their risk of major bleeding in the hospital did not increase.

The “early reperfusion” associated with IRA patency at angiography “could have long-term benefit due to smaller infarct size,” potentially explaining the observed 30-day survival gain in the pretreatment group, Oskar Love Emilsson, Lund (Sweden) University, said in an interview.

Mr. Emilsson, a third-year medical student, reported the analysis at the annual congress of the European Society of Cardiology, and is lead author on its same-day publication in the journal EuroIntervention.

He mentioned a few cautions in interpreting the study, which is based primarily on data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). It included several sensitivity analyses that continued to back pretreatment heparin as a significant predictor of an unoccluded IRA but didn’t consistently support the 30-day mortality benefit seen in the primary analysis.

And, although the pretreatment group overall didn’t have more major bleeds, the risk did go up significantly for those older than 75 or those who weighed less than 60 kg (132 pounds) or underwent catheterization with an access route other than the radial artery. Extra caution should be exercised in such patients who receive heparin before cath-lab arrival for PCI, Mr. Emilsson observed.

“Our results suggest that heparin pretreatment might be a good option to improve patency of infarct related arteries in STEMI,” and potentially clinical outcomes, he said. “However, a definite answer would require a randomized controlled trial.”

Meanwhile, the current study may be the largest yet to look at clinical outcomes after pretreatment with unfractionated heparin before PCI for acute STEMI, the report states. There have been some observational studies, subanalyses of STEMI trials, and even a few limited randomized trials – including the HEAP trial published in 2000 – to weigh in on the subject. Some have supported the strategy, others have not.

“With rapid door-to-balloon times in STEMI, it can be challenging to show a significant difference between a prehospital heparin approach and heparin given in the lab,” observed Sunil V. Rao, MD, NYU Langone Health System, New York, who is not connected with the current study.

Many EDs in the United States have “a STEMI protocol that calls for an IV bolus of heparin. It would be tougher in the U.S. to give it in the ambulance but again, it’s not clear how much advantage that would really provide,” he told this news organization.

Support from randomized trials would be needed before the practice could be formally recommended. “The SCAAR registries have set the standard for how registries should be conducted,” Dr. Rao said. “This is a very well done observational study, but it is observational.”

The priority for STEMI patients, he added, “really should be to get them to the lab as fast as possible. If the ED protocol includes heparin before the cath lab, that’s great, but I don’t think we should delay getting these patients to the lab to accommodate pre–cath-lab heparin.”

The current analysis covered 41,631 patients with STEMI from 2008 through to 2016, of whom 38% were pretreated with heparin in an ambulance or the ED. The remaining 62% initiated heparin in the cath lab.

About one-third of the group had an open IRA at angiography. The adjusted risk ratio (RR) for IRA occlusion at angiography for patients pretreated vs. not pretreated with heparin was 0.89 (95% confidence interval [CI], 0.87-0.90).

The corresponding RR for death within 30 days was 0.87 (95% CI, 0.77-0.99), and for major in-hospital bleeding it was 1.01 (95% CI, 0.86-1.18).

The analysis was adjusted for other medications received before cath-lab arrival, especially a long list of antiplatelets and non-heparin antithrombins. That strengthens the case for heparin pretreatment as an independent predictor of an open IRA at initial angiography, Mr. Emilsson said.

Comparisons of propensity-score–matched subgroups of the total cohort, conducted separately for the IRA-occlusion endpoint and the endpoints of 30-day mortality and major bleeding, produced similar results.

Some observational data suggest that antiplatelet pretreatment with a P2Y12 inhibitor may promote IRA patency on angiography after cath lab arrival, Dr. Rao observed. “This indicates that there probably is a role of earlier antithrombotic therapy in STEMI patients, but the randomized trials have not shown a consistent benefit,” he said, referring in particular to the ATLANTIC trial.

Mr. Emilsson and Dr. Rao disclosed no relevant financial relationships.

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

A post hoc analysis of the PARADISE-MI trial, although not intended to alter the conclusions generated by the published data, suggests that clinically relevant benefits were obscured, providing the basis for recommending different analyses for future studies that are more suited to capture the most clinically significant endpoints.

“What these data show us is that we need clinical trial designs moving towards more pragmatic information that better reflect clinical practice,” reported Otavio Berwanger, MD, PhD, director of the Academic Research Organization at Hospital Israelita Albert Einstein, São Paulo, Brazil.

Mitchel L. Zoler/MDedge News

The reevaluation of the PARADISE-MI data, presented at the annual congress of the European Society of Cardiology in Barcelona, was based on a win ratio analysis and on the inclusion of investigator-reported endpoints, not just adjudicated events. Both appear to reveal clinically meaningful benefits not reflected in the published study, according to Dr. Berwanger.

In PARADISE-MI, which was published in the New England Journal of Medicine last year, more than 5,500 patients were randomized to the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan or the ACE inhibitor ramipril after a myocardial infarction. A reduced left ventricular ejection fraction (LVEF), pulmonary congestion, or both were required for enrollment.

For the primary composite outcomes of death from cardiovascular (CV) causes or incident heart failure, the ARNI had a 10% numerical advantage, but it did not reach statistical significance (hazard ratio [HR], 0.90; P = .17).

“PARADISE-MI was a neutral trial. This post hoc analysis will not change that result,” Dr. Berwanger emphasized. However, the post hoc analysis does provide a basis for exploring why conventional trial designs might not be providing answers that are relevant and helpful for clinical practice.

New analysis provides positive trial result

When the data from PARADISE-MI are reevaluated in a hierarchical win ratio analysis with CV death serving as the most severe and important outcome, the principal conclusion changes. Whether events are reevaluated in this format by the clinical events committee (CEC) or by investigators, there is a greater number of total wins than total losses for the ARNI. Combined, sacubitril/valsartan was associated with a win ratio of 1.17 (95% confidence interval, 1.03-1.33; P = 0.015) over ramipril.

Using a sports analogy, Dr. Berwanger explained that the win ratio analysis divides the total number of wins to the total number of losses to provide a much more clinically relevant approach to keeping score. It also used a hierarchical analysis so that the most serious and important events are considered first.

In addition to CV death, this analysis included first hospitalization for heart failure and first outpatient heart failure events. CEC-defined events and events reported by investigators were evaluated separately.

The ARNI had more wins than losses in every category for all outcomes, whether CEC adjudicated or investigator reported, but most of this benefit was generated by the endpoint of CEC-adjudicated CV deaths. This accounted for 36.9% of all events (investigator-documented CV death accounted for 0.7%). This is important because PARADISE-MI, like many standard trials, was conducted on a time-to-primary event basis.

“In this type of analysis, the first event is what counts. Usually time-to-first-event analyses are dominated by nonfatal events,” Dr. Berwanger explained. He believes that placing more weight on the most serious events results in an emphasis on what outcomes are of greatest clinical interest.

In addition, Dr. Berwanger argued that it is important to consider investigator-reported events, not just CEC-adjudicated events. While adjudicated events improve the rigor of the data, Dr. Berwanger suggested it omits outcomes with which clinicians are most concerned.
 

Investigator, adjudicated outcomes differ

Again, using PARADISE-MI as an example, he reevaluated the primary outcome based on investigator reports. When investigator-reported events are included, the number of events increased in both the ARNI (443 vs. 338) and ramipril (516 vs. 373) arms, but the advantage of the ARNI over the ACE inhibitors now reached statistical significance (HR, 0.85; P = .01).

“The data suggest that maybe we should find definitions for adjudication that are closer to clinical judgment in the real world and clinical practice,” Dr. Berwanger said.

One possible explanation for the neutral result in PARADISE-MI is that benefit of an ARNI over an ACE inhibitor would only be expected in those at risk for progressive left ventricular dysfunction, and it is likely that a substantial proportion of patients enrolled in this trial recovered, according to Johann Bauersachs, MD, PhD, professor and head of cardiology at Hannover (Germany) Medical School.

“You cannot predict which patients with reduced LV function following an MI will go on to chronic remodeling and which will recover,” said Dr. Bauersachs, who was an ESC-invited discussant of Dr. Berwanger’s post hoc analysis.

Mitchel L. Zoler/MDedge News

He agreed that Dr. Berwanger has raised several important issues in standard trial design that might have prevented PARADISE-MI from showing a benefit from an ARNI, but he pointed out that there are other potential issues, such as the low use of mineralocorticoid antagonists in PARADISE-MI, that may have skewed results.

However, he agreed generally with the premise that there is a need for trial design likely to generate more clinically useful information.

“We have now seen the win-ratio approach used in several studies,” said Dr. Bauersachs, citing in particular the EMPULSE trial presented at the 2022 meeting of the American College of Cardiology. “It is a very useful tool, and I think we will be seeing it used more in the future.”

However, he indicated that the issues raised by Dr. Berwanger are not necessarily easily resolved. Dr. Bauersachs endorsed the effort to consider trial designs that generate data that are more immediately clinically applicable but suggested that different types of designs may be required for different types of clinical questions.

Dr. Berwanger reports financial relationships with Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Pfizer, Servier, and Novartis, which provided funding for the PARADISE-MI trial. Dr. Bauersachs reports financial relationships with Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Cardior, Corvia, CVRx, Novartis, Pfizer, Vifor, and Zoll.

A post hoc analysis of the PARADISE-MI trial, although not intended to alter the conclusions generated by the published data, suggests that clinically relevant benefits were obscured, providing the basis for recommending different analyses for future studies that are more suited to capture the most clinically significant endpoints.

“What these data show us is that we need clinical trial designs moving towards more pragmatic information that better reflect clinical practice,” reported Otavio Berwanger, MD, PhD, director of the Academic Research Organization at Hospital Israelita Albert Einstein, São Paulo, Brazil.

Mitchel L. Zoler/MDedge News

The reevaluation of the PARADISE-MI data, presented at the annual congress of the European Society of Cardiology in Barcelona, was based on a win ratio analysis and on the inclusion of investigator-reported endpoints, not just adjudicated events. Both appear to reveal clinically meaningful benefits not reflected in the published study, according to Dr. Berwanger.

In PARADISE-MI, which was published in the New England Journal of Medicine last year, more than 5,500 patients were randomized to the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan or the ACE inhibitor ramipril after a myocardial infarction. A reduced left ventricular ejection fraction (LVEF), pulmonary congestion, or both were required for enrollment.

For the primary composite outcomes of death from cardiovascular (CV) causes or incident heart failure, the ARNI had a 10% numerical advantage, but it did not reach statistical significance (hazard ratio [HR], 0.90; P = .17).

“PARADISE-MI was a neutral trial. This post hoc analysis will not change that result,” Dr. Berwanger emphasized. However, the post hoc analysis does provide a basis for exploring why conventional trial designs might not be providing answers that are relevant and helpful for clinical practice.

New analysis provides positive trial result

When the data from PARADISE-MI are reevaluated in a hierarchical win ratio analysis with CV death serving as the most severe and important outcome, the principal conclusion changes. Whether events are reevaluated in this format by the clinical events committee (CEC) or by investigators, there is a greater number of total wins than total losses for the ARNI. Combined, sacubitril/valsartan was associated with a win ratio of 1.17 (95% confidence interval, 1.03-1.33; P = 0.015) over ramipril.

Using a sports analogy, Dr. Berwanger explained that the win ratio analysis divides the total number of wins to the total number of losses to provide a much more clinically relevant approach to keeping score. It also used a hierarchical analysis so that the most serious and important events are considered first.

