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MitraClip learning curve may top 200 cases
SAN FRANCISCO – It took in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry from November 2013 to March 2018.
“These findings demonstrate the key role of operator experience in optimizing outcomes” of transcatheter mitral valve repair (TMVr) with MitraClip (Abbott Structural), said investigators, led by Adnan Chhatriwalla, MD, an interventional cardiologist at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.
“New operators may experience a ‘learning curve’ irrespective of the overall site experience or experience of other members of the Heart Team,” they wrote in the study (JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014).
“As TMVr becomes more prevalent in the U.S., it may be prudent for less experienced operators to be cognizant of where they sit on the ‘learning curve’ and to pay particular attention to case selection in their early experience, considering that more complex patients may be referred to more experienced centers for treatment when prudent,” they noted.
“The overall duration of the learning curve may exceed 200 cases,” Dr. Chhatriwalla said at the Transcatheter Cardiovascular Therapeutics annual meeting in a presentation that coincided with the study’s publication.
“This is a more complex procedure than [transcatheter aortic valve replacement], and the volume/outcome relationship is stronger. We are seeing issues that are related to early experience in low-volume programs. Public reporting so consumers can determine how many cases a center does is going to be critical,” said cardiothoracic surgeon Michael Mack, MD, director of the cardiovascular service line at a health system in Dallas, after the talk. He was one of the authors of the study.
The investigators compared outcomes among 549 operators who had done 1-25 MitraClip cases, 230 who had performed 26-50 cases, and 116 who had performed 50 or more.
Optimal procedural success – defined as less than or equal to 1+ residual mitral regurgitation (MR) without death or cardiac surgery – was 63.9%, 68.4%, and 75.1%, respectively, across the three groups (P less than .001). The “acceptable” procedural success rate – less than or equal to 2+ residual MR without death or cardiac surgery – was 91.4%, 92.4%, and 93.8% (P less than .001). No interaction was observed between the mechanism of mitral valve regurgitation and procedural outcomes.
Procedure time decreased as operators gained experience (145, 118, and 99 minutes), and atrial septal defect closure rates increased (0.9%, 1.4%, and 2.2%, respectively).
Composite complications rates also fell (9.7%, 8.1%, and 7.3%), driven mostly by less frequent cardiac perforation (1.0%, 1.1%, and 0.4%) and less frequent blood transfusion (9.6%, 8.6%, and 6.5%). The results were statistically significant.
“Adjusted learning curves for procedural success were visually evident after approximately 50 cases, and continued improvement in clinical outcomes was observed for the entire case sequence up to 200 cases,” the investigators wrote. The improvements could not be attributed to patient selection alone, they said.
More experienced operators were more likely to use more than one clip per case, and more frequently treated central and medial, as opposed to lateral, pathology. Operators with more than 50 cases were less likely to treat patients who had preexisting mitral stenosis or required home oxygen, and experienced operators were more likely to perform the procedure in unstable patients, when appropriate. The proportion of patients with functional MR – as opposed to degenerative disease – increased with increasing experience.
There were no statistically significant differences across the groups in stroke rates (P = .26), single-leaflet device attachments (P = .11), trans-septal complications (P = .25), urgent cardiac surgery (P = .42), or in-hospital mortality (P = .55).
Patients were a median of 81 years old, and most were white; 93% had 3+ or 4+ MR at baseline, and 86.3% had degenerative mitral disease. Two-thirds had atrial fibrillation/flutter.
The work was supported by the ACC/STS TVT Registry. Dr. Chhatriwalla is a proctor for Edwards Lifesciences and Medtronic, and is a speaker for Abbott, Edwards Lifesciences, and Medtronic. Dr. Mack has served as an investigator for Edwards Lifesciences and Abbott, and as a study chair for Medtronic. Other investigators reported similar industry disclosures.
The meeting is sponsored by the Cardiovascular Research Foundation.
SOURCE: Chhatriwalla A et. al. JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014.
SAN FRANCISCO – It took in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry from November 2013 to March 2018.
“These findings demonstrate the key role of operator experience in optimizing outcomes” of transcatheter mitral valve repair (TMVr) with MitraClip (Abbott Structural), said investigators, led by Adnan Chhatriwalla, MD, an interventional cardiologist at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.
“New operators may experience a ‘learning curve’ irrespective of the overall site experience or experience of other members of the Heart Team,” they wrote in the study (JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014).
“As TMVr becomes more prevalent in the U.S., it may be prudent for less experienced operators to be cognizant of where they sit on the ‘learning curve’ and to pay particular attention to case selection in their early experience, considering that more complex patients may be referred to more experienced centers for treatment when prudent,” they noted.
“The overall duration of the learning curve may exceed 200 cases,” Dr. Chhatriwalla said at the Transcatheter Cardiovascular Therapeutics annual meeting in a presentation that coincided with the study’s publication.
“This is a more complex procedure than [transcatheter aortic valve replacement], and the volume/outcome relationship is stronger. We are seeing issues that are related to early experience in low-volume programs. Public reporting so consumers can determine how many cases a center does is going to be critical,” said cardiothoracic surgeon Michael Mack, MD, director of the cardiovascular service line at a health system in Dallas, after the talk. He was one of the authors of the study.
The investigators compared outcomes among 549 operators who had done 1-25 MitraClip cases, 230 who had performed 26-50 cases, and 116 who had performed 50 or more.
Optimal procedural success – defined as less than or equal to 1+ residual mitral regurgitation (MR) without death or cardiac surgery – was 63.9%, 68.4%, and 75.1%, respectively, across the three groups (P less than .001). The “acceptable” procedural success rate – less than or equal to 2+ residual MR without death or cardiac surgery – was 91.4%, 92.4%, and 93.8% (P less than .001). No interaction was observed between the mechanism of mitral valve regurgitation and procedural outcomes.
Procedure time decreased as operators gained experience (145, 118, and 99 minutes), and atrial septal defect closure rates increased (0.9%, 1.4%, and 2.2%, respectively).
Composite complications rates also fell (9.7%, 8.1%, and 7.3%), driven mostly by less frequent cardiac perforation (1.0%, 1.1%, and 0.4%) and less frequent blood transfusion (9.6%, 8.6%, and 6.5%). The results were statistically significant.
“Adjusted learning curves for procedural success were visually evident after approximately 50 cases, and continued improvement in clinical outcomes was observed for the entire case sequence up to 200 cases,” the investigators wrote. The improvements could not be attributed to patient selection alone, they said.
More experienced operators were more likely to use more than one clip per case, and more frequently treated central and medial, as opposed to lateral, pathology. Operators with more than 50 cases were less likely to treat patients who had preexisting mitral stenosis or required home oxygen, and experienced operators were more likely to perform the procedure in unstable patients, when appropriate. The proportion of patients with functional MR – as opposed to degenerative disease – increased with increasing experience.
There were no statistically significant differences across the groups in stroke rates (P = .26), single-leaflet device attachments (P = .11), trans-septal complications (P = .25), urgent cardiac surgery (P = .42), or in-hospital mortality (P = .55).
Patients were a median of 81 years old, and most were white; 93% had 3+ or 4+ MR at baseline, and 86.3% had degenerative mitral disease. Two-thirds had atrial fibrillation/flutter.
The work was supported by the ACC/STS TVT Registry. Dr. Chhatriwalla is a proctor for Edwards Lifesciences and Medtronic, and is a speaker for Abbott, Edwards Lifesciences, and Medtronic. Dr. Mack has served as an investigator for Edwards Lifesciences and Abbott, and as a study chair for Medtronic. Other investigators reported similar industry disclosures.
The meeting is sponsored by the Cardiovascular Research Foundation.
SOURCE: Chhatriwalla A et. al. JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014.
SAN FRANCISCO – It took in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry from November 2013 to March 2018.
“These findings demonstrate the key role of operator experience in optimizing outcomes” of transcatheter mitral valve repair (TMVr) with MitraClip (Abbott Structural), said investigators, led by Adnan Chhatriwalla, MD, an interventional cardiologist at Saint Luke’s Mid America Heart Institute in Kansas City, Mo.
“New operators may experience a ‘learning curve’ irrespective of the overall site experience or experience of other members of the Heart Team,” they wrote in the study (JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014).
“As TMVr becomes more prevalent in the U.S., it may be prudent for less experienced operators to be cognizant of where they sit on the ‘learning curve’ and to pay particular attention to case selection in their early experience, considering that more complex patients may be referred to more experienced centers for treatment when prudent,” they noted.
“The overall duration of the learning curve may exceed 200 cases,” Dr. Chhatriwalla said at the Transcatheter Cardiovascular Therapeutics annual meeting in a presentation that coincided with the study’s publication.
“This is a more complex procedure than [transcatheter aortic valve replacement], and the volume/outcome relationship is stronger. We are seeing issues that are related to early experience in low-volume programs. Public reporting so consumers can determine how many cases a center does is going to be critical,” said cardiothoracic surgeon Michael Mack, MD, director of the cardiovascular service line at a health system in Dallas, after the talk. He was one of the authors of the study.
The investigators compared outcomes among 549 operators who had done 1-25 MitraClip cases, 230 who had performed 26-50 cases, and 116 who had performed 50 or more.
Optimal procedural success – defined as less than or equal to 1+ residual mitral regurgitation (MR) without death or cardiac surgery – was 63.9%, 68.4%, and 75.1%, respectively, across the three groups (P less than .001). The “acceptable” procedural success rate – less than or equal to 2+ residual MR without death or cardiac surgery – was 91.4%, 92.4%, and 93.8% (P less than .001). No interaction was observed between the mechanism of mitral valve regurgitation and procedural outcomes.
Procedure time decreased as operators gained experience (145, 118, and 99 minutes), and atrial septal defect closure rates increased (0.9%, 1.4%, and 2.2%, respectively).
Composite complications rates also fell (9.7%, 8.1%, and 7.3%), driven mostly by less frequent cardiac perforation (1.0%, 1.1%, and 0.4%) and less frequent blood transfusion (9.6%, 8.6%, and 6.5%). The results were statistically significant.
“Adjusted learning curves for procedural success were visually evident after approximately 50 cases, and continued improvement in clinical outcomes was observed for the entire case sequence up to 200 cases,” the investigators wrote. The improvements could not be attributed to patient selection alone, they said.
More experienced operators were more likely to use more than one clip per case, and more frequently treated central and medial, as opposed to lateral, pathology. Operators with more than 50 cases were less likely to treat patients who had preexisting mitral stenosis or required home oxygen, and experienced operators were more likely to perform the procedure in unstable patients, when appropriate. The proportion of patients with functional MR – as opposed to degenerative disease – increased with increasing experience.
There were no statistically significant differences across the groups in stroke rates (P = .26), single-leaflet device attachments (P = .11), trans-septal complications (P = .25), urgent cardiac surgery (P = .42), or in-hospital mortality (P = .55).
Patients were a median of 81 years old, and most were white; 93% had 3+ or 4+ MR at baseline, and 86.3% had degenerative mitral disease. Two-thirds had atrial fibrillation/flutter.
The work was supported by the ACC/STS TVT Registry. Dr. Chhatriwalla is a proctor for Edwards Lifesciences and Medtronic, and is a speaker for Abbott, Edwards Lifesciences, and Medtronic. Dr. Mack has served as an investigator for Edwards Lifesciences and Abbott, and as a study chair for Medtronic. Other investigators reported similar industry disclosures.
The meeting is sponsored by the Cardiovascular Research Foundation.
SOURCE: Chhatriwalla A et. al. JACC Cardiovasc Interv. 2019 Sep 27. doi: 10.1016/j.jacc.2019.09.014.
REPORTING FROM TCT 2019
Ticagrelor monotherapy tops DAPT for high-risk PCI patients
SAN FRANCISCO – After 3 months of ticagrelor (Brilinta) plus aspirin following cardiac stenting, stopping the aspirin but continuing the ticagrelor resulted in less bleeding with no increase in ischemic events in a randomized trial with more than 7,000 drug-eluting stent patients at high risk for both.
“This was a superior therapy” to staying on both drugs, the more usual approach, said lead investigator Roxana Mehran, MD, director of interventional cardiovascular research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York.
“We can’t say this is for all comers, but for patients whose physician felt comfortable putting them on aspirin and ticagrelor,” who tolerated it well for the first 3 months, and who had clinical and angiographic indications of risk, “I think these patients can be peeled away” from aspirin, she said in a presentation at the Transcatheter Cardiovascular Therapeutics annual meeting that coincided with publication of the trial, dubbed TWILIGHT (Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention).
Interventional cardiologists have long sought the sweet spot for dual-antiplatelet therapy (DAPT) after stenting; the idea is to maximize thrombosis prevention while minimizing bleeding risk. The trial supports the trend in recent years towards shorter DAPT. Often, however, it’s the P2Y12 inhibitor – ticagrelor, clopidogrel (Plavix), or prasugrel (Effient) – that goes first, not the aspirin.
Responding to an audience question about why the trial didn’t include an aspirin monotherapy arm, Dr. Mehran said that aspirin alone wouldn’t have been sufficient in high-risk patients “in whom you have almost 70% acute coronary syndrome.” She added that her team has data showing that aspirin itself doesn’t have much effect on blood thrombogenicity.
The 7,119 patients in TWILIGHT were on ticagrelor 90 mg twice daily and aspirin 81-100 mg daily for 3 months, then evenly randomized to continued treatment or ticagrelor plus an aspirin placebo for a year.
Subjects had to have at least one clinical and angiographic finding that put them at high risk for bleeding or an ischemic event, such as chronic kidney disease, acute coronary syndrome, diabetes, or a bifurcated target lesion treated with two stents.
One year after randomization, 4% in the ticagrelor monotherapy group versus 7.1% in the ticagrelor plus aspirin arm reached the primary end point, actionable (type 2), severe (type 3), or fatal (type 5) bleeding on the Bleeding Academic Research Consortium scale (hazard ratio, 0.56; 95% confidence interval, 0.45 - 0.68, P less than .001).
The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (HR, 0.99; 95% CI, 0.78-1.25; P less than .001 for noninferiority).
There were more ischemic strokes in the ticagrelor monotherapy arm (0.5% versus 0.2%). All-cause mortality (1.3% versus 1%) and stent thrombosis (0.6% versus 0.4%) were more frequent in the ticagrelor/aspirin group, but the differences were not statistically significant.
The two groups were well balanced. The mean age was 65 years, 23.8% of the patients were female, 37% had diabetes, and 65% had percutaneous coronary intervention for an acute coronary syndrome. Almost two-thirds had multivessel disease. Mean stent length was about 40 mm. The trial excluded patients with prior strokes.
Almost 2,000 patients originally enrolled in the trial never made it to randomization because they had a major bleeding or ischemic event in the 3-month run up, or dyspnea or some other reaction to ticagrelor.
The recent STOPDAPT-2 trial had a similar outcome – less bleeding with no increase in ischemic events – with clopidogrel monotherapy after a month-long run in of dual therapy with aspirin, versus continued treatment with both, in patients at low risk for ischemic events after stenting (JAMA. 2019 Jun 25;321[24]:2414-27).
Another recent study, GLOBAL LEADERS, concluded that 1 month of DAPT followed by ticagrelor monotherapy for 23 months was not superior to 12 months of DAPT followed by a year of aspirin. There was a numerical advantage for solo ticagrelor on death, myocardial infarction, and bleeding, but it did not reach statistical significance (Lancet. 2018 Sep 15;392[10151]:940-9).
The work was funded by ticagrelor’s maker, AstraZeneca. Dr. Mehran reported consulting and other relationships with Abbott, Janssen, and other companies.
SOURCE: Mehran A et al. N Engl J Med. 2019 Sep 26. doi: 10.1056/NEJMoa1908419.
SAN FRANCISCO – After 3 months of ticagrelor (Brilinta) plus aspirin following cardiac stenting, stopping the aspirin but continuing the ticagrelor resulted in less bleeding with no increase in ischemic events in a randomized trial with more than 7,000 drug-eluting stent patients at high risk for both.
“This was a superior therapy” to staying on both drugs, the more usual approach, said lead investigator Roxana Mehran, MD, director of interventional cardiovascular research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York.
“We can’t say this is for all comers, but for patients whose physician felt comfortable putting them on aspirin and ticagrelor,” who tolerated it well for the first 3 months, and who had clinical and angiographic indications of risk, “I think these patients can be peeled away” from aspirin, she said in a presentation at the Transcatheter Cardiovascular Therapeutics annual meeting that coincided with publication of the trial, dubbed TWILIGHT (Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention).
Interventional cardiologists have long sought the sweet spot for dual-antiplatelet therapy (DAPT) after stenting; the idea is to maximize thrombosis prevention while minimizing bleeding risk. The trial supports the trend in recent years towards shorter DAPT. Often, however, it’s the P2Y12 inhibitor – ticagrelor, clopidogrel (Plavix), or prasugrel (Effient) – that goes first, not the aspirin.
Responding to an audience question about why the trial didn’t include an aspirin monotherapy arm, Dr. Mehran said that aspirin alone wouldn’t have been sufficient in high-risk patients “in whom you have almost 70% acute coronary syndrome.” She added that her team has data showing that aspirin itself doesn’t have much effect on blood thrombogenicity.
The 7,119 patients in TWILIGHT were on ticagrelor 90 mg twice daily and aspirin 81-100 mg daily for 3 months, then evenly randomized to continued treatment or ticagrelor plus an aspirin placebo for a year.
