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European Society of Cardiology (ESC): Annual Congress
Equally Low Thrombosis Seen With Zotarolimus-, Sirolimus-Eluting Stents
Rates of stent thrombosis were low and similar between patients implanted with zotarolimus-eluting stents and those with sirolimus-eluting stents in a large, randomized controlled trial.
Over a 3-year period, thrombosis occurred in less than 2% of each group. Furthermore, there were no significant between-group differences in overall mortality, myocardial infarction, or cardiac death, Dr. Edoardo Camenzind and colleagues reported in the August 27 online issue of the Lancet. The study results were simultaneously presented at the annual congress of the European Society of Cardiology.
The 1.4% rate of stent thrombosis noted with the zotarolimus stent matched the expected rate of 1.5%, but the rate with the sirolimus stent was lower than anticipated, with an expected rate of 2.5% and an observed rate of 1.8%, wrote Dr. Camenzind of the University of Geneva and his coauthors (Lancet Aug. 27, 2012 [doi: 10.1016/S0140-6736(12)61336-1]).
But the Patient Related Outcomes With Endeavor Versus Cypher Stenting Trial (PROTECT) did show some time-related differences between the two devices, finding more thromboses in the first year with the zotarolimus stent (Z-ES, Endeavor), but more in years 2 and 3 with the sirolimus stent (S-ES, Cypher).
"Interestingly, the pattern of events over time was distributed differentially, with both devices having the same incidence of stent thrombosis, but C-ES having fewer late, but more very late, stent thrombosis than Z-ES," the authors noted. "The higher incidence of late stent thrombosis in the Z-ES group was driven by an increased incidence of definite stent thrombosis."
The study enrolled 8,709 patients who underwent an elective, unplanned, or emergency stenting of coronary arteries. They were a mean of 63 years old. The most common reason for stent placement was acute myocardial infarction (26%). Other reasons for stenting included unstable or stable angina or silent ischemia.
At discharge, 96% were on dual antiplatelet therapy. This number had dropped to 88% at 1 year, 37% at 2 years, and 30% by 3 years.
At the end of follow-up, definite or probable stent thrombosis had occurred in 61 (1.4%) of the Z-ES group and in 75 (1.8%) of the S-ES group – not a significant difference. Nor were there significant differences in any of the main secondary end points of total death and nonfatal MI, or cardiac death and nonfatal MI.
The study revealed a distinct time-associated pattern of thrombosis. In the first month after the procedure, definite or probable thrombosis occurred in 31 of the Z-ES group and 26 of the S-ES group. From days 31 to 360, the numbers were 17 and 5, respectively. During the last 2 years of follow-up, there were 13 definite or probable thromboses in the Z-ES group and 44 in the S-ES group.
Over the entire study period, the Z-ES was associated with a lower incidence of definite stent thrombosis than the S-ES (0.7% vs. 1.2%), but the S-ES had a lower incidence of target vessel revascularization (7.1% vs. 8.2%). None of these differences were significant, however.
Those findings also showed time-related differences. During the first year of the study, significantly more target vessel revascularizations occurred in the Z-ES group (5.8% vs. 3.4%), but that difference was reversed in years 2-3 (4.0% S-ES vs. 2.9% Z-ES).
Although slight, the differences observed in PROTECT are still important, the investigators said: "Given the seriousness of clinical manifestation of stent thrombosis, typically death or myocardial infarction, any reduction has clinical relevance. Furthermore, hundreds of thousands of patients worldwide have been implanted with these devices."
Follow-up on these patients will continue for another 2 years. This "will show whether curves of definite and definite or probable stent thrombosis further diverge and will translate into differences in clinical safety outcomes," Dr. Camenzind and his associates said.
The study was funded by Medtronic, maker of the Endeavor stent. Dr. Camenzind had no financial disclosures but several of his coauthors noted receiving financial remuneration from Medtronic and from other pharmaceutical companies and device manufacturers.
Results of the PROTECT study are academic now, but perhaps still interesting to physicians caring for the millions of patients who still carry the zotarolimus- and sirolimus-eluting stents, Dr. Robert A. Byrne and his colleagues wrote in an accompanying editorial.
"Since the study began in 2007, a significant shift has occurred in interventional cardiology practice, such that both study devices have largely fallen out of use worldwide, being superseded by new devices with increased efficacy and decreased rates of stent thrombosis," wrote Dr. Byrne. "This shift undoubtedly limits the immediate clinical relevance of these findings."
Dr. Byrne and his coauthors also said that PROTECT investigators problematically searched too hard for any interesting tidbits in their secondary analyses.
"The authors report a negative clinical trial with no differences in the primary endpoint. This finding is supported by an absence of difference in the main secondary endpoints. For this reason, the value of all additional analyses presented in the article is restricted, and to highlight differences in the temporal distribution of stent thrombosis between the two devices is inadvisable. This analysis was not prespecified and the probability of a chance finding is high."
The time-driven conclusions can be seeing as a never-ending division problem, they suggested.
"If one notes that stent thrombosis beyond 1 year is higher with [the sirolimus-eluting stent] ... then one must also observe that the number of patients with stent thrombosis up to 1 year is higher with [the zotarolimus-eluting stent]. To take the argument further, one must then question whether it is preferable for a patient to suffer stent thrombosis during the first year or after it: reductio ad absurdum" – arguing on and on that the finding is true because a false result follows from its denial, they wrote.
Dr. Byrne is an interventional cardiologist at Deutsches Herzzentrum, Munich. He had no financial disclosures, but a coauthor disclosed that he has received lecture fees from Medtronic, as well as other device and pharmaceutical companies.
Results of the PROTECT study are academic now, but perhaps still interesting to physicians caring for the millions of patients who still carry the zotarolimus- and sirolimus-eluting stents, Dr. Robert A. Byrne and his colleagues wrote in an accompanying editorial.
"Since the study began in 2007, a significant shift has occurred in interventional cardiology practice, such that both study devices have largely fallen out of use worldwide, being superseded by new devices with increased efficacy and decreased rates of stent thrombosis," wrote Dr. Byrne. "This shift undoubtedly limits the immediate clinical relevance of these findings."
Dr. Byrne and his coauthors also said that PROTECT investigators problematically searched too hard for any interesting tidbits in their secondary analyses.
"The authors report a negative clinical trial with no differences in the primary endpoint. This finding is supported by an absence of difference in the main secondary endpoints. For this reason, the value of all additional analyses presented in the article is restricted, and to highlight differences in the temporal distribution of stent thrombosis between the two devices is inadvisable. This analysis was not prespecified and the probability of a chance finding is high."
The time-driven conclusions can be seeing as a never-ending division problem, they suggested.
"If one notes that stent thrombosis beyond 1 year is higher with [the sirolimus-eluting stent] ... then one must also observe that the number of patients with stent thrombosis up to 1 year is higher with [the zotarolimus-eluting stent]. To take the argument further, one must then question whether it is preferable for a patient to suffer stent thrombosis during the first year or after it: reductio ad absurdum" – arguing on and on that the finding is true because a false result follows from its denial, they wrote.
Dr. Byrne is an interventional cardiologist at Deutsches Herzzentrum, Munich. He had no financial disclosures, but a coauthor disclosed that he has received lecture fees from Medtronic, as well as other device and pharmaceutical companies.
Results of the PROTECT study are academic now, but perhaps still interesting to physicians caring for the millions of patients who still carry the zotarolimus- and sirolimus-eluting stents, Dr. Robert A. Byrne and his colleagues wrote in an accompanying editorial.
"Since the study began in 2007, a significant shift has occurred in interventional cardiology practice, such that both study devices have largely fallen out of use worldwide, being superseded by new devices with increased efficacy and decreased rates of stent thrombosis," wrote Dr. Byrne. "This shift undoubtedly limits the immediate clinical relevance of these findings."
Dr. Byrne and his coauthors also said that PROTECT investigators problematically searched too hard for any interesting tidbits in their secondary analyses.
"The authors report a negative clinical trial with no differences in the primary endpoint. This finding is supported by an absence of difference in the main secondary endpoints. For this reason, the value of all additional analyses presented in the article is restricted, and to highlight differences in the temporal distribution of stent thrombosis between the two devices is inadvisable. This analysis was not prespecified and the probability of a chance finding is high."
The time-driven conclusions can be seeing as a never-ending division problem, they suggested.
"If one notes that stent thrombosis beyond 1 year is higher with [the sirolimus-eluting stent] ... then one must also observe that the number of patients with stent thrombosis up to 1 year is higher with [the zotarolimus-eluting stent]. To take the argument further, one must then question whether it is preferable for a patient to suffer stent thrombosis during the first year or after it: reductio ad absurdum" – arguing on and on that the finding is true because a false result follows from its denial, they wrote.
Dr. Byrne is an interventional cardiologist at Deutsches Herzzentrum, Munich. He had no financial disclosures, but a coauthor disclosed that he has received lecture fees from Medtronic, as well as other device and pharmaceutical companies.
Rates of stent thrombosis were low and similar between patients implanted with zotarolimus-eluting stents and those with sirolimus-eluting stents in a large, randomized controlled trial.
Over a 3-year period, thrombosis occurred in less than 2% of each group. Furthermore, there were no significant between-group differences in overall mortality, myocardial infarction, or cardiac death, Dr. Edoardo Camenzind and colleagues reported in the August 27 online issue of the Lancet. The study results were simultaneously presented at the annual congress of the European Society of Cardiology.
The 1.4% rate of stent thrombosis noted with the zotarolimus stent matched the expected rate of 1.5%, but the rate with the sirolimus stent was lower than anticipated, with an expected rate of 2.5% and an observed rate of 1.8%, wrote Dr. Camenzind of the University of Geneva and his coauthors (Lancet Aug. 27, 2012 [doi: 10.1016/S0140-6736(12)61336-1]).
But the Patient Related Outcomes With Endeavor Versus Cypher Stenting Trial (PROTECT) did show some time-related differences between the two devices, finding more thromboses in the first year with the zotarolimus stent (Z-ES, Endeavor), but more in years 2 and 3 with the sirolimus stent (S-ES, Cypher).
"Interestingly, the pattern of events over time was distributed differentially, with both devices having the same incidence of stent thrombosis, but C-ES having fewer late, but more very late, stent thrombosis than Z-ES," the authors noted. "The higher incidence of late stent thrombosis in the Z-ES group was driven by an increased incidence of definite stent thrombosis."
The study enrolled 8,709 patients who underwent an elective, unplanned, or emergency stenting of coronary arteries. They were a mean of 63 years old. The most common reason for stent placement was acute myocardial infarction (26%). Other reasons for stenting included unstable or stable angina or silent ischemia.
At discharge, 96% were on dual antiplatelet therapy. This number had dropped to 88% at 1 year, 37% at 2 years, and 30% by 3 years.
At the end of follow-up, definite or probable stent thrombosis had occurred in 61 (1.4%) of the Z-ES group and in 75 (1.8%) of the S-ES group – not a significant difference. Nor were there significant differences in any of the main secondary end points of total death and nonfatal MI, or cardiac death and nonfatal MI.
The study revealed a distinct time-associated pattern of thrombosis. In the first month after the procedure, definite or probable thrombosis occurred in 31 of the Z-ES group and 26 of the S-ES group. From days 31 to 360, the numbers were 17 and 5, respectively. During the last 2 years of follow-up, there were 13 definite or probable thromboses in the Z-ES group and 44 in the S-ES group.
Over the entire study period, the Z-ES was associated with a lower incidence of definite stent thrombosis than the S-ES (0.7% vs. 1.2%), but the S-ES had a lower incidence of target vessel revascularization (7.1% vs. 8.2%). None of these differences were significant, however.
Those findings also showed time-related differences. During the first year of the study, significantly more target vessel revascularizations occurred in the Z-ES group (5.8% vs. 3.4%), but that difference was reversed in years 2-3 (4.0% S-ES vs. 2.9% Z-ES).
Although slight, the differences observed in PROTECT are still important, the investigators said: "Given the seriousness of clinical manifestation of stent thrombosis, typically death or myocardial infarction, any reduction has clinical relevance. Furthermore, hundreds of thousands of patients worldwide have been implanted with these devices."
Follow-up on these patients will continue for another 2 years. This "will show whether curves of definite and definite or probable stent thrombosis further diverge and will translate into differences in clinical safety outcomes," Dr. Camenzind and his associates said.
The study was funded by Medtronic, maker of the Endeavor stent. Dr. Camenzind had no financial disclosures but several of his coauthors noted receiving financial remuneration from Medtronic and from other pharmaceutical companies and device manufacturers.
Rates of stent thrombosis were low and similar between patients implanted with zotarolimus-eluting stents and those with sirolimus-eluting stents in a large, randomized controlled trial.
Over a 3-year period, thrombosis occurred in less than 2% of each group. Furthermore, there were no significant between-group differences in overall mortality, myocardial infarction, or cardiac death, Dr. Edoardo Camenzind and colleagues reported in the August 27 online issue of the Lancet. The study results were simultaneously presented at the annual congress of the European Society of Cardiology.
The 1.4% rate of stent thrombosis noted with the zotarolimus stent matched the expected rate of 1.5%, but the rate with the sirolimus stent was lower than anticipated, with an expected rate of 2.5% and an observed rate of 1.8%, wrote Dr. Camenzind of the University of Geneva and his coauthors (Lancet Aug. 27, 2012 [doi: 10.1016/S0140-6736(12)61336-1]).
But the Patient Related Outcomes With Endeavor Versus Cypher Stenting Trial (PROTECT) did show some time-related differences between the two devices, finding more thromboses in the first year with the zotarolimus stent (Z-ES, Endeavor), but more in years 2 and 3 with the sirolimus stent (S-ES, Cypher).
"Interestingly, the pattern of events over time was distributed differentially, with both devices having the same incidence of stent thrombosis, but C-ES having fewer late, but more very late, stent thrombosis than Z-ES," the authors noted. "The higher incidence of late stent thrombosis in the Z-ES group was driven by an increased incidence of definite stent thrombosis."
The study enrolled 8,709 patients who underwent an elective, unplanned, or emergency stenting of coronary arteries. They were a mean of 63 years old. The most common reason for stent placement was acute myocardial infarction (26%). Other reasons for stenting included unstable or stable angina or silent ischemia.
At discharge, 96% were on dual antiplatelet therapy. This number had dropped to 88% at 1 year, 37% at 2 years, and 30% by 3 years.
At the end of follow-up, definite or probable stent thrombosis had occurred in 61 (1.4%) of the Z-ES group and in 75 (1.8%) of the S-ES group – not a significant difference. Nor were there significant differences in any of the main secondary end points of total death and nonfatal MI, or cardiac death and nonfatal MI.
The study revealed a distinct time-associated pattern of thrombosis. In the first month after the procedure, definite or probable thrombosis occurred in 31 of the Z-ES group and 26 of the S-ES group. From days 31 to 360, the numbers were 17 and 5, respectively. During the last 2 years of follow-up, there were 13 definite or probable thromboses in the Z-ES group and 44 in the S-ES group.
Over the entire study period, the Z-ES was associated with a lower incidence of definite stent thrombosis than the S-ES (0.7% vs. 1.2%), but the S-ES had a lower incidence of target vessel revascularization (7.1% vs. 8.2%). None of these differences were significant, however.
Those findings also showed time-related differences. During the first year of the study, significantly more target vessel revascularizations occurred in the Z-ES group (5.8% vs. 3.4%), but that difference was reversed in years 2-3 (4.0% S-ES vs. 2.9% Z-ES).
Although slight, the differences observed in PROTECT are still important, the investigators said: "Given the seriousness of clinical manifestation of stent thrombosis, typically death or myocardial infarction, any reduction has clinical relevance. Furthermore, hundreds of thousands of patients worldwide have been implanted with these devices."
Follow-up on these patients will continue for another 2 years. This "will show whether curves of definite and definite or probable stent thrombosis further diverge and will translate into differences in clinical safety outcomes," Dr. Camenzind and his associates said.
The study was funded by Medtronic, maker of the Endeavor stent. Dr. Camenzind had no financial disclosures but several of his coauthors noted receiving financial remuneration from Medtronic and from other pharmaceutical companies and device manufacturers.
FROM THE LANCET
Major Finding: Over 3 years, the incidence of stent thrombosis was 1.4% with a zotarolimus-eluting device and 1.8% with a sirolumus-eluting stent.
Data Source: PROTECT was a randomized controlled trial involving 8,709 patients implanted with drug-eluting stents and followed for 3 years.
Disclosures: The study was funded by Medtronic. Dr. Camenzind had no financial disclosures, but several of his coauthors noted receiving financial remuneration from Medtronic and other pharmaceutical companies and device manufacturers.
Third Universal MI Definition Unveiled
MUNICH – A new universal definition of myocardial infarction has been unveiled, sparked by the development of ever more sensitive cardiac biomarker assays and imaging techniques.
These assays, including the new high-sensitivity cardiac troponin (cTn) assays available throughout Europe and awaiting approval in the United States, have created confusion in the diagnosis of myocardial infarction because they detect small cTn elevations associated with many other clinical conditions such as heart failure, arrhythmias, and pulmonary embolism that are not MIs, but rather myocardial injury with necrosis.
"I think there has been a little bit of a problem in the past where we’ve had too many infarctions [diagnosed] ... where there is some damage or injury to the myocardial cells," said document task force cochair Dr. Kristian Thygeysen, who presented the third universal MI definition at the annual meeting of the European Society of Cardiology (ESC).
The expert consensus document, developed by the ESC, American College of Cardiology (ACC), American Heart Association (AHA), and World Heart Federation (WHF), maintains the pathological definition of acute MI as myocardial cell death due to prolonged myocardial ischemia, but goes on to refine the definition of MI in five settings, including the controversial area of MIs associated with revascularization procedures.
MI in the PCI Setting
An MI related to percutaneous coronary intervention (PCI) is defined as an elevation of cTn values more than five times the 99th percentile upper reference limit (URL) in the first 48 hours after a procedure in patients with normal baseline troponin values, or a rise of cTn values of more than 20% in patients with elevated baseline levels that are stable or falling.
It also requires one of the following events: symptoms suggestive of myocardial ischemia, new ischemic ECG changes, angiographic findings consistent with a procedural complication, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
In the previous 2007 document, the troponin threshold had been more than three times the 99th percentile, and was raised based on new prognostic information from long-term follow-up of patients undergoing PCI showing that there is unavoidable injury associated with the procedure, document task force codirector Dr. Joseph Alpert said during the presentation.
CABG-Related MI
Similarly, the 2012 version raises the troponin threshold for MI related to coronary artery bypass graft surgery from five times the 99th percentile URL in the 2007 document to 10 times the 99th percentile in patients with normal cTn baseline values.
It also requires one of the following: new pathological Q waves or new left bundle branch block (LBBB), angiographically documented new graft or new native coronary artery occlusion, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
Once again, the decision to raise the troponin threshold was made because there is unavoidable injury to the heart during CABG from needle sticks, handling of the heart, and the myocardial preservation procedure, said Dr. Alpert, a professor of medicine at the University of Arizona, Tucson.