In addition to CV death, this analysis included first hospitalization for heart failure and first outpatient heart failure events. CEC-defined events and events reported by investigators were evaluated separately.

The ARNI had more wins than losses in every category for all outcomes, whether CEC adjudicated or investigator reported, but most of this benefit was generated by the endpoint of CEC-adjudicated CV deaths. This accounted for 36.9% of all events (investigator-documented CV death accounted for 0.7%). This is important because PARADISE-MI, like many standard trials, was conducted on a time-to-primary event basis.

“In this type of analysis, the first event is what counts. Usually time-to-first-event analyses are dominated by nonfatal events,” Dr. Berwanger explained. He believes that placing more weight on the most serious events results in an emphasis on what outcomes are of greatest clinical interest.

In addition, Dr. Berwanger argued that it is important to consider investigator-reported events, not just CEC-adjudicated events. While adjudicated events improve the rigor of the data, Dr. Berwanger suggested it omits outcomes with which clinicians are most concerned.
 

Investigator, adjudicated outcomes differ

Again, using PARADISE-MI as an example, he reevaluated the primary outcome based on investigator reports. When investigator-reported events are included, the number of events increased in both the ARNI (443 vs. 338) and ramipril (516 vs. 373) arms, but the advantage of the ARNI over the ACE inhibitors now reached statistical significance (HR, 0.85; P = .01).

“The data suggest that maybe we should find definitions for adjudication that are closer to clinical judgment in the real world and clinical practice,” Dr. Berwanger said.

One possible explanation for the neutral result in PARADISE-MI is that benefit of an ARNI over an ACE inhibitor would only be expected in those at risk for progressive left ventricular dysfunction, and it is likely that a substantial proportion of patients enrolled in this trial recovered, according to Johann Bauersachs, MD, PhD, professor and head of cardiology at Hannover (Germany) Medical School.

“You cannot predict which patients with reduced LV function following an MI will go on to chronic remodeling and which will recover,” said Dr. Bauersachs, who was an ESC-invited discussant of Dr. Berwanger’s post hoc analysis.

Mitchel L. Zoler/MDedge News

He agreed that Dr. Berwanger has raised several important issues in standard trial design that might have prevented PARADISE-MI from showing a benefit from an ARNI, but he pointed out that there are other potential issues, such as the low use of mineralocorticoid antagonists in PARADISE-MI, that may have skewed results.

However, he agreed generally with the premise that there is a need for trial design likely to generate more clinically useful information.

“We have now seen the win-ratio approach used in several studies,” said Dr. Bauersachs, citing in particular the EMPULSE trial presented at the 2022 meeting of the American College of Cardiology. “It is a very useful tool, and I think we will be seeing it used more in the future.”

However, he indicated that the issues raised by Dr. Berwanger are not necessarily easily resolved. Dr. Bauersachs endorsed the effort to consider trial designs that generate data that are more immediately clinically applicable but suggested that different types of designs may be required for different types of clinical questions.

Dr. Berwanger reports financial relationships with Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Pfizer, Servier, and Novartis, which provided funding for the PARADISE-MI trial. Dr. Bauersachs reports financial relationships with Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Cardior, Corvia, CVRx, Novartis, Pfizer, Vifor, and Zoll.

A post hoc analysis of the PARADISE-MI trial, although not intended to alter the conclusions generated by the published data, suggests that clinically relevant benefits were obscured, providing the basis for recommending different analyses for future studies that are more suited to capture the most clinically significant endpoints.

“What these data show us is that we need clinical trial designs moving towards more pragmatic information that better reflect clinical practice,” reported Otavio Berwanger, MD, PhD, director of the Academic Research Organization at Hospital Israelita Albert Einstein, São Paulo, Brazil.

Mitchel L. Zoler/MDedge News

The reevaluation of the PARADISE-MI data, presented at the annual congress of the European Society of Cardiology in Barcelona, was based on a win ratio analysis and on the inclusion of investigator-reported endpoints, not just adjudicated events. Both appear to reveal clinically meaningful benefits not reflected in the published study, according to Dr. Berwanger.

In PARADISE-MI, which was published in the New England Journal of Medicine last year, more than 5,500 patients were randomized to the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan or the ACE inhibitor ramipril after a myocardial infarction. A reduced left ventricular ejection fraction (LVEF), pulmonary congestion, or both were required for enrollment.

For the primary composite outcomes of death from cardiovascular (CV) causes or incident heart failure, the ARNI had a 10% numerical advantage, but it did not reach statistical significance (hazard ratio [HR], 0.90; P = .17).

“PARADISE-MI was a neutral trial. This post hoc analysis will not change that result,” Dr. Berwanger emphasized. However, the post hoc analysis does provide a basis for exploring why conventional trial designs might not be providing answers that are relevant and helpful for clinical practice.

New analysis provides positive trial result

When the data from PARADISE-MI are reevaluated in a hierarchical win ratio analysis with CV death serving as the most severe and important outcome, the principal conclusion changes. Whether events are reevaluated in this format by the clinical events committee (CEC) or by investigators, there is a greater number of total wins than total losses for the ARNI. Combined, sacubitril/valsartan was associated with a win ratio of 1.17 (95% confidence interval, 1.03-1.33; P = 0.015) over ramipril.

Using a sports analogy, Dr. Berwanger explained that the win ratio analysis divides the total number of wins to the total number of losses to provide a much more clinically relevant approach to keeping score. It also used a hierarchical analysis so that the most serious and important events are considered first.

In addition to CV death, this analysis included first hospitalization for heart failure and first outpatient heart failure events. CEC-defined events and events reported by investigators were evaluated separately.

The ARNI had more wins than losses in every category for all outcomes, whether CEC adjudicated or investigator reported, but most of this benefit was generated by the endpoint of CEC-adjudicated CV deaths. This accounted for 36.9% of all events (investigator-documented CV death accounted for 0.7%). This is important because PARADISE-MI, like many standard trials, was conducted on a time-to-primary event basis.

“In this type of analysis, the first event is what counts. Usually time-to-first-event analyses are dominated by nonfatal events,” Dr. Berwanger explained. He believes that placing more weight on the most serious events results in an emphasis on what outcomes are of greatest clinical interest.

In addition, Dr. Berwanger argued that it is important to consider investigator-reported events, not just CEC-adjudicated events. While adjudicated events improve the rigor of the data, Dr. Berwanger suggested it omits outcomes with which clinicians are most concerned.
 

Investigator, adjudicated outcomes differ

Again, using PARADISE-MI as an example, he reevaluated the primary outcome based on investigator reports. When investigator-reported events are included, the number of events increased in both the ARNI (443 vs. 338) and ramipril (516 vs. 373) arms, but the advantage of the ARNI over the ACE inhibitors now reached statistical significance (HR, 0.85; P = .01).

“The data suggest that maybe we should find definitions for adjudication that are closer to clinical judgment in the real world and clinical practice,” Dr. Berwanger said.

One possible explanation for the neutral result in PARADISE-MI is that benefit of an ARNI over an ACE inhibitor would only be expected in those at risk for progressive left ventricular dysfunction, and it is likely that a substantial proportion of patients enrolled in this trial recovered, according to Johann Bauersachs, MD, PhD, professor and head of cardiology at Hannover (Germany) Medical School.

“You cannot predict which patients with reduced LV function following an MI will go on to chronic remodeling and which will recover,” said Dr. Bauersachs, who was an ESC-invited discussant of Dr. Berwanger’s post hoc analysis.

Mitchel L. Zoler/MDedge News

He agreed that Dr. Berwanger has raised several important issues in standard trial design that might have prevented PARADISE-MI from showing a benefit from an ARNI, but he pointed out that there are other potential issues, such as the low use of mineralocorticoid antagonists in PARADISE-MI, that may have skewed results.

However, he agreed generally with the premise that there is a need for trial design likely to generate more clinically useful information.

“We have now seen the win-ratio approach used in several studies,” said Dr. Bauersachs, citing in particular the EMPULSE trial presented at the 2022 meeting of the American College of Cardiology. “It is a very useful tool, and I think we will be seeing it used more in the future.”

However, he indicated that the issues raised by Dr. Berwanger are not necessarily easily resolved. Dr. Bauersachs endorsed the effort to consider trial designs that generate data that are more immediately clinically applicable but suggested that different types of designs may be required for different types of clinical questions.

Dr. Berwanger reports financial relationships with Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Pfizer, Servier, and Novartis, which provided funding for the PARADISE-MI trial. Dr. Bauersachs reports financial relationships with Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Cardior, Corvia, CVRx, Novartis, Pfizer, Vifor, and Zoll.

Young women (under 50) are increasingly having heart attacks without doctors really knowing why. This is where the Young Women Presenting Acute Myocardial Infarction in France (WAMIF) study comes in, the results of which were presented in an e-poster at the annual congress of the European Society of Cardiology by Stéphane Manzo-Silberman, MD, Institute of Cardiology, Pitié-Salpétrière, Paris. The results (yet to be published) fight several of the preconceived ideas on the topic, Dr. Manzo-Silberman commented in an interview.

Significantly higher hospital death rates in women

“Cardiovascular disease is the main cause of death in women, killing seven times more than breast cancer,” notes Dr. Manzo-Silberman. The hospital death rate is significantly higher in women and, despite going down, is significantly higher than in men (more than double), particularly in women under 50. What’s more, in addition to the typical risk factors, women present specific risk factors related to hormone changes, high-risk inflammatory profiles, and thrombophilia.”

The WAMIF study was designed to determine the clinical, biological, and morphological features linked to hospital mortality after 12 months in women under 50. The prospective, observational study included all women in this age range from 30 sites in France between May 2017 and June 2019.
 

90% with retrosternal chest pain

The age of the 314 women enrolled was 44.9 years on average. Nearly two-thirds (192) presented with ST-segment elevation myocardial infarction and the other 122 without. In terms of symptoms, 91.6% of these women presented with typical chest pain, and 59.7% had related symptoms.

“With more than 90% having retrosternal pain, the idea that myocardial infarction presents with atypical symptoms in women has been widely challenged, despite the fact that more than half present with related symptoms and it isn’t known in which order these symptoms occur, Dr. Manzo-Silberman said in an interview. But what we can say is that if at any point a young woman mentions chest pain, even when occurring as part of several other symptoms, MI must be deemed a possibility until it has been ruled out.”

The risk profile revealed that 75.5% were smokers, 35% had a family history of heart disease, 33% had pregnancy complications, and 55% had recently experienced a stressful situation. The analysis also showed that cannabis use and oral contraception were primary risk factors in women younger than 35.

“With regard to risk factors, when designing this study we expected that lots of these young women would have largely atypical autoimmune conditions, with high levels of inflammation. We looked for everything, but this was not actually the case. Instead, we found very many women to have classic risk factors; three-quarters were smokers, a modifiable risk factor, which can largely be prevented. The other aspect concerns contraception, and it’s why I insist that gynecologists must be involved insofar as they must inform their patients how to manage their risk factors and tweak their contraception.”

Coronary angiography findings showed that only 1% received a normal result, 29.3% had vessel damage, and 14.6% had aortic dissection. “We were surprised again here because we expected that with young women we would see lots of heart attacks without obstruction, [in other words] normal coronary arteries, atypical forms of MI,” commented Dr. Manzo-Silberman. “In fact, most presented with atheroma, often obstructive lesions, or even triple-vessel disease, in nearly a third of the cohort. So that’s another misconception dispelled – we can’t just think that because a woman is young, nothing will be found. Coronary catheterization should be considered, and the diagnostic process should be completed in full.”

