Half of Recurrent ACS Due to Existing 'Mild' Lesions

It should not come as a surprise that approximately half of the acute coronary syndromes that recur within 3 years of an index ACS treated percutaneously involve a different lesion that was visualized on angiography at that time but was not severe enough to require treatment, as has been recently reported in the New England Journal of Medicine.

“Pathologic studies … have illustrated that plaques when ruptured were substantially bulky and associated with thin fibrous caps. These lesions at the time of diagnosis may not have been sizable but grow at a faster rate to become eligible for rupture,” Dr. Jagat Narula, who is chief of cardiology at the University of California in Irvine, said in an interview.

The bigger question concerns the potential role for newly available radiofrequency intravascular ultrasonography (RF IVUS) in early assessment of patients with ACS.

The study in question showed that the rate of recurrent major adverse cardiovascular events was 20% in this multicenter prospective study involving 697 patients with ACS who were successfully treated with PCI and medical therapy, then followed for 3 years, reported Dr. Gregg W. Stone of Columbia University Medical Center/New York Presbyterian Hospital and the Cardiovascular Research Foundation, New York, and his associates.

The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study was conducted at 37 medical centers in the United States and Europe.

Study subjects were enrolled after undergoing successful and uncomplicated PCI for all coronary lesions thought to be responsible for their index ACS. At that time, the subjects underwent angiography, then conventional gray-scale intravascular ultrasonography and the newly available RF IVUS of the left main coronary artery and the proximal 6-8 cm of each of the major epicardial coronary arteries.

The median age of the study subjects was 58 years; 24% were women, and 17% had diabetes.

“We found that approximately one in five patients with [ACS] ... had recurrent major adverse cardiovascular events within 3 years. Events were nearly equally divided between those related to initially treated lesions and those related to previously untreated lesions,” Dr. Stone and his colleagues said.

“Most events were rehospitalizations for unstable or progressive angina; death from cardiac causes, cardiac arrest, and MI were less common,” they noted.

“Despite [certain] caveats, PROSPECT study has contributed immensely to understanding plaque anatomy, plaque composition and the prognostic relevance of the atherosclerotic lesions,” said Dr. Narula.

RF IVUS at baseline revealed that most of the “nonculprit” coronary lesions - those that had been considered mild on the index angiography and were not treated at that time - were characterized by a large plaque burden, a small luminal area, or both. Half of them also were thin-cap fibroatheromas. These traits had not been visible on conventional angiography.

“I think the major message is that the angiogram is a very poor discriminator of how much atherosclerosis is present and which type of atherosclerosis is going to go on and cause unexpected events,” Dr. Stone said in an interview. “Radiofrequency IVUS provides significantly more information than just regular gray-scale IVUS in helping differentiate the nature of these plaques and which ones are going to progress.”

Conventional gray-scale IVUS works by sending out ultrasound waves and the resulting reflection signal can reveal structural information. Gray-scale IVUS measures only the amplitude of the reflected waves. However, RF IVUS also interprets frequency information from the reflected waves.

“That radiofrequency signal has been mapped pixel by pixel to actual histology from human pathologic specimens.” So a four-color coded map with four different types of tissue can be created to map plaque composition.

“RF IVUS has a much higher signal-to-noise ratio because it's a catheter that is right next to the coronary plaque. So the resolution is much greater and you can see plaque composition the way that noninvasive modalities currently can't,” Dr. Stone said.

However, “there are several reasons why the methods we have used are not currently suitable for clinical application as a means of identifying sites in the coronary vasculature for potential intervention,” the investigators noted (N. Engl. J. Med. 2011:364:226-35).

First, this method lacks specificity at present. RF IVUS identified a total of 595 thin-cap atheromas in these subjects, but only 26 of them caused recurrent ACS. Similarly, fewer than 10% of the lesions that carried plaque burdens of 70% or more and the lesions with a 4-mm or smaller luminal area caused recurrent ACS.

“Even when all three predictive variables were present, the event rate rose to only 18%,” they said.

Second, catheters used for this type of ultrasonography could only access the proximal 6-8 cm of the coronary tree. This meant that only 51 of the 106 “nonculprit” lesions seen on angiography could be evaluated by RF IVUS.

Third, the technique was associated with very serious adverse events in 11 patients in this study: 10 coronary dissections and 1 perforation, which in turn caused 4 nonfatal MIs.