Many Sources of Heart Injury
"The problem that every clinician – not just cardiologists, but internists and surgeons – is having with these troponin tests, and particularly with the high-sensitivity test, is that it turns out we’re finding that there are lots and lots of people having heart injuries," he said in an interview. "We’ve known for decades that it’s not uncommon for a very sick patient to have liver injuries, but now we’re saying, ‘My goodness, they’re having heart injuries, and these injuries are not MIs, or at least we have no evidence there is ischemia.’ "
The updated guideline points out that novel procedures such as transcatheter aortic valve implantation or mitral clip may also cause myocardial injury with necrosis, and that "it is likely that, similarly to CABG, the more marked the elevation of the biomarker values, the worse the prognosis – but data on that are not available.&qu
Although high-sensitivity troponin assays are not yet approved in the United States, it is only a matter of time before they are and the financial battle heats up over the distinction between myocardial injury and MI, according to Dr. Alpert. The reason is that there is currently no reimbursement code for patients with myocardial injury, who require substantial time and resources that currently are not being reimbursed.
"We’re pushing to get that code, because when you have an elevated troponin it means something, and it always means something not good," he said in the interview.
Cardiac troponin (I or T) is the preferred biomarker for the definition of acute MI, although less sensitive biomarkers such as the creatine kinase-MB (CKMB) mass can still be used when cardiac troponin is not available, said Dr. Thygesen, with the department of cardiological medicine, Aarhus (Denmark) University.
The criteria for an acute MI include detection of a rise and/or fall of cardiac biomarker values exceeding the 99th percentile URL, plus at least one of the following:
• Symptoms of ischemia.
• New or presumably new significant ST-segment/T wave changes or new LBBB.
• Development of pathological Q waves in the ECG.
• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
• Identification of an intracoronary thrombus by angiography or autopsy.
The new MI definition is expected to become the gold standard for diagnosis and to be adopted by the U.S. Food and Drug Administration for use in clinical trial protocols accepted by the agency. This is significant because it will help standardize the way MI is defined in clinical trials, making comparisons between studies more meaningful, Dr. Thygesen observed.
The expert consensus document, as well as pocket versions, are available on the websites of the ESC, ACC, AHA, and World Heart Federation.
The document is also being copublished in five journals: the Journal of the American College of Cardiology, European Heart Journal, Circulation, Global Heart, and Nature Reviews of Cardiology.
Dr. Thygesen reported no conflicts of interest. Dr. Alpert reported consulting for several pharmaceutical firms as well as the North American Center for Continuing Medical Education.
MUNICH – A new universal definition of myocardial infarction has been unveiled, sparked by the development of ever more sensitive cardiac biomarker assays and imaging techniques.
These assays, including the new high-sensitivity cardiac troponin (cTn) assays available throughout Europe and awaiting approval in the United States, have created confusion in the diagnosis of myocardial infarction because they detect small cTn elevations associated with many other clinical conditions such as heart failure, arrhythmias, and pulmonary embolism that are not MIs, but rather myocardial injury with necrosis.
"I think there has been a little bit of a problem in the past where we’ve had too many infarctions [diagnosed] ... where there is some damage or injury to the myocardial cells," said document task force cochair Dr. Kristian Thygeysen, who presented the third universal MI definition at the annual meeting of the European Society of Cardiology (ESC).
The expert consensus document, developed by the ESC, American College of Cardiology (ACC), American Heart Association (AHA), and World Heart Federation (WHF), maintains the pathological definition of acute MI as myocardial cell death due to prolonged myocardial ischemia, but goes on to refine the definition of MI in five settings, including the controversial area of MIs associated with revascularization procedures.
MI in the PCI Setting
An MI related to percutaneous coronary intervention (PCI) is defined as an elevation of cTn values more than five times the 99th percentile upper reference limit (URL) in the first 48 hours after a procedure in patients with normal baseline troponin values, or a rise of cTn values of more than 20% in patients with elevated baseline levels that are stable or falling.
It also requires one of the following events: symptoms suggestive of myocardial ischemia, new ischemic ECG changes, angiographic findings consistent with a procedural complication, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
In the previous 2007 document, the troponin threshold had been more than three times the 99th percentile, and was raised based on new prognostic information from long-term follow-up of patients undergoing PCI showing that there is unavoidable injury associated with the procedure, document task force codirector Dr. Joseph Alpert said during the presentation.
CABG-Related MI
Similarly, the 2012 version raises the troponin threshold for MI related to coronary artery bypass graft surgery from five times the 99th percentile URL in the 2007 document to 10 times the 99th percentile in patients with normal cTn baseline values.
It also requires one of the following: new pathological Q waves or new left bundle branch block (LBBB), angiographically documented new graft or new native coronary artery occlusion, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
Once again, the decision to raise the troponin threshold was made because there is unavoidable injury to the heart during CABG from needle sticks, handling of the heart, and the myocardial preservation procedure, said Dr. Alpert, a professor of medicine at the University of Arizona, Tucson.
Many Sources of Heart Injury
"The problem that every clinician – not just cardiologists, but internists and surgeons – is having with these troponin tests, and particularly with the high-sensitivity test, is that it turns out we’re finding that there are lots and lots of people having heart injuries," he said in an interview. "We’ve known for decades that it’s not uncommon for a very sick patient to have liver injuries, but now we’re saying, ‘My goodness, they’re having heart injuries, and these injuries are not MIs, or at least we have no evidence there is ischemia.’ "
The updated guideline points out that novel procedures such as transcatheter aortic valve implantation or mitral clip may also cause myocardial injury with necrosis, and that "it is likely that, similarly to CABG, the more marked the elevation of the biomarker values, the worse the prognosis – but data on that are not available.&qu
Although high-sensitivity troponin assays are not yet approved in the United States, it is only a matter of time before they are and the financial battle heats up over the distinction between myocardial injury and MI, according to Dr. Alpert. The reason is that there is currently no reimbursement code for patients with myocardial injury, who require substantial time and resources that currently are not being reimbursed.
"We’re pushing to get that code, because when you have an elevated troponin it means something, and it always means something not good," he said in the interview.
Cardiac troponin (I or T) is the preferred biomarker for the definition of acute MI, although less sensitive biomarkers such as the creatine kinase-MB (CKMB) mass can still be used when cardiac troponin is not available, said Dr. Thygesen, with the department of cardiological medicine, Aarhus (Denmark) University.
The criteria for an acute MI include detection of a rise and/or fall of cardiac biomarker values exceeding the 99th percentile URL, plus at least one of the following:
• Symptoms of ischemia.
• New or presumably new significant ST-segment/T wave changes or new LBBB.
• Development of pathological Q waves in the ECG.
• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
• Identification of an intracoronary thrombus by angiography or autopsy.
The new MI definition is expected to become the gold standard for diagnosis and to be adopted by the U.S. Food and Drug Administration for use in clinical trial protocols accepted by the agency. This is significant because it will help standardize the way MI is defined in clinical trials, making comparisons between studies more meaningful, Dr. Thygesen observed.
The expert consensus document, as well as pocket versions, are available on the websites of the ESC, ACC, AHA, and World Heart Federation.
The document is also being copublished in five journals: the Journal of the American College of Cardiology, European Heart Journal, Circulation, Global Heart, and Nature Reviews of Cardiology.
Dr. Thygesen reported no conflicts of interest. Dr. Alpert reported consulting for several pharmaceutical firms as well as the North American Center for Continuing Medical Education.
MUNICH – A new universal definition of myocardial infarction has been unveiled, sparked by the development of ever more sensitive cardiac biomarker assays and imaging techniques.
These assays, including the new high-sensitivity cardiac troponin (cTn) assays available throughout Europe and awaiting approval in the United States, have created confusion in the diagnosis of myocardial infarction because they detect small cTn elevations associated with many other clinical conditions such as heart failure, arrhythmias, and pulmonary embolism that are not MIs, but rather myocardial injury with necrosis.
"I think there has been a little bit of a problem in the past where we’ve had too many infarctions [diagnosed] ... where there is some damage or injury to the myocardial cells," said document task force cochair Dr. Kristian Thygeysen, who presented the third universal MI definition at the annual meeting of the European Society of Cardiology (ESC).
The expert consensus document, developed by the ESC, American College of Cardiology (ACC), American Heart Association (AHA), and World Heart Federation (WHF), maintains the pathological definition of acute MI as myocardial cell death due to prolonged myocardial ischemia, but goes on to refine the definition of MI in five settings, including the controversial area of MIs associated with revascularization procedures.
MI in the PCI Setting
An MI related to percutaneous coronary intervention (PCI) is defined as an elevation of cTn values more than five times the 99th percentile upper reference limit (URL) in the first 48 hours after a procedure in patients with normal baseline troponin values, or a rise of cTn values of more than 20% in patients with elevated baseline levels that are stable or falling.
It also requires one of the following events: symptoms suggestive of myocardial ischemia, new ischemic ECG changes, angiographic findings consistent with a procedural complication, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
In the previous 2007 document, the troponin threshold had been more than three times the 99th percentile, and was raised based on new prognostic information from long-term follow-up of patients undergoing PCI showing that there is unavoidable injury associated with the procedure, document task force codirector Dr. Joseph Alpert said during the presentation.
CABG-Related MI
Similarly, the 2012 version raises the troponin threshold for MI related to coronary artery bypass graft surgery from five times the 99th percentile URL in the 2007 document to 10 times the 99th percentile in patients with normal cTn baseline values.
It also requires one of the following: new pathological Q waves or new left bundle branch block (LBBB), angiographically documented new graft or new native coronary artery occlusion, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
Once again, the decision to raise the troponin threshold was made because there is unavoidable injury to the heart during CABG from needle sticks, handling of the heart, and the myocardial preservation procedure, said Dr. Alpert, a professor of medicine at the University of Arizona, Tucson.
Many Sources of Heart Injury
"The problem that every clinician – not just cardiologists, but internists and surgeons – is having with these troponin tests, and particularly with the high-sensitivity test, is that it turns out we’re finding that there are lots and lots of people having heart injuries," he said in an interview. "We’ve known for decades that it’s not uncommon for a very sick patient to have liver injuries, but now we’re saying, ‘My goodness, they’re having heart injuries, and these injuries are not MIs, or at least we have no evidence there is ischemia.’ "
The updated guideline points out that novel procedures such as transcatheter aortic valve implantation or mitral clip may also cause myocardial injury with necrosis, and that "it is likely that, similarly to CABG, the more marked the elevation of the biomarker values, the worse the prognosis – but data on that are not available.&qu
Although high-sensitivity troponin assays are not yet approved in the United States, it is only a matter of time before they are and the financial battle heats up over the distinction between myocardial injury and MI, according to Dr. Alpert. The reason is that there is currently no reimbursement code for patients with myocardial injury, who require substantial time and resources that currently are not being reimbursed.
"We’re pushing to get that code, because when you have an elevated troponin it means something, and it always means something not good," he said in the interview.
Cardiac troponin (I or T) is the preferred biomarker for the definition of acute MI, although less sensitive biomarkers such as the creatine kinase-MB (CKMB) mass can still be used when cardiac troponin is not available, said Dr. Thygesen, with the department of cardiological medicine, Aarhus (Denmark) University.
The criteria for an acute MI include detection of a rise and/or fall of cardiac biomarker values exceeding the 99th percentile URL, plus at least one of the following:
• Symptoms of ischemia.
• New or presumably new significant ST-segment/T wave changes or new LBBB.
• Development of pathological Q waves in the ECG.
• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
• Identification of an intracoronary thrombus by angiography or autopsy.
The new MI definition is expected to become the gold standard for diagnosis and to be adopted by the U.S. Food and Drug Administration for use in clinical trial protocols accepted by the agency. This is significant because it will help standardize the way MI is defined in clinical trials, making comparisons between studies more meaningful, Dr. Thygesen observed.
The expert consensus document, as well as pocket versions, are available on the websites of the ESC, ACC, AHA, and World Heart Federation.
The document is also being copublished in five journals: the Journal of the American College of Cardiology, European Heart Journal, Circulation, Global Heart, and Nature Reviews of Cardiology.
Dr. Thygesen reported no conflicts of interest. Dr. Alpert reported consulting for several pharmaceutical firms as well as the North American Center for Continuing Medical Education.
AT THE ANNUAL MEETING OF THE EUROPEAN SOCIETY OF CARDIOLOGY
DeFACTO Propels CT Fractional Flow Reserve Closer to Clinical Practice
The addition of CT-based fractional flow reserve information to CT alone improved the diagnostic accuracy of stenoses, allowing noninvasive assessment of the physiologic consequences of lesions, according to the long-awaited results of the Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography (DeFACTO) study.
However, CT fractional flow reserve (FFR-CT) plus CT narrowly failed to meet the trial’s primary end point – diagnostic accuracy greater than 70% for the lower bound of the 95% confidence interval. Per-patient performance diagnostic accuracy of FFR-CT plus CT was 73% with a 95% CI of 67%-78%.
Nevertheless, the addition of FFR-CT "demonstrated superior diagnostic performance characteristics, as compared with CT stenosis alone, in all patients, in all vessels, and also in vessels of intermediate stenosis severity," lead author Dr. James K. Min said during a press conference.
The results of the study were released in JAMA on Aug. 26th to coincide with the presentation of the study at the European Society of Cardiology meeting (JAMA 2012;308 [doi: 10.1001/2012.jama.11274]).
Fractional flow reserve (FFR) is currently assessed during invasive coronary angiography (ICA) to determine whether a coronary stenosis results in ischemia, and is the currently accepted reference standard for determining lesion-specific ischemia. FFR is the ratio of the mean coronary pressure distal to a coronary stenosis to the mean aortic pressure during maximal coronary blood flow. This value describes coronary flow still attainable despite the presence of a stenotic lesion.
While CT angiography has long been used to accurately and noninvasively assess the anatomic severity of stenoses, the technique has been criticized because it does not yield functional information about the hemodynamic effect of lesions.
Noninvasive calculation of FFR from CT "is a novel method that applies computational fluid dynamics to determine the physiologic significance of CAD [coronary artery disease]. Fractional flow reserve from CT enables calculation of rest and hyperemic pressure fields in coronary arteries without additional imaging, modification of CT acquisition protocols, or administration of medications," the investigators wrote.
"Taken together, these study results suggest the potential of FFR-CT as a promising noninvasive method for identification of individuals with ischemia. The present study findings can be considered proof of concept of the feasibility of this novel technology."
A total of 252 patients were included in the final analysis of the DeFACTO study. These patients had CAD and underwent clinically indicated ICA after CT with no intervening coronary event. Patients were not eligible if they had a history of coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention. About 77% of patients had experienced angina within the past month.
Among 615 study vessels, 271 had less than 30% stenosis and 101 had at least 90% stenosis. In all, 407 vessels were directly assessed by both FFR and FFR-CT.
Computed tomographic angiography was performed on 64- or greater detector scanners with prospective or retrospective electrocardiographic gating.
The investigators evaluated CTs for maximal patient-, vessel-, and segment-based diameter stenosis (characterized as 0%, 1%-29%, 30%-49%, or 50% or larger).
Per-patient and per-vessel CAD stenosis were the maximal stenoses identified in all segments or in all segments within a vessel distribution, respectively. Vessel distributions were categorized for the left anterior descending, left circumflex, and right coronary artery. Computed tomographic angiograms (CTAs) were judged as excellent, good, adequate, or nondiagnostic.
Selective ICA was performed by standard protocol, and FFR was performed at the time of ICA. Fractional flow reserve was considered diagnostic of ischemia at a threshold of 0.80 or less. Computation of FFR-CT was performed in blinded fashion by the FFR-CT core laboratory at HeartFlow, the study’s sponsor.
Per-patient diagnostic accuracy for FFR-CT plus CT was 73%. By comparison, diagnostic accuracy of CT alone was 64%.
FFR-CT also demonstrated greater discriminatory power than CT alone for vessels directly assessed by invasive FFR. For these vessels, the diagnostic sensitivity and specificity of FFR-CT alone were 80% and 61%, respectively.
Importantly, the researchers performed a secondary analysis of patients with an intermediate stenosis ranging from 30% to 70%, "wherein the clinical utility of FFR-CT would be most commonly expected for use." Diagnostic accuracy (73% for FFR-CT and 57% for CT), sensitivity (82% and 37%, respectively), positive predictive value (54% and 34%) and negative predictive value (88% and 68%) were greater for FFR-CT than for CT, though specificity was similar at 66%.
This intermediate group is an important patient population. "We know that patients with 30%-70% stenosis – even though they don’t look high-risk anatomically – actually, some of them experience ischemia and physiologic consequences of their coronary artery disease," said Dr. Min, director of cardiac imaging research and co-director of cardiac imaging at the Cedars-Sinai Heart Institute in Los Angeles.
High sensitivity/low specificity among patients with intermediate stenoses suggests "a low false-negative rate if assessments by FFR-CT were used to identify ischemia causing intermediate lesions, with negligible effects on reductions of false positive results. In this regard, the use of FFR-CT may significantly advance clinical assessment of patients without conventional measures of anatomic high-grade coronary stenosis, largely by proper identification of a significantly greater proportion of patients with manifest ischemia rather than as a safeguard to further invasive evaluation," the researchers noted.
They also pointed out that the prespecified primary end point for FFR-CT – a lower bound of the 95% confidence interval greater than 70% – "represents a 15% increase over traditional noninvasive histologic imaging methods, including myocardial perfusion imaging by SPECT or stress echocardiography," Dr. Min said.
Dr. Min and several of his coauthors reported significant financial relationships with GE Healthcare and Philips Medical, as well as other medical imaging/pharmaceutical companies. Dr. Jason H. Cole reported a grant for research support from HeartFlow. Dr. John Mancini reported a grant to his institution from HeartFlow. This study was funded by HeartFlow.
"Technologies that provide both a highly sensitive anatomic evaluation for obstructive disease and a highly specific physiologic evaluation for ischemia represent the ‘Holy Grail’ for noninvasive imaging for CAD," Dr. Manesh R. Patel wrote in an accompanying editorial (JAMA 2012 Aug. 26 [doi: 10.1001/2012.jama.11383]).
One possible investigational approach is the combination of anatomic analysis using CT and functional analysis using fractional flow reserve based on CT data (FFR-CT).
The DeFACTO investigators "raise the bar by comparing this diagnostic technology with a reference standard of both invasive angiography and invasive FFR. This change in reference standard may in part explain some of the accuracy findings. So how should these findings be considered with regard to current clinical evaluation for chest pain?" asked Dr. Patel.
It’s important to put the findings on the performance of CT angiography into context, he wrote. "Several recent multicenter studies have reported diagnostic performance of CT angiography to have high sensitivity (i.e., between 85%-95%) compared with conventional invasive angiography for stenoses of 50% or greater." The high sensitivity of CTA has been used to triage low-risk patients in acute settings.
"However, in stable intermediate-risk patients, for whom a higher degree of specificity (low rate of false positive results) may be desirable to reduce referrals for invasive angiography, concerns exist about the specificity of CT angiography," Dr. Patel noted. In the present study, CT angiography had a sensitivity of 84% but a specificity of only 42% with the more rigorous reference standard.
