- Email: [email protected]
Learning to Walk Before We Run
Journal of the American College of Cardiology © 2011 by the American College of Cardiology Foundation Published by Elsevier Inc.
EDITORIAL COMMENT
Learning to Walk Before We Run The Mechanics of Medical Intervention for Peripheral Arterial Disease* Mitchell W. Krucoff, MD, W. Schuyler Jones, MD, Manesh R. Patel, MD Durham, North Carolina
Clinicians are often faced with 2 important issues when treating patients with peripheral arterial disease (PAD) and coronary artery disease (CAD): 1) reduction of cardiovascular risk and 2) improvement of symptoms. Although multiple therapies (antiplatelet agents, statins, antihypertensive agents) have been proven to reduce cardiovascular risk in both CAD and PAD patients, unlike CAD, very few therapeutic agents have been shown to improve leg symptoms in PAD patients. Statins are currently listed as a Class IB recommendation in the PAD guidelines with specific recommendations about low-density lipoprotein (LDL) goals, but no recommendation about their use for symptom management (1). The current guideline-based approach for See page 1068
PAD patients with intermittent claudication is to recommend aerobic exercise training and cilostazol, a phosphodiesterase inhibitor that has been shown to improve walking performance (1). If symptoms do not improve with these measures, patients may be referred for angiography and consideration for endovascular or surgical revascularization for lifestyle-limiting symptoms. Despite these therapies, there is a large unmet need and corresponding knowledge gap in terms of leg-specific therapies that lead to improved long-term walking performance and functional capacity. Similar to angina in CAD patients, the mechanism of functional improvement in PAD patients most often tar-
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Division of Cardiology, Duke University Medical Center, Durham, North Carolina. Dr. Patel has served on the advisory boards of Genzyme and Bayer Heathcare; and has received a research grant from Johnson & Johnson. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Vol. 58, No. 10, 2011 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2011.04.035
geted has been the macrovasculature, either through plaque stabilization or regression or vasodilatory effects. Despite a lack of previous evidence demonstrating an improvement in angina in CAD patients with statin therapy, many investigators have studied the effect of statins on leg symptoms in PAD. Two previous studies reported that high-dose statin therapy was associated with improved pain-free walking time, but the effects on maximal walking time were incongruent (2,3). Another observational study reported that statins were associated with improved walking velocity and 6-min walking distance (4). Considerable debate remains about the association of statins with improved functional outcomes and the proposed mechanism of improvement. In this issue of the Journal, West et al. (5) tested the hypothesis that LDL reduction would improve calf muscle perfusion, metabolism, and walking performance in PAD patients. In the 68 patients randomized to simvastatin, a combination of simvastatin and ezetemibe, or ezetemibe added to an already existing statin medication, there was no change in calf muscle perfusion as detected by magnetic resonance imaging (MRI), calf muscle metabolism as detected by magnetic resonance spectroscopy (MRS), or walking performance. It should be noted that all groups were on guideline-recommended statin therapy, and therefore the effects of statin therapy versus placebo cannot be ascertained from the current study. These findings build logically on previous work by this group that has focused on noninvasive imaging and calf muscle perfusion in PAD (6 –10). Although the study essentially fails to show a significant difference in functional outcomes, the results add to mechanistic observations on the effects of statins. With the limited number of patients studied, the conclusiveness of these observations or their association with functional outcomes in PAD patients remains speculative. The study’s largely negative endpoints thus still leave several unanswered questions about both the role of medical therapies affecting lipid metabolism and the mechanistic assumptions underlying the role of such therapies in PAD patients. Three such questions include: 1) the causality of plaque regression and improved clinical outcomes; 2) the potential adjunctive use of statins and mechanical revascularization with peripheral vascular intervention (PVI) in PAD patients; and 3) the optimal measurement and endpoints of functional capacity in PAD. The first question can be put into context by reviewing the findings of statin trials in patients with atherosclerosis in other vascular beds. It is now accepted that patients with atherosclerosis have improved clinical outcomes with statins, particularly with high doses of selected statins (11,12). Studies from the coronary and carotid vasculature have documented atherosclerotic plaque stabilization and even plaque regression with statins. In addition to plaque stabilization/regression, the improvement in clinical outcomes with statins has been hypothesized to be caused by a reduction in LDL levels, a reduction in systemic inflammation, and other pleiotropic effects