After 1 year, there had been two cancer-related deaths and 25 patients had undergone several angioplasty procedures. Nevertheless, 90.4% had not experienced any type of CV event, and 72% had not even had any symptoms.

“The final surprise was prognosis,” he said. “Previous studies, especially some authored by Viola Vaccarino, MD, PhD, showed an excess hospital rate in women and we had expected this to be the case here, but no hospital deaths were recorded. However, not far off 10% of women attended (at least once) the emergency department in the year following for recurrent chest pain which was not ischemic – ECG normal, troponin normal – so something was missing in their education as a patient.”

“So, there are improvements to be made in terms of secondary prevention, follow-up, and in the education of these young female patients who have experienced the major event that is a myocardial infarction,” concluded Dr. Manzo-Silberman.

This content was originally published on Medscape French edition.

Young women (under 50) are increasingly having heart attacks without doctors really knowing why. This is where the Young Women Presenting Acute Myocardial Infarction in France (WAMIF) study comes in, the results of which were presented in an e-poster at the annual congress of the European Society of Cardiology by Stéphane Manzo-Silberman, MD, Institute of Cardiology, Pitié-Salpétrière, Paris. The results (yet to be published) fight several of the preconceived ideas on the topic, Dr. Manzo-Silberman commented in an interview.

Significantly higher hospital death rates in women

“Cardiovascular disease is the main cause of death in women, killing seven times more than breast cancer,” notes Dr. Manzo-Silberman. The hospital death rate is significantly higher in women and, despite going down, is significantly higher than in men (more than double), particularly in women under 50. What’s more, in addition to the typical risk factors, women present specific risk factors related to hormone changes, high-risk inflammatory profiles, and thrombophilia.”

The WAMIF study was designed to determine the clinical, biological, and morphological features linked to hospital mortality after 12 months in women under 50. The prospective, observational study included all women in this age range from 30 sites in France between May 2017 and June 2019.
 

90% with retrosternal chest pain

The age of the 314 women enrolled was 44.9 years on average. Nearly two-thirds (192) presented with ST-segment elevation myocardial infarction and the other 122 without. In terms of symptoms, 91.6% of these women presented with typical chest pain, and 59.7% had related symptoms.

“With more than 90% having retrosternal pain, the idea that myocardial infarction presents with atypical symptoms in women has been widely challenged, despite the fact that more than half present with related symptoms and it isn’t known in which order these symptoms occur, Dr. Manzo-Silberman said in an interview. But what we can say is that if at any point a young woman mentions chest pain, even when occurring as part of several other symptoms, MI must be deemed a possibility until it has been ruled out.”

The risk profile revealed that 75.5% were smokers, 35% had a family history of heart disease, 33% had pregnancy complications, and 55% had recently experienced a stressful situation. The analysis also showed that cannabis use and oral contraception were primary risk factors in women younger than 35.

“With regard to risk factors, when designing this study we expected that lots of these young women would have largely atypical autoimmune conditions, with high levels of inflammation. We looked for everything, but this was not actually the case. Instead, we found very many women to have classic risk factors; three-quarters were smokers, a modifiable risk factor, which can largely be prevented. The other aspect concerns contraception, and it’s why I insist that gynecologists must be involved insofar as they must inform their patients how to manage their risk factors and tweak their contraception.”

Coronary angiography findings showed that only 1% received a normal result, 29.3% had vessel damage, and 14.6% had aortic dissection. “We were surprised again here because we expected that with young women we would see lots of heart attacks without obstruction, [in other words] normal coronary arteries, atypical forms of MI,” commented Dr. Manzo-Silberman. “In fact, most presented with atheroma, often obstructive lesions, or even triple-vessel disease, in nearly a third of the cohort. So that’s another misconception dispelled – we can’t just think that because a woman is young, nothing will be found. Coronary catheterization should be considered, and the diagnostic process should be completed in full.”

After 1 year, there had been two cancer-related deaths and 25 patients had undergone several angioplasty procedures. Nevertheless, 90.4% had not experienced any type of CV event, and 72% had not even had any symptoms.

“The final surprise was prognosis,” he said. “Previous studies, especially some authored by Viola Vaccarino, MD, PhD, showed an excess hospital rate in women and we had expected this to be the case here, but no hospital deaths were recorded. However, not far off 10% of women attended (at least once) the emergency department in the year following for recurrent chest pain which was not ischemic – ECG normal, troponin normal – so something was missing in their education as a patient.”

“So, there are improvements to be made in terms of secondary prevention, follow-up, and in the education of these young female patients who have experienced the major event that is a myocardial infarction,” concluded Dr. Manzo-Silberman.

This content was originally published on Medscape French edition.

Young women (under 50) are increasingly having heart attacks without doctors really knowing why. This is where the Young Women Presenting Acute Myocardial Infarction in France (WAMIF) study comes in, the results of which were presented in an e-poster at the annual congress of the European Society of Cardiology by Stéphane Manzo-Silberman, MD, Institute of Cardiology, Pitié-Salpétrière, Paris. The results (yet to be published) fight several of the preconceived ideas on the topic, Dr. Manzo-Silberman commented in an interview.

Significantly higher hospital death rates in women

“Cardiovascular disease is the main cause of death in women, killing seven times more than breast cancer,” notes Dr. Manzo-Silberman. The hospital death rate is significantly higher in women and, despite going down, is significantly higher than in men (more than double), particularly in women under 50. What’s more, in addition to the typical risk factors, women present specific risk factors related to hormone changes, high-risk inflammatory profiles, and thrombophilia.”

The WAMIF study was designed to determine the clinical, biological, and morphological features linked to hospital mortality after 12 months in women under 50. The prospective, observational study included all women in this age range from 30 sites in France between May 2017 and June 2019.
 

90% with retrosternal chest pain

The age of the 314 women enrolled was 44.9 years on average. Nearly two-thirds (192) presented with ST-segment elevation myocardial infarction and the other 122 without. In terms of symptoms, 91.6% of these women presented with typical chest pain, and 59.7% had related symptoms.

“With more than 90% having retrosternal pain, the idea that myocardial infarction presents with atypical symptoms in women has been widely challenged, despite the fact that more than half present with related symptoms and it isn’t known in which order these symptoms occur, Dr. Manzo-Silberman said in an interview. But what we can say is that if at any point a young woman mentions chest pain, even when occurring as part of several other symptoms, MI must be deemed a possibility until it has been ruled out.”

The risk profile revealed that 75.5% were smokers, 35% had a family history of heart disease, 33% had pregnancy complications, and 55% had recently experienced a stressful situation. The analysis also showed that cannabis use and oral contraception were primary risk factors in women younger than 35.

“With regard to risk factors, when designing this study we expected that lots of these young women would have largely atypical autoimmune conditions, with high levels of inflammation. We looked for everything, but this was not actually the case. Instead, we found very many women to have classic risk factors; three-quarters were smokers, a modifiable risk factor, which can largely be prevented. The other aspect concerns contraception, and it’s why I insist that gynecologists must be involved insofar as they must inform their patients how to manage their risk factors and tweak their contraception.”

Coronary angiography findings showed that only 1% received a normal result, 29.3% had vessel damage, and 14.6% had aortic dissection. “We were surprised again here because we expected that with young women we would see lots of heart attacks without obstruction, [in other words] normal coronary arteries, atypical forms of MI,” commented Dr. Manzo-Silberman. “In fact, most presented with atheroma, often obstructive lesions, or even triple-vessel disease, in nearly a third of the cohort. So that’s another misconception dispelled – we can’t just think that because a woman is young, nothing will be found. Coronary catheterization should be considered, and the diagnostic process should be completed in full.”

After 1 year, there had been two cancer-related deaths and 25 patients had undergone several angioplasty procedures. Nevertheless, 90.4% had not experienced any type of CV event, and 72% had not even had any symptoms.

“The final surprise was prognosis,” he said. “Previous studies, especially some authored by Viola Vaccarino, MD, PhD, showed an excess hospital rate in women and we had expected this to be the case here, but no hospital deaths were recorded. However, not far off 10% of women attended (at least once) the emergency department in the year following for recurrent chest pain which was not ischemic – ECG normal, troponin normal – so something was missing in their education as a patient.”

“So, there are improvements to be made in terms of secondary prevention, follow-up, and in the education of these young female patients who have experienced the major event that is a myocardial infarction,” concluded Dr. Manzo-Silberman.

This content was originally published on Medscape French edition.

BARCELONA – Hospitalized patients in the ICU because of an acute COVID-19 infection had significantly fewer thrombotic events and complications when treated with full-dose anticoagulation, compared with patients who received standard-dose anticoagulation prophylaxis, but full-dose anticoagulation also triggered an excess of moderate and severe bleeding events, randomized trial results show.

The new findings from the COVID-PACT trial in an exclusively U.S.-based cohort of 382 on-treatment patients in the ICU with COVID-19 infection may lead to a change in existing guidelines, which currently recommend standard-dose prophylaxis based on results from prior head-to-head comparisons, such as guidelines posted March 2022 from the American Society of Hematology.

The new findings suggest “full-dose anticoagulation should be considered to prevent thrombotic complications in selected critically ill patients with COVID-19” after weighing an individual patient’s risk for both thrombotic events and bleeding, David D. Berg, MD, said at the annual congress of the European Society of Cardiology. Simultaneous with his report at the congress, the results also appeared online in the journal Circulation.

“What the results tell us is that full-dose anticoagulation in critically ill patients with COVID-19 is highly effective for reducing thrombotic complications,” said Dr. Berg, a cardiologist and critical care physician at Brigham and Women’s Hospital, Boston.

The report’s designated discussant agreed with Dr. Berg’s conclusions.
 

‘Need to replace the guidelines’

“We probably need to replace the guidelines,” said Eduardo Ramacciotti, MD, PhD, MPH, a professor of vascular surgery at Santa Casa School of Medicine, São Paulo. Dr. Ramacciotti praised the study’s design, the endpoints, and the fact that the design excluded patients at high risk for bleeding complications, particularly those with a fibrinogen level below 200 mg/dL (2 g/L).

But other experts questioned the significance of the COVID-PACT results given that the outcomes did not show that full-dose anticoagulation produced incremental improvement in patient survival.

“We should abandon the thought that intensified anticoagulation should be routine, because it did not overall increase the number of patients discharged from the hospital alive,” commented John W. Eikelboom, MBBS, a professor of hematology and thromboembolism at McMaster University, Hamilton, Ont.

“Preventing venous thrombosis is a good thing, but the money is in saving lives and stopping need for ventilation, and we haven’t been successful doing that with an antithrombotic strategy,” said Dr. Eikelboom. “It is useful to prevent venous thrombosis, but we need to look elsewhere to improve the outcomes of [critically ill] patients with COVID-19.”
 

Reducing thromboembolism is a ‘valid goal’

Dr. Berg took a different view. “It’s a valid goal to try to reduce venous thromboembolism complications,” the major benefit seen in his study, he said. “There is clinical significance to reducing thrombotic events in terms of how people feel, their functional status, and their complications. There are a lot of clinically relevant consequences of thrombosis beyond mortality.”