"It is in this context that FFR-CT represents a novel and important innovation, with the possibility not only to diagnose but also to help direct invasive treatment. The current ... multicenter report by Min et al. confirms a high sensitivity (90%) but demonstrates modest specificity (54%), albeit better than CTA alone," he wrote.
"At first glance, readers of the study may consider FFR-CT technology to be limited based on the results presented. However, this would be a naive conclusion, likely based on the published diagnostic performance of noninvasive tests compared only with invasive angiography," Dr. Patel warned. By comparing existing noninvasive imaging technologies with invasive angiography plus FFR, it is highly likely that the published diagnostic performance would be reduced. "In fact, in clinical practice, the sole use of invasive angiography for lesion evaluation has decreased. Additionally, in real-world practice, the current noninvasive technologies used for diagnosis and risk stratification in stable elective patients prior to invasive angiography do not perform at the published diagnostic levels, as evidenced by the low rates of obstructive CAD at elective catheterization. Hence, the current report describes an important noninvasive technology that may improve existing care and has the potential to outperform established noninvasive technologies," according to Dr. Patel.
DR. PATEL is the cardiology section leader in the peripheral vascular program at Duke University in Durham, N.C., and is assistant director of the cardiac catheterization laboratory. Dr. Patel reports consultancy for Bayer, Jansen, Baxter, and Otsuka, and grants from Johnson & Johnson and AstraZeneca.
"Technologies that provide both a highly sensitive anatomic evaluation for obstructive disease and a highly specific physiologic evaluation for ischemia represent the ‘Holy Grail’ for noninvasive imaging for CAD," Dr. Manesh R. Patel wrote in an accompanying editorial (JAMA 2012 Aug. 26 [doi: 10.1001/2012.jama.11383]).
One possible investigational approach is the combination of anatomic analysis using CT and functional analysis using fractional flow reserve based on CT data (FFR-CT).
The DeFACTO investigators "raise the bar by comparing this diagnostic technology with a reference standard of both invasive angiography and invasive FFR. This change in reference standard may in part explain some of the accuracy findings. So how should these findings be considered with regard to current clinical evaluation for chest pain?" asked Dr. Patel.
It’s important to put the findings on the performance of CT angiography into context, he wrote. "Several recent multicenter studies have reported diagnostic performance of CT angiography to have high sensitivity (i.e., between 85%-95%) compared with conventional invasive angiography for stenoses of 50% or greater." The high sensitivity of CTA has been used to triage low-risk patients in acute settings.
"However, in stable intermediate-risk patients, for whom a higher degree of specificity (low rate of false positive results) may be desirable to reduce referrals for invasive angiography, concerns exist about the specificity of CT angiography," Dr. Patel noted. In the present study, CT angiography had a sensitivity of 84% but a specificity of only 42% with the more rigorous reference standard.
"It is in this context that FFR-CT represents a novel and important innovation, with the possibility not only to diagnose but also to help direct invasive treatment. The current ... multicenter report by Min et al. confirms a high sensitivity (90%) but demonstrates modest specificity (54%), albeit better than CTA alone," he wrote.
"At first glance, readers of the study may consider FFR-CT technology to be limited based on the results presented. However, this would be a naive conclusion, likely based on the published diagnostic performance of noninvasive tests compared only with invasive angiography," Dr. Patel warned. By comparing existing noninvasive imaging technologies with invasive angiography plus FFR, it is highly likely that the published diagnostic performance would be reduced. "In fact, in clinical practice, the sole use of invasive angiography for lesion evaluation has decreased. Additionally, in real-world practice, the current noninvasive technologies used for diagnosis and risk stratification in stable elective patients prior to invasive angiography do not perform at the published diagnostic levels, as evidenced by the low rates of obstructive CAD at elective catheterization. Hence, the current report describes an important noninvasive technology that may improve existing care and has the potential to outperform established noninvasive technologies," according to Dr. Patel.
DR. PATEL is the cardiology section leader in the peripheral vascular program at Duke University in Durham, N.C., and is assistant director of the cardiac catheterization laboratory. Dr. Patel reports consultancy for Bayer, Jansen, Baxter, and Otsuka, and grants from Johnson & Johnson and AstraZeneca.
"Technologies that provide both a highly sensitive anatomic evaluation for obstructive disease and a highly specific physiologic evaluation for ischemia represent the ‘Holy Grail’ for noninvasive imaging for CAD," Dr. Manesh R. Patel wrote in an accompanying editorial (JAMA 2012 Aug. 26 [doi: 10.1001/2012.jama.11383]).
One possible investigational approach is the combination of anatomic analysis using CT and functional analysis using fractional flow reserve based on CT data (FFR-CT).
The DeFACTO investigators "raise the bar by comparing this diagnostic technology with a reference standard of both invasive angiography and invasive FFR. This change in reference standard may in part explain some of the accuracy findings. So how should these findings be considered with regard to current clinical evaluation for chest pain?" asked Dr. Patel.
It’s important to put the findings on the performance of CT angiography into context, he wrote. "Several recent multicenter studies have reported diagnostic performance of CT angiography to have high sensitivity (i.e., between 85%-95%) compared with conventional invasive angiography for stenoses of 50% or greater." The high sensitivity of CTA has been used to triage low-risk patients in acute settings.
"However, in stable intermediate-risk patients, for whom a higher degree of specificity (low rate of false positive results) may be desirable to reduce referrals for invasive angiography, concerns exist about the specificity of CT angiography," Dr. Patel noted. In the present study, CT angiography had a sensitivity of 84% but a specificity of only 42% with the more rigorous reference standard.
"It is in this context that FFR-CT represents a novel and important innovation, with the possibility not only to diagnose but also to help direct invasive treatment. The current ... multicenter report by Min et al. confirms a high sensitivity (90%) but demonstrates modest specificity (54%), albeit better than CTA alone," he wrote.
"At first glance, readers of the study may consider FFR-CT technology to be limited based on the results presented. However, this would be a naive conclusion, likely based on the published diagnostic performance of noninvasive tests compared only with invasive angiography," Dr. Patel warned. By comparing existing noninvasive imaging technologies with invasive angiography plus FFR, it is highly likely that the published diagnostic performance would be reduced. "In fact, in clinical practice, the sole use of invasive angiography for lesion evaluation has decreased. Additionally, in real-world practice, the current noninvasive technologies used for diagnosis and risk stratification in stable elective patients prior to invasive angiography do not perform at the published diagnostic levels, as evidenced by the low rates of obstructive CAD at elective catheterization. Hence, the current report describes an important noninvasive technology that may improve existing care and has the potential to outperform established noninvasive technologies," according to Dr. Patel.
DR. PATEL is the cardiology section leader in the peripheral vascular program at Duke University in Durham, N.C., and is assistant director of the cardiac catheterization laboratory. Dr. Patel reports consultancy for Bayer, Jansen, Baxter, and Otsuka, and grants from Johnson & Johnson and AstraZeneca.
The addition of CT-based fractional flow reserve information to CT alone improved the diagnostic accuracy of stenoses, allowing noninvasive assessment of the physiologic consequences of lesions, according to the long-awaited results of the Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography (DeFACTO) study.
However, CT fractional flow reserve (FFR-CT) plus CT narrowly failed to meet the trial’s primary end point – diagnostic accuracy greater than 70% for the lower bound of the 95% confidence interval. Per-patient performance diagnostic accuracy of FFR-CT plus CT was 73% with a 95% CI of 67%-78%.
Nevertheless, the addition of FFR-CT "demonstrated superior diagnostic performance characteristics, as compared with CT stenosis alone, in all patients, in all vessels, and also in vessels of intermediate stenosis severity," lead author Dr. James K. Min said during a press conference.
The results of the study were released in JAMA on Aug. 26th to coincide with the presentation of the study at the European Society of Cardiology meeting (JAMA 2012;308 [doi: 10.1001/2012.jama.11274]).
Fractional flow reserve (FFR) is currently assessed during invasive coronary angiography (ICA) to determine whether a coronary stenosis results in ischemia, and is the currently accepted reference standard for determining lesion-specific ischemia. FFR is the ratio of the mean coronary pressure distal to a coronary stenosis to the mean aortic pressure during maximal coronary blood flow. This value describes coronary flow still attainable despite the presence of a stenotic lesion.
While CT angiography has long been used to accurately and noninvasively assess the anatomic severity of stenoses, the technique has been criticized because it does not yield functional information about the hemodynamic effect of lesions.
Noninvasive calculation of FFR from CT "is a novel method that applies computational fluid dynamics to determine the physiologic significance of CAD [coronary artery disease]. Fractional flow reserve from CT enables calculation of rest and hyperemic pressure fields in coronary arteries without additional imaging, modification of CT acquisition protocols, or administration of medications," the investigators wrote.
"Taken together, these study results suggest the potential of FFR-CT as a promising noninvasive method for identification of individuals with ischemia. The present study findings can be considered proof of concept of the feasibility of this novel technology."
A total of 252 patients were included in the final analysis of the DeFACTO study. These patients had CAD and underwent clinically indicated ICA after CT with no intervening coronary event. Patients were not eligible if they had a history of coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention. About 77% of patients had experienced angina within the past month.
Among 615 study vessels, 271 had less than 30% stenosis and 101 had at least 90% stenosis. In all, 407 vessels were directly assessed by both FFR and FFR-CT.
Computed tomographic angiography was performed on 64- or greater detector scanners with prospective or retrospective electrocardiographic gating.
The investigators evaluated CTs for maximal patient-, vessel-, and segment-based diameter stenosis (characterized as 0%, 1%-29%, 30%-49%, or 50% or larger).
Per-patient and per-vessel CAD stenosis were the maximal stenoses identified in all segments or in all segments within a vessel distribution, respectively. Vessel distributions were categorized for the left anterior descending, left circumflex, and right coronary artery. Computed tomographic angiograms (CTAs) were judged as excellent, good, adequate, or nondiagnostic.
Selective ICA was performed by standard protocol, and FFR was performed at the time of ICA. Fractional flow reserve was considered diagnostic of ischemia at a threshold of 0.80 or less. Computation of FFR-CT was performed in blinded fashion by the FFR-CT core laboratory at HeartFlow, the study’s sponsor.
Per-patient diagnostic accuracy for FFR-CT plus CT was 73%. By comparison, diagnostic accuracy of CT alone was 64%.
FFR-CT also demonstrated greater discriminatory power than CT alone for vessels directly assessed by invasive FFR. For these vessels, the diagnostic sensitivity and specificity of FFR-CT alone were 80% and 61%, respectively.
Importantly, the researchers performed a secondary analysis of patients with an intermediate stenosis ranging from 30% to 70%, "wherein the clinical utility of FFR-CT would be most commonly expected for use." Diagnostic accuracy (73% for FFR-CT and 57% for CT), sensitivity (82% and 37%, respectively), positive predictive value (54% and 34%) and negative predictive value (88% and 68%) were greater for FFR-CT than for CT, though specificity was similar at 66%.
This intermediate group is an important patient population. "We know that patients with 30%-70% stenosis – even though they don’t look high-risk anatomically – actually, some of them experience ischemia and physiologic consequences of their coronary artery disease," said Dr. Min, director of cardiac imaging research and co-director of cardiac imaging at the Cedars-Sinai Heart Institute in Los Angeles.
High sensitivity/low specificity among patients with intermediate stenoses suggests "a low false-negative rate if assessments by FFR-CT were used to identify ischemia causing intermediate lesions, with negligible effects on reductions of false positive results. In this regard, the use of FFR-CT may significantly advance clinical assessment of patients without conventional measures of anatomic high-grade coronary stenosis, largely by proper identification of a significantly greater proportion of patients with manifest ischemia rather than as a safeguard to further invasive evaluation," the researchers noted.
They also pointed out that the prespecified primary end point for FFR-CT – a lower bound of the 95% confidence interval greater than 70% – "represents a 15% increase over traditional noninvasive histologic imaging methods, including myocardial perfusion imaging by SPECT or stress echocardiography," Dr. Min said.
Dr. Min and several of his coauthors reported significant financial relationships with GE Healthcare and Philips Medical, as well as other medical imaging/pharmaceutical companies. Dr. Jason H. Cole reported a grant for research support from HeartFlow. Dr. John Mancini reported a grant to his institution from HeartFlow. This study was funded by HeartFlow.
The addition of CT-based fractional flow reserve information to CT alone improved the diagnostic accuracy of stenoses, allowing noninvasive assessment of the physiologic consequences of lesions, according to the long-awaited results of the Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography (DeFACTO) study.
However, CT fractional flow reserve (FFR-CT) plus CT narrowly failed to meet the trial’s primary end point – diagnostic accuracy greater than 70% for the lower bound of the 95% confidence interval. Per-patient performance diagnostic accuracy of FFR-CT plus CT was 73% with a 95% CI of 67%-78%.
Nevertheless, the addition of FFR-CT "demonstrated superior diagnostic performance characteristics, as compared with CT stenosis alone, in all patients, in all vessels, and also in vessels of intermediate stenosis severity," lead author Dr. James K. Min said during a press conference.
The results of the study were released in JAMA on Aug. 26th to coincide with the presentation of the study at the European Society of Cardiology meeting (JAMA 2012;308 [doi: 10.1001/2012.jama.11274]).
Fractional flow reserve (FFR) is currently assessed during invasive coronary angiography (ICA) to determine whether a coronary stenosis results in ischemia, and is the currently accepted reference standard for determining lesion-specific ischemia. FFR is the ratio of the mean coronary pressure distal to a coronary stenosis to the mean aortic pressure during maximal coronary blood flow. This value describes coronary flow still attainable despite the presence of a stenotic lesion.
While CT angiography has long been used to accurately and noninvasively assess the anatomic severity of stenoses, the technique has been criticized because it does not yield functional information about the hemodynamic effect of lesions.
Noninvasive calculation of FFR from CT "is a novel method that applies computational fluid dynamics to determine the physiologic significance of CAD [coronary artery disease]. Fractional flow reserve from CT enables calculation of rest and hyperemic pressure fields in coronary arteries without additional imaging, modification of CT acquisition protocols, or administration of medications," the investigators wrote.
"Taken together, these study results suggest the potential of FFR-CT as a promising noninvasive method for identification of individuals with ischemia. The present study findings can be considered proof of concept of the feasibility of this novel technology."
A total of 252 patients were included in the final analysis of the DeFACTO study. These patients had CAD and underwent clinically indicated ICA after CT with no intervening coronary event. Patients were not eligible if they had a history of coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention. About 77% of patients had experienced angina within the past month.
Among 615 study vessels, 271 had less than 30% stenosis and 101 had at least 90% stenosis. In all, 407 vessels were directly assessed by both FFR and FFR-CT.
Computed tomographic angiography was performed on 64- or greater detector scanners with prospective or retrospective electrocardiographic gating.
The investigators evaluated CTs for maximal patient-, vessel-, and segment-based diameter stenosis (characterized as 0%, 1%-29%, 30%-49%, or 50% or larger).
Per-patient and per-vessel CAD stenosis were the maximal stenoses identified in all segments or in all segments within a vessel distribution, respectively. Vessel distributions were categorized for the left anterior descending, left circumflex, and right coronary artery. Computed tomographic angiograms (CTAs) were judged as excellent, good, adequate, or nondiagnostic.
Selective ICA was performed by standard protocol, and FFR was performed at the time of ICA. Fractional flow reserve was considered diagnostic of ischemia at a threshold of 0.80 or less. Computation of FFR-CT was performed in blinded fashion by the FFR-CT core laboratory at HeartFlow, the study’s sponsor.
Per-patient diagnostic accuracy for FFR-CT plus CT was 73%. By comparison, diagnostic accuracy of CT alone was 64%.
FFR-CT also demonstrated greater discriminatory power than CT alone for vessels directly assessed by invasive FFR. For these vessels, the diagnostic sensitivity and specificity of FFR-CT alone were 80% and 61%, respectively.
Importantly, the researchers performed a secondary analysis of patients with an intermediate stenosis ranging from 30% to 70%, "wherein the clinical utility of FFR-CT would be most commonly expected for use." Diagnostic accuracy (73% for FFR-CT and 57% for CT), sensitivity (82% and 37%, respectively), positive predictive value (54% and 34%) and negative predictive value (88% and 68%) were greater for FFR-CT than for CT, though specificity was similar at 66%.
This intermediate group is an important patient population. "We know that patients with 30%-70% stenosis – even though they don’t look high-risk anatomically – actually, some of them experience ischemia and physiologic consequences of their coronary artery disease," said Dr. Min, director of cardiac imaging research and co-director of cardiac imaging at the Cedars-Sinai Heart Institute in Los Angeles.
High sensitivity/low specificity among patients with intermediate stenoses suggests "a low false-negative rate if assessments by FFR-CT were used to identify ischemia causing intermediate lesions, with negligible effects on reductions of false positive results. In this regard, the use of FFR-CT may significantly advance clinical assessment of patients without conventional measures of anatomic high-grade coronary stenosis, largely by proper identification of a significantly greater proportion of patients with manifest ischemia rather than as a safeguard to further invasive evaluation," the researchers noted.
They also pointed out that the prespecified primary end point for FFR-CT – a lower bound of the 95% confidence interval greater than 70% – "represents a 15% increase over traditional noninvasive histologic imaging methods, including myocardial perfusion imaging by SPECT or stress echocardiography," Dr. Min said.
Dr. Min and several of his coauthors reported significant financial relationships with GE Healthcare and Philips Medical, as well as other medical imaging/pharmaceutical companies. Dr. Jason H. Cole reported a grant for research support from HeartFlow. Dr. John Mancini reported a grant to his institution from HeartFlow. This study was funded by HeartFlow.
FROM JAMA
Major Finding: CT fractional flow reserve (FFR-CT) plus CT had a per-patient performance diagnostic accuracy of 73% with a 95% confidence interval of 67%-78% – narrowly failing to meet the trial’s primary end point of diagnostic accuracy greater than 70% for the lower bound of the 95% confidence interval.
Data Source: DeFACTO was a multicenter prospective study of 252 patients with CAD, who underwent clinically indicated invasive coronary angiography after CT.
Disclosures: Dr. Min and several of his coauthors reported significant financial relationships with GE Healthcare and Philips Medical, as well as other medical imaging/pharmaceutical companies. Dr. Jason H. Cole reported a grant for research support from HeartFlow. Dr. John Mancini reported a grant to his institution from HeartFlow. This study was funded by HeartFlow.
TRILOGY: Prasugrel, Clopidogrel Look Similar in ACS Patients
MUNICH – Prasugrel had no overall efficacy advantage over clopidogrel when treating patients with non–ST-elevation acute coronary syndrome in a prospective, randomized trial with more than 9,000 patients.
Results from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndrome (TRILOGY ACS) did provide reassuring, new safety data for prasugrel compared with clopidogrel in the enrolled patient population.
The study outcomes also supplied very suggestive evidence for certain efficacy advantages of prasugrel compared with clopidogrel in the study’s target patients. But prasugrel’s inability to beat clopidogrel for the study’s primary efficacy end point produced an inescapable argument against springing for the more expensive prasugrel rather than the cheaper clopidogrel in most non–ST-elevation ACS patients who initially undergo medical management rather than revascularization therapy.
