- Email: [email protected]
Angiogenesis with recombinant fibroblast growth factor-2 for claudication
CORRESPONDENCE
Angiogenesis with recombinant fibroblast growth factor-2 for claudication Sir—We think the patients and treatment reported in Robert Lederman and colleagues’ study of therapeutic angiogenesis for intermittent claudication (June 15, p 2053)1 bear little relation to our current referral pattern or vascular practice in the West Midlands, UK. First, the walking time that the participants could achieve at enrolment was roughly 5 min, equating to a distance of over 250 m at the quoted treadmill speed of 3·22 km/h. This degree of function would be treated by modification of risk factors, aspirin, and advice about regular walking-based exercise rather than any surgical or interventional radiological procedure. Second, Lederman and colleagues used transfemoral angiography, which has associated complications, cost implications, and takes up hospital beds during screening of patients for inclusion, compared with a non-invasive test such as duplex, CT angiography, or MR angiography, which can be done as outpatient procedures. Third, the difference between treatment and placebo groups in onset of claudication pain and maximum walking time after 180 days can be measured in seconds. However, for this minor benefit, the patients in Lederman and colleagues’ trial underwent three arterial studies and exposure to a drug that can cause renal abnormalities. Fourth, the investigators state that they detected no evidence of the theoretical risks of angiogenesis (nontarget organ neovascularisation, acceleration of atherosclerosis, and spread of undetected malignant disease), but the follow-up is so far short. In addition, they do not mention whether this treatment could make aneurysmal disease progress at an increased rate, and some vascular patients have mixed occlusive and aneurysmal disease. Overall, Lederman and colleagues’ report adds to the knowledge base of vascular biology, but it offers no new treatment for intermittent claudication. *David Williams, Kim Davenport, Yih Tan Department of Surgery, City General Hospital, Stoke on Trent ST4 6QG, UK (e-mail: [email protected]) 1
Lederman RJ, Mendelsohn FO, Anderson RD, et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 2002; 359: 2053–58.
256
Authors’ reply Sir—Symptoms are in the mind of the beholder, and may be more compelling in peripheral artery disease than some physicians recognise.1 Quality of life is clearly impaired in patients who have intermittent claudication2 and specifically those included in our trial, as shown by their low baseline short form 36 questionnaire scores. Indeed, these patients had sufficiently limiting intermittent claudication that they accepted multiple invasive procedures and a one-third chance of receiving placebo. Our study protocol mandated intensive treatment before entry, including attempts at smoking cessation, exercise, and pharmacotherapy. Most patients had participated in an exercise programme, and many used antiplatelet or antithrombotic medications, cholesterol-lowering medications, -adrenergic antagonists, and angiotensin-converting-enzyme inhibitors. Although practice patterns may vary, we believe strongly that patients as impaired as those in our study should receive comprehensive cardiovascular management, including risk-factor modification and pharmacological therapy for atherosclerosis, structured exercise training, percutaneous revascularisation when suitable, and pharmacological treatment for claudication symptoms. Unfortunately, the list of available effective agents for intermittent claudication is short. David Williams and colleagues should not confuse study-specific diagnostic procedures, such as radio contrast arteriography intended to characterise a selected research population, with clinical care. TRAFFIC was a phase 2 study that established a clinical proof of concept for therapeutic angiogenesis.3 Moreover, the walking time or distance on a maximum research Gardner ETT probably differs significantly from selfreported home walking distances. We agree that recombinant fibroblast growth factor-2 (rFGF-2) requires additional clinical testing, specifically to find an optimum dose4 and duration of benefit. If intra-arterial rFGF-2 were to become available, administration probably would not require multiple arterial punctures. Repeat administration of 30 g/kg rFGF-2 after 30 days offered no advantage over one administration. We know of no association of rFGF-2 on the evolution of aneurysmal arterial disease in human beings or animals. Few patients in our study had recognised aortoiliac or femoropopliteal aneurysms. Moreover, radiocontrast
angiography we used does not image arterial walls, so we have no information to address the question. Therapeutic angiogenesis remains an investigational therapeutic approach for coronary and peripheral artery disease, including intermittent claudication. We believe our study is important because we show efficacy of a therapeutic angiogenesis agent in a sizeable, randomised, controlled clinical trial. *Robert J Lederman, Brian H Annex, on behalf of the TRAFFIC investigators *Cardiovascular Branch, National Heart Lung and Blood Institute, National Institutes of Health, Building 10, Room 2c713, Bethesda, MD 20892, USA (RJL); and Division of Cardiology, Duke University Medical Center, Durham, NC (BHA) (e-mail: [email protected]) 1
2
3
4
Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001; 286: 1317–24. McDermott MM, Greenland P, Liu K, et al. Leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment. JAMA 2001; 286: 1599–606. Donnelly R, Yeung JM. Therapeutic angiogenesis: a step forward in intermittent claudication. Lancet 2002; 359: 2048–50. Simons M, Annex BH, Laham RJ, et al. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial. Circulation 2002; 105: 788–93.