Subjects had to have at least one clinical and angiographic finding that put them at high risk for bleeding or an ischemic event, such as chronic kidney disease, acute coronary syndrome, diabetes, or a bifurcated target lesion treated with two stents.
One year after randomization, 4% in the ticagrelor monotherapy group versus 7.1% in the ticagrelor plus aspirin arm reached the primary end point, actionable (type 2), severe (type 3), or fatal (type 5) bleeding on the Bleeding Academic Research Consortium scale (hazard ratio, 0.56; 95% confidence interval, 0.45 - 0.68, P less than .001).
The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (HR, 0.99; 95% CI, 0.78-1.25; P less than .001 for noninferiority).
There were more ischemic strokes in the ticagrelor monotherapy arm (0.5% versus 0.2%). All-cause mortality (1.3% versus 1%) and stent thrombosis (0.6% versus 0.4%) were more frequent in the ticagrelor/aspirin group, but the differences were not statistically significant.
The two groups were well balanced. The mean age was 65 years, 23.8% of the patients were female, 37% had diabetes, and 65% had percutaneous coronary intervention for an acute coronary syndrome. Almost two-thirds had multivessel disease. Mean stent length was about 40 mm. The trial excluded patients with prior strokes.
Almost 2,000 patients originally enrolled in the trial never made it to randomization because they had a major bleeding or ischemic event in the 3-month run up, or dyspnea or some other reaction to ticagrelor.
The recent STOPDAPT-2 trial had a similar outcome – less bleeding with no increase in ischemic events – with clopidogrel monotherapy after a month-long run in of dual therapy with aspirin, versus continued treatment with both, in patients at low risk for ischemic events after stenting (JAMA. 2019 Jun 25;321[24]:2414-27).
Another recent study, GLOBAL LEADERS, concluded that 1 month of DAPT followed by ticagrelor monotherapy for 23 months was not superior to 12 months of DAPT followed by a year of aspirin. There was a numerical advantage for solo ticagrelor on death, myocardial infarction, and bleeding, but it did not reach statistical significance (Lancet. 2018 Sep 15;392[10151]:940-9).
The work was funded by ticagrelor’s maker, AstraZeneca. Dr. Mehran reported consulting and other relationships with Abbott, Janssen, and other companies.
SOURCE: Mehran A et al. N Engl J Med. 2019 Sep 26. doi: 10.1056/NEJMoa1908419.
SAN FRANCISCO – After 3 months of ticagrelor (Brilinta) plus aspirin following cardiac stenting, stopping the aspirin but continuing the ticagrelor resulted in less bleeding with no increase in ischemic events in a randomized trial with more than 7,000 drug-eluting stent patients at high risk for both.
“This was a superior therapy” to staying on both drugs, the more usual approach, said lead investigator Roxana Mehran, MD, director of interventional cardiovascular research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York.
“We can’t say this is for all comers, but for patients whose physician felt comfortable putting them on aspirin and ticagrelor,” who tolerated it well for the first 3 months, and who had clinical and angiographic indications of risk, “I think these patients can be peeled away” from aspirin, she said in a presentation at the Transcatheter Cardiovascular Therapeutics annual meeting that coincided with publication of the trial, dubbed TWILIGHT (Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention).
Interventional cardiologists have long sought the sweet spot for dual-antiplatelet therapy (DAPT) after stenting; the idea is to maximize thrombosis prevention while minimizing bleeding risk. The trial supports the trend in recent years towards shorter DAPT. Often, however, it’s the P2Y12 inhibitor – ticagrelor, clopidogrel (Plavix), or prasugrel (Effient) – that goes first, not the aspirin.
Responding to an audience question about why the trial didn’t include an aspirin monotherapy arm, Dr. Mehran said that aspirin alone wouldn’t have been sufficient in high-risk patients “in whom you have almost 70% acute coronary syndrome.” She added that her team has data showing that aspirin itself doesn’t have much effect on blood thrombogenicity.
The 7,119 patients in TWILIGHT were on ticagrelor 90 mg twice daily and aspirin 81-100 mg daily for 3 months, then evenly randomized to continued treatment or ticagrelor plus an aspirin placebo for a year.
Subjects had to have at least one clinical and angiographic finding that put them at high risk for bleeding or an ischemic event, such as chronic kidney disease, acute coronary syndrome, diabetes, or a bifurcated target lesion treated with two stents.
One year after randomization, 4% in the ticagrelor monotherapy group versus 7.1% in the ticagrelor plus aspirin arm reached the primary end point, actionable (type 2), severe (type 3), or fatal (type 5) bleeding on the Bleeding Academic Research Consortium scale (hazard ratio, 0.56; 95% confidence interval, 0.45 - 0.68, P less than .001).
The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (HR, 0.99; 95% CI, 0.78-1.25; P less than .001 for noninferiority).
There were more ischemic strokes in the ticagrelor monotherapy arm (0.5% versus 0.2%). All-cause mortality (1.3% versus 1%) and stent thrombosis (0.6% versus 0.4%) were more frequent in the ticagrelor/aspirin group, but the differences were not statistically significant.
The two groups were well balanced. The mean age was 65 years, 23.8% of the patients were female, 37% had diabetes, and 65% had percutaneous coronary intervention for an acute coronary syndrome. Almost two-thirds had multivessel disease. Mean stent length was about 40 mm. The trial excluded patients with prior strokes.
Almost 2,000 patients originally enrolled in the trial never made it to randomization because they had a major bleeding or ischemic event in the 3-month run up, or dyspnea or some other reaction to ticagrelor.
The recent STOPDAPT-2 trial had a similar outcome – less bleeding with no increase in ischemic events – with clopidogrel monotherapy after a month-long run in of dual therapy with aspirin, versus continued treatment with both, in patients at low risk for ischemic events after stenting (JAMA. 2019 Jun 25;321[24]:2414-27).
Another recent study, GLOBAL LEADERS, concluded that 1 month of DAPT followed by ticagrelor monotherapy for 23 months was not superior to 12 months of DAPT followed by a year of aspirin. There was a numerical advantage for solo ticagrelor on death, myocardial infarction, and bleeding, but it did not reach statistical significance (Lancet. 2018 Sep 15;392[10151]:940-9).
The work was funded by ticagrelor’s maker, AstraZeneca. Dr. Mehran reported consulting and other relationships with Abbott, Janssen, and other companies.
SOURCE: Mehran A et al. N Engl J Med. 2019 Sep 26. doi: 10.1056/NEJMoa1908419.
REPORTING FROM TCT 2019
Hypoattenuated leaflet thickening often present in bioprosthetic valves
SAN FRANCISCO – The was 10% at 30 days and increased to 24% at 1 year, results from a PARTNER 3 substudy demonstrated.
However, the lack of a clear association with serious clinical events such as death, MI, and stroke “does not justify the routine prophylactic use of anticoagulation [following TAVR] in all patients,” lead study investigator Raj R. Makkar, MD, said during a press briefing at the Transcatheter Cardiovascular Therapeutics annual meeting.
“Subclinical leaflet thrombosis characterized by hypoattenuated leaflet thickening and reduced leaflet motion has been frequently observed in transcatheter and surgical aortic bioprosthetic valves,” said Dr. Makkar, director of the interventional cardiology division, Cedars-Sinai Medical Center, Los Angeles. “Thrombus on bioprosthetic valves can present as a spectrum: HALT with relatively normal leaflet motion, HALT with reduced leaflet motion but normal gradients, and clinical valve thrombosis with elevated gradients.”
The primary objective of the current Food and Drug Administration–mandated study, known as the PARTNER 3 Low-Risk Computed Tomography Sub-study, was to evaluate HALT and reduced leaflet motion in terms of differences in transcatheter and surgical bioprosthetic aortic valves among patients enrolled in the randomized PARTNER 3 cohort, to understand the natural history of HALT and reduced leaflet motion in the absence of anticoagulation, and to understand its impact on valve hemodynamics and clinical outcomes. Patients underwent specialized serial CTs at 30 days and at 1 year post TAVR or surgical aortic valve replacement (SAVR). All scans were analyzed by a CT core lab blinded to patient information or time of the scans, and the treating investigators were blinded to the results of the 30-day and 1-year CT scans. A clinical events committee adjudicated key clinical events.
Dr. Makkar reported outcomes from 408 patients: 213 who underwent TAVR and 195 who underwent surgery. There were 348 evaluable serial CT scans at 30 days and 312 at 1 year. The incidence of HALT at 30 days was 13.3% in the TAVR group and 5% in the surgery group, a difference that reached statistical significance (P = .03). At 1 year, however, the difference was not significant (27.5% vs. 20.2%, respectively; P = .19). In the overall cohort, he said, the incidence of HALT was 10% at 30 days and increased to 24% at 1 year.
The researchers also found that HALT was dynamic and spontaneously resolved in 56% of patients in the absence of anticoagulation at 30 days, while new HALT appeared in 21% of patients at 1 year.
“In terms of its impact on valve gradient, the impact was minimal,” Dr. Makkar said. “There was an increase of 1-2 mm Hg in patients who had HALT and in patients who had reduced leaflet motion.”
As for impact on clinical outcomes, the researchers observed no deaths or any myocardial infarction at any time point in patients who had HALT. “There were four cases of valve thrombosis, three of which occurred in patients who had HALT,” Dr. Makkar said at the meeting, sponsored by the Cardiovascular Research Foundation. “One stroke occurred in each group. TIA [transient ischemic attack] occurred in 1 patient out of 35 in the HALT group and 3 out of 311 in the no-HALT group. There was one case of retinal artery embolism in each group.”
In a pooled analysis of clinical events, he and his colleagues observed a numerical increase in death, stroke, TIA, and thrombotic events in patients who had HALT at 30 days, compared with those who did not (8.6% vs. 2.9%, respectively), but the difference did not reach statistical significance (P = .11). “However, given the low total number of events, the data are inconclusive and only hypothesis generating,” he said. “A longer-term follow-up and [a] larger data set will further clarify the impact on clinical outcomes.”
Dr. Makkar emphasized that routine post–TAVR/SAVR CT scans outside of research protocols are not indicated. “CTs should be prompted by increased gradients or thromboembolic events,” he said.
One of the discussants at the briefing, Michael J. Mack, MD, chair of the cardiovascular service line at Baylor Scott and White Health in Dallas and primary author of the PARTNER 3 study, said that prior to the substudy results, “I’ve always thought that the incidence of valve thrombosis would be higher with TAVR than with surgery. So the fact that it was higher at 30 days didn’t surprise me. One of the reasons is that you lose the backwashing effect by changing flow dynamics in the aortic route. What did surprise me is the percent that resolved without anticoagulation.”
He added, “The impact of all this is that we are not justified recommending routine anticoagulation [after bioprosthetic aortic valve replacement surgery]. I think it does call into question the guidelines for surgical valves, because we did that based on smaller observational studies. Now that we have routine surveillance of surgical valves, I think it calls into question the class IIa recommendation for 3 months of anticoagulation. It’s what we’ve always done, and we’ll probably stop doing it on the basis of this. The other shoe that hasn’t dropped is its effect on long-term structural valve deterioration. I do think that early HALT does explain premature structural valve deterioration.”
The trial was sponsored by Edwards Lifesciences. Dr. Makkar disclosed that he is a consultant for and has received research grants from Edwards Lifesciences, Abbott, Medtronic, and Boston Scientific. Dr. Mack is a consultant to Gore and an investigator for Abbott, Edwards Lifesciences, and Medtronic.
SAN FRANCISCO – The was 10% at 30 days and increased to 24% at 1 year, results from a PARTNER 3 substudy demonstrated.
However, the lack of a clear association with serious clinical events such as death, MI, and stroke “does not justify the routine prophylactic use of anticoagulation [following TAVR] in all patients,” lead study investigator Raj R. Makkar, MD, said during a press briefing at the Transcatheter Cardiovascular Therapeutics annual meeting.
“Subclinical leaflet thrombosis characterized by hypoattenuated leaflet thickening and reduced leaflet motion has been frequently observed in transcatheter and surgical aortic bioprosthetic valves,” said Dr. Makkar, director of the interventional cardiology division, Cedars-Sinai Medical Center, Los Angeles. “Thrombus on bioprosthetic valves can present as a spectrum: HALT with relatively normal leaflet motion, HALT with reduced leaflet motion but normal gradients, and clinical valve thrombosis with elevated gradients.”
The primary objective of the current Food and Drug Administration–mandated study, known as the PARTNER 3 Low-Risk Computed Tomography Sub-study, was to evaluate HALT and reduced leaflet motion in terms of differences in transcatheter and surgical bioprosthetic aortic valves among patients enrolled in the randomized PARTNER 3 cohort, to understand the natural history of HALT and reduced leaflet motion in the absence of anticoagulation, and to understand its impact on valve hemodynamics and clinical outcomes. Patients underwent specialized serial CTs at 30 days and at 1 year post TAVR or surgical aortic valve replacement (SAVR). All scans were analyzed by a CT core lab blinded to patient information or time of the scans, and the treating investigators were blinded to the results of the 30-day and 1-year CT scans. A clinical events committee adjudicated key clinical events.
Dr. Makkar reported outcomes from 408 patients: 213 who underwent TAVR and 195 who underwent surgery. There were 348 evaluable serial CT scans at 30 days and 312 at 1 year. The incidence of HALT at 30 days was 13.3% in the TAVR group and 5% in the surgery group, a difference that reached statistical significance (P = .03). At 1 year, however, the difference was not significant (27.5% vs. 20.2%, respectively; P = .19). In the overall cohort, he said, the incidence of HALT was 10% at 30 days and increased to 24% at 1 year.
The researchers also found that HALT was dynamic and spontaneously resolved in 56% of patients in the absence of anticoagulation at 30 days, while new HALT appeared in 21% of patients at 1 year.
“In terms of its impact on valve gradient, the impact was minimal,” Dr. Makkar said. “There was an increase of 1-2 mm Hg in patients who had HALT and in patients who had reduced leaflet motion.”
As for impact on clinical outcomes, the researchers observed no deaths or any myocardial infarction at any time point in patients who had HALT. “There were four cases of valve thrombosis, three of which occurred in patients who had HALT,” Dr. Makkar said at the meeting, sponsored by the Cardiovascular Research Foundation. “One stroke occurred in each group. TIA [transient ischemic attack] occurred in 1 patient out of 35 in the HALT group and 3 out of 311 in the no-HALT group. There was one case of retinal artery embolism in each group.”
In a pooled analysis of clinical events, he and his colleagues observed a numerical increase in death, stroke, TIA, and thrombotic events in patients who had HALT at 30 days, compared with those who did not (8.6% vs. 2.9%, respectively), but the difference did not reach statistical significance (P = .11). “However, given the low total number of events, the data are inconclusive and only hypothesis generating,” he said. “A longer-term follow-up and [a] larger data set will further clarify the impact on clinical outcomes.”
Dr. Makkar emphasized that routine post–TAVR/SAVR CT scans outside of research protocols are not indicated. “CTs should be prompted by increased gradients or thromboembolic events,” he said.
One of the discussants at the briefing, Michael J. Mack, MD, chair of the cardiovascular service line at Baylor Scott and White Health in Dallas and primary author of the PARTNER 3 study, said that prior to the substudy results, “I’ve always thought that the incidence of valve thrombosis would be higher with TAVR than with surgery. So the fact that it was higher at 30 days didn’t surprise me. One of the reasons is that you lose the backwashing effect by changing flow dynamics in the aortic route. What did surprise me is the percent that resolved without anticoagulation.”
He added, “The impact of all this is that we are not justified recommending routine anticoagulation [after bioprosthetic aortic valve replacement surgery]. I think it does call into question the guidelines for surgical valves, because we did that based on smaller observational studies. Now that we have routine surveillance of surgical valves, I think it calls into question the class IIa recommendation for 3 months of anticoagulation. It’s what we’ve always done, and we’ll probably stop doing it on the basis of this. The other shoe that hasn’t dropped is its effect on long-term structural valve deterioration. I do think that early HALT does explain premature structural valve deterioration.”
The trial was sponsored by Edwards Lifesciences. Dr. Makkar disclosed that he is a consultant for and has received research grants from Edwards Lifesciences, Abbott, Medtronic, and Boston Scientific. Dr. Mack is a consultant to Gore and an investigator for Abbott, Edwards Lifesciences, and Medtronic.
SAN FRANCISCO – The was 10% at 30 days and increased to 24% at 1 year, results from a PARTNER 3 substudy demonstrated.
However, the lack of a clear association with serious clinical events such as death, MI, and stroke “does not justify the routine prophylactic use of anticoagulation [following TAVR] in all patients,” lead study investigator Raj R. Makkar, MD, said during a press briefing at the Transcatheter Cardiovascular Therapeutics annual meeting.
“Subclinical leaflet thrombosis characterized by hypoattenuated leaflet thickening and reduced leaflet motion has been frequently observed in transcatheter and surgical aortic bioprosthetic valves,” said Dr. Makkar, director of the interventional cardiology division, Cedars-Sinai Medical Center, Los Angeles. “Thrombus on bioprosthetic valves can present as a spectrum: HALT with relatively normal leaflet motion, HALT with reduced leaflet motion but normal gradients, and clinical valve thrombosis with elevated gradients.”