While the ability of RF IVUS to assess luminal stenosis, plaque burden and positive remodeling is a useful tool, there are other diagnostic modalities to consider as well, said Dr. Narula. “Optical coherence tomography is the only technique that may accurately measure the cap thickness [and] CT angiography allows an assessment of both positive remodeling and the magnitude of necrotic cores.”

Intravascular optical coherence tomography (OCT) is similar to IVUS but light is used instead and resolution is greater. OCT uses a single fiberoptic wire that emits light and records the reflection as it is rotated and pulled back along the artery. OCT can be used to guide interventions, assess the lumen, visualize thrombi and dissections. It can also allow physicians to evaluate lesion cap thickness.

The advent of multislice CT - 264 slices and even greater - offers better and better resolution for non-invasive CT angiography. CTA can identify the presence of positive vessel remodeling and low-attenuation plaques, which along with a necrotic core, are thought to be associated with subsequent plaque rupture.

In the PROSPECT study, they also found that no major events arose from arterial segments with a plaque burden that blocked less than 40% of the lumen. And nonfibroatheromas rarely caused such events, regardless of their plaque burden or the luminal area they blocked.

These study findings suggest that thin-cap fibroatheromas, lesions with a large plaque burden, and lesions with a small luminal area are particularly prone to cause recurrent ACS.

For now though, the early identification of such lesions needs to be validated in randomized trials and is limited by unclear therapeutical options.

“We need to answer two questions,” said Dr. Narula. “First, can we define the high-risk lesions especially when of intermediate angiographic severity? Second, even if it is possible, are we justified in recommending widespread imaging studies, especially when only a small fraction of nonculprit vessel plaques progress to acute events … plaques form, rupture, and heal all the time, and it would be difficult to precisely identify a high-risk plaque associated with a major event, let alone identify it in a treatable proximity to an event.”

Dr. Stone agreed. “We haven't yet done the randomized trials to say that if we find one of these lesions that the patients are better off if we then treat them. If so, what do we treat them with?”

“For now, statins remain the cornerstone of management of the non-obstructive disease. Whether new agents targeted at inflammation … or non-injurious stent implantation become worthy of clinical application, would depend upon the capability of imaging techniques to identify temporo-spatial proclivity of lesions for the occurrence of events, as also the demonstration of the virtue and benign nature of the intervention,” said Dr. Narula.

PROSPECT was funded by Abbott Vascular and Volcano. Abbott participated in the study design, site selection, data collection, and data analysis.

Dr. Stone reports receiving grant support, consulting fees, and/or lecture fees from numerous pharmaceutical and device firms, including Abbott Vascular, TherOx, the Medicines Company, and Boston Scientific. Other investigators reported financial relationships with Abbott Vascular, Boston Scientific, Volcano, Bristol-Myers Squibb, Sanofi-Aventis, the Medicines Company, and others.

It should not come as a surprise that approximately half of the acute coronary syndromes that recur within 3 years of an index ACS treated percutaneously involve a different lesion that was visualized on angiography at that time but was not severe enough to require treatment, as has been recently reported in the New England Journal of Medicine.

“Pathologic studies … have illustrated that plaques when ruptured were substantially bulky and associated with thin fibrous caps. These lesions at the time of diagnosis may not have been sizable but grow at a faster rate to become eligible for rupture,” Dr. Jagat Narula, who is chief of cardiology at the University of California in Irvine, said in an interview.

The bigger question concerns the potential role for newly available radiofrequency intravascular ultrasonography (RF IVUS) in early assessment of patients with ACS.

The study in question showed that the rate of recurrent major adverse cardiovascular events was 20% in this multicenter prospective study involving 697 patients with ACS who were successfully treated with PCI and medical therapy, then followed for 3 years, reported Dr. Gregg W. Stone of Columbia University Medical Center/New York Presbyterian Hospital and the Cardiovascular Research Foundation, New York, and his associates.

The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study was conducted at 37 medical centers in the United States and Europe.

Study subjects were enrolled after undergoing successful and uncomplicated PCI for all coronary lesions thought to be responsible for their index ACS. At that time, the subjects underwent angiography, then conventional gray-scale intravascular ultrasonography and the newly available RF IVUS of the left main coronary artery and the proximal 6-8 cm of each of the major epicardial coronary arteries.