"In the largest trial to date of ACS patients managed medically without revascularization, prasugrel was not statistically different from clopidogrel during 2.5 years of follow-up among patients less than 75 years of age," Dr. Matthew T. Roe said at the meeting. Concurrent with his presentation, the results appeared online (N.Engl.J.Med.2012;367:doi:10.1056/NEJMoa1205512).
Current European Society of Cardiology guidelines for managing patients with ACS without ST-segment elevation say that prasugrel is indicated for patients with known coronary anatomy who are proceeding to PCI (Eur. Heart J. 2011;32:2999-3054). "I believe these recommendations should not be changed," commented Dr. Raffaele De Caterina, professor and director of the division of cardiology at G. d’Annunzio University in Chieti, Italy. In contrast, the same guidelines say that another potent antiplatelet drug, ticagrelor, is recommended for all patients at moderate-to-high risk of ischemic events regardless of their initial treatment strategy. The ticagrelor recommendation was largely based on the results of a prespecified sub-analysis from the Platelet Inhibition and Patient Outcomes (PLATO) trial published last year (BMJ 2011;342:d3527), Dr. De Caterina said.
The new safety findings came from the TRILOGY ACS study design, which called for cutting the standard 10 mg daily dosage of prasugrel in half for patients aged 75 or older, and for patients who weighed less than 60 kg. The consequence was that the rates of severe or intracranial bleeds in patients in the prasugrel arm were not significantly different from patients in the clopidogrel arm, a marked contrast to the results from an earlier major trial that compared prasugrel and clopidogrel, the Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial (N. Engl. J. Med. 2007;357:2001-15).
"A reasonable solution for the problem of excess bleeding in the elderly appears to have been successfully arrived at by modifying the dose," commented Dr. Elliott M. Antman, director of the cardiac unit at Brigham and Women’s Hospital in Boston and lead investigator for the TRITON-TIMI 38 trial.
"The safety here was very comforting, because this trial had the longest follow-up of any antiplatelet treatment agent. The results point out clearly that one drug dose does not fit all," said Dr. E. Magnus Ohman, professor of medicine at Duke University in Durham, N.C., and co-lead investigator for the TRILOGY ACS trial along with Dr. Roe.
The trial’s main efficacy end point focused on the 7,243 enrolled patients who were younger than 75 years old. During a median follow-up of 17 months and as long as 30 months, patients treated with prasugrel had a 13.9% rate of the primary, combined end point of cardiovascular death, myocardial infarction, or stroke, compared with a 16% rate among patients randomized to clopidogrel. This difference did not reach statistical significance, reported Dr. Roe, a Duke cardiologist.
The trial included a prespecified, secondary analysis that focused on recurrent cardiovascular events (not just the incidence of initial events used for the primary analysis). Total recurrent events occurred in 459 patients treated with prasugrel and 530 patients treated with clopidogrel, a 15% relative hazard reduction in favor of prasugrel that reached statistical significance.
In addition, the rate of the primary efficacy end point in the two treatment arms was virtually identical during the first 12 months of follow-up. Subsequently the two arms showed a clear split, with the prasugrel-treated patients having a significant, 28% reduced rate of primary outcomes after the study’s first 12 months, a statistically significant difference in a post-hoc analysis.
The delayed benefit from prasugrel compared with clopidogrel in this trial contrasted with the TRITON-TIMI 38 results, which showed an immediate benefit from prasugrel in patients who underwent percutaneous coronary interventions. A likely explanation is that the highly thrombogenic stents that the TRITON-TIMI 38 patients received posed an acute thrombotic risk, while thrombotic events occurred more slowly in the medically managed patients enrolled in TRILOGY ASC, Dr. Antman suggested in an interview.
The TRILOGY ACS trial was sponsored by Eli Lilly and Daiichi Sankyo, the companies that market prasugrel (Effient). Dr. Roe said that he has received consulting fees from Eli Lilly and Daiichi Sankyo and other drug companies, research grants from Eli Lilly and other drug companies, and lecture fees from AstraZeneca and Janssen. Dr. De Caterina said that he has been a speaker for and received honoraria from Lilly, Daiichi Sankyo, AstraZeneca, and Bayer. Dr. Antman said that he served as lead investigator for the TRITON-TIMI 38 trial. Dr. Ohman said that he received grant support and travel expenses from Eli Lilly and Daiichi Sankyo, and consulting and lecture fees from other drug companies.
The results from TRILOGY ACS clearly showed no overall advantage for treating acute coronary syndrome patients who are managed medically with prasugrel compared with clopidogrel for the study’s primary outcome. The efficacy results showed two very interesting advantages to prasugrel treatment: a statistically significant reduction in recurrent ischemic coronary events, and a statistically significant reduction in events starting a year after the onset of treatment. The recurrent-event analysis was prespecified, and is a very clinically relevant endpoint; the 1-year landmark analysis was done post hoc. Because the primary end point showed no significant benefit, both of these other outcomes must be considered just hypothesis generating.
The safety results for prasugrel were very reassuring. They indicated that barring patients with a history of stroke from the trial and using a reduced, 5 mg/day dosage for patients aged 75 or older and for patients who weighed less than 60 kg eliminated the excess risk for major bleeding events compared with clopidogrel, which were seen in the prior comparison of prasugrel and clopidogrel, the TRITON-TIMI 38 study.
In the United States clopidogrel is now available as a generic drug and is substantially cheaper than prasugrel. If cost were not an issue, then I might be inclined to use prasugrel over clopidogrel in the types of patients enrolled in TRILOGY ACS because of the signals of possible superior efficacy and no added safety risk. But cost is an issue and will remain so for several more years until prasugrel goes off patent. Until then, the possible advantages of prasugrel over clopidogrel do not tip the balance compared with prasugrel’s excess expense.
But the issue of which drug to choose in these patients doesn’t end there, because there is a third option, ticagrelor. A prespecified sub-analysis of the PLATO trial, which compared ticagrelor with clopidogrel in acute coronary syndrome patients, looked at the comparison between the two drugs specifically in patients with non–ST-segment elevation acute coronary syndrome who did not initially undergo invasive management. This is a population of patients very similar to those enrolled into TRILOGY ACS. The subanalysis showed that ticagrelor had a significant efficacy advantage over clopidogrel that was similar to what was seen in the entire PLATO trial, and that provides a compelling reason to consider ticagrelor over clopidogrel in these patients.
But the overall PLATO results as well as this subanalysis also showed a statistically significant excess risk for major bleeding events for ticagrelor, compared with clopidogrel. And ticagrelor, like prasugrel, is substantially more expensive than clopidogrel.
A further complication is that ticagrelor is a twice-daily drug, while clopidogrel and prasugrel are administered once daily.
If I were treating the TRILOGY ACS type of patients, cost were no object, the patients seemed likely to be compliant with their drug regimen, and their bleeding risk was relatively low, then I might want to go with ticagrelor to take advantage of its efficacy edge over clopidogrel. But if cost were a significant consideration, or I had doubts about regular patient compliance with a b.i.d. regimen, or the patient had a high risk for bleeding complications, then clopidogrel might seem like the most attractive option.
DEEPAK L. BHATT, M.D., is chief of cardiology at the VA Boston Healthcare System. Dr. Bhatt served as a coinvestigator and a member of the steering committee for TRILOGY ACS. He said that he has received grant support from several drug companies, but not from the companies that sponsored TRILOGY ACS. Dr. Bhatt made these comments in an interview.
The results from TRILOGY ACS clearly showed no overall advantage for treating acute coronary syndrome patients who are managed medically with prasugrel compared with clopidogrel for the study’s primary outcome. The efficacy results showed two very interesting advantages to prasugrel treatment: a statistically significant reduction in recurrent ischemic coronary events, and a statistically significant reduction in events starting a year after the onset of treatment. The recurrent-event analysis was prespecified, and is a very clinically relevant endpoint; the 1-year landmark analysis was done post hoc. Because the primary end point showed no significant benefit, both of these other outcomes must be considered just hypothesis generating.
The safety results for prasugrel were very reassuring. They indicated that barring patients with a history of stroke from the trial and using a reduced, 5 mg/day dosage for patients aged 75 or older and for patients who weighed less than 60 kg eliminated the excess risk for major bleeding events compared with clopidogrel, which were seen in the prior comparison of prasugrel and clopidogrel, the TRITON-TIMI 38 study.
In the United States clopidogrel is now available as a generic drug and is substantially cheaper than prasugrel. If cost were not an issue, then I might be inclined to use prasugrel over clopidogrel in the types of patients enrolled in TRILOGY ACS because of the signals of possible superior efficacy and no added safety risk. But cost is an issue and will remain so for several more years until prasugrel goes off patent. Until then, the possible advantages of prasugrel over clopidogrel do not tip the balance compared with prasugrel’s excess expense.
But the issue of which drug to choose in these patients doesn’t end there, because there is a third option, ticagrelor. A prespecified sub-analysis of the PLATO trial, which compared ticagrelor with clopidogrel in acute coronary syndrome patients, looked at the comparison between the two drugs specifically in patients with non–ST-segment elevation acute coronary syndrome who did not initially undergo invasive management. This is a population of patients very similar to those enrolled into TRILOGY ACS. The subanalysis showed that ticagrelor had a significant efficacy advantage over clopidogrel that was similar to what was seen in the entire PLATO trial, and that provides a compelling reason to consider ticagrelor over clopidogrel in these patients.
But the overall PLATO results as well as this subanalysis also showed a statistically significant excess risk for major bleeding events for ticagrelor, compared with clopidogrel. And ticagrelor, like prasugrel, is substantially more expensive than clopidogrel.
A further complication is that ticagrelor is a twice-daily drug, while clopidogrel and prasugrel are administered once daily.
If I were treating the TRILOGY ACS type of patients, cost were no object, the patients seemed likely to be compliant with their drug regimen, and their bleeding risk was relatively low, then I might want to go with ticagrelor to take advantage of its efficacy edge over clopidogrel. But if cost were a significant consideration, or I had doubts about regular patient compliance with a b.i.d. regimen, or the patient had a high risk for bleeding complications, then clopidogrel might seem like the most attractive option.
DEEPAK L. BHATT, M.D., is chief of cardiology at the VA Boston Healthcare System. Dr. Bhatt served as a coinvestigator and a member of the steering committee for TRILOGY ACS. He said that he has received grant support from several drug companies, but not from the companies that sponsored TRILOGY ACS. Dr. Bhatt made these comments in an interview.
The results from TRILOGY ACS clearly showed no overall advantage for treating acute coronary syndrome patients who are managed medically with prasugrel compared with clopidogrel for the study’s primary outcome. The efficacy results showed two very interesting advantages to prasugrel treatment: a statistically significant reduction in recurrent ischemic coronary events, and a statistically significant reduction in events starting a year after the onset of treatment. The recurrent-event analysis was prespecified, and is a very clinically relevant endpoint; the 1-year landmark analysis was done post hoc. Because the primary end point showed no significant benefit, both of these other outcomes must be considered just hypothesis generating.
The safety results for prasugrel were very reassuring. They indicated that barring patients with a history of stroke from the trial and using a reduced, 5 mg/day dosage for patients aged 75 or older and for patients who weighed less than 60 kg eliminated the excess risk for major bleeding events compared with clopidogrel, which were seen in the prior comparison of prasugrel and clopidogrel, the TRITON-TIMI 38 study.
In the United States clopidogrel is now available as a generic drug and is substantially cheaper than prasugrel. If cost were not an issue, then I might be inclined to use prasugrel over clopidogrel in the types of patients enrolled in TRILOGY ACS because of the signals of possible superior efficacy and no added safety risk. But cost is an issue and will remain so for several more years until prasugrel goes off patent. Until then, the possible advantages of prasugrel over clopidogrel do not tip the balance compared with prasugrel’s excess expense.
But the issue of which drug to choose in these patients doesn’t end there, because there is a third option, ticagrelor. A prespecified sub-analysis of the PLATO trial, which compared ticagrelor with clopidogrel in acute coronary syndrome patients, looked at the comparison between the two drugs specifically in patients with non–ST-segment elevation acute coronary syndrome who did not initially undergo invasive management. This is a population of patients very similar to those enrolled into TRILOGY ACS. The subanalysis showed that ticagrelor had a significant efficacy advantage over clopidogrel that was similar to what was seen in the entire PLATO trial, and that provides a compelling reason to consider ticagrelor over clopidogrel in these patients.
But the overall PLATO results as well as this subanalysis also showed a statistically significant excess risk for major bleeding events for ticagrelor, compared with clopidogrel. And ticagrelor, like prasugrel, is substantially more expensive than clopidogrel.
A further complication is that ticagrelor is a twice-daily drug, while clopidogrel and prasugrel are administered once daily.
If I were treating the TRILOGY ACS type of patients, cost were no object, the patients seemed likely to be compliant with their drug regimen, and their bleeding risk was relatively low, then I might want to go with ticagrelor to take advantage of its efficacy edge over clopidogrel. But if cost were a significant consideration, or I had doubts about regular patient compliance with a b.i.d. regimen, or the patient had a high risk for bleeding complications, then clopidogrel might seem like the most attractive option.
DEEPAK L. BHATT, M.D., is chief of cardiology at the VA Boston Healthcare System. Dr. Bhatt served as a coinvestigator and a member of the steering committee for TRILOGY ACS. He said that he has received grant support from several drug companies, but not from the companies that sponsored TRILOGY ACS. Dr. Bhatt made these comments in an interview.
MUNICH – Prasugrel had no overall efficacy advantage over clopidogrel when treating patients with non–ST-elevation acute coronary syndrome in a prospective, randomized trial with more than 9,000 patients.
Results from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndrome (TRILOGY ACS) did provide reassuring, new safety data for prasugrel compared with clopidogrel in the enrolled patient population.
The study outcomes also supplied very suggestive evidence for certain efficacy advantages of prasugrel compared with clopidogrel in the study’s target patients. But prasugrel’s inability to beat clopidogrel for the study’s primary efficacy end point produced an inescapable argument against springing for the more expensive prasugrel rather than the cheaper clopidogrel in most non–ST-elevation ACS patients who initially undergo medical management rather than revascularization therapy.
"In the largest trial to date of ACS patients managed medically without revascularization, prasugrel was not statistically different from clopidogrel during 2.5 years of follow-up among patients less than 75 years of age," Dr. Matthew T. Roe said at the meeting. Concurrent with his presentation, the results appeared online (N.Engl.J.Med.2012;367:doi:10.1056/NEJMoa1205512).
Current European Society of Cardiology guidelines for managing patients with ACS without ST-segment elevation say that prasugrel is indicated for patients with known coronary anatomy who are proceeding to PCI (Eur. Heart J. 2011;32:2999-3054). "I believe these recommendations should not be changed," commented Dr. Raffaele De Caterina, professor and director of the division of cardiology at G. d’Annunzio University in Chieti, Italy. In contrast, the same guidelines say that another potent antiplatelet drug, ticagrelor, is recommended for all patients at moderate-to-high risk of ischemic events regardless of their initial treatment strategy. The ticagrelor recommendation was largely based on the results of a prespecified sub-analysis from the Platelet Inhibition and Patient Outcomes (PLATO) trial published last year (BMJ 2011;342:d3527), Dr. De Caterina said.
The new safety findings came from the TRILOGY ACS study design, which called for cutting the standard 10 mg daily dosage of prasugrel in half for patients aged 75 or older, and for patients who weighed less than 60 kg. The consequence was that the rates of severe or intracranial bleeds in patients in the prasugrel arm were not significantly different from patients in the clopidogrel arm, a marked contrast to the results from an earlier major trial that compared prasugrel and clopidogrel, the Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial (N. Engl. J. Med. 2007;357:2001-15).
"A reasonable solution for the problem of excess bleeding in the elderly appears to have been successfully arrived at by modifying the dose," commented Dr. Elliott M. Antman, director of the cardiac unit at Brigham and Women’s Hospital in Boston and lead investigator for the TRITON-TIMI 38 trial.
"The safety here was very comforting, because this trial had the longest follow-up of any antiplatelet treatment agent. The results point out clearly that one drug dose does not fit all," said Dr. E. Magnus Ohman, professor of medicine at Duke University in Durham, N.C., and co-lead investigator for the TRILOGY ACS trial along with Dr. Roe.
The trial’s main efficacy end point focused on the 7,243 enrolled patients who were younger than 75 years old. During a median follow-up of 17 months and as long as 30 months, patients treated with prasugrel had a 13.9% rate of the primary, combined end point of cardiovascular death, myocardial infarction, or stroke, compared with a 16% rate among patients randomized to clopidogrel. This difference did not reach statistical significance, reported Dr. Roe, a Duke cardiologist.
The trial included a prespecified, secondary analysis that focused on recurrent cardiovascular events (not just the incidence of initial events used for the primary analysis). Total recurrent events occurred in 459 patients treated with prasugrel and 530 patients treated with clopidogrel, a 15% relative hazard reduction in favor of prasugrel that reached statistical significance.
In addition, the rate of the primary efficacy end point in the two treatment arms was virtually identical during the first 12 months of follow-up. Subsequently the two arms showed a clear split, with the prasugrel-treated patients having a significant, 28% reduced rate of primary outcomes after the study’s first 12 months, a statistically significant difference in a post-hoc analysis.
The delayed benefit from prasugrel compared with clopidogrel in this trial contrasted with the TRITON-TIMI 38 results, which showed an immediate benefit from prasugrel in patients who underwent percutaneous coronary interventions. A likely explanation is that the highly thrombogenic stents that the TRITON-TIMI 38 patients received posed an acute thrombotic risk, while thrombotic events occurred more slowly in the medically managed patients enrolled in TRILOGY ASC, Dr. Antman suggested in an interview.
The TRILOGY ACS trial was sponsored by Eli Lilly and Daiichi Sankyo, the companies that market prasugrel (Effient). Dr. Roe said that he has received consulting fees from Eli Lilly and Daiichi Sankyo and other drug companies, research grants from Eli Lilly and other drug companies, and lecture fees from AstraZeneca and Janssen. Dr. De Caterina said that he has been a speaker for and received honoraria from Lilly, Daiichi Sankyo, AstraZeneca, and Bayer. Dr. Antman said that he served as lead investigator for the TRITON-TIMI 38 trial. Dr. Ohman said that he received grant support and travel expenses from Eli Lilly and Daiichi Sankyo, and consulting and lecture fees from other drug companies.
MUNICH – Prasugrel had no overall efficacy advantage over clopidogrel when treating patients with non–ST-elevation acute coronary syndrome in a prospective, randomized trial with more than 9,000 patients.
Results from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndrome (TRILOGY ACS) did provide reassuring, new safety data for prasugrel compared with clopidogrel in the enrolled patient population.
The study outcomes also supplied very suggestive evidence for certain efficacy advantages of prasugrel compared with clopidogrel in the study’s target patients. But prasugrel’s inability to beat clopidogrel for the study’s primary efficacy end point produced an inescapable argument against springing for the more expensive prasugrel rather than the cheaper clopidogrel in most non–ST-elevation ACS patients who initially undergo medical management rather than revascularization therapy.
