Editorial 189
Shockwave therapy for refractory angina: promising but not definitive Ori Ben-Yehuda Coronary Artery Disease 2015, 26:189–191 Cardiovascular Research Foundation and Columbia University Medical Center, New York, New York, USA
Correspondence to Ori Ben-Yehuda, MD, FACC, Cardiovascular Research Foundation, 111 East 59th St., New York, NY 10022, USA Tel: + 1 646 582 6582; fax: + 1 646 434 4711; e-mail: [email protected] Received 5 January 2015 Accepted 5 January 2015
Despite advances in revascularization techniques, whether surgical or percutaneous, persistent and recurrent angina remain significant issues in a subset of patients. In randomized clinical trials, approximately a third of postpercutaneous coronary intervention (PCI) patients report recurrent angina within a year after PCI [1,2]. A recent analysis using claims-based data revealed a similar incidence of post-PCI recurrence in a real-world population [3]; recurrent angina post PCI was also associated with significant increases in healthcare-related costs [4]. For some patients, repeat revascularization may alleviate the symptoms or they may be controlled by intensified medical therapy. For others, particularly those without the option of revascularization, angina may be refractory and additional novel therapies are needed. Along with novel pharmacologic therapies, various nonpharmacologic approaches for the treatment of refractory angina have been developed, including stem cell therapy, therapeutic angiogenesis, spinal cord stimulation, and partial occlusion of the coronary sinus, which is aimed to increase coronary flow to the subendocardium, and, although not widely adopted in the western world, External Enhanced Counter Pulsation (EECP) has been used for the treatment of angina for several decades, with wide use in China. In this issue of the journal, Prasad et al. [5] report on the safety and efficacy of extracorporeal myocardial shockwave therapy in patients with angina who are not candidates for revascularization. This nonpharmacologic mechanical therapy relies on the delivery of shockwaves similar to those used in lithotripsy (but at only 10% of the intensity) to ischemic areas of the myocardium. These areas are predefined on imaging stress tests, with the use of echocardiography to define the areas targeted for shockwave therapy. Animal studies have demonstrated increased angiogenesis in ischemic areas [6], and preliminary human studies have demonstrated an antianginal effect [7,8]. The mechanisms by which extracorporeal myocardial shockwave therapy may exert its effect may include an increase in sheer stress, increased expression of vascular endothelial growth factor, and an increase in circulating endothelial progenitor cells and chemokines that home endothelial progenitor cells to ischemic areas. 0954-6928 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
The study by Prasad and colleagues was led by a group from the Mayo Clinic but was carried out in East Asia, namely Malaysia, Indonesia, and the Philippines. To be eligible, the patients had to be deemed ineligible for further revascularization, be on maximal medical therapy, and have at least Canadian Cardiovascular Society class II angina. Evidence of ischemia was documented by nuclear or echocardiographic stress testing, but all patients at baseline underwent a dipyridamole SPECT nuclear test. Significantly, 76% of the 111 participants enrolled had a history of three-vessel disease, with approximately a half having had a previous myocardial infarction and a third having undergone coronary bypass surgery. The participants then received nine shockwave treatments – these were delivered over a 9-week period, with three treatments delivered during weeks 1, 5, and 9. Patients were then reassessed at 3–6 months for signs of efficacy. Efficacy was assessed with a wide range of endpoints, including maximal exercise time on the modified or standard Bruce protocols, size of the stress perfusion defect on SPECT, nitroglycerin use, Seattle Angina Questionnaire scores, and the Canadian Classification Score for angina. There was a significant change in all of the ischemic parameters, with approximately two-thirds of the patients showing improvement in the size of the perfusion defects, with a similar percentage showing improvement in their exercise duration, and there was a reduction in sublingual nitroglycerin use from 1.14 ± 1.01 to 0.52 ± 0.68 tablets/week. The relatively low use of sublingual nitroglycerin at baseline raises questions on the refractoriness of the patients in the study, although patients with severe angina do often downgrade their activity to avoid precipitating angina episodes. On first blush, these results point to significant efficacy of this novel treatment and are very encouraging, especially given that the treatment was well tolerated without any significant adverse events related to shockwave therapy. There is, however, a very significant limitation to this study, which should give us pause. Angina studies are notoriously prone to a marked placebo effect, whether they are evaluating pharmacologic therapy or mechanical approaches. In pharmacologic studies, the use of a placebo is relatively straightforward and has become DOI: 10.1097/MCA.0000000000000228
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
190 Coronary Artery Disease 2015, Vol 26 No 3
standard in the evaluation of the efficacy of any drug for angina. The recent Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina (TERISA) trial [9], which randomized 949 patients with diabetes and angina to ranolazine versus placebo, in addition to background antianginal therapy, is a case in point. Angina frequency was captured over an 8-week period with the use of a novel electronic angina diary. Compliance with the diary was remarkably high at 98%. Whereas ranolazine decreased angina frequency by 42%, patients on placebo had a 37% reduction in angina frequency, highlighting that, although statistically significant, the reduction in angina with ranolazine, corrected for the placebo effect, was modest at best in this trial. The marked placebo effect occurred despite a 4-week placebo run-in period.
