Treatment of Peripheral Arterial Disease — Extending "Intervention" to "Therapeutic Choice"
http://www.100md.com
《新英格兰医药杂志》
Lower-extremity peripheral arterial disease is an important manifestation of systemic atherosclerosis that is associated with markedly increased rates of cardiovascular ischemic events and death.1 Although most patients with peripheral arterial disease are asymptomatic, many have claudication, chronic critical limb ischemia, or acute limb ischemia. As a result, peripheral arterial disease considerably impairs functional status and the quality of life, and it is the most important cause of limb amputation. These effects are magnified by the high prevalence of peripheral arterial disease and the lack of provision of timely care.2
The recognition that standards of care for patients with peripheral arterial disease could be improved has led to the creation of new care guidelines.3,4 In addition, a better-informed public will demand therapeutic interventions for the disease.5 Thus, it is anticipated that both medical and endovascular techniques will be used increasingly to treat lower-extremity peripheral arterial disease.
The most common site of lower-extremity atherosclerosis is the superficial femoral artery, although the biologic basis for this fact is not clear. However, angioplasty and stent placement in the superficial femoral artery have, to date, been less successful than percutaneous coronary-artery intervention. Furthermore, primary stent placement in the superficial femoral artery has not been shown to be reliably superior to balloon angioplasty alone.6,7,8,9 In contrast to their performance in the coronary setting, sirolimus-eluting stents have not yet been shown to be superior to bare-metal stents for peripheral arterial disease.10,11
In this issue of the Journal, Schillinger et al. report on a potentially important therapeutic advance in endovascular therapy for peripheral arterial disease.12 The investigators randomly assigned 104 patients — nearly 90 percent of whom had claudication — to primary treatment with either implantation of a nitinol stent or balloon angioplasty. Nitinol, an alloy of nickel and titanium, is more flexible and more able to recover from being crushed than stainless steel. The rates of restenosis (stenosis of more than 50 percent of the luminal diameter), the primary end point, were significantly lower at 6 and 12 months in the stent group than in the angioplasty group, and the stent group had a greater median maximal distance walked on a treadmill (a secondary end point). Such a demonstration of superior patency, clinical efficacy, and safety in a randomized trial would appear to satisfy all criteria required for nitinol stents to be used in practice.
Yet, although these data are promising, the trial had some important limitations that constrain the clinical implementation of this treatment strategy. One limitation is the lack of a usual-care control group. Patients with claudication usually have symptoms that are stable and rarely worsen. Spontaneous improvement without intervention is often observed in clinical trials. Thus, short-term improvement in patency is a poor surrogate marker of long-term clinical benefit. Although walking distances increased as compared with baseline in both treatment groups, the relative clinical benefit cannot be defined in the absence of a medical-therapy group.
The limited duration of the clinical follow-up impedes an adequate appraisal of safety. As noted by the authors, stenting of the superficial femoral artery can be associated with stent fracture, because the artery is bounded by groups of powerful muscles that impose considerable mechanical stress. Such fracturing represents a potentially major limitation to long-term durability and safety of the stents. The rate of stent fracture in this study was small (2 percent at 12 months), but longer follow-up is required to define precisely the rate of fracture-associated late occlusion.
In contrast to patients with claudication alone, those with critical limb ischemia have severe symptoms and face a major risk of near-term amputation. Short-term endovascular success, reestablishing distal perfusion, is known to save limbs. However, only 13 patients in this trial had critical limb ischemia, far too few to offer any definitive assessment of benefit. The limited size of the sample in the trial also restricts the interpretation of the efficacy and risk of endovascular interventions in other important cohorts (those defined by age, sex, race or ethnic background, diabetes, cigarette-smoking status, or other characteristics).
A final limitation of the study by Schillinger et al. is the potential confounding effect of medical therapies. Antiplatelet agents may alter short-term arterial patency and lower post-treatment occlusion rates. Cilostazol or supervised exercise, or both, improves outcomes in patients with claudication. Current smoking by study participants can modify the effect of percutaneous treatment. In this study, several risk factors were assessed at baseline and at six months, but the use of claudication-specific therapies is rarely controlled or monitored in clinical trials of peripheral arterial disease.
The critical role of medical management for persons with claudication was not assessed directly in the study by Schillinger et al. The "real-world" choice between medical and endovascular management is guided by several factors. Patient factors include the intensity of the limb symptoms, the effects of these symptoms on the quality of life, the presence or absence of concomitant nonvascular limitations, the arterial anatomy, and the anticipated life span; treatment factors include the availability of the treatment and the associated risk. Patients with peripheral arterial disease and claudication could now be offered a true choice of therapies, depending on the specific characteristics of the patient. Yet the relative risk and benefit, durability, and cost of each potential therapy and the patient subgroups that are most likely to benefit from each therapy have not yet been defined.