COVID-PACT ran at 34 U.S. centers from August 2020 to March 2022 but stopped short of its enrollment goal of 750 patients because of waning numbers of patients with COVID-19 admitted to ICUs. In addition to randomly assigning patients within 96 hours of their ICU admission to full-dose anticoagulation or to standard-dose antithrombotic prophylaxis, the study included a second, concurrent randomization to the antiplatelet agent clopidogrel (Plavix) or to no antiplatelet drug. Both randomizations used an open-label design.

The results failed to show a discernable effect from adding clopidogrel on both the primary efficacy and primary safety endpoints, adding to accumulated evidence that treatment with an antiplatelet agent, including aspirin, confers no antithrombotic benefit in patients with COVID-19.

The trial’s participants averaged 61 years old, 68% were obese, 59% had hypertension, and 32% had diabetes. The median time after ICU admission when randomized treatment began was 2.1 days, and researchers followed patients for a median of 13 days, including a median time on anticoagulation of 10.6 days.

The trial design allowed clinicians to use either low molecular weight heparin or unfractionated heparin for anticoagulation, and 82% of patients received low molecular weight heparin as their initial treatment. The prespecified design called for an on-treatment analysis because of an anticipated high crossover rate. During the trial, 34% of patients who started on the prophylactic dose switched to full dose, and 17% had the reverse crossover.
 

95% increased win ratio with full dose

The study’s primary efficacy endpoint used a win-ratio analysis that included seven different adverse outcomes that ranged from death from venous or arterial thrombosis to clinically silent deep vein thrombosis. Treatment with full-dose anticoagulation led to a significant 95% increase in win ratio.

Researchers also applied a more conventional time-to-first-event secondary efficacy analysis, which showed that full-dose anticoagulation cut the incidence of an adverse outcome by a significant 44% relative to prophylactic dosing.

The two study groups showed no difference in all-cause death rates. The efficacy advantage of the full-dose regimen was driven by reduced rates of venous thrombotic events, especially a reduction in clinically evident deep vein thrombotic events.

The primary safety endpoint was the rate of fatal or life-threatening bleeding episodes, and while life-threatening bleeds were numerically more common among the full-dose recipients (four events, compared with one event on prophylaxis dosing) the difference was not significant, and no patients died from a bleeding event.
 

More secondary safety bleeds

The safety difference showed up in a secondary measure of bleeding severity, the rate of GUSTO moderate or severe bleeds. These occurred in 15 of the full-dose recipients, compared with 1 patient on the prophylactic dose.

Dr. Berg highlighted that several prior studies have assessed various anticoagulation regimens in critically ill (ICU-admitted and on respiratory or cardiovascular support) patients with COVID-19. For example, two influential reports published in 2021 by the same team of investigators in the New England Journal of Medicine had sharply divergent results.

One multicenter study, which tested full-dose heparin against prophylactic treatment in more than 1,000 critically ill patients, was stopped prematurely because it had not shown a significant difference between the treatment arms. The second study, in more than 2,000 multicenter patients with COVID-19 who did not require critical-level organ support, showed clear superiority of the full-dose heparin regimen.

Notably, both previous studies used a different primary efficacy endpoint than the COVID-PACT study. The earlier reports both measured efficacy in terms of patients being alive and off organ support by 21 days from randomization.
 

Patients to exclude

Although Dr. Berg stressed the clear positive result, he also cautioned that they should not apply to patients excluded from the study: those with severe coagulopathies, those with severe thrombocytopenia, and patients already maintained on dual antiplatelet therapy. He also cautioned against using the full-dose strategy in elderly patients, because in COVID-PACT, those who developed bleeding complications tended to be older.

Dr. Berg also noted that heparin prophylaxis is a well-established intervention for ICU-admitted patients without COVID-19 for the purpose of preventing venous thromboembolisms without evidence that this approach reduces deaths or organ failure.

But he conceded that “the priority of treatment depends on whether it saves lives, so anticoagulation is probably not as high a priority as other effective treatments” that reduce mortality. “Preventing venous thromboembolism has rarely been shown to have a mortality benefit,” Dr. Berg noted.

COVID-PACT received no direct commercial funding. Dr. Berg has been a consultant to AstraZeneca, Mobility Bio, and Youngene Therapeutics, and he participated in a trial sponsored by Kowa. Dr. Ramacciotti has been a consultant to or speaker on behalf of Aspen, Bayer, Daiichi Sankyo, Mylan, Pfizer, and Sanofi, and he has received research support from Bayer, Esperon, Novartis, and Pfizer. Dr. Eikelboom has received honoraria and research support from Bayer.

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

BARCELONA – Hospitalized patients in the ICU because of an acute COVID-19 infection had significantly fewer thrombotic events and complications when treated with full-dose anticoagulation, compared with patients who received standard-dose anticoagulation prophylaxis, but full-dose anticoagulation also triggered an excess of moderate and severe bleeding events, randomized trial results show.

The new findings from the COVID-PACT trial in an exclusively U.S.-based cohort of 382 on-treatment patients in the ICU with COVID-19 infection may lead to a change in existing guidelines, which currently recommend standard-dose prophylaxis based on results from prior head-to-head comparisons, such as guidelines posted March 2022 from the American Society of Hematology.

The new findings suggest “full-dose anticoagulation should be considered to prevent thrombotic complications in selected critically ill patients with COVID-19” after weighing an individual patient’s risk for both thrombotic events and bleeding, David D. Berg, MD, said at the annual congress of the European Society of Cardiology. Simultaneous with his report at the congress, the results also appeared online in the journal Circulation.

“What the results tell us is that full-dose anticoagulation in critically ill patients with COVID-19 is highly effective for reducing thrombotic complications,” said Dr. Berg, a cardiologist and critical care physician at Brigham and Women’s Hospital, Boston.

The report’s designated discussant agreed with Dr. Berg’s conclusions.
 

‘Need to replace the guidelines’

“We probably need to replace the guidelines,” said Eduardo Ramacciotti, MD, PhD, MPH, a professor of vascular surgery at Santa Casa School of Medicine, São Paulo. Dr. Ramacciotti praised the study’s design, the endpoints, and the fact that the design excluded patients at high risk for bleeding complications, particularly those with a fibrinogen level below 200 mg/dL (2 g/L).

But other experts questioned the significance of the COVID-PACT results given that the outcomes did not show that full-dose anticoagulation produced incremental improvement in patient survival.

“We should abandon the thought that intensified anticoagulation should be routine, because it did not overall increase the number of patients discharged from the hospital alive,” commented John W. Eikelboom, MBBS, a professor of hematology and thromboembolism at McMaster University, Hamilton, Ont.

“Preventing venous thrombosis is a good thing, but the money is in saving lives and stopping need for ventilation, and we haven’t been successful doing that with an antithrombotic strategy,” said Dr. Eikelboom. “It is useful to prevent venous thrombosis, but we need to look elsewhere to improve the outcomes of [critically ill] patients with COVID-19.”
 

Reducing thromboembolism is a ‘valid goal’

Dr. Berg took a different view. “It’s a valid goal to try to reduce venous thromboembolism complications,” the major benefit seen in his study, he said. “There is clinical significance to reducing thrombotic events in terms of how people feel, their functional status, and their complications. There are a lot of clinically relevant consequences of thrombosis beyond mortality.”

COVID-PACT ran at 34 U.S. centers from August 2020 to March 2022 but stopped short of its enrollment goal of 750 patients because of waning numbers of patients with COVID-19 admitted to ICUs. In addition to randomly assigning patients within 96 hours of their ICU admission to full-dose anticoagulation or to standard-dose antithrombotic prophylaxis, the study included a second, concurrent randomization to the antiplatelet agent clopidogrel (Plavix) or to no antiplatelet drug. Both randomizations used an open-label design.

The results failed to show a discernable effect from adding clopidogrel on both the primary efficacy and primary safety endpoints, adding to accumulated evidence that treatment with an antiplatelet agent, including aspirin, confers no antithrombotic benefit in patients with COVID-19.

The trial’s participants averaged 61 years old, 68% were obese, 59% had hypertension, and 32% had diabetes. The median time after ICU admission when randomized treatment began was 2.1 days, and researchers followed patients for a median of 13 days, including a median time on anticoagulation of 10.6 days.

The trial design allowed clinicians to use either low molecular weight heparin or unfractionated heparin for anticoagulation, and 82% of patients received low molecular weight heparin as their initial treatment. The prespecified design called for an on-treatment analysis because of an anticipated high crossover rate. During the trial, 34% of patients who started on the prophylactic dose switched to full dose, and 17% had the reverse crossover.
 

95% increased win ratio with full dose

The study’s primary efficacy endpoint used a win-ratio analysis that included seven different adverse outcomes that ranged from death from venous or arterial thrombosis to clinically silent deep vein thrombosis. Treatment with full-dose anticoagulation led to a significant 95% increase in win ratio.

Researchers also applied a more conventional time-to-first-event secondary efficacy analysis, which showed that full-dose anticoagulation cut the incidence of an adverse outcome by a significant 44% relative to prophylactic dosing.

The two study groups showed no difference in all-cause death rates. The efficacy advantage of the full-dose regimen was driven by reduced rates of venous thrombotic events, especially a reduction in clinically evident deep vein thrombotic events.

The primary safety endpoint was the rate of fatal or life-threatening bleeding episodes, and while life-threatening bleeds were numerically more common among the full-dose recipients (four events, compared with one event on prophylaxis dosing) the difference was not significant, and no patients died from a bleeding event.
 

More secondary safety bleeds

The safety difference showed up in a secondary measure of bleeding severity, the rate of GUSTO moderate or severe bleeds. These occurred in 15 of the full-dose recipients, compared with 1 patient on the prophylactic dose.

Dr. Berg highlighted that several prior studies have assessed various anticoagulation regimens in critically ill (ICU-admitted and on respiratory or cardiovascular support) patients with COVID-19. For example, two influential reports published in 2021 by the same team of investigators in the New England Journal of Medicine had sharply divergent results.

One multicenter study, which tested full-dose heparin against prophylactic treatment in more than 1,000 critically ill patients, was stopped prematurely because it had not shown a significant difference between the treatment arms. The second study, in more than 2,000 multicenter patients with COVID-19 who did not require critical-level organ support, showed clear superiority of the full-dose heparin regimen.

Notably, both previous studies used a different primary efficacy endpoint than the COVID-PACT study. The earlier reports both measured efficacy in terms of patients being alive and off organ support by 21 days from randomization.
 

Patients to exclude

Although Dr. Berg stressed the clear positive result, he also cautioned that they should not apply to patients excluded from the study: those with severe coagulopathies, those with severe thrombocytopenia, and patients already maintained on dual antiplatelet therapy. He also cautioned against using the full-dose strategy in elderly patients, because in COVID-PACT, those who developed bleeding complications tended to be older.

Dr. Berg also noted that heparin prophylaxis is a well-established intervention for ICU-admitted patients without COVID-19 for the purpose of preventing venous thromboembolisms without evidence that this approach reduces deaths or organ failure.

But he conceded that “the priority of treatment depends on whether it saves lives, so anticoagulation is probably not as high a priority as other effective treatments” that reduce mortality. “Preventing venous thromboembolism has rarely been shown to have a mortality benefit,” Dr. Berg noted.

