- Email: [email protected]
The PROSPECT of Changing Our Approach to Acute Coronary Syndromes⁎
JACC: CARDIOVASCULAR IMAGING
VOL. 5, NO. 3, SUPPL S, 2012
© 2012 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-878X/$36.00
PUBLISHED BY ELSEVIER INC.
DOI:10.1016/j.jcmg.2012.02.002
EDITORIAL COMMENT
The PROSPECT of Changing Our Approach to Acute Coronary Syndromes* Michael E. Farkouh, MD, MSC,†‡ Verghese Mathew, MD§ New York, New York; Toronto, Ontario, Canada; and Rochester, Minnesota
In acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI), identification of culprit lesions and other potentially significant stenoses most often utilizes coronary angiography. The PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study, used multimodality coronary artery imaging (greyscale and radiofrequency intravascular ultrasound, in addition to angiography) to describe the natural history of coronary atherosclerosis after PCI for ACS. PROSPECT was a landmark study that underscored the systemic nature of atherosclerosis, demonstrating that initially mild, nonculprit lesions (NCLs) accounted for about half of subsequent events in patients followed for 3 years. The characteristics associated with future events included See pages S42, S53, and S62
plaque burden ⬎70%, minimum lumen area ⬍4 mm2, and presence of thin-cap fibroatheroma in lesions that were assessed angiographically to be ⬍50% stenosed at the time of index presentation; adverse events were increasingly frequent if 1, 2, or all 3 of these features were present. The effects on outcome of the extent of CAD, the influence of NCLs on future MACE events, and the influence of plaque composition in the important subgroups
*Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology. From the †Peter Munk Cardiac Centre and Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Ontario, Canada; ‡Mount Sinai Cardiovascular Institute, New York, New York; and the §Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
of diabetic patients, women, and those patients with chronic kidney disease (CKD) from PROSPECT are addressed in this issue of iJACC. Such subanalyses may give important insight into potential mechanisms for what we have previously observed in large outcomes studies. In ACS, diabetes has long been associated with increased cardiovascular risk of events compared to nondiabetic patients (1–3). On the other hand, there is less understanding of the risk of metabolic syndrome or impaired glucose tolerance. Marso et al. (4) demonstrate a strong gradient of cardiovascular (CV) risk from diabetes to metabolic syndrome to normoglycemia for major adverse cardiac events (MACE) rates (29.4% vs. 21.3% vs. 17.4%). A most intriguing observation in their PROSPECT substudy was that there was a disproportionate number of MACE in the diabetic group attributable to NCLs (about two-thirds, 18.7% of 29.4%), compared with the approximately 50% contribution of NCLs to 3-year event rate in the main PROSPECT trial and the other 2 subgroups of women and CKD. This is complementary to the findings of Cutlip et al. (5), who described that for diabetic patients, nontarget lesions were associated with the majority of clinical events after the first year post-PCI. The finding that long lesions and lesions with a greater proportion of necrotic core and calcium were associated with increased risk also underscores the incremental value of multimodality coronary imaging in assessing future risk. Further study is required to determine the relationship between plaque composition, MACE, and degree of control of cardiovascular risk factors (6). Are the diabetic patients that are not meeting risk factor goals, or with more advanced stage/longer duration of diabetes, more likely to have NCLs with high-
S74
Farkouh and Mathew Editorial Comment
risk features and therefore more likely to experience MACE? In an accompanying paper, Lansky et al. (7) sought to evaluate the impact of sex on characteristics of coronary plaque in the PROSPECT study. Interestingly, women, as expected, were older and had more comorbid disease when compared with men, but had fewer NCLs overall. As expected from other studies, there were no differences in MACE rates between men and women although there were gender differences for which plaque subtypes predicted future risk (thin-cap fibroatheroma for women and plaque burden for men). Plaque rupture occurred less commonly in women, and the investigators hypothesize that this may explain why women present more often with typical or atypical chest pain syndromes rather than frank ACS. Although the pathophysiology and plaque composition of CAD leading to ACS may be quite different between the sexes, the differences appear to be off-setting with respect to clinical outcomes, and appear to validate the current practice whereby men and women are treated in a similar fashion (8). Baber et al. (9) reported on the influence of CKD on plaque composition morphology and outcomes in the PROSPECT study. As in patients with diabetes, patients with CKD are at increased risk for MACE at the time of an ACS (10). Even more importantly, patients with CKD may have increased risk even if they are treated for their traditional risk factors. Similar to the graded CV risk of dysglycemia from metabolic syndrome to diabetes, there is also a continuum that has been identified for CKD. In the current analysis from the PROSPECT investigators, CKD was defined by