The primary objective of the current Food and Drug Administration–mandated study, known as the PARTNER 3 Low-Risk Computed Tomography Sub-study, was to evaluate HALT and reduced leaflet motion in terms of differences in transcatheter and surgical bioprosthetic aortic valves among patients enrolled in the randomized PARTNER 3 cohort, to understand the natural history of HALT and reduced leaflet motion in the absence of anticoagulation, and to understand its impact on valve hemodynamics and clinical outcomes. Patients underwent specialized serial CTs at 30 days and at 1 year post TAVR or surgical aortic valve replacement (SAVR). All scans were analyzed by a CT core lab blinded to patient information or time of the scans, and the treating investigators were blinded to the results of the 30-day and 1-year CT scans. A clinical events committee adjudicated key clinical events.
Dr. Makkar reported outcomes from 408 patients: 213 who underwent TAVR and 195 who underwent surgery. There were 348 evaluable serial CT scans at 30 days and 312 at 1 year. The incidence of HALT at 30 days was 13.3% in the TAVR group and 5% in the surgery group, a difference that reached statistical significance (P = .03). At 1 year, however, the difference was not significant (27.5% vs. 20.2%, respectively; P = .19). In the overall cohort, he said, the incidence of HALT was 10% at 30 days and increased to 24% at 1 year.
The researchers also found that HALT was dynamic and spontaneously resolved in 56% of patients in the absence of anticoagulation at 30 days, while new HALT appeared in 21% of patients at 1 year.
“In terms of its impact on valve gradient, the impact was minimal,” Dr. Makkar said. “There was an increase of 1-2 mm Hg in patients who had HALT and in patients who had reduced leaflet motion.”
As for impact on clinical outcomes, the researchers observed no deaths or any myocardial infarction at any time point in patients who had HALT. “There were four cases of valve thrombosis, three of which occurred in patients who had HALT,” Dr. Makkar said at the meeting, sponsored by the Cardiovascular Research Foundation. “One stroke occurred in each group. TIA [transient ischemic attack] occurred in 1 patient out of 35 in the HALT group and 3 out of 311 in the no-HALT group. There was one case of retinal artery embolism in each group.”
In a pooled analysis of clinical events, he and his colleagues observed a numerical increase in death, stroke, TIA, and thrombotic events in patients who had HALT at 30 days, compared with those who did not (8.6% vs. 2.9%, respectively), but the difference did not reach statistical significance (P = .11). “However, given the low total number of events, the data are inconclusive and only hypothesis generating,” he said. “A longer-term follow-up and [a] larger data set will further clarify the impact on clinical outcomes.”
Dr. Makkar emphasized that routine post–TAVR/SAVR CT scans outside of research protocols are not indicated. “CTs should be prompted by increased gradients or thromboembolic events,” he said.
One of the discussants at the briefing, Michael J. Mack, MD, chair of the cardiovascular service line at Baylor Scott and White Health in Dallas and primary author of the PARTNER 3 study, said that prior to the substudy results, “I’ve always thought that the incidence of valve thrombosis would be higher with TAVR than with surgery. So the fact that it was higher at 30 days didn’t surprise me. One of the reasons is that you lose the backwashing effect by changing flow dynamics in the aortic route. What did surprise me is the percent that resolved without anticoagulation.”
He added, “The impact of all this is that we are not justified recommending routine anticoagulation [after bioprosthetic aortic valve replacement surgery]. I think it does call into question the guidelines for surgical valves, because we did that based on smaller observational studies. Now that we have routine surveillance of surgical valves, I think it calls into question the class IIa recommendation for 3 months of anticoagulation. It’s what we’ve always done, and we’ll probably stop doing it on the basis of this. The other shoe that hasn’t dropped is its effect on long-term structural valve deterioration. I do think that early HALT does explain premature structural valve deterioration.”
The trial was sponsored by Edwards Lifesciences. Dr. Makkar disclosed that he is a consultant for and has received research grants from Edwards Lifesciences, Abbott, Medtronic, and Boston Scientific. Dr. Mack is a consultant to Gore and an investigator for Abbott, Edwards Lifesciences, and Medtronic.
REPORTING FROM TCT 2019
Key clinical point: Hypo-attenuated leaflet thickening (HALT) and reduced leaflet motion resulted in a minimal increase in valve gradients, which can be considered clinically insignificant.
Major finding: The incidence of HALT at 30 days was 13.3% in the TAVR group and 5% in the surgery group, a difference that reached statistical significance (P = .03). At 1 year, however, the difference did not differ significantly (27.5% vs. 20.2%, respectively; P = .19).
Study details: An analysis of 408 patients in the PARTNER 3 Low-Risk Computed Tomography Sub-study.
Disclosures: The trial was sponsored by Edwards Lifesciences. Dr. Makkar disclosed that he is a consultant for and has received research grants from Edwards Lifesciences, Abbott, Medtronic, and Boston Scientific. Dr. Mack is a consultant to Gore and an investigator for Abbott, Edwards Lifesciences, and Medtronic.
Source: Makkar R et al. TCT 2019.
European postmarket trial confirms findings of Disrupt CAD I
SAN FRANCISCO – A postmarket analysis of the coronary intravascular lithotripsy (IVL) system validated the safety and utility of the procedure first described in the Disrupt CAD I study.
“We now have an efficient technology to treat calcium that is safe to use, simple to learn, and able to achieve 100% success in delivering stents, with low final residual stenosis (7.8%),” Carlo Di Mario, MD, said in an interview in advance of the Transcatheter Cardiovascular Therapeutics annual meeting. “This was accomplished with a low rate of complications.”
Developed by Shockwave Medical, coronary IVL is an innovative lesion preparation tool designed to fracture challenging calcium using sonic pressure waves in order to facilitate stent delivery, deployment, and optimal expansion. In a feasibility study known as DISRUPT CAD I, Dr. Di Mario, director of structural interventional cardiology at Careggi University Hospital in Florence, Italy, and his colleagues performed the procedure in 60 patients (Circulation 2019;139:834-6). Clinical success, defined as residual stenosis of less than 50% post PCI with no evidence of in-hospital major adverse cardiac events (MACE), was 95%, while device success, defined as successful delivery and IVL treatment at target lesion, reached 98.3%.
In an effort to ensure that results of DISRUPT CAD 1 were generalizable to a broader population, Dr. Di Mario and his colleagues enrolled 120 subjects at 15 sites in nine European countries into DISRUPT CAD II, a postmarket, single-arm study. They underwent vessel preparation for stent implantation with IVL, and the primary endpoint was in-hospital MACE, defined as cardiac death, myocardial infarction, or target vessel revascularization. The researchers also performed an optical coherence tomography (OCT) substudy to evaluate the mechanism of action of IVL and to quantify coronary artery calcium characteristics and calcium plaque fracture.
The mean age of the 120 patients was 72 years, 78% were male, 80% had hypertension, 72% had hyperlipidemia, 32% had diabetes, and 65% had class I or II angina. Most of the patients (94%) had severe calcification, with a mean lesion length of about 26 mm. The lesions were concentric in 70% of cases, and 30% had side-branch involvement.
Dr. Di Mario and his associates reported that IVL was delivered successfully in all cases. It also delivered stents successfully in all cases, with a high acute luminal gain (a mean of 1.7 mm2), and low residual stenosis (7.8%). The primary endpoint occurred in 5.8% of patients, consisting of seven non–Q-wave myocardial infarctions. The IVL mechanism of action was shown to be intraplaque calcium fracture, which occurred in about 80% of lesions analyzed by OCT.
“Based on my previous experience with IVL, I was confident that it could modify the calcium, but the results of the OCT substudy of the Disrupt CAD II utilizing OCT to evaluate the mechanism of action was clearly more positive than expected,” said Dr. Di Mario, who was a coprincipal investigator for the trial. “It demonstrated that IVL creates visible calcium fractures in the majority of cases and confirmed that full stent expansion secondary to the circumferential calcium modification is achievable, despite that nearly all the patients (94%) had severe coronary artery calcification. We know from previous work that full stent expansion is required to minimize complications and improve clinical outcomes, which was not always achievable before IVL.”
He acknowledged certain limitations of the study, including the fact that it lacked a concurrent control group, “but it was run very carefully with complete monitoring of events and core lab and CEC [clinical endpoint committee] adjudication,” he said. “Also, the study was used to confirm short-term safety, and as such, did not include long term follow-up.”
In an interview at the meeting, Ajay J. Kirtane, MD, an interventional cardiologist at Columbia University Medical Center, New York, called the findings “reassuring,” but said that he looks forward to results from the trial of the system currently under way in the United States known as the DISRUPT CAD III IDE Study. “The technology is accessible to many physicians because it’s a balloon-based technology,” he said. “Yet in terms of performance, we need to not only evaluate short-term outcomes, we need to see long-term outcomes as well, to make sure there are no untoward effects.”
Shockwave C2 Coronary IVL catheters are commercially available for the treatment of de novo coronary artery disease in Europe and other select countries; in the United States they are limited to investigational use within the DISRUPT CAD III IDE Study.
At the meeting, Ziad A. Ali, MD, an interventional cardiologist at Columbia University/New York–Presbyterian Hospital, presented results from Disrupt CAD II, and the content was published online at the time of presentation. The meeting was sponsored by the Cardiovascular Research Foundation. Dr. Di Mario disclosed that Shockwave Medical provided a grant for the study to Careggi University Hospital. Dr. Ali reported having personal equity and fees from Shockwave Medical, as well as grants from other companies outside the scope of the study.
SOURCE: Di Mario C et al. Circ Cardiovasc Interv. 2019 Sep 25 doi: 10.1161/CIRCINTERVENTIONS.119.008434.
SAN FRANCISCO – A postmarket analysis of the coronary intravascular lithotripsy (IVL) system validated the safety and utility of the procedure first described in the Disrupt CAD I study.
“We now have an efficient technology to treat calcium that is safe to use, simple to learn, and able to achieve 100% success in delivering stents, with low final residual stenosis (7.8%),” Carlo Di Mario, MD, said in an interview in advance of the Transcatheter Cardiovascular Therapeutics annual meeting. “This was accomplished with a low rate of complications.”
Developed by Shockwave Medical, coronary IVL is an innovative lesion preparation tool designed to fracture challenging calcium using sonic pressure waves in order to facilitate stent delivery, deployment, and optimal expansion. In a feasibility study known as DISRUPT CAD I, Dr. Di Mario, director of structural interventional cardiology at Careggi University Hospital in Florence, Italy, and his colleagues performed the procedure in 60 patients (Circulation 2019;139:834-6). Clinical success, defined as residual stenosis of less than 50% post PCI with no evidence of in-hospital major adverse cardiac events (MACE), was 95%, while device success, defined as successful delivery and IVL treatment at target lesion, reached 98.3%.
In an effort to ensure that results of DISRUPT CAD 1 were generalizable to a broader population, Dr. Di Mario and his colleagues enrolled 120 subjects at 15 sites in nine European countries into DISRUPT CAD II, a postmarket, single-arm study. They underwent vessel preparation for stent implantation with IVL, and the primary endpoint was in-hospital MACE, defined as cardiac death, myocardial infarction, or target vessel revascularization. The researchers also performed an optical coherence tomography (OCT) substudy to evaluate the mechanism of action of IVL and to quantify coronary artery calcium characteristics and calcium plaque fracture.
The mean age of the 120 patients was 72 years, 78% were male, 80% had hypertension, 72% had hyperlipidemia, 32% had diabetes, and 65% had class I or II angina. Most of the patients (94%) had severe calcification, with a mean lesion length of about 26 mm. The lesions were concentric in 70% of cases, and 30% had side-branch involvement.
Dr. Di Mario and his associates reported that IVL was delivered successfully in all cases. It also delivered stents successfully in all cases, with a high acute luminal gain (a mean of 1.7 mm2), and low residual stenosis (7.8%). The primary endpoint occurred in 5.8% of patients, consisting of seven non–Q-wave myocardial infarctions. The IVL mechanism of action was shown to be intraplaque calcium fracture, which occurred in about 80% of lesions analyzed by OCT.
“Based on my previous experience with IVL, I was confident that it could modify the calcium, but the results of the OCT substudy of the Disrupt CAD II utilizing OCT to evaluate the mechanism of action was clearly more positive than expected,” said Dr. Di Mario, who was a coprincipal investigator for the trial. “It demonstrated that IVL creates visible calcium fractures in the majority of cases and confirmed that full stent expansion secondary to the circumferential calcium modification is achievable, despite that nearly all the patients (94%) had severe coronary artery calcification. We know from previous work that full stent expansion is required to minimize complications and improve clinical outcomes, which was not always achievable before IVL.”
He acknowledged certain limitations of the study, including the fact that it lacked a concurrent control group, “but it was run very carefully with complete monitoring of events and core lab and CEC [clinical endpoint committee] adjudication,” he said. “Also, the study was used to confirm short-term safety, and as such, did not include long term follow-up.”
In an interview at the meeting, Ajay J. Kirtane, MD, an interventional cardiologist at Columbia University Medical Center, New York, called the findings “reassuring,” but said that he looks forward to results from the trial of the system currently under way in the United States known as the DISRUPT CAD III IDE Study. “The technology is accessible to many physicians because it’s a balloon-based technology,” he said. “Yet in terms of performance, we need to not only evaluate short-term outcomes, we need to see long-term outcomes as well, to make sure there are no untoward effects.”
Shockwave C2 Coronary IVL catheters are commercially available for the treatment of de novo coronary artery disease in Europe and other select countries; in the United States they are limited to investigational use within the DISRUPT CAD III IDE Study.
At the meeting, Ziad A. Ali, MD, an interventional cardiologist at Columbia University/New York–Presbyterian Hospital, presented results from Disrupt CAD II, and the content was published online at the time of presentation. The meeting was sponsored by the Cardiovascular Research Foundation. Dr. Di Mario disclosed that Shockwave Medical provided a grant for the study to Careggi University Hospital. Dr. Ali reported having personal equity and fees from Shockwave Medical, as well as grants from other companies outside the scope of the study.
SOURCE: Di Mario C et al. Circ Cardiovasc Interv. 2019 Sep 25 doi: 10.1161/CIRCINTERVENTIONS.119.008434.
SAN FRANCISCO – A postmarket analysis of the coronary intravascular lithotripsy (IVL) system validated the safety and utility of the procedure first described in the Disrupt CAD I study.
“We now have an efficient technology to treat calcium that is safe to use, simple to learn, and able to achieve 100% success in delivering stents, with low final residual stenosis (7.8%),” Carlo Di Mario, MD, said in an interview in advance of the Transcatheter Cardiovascular Therapeutics annual meeting. “This was accomplished with a low rate of complications.”
Developed by Shockwave Medical, coronary IVL is an innovative lesion preparation tool designed to fracture challenging calcium using sonic pressure waves in order to facilitate stent delivery, deployment, and optimal expansion. In a feasibility study known as DISRUPT CAD I, Dr. Di Mario, director of structural interventional cardiology at Careggi University Hospital in Florence, Italy, and his colleagues performed the procedure in 60 patients (Circulation 2019;139:834-6). Clinical success, defined as residual stenosis of less than 50% post PCI with no evidence of in-hospital major adverse cardiac events (MACE), was 95%, while device success, defined as successful delivery and IVL treatment at target lesion, reached 98.3%.
In an effort to ensure that results of DISRUPT CAD 1 were generalizable to a broader population, Dr. Di Mario and his colleagues enrolled 120 subjects at 15 sites in nine European countries into DISRUPT CAD II, a postmarket, single-arm study. They underwent vessel preparation for stent implantation with IVL, and the primary endpoint was in-hospital MACE, defined as cardiac death, myocardial infarction, or target vessel revascularization. The researchers also performed an optical coherence tomography (OCT) substudy to evaluate the mechanism of action of IVL and to quantify coronary artery calcium characteristics and calcium plaque fracture.
The mean age of the 120 patients was 72 years, 78% were male, 80% had hypertension, 72% had hyperlipidemia, 32% had diabetes, and 65% had class I or II angina. Most of the patients (94%) had severe calcification, with a mean lesion length of about 26 mm. The lesions were concentric in 70% of cases, and 30% had side-branch involvement.
Dr. Di Mario and his associates reported that IVL was delivered successfully in all cases. It also delivered stents successfully in all cases, with a high acute luminal gain (a mean of 1.7 mm2), and low residual stenosis (7.8%). The primary endpoint occurred in 5.8% of patients, consisting of seven non–Q-wave myocardial infarctions. The IVL mechanism of action was shown to be intraplaque calcium fracture, which occurred in about 80% of lesions analyzed by OCT.
“Based on my previous experience with IVL, I was confident that it could modify the calcium, but the results of the OCT substudy of the Disrupt CAD II utilizing OCT to evaluate the mechanism of action was clearly more positive than expected,” said Dr. Di Mario, who was a coprincipal investigator for the trial. “It demonstrated that IVL creates visible calcium fractures in the majority of cases and confirmed that full stent expansion secondary to the circumferential calcium modification is achievable, despite that nearly all the patients (94%) had severe coronary artery calcification. We know from previous work that full stent expansion is required to minimize complications and improve clinical outcomes, which was not always achievable before IVL.”
He acknowledged certain limitations of the study, including the fact that it lacked a concurrent control group, “but it was run very carefully with complete monitoring of events and core lab and CEC [clinical endpoint committee] adjudication,” he said. “Also, the study was used to confirm short-term safety, and as such, did not include long term follow-up.”