"In the largest trial to date of ACS patients managed medically without revascularization, prasugrel was not statistically different from clopidogrel during 2.5 years of follow-up among patients less than 75 years of age," Dr. Matthew T. Roe said at the meeting. Concurrent with his presentation, the results appeared online (N.Engl.J.Med.2012;367:doi:10.1056/NEJMoa1205512).
Current European Society of Cardiology guidelines for managing patients with ACS without ST-segment elevation say that prasugrel is indicated for patients with known coronary anatomy who are proceeding to PCI (Eur. Heart J. 2011;32:2999-3054). "I believe these recommendations should not be changed," commented Dr. Raffaele De Caterina, professor and director of the division of cardiology at G. d’Annunzio University in Chieti, Italy. In contrast, the same guidelines say that another potent antiplatelet drug, ticagrelor, is recommended for all patients at moderate-to-high risk of ischemic events regardless of their initial treatment strategy. The ticagrelor recommendation was largely based on the results of a prespecified sub-analysis from the Platelet Inhibition and Patient Outcomes (PLATO) trial published last year (BMJ 2011;342:d3527), Dr. De Caterina said.
The new safety findings came from the TRILOGY ACS study design, which called for cutting the standard 10 mg daily dosage of prasugrel in half for patients aged 75 or older, and for patients who weighed less than 60 kg. The consequence was that the rates of severe or intracranial bleeds in patients in the prasugrel arm were not significantly different from patients in the clopidogrel arm, a marked contrast to the results from an earlier major trial that compared prasugrel and clopidogrel, the Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial (N. Engl. J. Med. 2007;357:2001-15).
"A reasonable solution for the problem of excess bleeding in the elderly appears to have been successfully arrived at by modifying the dose," commented Dr. Elliott M. Antman, director of the cardiac unit at Brigham and Women’s Hospital in Boston and lead investigator for the TRITON-TIMI 38 trial.
"The safety here was very comforting, because this trial had the longest follow-up of any antiplatelet treatment agent. The results point out clearly that one drug dose does not fit all," said Dr. E. Magnus Ohman, professor of medicine at Duke University in Durham, N.C., and co-lead investigator for the TRILOGY ACS trial along with Dr. Roe.
The trial’s main efficacy end point focused on the 7,243 enrolled patients who were younger than 75 years old. During a median follow-up of 17 months and as long as 30 months, patients treated with prasugrel had a 13.9% rate of the primary, combined end point of cardiovascular death, myocardial infarction, or stroke, compared with a 16% rate among patients randomized to clopidogrel. This difference did not reach statistical significance, reported Dr. Roe, a Duke cardiologist.
The trial included a prespecified, secondary analysis that focused on recurrent cardiovascular events (not just the incidence of initial events used for the primary analysis). Total recurrent events occurred in 459 patients treated with prasugrel and 530 patients treated with clopidogrel, a 15% relative hazard reduction in favor of prasugrel that reached statistical significance.
In addition, the rate of the primary efficacy end point in the two treatment arms was virtually identical during the first 12 months of follow-up. Subsequently the two arms showed a clear split, with the prasugrel-treated patients having a significant, 28% reduced rate of primary outcomes after the study’s first 12 months, a statistically significant difference in a post-hoc analysis.
The delayed benefit from prasugrel compared with clopidogrel in this trial contrasted with the TRITON-TIMI 38 results, which showed an immediate benefit from prasugrel in patients who underwent percutaneous coronary interventions. A likely explanation is that the highly thrombogenic stents that the TRITON-TIMI 38 patients received posed an acute thrombotic risk, while thrombotic events occurred more slowly in the medically managed patients enrolled in TRILOGY ASC, Dr. Antman suggested in an interview.
The TRILOGY ACS trial was sponsored by Eli Lilly and Daiichi Sankyo, the companies that market prasugrel (Effient). Dr. Roe said that he has received consulting fees from Eli Lilly and Daiichi Sankyo and other drug companies, research grants from Eli Lilly and other drug companies, and lecture fees from AstraZeneca and Janssen. Dr. De Caterina said that he has been a speaker for and received honoraria from Lilly, Daiichi Sankyo, AstraZeneca, and Bayer. Dr. Antman said that he served as lead investigator for the TRITON-TIMI 38 trial. Dr. Ohman said that he received grant support and travel expenses from Eli Lilly and Daiichi Sankyo, and consulting and lecture fees from other drug companies.
AT THE ANNUAL CONGRESS OF THE EUROPEAN SOCIETY OF CARDIOLOGY
Major Finding: Prasugrel showed no overall efficacy edge over clopidogrel in medically managed patients with non–ST-segment elevation acute coronary syndrome.
Data Source: The TRILOGY ACS trial randomized 9,326 patients with non–ST-elevation ACS who did not undergo initial revascularization therapy.
Disclosures: TRILOGY ACS was sponsored by Eli Lilly and Daiichi Sankyo, the companies that market prasugrel (Effient).
ESC Guidelines Tackle TAVI
MUNICH – Transcatheter aortic valve implantation should not be performed in patients at intermediate risk for surgery, according to new European guidelines on the management of valvular heart disease.
"We strongly stress that today, TAVI should not be performed in patients at intermediate risk," said task force chair Dr. Alec Vahanian of the department of cardiology at Bichat Hospital, Paris.
This is the first time that TAVI has been addressed in the guidelines, a joint collaboration between the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery.
The use of TAVI has mushroomed in recent years among high-risk patients with severe aortic stenosis and in those who are not candidates for surgery, but also has been performed in patients at lower risk.
The new guidelines update those issued in 2010, and were prompted by new evidence on risk stratification, diagnostic methods, therapeutic options, and the importance of the collaborative approach between cardiologists and cardiac surgeons, Dr. Vahanian said at the annual congress of the European Society of Cardiology.
"The key message – the core of the document – is to stress teamwork," he said.
The guidelines state that TAVI should be undertaken only with a multidisciplinary "heart team" including cardiologists, cardiac surgeons, and other specialists, if necessary, and only in hospitals with cardiac surgery on-site.
The indications for TAVI, based on results of the randomized PARTNER trial and large European registries, include patients with severe, symptomatic aortic stenosis (AS) who are not suitable for aortic valve replacement (AVR) as assessed by a heart team, and who are likely to gain improvement in their quality of life and are expected to live more than 1 year.
TAVI also should be considered in high-risk patients with severe symptomatic AS who may still be suitable for surgery, but in whom TAVI is favored by a heart team based on the individual risk profile and anatomic suitability, Dr. Vahanian said.
He reported a virtual laundry list of absolute and relative contraindications to TAVI, including an inadequate annulus size, defined as less than 10 mm or greater than 29 mm; thrombus in the left ventricle; active endocarditis; plaques with mobile thrombi in the ascending aorta or arch; inadequate vascular access for a transfemoral/subclavian approach; and a very low left ventricular ejection fraction of less than 20%.
Dr. Vahanian said AVR remains suitable for patients with severe symptomatic AS, including those undergoing coronary artery bypass surgery or surgery of the ascending aorta or another valve, as well as those who are suitable for TAVI, but in whom surgery is favored by a heart team. He observed that there was a great deal of debate among the task force members regarding surgery in symptomatic patients with low flow, low- gradient (defined as less than 40 mm Hg) aortic stenosis, and a normal ejection fraction.
"We have to be extremely cautious and treat only the patient while symptomatic and we are absolutely sure, if we can be sure, that the aortic disease is severe," he remarked.
Disclosures were not provided. The Organizing Committee assumed responsibility for ensuring that all potential conflicts of interest relevant to the program are declared to the participants.
MUNICH – Transcatheter aortic valve implantation should not be performed in patients at intermediate risk for surgery, according to new European guidelines on the management of valvular heart disease.
"We strongly stress that today, TAVI should not be performed in patients at intermediate risk," said task force chair Dr. Alec Vahanian of the department of cardiology at Bichat Hospital, Paris.
This is the first time that TAVI has been addressed in the guidelines, a joint collaboration between the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery.
The use of TAVI has mushroomed in recent years among high-risk patients with severe aortic stenosis and in those who are not candidates for surgery, but also has been performed in patients at lower risk.
The new guidelines update those issued in 2010, and were prompted by new evidence on risk stratification, diagnostic methods, therapeutic options, and the importance of the collaborative approach between cardiologists and cardiac surgeons, Dr. Vahanian said at the annual congress of the European Society of Cardiology.
"The key message – the core of the document – is to stress teamwork," he said.
The guidelines state that TAVI should be undertaken only with a multidisciplinary "heart team" including cardiologists, cardiac surgeons, and other specialists, if necessary, and only in hospitals with cardiac surgery on-site.
The indications for TAVI, based on results of the randomized PARTNER trial and large European registries, include patients with severe, symptomatic aortic stenosis (AS) who are not suitable for aortic valve replacement (AVR) as assessed by a heart team, and who are likely to gain improvement in their quality of life and are expected to live more than 1 year.
TAVI also should be considered in high-risk patients with severe symptomatic AS who may still be suitable for surgery, but in whom TAVI is favored by a heart team based on the individual risk profile and anatomic suitability, Dr. Vahanian said.
He reported a virtual laundry list of absolute and relative contraindications to TAVI, including an inadequate annulus size, defined as less than 10 mm or greater than 29 mm; thrombus in the left ventricle; active endocarditis; plaques with mobile thrombi in the ascending aorta or arch; inadequate vascular access for a transfemoral/subclavian approach; and a very low left ventricular ejection fraction of less than 20%.
Dr. Vahanian said AVR remains suitable for patients with severe symptomatic AS, including those undergoing coronary artery bypass surgery or surgery of the ascending aorta or another valve, as well as those who are suitable for TAVI, but in whom surgery is favored by a heart team. He observed that there was a great deal of debate among the task force members regarding surgery in symptomatic patients with low flow, low- gradient (defined as less than 40 mm Hg) aortic stenosis, and a normal ejection fraction.
"We have to be extremely cautious and treat only the patient while symptomatic and we are absolutely sure, if we can be sure, that the aortic disease is severe," he remarked.
Disclosures were not provided. The Organizing Committee assumed responsibility for ensuring that all potential conflicts of interest relevant to the program are declared to the participants.
MUNICH – Transcatheter aortic valve implantation should not be performed in patients at intermediate risk for surgery, according to new European guidelines on the management of valvular heart disease.
"We strongly stress that today, TAVI should not be performed in patients at intermediate risk," said task force chair Dr. Alec Vahanian of the department of cardiology at Bichat Hospital, Paris.
This is the first time that TAVI has been addressed in the guidelines, a joint collaboration between the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery.
The use of TAVI has mushroomed in recent years among high-risk patients with severe aortic stenosis and in those who are not candidates for surgery, but also has been performed in patients at lower risk.
The new guidelines update those issued in 2010, and were prompted by new evidence on risk stratification, diagnostic methods, therapeutic options, and the importance of the collaborative approach between cardiologists and cardiac surgeons, Dr. Vahanian said at the annual congress of the European Society of Cardiology.
"The key message – the core of the document – is to stress teamwork," he said.
The guidelines state that TAVI should be undertaken only with a multidisciplinary "heart team" including cardiologists, cardiac surgeons, and other specialists, if necessary, and only in hospitals with cardiac surgery on-site.
The indications for TAVI, based on results of the randomized PARTNER trial and large European registries, include patients with severe, symptomatic aortic stenosis (AS) who are not suitable for aortic valve replacement (AVR) as assessed by a heart team, and who are likely to gain improvement in their quality of life and are expected to live more than 1 year.
TAVI also should be considered in high-risk patients with severe symptomatic AS who may still be suitable for surgery, but in whom TAVI is favored by a heart team based on the individual risk profile and anatomic suitability, Dr. Vahanian said.
He reported a virtual laundry list of absolute and relative contraindications to TAVI, including an inadequate annulus size, defined as less than 10 mm or greater than 29 mm; thrombus in the left ventricle; active endocarditis; plaques with mobile thrombi in the ascending aorta or arch; inadequate vascular access for a transfemoral/subclavian approach; and a very low left ventricular ejection fraction of less than 20%.
Dr. Vahanian said AVR remains suitable for patients with severe symptomatic AS, including those undergoing coronary artery bypass surgery or surgery of the ascending aorta or another valve, as well as those who are suitable for TAVI, but in whom surgery is favored by a heart team. He observed that there was a great deal of debate among the task force members regarding surgery in symptomatic patients with low flow, low- gradient (defined as less than 40 mm Hg) aortic stenosis, and a normal ejection fraction.
"We have to be extremely cautious and treat only the patient while symptomatic and we are absolutely sure, if we can be sure, that the aortic disease is severe," he remarked.
Disclosures were not provided. The Organizing Committee assumed responsibility for ensuring that all potential conflicts of interest relevant to the program are declared to the participants.
AT THE ANNUAL CONGRESS OF THE EUROPEAN SOCIETY OF CARDIOLOGY
Youth Smoking Linked to Carotid Intima-Media Thickening
MUNICH – Smoking in young people can induce structural changes to the arterial wall and possibly lead to the development of atherosclerosis before adulthood, according to a Swiss study.
Ultrasound analysis of the common carotid artery of adolescents who actively smoked showed that their intima-media was as much as 0.03 mm thicker than those of youth who didn’t smoke, researchers reported at the annual congress of the European Society of Cardiology.
While the preliminary findings may not dissuade adolescents from smoking, they highlight the need for prevention efforts, such as implementing smoking bans in cities and states, said study investigator Dr. Julia Dratva, a research fellow at the Swiss Tropical and Public Health Institute, Basel.
Studies have established the negative health effects of tobacco exposure in adolescents, but the Swiss study is one of the first to show the impact of smoking on the arterial walls of youths.
"What the study does is make it clear that the vascular wall starts falling into pieces," in youth who smoke, session moderator Dr. Joep Perk said in an interview. "So you are starting on a path that your vascular wall is going to be eventually plugged," added Dr. Perk, professor of health sciences at Linnaeus University, Sweden.
Researchers recruited 279 subjects in the Swiss Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA) Youth Study. Study participants were between ages 9 and 20. Their clinical examination included anthropometry, blood pressure measurement, ultrasound assessment of the carotid artery intima-media thickness, and blood tests for cardiovascular biomarkers.
Many of the study participants had cardiovascular disease risk factors that are known to continue into adulthood and are associated with increased atherosclerotic risk, the authors reported. Thirteen percent of the youth were overweight, 3% had elevated cholesterol, 5% had an HbA1c level higher than 5.7%, and blood pressure was elevated in 7%.
Ten percent of the participants reported weekly smoking (at least one cigarette per week), and 14% reported smoking monthly. Very few reported daily smoking habits, said Dr. Dratva. Mean smoking duration was 2.3 years in ever-smokers. Exposure to passive smoke up to 10 years of age was reported by 31% and current parental smoking by 25%.
Results showed that smoking duration was positively associated with common carotid intima-media thickness (0.014-mm increase/year). The carotid intima-media was significantly thicker in youth who smoked weekly (0.03 mm) compared with those who didn’t smoke. The results remained consistent after adjustment for parental smoking.
Meanwhile, there was not a significant difference in the intima-media thickness among those who reported smoking at least once a month and those who said they didn’t smoke (slightly more than a 0.01-mm difference).
"The thickening of the intima-media is reversible," said Dr. Dratva. "But we don’t know for how long this reversibility will stay," and there’s a need for further investigations, she said.
Dr. Dratva reported no financial conflicts.
MUNICH – Smoking in young people can induce structural changes to the arterial wall and possibly lead to the development of atherosclerosis before adulthood, according to a Swiss study.
Ultrasound analysis of the common carotid artery of adolescents who actively smoked showed that their intima-media was as much as 0.03 mm thicker than those of youth who didn’t smoke, researchers reported at the annual congress of the European Society of Cardiology.
While the preliminary findings may not dissuade adolescents from smoking, they highlight the need for prevention efforts, such as implementing smoking bans in cities and states, said study investigator Dr. Julia Dratva, a research fellow at the Swiss Tropical and Public Health Institute, Basel.
Studies have established the negative health effects of tobacco exposure in adolescents, but the Swiss study is one of the first to show the impact of smoking on the arterial walls of youths.
"What the study does is make it clear that the vascular wall starts falling into pieces," in youth who smoke, session moderator Dr. Joep Perk said in an interview. "So you are starting on a path that your vascular wall is going to be eventually plugged," added Dr. Perk, professor of health sciences at Linnaeus University, Sweden.
Researchers recruited 279 subjects in the Swiss Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA) Youth Study. Study participants were between ages 9 and 20. Their clinical examination included anthropometry, blood pressure measurement, ultrasound assessment of the carotid artery intima-media thickness, and blood tests for cardiovascular biomarkers.
Many of the study participants had cardiovascular disease risk factors that are known to continue into adulthood and are associated with increased atherosclerotic risk, the authors reported. Thirteen percent of the youth were overweight, 3% had elevated cholesterol, 5% had an HbA1c level higher than 5.7%, and blood pressure was elevated in 7%.
Ten percent of the participants reported weekly smoking (at least one cigarette per week), and 14% reported smoking monthly. Very few reported daily smoking habits, said Dr. Dratva. Mean smoking duration was 2.3 years in ever-smokers. Exposure to passive smoke up to 10 years of age was reported by 31% and current parental smoking by 25%.
Results showed that smoking duration was positively associated with common carotid intima-media thickness (0.014-mm increase/year). The carotid intima-media was significantly thicker in youth who smoked weekly (0.03 mm) compared with those who didn’t smoke. The results remained consistent after adjustment for parental smoking.
Meanwhile, there was not a significant difference in the intima-media thickness among those who reported smoking at least once a month and those who said they didn’t smoke (slightly more than a 0.01-mm difference).
"The thickening of the intima-media is reversible," said Dr. Dratva. "But we don’t know for how long this reversibility will stay," and there’s a need for further investigations, she said.
Dr. Dratva reported no financial conflicts.
MUNICH – Smoking in young people can induce structural changes to the arterial wall and possibly lead to the development of atherosclerosis before adulthood, according to a Swiss study.
Ultrasound analysis of the common carotid artery of adolescents who actively smoked showed that their intima-media was as much as 0.03 mm thicker than those of youth who didn’t smoke, researchers reported at the annual congress of the European Society of Cardiology.
While the preliminary findings may not dissuade adolescents from smoking, they highlight the need for prevention efforts, such as implementing smoking bans in cities and states, said study investigator Dr. Julia Dratva, a research fellow at the Swiss Tropical and Public Health Institute, Basel.
Studies have established the negative health effects of tobacco exposure in adolescents, but the Swiss study is one of the first to show the impact of smoking on the arterial walls of youths.
"What the study does is make it clear that the vascular wall starts falling into pieces," in youth who smoke, session moderator Dr. Joep Perk said in an interview. "So you are starting on a path that your vascular wall is going to be eventually plugged," added Dr. Perk, professor of health sciences at Linnaeus University, Sweden.
Researchers recruited 279 subjects in the Swiss Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA) Youth Study. Study participants were between ages 9 and 20. Their clinical examination included anthropometry, blood pressure measurement, ultrasound assessment of the carotid artery intima-media thickness, and blood tests for cardiovascular biomarkers.