COVID-PACT received no direct commercial funding. Dr. Berg has been a consultant to AstraZeneca, Mobility Bio, and Youngene Therapeutics, and he participated in a trial sponsored by Kowa. Dr. Ramacciotti has been a consultant to or speaker on behalf of Aspen, Bayer, Daiichi Sankyo, Mylan, Pfizer, and Sanofi, and he has received research support from Bayer, Esperon, Novartis, and Pfizer. Dr. Eikelboom has received honoraria and research support from Bayer.

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

BARCELONA – Hospitalized patients in the ICU because of an acute COVID-19 infection had significantly fewer thrombotic events and complications when treated with full-dose anticoagulation, compared with patients who received standard-dose anticoagulation prophylaxis, but full-dose anticoagulation also triggered an excess of moderate and severe bleeding events, randomized trial results show.

The new findings from the COVID-PACT trial in an exclusively U.S.-based cohort of 382 on-treatment patients in the ICU with COVID-19 infection may lead to a change in existing guidelines, which currently recommend standard-dose prophylaxis based on results from prior head-to-head comparisons, such as guidelines posted March 2022 from the American Society of Hematology.

The new findings suggest “full-dose anticoagulation should be considered to prevent thrombotic complications in selected critically ill patients with COVID-19” after weighing an individual patient’s risk for both thrombotic events and bleeding, David D. Berg, MD, said at the annual congress of the European Society of Cardiology. Simultaneous with his report at the congress, the results also appeared online in the journal Circulation.

“What the results tell us is that full-dose anticoagulation in critically ill patients with COVID-19 is highly effective for reducing thrombotic complications,” said Dr. Berg, a cardiologist and critical care physician at Brigham and Women’s Hospital, Boston.

The report’s designated discussant agreed with Dr. Berg’s conclusions.
 

‘Need to replace the guidelines’

“We probably need to replace the guidelines,” said Eduardo Ramacciotti, MD, PhD, MPH, a professor of vascular surgery at Santa Casa School of Medicine, São Paulo. Dr. Ramacciotti praised the study’s design, the endpoints, and the fact that the design excluded patients at high risk for bleeding complications, particularly those with a fibrinogen level below 200 mg/dL (2 g/L).

But other experts questioned the significance of the COVID-PACT results given that the outcomes did not show that full-dose anticoagulation produced incremental improvement in patient survival.

“We should abandon the thought that intensified anticoagulation should be routine, because it did not overall increase the number of patients discharged from the hospital alive,” commented John W. Eikelboom, MBBS, a professor of hematology and thromboembolism at McMaster University, Hamilton, Ont.

“Preventing venous thrombosis is a good thing, but the money is in saving lives and stopping need for ventilation, and we haven’t been successful doing that with an antithrombotic strategy,” said Dr. Eikelboom. “It is useful to prevent venous thrombosis, but we need to look elsewhere to improve the outcomes of [critically ill] patients with COVID-19.”
 

Reducing thromboembolism is a ‘valid goal’

Dr. Berg took a different view. “It’s a valid goal to try to reduce venous thromboembolism complications,” the major benefit seen in his study, he said. “There is clinical significance to reducing thrombotic events in terms of how people feel, their functional status, and their complications. There are a lot of clinically relevant consequences of thrombosis beyond mortality.”

COVID-PACT ran at 34 U.S. centers from August 2020 to March 2022 but stopped short of its enrollment goal of 750 patients because of waning numbers of patients with COVID-19 admitted to ICUs. In addition to randomly assigning patients within 96 hours of their ICU admission to full-dose anticoagulation or to standard-dose antithrombotic prophylaxis, the study included a second, concurrent randomization to the antiplatelet agent clopidogrel (Plavix) or to no antiplatelet drug. Both randomizations used an open-label design.

The results failed to show a discernable effect from adding clopidogrel on both the primary efficacy and primary safety endpoints, adding to accumulated evidence that treatment with an antiplatelet agent, including aspirin, confers no antithrombotic benefit in patients with COVID-19.

The trial’s participants averaged 61 years old, 68% were obese, 59% had hypertension, and 32% had diabetes. The median time after ICU admission when randomized treatment began was 2.1 days, and researchers followed patients for a median of 13 days, including a median time on anticoagulation of 10.6 days.

The trial design allowed clinicians to use either low molecular weight heparin or unfractionated heparin for anticoagulation, and 82% of patients received low molecular weight heparin as their initial treatment. The prespecified design called for an on-treatment analysis because of an anticipated high crossover rate. During the trial, 34% of patients who started on the prophylactic dose switched to full dose, and 17% had the reverse crossover.
 

95% increased win ratio with full dose

The study’s primary efficacy endpoint used a win-ratio analysis that included seven different adverse outcomes that ranged from death from venous or arterial thrombosis to clinically silent deep vein thrombosis. Treatment with full-dose anticoagulation led to a significant 95% increase in win ratio.

Researchers also applied a more conventional time-to-first-event secondary efficacy analysis, which showed that full-dose anticoagulation cut the incidence of an adverse outcome by a significant 44% relative to prophylactic dosing.

The two study groups showed no difference in all-cause death rates. The efficacy advantage of the full-dose regimen was driven by reduced rates of venous thrombotic events, especially a reduction in clinically evident deep vein thrombotic events.

The primary safety endpoint was the rate of fatal or life-threatening bleeding episodes, and while life-threatening bleeds were numerically more common among the full-dose recipients (four events, compared with one event on prophylaxis dosing) the difference was not significant, and no patients died from a bleeding event.
 

More secondary safety bleeds

The safety difference showed up in a secondary measure of bleeding severity, the rate of GUSTO moderate or severe bleeds. These occurred in 15 of the full-dose recipients, compared with 1 patient on the prophylactic dose.

Dr. Berg highlighted that several prior studies have assessed various anticoagulation regimens in critically ill (ICU-admitted and on respiratory or cardiovascular support) patients with COVID-19. For example, two influential reports published in 2021 by the same team of investigators in the New England Journal of Medicine had sharply divergent results.

One multicenter study, which tested full-dose heparin against prophylactic treatment in more than 1,000 critically ill patients, was stopped prematurely because it had not shown a significant difference between the treatment arms. The second study, in more than 2,000 multicenter patients with COVID-19 who did not require critical-level organ support, showed clear superiority of the full-dose heparin regimen.

Notably, both previous studies used a different primary efficacy endpoint than the COVID-PACT study. The earlier reports both measured efficacy in terms of patients being alive and off organ support by 21 days from randomization.
 

Patients to exclude

Although Dr. Berg stressed the clear positive result, he also cautioned that they should not apply to patients excluded from the study: those with severe coagulopathies, those with severe thrombocytopenia, and patients already maintained on dual antiplatelet therapy. He also cautioned against using the full-dose strategy in elderly patients, because in COVID-PACT, those who developed bleeding complications tended to be older.

Dr. Berg also noted that heparin prophylaxis is a well-established intervention for ICU-admitted patients without COVID-19 for the purpose of preventing venous thromboembolisms without evidence that this approach reduces deaths or organ failure.

But he conceded that “the priority of treatment depends on whether it saves lives, so anticoagulation is probably not as high a priority as other effective treatments” that reduce mortality. “Preventing venous thromboembolism has rarely been shown to have a mortality benefit,” Dr. Berg noted.

COVID-PACT received no direct commercial funding. Dr. Berg has been a consultant to AstraZeneca, Mobility Bio, and Youngene Therapeutics, and he participated in a trial sponsored by Kowa. Dr. Ramacciotti has been a consultant to or speaker on behalf of Aspen, Bayer, Daiichi Sankyo, Mylan, Pfizer, and Sanofi, and he has received research support from Bayer, Esperon, Novartis, and Pfizer. Dr. Eikelboom has received honoraria and research support from Bayer.

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

A trip to the cath lab for possible revascularization after a positive stress test, compared with a wait-and-see approach backed by optimal medications, did not improve 5-year survival for patients with advanced chronic kidney disease (CKD) in the ISCHEMIA-CKD trial’s extension study, ISCHEMIA-CKD EXTEND.

The long-term results, from the same 777 patients followed for an average of 2.2 years in the main trial, are consistent with the overall findings of no survival advantage with an initially invasive strategy, compared with one that is initially conservative. The finding applies to patients like those in the trial who had moderate to severe ischemia at stress testing and whose CKD put them in an especially high-risk and little-studied coronary artery disease (CAD) category.

Indeed, in a reflection of that high-risk status, 5-year all-cause mortality reached about 40% and cardiovascular (CV) mortality approached 30%, with no significant differences between patients in the invasive- and conservative-strategy groups.

MDedge News/Mitchel L. Zoler

Those numbers arguably put CKD’s effect on CAD survival in about the same league as an ejection fraction (EF) of 35% or less. For context, all-cause mortality over 3-4 years was about 32% in the REVIVED-BCIS2 trial of such patients with ischemic reduced-EF cardiomyopathy, whether or not they were revascularized, observed Sripal Bangalore, MD, MHA.

Yet in ISCHEMIA-CKD EXTEND, “you’re seeing in a group of patients, with largely preserved EF but advanced CKD, a mortality rate close to 40% at 5 years,” said Dr. Bangalore of New York University.

Although the study doesn’t show benefit from the initially invasive approach in CKD patients with stable CAD, for those with acute coronary syndromes (ACS), it seems to suggest that “at least the invasive strategy is safe,” Dr. Bangalore said during a press conference preceding his presentation of the study Aug. 29 at the annual congress of the European Society of Cardiology, held in Barcelona.

REVIVED-BCIS2 was also presented at the ESC sessions on Aug. 27, as reported by this news organization.

ISCHEMIA-CKD EXTEND “is a large trial and a very well-done trial. The results are robust, and they should influence clinical practice,” Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart & Vascular Center, Boston, said as the invited discussant after Dr. Bangalore’s presentation.

“The main message here, really, is don’t just go looking for ischemia, at least with the modalities used in this trial, in your CKD patients as a routine practice, and then try to stomp out that ischemia with revascularization,” Dr. Bhatt said. “The right thing to do in these high-risk patients is to focus on lifestyle modification and intensive medical therapy.”

A caveat, he said, is that the trial’s results don’t apply to the types of patients excluded from it, including those with recent ACS and those who are highly symptomatic or have an EF of less than 35%.

“Those CKD patients likely benefit from an invasive strategy with anatomically appropriate revascularization,” whether percutaneous coronary intervention (PCI) or coronary bypass surgery, Dr. Bhatt said.

At a median follow-up of 5 years in the extension study, the rates of death from any cause were 40.6% for patients in the invasive-strategy group and 37.4% for those in the conservative-strategy group. That yielded a hazard ratio of 1.12 (95% confidence interval, 0.89-1.41; P = .32) after adjustment for age, sex, diabetes status, EF, dialysis status, and – for patients not on dialysis – baseline estimated glomerular filtration rate.

The rates of CV death were 29% for patients managed invasively and 27% for those initially managed conservatively, for a similarly adjusted HR of 1.04 (95% CI, 0.80-1.37; P = .75).

In subgroup analyses, Dr. Bangalore reported, there were no significant differences in all-cause or CV mortality by diabetes status, by severity of baseline ischemia, or by whether the patient had recently experienced new or more frequent angina at study entry, was on guideline-directed medical therapy at baseline, or was on dialysis.

Among the contributions of ISCHEMIA-CKD and its 5-year extension study, Dr. Bangalore told this news organization, is that the relative safety of revascularization they showed may help to counter “renalism,” that is, the aversion to invasive intervention in patients with advanced CKD in clinical practice.