In an interview at the meeting, Ajay J. Kirtane, MD, an interventional cardiologist at Columbia University Medical Center, New York, called the findings “reassuring,” but said that he looks forward to results from the trial of the system currently under way in the United States known as the DISRUPT CAD III IDE Study. “The technology is accessible to many physicians because it’s a balloon-based technology,” he said. “Yet in terms of performance, we need to not only evaluate short-term outcomes, we need to see long-term outcomes as well, to make sure there are no untoward effects.”
Shockwave C2 Coronary IVL catheters are commercially available for the treatment of de novo coronary artery disease in Europe and other select countries; in the United States they are limited to investigational use within the DISRUPT CAD III IDE Study.
At the meeting, Ziad A. Ali, MD, an interventional cardiologist at Columbia University/New York–Presbyterian Hospital, presented results from Disrupt CAD II, and the content was published online at the time of presentation. The meeting was sponsored by the Cardiovascular Research Foundation. Dr. Di Mario disclosed that Shockwave Medical provided a grant for the study to Careggi University Hospital. Dr. Ali reported having personal equity and fees from Shockwave Medical, as well as grants from other companies outside the scope of the study.
SOURCE: Di Mario C et al. Circ Cardiovasc Interv. 2019 Sep 25 doi: 10.1161/CIRCINTERVENTIONS.119.008434.
REPORTING FROM TCT 2019
TAVI simpler, shorter with left ventricular pacing
SAN FRANCISCO – Using the guidewire for rapid pacing of the left ventricle during transcatheter aortic valve implantation (TAVI) instead of the usual approach – right ventricular pacing through a lead snaked up the femoral vein – significantly reduced procedure duration, fluoroscopy time, and cost, without affecting efficacy or safety, in a 10-center randomized controlled trial in France.
Pacing using the 0.035-inch guidewire in the left ventricle eliminates “the need for a transvenous temporary pacing lead or additional venous access in most cases,”said investigators led by Benjamin Faurie, MD, an interventional cardiologist at the Cardiovascular Institute, Groupe Hospitalier Mutualiste, Grenoble, France. It simplifies TAVI “and should be considered as the default strategy for rapid ventricular pacing.”
“If risk factors for development of high-grade conduction disturbances are present, upfront RV [right ventricular] stimulation with a temporary pacing lead should be considered; otherwise LV [left ventricular] stimulation might be used.” LV stimulation in TAVI “is particularly attractive in patients with an indwelling permanent pacemaker to avoid the risk of pacemaker lead dislodgement with a temporary pacing lead,” they said.
“This technique may also be useful in transcatheter heart valve implantation in the mitral position and in transcatheter tricuspid valve interventions, where having a standard temporary pacing lead across the tricuspid valve may interfere with the procedure,” the investigators said.
Rapid ventricular pacing ensures cardiac standstill during TAVI, but the RV approach carries the risk of vascular complications and RV perforation. LV guidewire pacing, a technique borrowed from pediatric balloon aortic valvuloplasty, avoids the risks. The French study – dubbed Direct Left Ventricular Rapid Pacing Via the Valve Delivery Guide-wire in TAVI (EASY-TAVI) – is the first randomized trial to compare the technique with conventional RV stimulation, and it was published to coincide with a presentation at Transcatheter Cardiovascular Therapeutics annual meeting (JACC Cardiovasc Interv. 2019 Sep 14. doi: 10.1016/j.jcin.2019.09.029).
The patients were undergoing transfemoral TAVI with a Sapien 3 valve (Edwards Lifesciences); 151 were randomized to LV stimulation through the guidewire, and 152 to RV stimulation through a temporary pacing lead.
Both procedure duration (48.4 minutes vs. 55.6 minutes) and fluoroscopy time (13.48 minutes vs. 14.6 minutes) were significantly shorter in the LV group than in the RV group. The procedure was also less costly (€18,807 vs. €19,437) because of shorter catheterization lab time and materials savings.
There were no significant difference between LV and RV groups in rates of effective stimulation (84.9% vs. 87.1%, respectively), procedural success (100% vs. 99.3%), 30-day TAVI-related major adverse cardiovascular events (13.9% vs. 17.1%), or permanent pacemaker implantation within 30 days (17.9% vs. 11.8%). There were two cases of cardiac tamponade in the RV group from the temporary lead; there were no guidewire related tamponades in the LV group.
Fourteen LV patients (9%) needed bailout with an RV lead because of new-onset left bundle branch block or atrioventricular block. The temporary pacing lead, meanwhile, was left in place in 38 RV patients (25%), which suggests “a lower threshold for an indwelling temporary pacing lead post procedure when there is already one in place,” the investigators said.
To deliver LV stimulation, the cathode of an external pacemaker was attached to the distal external end of the guidewire using a crocodile clip. A second crocodile clip – the anode – was attached to the incised skin at the sheath insertion site in the groin. The valve delivery system provided the required insulation.
The investigators noted that “the benefit of LV-stimulation may be less with self-expanding valves due to the significantly higher incidence of conduction disturbances requiring permanent pacemaker implantation post procedure.”
Patients were a mean age of 83 years, with about equal numbers of men and women. They had an intermediate risk of dying during the procedure. “However, we feel that the results are generalizable to the classical patient at high predicted risk of surgical mortality undergoing TAVI. Such patients tend to have higher rates of comorbidities, including peripheral vascular disease, placing them at higher risk of vascular complications and tend to have thinner RV walls, placing them at higher risk of RV-perforation,” the investigators said.
The work was funded by Edwards Lifesciences and others. Dr. Faurie had no disclosures. The senior author is a proctor for Edwards Lifesciences
SOURCE: Faurie B et al. TCT 2019. JACC Cardiovasc Interv. 2019 Sep 14. doi: 10.1016/j.jcin.2019.09.029.
SAN FRANCISCO – Using the guidewire for rapid pacing of the left ventricle during transcatheter aortic valve implantation (TAVI) instead of the usual approach – right ventricular pacing through a lead snaked up the femoral vein – significantly reduced procedure duration, fluoroscopy time, and cost, without affecting efficacy or safety, in a 10-center randomized controlled trial in France.
Pacing using the 0.035-inch guidewire in the left ventricle eliminates “the need for a transvenous temporary pacing lead or additional venous access in most cases,”said investigators led by Benjamin Faurie, MD, an interventional cardiologist at the Cardiovascular Institute, Groupe Hospitalier Mutualiste, Grenoble, France. It simplifies TAVI “and should be considered as the default strategy for rapid ventricular pacing.”
“If risk factors for development of high-grade conduction disturbances are present, upfront RV [right ventricular] stimulation with a temporary pacing lead should be considered; otherwise LV [left ventricular] stimulation might be used.” LV stimulation in TAVI “is particularly attractive in patients with an indwelling permanent pacemaker to avoid the risk of pacemaker lead dislodgement with a temporary pacing lead,” they said.
“This technique may also be useful in transcatheter heart valve implantation in the mitral position and in transcatheter tricuspid valve interventions, where having a standard temporary pacing lead across the tricuspid valve may interfere with the procedure,” the investigators said.
Rapid ventricular pacing ensures cardiac standstill during TAVI, but the RV approach carries the risk of vascular complications and RV perforation. LV guidewire pacing, a technique borrowed from pediatric balloon aortic valvuloplasty, avoids the risks. The French study – dubbed Direct Left Ventricular Rapid Pacing Via the Valve Delivery Guide-wire in TAVI (EASY-TAVI) – is the first randomized trial to compare the technique with conventional RV stimulation, and it was published to coincide with a presentation at Transcatheter Cardiovascular Therapeutics annual meeting (JACC Cardiovasc Interv. 2019 Sep 14. doi: 10.1016/j.jcin.2019.09.029).
The patients were undergoing transfemoral TAVI with a Sapien 3 valve (Edwards Lifesciences); 151 were randomized to LV stimulation through the guidewire, and 152 to RV stimulation through a temporary pacing lead.
Both procedure duration (48.4 minutes vs. 55.6 minutes) and fluoroscopy time (13.48 minutes vs. 14.6 minutes) were significantly shorter in the LV group than in the RV group. The procedure was also less costly (€18,807 vs. €19,437) because of shorter catheterization lab time and materials savings.
There were no significant difference between LV and RV groups in rates of effective stimulation (84.9% vs. 87.1%, respectively), procedural success (100% vs. 99.3%), 30-day TAVI-related major adverse cardiovascular events (13.9% vs. 17.1%), or permanent pacemaker implantation within 30 days (17.9% vs. 11.8%). There were two cases of cardiac tamponade in the RV group from the temporary lead; there were no guidewire related tamponades in the LV group.
Fourteen LV patients (9%) needed bailout with an RV lead because of new-onset left bundle branch block or atrioventricular block. The temporary pacing lead, meanwhile, was left in place in 38 RV patients (25%), which suggests “a lower threshold for an indwelling temporary pacing lead post procedure when there is already one in place,” the investigators said.
To deliver LV stimulation, the cathode of an external pacemaker was attached to the distal external end of the guidewire using a crocodile clip. A second crocodile clip – the anode – was attached to the incised skin at the sheath insertion site in the groin. The valve delivery system provided the required insulation.
The investigators noted that “the benefit of LV-stimulation may be less with self-expanding valves due to the significantly higher incidence of conduction disturbances requiring permanent pacemaker implantation post procedure.”
Patients were a mean age of 83 years, with about equal numbers of men and women. They had an intermediate risk of dying during the procedure. “However, we feel that the results are generalizable to the classical patient at high predicted risk of surgical mortality undergoing TAVI. Such patients tend to have higher rates of comorbidities, including peripheral vascular disease, placing them at higher risk of vascular complications and tend to have thinner RV walls, placing them at higher risk of RV-perforation,” the investigators said.
The work was funded by Edwards Lifesciences and others. Dr. Faurie had no disclosures. The senior author is a proctor for Edwards Lifesciences
SOURCE: Faurie B et al. TCT 2019. JACC Cardiovasc Interv. 2019 Sep 14. doi: 10.1016/j.jcin.2019.09.029.
SAN FRANCISCO – Using the guidewire for rapid pacing of the left ventricle during transcatheter aortic valve implantation (TAVI) instead of the usual approach – right ventricular pacing through a lead snaked up the femoral vein – significantly reduced procedure duration, fluoroscopy time, and cost, without affecting efficacy or safety, in a 10-center randomized controlled trial in France.
Pacing using the 0.035-inch guidewire in the left ventricle eliminates “the need for a transvenous temporary pacing lead or additional venous access in most cases,”said investigators led by Benjamin Faurie, MD, an interventional cardiologist at the Cardiovascular Institute, Groupe Hospitalier Mutualiste, Grenoble, France. It simplifies TAVI “and should be considered as the default strategy for rapid ventricular pacing.”
“If risk factors for development of high-grade conduction disturbances are present, upfront RV [right ventricular] stimulation with a temporary pacing lead should be considered; otherwise LV [left ventricular] stimulation might be used.” LV stimulation in TAVI “is particularly attractive in patients with an indwelling permanent pacemaker to avoid the risk of pacemaker lead dislodgement with a temporary pacing lead,” they said.
“This technique may also be useful in transcatheter heart valve implantation in the mitral position and in transcatheter tricuspid valve interventions, where having a standard temporary pacing lead across the tricuspid valve may interfere with the procedure,” the investigators said.
Rapid ventricular pacing ensures cardiac standstill during TAVI, but the RV approach carries the risk of vascular complications and RV perforation. LV guidewire pacing, a technique borrowed from pediatric balloon aortic valvuloplasty, avoids the risks. The French study – dubbed Direct Left Ventricular Rapid Pacing Via the Valve Delivery Guide-wire in TAVI (EASY-TAVI) – is the first randomized trial to compare the technique with conventional RV stimulation, and it was published to coincide with a presentation at Transcatheter Cardiovascular Therapeutics annual meeting (JACC Cardiovasc Interv. 2019 Sep 14. doi: 10.1016/j.jcin.2019.09.029).
The patients were undergoing transfemoral TAVI with a Sapien 3 valve (Edwards Lifesciences); 151 were randomized to LV stimulation through the guidewire, and 152 to RV stimulation through a temporary pacing lead.
Both procedure duration (48.4 minutes vs. 55.6 minutes) and fluoroscopy time (13.48 minutes vs. 14.6 minutes) were significantly shorter in the LV group than in the RV group. The procedure was also less costly (€18,807 vs. €19,437) because of shorter catheterization lab time and materials savings.
There were no significant difference between LV and RV groups in rates of effective stimulation (84.9% vs. 87.1%, respectively), procedural success (100% vs. 99.3%), 30-day TAVI-related major adverse cardiovascular events (13.9% vs. 17.1%), or permanent pacemaker implantation within 30 days (17.9% vs. 11.8%). There were two cases of cardiac tamponade in the RV group from the temporary lead; there were no guidewire related tamponades in the LV group.
Fourteen LV patients (9%) needed bailout with an RV lead because of new-onset left bundle branch block or atrioventricular block. The temporary pacing lead, meanwhile, was left in place in 38 RV patients (25%), which suggests “a lower threshold for an indwelling temporary pacing lead post procedure when there is already one in place,” the investigators said.
To deliver LV stimulation, the cathode of an external pacemaker was attached to the distal external end of the guidewire using a crocodile clip. A second crocodile clip – the anode – was attached to the incised skin at the sheath insertion site in the groin. The valve delivery system provided the required insulation.
The investigators noted that “the benefit of LV-stimulation may be less with self-expanding valves due to the significantly higher incidence of conduction disturbances requiring permanent pacemaker implantation post procedure.”
Patients were a mean age of 83 years, with about equal numbers of men and women. They had an intermediate risk of dying during the procedure. “However, we feel that the results are generalizable to the classical patient at high predicted risk of surgical mortality undergoing TAVI. Such patients tend to have higher rates of comorbidities, including peripheral vascular disease, placing them at higher risk of vascular complications and tend to have thinner RV walls, placing them at higher risk of RV-perforation,” the investigators said.
The work was funded by Edwards Lifesciences and others. Dr. Faurie had no disclosures. The senior author is a proctor for Edwards Lifesciences
SOURCE: Faurie B et al. TCT 2019. JACC Cardiovasc Interv. 2019 Sep 14. doi: 10.1016/j.jcin.2019.09.029.
REPORTING FROM TCT 2019
Dual therapy best for AFib with ACS no matter the treatment strategy
SAN FRANCISCO – Anticoagulation with apixaban and a P2Y12 inhibitor without aspirin provides superior safety and similar efficacy in patients with atrial fibrillation who have an acute coronary syndrome, compared with regimens that include vitamin K antagonists, aspirin, or both.
The findings come from a prespecified analysis of data from the AUGUSTUS trial presented by Stephan Windecker, MD, at the Transcatheter Cardiovascular Therapeutics annual meeting.
“This study adds very important information [to the notion] that triple therapy in the setting of atrial fibrillation and PCI [percutaneous coronary intervention] is really not the way to go,” Ori Ben-Yehuda, MD, FACC, executive director of the Cardiovascular Research Foundation’s Clinical Trials Center, said during a media briefing.
In the recent multicenter AUGUSTUS trial, Dr. Windecker, of the department of cardiology at Bern University Hospital, Switzerland, and colleagues found that among 4,614 patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, apixaban without aspirin resulted in less bleeding, fewer hospitalizations, and no significant differences in ischemic events compared with regimens that included a vitamin K antagonist (VKA), aspirin, or both (N Engl J Med. 2019;380:1509-24). For this prespecified analysis, the researchers used a 2×2 factorial design to compare apixaban with VKA and aspirin with placebo in the AUGUSTUS trial participants with ACS treated medically (group 1; 1,097 patients, or 24%), those with ACS treated with PCI (group 2; 1,714 patients, or 37%), and those undergoing elective PCI (group 3; 1,784 patients, or 39%). The outcomes of interest were bleeding, death, and hospitalization as well as death and ischemic events by antithrombotic strategy in the study participants. This marks the only trial in the field that included patients with ACS managed medically, Dr. Windecker said.
At baseline, the median age of patients was 71 years, 30% were female, 36% had diabetes, and 45% had heart failure. Patients managed medically were younger (a median age of 70) and more frequently female; 57% presented with heart failure. The groups had identical CHA2DS2VASc scores (4), and very similar HAS-BLED scores (2 in groups 1 and 2, and 3 in group 3).
Apixaban compared with VKA showed lower International Society on Thrombosis and Haemostasis–defined major or clinically relevant nonmajor bleeding among patients in group 1 (HR, 0.44), group 2 (HR, 0.68), and group 3 (HR, 0.82) (P for interaction = .052). Apixaban compared with VKA reduced death or hospitalization among patients in group 1 (HR, 0.71), group 2 (HR 0.88), and group 3 (HR, 0.87) (P for interaction = .345). Compared with VKA, apixaban resulted in a similar effect on death and ischemic events among patients in all three treatment groups (P for interaction = .356).
Compared with placebo, aspirin had a higher rate of bleeding among patients in group 1 (HR, 1.49), group 2 (HR, 2.02) and group 3 (HR, 1.91) (P for interaction = .479). For the same comparison, there was no difference in outcomes among the three groups for the composite of death or hospitalization and death and ischemic events.
“The overall results of the AUGUSTUS trial are consistent across the three clinically important subgroups,” Dr. Windecker said. The reasons why patients received medical therapy remain unclear, “because it was at the physician’s discretion as to whether they were treated medically or underwent PCI,” he said. “The proportion very much reflects our clinical practice, where 20%-25% of patients are treated medically. What was surprising for me is that I would have anticipated there would be more elderly patients with comorbidities, but I did anticipate that there would be more female patients (in this subgroup).”