Many of the study participants had cardiovascular disease risk factors that are known to continue into adulthood and are associated with increased atherosclerotic risk, the authors reported. Thirteen percent of the youth were overweight, 3% had elevated cholesterol, 5% had an HbA1c level higher than 5.7%, and blood pressure was elevated in 7%.
Ten percent of the participants reported weekly smoking (at least one cigarette per week), and 14% reported smoking monthly. Very few reported daily smoking habits, said Dr. Dratva. Mean smoking duration was 2.3 years in ever-smokers. Exposure to passive smoke up to 10 years of age was reported by 31% and current parental smoking by 25%.
Results showed that smoking duration was positively associated with common carotid intima-media thickness (0.014-mm increase/year). The carotid intima-media was significantly thicker in youth who smoked weekly (0.03 mm) compared with those who didn’t smoke. The results remained consistent after adjustment for parental smoking.
Meanwhile, there was not a significant difference in the intima-media thickness among those who reported smoking at least once a month and those who said they didn’t smoke (slightly more than a 0.01-mm difference).
"The thickening of the intima-media is reversible," said Dr. Dratva. "But we don’t know for how long this reversibility will stay," and there’s a need for further investigations, she said.
Dr. Dratva reported no financial conflicts.
AT THE ANNUAL CONGRESS OF THE EUROPEAN SOCIETY OF CARDIOLOGY
Major Finding: Smoking duration in youth was positively associated with common carotid intima-media thickness (0.014-mm increase/year). Intima-media thickness in adolescents who actively smoked was as much as 0.03 mm greater than in youth who didn’t smoke.
Data Source: The SAPALDIA Youth Study is a nested study of 279 subjects between the ages of 9 and 20 years.
Disclosures: Dr. Dratva reported no financial conflicts.
Stroke Treatment Gets Boost From New Clot Retrievers
Two novel "next generation" mechanical flow restoration devices, or "clot retrievers," show promise for improving the treatment of stroke patients who fail or aren’t eligible for treatment with tissue plasminogen activator, according to findings from separate randomized controlled clinical trials.
In the SWIFT (Solitaire With the Intention of Thrombectomy) trial, the new Solitaire flow restoration device, a self-expanding stent retriever designed to restore blood flow in patients with ischemic stroke due to a large intracranial vessel occlusion, proved significantly more likely to successfully recanalize occlusions of the proximal cerebral arteries than did the Merci retriever, a first-generation mechanical thrombectomy device approved for use in 2004. The results showed that 58 patients treated with the Solitaire device had nearly fivefold greater odds of meeting the primary end point of a Thrombolysis in Myocardial Ischemia (TIMI) scale 2 or 3 flow in all treatable vessels than did 55 patients treated with the Merci retriever (61% vs. 24%; odds ratio, 4.87).
In another trial called TREVO 2, 88 patients treated with the new Trevo Retriever, a stentlike device similar to the Solitaire device, had greater than fourfold higher odds of successful revascularization than did 90 patients treated with the Merci retriever (86% vs. 60%; OR, 4.22). This trial used a slightly different definition of successful recanalization than did the SWIFT trial, defining it as a Thrombolysis in Cerebral Infarction (TICI) score of 2 or greater.
The findings of both trials were published Aug. 26 in the Lancet and were simultaneously presented at the annual congress of the European Society of Cardiology.
Dr. Jeffrey L. Saver of the University of California, Los Angeles, and his colleagues enrolled patients in the SWIFT trial at 18 sites between February 2010 and February 2011, if they had acute ischemic stroke with moderate to severe neurological deficits and angiographically confirmed occlusions of the proximal cerebral arteries, that were treatable by thrombectomy within 8 hours of symptom onset.
In addition to the greater likelihood of achieving the primary end point, the Solitaire patients were more likely to have good 90-day neurological outcomes (58% vs. 33%; OR, 2.78), and to require fewer passes with the device (mean of 1.7 vs. 2.2 passes), the investigators said (Lancet 2012 Aug. 26 [doi: 10.1016/S0140-6736(12)61384-1]).
Furthermore, the frequency of total device-related and procedure-related adverse events did not differ between the two groups, and the 90-day mortality rate was lower in the Solitaire group (OR, 0.29 after adjusting for age and time to treatment), the investigators said.
"On the basis of these results, when endovascular recanalization is done in patients with acute ischemic stroke, initial treatment with Solitaire might be a future treatment of choice," they concluded.
Dr. Raul G. Nogueira of Emory University in Atlanta and his colleagues enrolled patients in the TREVO 2 trial at 26 sites between February 2011 and December 2011, if they had acute onset of stroke symptoms leading to significant clinical deficits, angiographically proven occlusion of a proximal intracranial artery, and eligibility for endovascular therapy within 8 hours of symptom onset.
In addition to the greater likelihood of achieving the primary end point, the Trevo patients were less likely to require adjunctive treatment of any kind (18% vs. 31%; OR, 0.49), and after adjunctive interventions, the rate of TICI 2 or greater reperfusion was higher in the Trevo patients, the investigators said (Lancet 2012 Aug. 26 [doi: 10.1016/S0140-6736(12)61299-9]).
The Trevo patients also were more likely to have good 90-day functional outcomes (40% vs. 22%; OR, 2.39).
No significant differences were seen between the Trevo and Merci patients with respect to the primary safety end point (a composite of multiple device- and procedure-related events), although vessel perforations were 10 times more common with the Merci device, the investigators reported.
Mortality was also similar in both groups at 30 and 90 days.
The investigators noted that although the Trevo device was not compared with medical treatment alone in this study, the findings are encouraging when considered in the context of those from studies of the Trevo predecessor – PROACT II. In the current study, patients treated using the Trevo Retriever achieved the same rate of good clinical outcomes as reported in a pro-urokinase group in the PROACT II trial despite older age, higher baseline National Institutes of Health Stroke Scale score, more proximal occlusions, and more refractory occlusions.
"Our results are therefore encouraging and support the use of the Trevo Retriever in a prospective randomized trial of endovascular therapy against medical treatment alone," the investigators concluded.
As for how the Solitaire and Trevo devices compare with each other, no conclusions can be drawn from SWIFT and TREVO 2 because the two studies used different definitions of reperfusion and good neurological outcomes. However, the devices, both of which have been cleared for general use in the United States and Europe, appear to have a similar or better safety profile than the Merci retriever, and the results thus far suggest that "significant improvement could be forthcoming in stroke patients for whom drug treatment is ineffective," according to a Lancet press statement.
The SWIFT trial was funded by Covidien/ev3, the maker of the Solitaire device. TREVO 2 was funded by Stryker Neurological, the maker of Trevo. Many of the investigators disclosed conflicts of interest involving Covidien/ev3 Neurovascular or Stryker Neurological, as well as other manufacturers of endovascular therapies for stroke.
Despite modest sample sizes, the "carefully done" SWIFT and TREVO 2 trials begin to answer the call for high-level evidence about the efficacy and safety of mechanical clot retrieval devices in acute ischemic stroke, Dr. Philip B. Gorelick wrote in an editorial accompanying the Lancet articles.
"It will be interesting to learn, on the basis of future non-primary analyses, whether collateral flow patterns or clot characteristics elucidate propensity for treatment response," he said (Lancet 2012 Aug. 26 [doi: 10.1016/S0140-6736(12)61302-6]).
He also stated that the "mechanistic basis for superiority" of these next-generation devices might relate to retention of structural integrity of the clot and vessel wall during the procedure.
"Future randomized trials of these and other, newer devices will need to take into account comparison or complementary treatment with rt-PA [recombinant tissue plasminogen activator], or with newer-generation thrombolytics such as desmoteplase and tenecteplase," he said.
Meanwhile, SWIFT and TREVO 2 represent major steps forward, and pave the way for new treatment options, as well as for further validation by additional study, he said.
Dr. Gorelick is with the Hauenstein Neuroscience Center and Michigan State University College of Human Medicine in Grand Rapids. He disclosed that he receives remuneration as co-director of the clinical coordinating center for the DIAS trial that involves desmoteplase.
Despite modest sample sizes, the "carefully done" SWIFT and TREVO 2 trials begin to answer the call for high-level evidence about the efficacy and safety of mechanical clot retrieval devices in acute ischemic stroke, Dr. Philip B. Gorelick wrote in an editorial accompanying the Lancet articles.
"It will be interesting to learn, on the basis of future non-primary analyses, whether collateral flow patterns or clot characteristics elucidate propensity for treatment response," he said (Lancet 2012 Aug. 26 [doi: 10.1016/S0140-6736(12)61302-6]).
He also stated that the "mechanistic basis for superiority" of these next-generation devices might relate to retention of structural integrity of the clot and vessel wall during the procedure.
"Future randomized trials of these and other, newer devices will need to take into account comparison or complementary treatment with rt-PA [recombinant tissue plasminogen activator], or with newer-generation thrombolytics such as desmoteplase and tenecteplase," he said.
Meanwhile, SWIFT and TREVO 2 represent major steps forward, and pave the way for new treatment options, as well as for further validation by additional study, he said.
Dr. Gorelick is with the Hauenstein Neuroscience Center and Michigan State University College of Human Medicine in Grand Rapids. He disclosed that he receives remuneration as co-director of the clinical coordinating center for the DIAS trial that involves desmoteplase.
Despite modest sample sizes, the "carefully done" SWIFT and TREVO 2 trials begin to answer the call for high-level evidence about the efficacy and safety of mechanical clot retrieval devices in acute ischemic stroke, Dr. Philip B. Gorelick wrote in an editorial accompanying the Lancet articles.
"It will be interesting to learn, on the basis of future non-primary analyses, whether collateral flow patterns or clot characteristics elucidate propensity for treatment response," he said (Lancet 2012 Aug. 26 [doi: 10.1016/S0140-6736(12)61302-6]).
He also stated that the "mechanistic basis for superiority" of these next-generation devices might relate to retention of structural integrity of the clot and vessel wall during the procedure.
"Future randomized trials of these and other, newer devices will need to take into account comparison or complementary treatment with rt-PA [recombinant tissue plasminogen activator], or with newer-generation thrombolytics such as desmoteplase and tenecteplase," he said.
Meanwhile, SWIFT and TREVO 2 represent major steps forward, and pave the way for new treatment options, as well as for further validation by additional study, he said.
Dr. Gorelick is with the Hauenstein Neuroscience Center and Michigan State University College of Human Medicine in Grand Rapids. He disclosed that he receives remuneration as co-director of the clinical coordinating center for the DIAS trial that involves desmoteplase.
Two novel "next generation" mechanical flow restoration devices, or "clot retrievers," show promise for improving the treatment of stroke patients who fail or aren’t eligible for treatment with tissue plasminogen activator, according to findings from separate randomized controlled clinical trials.
In the SWIFT (Solitaire With the Intention of Thrombectomy) trial, the new Solitaire flow restoration device, a self-expanding stent retriever designed to restore blood flow in patients with ischemic stroke due to a large intracranial vessel occlusion, proved significantly more likely to successfully recanalize occlusions of the proximal cerebral arteries than did the Merci retriever, a first-generation mechanical thrombectomy device approved for use in 2004. The results showed that 58 patients treated with the Solitaire device had nearly fivefold greater odds of meeting the primary end point of a Thrombolysis in Myocardial Ischemia (TIMI) scale 2 or 3 flow in all treatable vessels than did 55 patients treated with the Merci retriever (61% vs. 24%; odds ratio, 4.87).
In another trial called TREVO 2, 88 patients treated with the new Trevo Retriever, a stentlike device similar to the Solitaire device, had greater than fourfold higher odds of successful revascularization than did 90 patients treated with the Merci retriever (86% vs. 60%; OR, 4.22). This trial used a slightly different definition of successful recanalization than did the SWIFT trial, defining it as a Thrombolysis in Cerebral Infarction (TICI) score of 2 or greater.
The findings of both trials were published Aug. 26 in the Lancet and were simultaneously presented at the annual congress of the European Society of Cardiology.
Dr. Jeffrey L. Saver of the University of California, Los Angeles, and his colleagues enrolled patients in the SWIFT trial at 18 sites between February 2010 and February 2011, if they had acute ischemic stroke with moderate to severe neurological deficits and angiographically confirmed occlusions of the proximal cerebral arteries, that were treatable by thrombectomy within 8 hours of symptom onset.
In addition to the greater likelihood of achieving the primary end point, the Solitaire patients were more likely to have good 90-day neurological outcomes (58% vs. 33%; OR, 2.78), and to require fewer passes with the device (mean of 1.7 vs. 2.2 passes), the investigators said (Lancet 2012 Aug. 26 [doi: 10.1016/S0140-6736(12)61384-1]).
Furthermore, the frequency of total device-related and procedure-related adverse events did not differ between the two groups, and the 90-day mortality rate was lower in the Solitaire group (OR, 0.29 after adjusting for age and time to treatment), the investigators said.
"On the basis of these results, when endovascular recanalization is done in patients with acute ischemic stroke, initial treatment with Solitaire might be a future treatment of choice," they concluded.
Dr. Raul G. Nogueira of Emory University in Atlanta and his colleagues enrolled patients in the TREVO 2 trial at 26 sites between February 2011 and December 2011, if they had acute onset of stroke symptoms leading to significant clinical deficits, angiographically proven occlusion of a proximal intracranial artery, and eligibility for endovascular therapy within 8 hours of symptom onset.
In addition to the greater likelihood of achieving the primary end point, the Trevo patients were less likely to require adjunctive treatment of any kind (18% vs. 31%; OR, 0.49), and after adjunctive interventions, the rate of TICI 2 or greater reperfusion was higher in the Trevo patients, the investigators said (Lancet 2012 Aug. 26 [doi: 10.1016/S0140-6736(12)61299-9]).
The Trevo patients also were more likely to have good 90-day functional outcomes (40% vs. 22%; OR, 2.39).
No significant differences were seen between the Trevo and Merci patients with respect to the primary safety end point (a composite of multiple device- and procedure-related events), although vessel perforations were 10 times more common with the Merci device, the investigators reported.
Mortality was also similar in both groups at 30 and 90 days.
The investigators noted that although the Trevo device was not compared with medical treatment alone in this study, the findings are encouraging when considered in the context of those from studies of the Trevo predecessor – PROACT II. In the current study, patients treated using the Trevo Retriever achieved the same rate of good clinical outcomes as reported in a pro-urokinase group in the PROACT II trial despite older age, higher baseline National Institutes of Health Stroke Scale score, more proximal occlusions, and more refractory occlusions.
"Our results are therefore encouraging and support the use of the Trevo Retriever in a prospective randomized trial of endovascular therapy against medical treatment alone," the investigators concluded.
As for how the Solitaire and Trevo devices compare with each other, no conclusions can be drawn from SWIFT and TREVO 2 because the two studies used different definitions of reperfusion and good neurological outcomes. However, the devices, both of which have been cleared for general use in the United States and Europe, appear to have a similar or better safety profile than the Merci retriever, and the results thus far suggest that "significant improvement could be forthcoming in stroke patients for whom drug treatment is ineffective," according to a Lancet press statement.
The SWIFT trial was funded by Covidien/ev3, the maker of the Solitaire device. TREVO 2 was funded by Stryker Neurological, the maker of Trevo. Many of the investigators disclosed conflicts of interest involving Covidien/ev3 Neurovascular or Stryker Neurological, as well as other manufacturers of endovascular therapies for stroke.
Two novel "next generation" mechanical flow restoration devices, or "clot retrievers," show promise for improving the treatment of stroke patients who fail or aren’t eligible for treatment with tissue plasminogen activator, according to findings from separate randomized controlled clinical trials.
In the SWIFT (Solitaire With the Intention of Thrombectomy) trial, the new Solitaire flow restoration device, a self-expanding stent retriever designed to restore blood flow in patients with ischemic stroke due to a large intracranial vessel occlusion, proved significantly more likely to successfully recanalize occlusions of the proximal cerebral arteries than did the Merci retriever, a first-generation mechanical thrombectomy device approved for use in 2004. The results showed that 58 patients treated with the Solitaire device had nearly fivefold greater odds of meeting the primary end point of a Thrombolysis in Myocardial Ischemia (TIMI) scale 2 or 3 flow in all treatable vessels than did 55 patients treated with the Merci retriever (61% vs. 24%; odds ratio, 4.87).
In another trial called TREVO 2, 88 patients treated with the new Trevo Retriever, a stentlike device similar to the Solitaire device, had greater than fourfold higher odds of successful revascularization than did 90 patients treated with the Merci retriever (86% vs. 60%; OR, 4.22). This trial used a slightly different definition of successful recanalization than did the SWIFT trial, defining it as a Thrombolysis in Cerebral Infarction (TICI) score of 2 or greater.
The findings of both trials were published Aug. 26 in the Lancet and were simultaneously presented at the annual congress of the European Society of Cardiology.
Dr. Jeffrey L. Saver of the University of California, Los Angeles, and his colleagues enrolled patients in the SWIFT trial at 18 sites between February 2010 and February 2011, if they had acute ischemic stroke with moderate to severe neurological deficits and angiographically confirmed occlusions of the proximal cerebral arteries, that were treatable by thrombectomy within 8 hours of symptom onset.
In addition to the greater likelihood of achieving the primary end point, the Solitaire patients were more likely to have good 90-day neurological outcomes (58% vs. 33%; OR, 2.78), and to require fewer passes with the device (mean of 1.7 vs. 2.2 passes), the investigators said (Lancet 2012 Aug. 26 [doi: 10.1016/S0140-6736(12)61384-1]).
Furthermore, the frequency of total device-related and procedure-related adverse events did not differ between the two groups, and the 90-day mortality rate was lower in the Solitaire group (OR, 0.29 after adjusting for age and time to treatment), the investigators said.
"On the basis of these results, when endovascular recanalization is done in patients with acute ischemic stroke, initial treatment with Solitaire might be a future treatment of choice," they concluded.
Dr. Raul G. Nogueira of Emory University in Atlanta and his colleagues enrolled patients in the TREVO 2 trial at 26 sites between February 2011 and December 2011, if they had acute onset of stroke symptoms leading to significant clinical deficits, angiographically proven occlusion of a proximal intracranial artery, and eligibility for endovascular therapy within 8 hours of symptom onset.
In addition to the greater likelihood of achieving the primary end point, the Trevo patients were less likely to require adjunctive treatment of any kind (18% vs. 31%; OR, 0.49), and after adjunctive interventions, the rate of TICI 2 or greater reperfusion was higher in the Trevo patients, the investigators said (Lancet 2012 Aug. 26 [doi: 10.1016/S0140-6736(12)61299-9]).
The Trevo patients also were more likely to have good 90-day functional outcomes (40% vs. 22%; OR, 2.39).
No significant differences were seen between the Trevo and Merci patients with respect to the primary safety end point (a composite of multiple device- and procedure-related events), although vessel perforations were 10 times more common with the Merci device, the investigators reported.
Mortality was also similar in both groups at 30 and 90 days.
The investigators noted that although the Trevo device was not compared with medical treatment alone in this study, the findings are encouraging when considered in the context of those from studies of the Trevo predecessor – PROACT II. In the current study, patients treated using the Trevo Retriever achieved the same rate of good clinical outcomes as reported in a pro-urokinase group in the PROACT II trial despite older age, higher baseline National Institutes of Health Stroke Scale score, more proximal occlusions, and more refractory occlusions.