The median age of the study subjects was 58 years; 24% were women, and 17% had diabetes.

“We found that approximately one in five patients with [ACS] ... had recurrent major adverse cardiovascular events within 3 years. Events were nearly equally divided between those related to initially treated lesions and those related to previously untreated lesions,” Dr. Stone and his colleagues said.

“Most events were rehospitalizations for unstable or progressive angina; death from cardiac causes, cardiac arrest, and MI were less common,” they noted.

“Despite [certain] caveats, PROSPECT study has contributed immensely to understanding plaque anatomy, plaque composition and the prognostic relevance of the atherosclerotic lesions,” said Dr. Narula.

RF IVUS at baseline revealed that most of the “nonculprit” coronary lesions - those that had been considered mild on the index angiography and were not treated at that time - were characterized by a large plaque burden, a small luminal area, or both. Half of them also were thin-cap fibroatheromas. These traits had not been visible on conventional angiography.

“I think the major message is that the angiogram is a very poor discriminator of how much atherosclerosis is present and which type of atherosclerosis is going to go on and cause unexpected events,” Dr. Stone said in an interview. “Radiofrequency IVUS provides significantly more information than just regular gray-scale IVUS in helping differentiate the nature of these plaques and which ones are going to progress.”

Conventional gray-scale IVUS works by sending out ultrasound waves and the resulting reflection signal can reveal structural information. Gray-scale IVUS measures only the amplitude of the reflected waves. However, RF IVUS also interprets frequency information from the reflected waves.

“That radiofrequency signal has been mapped pixel by pixel to actual histology from human pathologic specimens.” So a four-color coded map with four different types of tissue can be created to map plaque composition.

“RF IVUS has a much higher signal-to-noise ratio because it's a catheter that is right next to the coronary plaque. So the resolution is much greater and you can see plaque composition the way that noninvasive modalities currently can't,” Dr. Stone said.

However, “there are several reasons why the methods we have used are not currently suitable for clinical application as a means of identifying sites in the coronary vasculature for potential intervention,” the investigators noted (N. Engl. J. Med. 2011:364:226-35).

First, this method lacks specificity at present. RF IVUS identified a total of 595 thin-cap atheromas in these subjects, but only 26 of them caused recurrent ACS. Similarly, fewer than 10% of the lesions that carried plaque burdens of 70% or more and the lesions with a 4-mm or smaller luminal area caused recurrent ACS.

“Even when all three predictive variables were present, the event rate rose to only 18%,” they said.

Second, catheters used for this type of ultrasonography could only access the proximal 6-8 cm of the coronary tree. This meant that only 51 of the 106 “nonculprit” lesions seen on angiography could be evaluated by RF IVUS.

Third, the technique was associated with very serious adverse events in 11 patients in this study: 10 coronary dissections and 1 perforation, which in turn caused 4 nonfatal MIs.

While the ability of RF IVUS to assess luminal stenosis, plaque burden and positive remodeling is a useful tool, there are other diagnostic modalities to consider as well, said Dr. Narula. “Optical coherence tomography is the only technique that may accurately measure the cap thickness [and] CT angiography allows an assessment of both positive remodeling and the magnitude of necrotic cores.”

Intravascular optical coherence tomography (OCT) is similar to IVUS but light is used instead and resolution is greater. OCT uses a single fiberoptic wire that emits light and records the reflection as it is rotated and pulled back along the artery. OCT can be used to guide interventions, assess the lumen, visualize thrombi and dissections. It can also allow physicians to evaluate lesion cap thickness.

The advent of multislice CT - 264 slices and even greater - offers better and better resolution for non-invasive CT angiography. CTA can identify the presence of positive vessel remodeling and low-attenuation plaques, which along with a necrotic core, are thought to be associated with subsequent plaque rupture.

In the PROSPECT study, they also found that no major events arose from arterial segments with a plaque burden that blocked less than 40% of the lumen. And nonfibroatheromas rarely caused such events, regardless of their plaque burden or the luminal area they blocked.

These study findings suggest that thin-cap fibroatheromas, lesions with a large plaque burden, and lesions with a small luminal area are particularly prone to cause recurrent ACS.

For now though, the early identification of such lesions needs to be validated in randomized trials and is limited by unclear therapeutical options.