Robert A. Harrington, MD, an interventional cardiologist at Stanford (Calif.) University who served on the Data Safety and Monitoring Board for the trial, noted that the patients with atrial fibrillation represent 7%-10% of all ACS patients, “so it’s a big population,” he said. “What’s been disappointing is that none of the trials have been big enough to uncouple the bleeding vs. ischemic issue. We don’t know the answer for how long do you need the triple therapy versus when you can switch to the double therapy.”
Dr. Windecker said that the optimal duration of short-term aspirin remains unclear in this patient population. “Whether there is a benefit of giving aspirin for 2 weeks or 4 weeks remains unanswered,” he said. “Triple therapy is not the way to go, but we need to fine-tune, and probably individualize, which patients may benefit from a certain duration of aspirin.”
The study results were published online at the time of presentation (Circulation 2019 Sep 26. doi: 10.1161/CIRCULATIONAHA.119.043308.
AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer Inc. Dr. Windecker reported having received institutional research and educational grants to Bern University Hospital from Abbott, Amgen, Bayer, BMS, CSL Behring, Boston Scientific, Biotronik, Edwards Lifesciences, Medtronic, Polares, and Sinomed. His coauthors reported having numerous financial ties to the pharmaceutical and device industries.
SOURCE: Windecker S. TCT 2019, Late-Breaking Trials 1 session.
SAN FRANCISCO – Anticoagulation with apixaban and a P2Y12 inhibitor without aspirin provides superior safety and similar efficacy in patients with atrial fibrillation who have an acute coronary syndrome, compared with regimens that include vitamin K antagonists, aspirin, or both.
The findings come from a prespecified analysis of data from the AUGUSTUS trial presented by Stephan Windecker, MD, at the Transcatheter Cardiovascular Therapeutics annual meeting.
“This study adds very important information [to the notion] that triple therapy in the setting of atrial fibrillation and PCI [percutaneous coronary intervention] is really not the way to go,” Ori Ben-Yehuda, MD, FACC, executive director of the Cardiovascular Research Foundation’s Clinical Trials Center, said during a media briefing.
In the recent multicenter AUGUSTUS trial, Dr. Windecker, of the department of cardiology at Bern University Hospital, Switzerland, and colleagues found that among 4,614 patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, apixaban without aspirin resulted in less bleeding, fewer hospitalizations, and no significant differences in ischemic events compared with regimens that included a vitamin K antagonist (VKA), aspirin, or both (N Engl J Med. 2019;380:1509-24). For this prespecified analysis, the researchers used a 2×2 factorial design to compare apixaban with VKA and aspirin with placebo in the AUGUSTUS trial participants with ACS treated medically (group 1; 1,097 patients, or 24%), those with ACS treated with PCI (group 2; 1,714 patients, or 37%), and those undergoing elective PCI (group 3; 1,784 patients, or 39%). The outcomes of interest were bleeding, death, and hospitalization as well as death and ischemic events by antithrombotic strategy in the study participants. This marks the only trial in the field that included patients with ACS managed medically, Dr. Windecker said.
At baseline, the median age of patients was 71 years, 30% were female, 36% had diabetes, and 45% had heart failure. Patients managed medically were younger (a median age of 70) and more frequently female; 57% presented with heart failure. The groups had identical CHA2DS2VASc scores (4), and very similar HAS-BLED scores (2 in groups 1 and 2, and 3 in group 3).
Apixaban compared with VKA showed lower International Society on Thrombosis and Haemostasis–defined major or clinically relevant nonmajor bleeding among patients in group 1 (HR, 0.44), group 2 (HR, 0.68), and group 3 (HR, 0.82) (P for interaction = .052). Apixaban compared with VKA reduced death or hospitalization among patients in group 1 (HR, 0.71), group 2 (HR 0.88), and group 3 (HR, 0.87) (P for interaction = .345). Compared with VKA, apixaban resulted in a similar effect on death and ischemic events among patients in all three treatment groups (P for interaction = .356).
Compared with placebo, aspirin had a higher rate of bleeding among patients in group 1 (HR, 1.49), group 2 (HR, 2.02) and group 3 (HR, 1.91) (P for interaction = .479). For the same comparison, there was no difference in outcomes among the three groups for the composite of death or hospitalization and death and ischemic events.
“The overall results of the AUGUSTUS trial are consistent across the three clinically important subgroups,” Dr. Windecker said. The reasons why patients received medical therapy remain unclear, “because it was at the physician’s discretion as to whether they were treated medically or underwent PCI,” he said. “The proportion very much reflects our clinical practice, where 20%-25% of patients are treated medically. What was surprising for me is that I would have anticipated there would be more elderly patients with comorbidities, but I did anticipate that there would be more female patients (in this subgroup).”
Robert A. Harrington, MD, an interventional cardiologist at Stanford (Calif.) University who served on the Data Safety and Monitoring Board for the trial, noted that the patients with atrial fibrillation represent 7%-10% of all ACS patients, “so it’s a big population,” he said. “What’s been disappointing is that none of the trials have been big enough to uncouple the bleeding vs. ischemic issue. We don’t know the answer for how long do you need the triple therapy versus when you can switch to the double therapy.”
Dr. Windecker said that the optimal duration of short-term aspirin remains unclear in this patient population. “Whether there is a benefit of giving aspirin for 2 weeks or 4 weeks remains unanswered,” he said. “Triple therapy is not the way to go, but we need to fine-tune, and probably individualize, which patients may benefit from a certain duration of aspirin.”
The study results were published online at the time of presentation (Circulation 2019 Sep 26. doi: 10.1161/CIRCULATIONAHA.119.043308.
AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer Inc. Dr. Windecker reported having received institutional research and educational grants to Bern University Hospital from Abbott, Amgen, Bayer, BMS, CSL Behring, Boston Scientific, Biotronik, Edwards Lifesciences, Medtronic, Polares, and Sinomed. His coauthors reported having numerous financial ties to the pharmaceutical and device industries.
SOURCE: Windecker S. TCT 2019, Late-Breaking Trials 1 session.
SAN FRANCISCO – Anticoagulation with apixaban and a P2Y12 inhibitor without aspirin provides superior safety and similar efficacy in patients with atrial fibrillation who have an acute coronary syndrome, compared with regimens that include vitamin K antagonists, aspirin, or both.
The findings come from a prespecified analysis of data from the AUGUSTUS trial presented by Stephan Windecker, MD, at the Transcatheter Cardiovascular Therapeutics annual meeting.
“This study adds very important information [to the notion] that triple therapy in the setting of atrial fibrillation and PCI [percutaneous coronary intervention] is really not the way to go,” Ori Ben-Yehuda, MD, FACC, executive director of the Cardiovascular Research Foundation’s Clinical Trials Center, said during a media briefing.
In the recent multicenter AUGUSTUS trial, Dr. Windecker, of the department of cardiology at Bern University Hospital, Switzerland, and colleagues found that among 4,614 patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, apixaban without aspirin resulted in less bleeding, fewer hospitalizations, and no significant differences in ischemic events compared with regimens that included a vitamin K antagonist (VKA), aspirin, or both (N Engl J Med. 2019;380:1509-24). For this prespecified analysis, the researchers used a 2×2 factorial design to compare apixaban with VKA and aspirin with placebo in the AUGUSTUS trial participants with ACS treated medically (group 1; 1,097 patients, or 24%), those with ACS treated with PCI (group 2; 1,714 patients, or 37%), and those undergoing elective PCI (group 3; 1,784 patients, or 39%). The outcomes of interest were bleeding, death, and hospitalization as well as death and ischemic events by antithrombotic strategy in the study participants. This marks the only trial in the field that included patients with ACS managed medically, Dr. Windecker said.
At baseline, the median age of patients was 71 years, 30% were female, 36% had diabetes, and 45% had heart failure. Patients managed medically were younger (a median age of 70) and more frequently female; 57% presented with heart failure. The groups had identical CHA2DS2VASc scores (4), and very similar HAS-BLED scores (2 in groups 1 and 2, and 3 in group 3).
Apixaban compared with VKA showed lower International Society on Thrombosis and Haemostasis–defined major or clinically relevant nonmajor bleeding among patients in group 1 (HR, 0.44), group 2 (HR, 0.68), and group 3 (HR, 0.82) (P for interaction = .052). Apixaban compared with VKA reduced death or hospitalization among patients in group 1 (HR, 0.71), group 2 (HR 0.88), and group 3 (HR, 0.87) (P for interaction = .345). Compared with VKA, apixaban resulted in a similar effect on death and ischemic events among patients in all three treatment groups (P for interaction = .356).
Compared with placebo, aspirin had a higher rate of bleeding among patients in group 1 (HR, 1.49), group 2 (HR, 2.02) and group 3 (HR, 1.91) (P for interaction = .479). For the same comparison, there was no difference in outcomes among the three groups for the composite of death or hospitalization and death and ischemic events.
“The overall results of the AUGUSTUS trial are consistent across the three clinically important subgroups,” Dr. Windecker said. The reasons why patients received medical therapy remain unclear, “because it was at the physician’s discretion as to whether they were treated medically or underwent PCI,” he said. “The proportion very much reflects our clinical practice, where 20%-25% of patients are treated medically. What was surprising for me is that I would have anticipated there would be more elderly patients with comorbidities, but I did anticipate that there would be more female patients (in this subgroup).”
Robert A. Harrington, MD, an interventional cardiologist at Stanford (Calif.) University who served on the Data Safety and Monitoring Board for the trial, noted that the patients with atrial fibrillation represent 7%-10% of all ACS patients, “so it’s a big population,” he said. “What’s been disappointing is that none of the trials have been big enough to uncouple the bleeding vs. ischemic issue. We don’t know the answer for how long do you need the triple therapy versus when you can switch to the double therapy.”
Dr. Windecker said that the optimal duration of short-term aspirin remains unclear in this patient population. “Whether there is a benefit of giving aspirin for 2 weeks or 4 weeks remains unanswered,” he said. “Triple therapy is not the way to go, but we need to fine-tune, and probably individualize, which patients may benefit from a certain duration of aspirin.”
The study results were published online at the time of presentation (Circulation 2019 Sep 26. doi: 10.1161/CIRCULATIONAHA.119.043308.
AUGUSTUS was funded by Bristol-Myers Squibb and Pfizer Inc. Dr. Windecker reported having received institutional research and educational grants to Bern University Hospital from Abbott, Amgen, Bayer, BMS, CSL Behring, Boston Scientific, Biotronik, Edwards Lifesciences, Medtronic, Polares, and Sinomed. His coauthors reported having numerous financial ties to the pharmaceutical and device industries.
SOURCE: Windecker S. TCT 2019, Late-Breaking Trials 1 session.
AT TCT 2019
Drug abuse–linked infective endocarditis spiking in U.S.
Hospitalizations for infective endocarditis associated with drug abuse doubled in the United States from 2002 to 2016, in a trend investigators call “alarming,” and link to a concurrent rise in opioid abuse.
Patients tend to be younger, poorer white males, according to findings published online in the Journal of the American Heart Association.
For their research, Amer N. Kadri, MD, of the Cleveland Clinic and colleagues looked at records for nearly a million hospitalizations for infective endocarditis (IE) in the National Inpatient Sample registry. All U.S. regions saw increases in drug abuse–linked cases of IE as a share of IE hospitalizations. Incidence of drug abuse–associated IC rose from 48 cases/100,000 population in 2002 to 79/100,000 in 2016. The Midwest saw the highest rate of change, with an annual percent increase of 4.9%.
While most IE hospitalizations in the study cohort were of white men (including 68% for drug-linked cases), the drug abuse–related cases were younger (median age, 38 vs. 70 years for nondrug-related IE), and more likely male (55.5% vs. 50%). About 45% of the drug-related cases were in people receiving Medicaid, and 42% were in the lowest quartile of median household income.
The drug abuse cases had fewer renal and cardiovascular comorbidities, compared with the nondrug cases, but were significantly more likely to present with HIV, hepatitis C, alcohol abuse, and liver disease. Inpatient mortality was lower among the drug-linked cases – 6% vs. 9% – but the drug cases saw significantly more cardiac or valve surgeries, longer hospital stays, and higher costs.
“Hospitalizations for IE have been increasing side by side with the opioid epidemic,” the investigators wrote in their analysis. “The opioid crisis has reached epidemic levels, and now drug overdoses have been the leading cause of injury-related death in the U.S. Heroin deaths had remained relatively low from 1999 until 2010 whereas it then increased threefold from 2010-2015.” The analysis showed a rise in drug abuse–associated IE “that corresponds to this general period.” The findings argue, the investigators said, for better treatment for opioid addiction after hospitalization and greater efforts to make drug rehabilitation available after discharge. The researchers described as a limitation of their study the use of billing codes that changed late in the study period, increasing detection of drug abuse cases after 2015. They reported no outside funding or conflicts of interest.
SOURCE: Kadri AN et al. J Am Heart Assoc. 2019 Sep 18.
Hospitalizations for infective endocarditis associated with drug abuse doubled in the United States from 2002 to 2016, in a trend investigators call “alarming,” and link to a concurrent rise in opioid abuse.
Patients tend to be younger, poorer white males, according to findings published online in the Journal of the American Heart Association.
For their research, Amer N. Kadri, MD, of the Cleveland Clinic and colleagues looked at records for nearly a million hospitalizations for infective endocarditis (IE) in the National Inpatient Sample registry. All U.S. regions saw increases in drug abuse–linked cases of IE as a share of IE hospitalizations. Incidence of drug abuse–associated IC rose from 48 cases/100,000 population in 2002 to 79/100,000 in 2016. The Midwest saw the highest rate of change, with an annual percent increase of 4.9%.
While most IE hospitalizations in the study cohort were of white men (including 68% for drug-linked cases), the drug abuse–related cases were younger (median age, 38 vs. 70 years for nondrug-related IE), and more likely male (55.5% vs. 50%). About 45% of the drug-related cases were in people receiving Medicaid, and 42% were in the lowest quartile of median household income.
The drug abuse cases had fewer renal and cardiovascular comorbidities, compared with the nondrug cases, but were significantly more likely to present with HIV, hepatitis C, alcohol abuse, and liver disease. Inpatient mortality was lower among the drug-linked cases – 6% vs. 9% – but the drug cases saw significantly more cardiac or valve surgeries, longer hospital stays, and higher costs.
“Hospitalizations for IE have been increasing side by side with the opioid epidemic,” the investigators wrote in their analysis. “The opioid crisis has reached epidemic levels, and now drug overdoses have been the leading cause of injury-related death in the U.S. Heroin deaths had remained relatively low from 1999 until 2010 whereas it then increased threefold from 2010-2015.” The analysis showed a rise in drug abuse–associated IE “that corresponds to this general period.” The findings argue, the investigators said, for better treatment for opioid addiction after hospitalization and greater efforts to make drug rehabilitation available after discharge. The researchers described as a limitation of their study the use of billing codes that changed late in the study period, increasing detection of drug abuse cases after 2015. They reported no outside funding or conflicts of interest.
SOURCE: Kadri AN et al. J Am Heart Assoc. 2019 Sep 18.
Hospitalizations for infective endocarditis associated with drug abuse doubled in the United States from 2002 to 2016, in a trend investigators call “alarming,” and link to a concurrent rise in opioid abuse.
Patients tend to be younger, poorer white males, according to findings published online in the Journal of the American Heart Association.
For their research, Amer N. Kadri, MD, of the Cleveland Clinic and colleagues looked at records for nearly a million hospitalizations for infective endocarditis (IE) in the National Inpatient Sample registry. All U.S. regions saw increases in drug abuse–linked cases of IE as a share of IE hospitalizations. Incidence of drug abuse–associated IC rose from 48 cases/100,000 population in 2002 to 79/100,000 in 2016. The Midwest saw the highest rate of change, with an annual percent increase of 4.9%.
While most IE hospitalizations in the study cohort were of white men (including 68% for drug-linked cases), the drug abuse–related cases were younger (median age, 38 vs. 70 years for nondrug-related IE), and more likely male (55.5% vs. 50%). About 45% of the drug-related cases were in people receiving Medicaid, and 42% were in the lowest quartile of median household income.
The drug abuse cases had fewer renal and cardiovascular comorbidities, compared with the nondrug cases, but were significantly more likely to present with HIV, hepatitis C, alcohol abuse, and liver disease. Inpatient mortality was lower among the drug-linked cases – 6% vs. 9% – but the drug cases saw significantly more cardiac or valve surgeries, longer hospital stays, and higher costs.
“Hospitalizations for IE have been increasing side by side with the opioid epidemic,” the investigators wrote in their analysis. “The opioid crisis has reached epidemic levels, and now drug overdoses have been the leading cause of injury-related death in the U.S. Heroin deaths had remained relatively low from 1999 until 2010 whereas it then increased threefold from 2010-2015.” The analysis showed a rise in drug abuse–associated IE “that corresponds to this general period.” The findings argue, the investigators said, for better treatment for opioid addiction after hospitalization and greater efforts to make drug rehabilitation available after discharge. The researchers described as a limitation of their study the use of billing codes that changed late in the study period, increasing detection of drug abuse cases after 2015. They reported no outside funding or conflicts of interest.
SOURCE: Kadri AN et al. J Am Heart Assoc. 2019 Sep 18.
FROM THE JOURNAL OF THE AMERICAN HEART ASSOCIATION
Key clinical point:
Major finding: Incidence of drug abuse–associated IC increased from 48 cases/100,000 in 2002 to 79/100,000 in 2016.