To offer a true therapeutic choice, we will need knowledge from clinical trials that define the potential risks and benefits of each treatment. Combinations of exercise, medication, and revascularization therapies have rarely been evaluated in populations of patients with peripheral arterial disease. The Claudication: Exercise versus Endoluminal Revascularization (CLEVER) trial — sponsored by the National Heart, Lung, and Blood Institute and currently under way — is a prospective, multicenter clinical investigation that will compare the safety and efficacy of supervised exercise, endovascular stenting, and optimal pharmacotherapy for patients with aortoiliac peripheral arterial disease.
Until the completion of such large clinical trials specific to peripheral arterial disease, many fewer data are available for patients with peripheral arterial disease than for patients with coronary artery disease. A larger investment is needed in designing and performing prospective, adequately powered clinical investigations of peripheral arterial disease and in evaluating the results. Because traditional standards for the clinical investigation of peripheral arterial disease may not be adequate, a higher standard should be used (Table 1).
Table 1. Clinical Research for Lower-Extremity Peripheral Arterial Disease — Traditional and Recommended Future Standards.
It is not sufficient, however, merely to propose better clinical-trial designs. The translation of what we need to know into how we design and perform vascular trials is also constrained by a lack of clinicians devoted to vascular research. Investment in the training of new vascular clinician–investigators is also needed if standards of care are to improve.
As the population ages, it is anticipated that the prevalence of peripheral arterial disease will increase. The chief challenge in the care of peripheral arterial disease, therefore, may not be defining the optimal revascularization strategy for the superficial femoral artery. Instead, it may be the retooling of the health care system to focus on identifying the symptoms of limb ischemia so that they are as well known as the symptoms of atherosclerotic angina. An additional challenge will be to retool clinical research to ensure that investigators are trained to design and perform relevant studies. When the relative benefits, risks, and costs of each potentially beneficial treatment of peripheral arterial disease are known, we will be in a better position than we are now to offer therapeutic choices to the tens of millions of patients who are affected.
Dr. Hirsch reports having received grants from the Bristol-Myers Squibb/Sanofi Aventis partnership as well as from Sanofi Aventis, AstraZeneca, PreMD, SonoSite, and Vasogen; consulting fees from Kos Pharmaceuticals, SonoSite, Vasogen, and Pfizer; and lecture fees from the Bristol-Myers Squibb/Sanofi Aventis partnership. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, and the Minneapolis Heart Institute Foundation — both in Minneapolis.
References
Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992;326:381-386.
Belch JJ, Topol EJ, Agnelli G, et al. Critical issues in peripheral arterial disease detection and management: a call to action. Arch Intern Med 2003;163:884-892.
Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary: 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;47:1239-1312.
Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD): TransAtlantic Inter-Society Consensus (TASC). J Vasc Surg 2000;31:S1-S296.
National Heart, Lung, and Blood Institute workshop on peripheral arterial disease (PAD): developing a public awareness campaign meeting summary. Bethesda, Md.: Department of Health and Human Services, 2003. (Accessed April 13, 2006, at http://www.nhlbi.nih.gov/health/prof/heart/index.htm.)
Vroegindeweij D, Tielbeek AV, Buth J, Vos LD, van den Bosch HC. Patterns of recurrent disease after recanalization of femoropopliteal artery occlusions. Cardiovasc Intervent Radiol 1997;20:257-262.
Vroegindeweij D, Vos LD, Tielbeek AV, Buth J, van den Bosch HC. Balloon angioplasty combined with primary stenting versus balloon angioplasty alone in femoropopliteal obstructions: a comparative randomized study. Cardiovasc Intervent Radiol 1997;20:420-425.
Becquemin JP, Favre JP, Marzelle J, Nemoz C, Corsin C, Leizorovicz A. Systematic versus selective stent placement after superficial femoral artery balloon angioplasty: a multicenter prospective randomized study. J Vasc Surg 2003;37:487-494.
Muradin GS, Bosch JL, Stijnen T, Hunink MG. Balloon dilation and stent implantation for treatment of femoropopliteal arterial disease: meta-analysis. Radiology 2001;221:137-145.
Duda SH, Pusich B, Richter G, et al. Sirolimus-eluting stents for the treatment of obstructive superficial femoral artery disease: six-month results. Circulation 2002;106:1505-1509.