For example, if a patient with advanced CKD presents with an acute myocardial infarction, “people are hesitant to take them to the cath lab,” Dr. Bangalore said. But “if you follow protocols, if you follow strategies to minimize the risk, you can safely go ahead and do it.”

But in patients with stable CAD, as the ISCHEMIA-CKD studies show, “routinely revascularizing them may not have significant benefits.”

ISCHEMIC-CKD and its extension study were funded by the National Heart, Lung, and Blood Institute. Dr. Bangalore discloses receiving research grants from NHLBI and serving as a consultant for Abbott Vascular, Biotronik, Boston Scientific, Amgen, Pfizer, Merck, and Reata. Dr. Bhatt has disclosed grants and/or personal fees from many companies; personal fees from WebMD and other publications or organizations; and having other relationships with Medscape Cardiology and other publications or organizations.

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

A trip to the cath lab for possible revascularization after a positive stress test, compared with a wait-and-see approach backed by optimal medications, did not improve 5-year survival for patients with advanced chronic kidney disease (CKD) in the ISCHEMIA-CKD trial’s extension study, ISCHEMIA-CKD EXTEND.

The long-term results, from the same 777 patients followed for an average of 2.2 years in the main trial, are consistent with the overall findings of no survival advantage with an initially invasive strategy, compared with one that is initially conservative. The finding applies to patients like those in the trial who had moderate to severe ischemia at stress testing and whose CKD put them in an especially high-risk and little-studied coronary artery disease (CAD) category.

Indeed, in a reflection of that high-risk status, 5-year all-cause mortality reached about 40% and cardiovascular (CV) mortality approached 30%, with no significant differences between patients in the invasive- and conservative-strategy groups.

MDedge News/Mitchel L. Zoler

Those numbers arguably put CKD’s effect on CAD survival in about the same league as an ejection fraction (EF) of 35% or less. For context, all-cause mortality over 3-4 years was about 32% in the REVIVED-BCIS2 trial of such patients with ischemic reduced-EF cardiomyopathy, whether or not they were revascularized, observed Sripal Bangalore, MD, MHA.

Yet in ISCHEMIA-CKD EXTEND, “you’re seeing in a group of patients, with largely preserved EF but advanced CKD, a mortality rate close to 40% at 5 years,” said Dr. Bangalore of New York University.

Although the study doesn’t show benefit from the initially invasive approach in CKD patients with stable CAD, for those with acute coronary syndromes (ACS), it seems to suggest that “at least the invasive strategy is safe,” Dr. Bangalore said during a press conference preceding his presentation of the study Aug. 29 at the annual congress of the European Society of Cardiology, held in Barcelona.

REVIVED-BCIS2 was also presented at the ESC sessions on Aug. 27, as reported by this news organization.

ISCHEMIA-CKD EXTEND “is a large trial and a very well-done trial. The results are robust, and they should influence clinical practice,” Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart & Vascular Center, Boston, said as the invited discussant after Dr. Bangalore’s presentation.

“The main message here, really, is don’t just go looking for ischemia, at least with the modalities used in this trial, in your CKD patients as a routine practice, and then try to stomp out that ischemia with revascularization,” Dr. Bhatt said. “The right thing to do in these high-risk patients is to focus on lifestyle modification and intensive medical therapy.”

A caveat, he said, is that the trial’s results don’t apply to the types of patients excluded from it, including those with recent ACS and those who are highly symptomatic or have an EF of less than 35%.

“Those CKD patients likely benefit from an invasive strategy with anatomically appropriate revascularization,” whether percutaneous coronary intervention (PCI) or coronary bypass surgery, Dr. Bhatt said.

At a median follow-up of 5 years in the extension study, the rates of death from any cause were 40.6% for patients in the invasive-strategy group and 37.4% for those in the conservative-strategy group. That yielded a hazard ratio of 1.12 (95% confidence interval, 0.89-1.41; P = .32) after adjustment for age, sex, diabetes status, EF, dialysis status, and – for patients not on dialysis – baseline estimated glomerular filtration rate.

The rates of CV death were 29% for patients managed invasively and 27% for those initially managed conservatively, for a similarly adjusted HR of 1.04 (95% CI, 0.80-1.37; P = .75).

In subgroup analyses, Dr. Bangalore reported, there were no significant differences in all-cause or CV mortality by diabetes status, by severity of baseline ischemia, or by whether the patient had recently experienced new or more frequent angina at study entry, was on guideline-directed medical therapy at baseline, or was on dialysis.

Among the contributions of ISCHEMIA-CKD and its 5-year extension study, Dr. Bangalore told this news organization, is that the relative safety of revascularization they showed may help to counter “renalism,” that is, the aversion to invasive intervention in patients with advanced CKD in clinical practice.

For example, if a patient with advanced CKD presents with an acute myocardial infarction, “people are hesitant to take them to the cath lab,” Dr. Bangalore said. But “if you follow protocols, if you follow strategies to minimize the risk, you can safely go ahead and do it.”

But in patients with stable CAD, as the ISCHEMIA-CKD studies show, “routinely revascularizing them may not have significant benefits.”

ISCHEMIC-CKD and its extension study were funded by the National Heart, Lung, and Blood Institute. Dr. Bangalore discloses receiving research grants from NHLBI and serving as a consultant for Abbott Vascular, Biotronik, Boston Scientific, Amgen, Pfizer, Merck, and Reata. Dr. Bhatt has disclosed grants and/or personal fees from many companies; personal fees from WebMD and other publications or organizations; and having other relationships with Medscape Cardiology and other publications or organizations.

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

A trip to the cath lab for possible revascularization after a positive stress test, compared with a wait-and-see approach backed by optimal medications, did not improve 5-year survival for patients with advanced chronic kidney disease (CKD) in the ISCHEMIA-CKD trial’s extension study, ISCHEMIA-CKD EXTEND.

The long-term results, from the same 777 patients followed for an average of 2.2 years in the main trial, are consistent with the overall findings of no survival advantage with an initially invasive strategy, compared with one that is initially conservative. The finding applies to patients like those in the trial who had moderate to severe ischemia at stress testing and whose CKD put them in an especially high-risk and little-studied coronary artery disease (CAD) category.

Indeed, in a reflection of that high-risk status, 5-year all-cause mortality reached about 40% and cardiovascular (CV) mortality approached 30%, with no significant differences between patients in the invasive- and conservative-strategy groups.

MDedge News/Mitchel L. Zoler

Those numbers arguably put CKD’s effect on CAD survival in about the same league as an ejection fraction (EF) of 35% or less. For context, all-cause mortality over 3-4 years was about 32% in the REVIVED-BCIS2 trial of such patients with ischemic reduced-EF cardiomyopathy, whether or not they were revascularized, observed Sripal Bangalore, MD, MHA.

Yet in ISCHEMIA-CKD EXTEND, “you’re seeing in a group of patients, with largely preserved EF but advanced CKD, a mortality rate close to 40% at 5 years,” said Dr. Bangalore of New York University.

Although the study doesn’t show benefit from the initially invasive approach in CKD patients with stable CAD, for those with acute coronary syndromes (ACS), it seems to suggest that “at least the invasive strategy is safe,” Dr. Bangalore said during a press conference preceding his presentation of the study Aug. 29 at the annual congress of the European Society of Cardiology, held in Barcelona.

REVIVED-BCIS2 was also presented at the ESC sessions on Aug. 27, as reported by this news organization.

ISCHEMIA-CKD EXTEND “is a large trial and a very well-done trial. The results are robust, and they should influence clinical practice,” Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart & Vascular Center, Boston, said as the invited discussant after Dr. Bangalore’s presentation.

“The main message here, really, is don’t just go looking for ischemia, at least with the modalities used in this trial, in your CKD patients as a routine practice, and then try to stomp out that ischemia with revascularization,” Dr. Bhatt said. “The right thing to do in these high-risk patients is to focus on lifestyle modification and intensive medical therapy.”

A caveat, he said, is that the trial’s results don’t apply to the types of patients excluded from it, including those with recent ACS and those who are highly symptomatic or have an EF of less than 35%.

“Those CKD patients likely benefit from an invasive strategy with anatomically appropriate revascularization,” whether percutaneous coronary intervention (PCI) or coronary bypass surgery, Dr. Bhatt said.

At a median follow-up of 5 years in the extension study, the rates of death from any cause were 40.6% for patients in the invasive-strategy group and 37.4% for those in the conservative-strategy group. That yielded a hazard ratio of 1.12 (95% confidence interval, 0.89-1.41; P = .32) after adjustment for age, sex, diabetes status, EF, dialysis status, and – for patients not on dialysis – baseline estimated glomerular filtration rate.

The rates of CV death were 29% for patients managed invasively and 27% for those initially managed conservatively, for a similarly adjusted HR of 1.04 (95% CI, 0.80-1.37; P = .75).

In subgroup analyses, Dr. Bangalore reported, there were no significant differences in all-cause or CV mortality by diabetes status, by severity of baseline ischemia, or by whether the patient had recently experienced new or more frequent angina at study entry, was on guideline-directed medical therapy at baseline, or was on dialysis.

Among the contributions of ISCHEMIA-CKD and its 5-year extension study, Dr. Bangalore told this news organization, is that the relative safety of revascularization they showed may help to counter “renalism,” that is, the aversion to invasive intervention in patients with advanced CKD in clinical practice.

For example, if a patient with advanced CKD presents with an acute myocardial infarction, “people are hesitant to take them to the cath lab,” Dr. Bangalore said. But “if you follow protocols, if you follow strategies to minimize the risk, you can safely go ahead and do it.”

But in patients with stable CAD, as the ISCHEMIA-CKD studies show, “routinely revascularizing them may not have significant benefits.”

ISCHEMIC-CKD and its extension study were funded by the National Heart, Lung, and Blood Institute. Dr. Bangalore discloses receiving research grants from NHLBI and serving as a consultant for Abbott Vascular, Biotronik, Boston Scientific, Amgen, Pfizer, Merck, and Reata. Dr. Bhatt has disclosed grants and/or personal fees from many companies; personal fees from WebMD and other publications or organizations; and having other relationships with Medscape Cardiology and other publications or organizations.

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

BARCELONA – Two noninvasive imaging methods for assessing coronary artery disease – cardiac magnetic resonance (CMR) and positron emission tomography using rubidium stress (RbPET) – had nearly identical accuracy for ruling-in or ruling-out coronary disease, making them for at least the time being equally appropriate to use when assessing low- or intermediate-risk patients with symptoms suggestive of possible coronary disease in a prospective, multicenter study with 372 patients.

RbPET and CMR using a 3 Tesla device showed “absolutely similar performance,” in a head-to-head comparison that used fractional flow reserve assessment via invasive coronary angiography in each patient in the study as the arbiter of the true extent of coronary disease, reported Morten Bøttcher, MD, PhD, at the annual congress of the European Society of Cardiology.

Mitchel L. Zoler/MDedge

This result is good news for practice because clinicians can feel free to use whichever of the two assessment methods is most feasible for each patient, said Dr. Bøttcher, a researcher at Aarhus (Denmark) University Hospital. But the study was limited by its size, and he hopes to run a future study with many more patients to try to more definitively compare RbPET and CMR.