Study details: A retrospective cohort study identifying about a more than 950,000 cases of IC from the National Inpatient Sample registry.
Disclosures: None.
Source: Kadri AN et al. J Am Heart Assoc. 2019 Sep 18.
Rivaroxaban bests combo therapy in post-PCI AFib
PARIS – Rivaroxaban monotherapy bested combination therapy with rivaroxaban and an antiplatelet agent for patients with atrial fibrillation and stable coronary artery disease, with significantly more deaths and bleeding events seen with combination therapy.
The pronounced imbalance in all-cause and cardiovascular mortality (the hazard ratio favoring rivaroxaban monotherapy was 9.72) came as a surprise, and led to early cessation of the multisite Japanese trial, lead investigator Satoshi Yasuda, MD, said at the annual congress of the European Society of Cardiology.
Several previous clinical trials had studied a reduced antithrombotic regimen for patients with atrial fibrillation (AFib) after percutaneous coronary intervention (PCI), said Dr. Yasuda, professor of medicine at Tohoku University, Sendai, Japan. Current guidelines recommend triple therapy with an oral anticoagulant plus aspirin and a P2Y12 inhibitor for the shortest duration possible, with combination therapy of an anticoagulant plus a P2Y12 inhibitor for up to 12 months. Once the 1-year post-PCI mark is reached, current European and American guidelines or consensus documents recommend monotherapy with an oral anticoagulant if AFib persists and the patient has stable coronary artery disease (CAD), explained Dr. Yasuda. “However, this approach has yet to be supported by evidence from randomized, controlled trials,” he said, adding “substantial numbers of patients in this situation continue to be treated with combination therapy, which indicates a gap between guidelines and clinical practice.”
The Atrial Fibrillation and Ischemic events with Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE), he said, was designed to address this practice gap, randomizing 2,200 individuals to receive monotherapy with rivaroxaban or combination therapy. A total of 1,973 patients completed follow-up.
Patients were included in the randomized, open-label, parallel-group trial if they had AFib and stable CAD and were more than 1 year out from revascularization, or if they had angiographically confirmed CAD that did not need revascularization. All 294 AFIRE study sites were in Japan.
The study’s primary endpoint for efficacy was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, and all-cause death.
Most of the patients (79%) were male, and the mean age was 74 years. About 70% of patients in each treatment arm had received prior PCI, and 11% had undergone previous coronary artery bypass grafting (CABG).
The monotherapy arm received rivaroxaban 10 or 15 mg once daily depending on renal status. Patients in the combination therapy arm received rivaroxaban, plus a single antiplatelet drug. This could be 81 or 100 mg aspirin daily, clopidogrel at 50 or 75 mg/day, or prasugrel at 2.5 or 3.5 mg/day.
On the recommendation of the data and safety monitoring committee, the trial was terminated about 3 months early because significantly more all-cause deaths were being seen in the combination therapy group, said Dr. Yasuda. In the end, patients were treated under the study protocol for a median 23 months and followed up for a median 24.1 months.
Kaplan-Meier estimates for the first occurrence of the composite efficacy endpoint showed that monotherapy had a rate of 4.14% per patient-year, while combination therapy had a rate of occurrence for the efficacy endpoint of 5.75% per patient-year.
These figures yielded a statistically significant hazard ratio (HR) of 9.72 favoring monotherapy (P less than .001) for the prespecified noninferiority endpoint. In a post hoc analysis, rivaroxaban monotherapy achieved superiority over dual therapy (P = .02).
Breaking down the composite efficacy endpoint into its constituents, deaths by any cause and cardiovascular deaths primarily drove the difference in treatment arms. Seventy-three patients in the combo therapy arm and 41 in the rivaroxaban arm died of any cause, and the cause of death was cardiovascular for 43 combination therapy patients and 26 monotherapy patients. This yielded HRs favoring rivaroxaban of 0.55 for all-cause mortality and 0.59 for cardiovascular deaths.
Hazard ratios for individual cardiovascular events were not statistically significantly different between treatment arms, except for hemorrhagic stroke, which was seen in 13 patients receiving dual therapy and 4 receiving rivaroxaban alone, for a hazard ratio of 0.30.
Rivaroxaban monotherapy also bested dual therapy in safety: The HR was 0.59 for the incidence of a major bleed on rivaroxaban versus combination therapy, using International Society on Thrombosis and Haemostasis–established criteria for major bleeding. In the dual therapy arm, 58 individuals experienced major bleeding – the study’s primary safety endpoint – compared with 35 in the monotherapy arm, for a hazard ratio of 0.59; nonmajor bleeding occurred in 198 dual therapy patients and 121 monotherapy patients, yielding a hazard ratio of 0.58.
The Kaplan-Meier estimate for major bleeding on monotherapy was 1.62% per patient-year, compared with 2.76% per patient-year for those on combination therapy. These findings, said Dr. Yasuda, were “generally” consistent across prespecified subgroups that included participant stratification by age, sex, and bleeding risk, among others.
Dr. Yasuda acknowledged the many limitations of the trial. First, early termination introduced the possibility of overestimating the benefit of rivaroxaban monotherapy. Indeed, said Dr. Yasuda, “the reductions in rate of ischemic events and death from any cause with rivaroxaban monotherapy were unanticipated and are difficult to explain.”
Furthermore, the open-label trial design could be a source of bias and the use of both aspirin and P2Y12 inhibitors for antiplatelet therapy “makes it uncertain whether the benefit of rivaroxaban monotherapy applies equally to the two combination regimens,” said Dr. Yasuda.
Rivaroxaban dosing in AFIRE was tailored to the Japanese study population, noted Dr. Yasuda. This means that the study is not immediately generalizable to non-Asian populations, needing replication before fully closing the knowledge gap about best long-term management of patients with AFib and stable CAD in the United States and Western Europe.
However, Dr. Yasuda pointed out, serum rivaroxaban levels in Japanese patients taking the 10- or 15-mg dose are generally similar to those seen in white patients taking a 20-mg rivaroxaban dose.
Freek Verheugt, MD, of Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, was the discussant for the presentation. He raised an additional concern: “East Asian patients are poor metabolizers of clopidogrel, which may have resulted also in underestimation of bleeding.” He cautioned that the AFIRE results may not be applicable to patients on a novel anticoagulant other than clopidogrel, or on vitamin K antagonists.
In his detailed critique of the AFIRE results, Dr. Verheugt cited the OAC ALONE trial, which used a similar study design and was also conducted in Japan. For OAC ALONE, Dr. Verheugt pointed out that “You can see ... that it was not harmful in this 700-patient study to stop aspirin therapy 1 year after an intervention.” However, he said, “the net clinical benefit is not very different, either” between treatment arms in the OAC ALONE trial. “Given the low number of patients and the low number of events, this trial was not conclusive whatsoever” he added, so AFIRE’s findings were needed.
The safety data from AFIRE, with a study population triple that of OAC ALONE, makes the safety argument for monotherapy “a very easy winner,” said Dr. Verheugt.
Dr. Verheugt was not mystified by the lower all-cause and cardiovascular death rate in the monotherapy group. “What are the mechanisms that if you stop antiplatelet therapy you have a better ischemic outcome? How come?” asked Dr. Verheugt.
“Very likely, it is the bleeding ... that you prevent if you stop antiplatelet therapy,” he said, adding that it’s known from previous studies in individuals with acute coronary syndromes and AFib that “bleeding is correlated with mortality, and that’s also proven here.”
Though Dr. Verheugt joined Dr. Yasuda in calling for replication of the results in a non-Asian population, he concurred that the AFIRE results validate current practice for anticoagulation in AFib with stable CAD. “Stopping at 1 year is safer than continuation and, most of all, it saves lives,” he said.
Full results of AFIRE were published online at the time of Dr. Yasuda’s presentation (N Engl J Med. 2019 Sep 2. doi: 10.1056/NEJMoa1904143).
The study was funded by the Japanese Cardiovascular Research Foundation. Dr. Yasuda reported financial relationships with Abbott, Bristol-Myers, Daiichi-Sankyo, and Takeda. Dr. Verheugt reported financial relationships with BayerHealthcare, BMS/Pfizer, Boehringer-Ingelheim, and Daiichi-Sankyo.
SOURCE: Yasuda S. et al. ESC 2019, Hot Line Session 3, Abstract 3175.
PARIS – Rivaroxaban monotherapy bested combination therapy with rivaroxaban and an antiplatelet agent for patients with atrial fibrillation and stable coronary artery disease, with significantly more deaths and bleeding events seen with combination therapy.
The pronounced imbalance in all-cause and cardiovascular mortality (the hazard ratio favoring rivaroxaban monotherapy was 9.72) came as a surprise, and led to early cessation of the multisite Japanese trial, lead investigator Satoshi Yasuda, MD, said at the annual congress of the European Society of Cardiology.
Several previous clinical trials had studied a reduced antithrombotic regimen for patients with atrial fibrillation (AFib) after percutaneous coronary intervention (PCI), said Dr. Yasuda, professor of medicine at Tohoku University, Sendai, Japan. Current guidelines recommend triple therapy with an oral anticoagulant plus aspirin and a P2Y12 inhibitor for the shortest duration possible, with combination therapy of an anticoagulant plus a P2Y12 inhibitor for up to 12 months. Once the 1-year post-PCI mark is reached, current European and American guidelines or consensus documents recommend monotherapy with an oral anticoagulant if AFib persists and the patient has stable coronary artery disease (CAD), explained Dr. Yasuda. “However, this approach has yet to be supported by evidence from randomized, controlled trials,” he said, adding “substantial numbers of patients in this situation continue to be treated with combination therapy, which indicates a gap between guidelines and clinical practice.”
The Atrial Fibrillation and Ischemic events with Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE), he said, was designed to address this practice gap, randomizing 2,200 individuals to receive monotherapy with rivaroxaban or combination therapy. A total of 1,973 patients completed follow-up.
Patients were included in the randomized, open-label, parallel-group trial if they had AFib and stable CAD and were more than 1 year out from revascularization, or if they had angiographically confirmed CAD that did not need revascularization. All 294 AFIRE study sites were in Japan.
The study’s primary endpoint for efficacy was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, and all-cause death.
Most of the patients (79%) were male, and the mean age was 74 years. About 70% of patients in each treatment arm had received prior PCI, and 11% had undergone previous coronary artery bypass grafting (CABG).
The monotherapy arm received rivaroxaban 10 or 15 mg once daily depending on renal status. Patients in the combination therapy arm received rivaroxaban, plus a single antiplatelet drug. This could be 81 or 100 mg aspirin daily, clopidogrel at 50 or 75 mg/day, or prasugrel at 2.5 or 3.5 mg/day.
On the recommendation of the data and safety monitoring committee, the trial was terminated about 3 months early because significantly more all-cause deaths were being seen in the combination therapy group, said Dr. Yasuda. In the end, patients were treated under the study protocol for a median 23 months and followed up for a median 24.1 months.
Kaplan-Meier estimates for the first occurrence of the composite efficacy endpoint showed that monotherapy had a rate of 4.14% per patient-year, while combination therapy had a rate of occurrence for the efficacy endpoint of 5.75% per patient-year.
These figures yielded a statistically significant hazard ratio (HR) of 9.72 favoring monotherapy (P less than .001) for the prespecified noninferiority endpoint. In a post hoc analysis, rivaroxaban monotherapy achieved superiority over dual therapy (P = .02).
Breaking down the composite efficacy endpoint into its constituents, deaths by any cause and cardiovascular deaths primarily drove the difference in treatment arms. Seventy-three patients in the combo therapy arm and 41 in the rivaroxaban arm died of any cause, and the cause of death was cardiovascular for 43 combination therapy patients and 26 monotherapy patients. This yielded HRs favoring rivaroxaban of 0.55 for all-cause mortality and 0.59 for cardiovascular deaths.
Hazard ratios for individual cardiovascular events were not statistically significantly different between treatment arms, except for hemorrhagic stroke, which was seen in 13 patients receiving dual therapy and 4 receiving rivaroxaban alone, for a hazard ratio of 0.30.
Rivaroxaban monotherapy also bested dual therapy in safety: The HR was 0.59 for the incidence of a major bleed on rivaroxaban versus combination therapy, using International Society on Thrombosis and Haemostasis–established criteria for major bleeding. In the dual therapy arm, 58 individuals experienced major bleeding – the study’s primary safety endpoint – compared with 35 in the monotherapy arm, for a hazard ratio of 0.59; nonmajor bleeding occurred in 198 dual therapy patients and 121 monotherapy patients, yielding a hazard ratio of 0.58.
The Kaplan-Meier estimate for major bleeding on monotherapy was 1.62% per patient-year, compared with 2.76% per patient-year for those on combination therapy. These findings, said Dr. Yasuda, were “generally” consistent across prespecified subgroups that included participant stratification by age, sex, and bleeding risk, among others.
Dr. Yasuda acknowledged the many limitations of the trial. First, early termination introduced the possibility of overestimating the benefit of rivaroxaban monotherapy. Indeed, said Dr. Yasuda, “the reductions in rate of ischemic events and death from any cause with rivaroxaban monotherapy were unanticipated and are difficult to explain.”
Furthermore, the open-label trial design could be a source of bias and the use of both aspirin and P2Y12 inhibitors for antiplatelet therapy “makes it uncertain whether the benefit of rivaroxaban monotherapy applies equally to the two combination regimens,” said Dr. Yasuda.
Rivaroxaban dosing in AFIRE was tailored to the Japanese study population, noted Dr. Yasuda. This means that the study is not immediately generalizable to non-Asian populations, needing replication before fully closing the knowledge gap about best long-term management of patients with AFib and stable CAD in the United States and Western Europe.
However, Dr. Yasuda pointed out, serum rivaroxaban levels in Japanese patients taking the 10- or 15-mg dose are generally similar to those seen in white patients taking a 20-mg rivaroxaban dose.
Freek Verheugt, MD, of Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, was the discussant for the presentation. He raised an additional concern: “East Asian patients are poor metabolizers of clopidogrel, which may have resulted also in underestimation of bleeding.” He cautioned that the AFIRE results may not be applicable to patients on a novel anticoagulant other than clopidogrel, or on vitamin K antagonists.
In his detailed critique of the AFIRE results, Dr. Verheugt cited the OAC ALONE trial, which used a similar study design and was also conducted in Japan. For OAC ALONE, Dr. Verheugt pointed out that “You can see ... that it was not harmful in this 700-patient study to stop aspirin therapy 1 year after an intervention.” However, he said, “the net clinical benefit is not very different, either” between treatment arms in the OAC ALONE trial. “Given the low number of patients and the low number of events, this trial was not conclusive whatsoever” he added, so AFIRE’s findings were needed.
The safety data from AFIRE, with a study population triple that of OAC ALONE, makes the safety argument for monotherapy “a very easy winner,” said Dr. Verheugt.
Dr. Verheugt was not mystified by the lower all-cause and cardiovascular death rate in the monotherapy group. “What are the mechanisms that if you stop antiplatelet therapy you have a better ischemic outcome? How come?” asked Dr. Verheugt.
“Very likely, it is the bleeding ... that you prevent if you stop antiplatelet therapy,” he said, adding that it’s known from previous studies in individuals with acute coronary syndromes and AFib that “bleeding is correlated with mortality, and that’s also proven here.”
Though Dr. Verheugt joined Dr. Yasuda in calling for replication of the results in a non-Asian population, he concurred that the AFIRE results validate current practice for anticoagulation in AFib with stable CAD. “Stopping at 1 year is safer than continuation and, most of all, it saves lives,” he said.
Full results of AFIRE were published online at the time of Dr. Yasuda’s presentation (N Engl J Med. 2019 Sep 2. doi: 10.1056/NEJMoa1904143).
The study was funded by the Japanese Cardiovascular Research Foundation. Dr. Yasuda reported financial relationships with Abbott, Bristol-Myers, Daiichi-Sankyo, and Takeda. Dr. Verheugt reported financial relationships with BayerHealthcare, BMS/Pfizer, Boehringer-Ingelheim, and Daiichi-Sankyo.
SOURCE: Yasuda S. et al. ESC 2019, Hot Line Session 3, Abstract 3175.
PARIS – Rivaroxaban monotherapy bested combination therapy with rivaroxaban and an antiplatelet agent for patients with atrial fibrillation and stable coronary artery disease, with significantly more deaths and bleeding events seen with combination therapy.
The pronounced imbalance in all-cause and cardiovascular mortality (the hazard ratio favoring rivaroxaban monotherapy was 9.72) came as a surprise, and led to early cessation of the multisite Japanese trial, lead investigator Satoshi Yasuda, MD, said at the annual congress of the European Society of Cardiology.
Several previous clinical trials had studied a reduced antithrombotic regimen for patients with atrial fibrillation (AFib) after percutaneous coronary intervention (PCI), said Dr. Yasuda, professor of medicine at Tohoku University, Sendai, Japan. Current guidelines recommend triple therapy with an oral anticoagulant plus aspirin and a P2Y12 inhibitor for the shortest duration possible, with combination therapy of an anticoagulant plus a P2Y12 inhibitor for up to 12 months. Once the 1-year post-PCI mark is reached, current European and American guidelines or consensus documents recommend monotherapy with an oral anticoagulant if AFib persists and the patient has stable coronary artery disease (CAD), explained Dr. Yasuda. “However, this approach has yet to be supported by evidence from randomized, controlled trials,” he said, adding “substantial numbers of patients in this situation continue to be treated with combination therapy, which indicates a gap between guidelines and clinical practice.”