an estimated glomerular filtration rate ⬍60 ml/min, although the cohort on average had mild CKD (stage I) with a mean glomerular filtration rate of 51 ml/min. Those with CKD were characterized by a greater degree of diabetes and hypertension, were more likely to present with a non–ST-segment elevation MI, and experienced a higher rate of 3-year MACE events. Patients with CKD were more often noted to have lesions with MLA ⬍4 mm2, greater plaque burden, a trend toward longer lesion length, and had a higher proportion of necrotic core when compared with those without CKD. The difference in subsequent events between those with and without CKD was primarily attributable to culprit lesions; unlike diabetes, CKD was not associated with disproportionate number of MACE attributable to NCLs. Could this explain the reduced benefit of optimal medical therapy in
JACC: CARDIOVASCULAR IMAGING, VOL. 5, NO. 3, SUPPL S, 2012 MARCH 2012:S73–5
CKD patients compared with those with diabetes, or is it merely an inability to draw firm conclusions due to the small sample size and inclusion of relatively mild CRF patients. However, the findings do raise the question as to whether there is a different biology of atherosclerosis for CKD compared with diabetes, which merits further understanding (11). PROSPECT and these subanalyses highlight 3 major points that merit our attention. First, the fact that NCLs account for 50% and more of the events in the ensuing 3 years after angiographically targeted lesion revascularization for ACS underscores the nonfocal nature of atherosclerosis. These lesions to date are generally addressed with medical therapy, and the findings remind us of the importance of optimizing medical therapy and plaque stabilization after ACS PCI. Second, complementary coronary imaging aids in identifying NCLs that are more likely to lead to adverse events. Third, important baseline characteristics may dictate how we approach NCLs in the future. In diabetic patients, NCLs account for a disproportionate number of events, and therefore they may be of greater importance. This may mean that patients need to be treated more aggressively from a medical standpoint for systemic risk factor modification and stabilization of these lesions, or potentially have NCLs with multiple plaque characteristics that portend risk treated by novel interventional strategies that are yet to be tested. On the other hand, patients with CKD have greater MACE, but these events are not due primarily to differences in nonculprit lesions, but rather to differences in culprit lesions, and yet the beneficial effects of optimal lipid control have also been demonstrated in this population (12). Whether the discordant findings regarding the influence of NCLs on subsequent events in diabetic versus CKD patients is explained by biological differences in atherosclerosis between these 2 often overlapping subgroups merits further study. The insights from the PROSPECT study and substudies are intriguing to clinical cardiologists. The identification and characterization of NCLs that will account for future CV events appears to be an exciting area of ongoing investigation, and should utilize a patient-specific, plaque-specific approach. For the clinician, it reminds of the importance of systemic medical management with pharmacotherapy in the long-term treatment of patients after ACS. What is clear is that many of our patients are prescribed medications directed at treating risk factors, but only a fraction of patients reach targets for low-density lipoprotein choles-
Farkouh and Mathew Editorial Comment
JACC: CARDIOVASCULAR IMAGING, VOL. 5, NO. 3, SUPPL S, 2012 MARCH 2012:S73–5
terol, high-density lipoprotein cholesterol, HbA1c, and blood pressure. One might ask how the results from PROSPECT would look if patients were under optimal medical control. The objectives for the future should consider: 1) a patient-level scoring system to define those at high risk for NCL-associated MACE based on PROSPECT-driven lesion characterization at the time of PCI for ACS, which should include a measure of CV risk factors; 2) interventional trials to test the utility of defining and revascularizing high-risk non-
REFERENCES
1. Franklin K, Goldberg RJ, Spencer F, et al., GRACE Investigators. Implications of diabetes in patients with acute coronary syndromes. The Global Registry of Acute Coronary Events. Arch Intern Med 2004;164: 1457– 63. 2. Nicholls SJ, Murat ET, Kalidindi S, et al. Effect of diabetes on progression of coronary atherosclerosis and arterial remodeling. J Am Coll Cardiol 2008; 52:255– 62. 3. Donahoe SM, Stewart GC, McCabe CH, et al. Diabetes and mortality following acute coronary syndromes. JAMA 2007;298:765–75. 4. Marso SP, Mercado N, Maehara A, et al. Plaque composition and clinical outcomes in acute coronary syndrome patients with metabolic syndrome or diabetes. J Am Coll Cardiol Img 2012;5 Suppl S:S42–52. 5. Cutlip DE, Chhabra AG, Baim DS, et al. Beyond restenosis: five-year clinical outcomes from second-generation coronary stent trials. Circulation 2004; 110:1226 –30.
culprit lesions; and 3) utilizing emerging noninvasive strategies such magnetic resonance, computed tomography, and positron emission tomography to characterize plaque at the extracoronary and coronary level. These important studies introduce the prospect for major advances in the years to come. Reprint requests and correspondence: Prof. Michael E.
