- Email: [email protected]
Need for a moratorium on percutaneous transluminal coronary angioplasty in stable coronary artery disease
Need for a Moratorium on Percutaneous Transluminal Coronary Angioplasty in Stable Coronary Artery Disease David T. Nash,
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vailable evidence suggests that medical treatment of low-risk patients with stable coronary artery disease (CAD) may be at least equivalent in efficacy to percutaneous transluminal coronary angioplasty (PTCA) in reducing the occurrence of myocardial ischemic events.1 Despite extensive use of this procedure, the superiority of PTCA over medical therapy for prolongation of life has not been demonstrated.2 In fact, use of PTCA in patients with stable CAD without first attempting to modify risk factors is currently considered by some experts to be suboptimal therapy.3 Therefore, it is reasonable to suggest that a moratorium be declared on the use of PTCA in the treatment of chronic stable angina in low-risk patients until such patients undergo an aggressive program to control modifiable risk factors, particularly low-density lipoprotein (LDL) cholesterol levels, for a minimum of 6 weeks. This period of time will not unduly delay the effective use of invasive treatment, and, if patients are seen weekly, blood pressure and lipid levels can usually be controlled within this time frame. A moratorium on a procedure that occurs ⬎1,300 times every day in the United States alone may appear to be a draconian measure, but a review of the who, what, where, when, why, and how of this moratorium suggests it is appropriate, if not overdue.
WHO WOULD BE AFFECTED? Based on accumulated evidence, low-risk asymptomatic patients or those with mild to moderate angina would be the best candidates for a trial of aggressive medical treatment before intervention with PTCA.4 Low-risk patients include those with stable CAD, i.e., those with 1 or 2 major coronary arteries narrowed ⬎50% in diameter, no severe anginal symptoms, and relatively normal left ventricular function (ejection fraction ⱖ40%).1 Clearly, patients presenting with acute myocardial infarction or unstable angina pectoris should be excluded from the moratorium. In the United States, approximately 1.8 million cardiac catheterizations and at least 500,000 PTCA From Upstate Medical University, Syracuse, New York. Manuscript received August 29, 2001; revised manuscript received and accepted November 7, 2001. Address for reprints: David T. Nash, MD, Syracuse Preventive Cardiology, 600 East Genesee Street, Suite 204, Syracuse, New York 13202. E-mail: [email protected]. ©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 89 March 1, 2002
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procedures are performed yearly.5 The number of these procedures performed each year has steadily increased over the past decade. Although many PTCA procedures are performed to treat unstable angina or acute myocardial infarction, PTCA is also increasingly used as early intervention for patients with nonacute coronary disease.6 Although PTCA may provide more immediate symptom relief than medical therapy in these patients, its effects on long-term risk reduction and survival remain unproven.1,2,7 Patients who are asymptomatic may have little to gain from PTCA beyond what aggressive medical therapy with multiple drugs can offer. Duke University Medical Center has been collecting prospective observational data on survival outcomes of revascularization procedures since 1969.8 During the period from 1984 to 1990, 9,263 patients with symptomatic CAD were referred for cardiac catheterization.9 Of these, approximately 30% underwent PTCA, 37% had coronary bypass surgery, and the remaining 33% received medical therapy. Confirming earlier results,8,9 the effect of revascularization on survival was related to the extent of anatomic disease. For patients with 1-vessel CAD and less severe forms of 2-vessel CAD, there was no significant survival advantage for revascularization over medical therapy to 5 years. However, as would be expected, revascularization demonstrated survival benefit for the most severe forms of CAD. The second Randomized Intervention Treatment of Angina (RITA-2) trial2 demonstrated that PTCA reduces symptoms of angina in patients with CAD (n ⫽ 1,018) in whom either PTCA intervention or medical therapy would be appropriate. However, PTCA was associated with a greater risk of death or myocardial infarction than medical treatment (relative risk 1.92, 95% confidence interval 1.08 to 3.41; p ⫽ 0.02). Approximately 80% of patients in this trial had grade ⱕ2 angina and one-fifth were asymptomatic. A recent meta-analysis of PTCA and medical treatment in nonacute CAD found that PTCA was superior to medical treatment in reducing angina symptoms, but at the expense of an increased need for coronary artery bypass grafting.6 Again, medical therapy was not always ideally applied. Recently published results from the Atorvastatin VErsus Revascularization Treatment (AVERT) study1 0002-9149/02/$–see front matter PII S0002-9149(01)02298-6
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suggest that aggressive lipid-lowering therapy in select patients with stable CAD may provide greater reduction in risk of ischemic events than PTCA. In this trial, 341 patients with stable angina pectoris, relatively normal left ventricular function (ejection fraction ⱖ40%), asymptomatic or mild to moderate angina, and an LDL cholesterol level of at least 115 mg/dl who were initially referred for PTCA were randomized to 1 of 2 groups: treatment with atorvastatin 80 mg/day or intervention with PTCA followed by usual care, including lipid-lowering therapy. Asymptomatic patients accounted for 18% of the atorvastatin group and 15% of the PTCA group. Over 18 months of follow-up, treatment with atorvastatin was associated with a 36% reduction in the incidence of ischemic events compared with PTCA. Fewer patients in the atorvastatin group experienced ischemic events than those in the PTCA group (22 of 164 [13%] vs 37 of 177 [21%]; p ⫽ 