1078
Krucoff et al. Learning to Walk Before We Run
such as platelet activity inhibition. The largest intravascular ultrasound (IVUS) study in the coronary literature (REVERSAL [REVERSing Atherosclerosis with Aggressive Lipid Lowering]) showed that in patients treated with high-dose atorvastatin, there was no change in atheroma burden, whereas those treated with pravastatin had a progression in atheroma burden (13). A similar coronary IVUS trial (ASTEROID [A Study To Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden]) showed that in patients treated with 40 mg of rosuvastatin, there was a significant regression in atheroma burden (14). Although statin trials have now shown that plaque regression is possible and that clinical outcomes are improved, there has never been a correlation between plaque regression and improved angina or other functional outcomes (15). Moreover, the degree of plaque regression noted in the coronary trials may not be clinically significant in the large-vessel lower extremity vascular bed. The current study further weakens this link in PAD patients, and the authors suggest that targeting the microvasculature or skeletal muscle may be more important. They also importantly recognize that although PAD symptoms did not get better, functional status did not worsen, which is a potentially important and positive observation outside of the study’s primary analysis plan, but complemented by the 2-year follow-up in most of the study patients enrolled. Another potential benefit of statin therapy is in conjunction with mechanical revascularization. Acute statin therapy has been shown to potentially mitigate and/or reduce adverse events at the time of percutaneous coronary intervention (16). In the coronary bed, statin therapy may contribute to reduction of periprocedural myonecrosis, although such drug– device interactions are complex to establish. Unlike the coronary bed, the vasculature of the lower extremities is different in that it serves skeletal muscle and generally involves larger reference vessels at the point of intervention, and long-term adverse outcomes may be driven more by the overall burden of disease than by local events such as plaque rupture. These issues further highlight the need for specific studies targeting the effects of medical strategies such as statins in patients with PAD. Taken together, the results of the current study suggest that plaque regression is only 1 endpoint within a myriad of potential responses to the medical, or overall, treatment of patients with atherosclerosis. As stated, PAD represents a complex and heterogeneous disease with multiple vascular beds and physiological mechanisms for symptomatic progression and adverse outcomes. This complexity itself must be considered in study designs, especially in the selection of surrogate/mechanistic endpoint measures, and in the interpretation of study results as the basis by which clinicians make therapeutic decisions to treat PAD patients most effectively. The authors should be commended for continuing to investigate and understand the mechanisms of disease
JACC Vol. 58, No. 10, 2011 August 30, 2011:1077–9
and therapeutics in patients with PAD. Unfortunately, this also points to the enormous gap between how informative small studies can be and the many questions that remain to define optimal therapy in clinical practice, because even the definition of key patient subgroups by clinical presentation, macro- and microvascular anatomy, and physiology importantly intersect in real-world practice. Selection and timing of medical regimens, mechanical revascularization, and exercise prescription are still relegated to selection based more on experience and judgment than on definable, datadriven practice. To move the light of knowledge forward in this enormous arena of human suffering, clear and careful distinctions must be maintained between both tools and statistical analyses directed to mechanistic effects, symptoms, functional capacity, and clinical outcomes in either the relief from or the progression of PAD. So, specifically, how can the field of PAD research move forward along these lines? Much like therapeutic development in patients with CAD, only large observational registries and randomized trials will be able to provide information linking measured surrogate physiological markers such as ankle-brachial index, transcutaneous oxygen, and tissues perfusion by cardiac magnetic resonance to functional and clinical outcomes such as walking time, cardiovascular death, myocardial infarction, and amputation. The pace at which such changes may occur also mandate both measurements and follow-up over both the short and long term. These features are not only true of key benefits related to therapies targeting PAD, but also imperative to information about safety and relative cost-effectiveness. Underlying the overall utility of all PAD studies is a critical lesson learned about the value of information in complex areas that is being collected using