“We need to answer two questions,” said Dr. Narula. “First, can we define the high-risk lesions especially when of intermediate angiographic severity? Second, even if it is possible, are we justified in recommending widespread imaging studies, especially when only a small fraction of nonculprit vessel plaques progress to acute events … plaques form, rupture, and heal all the time, and it would be difficult to precisely identify a high-risk plaque associated with a major event, let alone identify it in a treatable proximity to an event.”

Dr. Stone agreed. “We haven't yet done the randomized trials to say that if we find one of these lesions that the patients are better off if we then treat them. If so, what do we treat them with?”

“For now, statins remain the cornerstone of management of the non-obstructive disease. Whether new agents targeted at inflammation … or non-injurious stent implantation become worthy of clinical application, would depend upon the capability of imaging techniques to identify temporo-spatial proclivity of lesions for the occurrence of events, as also the demonstration of the virtue and benign nature of the intervention,” said Dr. Narula.

PROSPECT was funded by Abbott Vascular and Volcano. Abbott participated in the study design, site selection, data collection, and data analysis.

Dr. Stone reports receiving grant support, consulting fees, and/or lecture fees from numerous pharmaceutical and device firms, including Abbott Vascular, TherOx, the Medicines Company, and Boston Scientific. Other investigators reported financial relationships with Abbott Vascular, Boston Scientific, Volcano, Bristol-Myers Squibb, Sanofi-Aventis, the Medicines Company, and others.

It should not come as a surprise that approximately half of the acute coronary syndromes that recur within 3 years of an index ACS treated percutaneously involve a different lesion that was visualized on angiography at that time but was not severe enough to require treatment, as has been recently reported in the New England Journal of Medicine.

“Pathologic studies … have illustrated that plaques when ruptured were substantially bulky and associated with thin fibrous caps. These lesions at the time of diagnosis may not have been sizable but grow at a faster rate to become eligible for rupture,” Dr. Jagat Narula, who is chief of cardiology at the University of California in Irvine, said in an interview.

The bigger question concerns the potential role for newly available radiofrequency intravascular ultrasonography (RF IVUS) in early assessment of patients with ACS.

The study in question showed that the rate of recurrent major adverse cardiovascular events was 20% in this multicenter prospective study involving 697 patients with ACS who were successfully treated with PCI and medical therapy, then followed for 3 years, reported Dr. Gregg W. Stone of Columbia University Medical Center/New York Presbyterian Hospital and the Cardiovascular Research Foundation, New York, and his associates.

The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study was conducted at 37 medical centers in the United States and Europe.

Study subjects were enrolled after undergoing successful and uncomplicated PCI for all coronary lesions thought to be responsible for their index ACS. At that time, the subjects underwent angiography, then conventional gray-scale intravascular ultrasonography and the newly available RF IVUS of the left main coronary artery and the proximal 6-8 cm of each of the major epicardial coronary arteries.

The median age of the study subjects was 58 years; 24% were women, and 17% had diabetes.

“We found that approximately one in five patients with [ACS] ... had recurrent major adverse cardiovascular events within 3 years. Events were nearly equally divided between those related to initially treated lesions and those related to previously untreated lesions,” Dr. Stone and his colleagues said.

“Most events were rehospitalizations for unstable or progressive angina; death from cardiac causes, cardiac arrest, and MI were less common,” they noted.

“Despite [certain] caveats, PROSPECT study has contributed immensely to understanding plaque anatomy, plaque composition and the prognostic relevance of the atherosclerotic lesions,” said Dr. Narula.

RF IVUS at baseline revealed that most of the “nonculprit” coronary lesions - those that had been considered mild on the index angiography and were not treated at that time - were characterized by a large plaque burden, a small luminal area, or both. Half of them also were thin-cap fibroatheromas. These traits had not been visible on conventional angiography.

“I think the major message is that the angiogram is a very poor discriminator of how much atherosclerosis is present and which type of atherosclerosis is going to go on and cause unexpected events,” Dr. Stone said in an interview. “Radiofrequency IVUS provides significantly more information than just regular gray-scale IVUS in helping differentiate the nature of these plaques and which ones are going to progress.”

Conventional gray-scale IVUS works by sending out ultrasound waves and the resulting reflection signal can reveal structural information. Gray-scale IVUS measures only the amplitude of the reflected waves. However, RF IVUS also interprets frequency information from the reflected waves.