"Our results are therefore encouraging and support the use of the Trevo Retriever in a prospective randomized trial of endovascular therapy against medical treatment alone," the investigators concluded.
As for how the Solitaire and Trevo devices compare with each other, no conclusions can be drawn from SWIFT and TREVO 2 because the two studies used different definitions of reperfusion and good neurological outcomes. However, the devices, both of which have been cleared for general use in the United States and Europe, appear to have a similar or better safety profile than the Merci retriever, and the results thus far suggest that "significant improvement could be forthcoming in stroke patients for whom drug treatment is ineffective," according to a Lancet press statement.
The SWIFT trial was funded by Covidien/ev3, the maker of the Solitaire device. TREVO 2 was funded by Stryker Neurological, the maker of Trevo. Many of the investigators disclosed conflicts of interest involving Covidien/ev3 Neurovascular or Stryker Neurological, as well as other manufacturers of endovascular therapies for stroke.
FROM THE LANCET
Major Finding: Successful recanalization was significantly more likely to occur in 58 patients treated with the Solitaire device than in 55 patients treated with the Merci retriever (61% vs. 24%; odds ratio, 4.87). In a separate study, successful revascularization was significantly more likely to occur in 88 patients treated with the Trevo Retriever than in 90 patients treated with the Merci retriever (86% vs. 60%; odds ratio, 4.22).
Data Source: This was an analysis of two separate randomized, controlled, open-label trials (SWIFT and TREVO 2).
Disclosures: The SWIFT trial was funded by Covidien/ev3, the maker of the Solitaire device. TREVO 2 was funded by Stryker Neurological, the maker of Trevo. Many of the investigators disclosed conflicts of interest involving Covidien/ev3 Neurovascular or Stryker Neurological, as well as other manufacturers of endovascular therapies for stroke.
Age, Weight May Define Benefits, Risks of Vorapaxar After MI
The investigational antiplatelet drug vorapaxar reduced the risk of cardiovascular death and ischemic events when it was added to standard antiplatelet treatment in a large, randomized, placebo-controlled trial of patients who had a previous myocardial infarction.
The findings, from a prespecified subgroup analysis of the TRA 2°P (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events)–TIMI 50 (Thrombolysis in Myocardial Infarction 50) trial, were most pronounced in patients younger than age 75 years with a body weight of at least 60 kg. Therefore, the benefits of treatment in this group may outweigh the risk of moderate or severe bleeding seen with treatment in this study, Dr. Benjamin M. Scirica of Harvard Medical School, Boston, and his colleagues from the TIMI Study Group reported Aug. 26 in the Lancet.
The study findings – the first to demonstrate the benefit of adding intense antiplatelet treatment to aspirin for long-term, secondary prevention of post-MI thrombotic events – were simultaneously presented at the annual congress of the European Society of Cardiology.
Of 26,449 patients in the TRA2°P–TIMI 50 trial, 17,769 experienced a qualifying MI and thus constituted the subgroup for the current analysis. These patients were randomized to receive treatment with 2.5 mg of a daily oral dose of either vorapaxar or placebo. In each group, 98% of patients concomitantly took aspirin, 78% took a thienopyridine, and 96% took a lipid-lowering agent. During a median follow-up of 2.5 years, cardiovascular death, MI, or stroke occurred in 610 of the 8,898 patients who received active treatment, compared with 750 of 8,881 patients who received placebo (3-year Kaplan-Meier estimates of 8.1% vs. 9.7%; hazard ratio, 0.80), the investigators said (Lancet 2012 Aug. 26 [doi:10.1016/S0140-6736(12)61269-0]).
However, the principal safety end point of moderate or severe bleeding, as defined by GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries), occurred significantly more often in the treatment group than in the placebo group, with 241 of 8,880 vorapaxar patients experiencing such bleeding, compared with 151 of 8,849 placebo patients (3-year Kaplan-Meier estimates of 3.4% vs. 2.1%; HR, 1.61).
Among those younger than age 75 years with no history of transient ischemic attack or stroke, and with a body weight of at least 60 kg (which represented 84% of the study subgroup), cardiovascular death, MI, or stroke occurred in 431 of 7,449 patients who received active treatment, compared with 570 of 7,640 who received placebo (3-year Kaplan Meier estimates of 6.8% vs. 8.6%; HR, 0.75), they noted.
"Moreover, cardiovascular death, myocardial infarction, stroke, urgent coronary revascularization, or GUSTO moderate or severe bleeding was less likely in the vorapaxar group than in the placebo group in these patients [HR, 0.86]. By contrast, for patients aged 75 years and older, with a history of transient ischemic attack or stroke, or patients weighing less than 60 kg, net clinical outcome was not significantly different with vorapaxar compared with placebo," the investigators wrote.
Patients in the multinational, double-blind TRA 2°P-TIMI 50 trial were adults with a history of atherothrombosis who were enrolled between September, 2007, and November, 2009. Those enrolled on the basis of MI had had a spontaneous MI in the 2 weeks to 12 months prior to enrollment.
Vorapaxar is a potent and selective antagonist of protease-activated receptor 1, which is the main receptor for thrombin on human platelets. The findings suggest that inhibiting this receptor "is a novel therapeutic target for long-term secondary prevention after myocardial infarction. The incremental benefit of vorapaxar existed even with high adherence to guidelines," the investigators wrote, noting that the findings add to existing evidence of a benefit of long-term antiplatelet treatment in addition to aspirin for reducing the risk of thrombotic events, and they also confirm the increased risk of bleeding with vorapaxar treatment.
"Identification of patients appropriate for treatment therefore depends on balance of the competing risks of ischemia and bleeding, which are largely based on the clinical setting, patient characteristics, concomitant anticoagulants, and drug dosing," they wrote.
Specifically, the findings of this and other studies indicate that clinical characteristics such as advanced age and low body weight are consistent predictor of increased bleeding risk with potent antithrombotic treatments.
"These simple clinical criteria seem to be useful for selection of patients with better potential for improved net clinical outcomes with vorapaxar," they wrote.
The TRA 2°P-TIMI 50 trial was supported by Merck. The TIMI Study Group and individual members of the group reported numerous disclosures with respect to grant funding, consulting work, and advisory board participation for various pharmaceutical companies. Details are available with the full text of the article at www.thelancet.com.
The findings of the TIMI Study Group’s TRA 2°P–TIMI 50 trial subgroup analysis support the addition of long-term antithrombotic treatment following MI, Dr. Stefan James and Dr. Claes Held wrote in an accompanying editorial.
However, it remains to be seen whether doctors, patients, health care providers, and funding agencies will accept the use of an expensive drug that reduces MI risk and possibly death, but also increases the risk of severe bleeding.
"For patients at low or moderate risk of bleeding, the ischemic benefit seems to outweigh the risk of bleeding. But patients at low risk of bleeding are also often at low risk of ischemic events. Therefore, clinical characteristics or biomarkers to separate ischemic risk and bleeding risk should be defined," they wrote (Lancet 2012 Aug. 26 [doi:10.1016/S0140-6736(12)61383-X]).
"Future research should assess antithrombotic drugs, such as inhibitors of protease-activated receptor 1, as monotherapy or in addition to low-dose aspirin, to balance safety and efficacy for long-term secondary prevention. Also, the effect of a lower dose of vorapaxar than that used in TRA 2°P-TIMI 50 should be investigated," they wrote.
Although the results of the TRA 2°P-TIMI 50 trial "provide data that [aid] our understanding of this topic and offer a step in the right direction," further research on blockade of protease-activated receptor 1 and other antithrombotic drugs is needed to optimize long-term, post-MI secondary prevention strategies, they concluded.
Dr. James and Dr. Held are with Uppsala (Sweden) Clinical Research Center at Uppsala University. Dr. James disclosed receiving institutional research grants from and/or serving on advisory boards for AstraZeneca, Eli Lilly, Merck, Bristol-Myers Squibb, Terumo, Medtronic, and Vascular Solutions. He also has received honoraria from AstraZeneca, Eli Lilly, and the Medicines Company. Dr. Held disclosed receiving institutional research grants from and/or serving on the advisory board for AstraZeneca, Merck, Bristol-Myers Squibb, GlaxoSmithKline, Roche, and Pfizer, and has received honoraria from AstraZeneca.
The findings of the TIMI Study Group’s TRA 2°P–TIMI 50 trial subgroup analysis support the addition of long-term antithrombotic treatment following MI, Dr. Stefan James and Dr. Claes Held wrote in an accompanying editorial.
However, it remains to be seen whether doctors, patients, health care providers, and funding agencies will accept the use of an expensive drug that reduces MI risk and possibly death, but also increases the risk of severe bleeding.
"For patients at low or moderate risk of bleeding, the ischemic benefit seems to outweigh the risk of bleeding. But patients at low risk of bleeding are also often at low risk of ischemic events. Therefore, clinical characteristics or biomarkers to separate ischemic risk and bleeding risk should be defined," they wrote (Lancet 2012 Aug. 26 [doi:10.1016/S0140-6736(12)61383-X]).
"Future research should assess antithrombotic drugs, such as inhibitors of protease-activated receptor 1, as monotherapy or in addition to low-dose aspirin, to balance safety and efficacy for long-term secondary prevention. Also, the effect of a lower dose of vorapaxar than that used in TRA 2°P-TIMI 50 should be investigated," they wrote.
Although the results of the TRA 2°P-TIMI 50 trial "provide data that [aid] our understanding of this topic and offer a step in the right direction," further research on blockade of protease-activated receptor 1 and other antithrombotic drugs is needed to optimize long-term, post-MI secondary prevention strategies, they concluded.
Dr. James and Dr. Held are with Uppsala (Sweden) Clinical Research Center at Uppsala University. Dr. James disclosed receiving institutional research grants from and/or serving on advisory boards for AstraZeneca, Eli Lilly, Merck, Bristol-Myers Squibb, Terumo, Medtronic, and Vascular Solutions. He also has received honoraria from AstraZeneca, Eli Lilly, and the Medicines Company. Dr. Held disclosed receiving institutional research grants from and/or serving on the advisory board for AstraZeneca, Merck, Bristol-Myers Squibb, GlaxoSmithKline, Roche, and Pfizer, and has received honoraria from AstraZeneca.
The findings of the TIMI Study Group’s TRA 2°P–TIMI 50 trial subgroup analysis support the addition of long-term antithrombotic treatment following MI, Dr. Stefan James and Dr. Claes Held wrote in an accompanying editorial.
However, it remains to be seen whether doctors, patients, health care providers, and funding agencies will accept the use of an expensive drug that reduces MI risk and possibly death, but also increases the risk of severe bleeding.
"For patients at low or moderate risk of bleeding, the ischemic benefit seems to outweigh the risk of bleeding. But patients at low risk of bleeding are also often at low risk of ischemic events. Therefore, clinical characteristics or biomarkers to separate ischemic risk and bleeding risk should be defined," they wrote (Lancet 2012 Aug. 26 [doi:10.1016/S0140-6736(12)61383-X]).
"Future research should assess antithrombotic drugs, such as inhibitors of protease-activated receptor 1, as monotherapy or in addition to low-dose aspirin, to balance safety and efficacy for long-term secondary prevention. Also, the effect of a lower dose of vorapaxar than that used in TRA 2°P-TIMI 50 should be investigated," they wrote.
Although the results of the TRA 2°P-TIMI 50 trial "provide data that [aid] our understanding of this topic and offer a step in the right direction," further research on blockade of protease-activated receptor 1 and other antithrombotic drugs is needed to optimize long-term, post-MI secondary prevention strategies, they concluded.
Dr. James and Dr. Held are with Uppsala (Sweden) Clinical Research Center at Uppsala University. Dr. James disclosed receiving institutional research grants from and/or serving on advisory boards for AstraZeneca, Eli Lilly, Merck, Bristol-Myers Squibb, Terumo, Medtronic, and Vascular Solutions. He also has received honoraria from AstraZeneca, Eli Lilly, and the Medicines Company. Dr. Held disclosed receiving institutional research grants from and/or serving on the advisory board for AstraZeneca, Merck, Bristol-Myers Squibb, GlaxoSmithKline, Roche, and Pfizer, and has received honoraria from AstraZeneca.
The investigational antiplatelet drug vorapaxar reduced the risk of cardiovascular death and ischemic events when it was added to standard antiplatelet treatment in a large, randomized, placebo-controlled trial of patients who had a previous myocardial infarction.
The findings, from a prespecified subgroup analysis of the TRA 2°P (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events)–TIMI 50 (Thrombolysis in Myocardial Infarction 50) trial, were most pronounced in patients younger than age 75 years with a body weight of at least 60 kg. Therefore, the benefits of treatment in this group may outweigh the risk of moderate or severe bleeding seen with treatment in this study, Dr. Benjamin M. Scirica of Harvard Medical School, Boston, and his colleagues from the TIMI Study Group reported Aug. 26 in the Lancet.
The study findings – the first to demonstrate the benefit of adding intense antiplatelet treatment to aspirin for long-term, secondary prevention of post-MI thrombotic events – were simultaneously presented at the annual congress of the European Society of Cardiology.
Of 26,449 patients in the TRA2°P–TIMI 50 trial, 17,769 experienced a qualifying MI and thus constituted the subgroup for the current analysis. These patients were randomized to receive treatment with 2.5 mg of a daily oral dose of either vorapaxar or placebo. In each group, 98% of patients concomitantly took aspirin, 78% took a thienopyridine, and 96% took a lipid-lowering agent. During a median follow-up of 2.5 years, cardiovascular death, MI, or stroke occurred in 610 of the 8,898 patients who received active treatment, compared with 750 of 8,881 patients who received placebo (3-year Kaplan-Meier estimates of 8.1% vs. 9.7%; hazard ratio, 0.80), the investigators said (Lancet 2012 Aug. 26 [doi:10.1016/S0140-6736(12)61269-0]).
However, the principal safety end point of moderate or severe bleeding, as defined by GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries), occurred significantly more often in the treatment group than in the placebo group, with 241 of 8,880 vorapaxar patients experiencing such bleeding, compared with 151 of 8,849 placebo patients (3-year Kaplan-Meier estimates of 3.4% vs. 2.1%; HR, 1.61).
Among those younger than age 75 years with no history of transient ischemic attack or stroke, and with a body weight of at least 60 kg (which represented 84% of the study subgroup), cardiovascular death, MI, or stroke occurred in 431 of 7,449 patients who received active treatment, compared with 570 of 7,640 who received placebo (3-year Kaplan Meier estimates of 6.8% vs. 8.6%; HR, 0.75), they noted.
"Moreover, cardiovascular death, myocardial infarction, stroke, urgent coronary revascularization, or GUSTO moderate or severe bleeding was less likely in the vorapaxar group than in the placebo group in these patients [HR, 0.86]. By contrast, for patients aged 75 years and older, with a history of transient ischemic attack or stroke, or patients weighing less than 60 kg, net clinical outcome was not significantly different with vorapaxar compared with placebo," the investigators wrote.
Patients in the multinational, double-blind TRA 2°P-TIMI 50 trial were adults with a history of atherothrombosis who were enrolled between September, 2007, and November, 2009. Those enrolled on the basis of MI had had a spontaneous MI in the 2 weeks to 12 months prior to enrollment.
Vorapaxar is a potent and selective antagonist of protease-activated receptor 1, which is the main receptor for thrombin on human platelets. The findings suggest that inhibiting this receptor "is a novel therapeutic target for long-term secondary prevention after myocardial infarction. The incremental benefit of vorapaxar existed even with high adherence to guidelines," the investigators wrote, noting that the findings add to existing evidence of a benefit of long-term antiplatelet treatment in addition to aspirin for reducing the risk of thrombotic events, and they also confirm the increased risk of bleeding with vorapaxar treatment.
"Identification of patients appropriate for treatment therefore depends on balance of the competing risks of ischemia and bleeding, which are largely based on the clinical setting, patient characteristics, concomitant anticoagulants, and drug dosing," they wrote.
Specifically, the findings of this and other studies indicate that clinical characteristics such as advanced age and low body weight are consistent predictor of increased bleeding risk with potent antithrombotic treatments.
"These simple clinical criteria seem to be useful for selection of patients with better potential for improved net clinical outcomes with vorapaxar," they wrote.
The TRA 2°P-TIMI 50 trial was supported by Merck. The TIMI Study Group and individual members of the group reported numerous disclosures with respect to grant funding, consulting work, and advisory board participation for various pharmaceutical companies. Details are available with the full text of the article at www.thelancet.com.
The investigational antiplatelet drug vorapaxar reduced the risk of cardiovascular death and ischemic events when it was added to standard antiplatelet treatment in a large, randomized, placebo-controlled trial of patients who had a previous myocardial infarction.
The findings, from a prespecified subgroup analysis of the TRA 2°P (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events)–TIMI 50 (Thrombolysis in Myocardial Infarction 50) trial, were most pronounced in patients younger than age 75 years with a body weight of at least 60 kg. Therefore, the benefits of treatment in this group may outweigh the risk of moderate or severe bleeding seen with treatment in this study, Dr. Benjamin M. Scirica of Harvard Medical School, Boston, and his colleagues from the TIMI Study Group reported Aug. 26 in the Lancet.
The study findings – the first to demonstrate the benefit of adding intense antiplatelet treatment to aspirin for long-term, secondary prevention of post-MI thrombotic events – were simultaneously presented at the annual congress of the European Society of Cardiology.
Of 26,449 patients in the TRA2°P–TIMI 50 trial, 17,769 experienced a qualifying MI and thus constituted the subgroup for the current analysis. These patients were randomized to receive treatment with 2.5 mg of a daily oral dose of either vorapaxar or placebo. In each group, 98% of patients concomitantly took aspirin, 78% took a thienopyridine, and 96% took a lipid-lowering agent. During a median follow-up of 2.5 years, cardiovascular death, MI, or stroke occurred in 610 of the 8,898 patients who received active treatment, compared with 750 of 8,881 patients who received placebo (3-year Kaplan-Meier estimates of 8.1% vs. 9.7%; hazard ratio, 0.80), the investigators said (Lancet 2012 Aug. 26 [doi:10.1016/S0140-6736(12)61269-0]).
However, the principal safety end point of moderate or severe bleeding, as defined by GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries), occurred significantly more often in the treatment group than in the placebo group, with 241 of 8,880 vorapaxar patients experiencing such bleeding, compared with 151 of 8,849 placebo patients (3-year Kaplan-Meier estimates of 3.4% vs. 2.1%; HR, 1.61).
Among those younger than age 75 years with no history of transient ischemic attack or stroke, and with a body weight of at least 60 kg (which represented 84% of the study subgroup), cardiovascular death, MI, or stroke occurred in 431 of 7,449 patients who received active treatment, compared with 570 of 7,640 who received placebo (3-year Kaplan Meier estimates of 6.8% vs. 8.6%; HR, 0.75), they noted.
"Moreover, cardiovascular death, myocardial infarction, stroke, urgent coronary revascularization, or GUSTO moderate or severe bleeding was less likely in the vorapaxar group than in the placebo group in these patients [HR, 0.86]. By contrast, for patients aged 75 years and older, with a history of transient ischemic attack or stroke, or patients weighing less than 60 kg, net clinical outcome was not significantly different with vorapaxar compared with placebo," the investigators wrote.