‘The techniques are probably interchangeable’

“There is a very clear result from the data: The performance of the two modalities is similar in the population studied,” commented Colin Berry, MBChB, PhD, professor of cardiology and imaging at the University of Glasgow (Scotland), and designated discussant for the report. “The techniques are probably interchangeable,” he said.

Mitchel L. Zoler/MDedge

Dr. Bøttcher and his associates designed the Danish Study of Non-Invasive Diagnostic Testing in Coronary Artery Disease 2 (Dan-NICAD 2) to address a knowledge gap highlighted in the 2019 guidelines of the European Society of Cardiology for the management of patients with chronic coronary syndromes, specifically low- or intermediate-risk patients who present with symptoms of possible coronary disease who have been identified as having possibly stenotic coronary lesions using coronary CT angiography. The guidelines cite using noninvasive imaging at this point prior to invasive angiography, but note that the relative performance of the various imaging options available for this step in unknown, said Dr. Bøttcher.

The researchers enrolled 372 patients at any of four hospitals in Denmark who agreed to participate and had a positive result on a coronary CT examination performed to assess their symptoms of coronary disease. (These 372 patients came from an initial pool of people that was fourfold larger, but three-quarters had negative findings on their coronary CT examination.) Clinicians had referred all of these patients to invasive angiography with fractional flow reserve assessment, and prior to that procedure they each underwent both a RbPET and a CMR examination for the purpose of this study. The researchers used each patient’s eventual invasive angiography result as the definitive determinant of their coronary disease. These patients averaged 64 years old, and 71% were men.

This analysis showed that for all 372 patients RbPET had 63% sensitivity and 87% specificity for identifying hemodynamically obstructive coronary disease, with rates of 60% and 85%, respectively, for CMR. In the subgroup of 71 patients (19%) who had obstructive coronary disease when examined by invasive angiography the sensitivity and specificity of the RbPET examination was 90% and 78%, and for CMR the sensitivity and specificity was 83% and 76%, Dr. Bøttcher reported.

Negative imaging, positive FFR

He also noted that it remains unclear how to best manage patients who show no signs of ischemia when examined by RbPET or CMR, but have an apparently hemodynamically meaningful coronary lesion when assessed by invasive angiography and fractional flow reserve. “We don’t know whether we should be guided by the negative scan or by the positive FFR result,” Dr. Bøttcher said. “There is a challenge when you get different results.”

In addition, the two compared imaging methods both have logistical limitations. RbPET involved radiation exposure, and CMR performed with a 3-tesla device may not be as widely available and requires more expensive equipment.

Dr. Berry also noted that imaging methods continue to advance. For example, the CMR examinations used in the study involved qualitative assessments, but quantitative CMR is now becoming more widely available and may provide enhanced diagnostic capabilities. Dr. Berry added that patients with symptoms of coronary disease but without an identifiable coronary obstruction may have microvascular coronary disease, a disorder that he has been at the forefront of describing.

Dan-NICAD 2 received no commercial funding. Dr. Bøttcher has been an adviser to Acarix, Amgen, AstraZeneca, Bayer, and Novo Nordisk. Dr. Berry had no disclosures.

BARCELONA – Two noninvasive imaging methods for assessing coronary artery disease – cardiac magnetic resonance (CMR) and positron emission tomography using rubidium stress (RbPET) – had nearly identical accuracy for ruling-in or ruling-out coronary disease, making them for at least the time being equally appropriate to use when assessing low- or intermediate-risk patients with symptoms suggestive of possible coronary disease in a prospective, multicenter study with 372 patients.

RbPET and CMR using a 3 Tesla device showed “absolutely similar performance,” in a head-to-head comparison that used fractional flow reserve assessment via invasive coronary angiography in each patient in the study as the arbiter of the true extent of coronary disease, reported Morten Bøttcher, MD, PhD, at the annual congress of the European Society of Cardiology.

Mitchel L. Zoler/MDedge

This result is good news for practice because clinicians can feel free to use whichever of the two assessment methods is most feasible for each patient, said Dr. Bøttcher, a researcher at Aarhus (Denmark) University Hospital. But the study was limited by its size, and he hopes to run a future study with many more patients to try to more definitively compare RbPET and CMR.

‘The techniques are probably interchangeable’

“There is a very clear result from the data: The performance of the two modalities is similar in the population studied,” commented Colin Berry, MBChB, PhD, professor of cardiology and imaging at the University of Glasgow (Scotland), and designated discussant for the report. “The techniques are probably interchangeable,” he said.

Mitchel L. Zoler/MDedge

Dr. Bøttcher and his associates designed the Danish Study of Non-Invasive Diagnostic Testing in Coronary Artery Disease 2 (Dan-NICAD 2) to address a knowledge gap highlighted in the 2019 guidelines of the European Society of Cardiology for the management of patients with chronic coronary syndromes, specifically low- or intermediate-risk patients who present with symptoms of possible coronary disease who have been identified as having possibly stenotic coronary lesions using coronary CT angiography. The guidelines cite using noninvasive imaging at this point prior to invasive angiography, but note that the relative performance of the various imaging options available for this step in unknown, said Dr. Bøttcher.

The researchers enrolled 372 patients at any of four hospitals in Denmark who agreed to participate and had a positive result on a coronary CT examination performed to assess their symptoms of coronary disease. (These 372 patients came from an initial pool of people that was fourfold larger, but three-quarters had negative findings on their coronary CT examination.) Clinicians had referred all of these patients to invasive angiography with fractional flow reserve assessment, and prior to that procedure they each underwent both a RbPET and a CMR examination for the purpose of this study. The researchers used each patient’s eventual invasive angiography result as the definitive determinant of their coronary disease. These patients averaged 64 years old, and 71% were men.

This analysis showed that for all 372 patients RbPET had 63% sensitivity and 87% specificity for identifying hemodynamically obstructive coronary disease, with rates of 60% and 85%, respectively, for CMR. In the subgroup of 71 patients (19%) who had obstructive coronary disease when examined by invasive angiography the sensitivity and specificity of the RbPET examination was 90% and 78%, and for CMR the sensitivity and specificity was 83% and 76%, Dr. Bøttcher reported.

Negative imaging, positive FFR

He also noted that it remains unclear how to best manage patients who show no signs of ischemia when examined by RbPET or CMR, but have an apparently hemodynamically meaningful coronary lesion when assessed by invasive angiography and fractional flow reserve. “We don’t know whether we should be guided by the negative scan or by the positive FFR result,” Dr. Bøttcher said. “There is a challenge when you get different results.”

In addition, the two compared imaging methods both have logistical limitations. RbPET involved radiation exposure, and CMR performed with a 3-tesla device may not be as widely available and requires more expensive equipment.

Dr. Berry also noted that imaging methods continue to advance. For example, the CMR examinations used in the study involved qualitative assessments, but quantitative CMR is now becoming more widely available and may provide enhanced diagnostic capabilities. Dr. Berry added that patients with symptoms of coronary disease but without an identifiable coronary obstruction may have microvascular coronary disease, a disorder that he has been at the forefront of describing.

Dan-NICAD 2 received no commercial funding. Dr. Bøttcher has been an adviser to Acarix, Amgen, AstraZeneca, Bayer, and Novo Nordisk. Dr. Berry had no disclosures.

BARCELONA – Two noninvasive imaging methods for assessing coronary artery disease – cardiac magnetic resonance (CMR) and positron emission tomography using rubidium stress (RbPET) – had nearly identical accuracy for ruling-in or ruling-out coronary disease, making them for at least the time being equally appropriate to use when assessing low- or intermediate-risk patients with symptoms suggestive of possible coronary disease in a prospective, multicenter study with 372 patients.

RbPET and CMR using a 3 Tesla device showed “absolutely similar performance,” in a head-to-head comparison that used fractional flow reserve assessment via invasive coronary angiography in each patient in the study as the arbiter of the true extent of coronary disease, reported Morten Bøttcher, MD, PhD, at the annual congress of the European Society of Cardiology.

Mitchel L. Zoler/MDedge

This result is good news for practice because clinicians can feel free to use whichever of the two assessment methods is most feasible for each patient, said Dr. Bøttcher, a researcher at Aarhus (Denmark) University Hospital. But the study was limited by its size, and he hopes to run a future study with many more patients to try to more definitively compare RbPET and CMR.

‘The techniques are probably interchangeable’

“There is a very clear result from the data: The performance of the two modalities is similar in the population studied,” commented Colin Berry, MBChB, PhD, professor of cardiology and imaging at the University of Glasgow (Scotland), and designated discussant for the report. “The techniques are probably interchangeable,” he said.

Mitchel L. Zoler/MDedge

Dr. Bøttcher and his associates designed the Danish Study of Non-Invasive Diagnostic Testing in Coronary Artery Disease 2 (Dan-NICAD 2) to address a knowledge gap highlighted in the 2019 guidelines of the European Society of Cardiology for the management of patients with chronic coronary syndromes, specifically low- or intermediate-risk patients who present with symptoms of possible coronary disease who have been identified as having possibly stenotic coronary lesions using coronary CT angiography. The guidelines cite using noninvasive imaging at this point prior to invasive angiography, but note that the relative performance of the various imaging options available for this step in unknown, said Dr. Bøttcher.

The researchers enrolled 372 patients at any of four hospitals in Denmark who agreed to participate and had a positive result on a coronary CT examination performed to assess their symptoms of coronary disease. (These 372 patients came from an initial pool of people that was fourfold larger, but three-quarters had negative findings on their coronary CT examination.) Clinicians had referred all of these patients to invasive angiography with fractional flow reserve assessment, and prior to that procedure they each underwent both a RbPET and a CMR examination for the purpose of this study. The researchers used each patient’s eventual invasive angiography result as the definitive determinant of their coronary disease. These patients averaged 64 years old, and 71% were men.

This analysis showed that for all 372 patients RbPET had 63% sensitivity and 87% specificity for identifying hemodynamically obstructive coronary disease, with rates of 60% and 85%, respectively, for CMR. In the subgroup of 71 patients (19%) who had obstructive coronary disease when examined by invasive angiography the sensitivity and specificity of the RbPET examination was 90% and 78%, and for CMR the sensitivity and specificity was 83% and 76%, Dr. Bøttcher reported.

Negative imaging, positive FFR

He also noted that it remains unclear how to best manage patients who show no signs of ischemia when examined by RbPET or CMR, but have an apparently hemodynamically meaningful coronary lesion when assessed by invasive angiography and fractional flow reserve. “We don’t know whether we should be guided by the negative scan or by the positive FFR result,” Dr. Bøttcher said. “There is a challenge when you get different results.”

In addition, the two compared imaging methods both have logistical limitations. RbPET involved radiation exposure, and CMR performed with a 3-tesla device may not be as widely available and requires more expensive equipment.

Dr. Berry also noted that imaging methods continue to advance. For example, the CMR examinations used in the study involved qualitative assessments, but quantitative CMR is now becoming more widely available and may provide enhanced diagnostic capabilities. Dr. Berry added that patients with symptoms of coronary disease but without an identifiable coronary obstruction may have microvascular coronary disease, a disorder that he has been at the forefront of describing.

Dan-NICAD 2 received no commercial funding. Dr. Bøttcher has been an adviser to Acarix, Amgen, AstraZeneca, Bayer, and Novo Nordisk. Dr. Berry had no disclosures.

Patients with aortic stenosis (AS) of sufficient severity to portend a high likelihood of early mortality can be detected by an artificial intelligence (AI) algorithm employed in the reading of routine echocardiograms, according to a study that tested this tool in a large national database.