published a single-center uncontrolled study of a small number of patients treated with ranolazine and claimed to observe marked improvements in perfusion defects following ranolazine treatment. In that study, 70% of patients showed an improvement in perfusion defect; in these ‘responders’, the area of reversible ischemia decreased from 16 ± 10 to 8 ± 6%. This preliminary uncontrolled finding was followed by a randomized placebo-controlled study [15] that enrolled 81 patients with perfusion defects on exercise-SESTAMIBI who were studied in a crossover design with ranolazine and placebo. A total of 61 patients had greater than 5% baseline reversible defects and completed both follow-up scans. Contrary to the preliminary study of Venkataraman and colleagues, this placebo-controlled study showed no difference in perfusion between the two groups.
Trials of various mechanical approaches to angina reduction have also demonstrated a marked placebo effect. Following on the Vinberg procedure pioneered in the 1940s, in which the internal mammary artery was implanted into the left ventricular muscle, transmyocardial laser revascularization (TMLR) was advocated in the 1990s. Nonblinded studies of TMLR have demonstrated impressive reductions [10] in angina, but these were not confirmed in the only sham-controlled study [11] of TMLR. Similarly, a study of TMLR in patients with nonrecanalizable chronic total occlusions, in which patients were blinded to whether TMLR was performed during the procedure using deep sedation, showed no benefit [12].
In summary, Prasad and colleagues have produced an intriguing dataset in a relatively large study in a challenging patient population. With the exception of ejection fraction, which did not change, all of the endpoints evaluated improved. We would need to await an adequately powered sham-controlled study, however, to be fully convinced of the efficacy of this innovative treatment.
Unlike placebo control in pharmacologic studies, instituting a sham procedure for mechanical procedures may be challenging, particularly when the therapy requires multiple sessions, but is possible. The MUST-EECP study [13], for example, randomized patients to EECP treatments in which up to 300 mmHg of counterpulsation was applied to the lower extremities, compared with a sham procedure in which EECP was performed with only 75 mmHg counterpulsation, a pressure sufficient to provide the sensation of EECP treatment without significant hemodynamic counterpulsation. Compared with the patients undergoing sham EECP treatment, the patients who received the full EECP treatment showed significant improvements in time to ST segment depression, angina frequency, and nitroglycerin use, whereas there was no difference in exercise duration. The study by Prasad and colleagues included ‘objective’ endpoints that some might consider less susceptible to a placebo effect, such as improvement in dipyridamole SPECT. However, the mechanism by which the placebo effect may influence outcomes in angina may include an actual amelioration in the disease process, whether due to a change in the patient’s lifestyle or through yet to be identified mechanisms. Here again, recent experience with ranolazine is illustrative. Venkataraman et al. [14]
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1
2
3
4
5
6
7
8
9
Serruys PW, Unger F, Sousa JE, Jatene A, Bonnier HJ, Schönberger JP, et al. Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease. N Engl J Med 2001; 344:1117–1124. Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, et al. COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007; 356:1503–1516. Ben-Yehuda O, Bonafede M, Hlatky M, Wade S, Machacz SF, Stephens L, Hernandez JB. Incidence of angina and chest pain following percutaneous coronary intervention: a retrospective analysis using administrative claims data in the United States [abstract]. J Am Coll Cardiol 2014; 64 (11_S). Kazi DS, Ben-Yehuda O, Bonafede M, Hernandez JB, Machacz SF, Hlatky MA. Economic burden of angina and chest pain following percutaneous coronary intervention: a real-world analysis of multi-payer US claims [abstract]. Circulation 2014; 130:A16951. Prasad M, Ahmad WAW, Sukmawan R, Magsombol E-BL, Cassar A, Vinshtok Y, et al. Extracorporeal shockwave myocardial therapy is efficacious in improving symptoms in patients with refractory angina pectoris – a multicenter study. Coron Artery Dis 2015; 26:194–200. Zimpfer D, Aharinejad S, Holfeld J, Thomas A, Dumfarth J, Rosenhek R, et al. Direct epicardial shock wave therapy improves ventricular function and induces angiogenesis in ischemic heart failure. J Thorac Cardiovasc Surg 2009; 137:963–970. Fukumoto Y, Ito A, Uwatoku T, Matoba T, Kishi T, Tanaka H, et al. Extracorporeal cardiac shock wave therapy ameliorates myocardial ischemia in patients with severe coronary artery disease. Coron Artery Dis 2006; 17:63–70. Khattab AA, Brodersen B, Schuermann-Kuchenbrandt D, Beurich H, Tölg R, Geist V, et al. Extracorporeal cardiac shock wave therapy: first experience in the everyday practice for treatment of chronic refractory angina pectoris. Int J Cardiol 2007; 121:84–85. Kosiborod M, Arnold SV, Spertus JA, McGuire DK, Li Y, Yue P, et al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina. results from the TERISA randomized clinical trial. J Am Coll Cardiol 2013; 61:2038–2045.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