Patients in the multinational, double-blind TRA 2°P-TIMI 50 trial were adults with a history of atherothrombosis who were enrolled between September, 2007, and November, 2009. Those enrolled on the basis of MI had had a spontaneous MI in the 2 weeks to 12 months prior to enrollment.
Vorapaxar is a potent and selective antagonist of protease-activated receptor 1, which is the main receptor for thrombin on human platelets. The findings suggest that inhibiting this receptor "is a novel therapeutic target for long-term secondary prevention after myocardial infarction. The incremental benefit of vorapaxar existed even with high adherence to guidelines," the investigators wrote, noting that the findings add to existing evidence of a benefit of long-term antiplatelet treatment in addition to aspirin for reducing the risk of thrombotic events, and they also confirm the increased risk of bleeding with vorapaxar treatment.
"Identification of patients appropriate for treatment therefore depends on balance of the competing risks of ischemia and bleeding, which are largely based on the clinical setting, patient characteristics, concomitant anticoagulants, and drug dosing," they wrote.
Specifically, the findings of this and other studies indicate that clinical characteristics such as advanced age and low body weight are consistent predictor of increased bleeding risk with potent antithrombotic treatments.
"These simple clinical criteria seem to be useful for selection of patients with better potential for improved net clinical outcomes with vorapaxar," they wrote.
The TRA 2°P-TIMI 50 trial was supported by Merck. The TIMI Study Group and individual members of the group reported numerous disclosures with respect to grant funding, consulting work, and advisory board participation for various pharmaceutical companies. Details are available with the full text of the article at www.thelancet.com.
FROM THE LANCET
Major Finding: During a median follow-up of 2.5 years, cardiovascular death, MI, or stroke occurred in 610 of the 8,898 patients who received active treatment, compared with 750 of 8,881 patients who received placebo (3-year Kaplan-Meier estimates of 8.1% vs. 9.7%; HR, 0.80).
Data Source: This was a subgroup analysis of 17,769 patients who experienced an MI in the randomized, placebo-controlled TRA 2°P–TIMI 50 trial.
Disclosures: The trial was supported by Merck. The TIMI Study Group and individual members of the group reported numerous disclosures with respect to grant funding, consulting work, and advisory board participation for various pharmaceutical companies. Details are available with the full text of the article at www.thelancet.com.
LCZ696 Promising in Subset of Heart Failure Patients
Heart failure patients with preserved ejection who received an investigational agent LCA696 experienced a significant reduction of NT-proBNP at 12 weeks, compared with those who received valsartan, a randomized, multicenter, phase II trial demonstrated.
In addition, a reduction in left atrial size at 36 weeks was observed in patients in the LCA696 group, compared with those who received the angiotensin receptor blocker, researchers led by Dr. Scott Solomon of the cardiovascular division at Brigham and Women’s Hospital, Boston, reported in a study published online Aug. 26, 2012, in the Lancet. The study was simultaneously presented at the annual congress of the European Society of Cardiology.
"Present treatment of heart failure with preserved ejection fraction remains both symptom based and empiric, with no specific treatment approved for this indication," the researchers wrote. "Although ACE inhibitors and ARBs have been associated with symptom improvement, increased functional capacity, and reduction in admission to hospital in these patients, existing guidelines state that no treatment has convincingly been shown to reduce morbidity or mortality.
In a phase II trial known as PARAMOUNT, Dr. Solomon and his associates at 65 centers in 13 countries set out to assess the efficacy and safety of LCZ696 in 301 heart failure patients with preserved ejection fraction. LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that includes valsartan. The researchers hypothesized that LCA696 works by augmenting the active natriuretic peptides to improve myocardial relaxation and reduce hypertrophy. They recruited patients from November 2009 through March 2011.
Patients were eligible for PARAMOUNT if they were at least 40 years of age, had New York Heart Association class II-III heart failure, a left ventricular ejection fraction (LVEF) of 45% or higher, and an NT-proBNP greater than 400 pg/mL (Lancet 2012 Aug. 26 [http://dx.doi.org/10.1016/S0140-6736(12)61227-6]).
After randomization, 149 patients were started on 50 mg LCZ696 twice daily and 152 were started on 40 mg valsartan twice daily and titrated to their final doses of 200 mg LCZ696 twice daily or 160 mg valsartan twice daily over a period of 2-4 weeks. All patients were treated for 36 weeks; the primary end point was change in NT-proBNP from baseline to 12 weeks. This end point was selected "because raised natriuretic peptide concentrations are associated with adverse outcomes in patients with heart failure, including those with preserved ejection fraction, and reductions in NT-proBNP have been associated with improved outcomes in heart failure," the researchers explained.
Dr. Solomon and his associates reported complete data from 134 patients in the LCZ696 group and 132 patients in the valsartan group. The mean age of patients in both groups was 71 years and more than half (57%) were women. The change in NT-proBNP from baseline to week 12 was significantly reduced in patients in the LCZ696 group (from 783 to 605 pg/mL), compared with patients in the valsartan group (from 862 to 835 pg/mL). This translated into a significant ratio of change between the two treatment groups of 0.77. By week 36, the differences in NT-proBNP between the two groups were no longer significant.
After 36 weeks of treatment, patients in the LCZ696 group experienced significant reductions in left atrial volume and in left atrial dimension, compared with their counterparts in the valsartan group. "Left atrial size has been one of the most powerful predictors of outcome in heart failure, including heart failure with preserved ejection fraction," the researchers wrote. "The reported reduction in left atrial size offers support to the notion that LCZ696 had a sustained physiological benefit to 36 weeks."
LCZ696 was well tolerated and the proportion of patients who experienced one or more serious adverse events was similar between the two groups (15% among those in the LCZ696 group vs. 20% among those in the valsartan group).
Novartis funded the study. Dr. Solomon and six of his coauthors disclosed having received research support from, and have consulted for, Novartis, which is developing LCZ696. Three other coauthors are employed by the company.
The positive signals from PARAMOUNT will surely trigger a definitive trial. However, what will the comparator be? Valsartan, a drug not known to be effective for heart failure with preserved ejection fraction? This comparison would show whether there was an advantage to adding a neprilysin inhibitor, but would not provide evidence that valsartan was useful in patients with heart failure with preserved ejection fraction. ACE inhibitors, which seem to have some effect in disease with preserved ejection fraction? An increase in diuretic dose – perhaps the best method of improving symptoms in a congested patient? Or simply placebo? A placebo-controlled design would be the easiest to interpret, but could be confounded by the widespread use of rennin-angiotensin-aldosterone system antagonists in patients with heart failure with preserved ejection fraction, often for problems such as hypertension and peripheral edema. Such background treatment might not easily be withdrawn, rendering enrollment difficult.
Another trial, in patients with heart failure with reduced ejection fraction and raised plasma natriuretic peptides, will show whether LCZ696 is superior to enalapril. If trials in disease with both preserved and reduced ejection fraction are positive (and use the same comparator), cardiac phenotype could become less important than plasma concentration of natriuretic peptides for management of heart failure. However, if LCZ696 proves ineffective in heart failure with preserved ejection fraction, then more attention should be paid to targeting of comorbid disease, to the individual phenotypes, to the causes underlying disease with preserved ejection fraction, or to the aging process itself, which could be the ultimate determinant of prognosis in these patients.
Dr. John G.F. Cleland and Dr. Andrew L. Clark are with the department of cardiology at Castle Hill Hospital in Kingston-Upon-Hull, United Kingdom. These remarks were adapted from a editorial accompanying the PARAMOUNT report (Lancet 2012 Aug. 26 [ http://dx.doi.org/10.1016/ S0140-6736(12)61349-X ]). Dr. Cleland disclosed that he has received honoraria from Novartis. Dr. Clark stated that he has no relevant financial conflicts of interest.
The positive signals from PARAMOUNT will surely trigger a definitive trial. However, what will the comparator be? Valsartan, a drug not known to be effective for heart failure with preserved ejection fraction? This comparison would show whether there was an advantage to adding a neprilysin inhibitor, but would not provide evidence that valsartan was useful in patients with heart failure with preserved ejection fraction. ACE inhibitors, which seem to have some effect in disease with preserved ejection fraction? An increase in diuretic dose – perhaps the best method of improving symptoms in a congested patient? Or simply placebo? A placebo-controlled design would be the easiest to interpret, but could be confounded by the widespread use of rennin-angiotensin-aldosterone system antagonists in patients with heart failure with preserved ejection fraction, often for problems such as hypertension and peripheral edema. Such background treatment might not easily be withdrawn, rendering enrollment difficult.
Another trial, in patients with heart failure with reduced ejection fraction and raised plasma natriuretic peptides, will show whether LCZ696 is superior to enalapril. If trials in disease with both preserved and reduced ejection fraction are positive (and use the same comparator), cardiac phenotype could become less important than plasma concentration of natriuretic peptides for management of heart failure. However, if LCZ696 proves ineffective in heart failure with preserved ejection fraction, then more attention should be paid to targeting of comorbid disease, to the individual phenotypes, to the causes underlying disease with preserved ejection fraction, or to the aging process itself, which could be the ultimate determinant of prognosis in these patients.
Dr. John G.F. Cleland and Dr. Andrew L. Clark are with the department of cardiology at Castle Hill Hospital in Kingston-Upon-Hull, United Kingdom. These remarks were adapted from a editorial accompanying the PARAMOUNT report (Lancet 2012 Aug. 26 [ http://dx.doi.org/10.1016/ S0140-6736(12)61349-X ]). Dr. Cleland disclosed that he has received honoraria from Novartis. Dr. Clark stated that he has no relevant financial conflicts of interest.
The positive signals from PARAMOUNT will surely trigger a definitive trial. However, what will the comparator be? Valsartan, a drug not known to be effective for heart failure with preserved ejection fraction? This comparison would show whether there was an advantage to adding a neprilysin inhibitor, but would not provide evidence that valsartan was useful in patients with heart failure with preserved ejection fraction. ACE inhibitors, which seem to have some effect in disease with preserved ejection fraction? An increase in diuretic dose – perhaps the best method of improving symptoms in a congested patient? Or simply placebo? A placebo-controlled design would be the easiest to interpret, but could be confounded by the widespread use of rennin-angiotensin-aldosterone system antagonists in patients with heart failure with preserved ejection fraction, often for problems such as hypertension and peripheral edema. Such background treatment might not easily be withdrawn, rendering enrollment difficult.
Another trial, in patients with heart failure with reduced ejection fraction and raised plasma natriuretic peptides, will show whether LCZ696 is superior to enalapril. If trials in disease with both preserved and reduced ejection fraction are positive (and use the same comparator), cardiac phenotype could become less important than plasma concentration of natriuretic peptides for management of heart failure. However, if LCZ696 proves ineffective in heart failure with preserved ejection fraction, then more attention should be paid to targeting of comorbid disease, to the individual phenotypes, to the causes underlying disease with preserved ejection fraction, or to the aging process itself, which could be the ultimate determinant of prognosis in these patients.
Dr. John G.F. Cleland and Dr. Andrew L. Clark are with the department of cardiology at Castle Hill Hospital in Kingston-Upon-Hull, United Kingdom. These remarks were adapted from a editorial accompanying the PARAMOUNT report (Lancet 2012 Aug. 26 [ http://dx.doi.org/10.1016/ S0140-6736(12)61349-X ]). Dr. Cleland disclosed that he has received honoraria from Novartis. Dr. Clark stated that he has no relevant financial conflicts of interest.
Heart failure patients with preserved ejection who received an investigational agent LCA696 experienced a significant reduction of NT-proBNP at 12 weeks, compared with those who received valsartan, a randomized, multicenter, phase II trial demonstrated.
In addition, a reduction in left atrial size at 36 weeks was observed in patients in the LCA696 group, compared with those who received the angiotensin receptor blocker, researchers led by Dr. Scott Solomon of the cardiovascular division at Brigham and Women’s Hospital, Boston, reported in a study published online Aug. 26, 2012, in the Lancet. The study was simultaneously presented at the annual congress of the European Society of Cardiology.
"Present treatment of heart failure with preserved ejection fraction remains both symptom based and empiric, with no specific treatment approved for this indication," the researchers wrote. "Although ACE inhibitors and ARBs have been associated with symptom improvement, increased functional capacity, and reduction in admission to hospital in these patients, existing guidelines state that no treatment has convincingly been shown to reduce morbidity or mortality.
In a phase II trial known as PARAMOUNT, Dr. Solomon and his associates at 65 centers in 13 countries set out to assess the efficacy and safety of LCZ696 in 301 heart failure patients with preserved ejection fraction. LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that includes valsartan. The researchers hypothesized that LCA696 works by augmenting the active natriuretic peptides to improve myocardial relaxation and reduce hypertrophy. They recruited patients from November 2009 through March 2011.
Patients were eligible for PARAMOUNT if they were at least 40 years of age, had New York Heart Association class II-III heart failure, a left ventricular ejection fraction (LVEF) of 45% or higher, and an NT-proBNP greater than 400 pg/mL (Lancet 2012 Aug. 26 [http://dx.doi.org/10.1016/S0140-6736(12)61227-6]).
After randomization, 149 patients were started on 50 mg LCZ696 twice daily and 152 were started on 40 mg valsartan twice daily and titrated to their final doses of 200 mg LCZ696 twice daily or 160 mg valsartan twice daily over a period of 2-4 weeks. All patients were treated for 36 weeks; the primary end point was change in NT-proBNP from baseline to 12 weeks. This end point was selected "because raised natriuretic peptide concentrations are associated with adverse outcomes in patients with heart failure, including those with preserved ejection fraction, and reductions in NT-proBNP have been associated with improved outcomes in heart failure," the researchers explained.
Dr. Solomon and his associates reported complete data from 134 patients in the LCZ696 group and 132 patients in the valsartan group. The mean age of patients in both groups was 71 years and more than half (57%) were women. The change in NT-proBNP from baseline to week 12 was significantly reduced in patients in the LCZ696 group (from 783 to 605 pg/mL), compared with patients in the valsartan group (from 862 to 835 pg/mL). This translated into a significant ratio of change between the two treatment groups of 0.77. By week 36, the differences in NT-proBNP between the two groups were no longer significant.
After 36 weeks of treatment, patients in the LCZ696 group experienced significant reductions in left atrial volume and in left atrial dimension, compared with their counterparts in the valsartan group. "Left atrial size has been one of the most powerful predictors of outcome in heart failure, including heart failure with preserved ejection fraction," the researchers wrote. "The reported reduction in left atrial size offers support to the notion that LCZ696 had a sustained physiological benefit to 36 weeks."
LCZ696 was well tolerated and the proportion of patients who experienced one or more serious adverse events was similar between the two groups (15% among those in the LCZ696 group vs. 20% among those in the valsartan group).
Novartis funded the study. Dr. Solomon and six of his coauthors disclosed having received research support from, and have consulted for, Novartis, which is developing LCZ696. Three other coauthors are employed by the company.
Heart failure patients with preserved ejection who received an investigational agent LCA696 experienced a significant reduction of NT-proBNP at 12 weeks, compared with those who received valsartan, a randomized, multicenter, phase II trial demonstrated.
In addition, a reduction in left atrial size at 36 weeks was observed in patients in the LCA696 group, compared with those who received the angiotensin receptor blocker, researchers led by Dr. Scott Solomon of the cardiovascular division at Brigham and Women’s Hospital, Boston, reported in a study published online Aug. 26, 2012, in the Lancet. The study was simultaneously presented at the annual congress of the European Society of Cardiology.
"Present treatment of heart failure with preserved ejection fraction remains both symptom based and empiric, with no specific treatment approved for this indication," the researchers wrote. "Although ACE inhibitors and ARBs have been associated with symptom improvement, increased functional capacity, and reduction in admission to hospital in these patients, existing guidelines state that no treatment has convincingly been shown to reduce morbidity or mortality.
In a phase II trial known as PARAMOUNT, Dr. Solomon and his associates at 65 centers in 13 countries set out to assess the efficacy and safety of LCZ696 in 301 heart failure patients with preserved ejection fraction. LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that includes valsartan. The researchers hypothesized that LCA696 works by augmenting the active natriuretic peptides to improve myocardial relaxation and reduce hypertrophy. They recruited patients from November 2009 through March 2011.
Patients were eligible for PARAMOUNT if they were at least 40 years of age, had New York Heart Association class II-III heart failure, a left ventricular ejection fraction (LVEF) of 45% or higher, and an NT-proBNP greater than 400 pg/mL (Lancet 2012 Aug. 26 [http://dx.doi.org/10.1016/S0140-6736(12)61227-6]).
After randomization, 149 patients were started on 50 mg LCZ696 twice daily and 152 were started on 40 mg valsartan twice daily and titrated to their final doses of 200 mg LCZ696 twice daily or 160 mg valsartan twice daily over a period of 2-4 weeks. All patients were treated for 36 weeks; the primary end point was change in NT-proBNP from baseline to 12 weeks. This end point was selected "because raised natriuretic peptide concentrations are associated with adverse outcomes in patients with heart failure, including those with preserved ejection fraction, and reductions in NT-proBNP have been associated with improved outcomes in heart failure," the researchers explained.
Dr. Solomon and his associates reported complete data from 134 patients in the LCZ696 group and 132 patients in the valsartan group. The mean age of patients in both groups was 71 years and more than half (57%) were women. The change in NT-proBNP from baseline to week 12 was significantly reduced in patients in the LCZ696 group (from 783 to 605 pg/mL), compared with patients in the valsartan group (from 862 to 835 pg/mL). This translated into a significant ratio of change between the two treatment groups of 0.77. By week 36, the differences in NT-proBNP between the two groups were no longer significant.
After 36 weeks of treatment, patients in the LCZ696 group experienced significant reductions in left atrial volume and in left atrial dimension, compared with their counterparts in the valsartan group. "Left atrial size has been one of the most powerful predictors of outcome in heart failure, including heart failure with preserved ejection fraction," the researchers wrote. "The reported reduction in left atrial size offers support to the notion that LCZ696 had a sustained physiological benefit to 36 weeks."
LCZ696 was well tolerated and the proportion of patients who experienced one or more serious adverse events was similar between the two groups (15% among those in the LCZ696 group vs. 20% among those in the valsartan group).
Novartis funded the study. Dr. Solomon and six of his coauthors disclosed having received research support from, and have consulted for, Novartis, which is developing LCZ696. Three other coauthors are employed by the company.
FROM THE LANCET
Major Finding: The change in NT-proBNP from baseline to week 12 was significantly reduced in patients in the LCZ696 group (from 783 to 605 pg/mL), compared with patients in the valsartan group (from 862 to 835 pg/mL). This translated into a ratio of change of 0.77.
Data Source: Data are from a phase II randomized trial of 301 heart failure patients with preserved ejection fraction that compared the angiotensin receptor neprilysin inhibitor LCZ696 with valsartan.
Disclosures: Novartis funded the study. Dr. Solomon and six of his coauthors disclosed having received research support from, and have consulted for, Novartis. Three other coauthors are employed by the company.