The artificial intelligence decision support algorithm (AI-DSA) “automatically identified patients with moderate to severe forms of AS associated with poor survival if left untreated,” reported Geoffrey A. Strange, PhD, professor, faculty of medicine, University of Sydney.

The AS-DSA was trained not only to recognize adverse changes in aortic valve morphology but to evaluate indices of impaired valve function, including those related to the left ventricle, the left atrium, and pulmonary circulation, according to Dr. Strange.
 

AI algorithm based on more than 800K echos

The training was performed on more than 1 million echocardiograms obtained from 630,000 patients in the National Echo Database (NEDA) of Australia. The testing phase of the study, called AI ENHANCED AS, was carried out on 179,054 individuals from the same database.

In the testing phase, mortality was compared for those determined by AI to have a low probability of clinically significant AS, a moderate to severe AS, or severe AS.

In the nearly 200,000 patients evaluated from the database, the AI-DSA classified 2.5% as having moderate to severe AS and 1.4% as having severe AS. Relative to a 22.9% mortality at 5 years in the low-risk reference group, the rates were 56.2% and 67.9% in the moderate to severe and severe groups, respectively.

When expressed as odds ratios, the mortality risk for the moderate to severe group (OR, 1.8; P < .001) and severe group (HR, 2.8; P < .001) “were about two to three times higher than the low probability group,” Dr. Strange reported.
 

All severe AS by guidelines AI identified

The algorithm picked up all patients identified with severe AS in current guidelines, but it also identified patients “missed by conventional definitions,” Dr. Strange reported.

The findings support the idea “that the AI algorithm could be used in clinical practice to alert physicians to patients who should undergo further investigations to determine if they qualify for aortic valve replacement,” he added.

Missing clinically significant AS is an important clinical problem, according to Catherine Otto, MD, director of the heart valve clinic and a professor of cardiology at the University of Washington Medical Center, Seattle.

“We focus on the patients who already have a diagnosis of AS,” she said. “The bigger issue is identification of patients with unknown AS.”

She praised the effort to develop AI that improves detection of AS, but also said that there are immediate steps to improve detection of AS even in the absence of AI support. In addition to the variability in the quality of how echocardiograms are read, she said a substantial proportion of echo reports omit key variables.

“We do not need AI to measure the aortic valve. It is simple to do in clinical practice,” she said. However, studies have repeatedly shown that values, such as maximal aortic jet velocity (Vmax) and the pressure difference across the ventricular septal defect (delta P), are not included. When AS is present, some reports do not include a characterization of the severity.

The AI-DSA described by Dr. Strange takes into account all of these variables along with additional information, but he acknowledged that it does have limitations. For example, the presence of cardiac impairments other than AS will not be included, and these can be relevant to prognostication and treatment.
 

AI does not eliminate clinical decision-making

“This algorithm is definitely not meant to take away from clinical decision-making,” Dr. Strange said, but he argued that there is an unmet need to do better in the detection of AS. He presented data to show that “even moderate AS is not benign” in regard to 5-year outcomes, and he believes AI-DSA can allow clinicians to detect significant disease earlier and intervene in a timelier manner.

“It is time to revisit the practice of watchful waiting and consider more proactive attempts to identify those at risk,” he said.

The next step is to determine if AI-DSA makes a clinical difference,

“Research is now needed to determine if aortic valve replacement in patients identified as being at risk by AI-DSA improves survival and quality of life, particularly in those who do not meet current guideline definitions of clinically significant disease,” he said.

Dr. Strange reports financial relationships with Edwards, Medtronic, Novartis, Pfizer, and Echo IQ, which is developing the artificial algorithm studied in this trial. Dr. Otto reports no relevant conflicts of interest.

Patients with aortic stenosis (AS) of sufficient severity to portend a high likelihood of early mortality can be detected by an artificial intelligence (AI) algorithm employed in the reading of routine echocardiograms, according to a study that tested this tool in a large national database.

The artificial intelligence decision support algorithm (AI-DSA) “automatically identified patients with moderate to severe forms of AS associated with poor survival if left untreated,” reported Geoffrey A. Strange, PhD, professor, faculty of medicine, University of Sydney.

The AS-DSA was trained not only to recognize adverse changes in aortic valve morphology but to evaluate indices of impaired valve function, including those related to the left ventricle, the left atrium, and pulmonary circulation, according to Dr. Strange.
 

AI algorithm based on more than 800K echos

The training was performed on more than 1 million echocardiograms obtained from 630,000 patients in the National Echo Database (NEDA) of Australia. The testing phase of the study, called AI ENHANCED AS, was carried out on 179,054 individuals from the same database.

In the testing phase, mortality was compared for those determined by AI to have a low probability of clinically significant AS, a moderate to severe AS, or severe AS.

In the nearly 200,000 patients evaluated from the database, the AI-DSA classified 2.5% as having moderate to severe AS and 1.4% as having severe AS. Relative to a 22.9% mortality at 5 years in the low-risk reference group, the rates were 56.2% and 67.9% in the moderate to severe and severe groups, respectively.

When expressed as odds ratios, the mortality risk for the moderate to severe group (OR, 1.8; P < .001) and severe group (HR, 2.8; P < .001) “were about two to three times higher than the low probability group,” Dr. Strange reported.
 

All severe AS by guidelines AI identified

The algorithm picked up all patients identified with severe AS in current guidelines, but it also identified patients “missed by conventional definitions,” Dr. Strange reported.

The findings support the idea “that the AI algorithm could be used in clinical practice to alert physicians to patients who should undergo further investigations to determine if they qualify for aortic valve replacement,” he added.

Missing clinically significant AS is an important clinical problem, according to Catherine Otto, MD, director of the heart valve clinic and a professor of cardiology at the University of Washington Medical Center, Seattle.

“We focus on the patients who already have a diagnosis of AS,” she said. “The bigger issue is identification of patients with unknown AS.”

She praised the effort to develop AI that improves detection of AS, but also said that there are immediate steps to improve detection of AS even in the absence of AI support. In addition to the variability in the quality of how echocardiograms are read, she said a substantial proportion of echo reports omit key variables.

“We do not need AI to measure the aortic valve. It is simple to do in clinical practice,” she said. However, studies have repeatedly shown that values, such as maximal aortic jet velocity (Vmax) and the pressure difference across the ventricular septal defect (delta P), are not included. When AS is present, some reports do not include a characterization of the severity.

The AI-DSA described by Dr. Strange takes into account all of these variables along with additional information, but he acknowledged that it does have limitations. For example, the presence of cardiac impairments other than AS will not be included, and these can be relevant to prognostication and treatment.
 

AI does not eliminate clinical decision-making

“This algorithm is definitely not meant to take away from clinical decision-making,” Dr. Strange said, but he argued that there is an unmet need to do better in the detection of AS. He presented data to show that “even moderate AS is not benign” in regard to 5-year outcomes, and he believes AI-DSA can allow clinicians to detect significant disease earlier and intervene in a timelier manner.

“It is time to revisit the practice of watchful waiting and consider more proactive attempts to identify those at risk,” he said.

The next step is to determine if AI-DSA makes a clinical difference,

“Research is now needed to determine if aortic valve replacement in patients identified as being at risk by AI-DSA improves survival and quality of life, particularly in those who do not meet current guideline definitions of clinically significant disease,” he said.

Dr. Strange reports financial relationships with Edwards, Medtronic, Novartis, Pfizer, and Echo IQ, which is developing the artificial algorithm studied in this trial. Dr. Otto reports no relevant conflicts of interest.

Patients with aortic stenosis (AS) of sufficient severity to portend a high likelihood of early mortality can be detected by an artificial intelligence (AI) algorithm employed in the reading of routine echocardiograms, according to a study that tested this tool in a large national database.

The artificial intelligence decision support algorithm (AI-DSA) “automatically identified patients with moderate to severe forms of AS associated with poor survival if left untreated,” reported Geoffrey A. Strange, PhD, professor, faculty of medicine, University of Sydney.

The AS-DSA was trained not only to recognize adverse changes in aortic valve morphology but to evaluate indices of impaired valve function, including those related to the left ventricle, the left atrium, and pulmonary circulation, according to Dr. Strange.
 

AI algorithm based on more than 800K echos

The training was performed on more than 1 million echocardiograms obtained from 630,000 patients in the National Echo Database (NEDA) of Australia. The testing phase of the study, called AI ENHANCED AS, was carried out on 179,054 individuals from the same database.

In the testing phase, mortality was compared for those determined by AI to have a low probability of clinically significant AS, a moderate to severe AS, or severe AS.

In the nearly 200,000 patients evaluated from the database, the AI-DSA classified 2.5% as having moderate to severe AS and 1.4% as having severe AS. Relative to a 22.9% mortality at 5 years in the low-risk reference group, the rates were 56.2% and 67.9% in the moderate to severe and severe groups, respectively.

When expressed as odds ratios, the mortality risk for the moderate to severe group (OR, 1.8; P < .001) and severe group (HR, 2.8; P < .001) “were about two to three times higher than the low probability group,” Dr. Strange reported.
 

All severe AS by guidelines AI identified

The algorithm picked up all patients identified with severe AS in current guidelines, but it also identified patients “missed by conventional definitions,” Dr. Strange reported.

The findings support the idea “that the AI algorithm could be used in clinical practice to alert physicians to patients who should undergo further investigations to determine if they qualify for aortic valve replacement,” he added.

Missing clinically significant AS is an important clinical problem, according to Catherine Otto, MD, director of the heart valve clinic and a professor of cardiology at the University of Washington Medical Center, Seattle.

“We focus on the patients who already have a diagnosis of AS,” she said. “The bigger issue is identification of patients with unknown AS.”

She praised the effort to develop AI that improves detection of AS, but also said that there are immediate steps to improve detection of AS even in the absence of AI support. In addition to the variability in the quality of how echocardiograms are read, she said a substantial proportion of echo reports omit key variables.

“We do not need AI to measure the aortic valve. It is simple to do in clinical practice,” she said. However, studies have repeatedly shown that values, such as maximal aortic jet velocity (Vmax) and the pressure difference across the ventricular septal defect (delta P), are not included. When AS is present, some reports do not include a characterization of the severity.

The AI-DSA described by Dr. Strange takes into account all of these variables along with additional information, but he acknowledged that it does have limitations. For example, the presence of cardiac impairments other than AS will not be included, and these can be relevant to prognostication and treatment.
 

AI does not eliminate clinical decision-making

“This algorithm is definitely not meant to take away from clinical decision-making,” Dr. Strange said, but he argued that there is an unmet need to do better in the detection of AS. He presented data to show that “even moderate AS is not benign” in regard to 5-year outcomes, and he believes AI-DSA can allow clinicians to detect significant disease earlier and intervene in a timelier manner.

“It is time to revisit the practice of watchful waiting and consider more proactive attempts to identify those at risk,” he said.

The next step is to determine if AI-DSA makes a clinical difference,

“Research is now needed to determine if aortic valve replacement in patients identified as being at risk by AI-DSA improves survival and quality of life, particularly in those who do not meet current guideline definitions of clinically significant disease,” he said.

Dr. Strange reports financial relationships with Edwards, Medtronic, Novartis, Pfizer, and Echo IQ, which is developing the artificial algorithm studied in this trial. Dr. Otto reports no relevant conflicts of interest.