Farkouh, University Health Network, Peter Munk Cardiac Centre, 585 University Avenue, Toronto, Ontario 4N474, Canada. E-mail: [email protected].
6. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358:580 –59. 7. Lansky AJ, Ng VG, Maehara A, et al. Gender and the extent of coronary atherosclerosis, plaque composition, and clinical outcomes in acute coronary syndromes. J Am Coll Cardiol Img 2012;5 Suppl S:S62–72. 8. Alfredsson J, Lindbäck J, Wallentin L, Swahn E. Similar outcome with an invasive strategy in men and women with non-ST-elevation acute coronary syndromes: from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART). Eur Heart J 2011;32:3128 –36. 9. Baber U, Stone GW, Weisz G, et al. Coronary plaque composition, morphology, and outcomes in patients with and without chronic kidney disease presenting with acute coronary syndromes. J Am Coll Cardiol Img 2012;5 Suppl S:S53– 61.
10. Ahmed S, Cannon CP, Giugliano RP, et al. The independent and combined risk of diabetes and nonendstage renal impairment in nonST-segment elevation acute coronary syndromes. Int J Cardiol 2008;131: 105–12. 11. Kestenbaum BR, Adeney KL, de Boer IH, Ix JH, Shlipak MG, Siscovick DS. Incidence and progression of coronary calcification in chronic kidney disease: the Multi-Ethnic Study of Atherosclerosis. Kidney Int 2009;76: 991– 8. 12. Shepherd J, Kastelein JJ, Bittner V, et al., TNT (Treating to New Targets) Investigators. Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study. J Am Coll Cardiol 2008;51:1448 –54.
Key Words: acute coronary syndrome y atherosclerosis y lesion characterization.
S75
VOL. 5, NO. 3, SUPPL S, 2012
© 2012 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-878X/$36.00
PUBLISHED BY ELSEVIER INC.
DOI:10.1016/j.jcmg.2012.02.002
EDITORIAL COMMENT
The PROSPECT of Changing Our Approach to Acute Coronary Syndromes* Michael E. Farkouh, MD, MSC,†‡ Verghese Mathew, MD§ New York, New York; Toronto, Ontario, Canada; and Rochester, Minnesota
In acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI), identification of culprit lesions and other potentially significant stenoses most often utilizes coronary angiography. The PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study, used multimodality coronary artery imaging (greyscale and radiofrequency intravascular ultrasound, in addition to angiography) to describe the natural history of coronary atherosclerosis after PCI for ACS. PROSPECT was a landmark study that underscored the systemic nature of atherosclerosis, demonstrating that initially mild, nonculprit lesions (NCLs) accounted for about half of subsequent events in patients followed for 3 years. The characteristics associated with future events included See pages S42, S53, and S62
plaque burden ⬎70%, minimum lumen area ⬍4 mm2, and presence of thin-cap fibroatheroma in lesions that were assessed angiographically to be ⬍50% stenosed at the time of index presentation; adverse events were increasingly frequent if 1, 2, or all 3 of these features were present. The effects on outcome of the extent of CAD, the influence of NCLs on future MACE events, and the influence of plaque composition in the important subgroups
*Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology. From the †Peter Munk Cardiac Centre and Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Ontario, Canada; ‡Mount Sinai Cardiovascular Institute, New York, New York; and the §Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
of diabetic patients, women, and those patients with chronic kidney disease (CKD) from PROSPECT are addressed in this issue of iJACC. Such subanalyses may give important insight into potential mechanisms for what we have previously observed in large outcomes studies. In ACS, diabetes has long been associated with increased cardiovascular risk of events compared to nondiabetic patients (1–3). On the other hand, there is less understanding of the risk of metabolic syndrome or impaired glucose tolerance. Marso et al. (4) demonstrate a strong gradient of cardiovascular (CV) risk from diabetes to metabolic syndrome to normoglycemia for major adverse cardiac events (MACE) rates (29.4% vs. 21.3% vs. 17.4%). A most intriguing observation in their PROSPECT substudy was that there was a disproportionate number of MACE in the diabetic group attributable to NCLs (about two-thirds, 18.7% of 29.4%), compared with the approximately 50% contribution of NCLs to 3-year event rate in the main PROSPECT trial and the other 2 subgroups of women and CKD. This is complementary to the findings of Cutlip et al. (5), who described that for diabetic patients, nontarget lesions were associated with the majority of clinical events after the first year post-PCI. The finding that long lesions and lesions with a greater proportion of necrotic core and calcium were associated with increased risk also underscores the incremental value of multimodality coronary imaging in assessing future risk. Further study is required to determine the relationship between plaque composition, MACE, and degree of control of cardiovascular risk factors (6). Are the diabetic patients that are not meeting risk factor goals, or with more advanced stage/longer duration of diabetes, more likely to have NCLs with high-