The Atrial Fibrillation and Ischemic events with Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE), he said, was designed to address this practice gap, randomizing 2,200 individuals to receive monotherapy with rivaroxaban or combination therapy. A total of 1,973 patients completed follow-up.
Patients were included in the randomized, open-label, parallel-group trial if they had AFib and stable CAD and were more than 1 year out from revascularization, or if they had angiographically confirmed CAD that did not need revascularization. All 294 AFIRE study sites were in Japan.
The study’s primary endpoint for efficacy was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, and all-cause death.
Most of the patients (79%) were male, and the mean age was 74 years. About 70% of patients in each treatment arm had received prior PCI, and 11% had undergone previous coronary artery bypass grafting (CABG).
The monotherapy arm received rivaroxaban 10 or 15 mg once daily depending on renal status. Patients in the combination therapy arm received rivaroxaban, plus a single antiplatelet drug. This could be 81 or 100 mg aspirin daily, clopidogrel at 50 or 75 mg/day, or prasugrel at 2.5 or 3.5 mg/day.
On the recommendation of the data and safety monitoring committee, the trial was terminated about 3 months early because significantly more all-cause deaths were being seen in the combination therapy group, said Dr. Yasuda. In the end, patients were treated under the study protocol for a median 23 months and followed up for a median 24.1 months.
Kaplan-Meier estimates for the first occurrence of the composite efficacy endpoint showed that monotherapy had a rate of 4.14% per patient-year, while combination therapy had a rate of occurrence for the efficacy endpoint of 5.75% per patient-year.
These figures yielded a statistically significant hazard ratio (HR) of 9.72 favoring monotherapy (P less than .001) for the prespecified noninferiority endpoint. In a post hoc analysis, rivaroxaban monotherapy achieved superiority over dual therapy (P = .02).
Breaking down the composite efficacy endpoint into its constituents, deaths by any cause and cardiovascular deaths primarily drove the difference in treatment arms. Seventy-three patients in the combo therapy arm and 41 in the rivaroxaban arm died of any cause, and the cause of death was cardiovascular for 43 combination therapy patients and 26 monotherapy patients. This yielded HRs favoring rivaroxaban of 0.55 for all-cause mortality and 0.59 for cardiovascular deaths.
Hazard ratios for individual cardiovascular events were not statistically significantly different between treatment arms, except for hemorrhagic stroke, which was seen in 13 patients receiving dual therapy and 4 receiving rivaroxaban alone, for a hazard ratio of 0.30.
Rivaroxaban monotherapy also bested dual therapy in safety: The HR was 0.59 for the incidence of a major bleed on rivaroxaban versus combination therapy, using International Society on Thrombosis and Haemostasis–established criteria for major bleeding. In the dual therapy arm, 58 individuals experienced major bleeding – the study’s primary safety endpoint – compared with 35 in the monotherapy arm, for a hazard ratio of 0.59; nonmajor bleeding occurred in 198 dual therapy patients and 121 monotherapy patients, yielding a hazard ratio of 0.58.
The Kaplan-Meier estimate for major bleeding on monotherapy was 1.62% per patient-year, compared with 2.76% per patient-year for those on combination therapy. These findings, said Dr. Yasuda, were “generally” consistent across prespecified subgroups that included participant stratification by age, sex, and bleeding risk, among others.
Dr. Yasuda acknowledged the many limitations of the trial. First, early termination introduced the possibility of overestimating the benefit of rivaroxaban monotherapy. Indeed, said Dr. Yasuda, “the reductions in rate of ischemic events and death from any cause with rivaroxaban monotherapy were unanticipated and are difficult to explain.”
Furthermore, the open-label trial design could be a source of bias and the use of both aspirin and P2Y12 inhibitors for antiplatelet therapy “makes it uncertain whether the benefit of rivaroxaban monotherapy applies equally to the two combination regimens,” said Dr. Yasuda.
Rivaroxaban dosing in AFIRE was tailored to the Japanese study population, noted Dr. Yasuda. This means that the study is not immediately generalizable to non-Asian populations, needing replication before fully closing the knowledge gap about best long-term management of patients with AFib and stable CAD in the United States and Western Europe.
However, Dr. Yasuda pointed out, serum rivaroxaban levels in Japanese patients taking the 10- or 15-mg dose are generally similar to those seen in white patients taking a 20-mg rivaroxaban dose.
Freek Verheugt, MD, of Onze Lieve Vrouwe Gasthuis Hospital, Amsterdam, was the discussant for the presentation. He raised an additional concern: “East Asian patients are poor metabolizers of clopidogrel, which may have resulted also in underestimation of bleeding.” He cautioned that the AFIRE results may not be applicable to patients on a novel anticoagulant other than clopidogrel, or on vitamin K antagonists.
In his detailed critique of the AFIRE results, Dr. Verheugt cited the OAC ALONE trial, which used a similar study design and was also conducted in Japan. For OAC ALONE, Dr. Verheugt pointed out that “You can see ... that it was not harmful in this 700-patient study to stop aspirin therapy 1 year after an intervention.” However, he said, “the net clinical benefit is not very different, either” between treatment arms in the OAC ALONE trial. “Given the low number of patients and the low number of events, this trial was not conclusive whatsoever” he added, so AFIRE’s findings were needed.
The safety data from AFIRE, with a study population triple that of OAC ALONE, makes the safety argument for monotherapy “a very easy winner,” said Dr. Verheugt.
Dr. Verheugt was not mystified by the lower all-cause and cardiovascular death rate in the monotherapy group. “What are the mechanisms that if you stop antiplatelet therapy you have a better ischemic outcome? How come?” asked Dr. Verheugt.
“Very likely, it is the bleeding ... that you prevent if you stop antiplatelet therapy,” he said, adding that it’s known from previous studies in individuals with acute coronary syndromes and AFib that “bleeding is correlated with mortality, and that’s also proven here.”
Though Dr. Verheugt joined Dr. Yasuda in calling for replication of the results in a non-Asian population, he concurred that the AFIRE results validate current practice for anticoagulation in AFib with stable CAD. “Stopping at 1 year is safer than continuation and, most of all, it saves lives,” he said.
Full results of AFIRE were published online at the time of Dr. Yasuda’s presentation (N Engl J Med. 2019 Sep 2. doi: 10.1056/NEJMoa1904143).
The study was funded by the Japanese Cardiovascular Research Foundation. Dr. Yasuda reported financial relationships with Abbott, Bristol-Myers, Daiichi-Sankyo, and Takeda. Dr. Verheugt reported financial relationships with BayerHealthcare, BMS/Pfizer, Boehringer-Ingelheim, and Daiichi-Sankyo.
SOURCE: Yasuda S. et al. ESC 2019, Hot Line Session 3, Abstract 3175.
AT THE ESC CONGRESS 2019
ISAR-REACT 5: Prasugrel superior to ticagrelor in ACS
PARIS – Prasugrel proved superior to ticagrelor in patients with acute coronary syndrome (ACS) in what was hailed as “a landmark study” presented at the annual congress of the European Society of Cardiology.
The results of ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) were unequivocal: “In ACS patients with or without ST-segment elevation, treatment with prasugrel as compared with ticagrelor significantly reduced the composite rate of death, myocardial infarction, or stroke at 1 year without an increase in major bleeding,” declared first author Stephanie Schuepke, MD, a cardiologist at the German Heart Center in Munich.
The study outcome was totally unexpected. Indeed, the result didn’t merely turn heads, it no doubt caused numerous wrenched necks caused by strenuous double-takes on the part of interventional cardiologists at the congress. That’s because, even though both ticagrelor and prasugrel enjoy a class I recommendation for use in ACS in the ESC guidelines, it has been widely assumed – based on previous evidence plus the fact that ticagrelor is the more potent platelet inhibitor – that ticagrelor is the superior drug in this setting. It turns out, however, that those earlier studies weren’t germane to the issue directly addressed in ISAR-REACT 5, the first-ever direct head-to-head comparison of the two potent P2Y12 inhibitors in the setting of ACS with a planned invasive strategy.
“Obviously, very surprising results,” commented Roxana Mehran, MD, professor of medicine and director of interventional cardiology research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York, who cochaired a press conference where Dr. Schuepke shared the study findings.
“We were surprised as well,” confessed Dr. Schuepke. “We assumed that ticagrelor is superior to prasugrel in terms of clinical outcomes in patients with ACS with a planned invasive strategy. But the results show us that the opposite is true.”
ISAR-REACT 5 was an open-label, investigator-initiated randomized trial conducted at 23 centers in Germany and Italy. It included 4,018 participants with ST-elevation segment MI (STEMI), without STEMI, or with unstable angina, all with scheduled coronary angiography. Participants were randomized to ticagrelor or prasugrel and were expected to remain on their assigned potent antiplatelet agent plus aspirin for 1 year of dual-antiplatelet therapy.
The primary outcome was the composite of death, MI, or stroke at 1 year of follow-up. This endpoint occurred in 9.3% of the ticagrelor group and 6.9% of patients in the prasugrel group, for a highly significant 36% increased relative risk in the ticagrelor-treated patients. Prasugrel had a numeric advantage in each of the individual components of the endpoint: the 1-year rate of all-cause mortality was 4.5% with ticagrelor versus 3.7% with prasugrel; for MI, the incidence was 4.8% with ticagrelor and 3.0% with prasugrel, a statistically significant difference; and for stroke, 1.1% versus 1.0%.
Major bleeding as defined by the Bleeding Academic Research Consortium scale occurred in 5.4% of patients in the ticagrelor arm, and was similar at 4.8% in the prasugrel group, Dr. Schuepke continued.
Definite or probable stent thrombosis occurred in 1.3% of the ticagrelor group and 1.0% of patients assigned to prasugrel.
The mechanism for prasugrel’s superior results is unclear, she said. Possibilities include the fact that it’s a once-daily drug, compared with twice-daily ticagrelor, which could affect adherence; a differential profile in terms of drug interactions; and prasugrel’s reversibility of action and capacity for step-down dosing in patients at high bleeding risk.
Discussant Gilles Montalescot, MD, PhD, called ISAR-REACT 5 a “fascinating” study. He elaborated: “It is a pragmatic study to answer a pragmatic question. It’s not a drug trial; really, it’s more a strategy trial, with a comparison of two drugs and two strategies.”
In ISAR-REACT 5, ticagrelor was utilized in standard fashion: Patients, regardless of their ACS type, received a 180-mg loading dose as soon as possible after randomization, typically about 3 hours after presentation. That was also the protocol in the prasugrel arm, but only in patients with STEMI, who quickly got a 60-mg loading dose. In contrast, patients without STEMI or with unstable angina didn’t get a loading dose of prasugrel until they’d undergone coronary angiography and their coronary anatomy was known. That was the ISAR-REACT 5 strategy in light of an earlier study, which concluded that giving prasugrel prior to angiography in such patients led to increased bleeding without any improvement in clinical outcomes.
The essence of ISAR-REACT 5 lies in that difference in treatment strategies and the impact it had on outcomes. “The one-size-fits-all strategy – here, with ticagrelor – was inferior to an individualized strategy, here with prasugrel,” observed Dr. Montalescot, professor of cardiology at the University of Paris VI and director of the cardiac care unit at Paris-Salpetriere Hospital.
The study results were notably consistent, favoring prasugrel over ticagrelor numerically across the board regardless of whether a patient presented with STEMI, without STEMI, or with unstable angina. Particularly noteworthy was the finding that this was also true in terms of the individual components of the 1-year composite endpoint. Dr. Montalescot drew special attention to the large subset of patients who had presented with STEMI and thus received the same treatment strategy involving a loading dose of their assigned P2Y12 inhibitor prior to angiography. This allowed for a direct head-to-head comparison of the clinical efficacy of the two antiplatelet agents in STEMI patients. The clear winner here was prasugrel, as the composite event rate was 10.1% in the ticagrelor group, compared with 7.9% in the prasugrel group.
“ISAR-REACT 5 is a landmark study which is going to impact our practice and the next set of guidelines to come in 2020,” the interventional cardiologist predicted.
Dr. Schuepke reported having no financial conflicts regarding the ISAR-REACT 5 study, sponsored by the German Heart Center and the German Center for Cardiovascular Research.
Simultaneous with her presentation of ISAR-REACT 5, the study results were published online (N Engl J Med. 2019 Sep 1. doi: 10.1056/NEJMoa1908973).
PARIS – Prasugrel proved superior to ticagrelor in patients with acute coronary syndrome (ACS) in what was hailed as “a landmark study” presented at the annual congress of the European Society of Cardiology.
The results of ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) were unequivocal: “In ACS patients with or without ST-segment elevation, treatment with prasugrel as compared with ticagrelor significantly reduced the composite rate of death, myocardial infarction, or stroke at 1 year without an increase in major bleeding,” declared first author Stephanie Schuepke, MD, a cardiologist at the German Heart Center in Munich.
The study outcome was totally unexpected. Indeed, the result didn’t merely turn heads, it no doubt caused numerous wrenched necks caused by strenuous double-takes on the part of interventional cardiologists at the congress. That’s because, even though both ticagrelor and prasugrel enjoy a class I recommendation for use in ACS in the ESC guidelines, it has been widely assumed – based on previous evidence plus the fact that ticagrelor is the more potent platelet inhibitor – that ticagrelor is the superior drug in this setting. It turns out, however, that those earlier studies weren’t germane to the issue directly addressed in ISAR-REACT 5, the first-ever direct head-to-head comparison of the two potent P2Y12 inhibitors in the setting of ACS with a planned invasive strategy.
“Obviously, very surprising results,” commented Roxana Mehran, MD, professor of medicine and director of interventional cardiology research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York, who cochaired a press conference where Dr. Schuepke shared the study findings.
“We were surprised as well,” confessed Dr. Schuepke. “We assumed that ticagrelor is superior to prasugrel in terms of clinical outcomes in patients with ACS with a planned invasive strategy. But the results show us that the opposite is true.”
ISAR-REACT 5 was an open-label, investigator-initiated randomized trial conducted at 23 centers in Germany and Italy. It included 4,018 participants with ST-elevation segment MI (STEMI), without STEMI, or with unstable angina, all with scheduled coronary angiography. Participants were randomized to ticagrelor or prasugrel and were expected to remain on their assigned potent antiplatelet agent plus aspirin for 1 year of dual-antiplatelet therapy.
The primary outcome was the composite of death, MI, or stroke at 1 year of follow-up. This endpoint occurred in 9.3% of the ticagrelor group and 6.9% of patients in the prasugrel group, for a highly significant 36% increased relative risk in the ticagrelor-treated patients. Prasugrel had a numeric advantage in each of the individual components of the endpoint: the 1-year rate of all-cause mortality was 4.5% with ticagrelor versus 3.7% with prasugrel; for MI, the incidence was 4.8% with ticagrelor and 3.0% with prasugrel, a statistically significant difference; and for stroke, 1.1% versus 1.0%.
Major bleeding as defined by the Bleeding Academic Research Consortium scale occurred in 5.4% of patients in the ticagrelor arm, and was similar at 4.8% in the prasugrel group, Dr. Schuepke continued.
Definite or probable stent thrombosis occurred in 1.3% of the ticagrelor group and 1.0% of patients assigned to prasugrel.
The mechanism for prasugrel’s superior results is unclear, she said. Possibilities include the fact that it’s a once-daily drug, compared with twice-daily ticagrelor, which could affect adherence; a differential profile in terms of drug interactions; and prasugrel’s reversibility of action and capacity for step-down dosing in patients at high bleeding risk.
Discussant Gilles Montalescot, MD, PhD, called ISAR-REACT 5 a “fascinating” study. He elaborated: “It is a pragmatic study to answer a pragmatic question. It’s not a drug trial; really, it’s more a strategy trial, with a comparison of two drugs and two strategies.”
In ISAR-REACT 5, ticagrelor was utilized in standard fashion: Patients, regardless of their ACS type, received a 180-mg loading dose as soon as possible after randomization, typically about 3 hours after presentation. That was also the protocol in the prasugrel arm, but only in patients with STEMI, who quickly got a 60-mg loading dose. In contrast, patients without STEMI or with unstable angina didn’t get a loading dose of prasugrel until they’d undergone coronary angiography and their coronary anatomy was known. That was the ISAR-REACT 5 strategy in light of an earlier study, which concluded that giving prasugrel prior to angiography in such patients led to increased bleeding without any improvement in clinical outcomes.
The essence of ISAR-REACT 5 lies in that difference in treatment strategies and the impact it had on outcomes. “The one-size-fits-all strategy – here, with ticagrelor – was inferior to an individualized strategy, here with prasugrel,” observed Dr. Montalescot, professor of cardiology at the University of Paris VI and director of the cardiac care unit at Paris-Salpetriere Hospital.
The study results were notably consistent, favoring prasugrel over ticagrelor numerically across the board regardless of whether a patient presented with STEMI, without STEMI, or with unstable angina. Particularly noteworthy was the finding that this was also true in terms of the individual components of the 1-year composite endpoint. Dr. Montalescot drew special attention to the large subset of patients who had presented with STEMI and thus received the same treatment strategy involving a loading dose of their assigned P2Y12 inhibitor prior to angiography. This allowed for a direct head-to-head comparison of the clinical efficacy of the two antiplatelet agents in STEMI patients. The clear winner here was prasugrel, as the composite event rate was 10.1% in the ticagrelor group, compared with 7.9% in the prasugrel group.