“Will not” or “does”? Sir—Error seems to have crept into the Uses of error by David Grimes (Oct 19, p 1242).1 He recounts how he temporarily doubted a diagnosis of ruptured ectopic pregnancy, because the blood he obtained on confirmatory culdocentesis clotted, which such blood is classically supposed not to do. Grimes goes on to say that he “later learned from published articles that a few such patients have blood that will not clot”. I am reminded of how, long ago in the Gold Coast (now Ghana), I tried to persuade the illiterate parents of a young woman that their daughter was bleeding from a ruptured ectopic pregnancy and urgently needed surgery. To help make my case, I aspirated and showed them a syringefull of (non-clotting) blood. They were unimpressed—would not any woman bleed if a large needle was stuck into her belly?—and took her home. Many months later, the young woman intercepted me as I passed through her village and smilingly showed me that she had not died after
THE LANCET • Vol 361 • January 18, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Angiogenesis with recombinant fibroblast growth factor-2 for claudication Sir—We think the patients and treatment reported in Robert Lederman and colleagues’ study of therapeutic angiogenesis for intermittent claudication (June 15, p 2053)1 bear little relation to our current referral pattern or vascular practice in the West Midlands, UK. First, the walking time that the participants could achieve at enrolment was roughly 5 min, equating to a distance of over 250 m at the quoted treadmill speed of 3·22 km/h. This degree of function would be treated by modification of risk factors, aspirin, and advice about regular walking-based exercise rather than any surgical or interventional radiological procedure. Second, Lederman and colleagues used transfemoral angiography, which has associated complications, cost implications, and takes up hospital beds during screening of patients for inclusion, compared with a non-invasive test such as duplex, CT angiography, or MR angiography, which can be done as outpatient procedures. Third, the difference between treatment and placebo groups in onset of claudication pain and maximum walking time after 180 days can be measured in seconds. However, for this minor benefit, the patients in Lederman and colleagues’ trial underwent three arterial studies and exposure to a drug that can cause renal abnormalities. Fourth, the investigators state that they detected no evidence of the theoretical risks of angiogenesis (nontarget organ neovascularisation, acceleration of atherosclerosis, and spread of undetected malignant disease), but the follow-up is so far short. In addition, they do not mention whether this treatment could make aneurysmal disease progress at an increased rate, and some vascular patients have mixed occlusive and aneurysmal disease. Overall, Lederman and colleagues’ report adds to the knowledge base of vascular biology, but it offers no new treatment for intermittent claudication. *David Williams, Kim Davenport, Yih Tan Department of Surgery, City General Hospital, Stoke on Trent ST4 6QG, UK (e-mail: [email protected]) 1
Lederman RJ, Mendelsohn FO, Anderson RD, et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 2002; 359: 2053–58.