Editorial Ben-Yehuda 191
10
11
12
Frazier OH, March RJ, Horvath KA. Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease. N Engl J Med 1999; 341:1021–1028. Leon MB, Kornowski R, Downey WE, Weisz G, Baim DS, Bonow RO, et al. A blinded, randomized, placebo-controlled trial of percutaneous laser myocardial revascularization to improve angina symptoms in patients with severe coronary disease. J Am Coll Cardiol 2005; 46:1812–1819. Stone GW, Teirstein PS, Rubenstein R, Schmidt D, Whitlow PL, Kosinski EJ, et al. A prospective, multicenter, randomized trial of percutaneous transmyocardial laser revascularization in patients with nonrecanalizable chronic total occlusions. J Am Coll Cardiol 2002; 39:1581–1587.
13
14
15
Arora RR, Chou TM, Jain D, Fleishman B, Crawford L, McKiernan T, Nesto RW. The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes. J Am Coll Cardiol 1999; 33:1833–1840. Venkataraman R, Belardinelli L, Blackburn B, Heo J, Iskandrian AE. A study of the effects of ranolazine using automated quantitative analysis of serial myocardial perfusion images. JACC Cardiovasc Imaging 2009; 2:1301–1309. Effect of ranolazine on myocardial perfusion assessed by serial quantitative exercise SPECT imaging. NCT01221272. Available at clinicaltrials.gov. [Accessed 24 December 2014].
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
Shockwave therapy for refractory angina: promising but not definitive Ori Ben-Yehuda Coronary Artery Disease 2015, 26:189–191 Cardiovascular Research Foundation and Columbia University Medical Center, New York, New York, USA
Correspondence to Ori Ben-Yehuda, MD, FACC, Cardiovascular Research Foundation, 111 East 59th St., New York, NY 10022, USA Tel: + 1 646 582 6582; fax: + 1 646 434 4711; e-mail: [email protected] Received 5 January 2015 Accepted 5 January 2015
Despite advances in revascularization techniques, whether surgical or percutaneous, persistent and recurrent angina remain significant issues in a subset of patients. In randomized clinical trials, approximately a third of postpercutaneous coronary intervention (PCI) patients report recurrent angina within a year after PCI [1,2]. A recent analysis using claims-based data revealed a similar incidence of post-PCI recurrence in a real-world population [3]; recurrent angina post PCI was also associated with significant increases in healthcare-related costs [4]. For some patients, repeat revascularization may alleviate the symptoms or they may be controlled by intensified medical therapy. For others, particularly those without the option of revascularization, angina may be refractory and additional novel therapies are needed. Along with novel pharmacologic therapies, various nonpharmacologic approaches for the treatment of refractory angina have been developed, including stem cell therapy, therapeutic angiogenesis, spinal cord stimulation, and partial occlusion of the coronary sinus, which is aimed to increase coronary flow to the subendocardium, and, although not widely adopted in the western world, External Enhanced Counter Pulsation (EECP) has been used for the treatment of angina for several decades, with wide use in China. In this issue of the journal, Prasad et al. [5] report on the safety and efficacy of extracorporeal myocardial shockwave therapy in patients with angina who are not candidates for revascularization. This nonpharmacologic mechanical therapy relies on the delivery of shockwaves similar to those used in lithotripsy (but at only 10% of the intensity) to ischemic areas of the myocardium. These areas are predefined on imaging stress tests, with the use of echocardiography to define the areas targeted for shockwave therapy. Animal studies have demonstrated increased angiogenesis in ischemic areas [6], and preliminary human studies have demonstrated an antianginal effect [7,8]. The mechanisms by which extracorporeal myocardial shockwave therapy may exert its effect may include an increase in sheer stress, increased expression of vascular endothelial growth factor, and an increase in circulating endothelial progenitor cells and chemokines that home endothelial progenitor cells to ischemic areas. 0954-6928 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