Duda SH, Bosiers M, Lammer J, et al. Sirolimus-eluting versus bare nitinol stent for obstructive superficial femoral artery disease: the SIROCCO II trial. J Vasc Interv Radiol 2005;16:331-338.
Schillinger M, Sabeti S, Loewe C, et al. Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery. N Engl J Med 2006;354:1879-1888.(Alan T. Hirsch, M.D.)
The recognition that standards of care for patients with peripheral arterial disease could be improved has led to the creation of new care guidelines.3,4 In addition, a better-informed public will demand therapeutic interventions for the disease.5 Thus, it is anticipated that both medical and endovascular techniques will be used increasingly to treat lower-extremity peripheral arterial disease.
The most common site of lower-extremity atherosclerosis is the superficial femoral artery, although the biologic basis for this fact is not clear. However, angioplasty and stent placement in the superficial femoral artery have, to date, been less successful than percutaneous coronary-artery intervention. Furthermore, primary stent placement in the superficial femoral artery has not been shown to be reliably superior to balloon angioplasty alone.6,7,8,9 In contrast to their performance in the coronary setting, sirolimus-eluting stents have not yet been shown to be superior to bare-metal stents for peripheral arterial disease.10,11
In this issue of the Journal, Schillinger et al. report on a potentially important therapeutic advance in endovascular therapy for peripheral arterial disease.12 The investigators randomly assigned 104 patients — nearly 90 percent of whom had claudication — to primary treatment with either implantation of a nitinol stent or balloon angioplasty. Nitinol, an alloy of nickel and titanium, is more flexible and more able to recover from being crushed than stainless steel. The rates of restenosis (stenosis of more than 50 percent of the luminal diameter), the primary end point, were significantly lower at 6 and 12 months in the stent group than in the angioplasty group, and the stent group had a greater median maximal distance walked on a treadmill (a secondary end point). Such a demonstration of superior patency, clinical efficacy, and safety in a randomized trial would appear to satisfy all criteria required for nitinol stents to be used in practice.
Yet, although these data are promising, the trial had some important limitations that constrain the clinical implementation of this treatment strategy. One limitation is the lack of a usual-care control group. Patients with claudication usually have symptoms that are stable and rarely worsen. Spontaneous improvement without intervention is often observed in clinical trials. Thus, short-term improvement in patency is a poor surrogate marker of long-term clinical benefit. Although walking distances increased as compared with baseline in both treatment groups, the relative clinical benefit cannot be defined in the absence of a medical-therapy group.
The limited duration of the clinical follow-up impedes an adequate appraisal of safety. As noted by the authors, stenting of the superficial femoral artery can be associated with stent fracture, because the artery is bounded by groups of powerful muscles that impose considerable mechanical stress. Such fracturing represents a potentially major limitation to long-term durability and safety of the stents. The rate of stent fracture in this study was small (2 percent at 12 months), but longer follow-up is required to define precisely the rate of fracture-associated late occlusion.
In contrast to patients with claudication alone, those with critical limb ischemia have severe symptoms and face a major risk of near-term amputation. Short-term endovascular success, reestablishing distal perfusion, is known to save limbs. However, only 13 patients in this trial had critical limb ischemia, far too few to offer any definitive assessment of benefit. The limited size of the sample in the trial also restricts the interpretation of the efficacy and risk of endovascular interventions in other important cohorts (those defined by age, sex, race or ethnic background, diabetes, cigarette-smoking status, or other characteristics).
A final limitation of the study by Schillinger et al. is the potential confounding effect of medical therapies. Antiplatelet agents may alter short-term arterial patency and lower post-treatment occlusion rates. Cilostazol or supervised exercise, or both, improves outcomes in patients with claudication. Current smoking by study participants can modify the effect of percutaneous treatment. In this study, several risk factors were assessed at baseline and at six months, but the use of claudication-specific therapies is rarely controlled or monitored in clinical trials of peripheral arterial disease.
The critical role of medical management for persons with claudication was not assessed directly in the study by Schillinger et al. The "real-world" choice between medical and endovascular management is guided by several factors. Patient factors include the intensity of the limb symptoms, the effects of these symptoms on the quality of life, the presence or absence of concomitant nonvascular limitations, the arterial anatomy, and the anticipated life span; treatment factors include the availability of the treatment and the associated risk. Patients with peripheral arterial disease and claudication could now be offered a true choice of therapies, depending on the specific characteristics of the patient. Yet the relative risk and benefit, durability, and cost of each potential therapy and the patient subgroups that are most likely to benefit from each therapy have not yet been defined.