consensus definitions that have pragmatic constructs supporting essential aspects of high-quality therapeutic trials, such as independent event adjudication and consistent core laboratory reporting. Examples of such definitions have been developed across academic, regulatory, and industry experts in the Academic Research Consortium and disseminated into the public domain through peer-reviewed publication for coronary stent studies (17), percutaneous aortic valve intervention (18), and bleeding events (19). Although no single definition may be perfectly sensitive and specific per se for any entity, the use of consensus definitions across study reports in developing areas supports more robust opportunities for data pooling and hence uniquely promotes the leveraged advance of knowledge in ways that individual studies using individualized definitions cannot. For PAD therapeutics, there is a clear need to develop consensus definitions of symptom status, anatomy, objective physiological measures, patient-reported outcomes, and key clinical outcomes. In developing such a consensus dictionary of nomenclature, work already done or in progress for clinical practice guidelines or other more generic areas (such as bleeding) should be incorporated as much as possible because both clinical trials and practice guide-
JACC Vol. 58, No. 10, 2011 August 30, 2011:1077–9
lines are most ideal when they best approximate one another. As reflected by the conundrum of how exactly to interpret the study reported by West et al. (5), now is the time for an international effort to establish such consensus because the field of PAD medical, mechanical, and overall optimal vascular therapies is poised to advance against the functional and clinical incapacity that PAD inflicts on patients around the world. Reprint requests and correspondence: Dr. Mitchell W. Krucoff, Duke Clinical Research Institute, 508 Fulton Street, Room A3006, Durham, North Carolina 27705. E-mail: kruco001@ mc.duke.edu. REFERENCES
1. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease). J Am Coll Cardiol 2006;47:e1–192. 2. Mohler ER 3rd, Hiatt WR, Creager MA. Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease. Circulation 2003;108:1481– 6. 3. Mondillo S, Ballo P, Barbati R, et al. Effects of simvastatin on walking performance and symptoms of intermittent claudication in hypercholesterolemic patients with peripheral vascular disease. Am J Med 2003;114:359 – 64. 4. McDermott MM, Guralnik JM, Greenland P, et al. Statin use and leg functioning in patients with and without lower-extremity peripheral arterial disease. Circulation 2003;107:757– 61. 5. West AM, Anderson JD, Epstein FH, et al. Low-density lipoprotein lowering does not improve calf muscle perfusion, energetics, or exercise performance in peripheral arterial disease. J Am Coll Cardiol 2011;58: 1068 –76. 6. Anderson JD, Epstein FH, Meyer CH, et al. Multifactorial determinants of functional capacity in peripheral arterial disease: uncoupling of calf muscle perfusion and metabolism. J Am Coll Cardiol 2009;54: 628 –35. 7. Kramer CM. Skeletal muscle perfusion in peripheral arterial disease a novel end point for cardiovascular imaging. J Am Coll Cardiol Img 2008;1:351–3.
Krucoff et al. Learning to Walk Before We Run
1079
8. Isbell DC, Epstein FH, Zhong X, et al. Calf muscle perfusion at peak exercise in peripheral arterial disease: measurement by first-pass contrast-enhanced magnetic resonance imaging. J Magn Reson Imaging 2007;25:1013–20. 9. Isbell DC, Meyer CH, Rogers WJ, et al. Reproducibility and reliability of atherosclerotic plaque volume measurements in peripheral arterial disease with cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2007;9:71– 6. 10. Isbell DC, Berr SS, Toledano AY, et al. Delayed calf muscle phosphocreatine recovery after exercise identifies peripheral arterial disease. J Am Coll Cardiol 2006;47:2289 –95. 11. Gibson CM, Pride YB, Hochberg CP, Sloan S, Sabatine MS, Cannon CP. Effect of intensive statin therapy on clinical outcomes among patients undergoing percutaneous coronary intervention for acute coronary syndrome. PCI-PROVE IT: A PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection TherapyThrombolysis in Myocardial Infarction 22) substudy. J Am Coll Cardiol 2009;54:2290 –5. 12. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet 2002;360:7-22. 13. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291:1071– 80. 14. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556 – 65. 15. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA 2007;297:499 –508. 16. Pasceri V, Patti G, Nusca A, Pristipino C, Richichi G, Di Sciascio G. Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention: results from the ARMYDA (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) study. Circulation 2004;110:674 – 8. 17. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344 –51. 18. Leon MB, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the Valve Academic Research Consortium. J Am Coll Cardiol 2011;57:253– 69. 19. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium (BARC). Circulation 2011;123: 2736 – 47. Key Words: lipids y magnetic resonance imaging y peripheral vascular disease.