The study by Prasad and colleagues was led by a group from the Mayo Clinic but was carried out in East Asia, namely Malaysia, Indonesia, and the Philippines. To be eligible, the patients had to be deemed ineligible for further revascularization, be on maximal medical therapy, and have at least Canadian Cardiovascular Society class II angina. Evidence of ischemia was documented by nuclear or echocardiographic stress testing, but all patients at baseline underwent a dipyridamole SPECT nuclear test. Significantly, 76% of the 111 participants enrolled had a history of three-vessel disease, with approximately a half having had a previous myocardial infarction and a third having undergone coronary bypass surgery. The participants then received nine shockwave treatments – these were delivered over a 9-week period, with three treatments delivered during weeks 1, 5, and 9. Patients were then reassessed at 3–6 months for signs of efficacy. Efficacy was assessed with a wide range of endpoints, including maximal exercise time on the modified or standard Bruce protocols, size of the stress perfusion defect on SPECT, nitroglycerin use, Seattle Angina Questionnaire scores, and the Canadian Classification Score for angina. There was a significant change in all of the ischemic parameters, with approximately two-thirds of the patients showing improvement in the size of the perfusion defects, with a similar percentage showing improvement in their exercise duration, and there was a reduction in sublingual nitroglycerin use from 1.14 ± 1.01 to 0.52 ± 0.68 tablets/week. The relatively low use of sublingual nitroglycerin at baseline raises questions on the refractoriness of the patients in the study, although patients with severe angina do often downgrade their activity to avoid precipitating angina episodes. On first blush, these results point to significant efficacy of this novel treatment and are very encouraging, especially given that the treatment was well tolerated without any significant adverse events related to shockwave therapy. There is, however, a very significant limitation to this study, which should give us pause. Angina studies are notoriously prone to a marked placebo effect, whether they are evaluating pharmacologic therapy or mechanical approaches. In pharmacologic studies, the use of a placebo is relatively straightforward and has become DOI: 10.1097/MCA.0000000000000228
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
190 Coronary Artery Disease 2015, Vol 26 No 3
standard in the evaluation of the efficacy of any drug for angina. The recent Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina (TERISA) trial [9], which randomized 949 patients with diabetes and angina to ranolazine versus placebo, in addition to background antianginal therapy, is a case in point. Angina frequency was captured over an 8-week period with the use of a novel electronic angina diary. Compliance with the diary was remarkably high at 98%. Whereas ranolazine decreased angina frequency by 42%, patients on placebo had a 37% reduction in angina frequency, highlighting that, although statistically significant, the reduction in angina with ranolazine, corrected for the placebo effect, was modest at best in this trial. The marked placebo effect occurred despite a 4-week placebo run-in period.
published a single-center uncontrolled study of a small number of patients treated with ranolazine and claimed to observe marked improvements in perfusion defects following ranolazine treatment. In that study, 70% of patients showed an improvement in perfusion defect; in these ‘responders’, the area of reversible ischemia decreased from 16 ± 10 to 8 ± 6%. This preliminary uncontrolled finding was followed by a randomized placebo-controlled study [15] that enrolled 81 patients with perfusion defects on exercise-SESTAMIBI who were studied in a crossover design with ranolazine and placebo. A total of 61 patients had greater than 5% baseline reversible defects and completed both follow-up scans. Contrary to the preliminary study of Venkataraman and colleagues, this placebo-controlled study showed no difference in perfusion between the two groups.
Trials of various mechanical approaches to angina reduction have also demonstrated a marked placebo effect. Following on the Vinberg procedure pioneered in the 1940s, in which the internal mammary artery was implanted into the left ventricular muscle, transmyocardial laser revascularization (TMLR) was advocated in the 1990s. Nonblinded studies of TMLR have demonstrated impressive reductions [10] in angina, but these were not confirmed in the only sham-controlled study [11] of TMLR. Similarly, a study of TMLR in patients with nonrecanalizable chronic total occlusions, in which patients were blinded to whether TMLR was performed during the procedure using deep sedation, showed no benefit [12].
In summary, Prasad and colleagues have produced an intriguing dataset in a relatively large study in a challenging patient population. With the exception of ejection fraction, which did not change, all of the endpoints evaluated improved. We would need to await an adequately powered sham-controlled study, however, to be fully convinced of the efficacy of this innovative treatment.