S74
Farkouh and Mathew Editorial Comment
risk features and therefore more likely to experience MACE? In an accompanying paper, Lansky et al. (7) sought to evaluate the impact of sex on characteristics of coronary plaque in the PROSPECT study. Interestingly, women, as expected, were older and had more comorbid disease when compared with men, but had fewer NCLs overall. As expected from other studies, there were no differences in MACE rates between men and women although there were gender differences for which plaque subtypes predicted future risk (thin-cap fibroatheroma for women and plaque burden for men). Plaque rupture occurred less commonly in women, and the investigators hypothesize that this may explain why women present more often with typical or atypical chest pain syndromes rather than frank ACS. Although the pathophysiology and plaque composition of CAD leading to ACS may be quite different between the sexes, the differences appear to be off-setting with respect to clinical outcomes, and appear to validate the current practice whereby men and women are treated in a similar fashion (8). Baber et al. (9) reported on the influence of CKD on plaque composition morphology and outcomes in the PROSPECT study. As in patients with diabetes, patients with CKD are at increased risk for MACE at the time of an ACS (10). Even more importantly, patients with CKD may have increased risk even if they are treated for their traditional risk factors. Similar to the graded CV risk of dysglycemia from metabolic syndrome to diabetes, there is also a continuum that has been identified for CKD. In the current analysis from the PROSPECT investigators, CKD was defined by an estimated glomerular filtration rate ⬍60 ml/min, although the cohort on average had mild CKD (stage I) with a mean glomerular filtration rate of 51 ml/min. Those with CKD were characterized by a greater degree of diabetes and hypertension, were more likely to present with a non–ST-segment elevation MI, and experienced a higher rate of 3-year MACE events. Patients with CKD were more often noted to have lesions with MLA ⬍4 mm2, greater plaque burden, a trend toward longer lesion length, and had a higher proportion of necrotic core when compared with those without CKD. The difference in subsequent events between those with and without CKD was primarily attributable to culprit lesions; unlike diabetes, CKD was not associated with disproportionate number of MACE attributable to NCLs. Could this explain the reduced benefit of optimal medical therapy in
JACC: CARDIOVASCULAR IMAGING, VOL. 5, NO. 3, SUPPL S, 2012 MARCH 2012:S73–5
CKD patients compared with those with diabetes, or is it merely an inability to draw firm conclusions due to the small sample size and inclusion of relatively mild CRF patients. However, the findings do raise the question as to whether there is a different biology of atherosclerosis for CKD compared with diabetes, which merits further understanding (11). PROSPECT and these subanalyses highlight 3 major points that merit our attention. First, the fact that NCLs account for 50% and more of the events in the ensuing 3 years after angiographically targeted lesion revascularization for ACS underscores the nonfocal nature of atherosclerosis. These lesions to date are generally addressed with medical therapy, and the findings remind us of the importance of optimizing medical therapy and plaque stabilization after ACS PCI. Second, complementary coronary imaging aids in identifying NCLs that are more likely to lead to adverse events. Third, important baseline characteristics may dictate how we approach NCLs in the future. In diabetic patients, NCLs account for a disproportionate number of events, and therefore they may be of greater importance. This may mean that patients need to be treated more aggressively from a medical standpoint for systemic risk factor modification and stabilization of these lesions, or potentially have NCLs with multiple plaque characteristics that portend risk treated by novel interventional strategies that are yet to