To offer a true therapeutic choice, we will need knowledge from clinical trials that define the potential risks and benefits of each treatment. Combinations of exercise, medication, and revascularization therapies have rarely been evaluated in populations of patients with peripheral arterial disease. The Claudication: Exercise versus Endoluminal Revascularization (CLEVER) trial — sponsored by the National Heart, Lung, and Blood Institute and currently under way — is a prospective, multicenter clinical investigation that will compare the safety and efficacy of supervised exercise, endovascular stenting, and optimal pharmacotherapy for patients with aortoiliac peripheral arterial disease.
Until the completion of such large clinical trials specific to peripheral arterial disease, many fewer data are available for patients with peripheral arterial disease than for patients with coronary artery disease. A larger investment is needed in designing and performing prospective, adequately powered clinical investigations of peripheral arterial disease and in evaluating the results. Because traditional standards for the clinical investigation of peripheral arterial disease may not be adequate, a higher standard should be used (Table 1).
Table 1. Clinical Research for Lower-Extremity Peripheral Arterial Disease — Traditional and Recommended Future Standards.
It is not sufficient, however, merely to propose better clinical-trial designs. The translation of what we need to know into how we design and perform vascular trials is also constrained by a lack of clinicians devoted to vascular research. Investment in the training of new vascular clinician–investigators is also needed if standards of care are to improve.
As the population ages, it is anticipated that the prevalence of peripheral arterial disease will increase. The chief challenge in the care of peripheral arterial disease, therefore, may not be defining the optimal revascularization strategy for the superficial femoral artery. Instead, it may be the retooling of the health care system to focus on identifying the symptoms of limb ischemia so that they are as well known as the symptoms of atherosclerotic angina. An additional challenge will be to retool clinical research to ensure that investigators are trained to design and perform relevant studies. When the relative benefits, risks, and costs of each potentially beneficial treatment of peripheral arterial disease are known, we will be in a better position than we are now to offer therapeutic choices to the tens of millions of patients who are affected.
Dr. Hirsch reports having received grants from the Bristol-Myers Squibb/Sanofi Aventis partnership as well as from Sanofi Aventis, AstraZeneca, PreMD, SonoSite, and Vasogen; consulting fees from Kos Pharmaceuticals, SonoSite, Vasogen, and Pfizer; and lecture fees from the Bristol-Myers Squibb/Sanofi Aventis partnership. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, and the Minneapolis Heart Institute Foundation — both in Minneapolis.
References
Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992;326:381-386.
Belch JJ, Topol EJ, Agnelli G, et al. Critical issues in peripheral arterial disease detection and management: a call to action. Arch Intern Med 2003;163:884-892.
Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary: 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;47:1239-1312.
Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD): TransAtlantic Inter-Society Consensus (TASC). J Vasc Surg 2000;31:S1-S296.
National Heart, Lung, and Blood Institute workshop on peripheral arterial disease (PAD): developing a public awareness campaign meeting summary. Bethesda, Md.: Department of Health and Human Services, 2003. (Accessed April 13, 2006, at http://www.nhlbi.nih.gov/health/prof/heart/index.htm.)
Vroegindeweij D, Tielbeek AV, Buth J, Vos LD, van den Bosch HC. Patterns of recurrent disease after recanalization of femoropopliteal artery occlusions. Cardiovasc Intervent Radiol 1997;20:257-262.
Vroegindeweij D, Vos LD, Tielbeek AV, Buth J, van den Bosch HC. Balloon angioplasty combined with primary stenting versus balloon angioplasty alone in femoropopliteal obstructions: a comparative randomized study. Cardiovasc Intervent Radiol 1997;20:420-425.
Becquemin JP, Favre JP, Marzelle J, Nemoz C, Corsin C, Leizorovicz A. Systematic versus selective stent placement after superficial femoral artery balloon angioplasty: a multicenter prospective randomized study. J Vasc Surg 2003;37:487-494.
Muradin GS, Bosch JL, Stijnen T, Hunink MG. Balloon dilation and stent implantation for treatment of femoropopliteal arterial disease: meta-analysis. Radiology 2001;221:137-145.
Duda SH, Pusich B, Richter G, et al. Sirolimus-eluting stents for the treatment of obstructive superficial femoral artery disease: six-month results. Circulation 2002;106:1505-1509.
Duda SH, Bosiers M, Lammer J, et al. Sirolimus-eluting versus bare nitinol stent for obstructive superficial femoral artery disease: the SIROCCO II trial. J Vasc Interv Radiol 2005;16:331-338.
Schillinger M, Sabeti S, Loewe C, et al. Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery. N Engl J Med 2006;354:1879-1888.(Alan T. Hirsch, M.D.)