EDITORIAL COMMENT
Learning to Walk Before We Run The Mechanics of Medical Intervention for Peripheral Arterial Disease* Mitchell W. Krucoff, MD, W. Schuyler Jones, MD, Manesh R. Patel, MD Durham, North Carolina
Clinicians are often faced with 2 important issues when treating patients with peripheral arterial disease (PAD) and coronary artery disease (CAD): 1) reduction of cardiovascular risk and 2) improvement of symptoms. Although multiple therapies (antiplatelet agents, statins, antihypertensive agents) have been proven to reduce cardiovascular risk in both CAD and PAD patients, unlike CAD, very few therapeutic agents have been shown to improve leg symptoms in PAD patients. Statins are currently listed as a Class IB recommendation in the PAD guidelines with specific recommendations about low-density lipoprotein (LDL) goals, but no recommendation about their use for symptom management (1). The current guideline-based approach for See page 1068
PAD patients with intermittent claudication is to recommend aerobic exercise training and cilostazol, a phosphodiesterase inhibitor that has been shown to improve walking performance (1). If symptoms do not improve with these measures, patients may be referred for angiography and consideration for endovascular or surgical revascularization for lifestyle-limiting symptoms. Despite these therapies, there is a large unmet need and corresponding knowledge gap in terms of leg-specific therapies that lead to improved long-term walking performance and functional capacity. Similar to angina in CAD patients, the mechanism of functional improvement in PAD patients most often tar-
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Division of Cardiology, Duke University Medical Center, Durham, North Carolina. Dr. Patel has served on the advisory boards of Genzyme and Bayer Heathcare; and has received a research grant from Johnson & Johnson. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Vol. 58, No. 10, 2011 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2011.04.035
geted has been the macrovasculature, either through plaque stabilization or regression or vasodilatory effects. Despite a lack of previous evidence demonstrating an improvement in angina in CAD patients with statin therapy, many investigators have studied the effect of statins on leg symptoms in PAD. Two previous studies reported that high-dose statin therapy was associated with improved pain-free walking time, but the effects on maximal walking time were incongruent (2,3). Another observational study reported that statins were associated with improved walking velocity and 6-min walking distance (4). Considerable debate remains about the association of statins with improved functional outcomes and the proposed mechanism of improvement. In this issue of the Journal, West et al. (5) tested the hypothesis that LDL reduction would improve calf muscle perfusion, metabolism, and walking performance in PAD patients. In the 68 patients randomized to simvastatin, a combination of simvastatin and ezetemibe, or ezetemibe added to an already existing statin medication, there was no change in calf muscle perfusion as detected by magnetic resonance imaging (MRI), calf muscle metabolism as detected by magnetic resonance spectroscopy (MRS), or walking performance. It should be noted that all groups were on guideline-recommended statin therapy, and therefore the effects of statin therapy versus placebo cannot be ascertained from the current study. These findings build logically on previous work by this group that has focused on noninvasive imaging and calf muscle perfusion in PAD (6 –10). Although the study essentially fails to show a significant difference in functional outcomes, the results add to mechanistic observations on the effects of statins. With the limited number of patients studied, the conclusiveness of these observations or their association with functional outcomes in PAD patients remains speculative. The study’s largely negative endpoints thus still leave several unanswered questions about both the role of medical therapies affecting lipid metabolism and the mechanistic assumptions underlying the role of such therapies in PAD patients. Three such questions include: 1) the causality of plaque regression and improved clinical outcomes; 2) the potential adjunctive use of statins and mechanical revascularization with peripheral vascular intervention (PVI) in PAD patients; and 3) the optimal measurement and endpoints of functional capacity in PAD. The first question can be put into context by reviewing the findings of statin trials in patients with atherosclerosis in other vascular beds. It is now accepted that patients with atherosclerosis have improved clinical outcomes with statins, particularly with high doses of selected statins (11,12). Studies from the coronary and carotid vasculature have documented atherosclerotic plaque stabilization and even plaque regression with statins. In addition to plaque stabilization/regression, the improvement in clinical outcomes with statins has been hypothesized to be caused by a reduction in LDL levels, a reduction in systemic inflammation, and other pleiotropic effects