be tested. On the other hand, patients with CKD have greater MACE, but these events are not due primarily to differences in nonculprit lesions, but rather to differences in culprit lesions, and yet the beneficial effects of optimal lipid control have also been demonstrated in this population (12). Whether the discordant findings regarding the influence of NCLs on subsequent events in diabetic versus CKD patients is explained by biological differences in atherosclerosis between these 2 often overlapping subgroups merits further study. The insights from the PROSPECT study and substudies are intriguing to clinical cardiologists. The identification and characterization of NCLs that will account for future CV events appears to be an exciting area of ongoing investigation, and should utilize a patient-specific, plaque-specific approach. For the clinician, it reminds of the importance of systemic medical management with pharmacotherapy in the long-term treatment of patients after ACS. What is clear is that many of our patients are prescribed medications directed at treating risk factors, but only a fraction of patients reach targets for low-density lipoprotein choles-
Farkouh and Mathew Editorial Comment
JACC: CARDIOVASCULAR IMAGING, VOL. 5, NO. 3, SUPPL S, 2012 MARCH 2012:S73–5
terol, high-density lipoprotein cholesterol, HbA1c, and blood pressure. One might ask how the results from PROSPECT would look if patients were under optimal medical control. The objectives for the future should consider: 1) a patient-level scoring system to define those at high risk for NCL-associated MACE based on PROSPECT-driven lesion characterization at the time of PCI for ACS, which should include a measure of CV risk factors; 2) interventional trials to test the utility of defining and revascularizing high-risk non-
REFERENCES
1. Franklin K, Goldberg RJ, Spencer F, et al., GRACE Investigators. Implications of diabetes in patients with acute coronary syndromes. The Global Registry of Acute Coronary Events. Arch Intern Med 2004;164: 1457– 63. 2. Nicholls SJ, Murat ET, Kalidindi S, et al. Effect of diabetes on progression of coronary atherosclerosis and arterial remodeling. J Am Coll Cardiol 2008; 52:255– 62. 3. Donahoe SM, Stewart GC, McCabe CH, et al. Diabetes and mortality following acute coronary syndromes. JAMA 2007;298:765–75. 4. Marso SP, Mercado N, Maehara A, et al. Plaque composition and clinical outcomes in acute coronary syndrome patients with metabolic syndrome or diabetes. J Am Coll Cardiol Img 2012;5 Suppl S:S42–52. 5. Cutlip DE, Chhabra AG, Baim DS, et al. Beyond restenosis: five-year clinical outcomes from second-generation coronary stent trials. Circulation 2004; 110:1226 –30.
culprit lesions; and 3) utilizing emerging noninvasive strategies such magnetic resonance, computed tomography, and positron emission tomography to characterize plaque at the extracoronary and coronary level. These important studies introduce the prospect for major advances in the years to come. Reprint requests and correspondence: Prof. Michael E.
Farkouh, University Health Network, Peter Munk Cardiac Centre, 585 University Avenue, Toronto, Ontario 4N474, Canada. E-mail: [email protected].
6. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358:580 –59. 7. Lansky AJ, Ng VG, Maehara A, et al. Gender and the extent of coronary atherosclerosis, plaque composition, and clinical outcomes in acute coronary syndromes. J Am Coll Cardiol Img 2012;5 Suppl S:S62–72. 8. Alfredsson J, Lindbäck J, Wallentin L, Swahn E. Similar outcome with an invasive strategy in men and women with non-ST-elevation acute coronary syndromes: from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART). Eur Heart J 2011;32:3128 –36. 9. Baber U, Stone GW, Weisz G, et al. Coronary plaque composition, morphology, and outcomes in patients with and without chronic kidney disease presenting with acute coronary syndromes. J Am Coll Cardiol Img 2012;5 Suppl S:S53– 61.
10. Ahmed S, Cannon CP, Giugliano RP, et al. The independent and combined risk of diabetes and nonendstage renal impairment in nonST-segment elevation acute coronary syndromes. Int J Cardiol 2008;131: 105–12. 11. Kestenbaum BR, Adeney KL, de Boer IH, Ix JH, Shlipak MG, Siscovick DS. Incidence and progression of coronary calcification in chronic kidney disease: the Multi-Ethnic Study of Atherosclerosis. Kidney Int 2009;76: 991– 8. 12. Shepherd J, Kastelein JJ, Bittner V, et al., TNT (Treating to New Targets) Investigators. Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study. J Am Coll Cardiol 2008;51:1448 –54.
Key Words: acute coronary syndrome y atherosclerosis y lesion characterization.
S75