256
Authors’ reply Sir—Symptoms are in the mind of the beholder, and may be more compelling in peripheral artery disease than some physicians recognise.1 Quality of life is clearly impaired in patients who have intermittent claudication2 and specifically those included in our trial, as shown by their low baseline short form 36 questionnaire scores. Indeed, these patients had sufficiently limiting intermittent claudication that they accepted multiple invasive procedures and a one-third chance of receiving placebo. Our study protocol mandated intensive treatment before entry, including attempts at smoking cessation, exercise, and pharmacotherapy. Most patients had participated in an exercise programme, and many used antiplatelet or antithrombotic medications, cholesterol-lowering medications, -adrenergic antagonists, and angiotensin-converting-enzyme inhibitors. Although practice patterns may vary, we believe strongly that patients as impaired as those in our study should receive comprehensive cardiovascular management, including risk-factor modification and pharmacological therapy for atherosclerosis, structured exercise training, percutaneous revascularisation when suitable, and pharmacological treatment for claudication symptoms. Unfortunately, the list of available effective agents for intermittent claudication is short. David Williams and colleagues should not confuse study-specific diagnostic procedures, such as radio contrast arteriography intended to characterise a selected research population, with clinical care. TRAFFIC was a phase 2 study that established a clinical proof of concept for therapeutic angiogenesis.3 Moreover, the walking time or distance on a maximum research Gardner ETT probably differs significantly from selfreported home walking distances. We agree that recombinant fibroblast growth factor-2 (rFGF-2) requires additional clinical testing, specifically to find an optimum dose4 and duration of benefit. If intra-arterial rFGF-2 were to become available, administration probably would not require multiple arterial punctures. Repeat administration of 30 g/kg rFGF-2 after 30 days offered no advantage over one administration. We know of no association of rFGF-2 on the evolution of aneurysmal arterial disease in human beings or animals. Few patients in our study had recognised aortoiliac or femoropopliteal aneurysms. Moreover, radiocontrast
angiography we used does not image arterial walls, so we have no information to address the question. Therapeutic angiogenesis remains an investigational therapeutic approach for coronary and peripheral artery disease, including intermittent claudication. We believe our study is important because we show efficacy of a therapeutic angiogenesis agent in a sizeable, randomised, controlled clinical trial. *Robert J Lederman, Brian H Annex, on behalf of the TRAFFIC investigators *Cardiovascular Branch, National Heart Lung and Blood Institute, National Institutes of Health, Building 10, Room 2c713, Bethesda, MD 20892, USA (RJL); and Division of Cardiology, Duke University Medical Center, Durham, NC (BHA) (e-mail: [email protected]) 1
2
3
4
Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001; 286: 1317–24. McDermott MM, Greenland P, Liu K, et al. Leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment. JAMA 2001; 286: 1599–606. Donnelly R, Yeung JM. Therapeutic angiogenesis: a step forward in intermittent claudication. Lancet 2002; 359: 2048–50. Simons M, Annex BH, Laham RJ, et al. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial. Circulation 2002; 105: 788–93.
“Will not” or “does”? Sir—Error seems to have crept into the Uses of error by David Grimes (Oct 19, p 1242).1 He recounts how he temporarily doubted a diagnosis of ruptured ectopic pregnancy, because the blood he obtained on confirmatory culdocentesis clotted, which such blood is classically supposed not to do. Grimes goes on to say that he “later learned from published articles that a few such patients have blood that will not clot”. I am reminded of how, long ago in the Gold Coast (now Ghana), I tried to persuade the illiterate parents of a young woman that their daughter was bleeding from a ruptured ectopic pregnancy and urgently needed surgery. To help make my case, I aspirated and showed them a syringefull of (non-clotting) blood. They were unimpressed—would not any woman bleed if a large needle was stuck into her belly?—and took her home. Many months later, the young woman intercepted me as I passed through her village and smilingly showed me that she had not died after
THE LANCET • Vol 361 • January 18, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.