Unlike placebo control in pharmacologic studies, instituting a sham procedure for mechanical procedures may be challenging, particularly when the therapy requires multiple sessions, but is possible. The MUST-EECP study [13], for example, randomized patients to EECP treatments in which up to 300 mmHg of counterpulsation was applied to the lower extremities, compared with a sham procedure in which EECP was performed with only 75 mmHg counterpulsation, a pressure sufficient to provide the sensation of EECP treatment without significant hemodynamic counterpulsation. Compared with the patients undergoing sham EECP treatment, the patients who received the full EECP treatment showed significant improvements in time to ST segment depression, angina frequency, and nitroglycerin use, whereas there was no difference in exercise duration. The study by Prasad and colleagues included ‘objective’ endpoints that some might consider less susceptible to a placebo effect, such as improvement in dipyridamole SPECT. However, the mechanism by which the placebo effect may influence outcomes in angina may include an actual amelioration in the disease process, whether due to a change in the patient’s lifestyle or through yet to be identified mechanisms. Here again, recent experience with ranolazine is illustrative. Venkataraman et al. [14]
Acknowledgements Conflicts of interest
There are no conflicts of interest.
References 1
2
3
4
5
6
7
8
9
Serruys PW, Unger F, Sousa JE, Jatene A, Bonnier HJ, Schönberger JP, et al. Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease. N Engl J Med 2001; 344:1117–1124. Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, et al. COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007; 356:1503–1516. Ben-Yehuda O, Bonafede M, Hlatky M, Wade S, Machacz SF, Stephens L, Hernandez JB. Incidence of angina and chest pain following percutaneous coronary intervention: a retrospective analysis using administrative claims data in the United States [abstract]. J Am Coll Cardiol 2014; 64 (11_S). Kazi DS, Ben-Yehuda O, Bonafede M, Hernandez JB, Machacz SF, Hlatky MA. Economic burden of angina and chest pain following percutaneous coronary intervention: a real-world analysis of multi-payer US claims [abstract]. Circulation 2014; 130:A16951. Prasad M, Ahmad WAW, Sukmawan R, Magsombol E-BL, Cassar A, Vinshtok Y, et al. Extracorporeal shockwave myocardial therapy is efficacious in improving symptoms in patients with refractory angina pectoris – a multicenter study. Coron Artery Dis 2015; 26:194–200. Zimpfer D, Aharinejad S, Holfeld J, Thomas A, Dumfarth J, Rosenhek R, et al. Direct epicardial shock wave therapy improves ventricular function and induces angiogenesis in ischemic heart failure. J Thorac Cardiovasc Surg 2009; 137:963–970. Fukumoto Y, Ito A, Uwatoku T, Matoba T, Kishi T, Tanaka H, et al. Extracorporeal cardiac shock wave therapy ameliorates myocardial ischemia in patients with severe coronary artery disease. Coron Artery Dis 2006; 17:63–70. Khattab AA, Brodersen B, Schuermann-Kuchenbrandt D, Beurich H, Tölg R, Geist V, et al. Extracorporeal cardiac shock wave therapy: first experience in the everyday practice for treatment of chronic refractory angina pectoris. Int J Cardiol 2007; 121:84–85. Kosiborod M, Arnold SV, Spertus JA, McGuire DK, Li Y, Yue P, et al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina. results from the TERISA randomized clinical trial. J Am Coll Cardiol 2013; 61:2038–2045.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
Editorial Ben-Yehuda 191
10
11
12
Frazier OH, March RJ, Horvath KA. Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease. N Engl J Med 1999; 341:1021–1028. Leon MB, Kornowski R, Downey WE, Weisz G, Baim DS, Bonow RO, et al. A blinded, randomized, placebo-controlled trial of percutaneous laser myocardial revascularization to improve angina symptoms in patients with severe coronary disease. J Am Coll Cardiol 2005; 46:1812–1819. Stone GW, Teirstein PS, Rubenstein R, Schmidt D, Whitlow PL, Kosinski EJ, et al. A prospective, multicenter, randomized trial of percutaneous transmyocardial laser revascularization in patients with nonrecanalizable chronic total occlusions. J Am Coll Cardiol 2002; 39:1581–1587.
13
14
15
Arora RR, Chou TM, Jain D, Fleishman B, Crawford L, McKiernan T, Nesto RW. The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes. J Am Coll Cardiol 1999; 33:1833–1840. Venkataraman R, Belardinelli L, Blackburn B, Heo J, Iskandrian AE. A study of the effects of ranolazine using automated quantitative analysis of serial myocardial perfusion images. JACC Cardiovasc Imaging 2009; 2:1301–1309. Effect of ranolazine on myocardial perfusion assessed by serial quantitative exercise SPECT imaging. NCT01221272. Available at clinicaltrials.gov. [Accessed 24 December 2014].
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of the article is prohibited.