“That radiofrequency signal has been mapped pixel by pixel to actual histology from human pathologic specimens.” So a four-color coded map with four different types of tissue can be created to map plaque composition.

“RF IVUS has a much higher signal-to-noise ratio because it's a catheter that is right next to the coronary plaque. So the resolution is much greater and you can see plaque composition the way that noninvasive modalities currently can't,” Dr. Stone said.

However, “there are several reasons why the methods we have used are not currently suitable for clinical application as a means of identifying sites in the coronary vasculature for potential intervention,” the investigators noted (N. Engl. J. Med. 2011:364:226-35).

First, this method lacks specificity at present. RF IVUS identified a total of 595 thin-cap atheromas in these subjects, but only 26 of them caused recurrent ACS. Similarly, fewer than 10% of the lesions that carried plaque burdens of 70% or more and the lesions with a 4-mm or smaller luminal area caused recurrent ACS.

“Even when all three predictive variables were present, the event rate rose to only 18%,” they said.

Second, catheters used for this type of ultrasonography could only access the proximal 6-8 cm of the coronary tree. This meant that only 51 of the 106 “nonculprit” lesions seen on angiography could be evaluated by RF IVUS.

Third, the technique was associated with very serious adverse events in 11 patients in this study: 10 coronary dissections and 1 perforation, which in turn caused 4 nonfatal MIs.

While the ability of RF IVUS to assess luminal stenosis, plaque burden and positive remodeling is a useful tool, there are other diagnostic modalities to consider as well, said Dr. Narula. “Optical coherence tomography is the only technique that may accurately measure the cap thickness [and] CT angiography allows an assessment of both positive remodeling and the magnitude of necrotic cores.”

Intravascular optical coherence tomography (OCT) is similar to IVUS but light is used instead and resolution is greater. OCT uses a single fiberoptic wire that emits light and records the reflection as it is rotated and pulled back along the artery. OCT can be used to guide interventions, assess the lumen, visualize thrombi and dissections. It can also allow physicians to evaluate lesion cap thickness.

The advent of multislice CT - 264 slices and even greater - offers better and better resolution for non-invasive CT angiography. CTA can identify the presence of positive vessel remodeling and low-attenuation plaques, which along with a necrotic core, are thought to be associated with subsequent plaque rupture.

In the PROSPECT study, they also found that no major events arose from arterial segments with a plaque burden that blocked less than 40% of the lumen. And nonfibroatheromas rarely caused such events, regardless of their plaque burden or the luminal area they blocked.

These study findings suggest that thin-cap fibroatheromas, lesions with a large plaque burden, and lesions with a small luminal area are particularly prone to cause recurrent ACS.

For now though, the early identification of such lesions needs to be validated in randomized trials and is limited by unclear therapeutical options.

“We need to answer two questions,” said Dr. Narula. “First, can we define the high-risk lesions especially when of intermediate angiographic severity? Second, even if it is possible, are we justified in recommending widespread imaging studies, especially when only a small fraction of nonculprit vessel plaques progress to acute events … plaques form, rupture, and heal all the time, and it would be difficult to precisely identify a high-risk plaque associated with a major event, let alone identify it in a treatable proximity to an event.”

Dr. Stone agreed. “We haven't yet done the randomized trials to say that if we find one of these lesions that the patients are better off if we then treat them. If so, what do we treat them with?”

“For now, statins remain the cornerstone of management of the non-obstructive disease. Whether new agents targeted at inflammation … or non-injurious stent implantation become worthy of clinical application, would depend upon the capability of imaging techniques to identify temporo-spatial proclivity of lesions for the occurrence of events, as also the demonstration of the virtue and benign nature of the intervention,” said Dr. Narula.

PROSPECT was funded by Abbott Vascular and Volcano. Abbott participated in the study design, site selection, data collection, and data analysis.

Dr. Stone reports receiving grant support, consulting fees, and/or lecture fees from numerous pharmaceutical and device firms, including Abbott Vascular, TherOx, the Medicines Company, and Boston Scientific. Other investigators reported financial relationships with Abbott Vascular, Boston Scientific, Volcano, Bristol-Myers Squibb, Sanofi-Aventis, the Medicines Company, and others.