“ISAR-REACT 5 is a landmark study which is going to impact our practice and the next set of guidelines to come in 2020,” the interventional cardiologist predicted.
Dr. Schuepke reported having no financial conflicts regarding the ISAR-REACT 5 study, sponsored by the German Heart Center and the German Center for Cardiovascular Research.
Simultaneous with her presentation of ISAR-REACT 5, the study results were published online (N Engl J Med. 2019 Sep 1. doi: 10.1056/NEJMoa1908973).
PARIS – Prasugrel proved superior to ticagrelor in patients with acute coronary syndrome (ACS) in what was hailed as “a landmark study” presented at the annual congress of the European Society of Cardiology.
The results of ISAR-REACT 5 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) were unequivocal: “In ACS patients with or without ST-segment elevation, treatment with prasugrel as compared with ticagrelor significantly reduced the composite rate of death, myocardial infarction, or stroke at 1 year without an increase in major bleeding,” declared first author Stephanie Schuepke, MD, a cardiologist at the German Heart Center in Munich.
The study outcome was totally unexpected. Indeed, the result didn’t merely turn heads, it no doubt caused numerous wrenched necks caused by strenuous double-takes on the part of interventional cardiologists at the congress. That’s because, even though both ticagrelor and prasugrel enjoy a class I recommendation for use in ACS in the ESC guidelines, it has been widely assumed – based on previous evidence plus the fact that ticagrelor is the more potent platelet inhibitor – that ticagrelor is the superior drug in this setting. It turns out, however, that those earlier studies weren’t germane to the issue directly addressed in ISAR-REACT 5, the first-ever direct head-to-head comparison of the two potent P2Y12 inhibitors in the setting of ACS with a planned invasive strategy.
“Obviously, very surprising results,” commented Roxana Mehran, MD, professor of medicine and director of interventional cardiology research and clinical trials at the Icahn School of Medicine at Mount Sinai, New York, who cochaired a press conference where Dr. Schuepke shared the study findings.
“We were surprised as well,” confessed Dr. Schuepke. “We assumed that ticagrelor is superior to prasugrel in terms of clinical outcomes in patients with ACS with a planned invasive strategy. But the results show us that the opposite is true.”
ISAR-REACT 5 was an open-label, investigator-initiated randomized trial conducted at 23 centers in Germany and Italy. It included 4,018 participants with ST-elevation segment MI (STEMI), without STEMI, or with unstable angina, all with scheduled coronary angiography. Participants were randomized to ticagrelor or prasugrel and were expected to remain on their assigned potent antiplatelet agent plus aspirin for 1 year of dual-antiplatelet therapy.
The primary outcome was the composite of death, MI, or stroke at 1 year of follow-up. This endpoint occurred in 9.3% of the ticagrelor group and 6.9% of patients in the prasugrel group, for a highly significant 36% increased relative risk in the ticagrelor-treated patients. Prasugrel had a numeric advantage in each of the individual components of the endpoint: the 1-year rate of all-cause mortality was 4.5% with ticagrelor versus 3.7% with prasugrel; for MI, the incidence was 4.8% with ticagrelor and 3.0% with prasugrel, a statistically significant difference; and for stroke, 1.1% versus 1.0%.
Major bleeding as defined by the Bleeding Academic Research Consortium scale occurred in 5.4% of patients in the ticagrelor arm, and was similar at 4.8% in the prasugrel group, Dr. Schuepke continued.
Definite or probable stent thrombosis occurred in 1.3% of the ticagrelor group and 1.0% of patients assigned to prasugrel.
The mechanism for prasugrel’s superior results is unclear, she said. Possibilities include the fact that it’s a once-daily drug, compared with twice-daily ticagrelor, which could affect adherence; a differential profile in terms of drug interactions; and prasugrel’s reversibility of action and capacity for step-down dosing in patients at high bleeding risk.
Discussant Gilles Montalescot, MD, PhD, called ISAR-REACT 5 a “fascinating” study. He elaborated: “It is a pragmatic study to answer a pragmatic question. It’s not a drug trial; really, it’s more a strategy trial, with a comparison of two drugs and two strategies.”
In ISAR-REACT 5, ticagrelor was utilized in standard fashion: Patients, regardless of their ACS type, received a 180-mg loading dose as soon as possible after randomization, typically about 3 hours after presentation. That was also the protocol in the prasugrel arm, but only in patients with STEMI, who quickly got a 60-mg loading dose. In contrast, patients without STEMI or with unstable angina didn’t get a loading dose of prasugrel until they’d undergone coronary angiography and their coronary anatomy was known. That was the ISAR-REACT 5 strategy in light of an earlier study, which concluded that giving prasugrel prior to angiography in such patients led to increased bleeding without any improvement in clinical outcomes.
The essence of ISAR-REACT 5 lies in that difference in treatment strategies and the impact it had on outcomes. “The one-size-fits-all strategy – here, with ticagrelor – was inferior to an individualized strategy, here with prasugrel,” observed Dr. Montalescot, professor of cardiology at the University of Paris VI and director of the cardiac care unit at Paris-Salpetriere Hospital.
The study results were notably consistent, favoring prasugrel over ticagrelor numerically across the board regardless of whether a patient presented with STEMI, without STEMI, or with unstable angina. Particularly noteworthy was the finding that this was also true in terms of the individual components of the 1-year composite endpoint. Dr. Montalescot drew special attention to the large subset of patients who had presented with STEMI and thus received the same treatment strategy involving a loading dose of their assigned P2Y12 inhibitor prior to angiography. This allowed for a direct head-to-head comparison of the clinical efficacy of the two antiplatelet agents in STEMI patients. The clear winner here was prasugrel, as the composite event rate was 10.1% in the ticagrelor group, compared with 7.9% in the prasugrel group.
“ISAR-REACT 5 is a landmark study which is going to impact our practice and the next set of guidelines to come in 2020,” the interventional cardiologist predicted.
Dr. Schuepke reported having no financial conflicts regarding the ISAR-REACT 5 study, sponsored by the German Heart Center and the German Center for Cardiovascular Research.
Simultaneous with her presentation of ISAR-REACT 5, the study results were published online (N Engl J Med. 2019 Sep 1. doi: 10.1056/NEJMoa1908973).
REPORTING FROM THE ESC CONGRESS 2019
Genotyping for thrombosis control in PCI equal to standard therapy
Genotype-guided selection of oral P2Y 12 inhibitors for patients having percutaneous coronary intervention with stent implantation derives no clinical benefits overall when compared to standard treatment, according to results of the large, randomized POPular Genetics trial, although genotype guidance did result in lower rates of primary minor bleeding.
The study was presented at the annual congress of the European Society of Cardiology Study in Paris and published simultaneously in the New England Journal of Medicine.
POPular Genetics (CYP2C19 Genotype-Guided Antiplatelet Therapy in ST-Segment Elevation Myocardial Infarction Patients – Patient Outcome After Primary PCI) randomized 2,488 patients who had PCI to either P2Y12 inhibitor on the basis of early genetic testing for the CYP2C19 gene (1,242 patients) or standard treatment with either ticagrelor or prasugrel (1,246 patients) for 12 months. In the genotype-guided group, patients were assigned to one of two arms depending on results; carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and non-carriers receive clopidogrel. The study was conducted from Jun. 2011 to Apr. 2018.
Net adverse clinical events, which included any-cause death, myocardial infarction, stent thrombosis, stroke or major bleeding based on the Platelet Inhibition and Patient Outcomes (PLATO) criteria at 12 months were similar between both groups: 5.1% in the genotype-guided patients and 5.9% in the standard-treatment group (P less than .001), but rates of PLATO major or minor bleeding were 9.8% and 12.5%, respectively (P = .04).
When secondary outcomes were evaluated, no significant differences emerged between the two groups. Secondary outcomes included combined thrombotic outcomes (death from vascular causes, myocardial infarction, stent thrombosis or stroke; 2.7% for the genotype-guided group vs. 3.3% in the standard-treatment group), and PLATO major bleeding (2.3% in both groups). The difference in the primary bleeding outcomes between the groups was driven by a lower incidence of PLATO minor bleeding in the genotype-guided group, 7.6% vs. 10.5%.
The two takeaways from POPular Genetics, said Daniel M.F. Claassens, MD, and coauthors, are that giving clopidogrel to patients without a CYP2C19 loss-of-function allele did not elevate their risk of combined any-cause death and other adverse cardiac outcomes, including major bleeding, 12 months after PCI; and that giving clopidogrel to the genotype-guided group lowered the risk of minor bleeding.
Dr. Claassens and coauthors noted that since the Netherlands trial was designed in 2011, the development of newer-generation stents has considerably lowered rates of thrombotic events after acute coronary syndromes. “With the lower-than-anticipated incidence of the primary combined outcome in our trial, the prespecified noninferiority margin was wider relative to the incidence than originally expected,” they said. While the primary combined outcome was 21% higher than the incidence in the standard-treatment group at the upper end of the 95% confidence interval, the incidence was 11% higher in the standard-treatment group at the observed upper end of the 95% CI. This “gives stronger support to the conclusion that genotype-guided P2Y12 treatment is noninferior to standard treatment for the occurrence of thrombotic events,” Dr. Claassens and coauthors said.
The study report noted a number of limitations, including that more polymorphisms of the CyP2C19 gene may be linked to increased thrombotic or bleeding risk. “Therefore, our strategy based solely on the CYP2C19 genotype may not be the most useful strategy for some patients,” Dr. Claassens and coauthors said.
POPular Genetics received funding from the Netherlands Organization for Health Research and Development (ZonMw). Dr. Claassens receives grants from ZonMw and non-financial support from Spartan Biosciences.
SOURCE: Claassens DMF, et al. N Engl J. Med. Published online September 3, doi.org/10.1016/S0140-6736(19)31996-8.
Genotype-guided selection of oral P2Y 12 inhibitors for patients having percutaneous coronary intervention with stent implantation derives no clinical benefits overall when compared to standard treatment, according to results of the large, randomized POPular Genetics trial, although genotype guidance did result in lower rates of primary minor bleeding.
The study was presented at the annual congress of the European Society of Cardiology Study in Paris and published simultaneously in the New England Journal of Medicine.
POPular Genetics (CYP2C19 Genotype-Guided Antiplatelet Therapy in ST-Segment Elevation Myocardial Infarction Patients – Patient Outcome After Primary PCI) randomized 2,488 patients who had PCI to either P2Y12 inhibitor on the basis of early genetic testing for the CYP2C19 gene (1,242 patients) or standard treatment with either ticagrelor or prasugrel (1,246 patients) for 12 months. In the genotype-guided group, patients were assigned to one of two arms depending on results; carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and non-carriers receive clopidogrel. The study was conducted from Jun. 2011 to Apr. 2018.
Net adverse clinical events, which included any-cause death, myocardial infarction, stent thrombosis, stroke or major bleeding based on the Platelet Inhibition and Patient Outcomes (PLATO) criteria at 12 months were similar between both groups: 5.1% in the genotype-guided patients and 5.9% in the standard-treatment group (P less than .001), but rates of PLATO major or minor bleeding were 9.8% and 12.5%, respectively (P = .04).
When secondary outcomes were evaluated, no significant differences emerged between the two groups. Secondary outcomes included combined thrombotic outcomes (death from vascular causes, myocardial infarction, stent thrombosis or stroke; 2.7% for the genotype-guided group vs. 3.3% in the standard-treatment group), and PLATO major bleeding (2.3% in both groups). The difference in the primary bleeding outcomes between the groups was driven by a lower incidence of PLATO minor bleeding in the genotype-guided group, 7.6% vs. 10.5%.
The two takeaways from POPular Genetics, said Daniel M.F. Claassens, MD, and coauthors, are that giving clopidogrel to patients without a CYP2C19 loss-of-function allele did not elevate their risk of combined any-cause death and other adverse cardiac outcomes, including major bleeding, 12 months after PCI; and that giving clopidogrel to the genotype-guided group lowered the risk of minor bleeding.
Dr. Claassens and coauthors noted that since the Netherlands trial was designed in 2011, the development of newer-generation stents has considerably lowered rates of thrombotic events after acute coronary syndromes. “With the lower-than-anticipated incidence of the primary combined outcome in our trial, the prespecified noninferiority margin was wider relative to the incidence than originally expected,” they said. While the primary combined outcome was 21% higher than the incidence in the standard-treatment group at the upper end of the 95% confidence interval, the incidence was 11% higher in the standard-treatment group at the observed upper end of the 95% CI. This “gives stronger support to the conclusion that genotype-guided P2Y12 treatment is noninferior to standard treatment for the occurrence of thrombotic events,” Dr. Claassens and coauthors said.
The study report noted a number of limitations, including that more polymorphisms of the CyP2C19 gene may be linked to increased thrombotic or bleeding risk. “Therefore, our strategy based solely on the CYP2C19 genotype may not be the most useful strategy for some patients,” Dr. Claassens and coauthors said.
POPular Genetics received funding from the Netherlands Organization for Health Research and Development (ZonMw). Dr. Claassens receives grants from ZonMw and non-financial support from Spartan Biosciences.
SOURCE: Claassens DMF, et al. N Engl J. Med. Published online September 3, doi.org/10.1016/S0140-6736(19)31996-8.
Genotype-guided selection of oral P2Y 12 inhibitors for patients having percutaneous coronary intervention with stent implantation derives no clinical benefits overall when compared to standard treatment, according to results of the large, randomized POPular Genetics trial, although genotype guidance did result in lower rates of primary minor bleeding.
The study was presented at the annual congress of the European Society of Cardiology Study in Paris and published simultaneously in the New England Journal of Medicine.
POPular Genetics (CYP2C19 Genotype-Guided Antiplatelet Therapy in ST-Segment Elevation Myocardial Infarction Patients – Patient Outcome After Primary PCI) randomized 2,488 patients who had PCI to either P2Y12 inhibitor on the basis of early genetic testing for the CYP2C19 gene (1,242 patients) or standard treatment with either ticagrelor or prasugrel (1,246 patients) for 12 months. In the genotype-guided group, patients were assigned to one of two arms depending on results; carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and non-carriers receive clopidogrel. The study was conducted from Jun. 2011 to Apr. 2018.
Net adverse clinical events, which included any-cause death, myocardial infarction, stent thrombosis, stroke or major bleeding based on the Platelet Inhibition and Patient Outcomes (PLATO) criteria at 12 months were similar between both groups: 5.1% in the genotype-guided patients and 5.9% in the standard-treatment group (P less than .001), but rates of PLATO major or minor bleeding were 9.8% and 12.5%, respectively (P = .04).
When secondary outcomes were evaluated, no significant differences emerged between the two groups. Secondary outcomes included combined thrombotic outcomes (death from vascular causes, myocardial infarction, stent thrombosis or stroke; 2.7% for the genotype-guided group vs. 3.3% in the standard-treatment group), and PLATO major bleeding (2.3% in both groups). The difference in the primary bleeding outcomes between the groups was driven by a lower incidence of PLATO minor bleeding in the genotype-guided group, 7.6% vs. 10.5%.
The two takeaways from POPular Genetics, said Daniel M.F. Claassens, MD, and coauthors, are that giving clopidogrel to patients without a CYP2C19 loss-of-function allele did not elevate their risk of combined any-cause death and other adverse cardiac outcomes, including major bleeding, 12 months after PCI; and that giving clopidogrel to the genotype-guided group lowered the risk of minor bleeding.
Dr. Claassens and coauthors noted that since the Netherlands trial was designed in 2011, the development of newer-generation stents has considerably lowered rates of thrombotic events after acute coronary syndromes. “With the lower-than-anticipated incidence of the primary combined outcome in our trial, the prespecified noninferiority margin was wider relative to the incidence than originally expected,” they said. While the primary combined outcome was 21% higher than the incidence in the standard-treatment group at the upper end of the 95% confidence interval, the incidence was 11% higher in the standard-treatment group at the observed upper end of the 95% CI. This “gives stronger support to the conclusion that genotype-guided P2Y12 treatment is noninferior to standard treatment for the occurrence of thrombotic events,” Dr. Claassens and coauthors said.
The study report noted a number of limitations, including that more polymorphisms of the CyP2C19 gene may be linked to increased thrombotic or bleeding risk. “Therefore, our strategy based solely on the CYP2C19 genotype may not be the most useful strategy for some patients,” Dr. Claassens and coauthors said.
POPular Genetics received funding from the Netherlands Organization for Health Research and Development (ZonMw). Dr. Claassens receives grants from ZonMw and non-financial support from Spartan Biosciences.
SOURCE: Claassens DMF, et al. N Engl J. Med. Published online September 3, doi.org/10.1016/S0140-6736(19)31996-8.
AT THE ESC CONGRESS 2019
Key clinical point: Genotype-guided selection for oral P2Y12 inhibitors may benefit some patients.
Major finding: The genotype-guided group had primary bleeding rates of 9.8% vs. 12.5% for standard treatment.
Study details: POPular Genetics, an open-label blinded trial of 2,488 patients randomized to genotype-guided treatment or standard treatment after PCI, conducted from June 2011 through April 2018.
Disclosures: The study received funding from the Netherlands Organization for Health Research and Development (ZonMw). Dr. Claassens received grants from ZonMw and nonfinancial support from Spartan Biosciences.
Source: Claassens DMF, et al. N Engl J. Med. Published online September 3,doi.org/10.1016/S0140-6736(19)31996-8