1078
Krucoff et al. Learning to Walk Before We Run
such as platelet activity inhibition. The largest intravascular ultrasound (IVUS) study in the coronary literature (REVERSAL [REVERSing Atherosclerosis with Aggressive Lipid Lowering]) showed that in patients treated with high-dose atorvastatin, there was no change in atheroma burden, whereas those treated with pravastatin had a progression in atheroma burden (13). A similar coronary IVUS trial (ASTEROID [A Study To Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden]) showed that in patients treated with 40 mg of rosuvastatin, there was a significant regression in atheroma burden (14). Although statin trials have now shown that plaque regression is possible and that clinical outcomes are improved, there has never been a correlation between plaque regression and improved angina or other functional outcomes (15). Moreover, the degree of plaque regression noted in the coronary trials may not be clinically significant in the large-vessel lower extremity vascular bed. The current study further weakens this link in PAD patients, and the authors suggest that targeting the microvasculature or skeletal muscle may be more important. They also importantly recognize that although PAD symptoms did not get better, functional status did not worsen, which is a potentially important and positive observation outside of the study’s primary analysis plan, but complemented by the 2-year follow-up in most of the study patients enrolled. Another potential benefit of statin therapy is in conjunction with mechanical revascularization. Acute statin therapy has been shown to potentially mitigate and/or reduce adverse events at the time of percutaneous coronary intervention (16). In the coronary bed, statin therapy may contribute to reduction of periprocedural myonecrosis, although such drug– device interactions are complex to establish. Unlike the coronary bed, the vasculature of the lower extremities is different in that it serves skeletal muscle and generally involves larger reference vessels at the point of intervention, and long-term adverse outcomes may be driven more by the overall burden of disease than by local events such as plaque rupture. These issues further highlight the need for specific studies targeting the effects of medical strategies such as statins in patients with PAD. Taken together, the results of the current study suggest that plaque regression is only 1 endpoint within a myriad of potential responses to the medical, or overall, treatment of patients with atherosclerosis. As stated, PAD represents a complex and heterogeneous disease with multiple vascular beds and physiological mechanisms for symptomatic progression and adverse outcomes. This complexity itself must be considered in study designs, especially in the selection of surrogate/mechanistic endpoint measures, and in the interpretation of study results as the basis by which clinicians make therapeutic decisions to treat PAD patients most effectively. The authors should be commended for continuing to investigate and understand the mechanisms of disease
JACC Vol. 58, No. 10, 2011 August 30, 2011:1077–9
and therapeutics in patients with PAD. Unfortunately, this also points to the enormous gap between how informative small studies can be and the many questions that remain to define optimal therapy in clinical practice, because even the definition of key patient subgroups by clinical presentation, macro- and microvascular anatomy, and physiology importantly intersect in real-world practice. Selection and timing of medical regimens, mechanical revascularization, and exercise prescription are still relegated to selection based more on experience and judgment than on definable, datadriven practice. To move the light of knowledge forward in this enormous arena of human suffering, clear and careful distinctions must be maintained between both tools and statistical analyses directed to mechanistic effects, symptoms, functional capacity, and clinical outcomes in either the relief from or the progression of PAD. So, specifically, how can the field of PAD research move forward along these lines? Much like therapeutic development in patients with CAD, only large observational registries and randomized trials will be able to provide information linking measured surrogate physiological markers such as ankle-brachial index, transcutaneous oxygen, and tissues perfusion by cardiac magnetic resonance to functional and clinical outcomes such as walking time, cardiovascular death, myocardial infarction, and amputation. The pace at which such changes may occur also mandate both measurements and follow-up over both the short and long term. These features are not only true of key benefits related to therapies targeting PAD, but also imperative to information about safety and relative cost-effectiveness. Underlying the overall utility of all PAD studies is a critical lesson learned about the value of information in complex areas that is being collected using consensus definitions that have pragmatic constructs supporting essential aspects of high-quality therapeutic trials, such as independent event adjudication and consistent core laboratory reporting. Examples of such definitions have been developed across academic, regulatory, and industry experts in the Academic Research Consortium and disseminated into the public domain through peer-reviewed publication for coronary stent studies (17), percutaneous aortic valve intervention (18), and bleeding events (19). Although no single definition may be perfectly sensitive and specific per se for any entity, the use of consensus definitions across study reports in developing areas supports more robust opportunities for data pooling and hence uniquely promotes the leveraged advance of knowledge in ways that individual studies using individualized definitions cannot. For PAD therapeutics, there is a clear need to develop consensus definitions of symptom status, anatomy, objective physiological measures, patient-reported outcomes, and key clinical outcomes. In developing such a consensus dictionary of nomenclature, work already done or in progress for clinical practice guidelines or other more generic areas (such as bleeding) should be incorporated as much as possible because both clinical trials and practice guide-
JACC Vol. 58, No. 10, 2011 August 30, 2011:1077–9
lines are most ideal when they best approximate one another. As reflected by the conundrum of how exactly to interpret the study reported by West et al. (5), now is the time for an international effort to establish such consensus because the field of PAD medical, mechanical, and overall optimal vascular therapies is poised to advance against the functional and clinical incapacity that PAD inflicts on patients around the world. Reprint requests and correspondence: Dr. Mitchell W. Krucoff, Duke Clinical Research Institute, 508 Fulton Street, Room A3006, Durham, North Carolina 27705. E-mail: kruco001@ mc.duke.edu. REFERENCES
1. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease). J Am Coll Cardiol 2006;47:e1–192. 2. Mohler ER 3rd, Hiatt WR, Creager MA. Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease. Circulation 2003;108:1481– 6. 3. Mondillo S, Ballo P, Barbati R, et al. Effects of simvastatin on walking performance and symptoms of intermittent claudication in hypercholesterolemic patients with peripheral vascular disease. Am J Med 2003;114:359 – 64. 4. McDermott MM, Guralnik JM, Greenland P, et al. Statin use and leg functioning in patients with and without lower-extremity peripheral arterial disease. Circulation 2003;107:757– 61. 5. West AM, Anderson JD, Epstein FH, et al. Low-density lipoprotein lowering does not improve calf muscle perfusion, energetics, or exercise performance in peripheral arterial disease. J Am Coll Cardiol 2011;58: 1068 –76. 6. Anderson JD, Epstein FH, Meyer CH, et al. Multifactorial determinants of functional capacity in peripheral arterial disease: uncoupling of calf muscle perfusion and metabolism. J Am Coll Cardiol 2009;54: 628 –35. 7. Kramer CM. Skeletal muscle perfusion in peripheral arterial disease a novel end point for cardiovascular imaging. J Am Coll Cardiol Img 2008;1:351–3.
Krucoff et al. Learning to Walk Before We Run
1079
8. Isbell DC, Epstein FH, Zhong X, et al. Calf muscle perfusion at peak exercise in peripheral arterial disease: measurement by first-pass contrast-enhanced magnetic resonance imaging. J Magn Reson Imaging 2007;25:1013–20. 9. Isbell DC, Meyer CH, Rogers WJ, et al. Reproducibility and reliability of atherosclerotic plaque volume measurements in peripheral arterial disease with cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2007;9:71– 6. 10. Isbell DC, Berr SS, Toledano AY, et al. Delayed calf muscle phosphocreatine recovery after exercise identifies peripheral arterial disease. J Am Coll Cardiol 2006;47:2289 –95. 11. Gibson CM, Pride YB, Hochberg CP, Sloan S, Sabatine MS, Cannon CP. Effect of intensive statin therapy on clinical outcomes among patients undergoing percutaneous coronary intervention for acute coronary syndrome. PCI-PROVE IT: A PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection TherapyThrombolysis in Myocardial Infarction 22) substudy. J Am Coll Cardiol 2009;54:2290 –5. 12. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet 2002;360:7-22. 13. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291:1071– 80. 14. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556 – 65. 15. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA 2007;297:499 –508. 16. Pasceri V, Patti G, Nusca A, Pristipino C, Richichi G, Di Sciascio G. Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention: results from the ARMYDA (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) study. Circulation 2004;110:674 – 8. 17. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344 –51. 18. Leon MB, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the Valve Academic Research Consortium. J Am Coll Cardiol 2011;57:253– 69. 19. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium (BARC). Circulation 2011;123: 2736 – 47. Key Words: lipids y magnetic resonance imaging y peripheral vascular disease.