0.048); however, the difference between the 2 treatment groups was not considered statistically significant because performance of interim analyses mandated an adjustment of the significance level for the incidence of ischemic events down to 4.5% rather than the conventional 5%.1 Fewer angioplasty procedures, fewer coronary bypass procedures, and fewer hospitalizations for worsening angina accounted for the overall reduction in ischemic events in the AVERT study. In addition, the time to a first ischemic event was significantly longer with atorvastatin treatment than with PTCA intervention (p ⫽ 0.03). Whereas significantly more patients in the PTCA group than in the atorvastatin group reported an improvement in anginal symptoms, this improvement was offset by the reduction in ischemic event incidence and prolongation of the time to a first event observed with atorvastatin.1 Use of antianginal medications, including  blockers, nitrates, and calcium channel blockers, was similar between treatment groups at the beginning and end of the study, but more patients in the PTCA group than in the atorvastatin group initiated use or increased their doses of antianginal medications. Could this mean that the atorvastatin group required less aggressive antianginal therapy because of their statin use? A recent trial10 examined the comparative benefits on survival of PTCA, left internal mammary artery bypass grafting, and medical therapy (as determined by each patient’s primary care physician and cardiologist) in 1,188 patients who presented with proximal 1-vessel disease over a 9-year period. The median follow-up period was 5.7 years. Interventional therapies led to no statistically significant mortality benefit over medical therapy, although patients in the medical therapy group had more congestive heart failure, a greater history of acute myocardial infarction, and a longer duration of anginal symptoms. Because the medically treated patients did not uniformly receive 568 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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ideal medical therapy, the comparative data were stacked against the medical group. Yet these findings suggest that there would be no increased risk of mortality associated with implementing a trial of medical therapy as the initial treatment of mild angina during a moratorium on PTCA. An ongoing large-scale, multicenter, randomized controlled trial, the Clinical Outcomes Utilizing Revascularization and Aggressive drug Evaluation (COURAGE) trial, is comparing optimal catheterbased coronary revascularization plus intensive medical therapy versus intensive medical therapy alone. Patients eligible for inclusion will consist of all but very high-risk subjects, and will include those with chronic angina pectoris, uncomplicated myocardial infarction, and asymptomatic myocardial ischemia. The trial is expected to accrue ⬎3,000 patients and to be completed in 2005.11 Symptomatic patients are not the only patients referred for PTCA. Numerous asymptomatic patients undergo an exercise treadmill test as a routine examination for the evaluation of risk factors. Frequently, a positive test is followed by an angiogram and often an angioplasty (“the ocular-stenotic reflex,” i.e., if the artery is narrowed it should be treated). All these procedures are performed in an asymptomatic middleaged adult, with no likelihood of prolonging life!
WHAT SHOULD AGGRESSIVE MEDICAL THERAPY INCLUDE? An aggressive medical therapy program would include strategies that facilitate achievement and maintenance of optimal control of modifiable risk factors.3 All low-risk CAD patients with stable angina would be treated with lipid-lowering drugs to achieve an LDL cholesterol level of ⱕ100 mg/dl, unless otherwise contraindicated. Where appropriate, patients would also receive adequate treatment with nitrates,  blockers, aspirin, calcium antagonists, and angiotensin-converting enzyme inhibitors.3,12 Control and modification of other risk factors, such as hypertension, obesity, diabetes, and cigarette smoking, would also be required. In addition, patient education about their condition and how to modify their risk factors would be an essential part of treatment.12 Patients who remain significantly symptomatic after 6 weeks of a vigorously implemented medical regimen would then be offered interventional therapy with PTCA where appropriate.
HOW AGGRESSIVE SHOULD LIPIDALTERING THERAPY BE? Certainly, at the present time, we are falling short of reaching the currently accepted goal of LDL cholesterol levels ⬍100 mg/dl in most patients with CAD, despite excellent evidence establishing the value of lowering LDL cholesterol to at least this level.13 A MARCH 1, 2002
recent chart review of 48,586 patients with CAD14 assessed the degree of undertreatment of hyperlipidemia. Results revealed that only 25% of patients were treated with the 1993 National Cholesterol Education Program Adult Treatment Panel II LDL cholesterol goal of ⱕ100 mg/dl.14 Recently published data from the Third National Health and Nutrition Examination Survey indicate ineffective modification of risk factors (including systemic hypertension, diabetes mellitus, cigarette smoking, alcohol use, and hypercholesterolemia) in the context of secondary prevention. Among 1,252 survivors of myocardial infarction and/or stroke, 46% of those with previously diagnosed hypercholesterolemia had total cholesterol levels ⬎240 mg/dl, and hypercholesterolemia was detected for the first time in an additional 13% of the study population. Most of these patients (⬎80%) had been evaluated by a medical professional within the previous 6 months.15 Thus, even in the acute setting, cholesterol levels are not routinely tested and, therefore, patients do not receive adequate therapy. Additional observational data (n ⫽ 5,204) suggest that only 24% of patients hospitalized for acute myocardial infarction have their cholesterol levels measured, and of those with levels ⱖ240 mg/dl, only approximately 37% receive lipid-lowering therapy.16 Furthermore, once the Treating to New Targets (TNT)17 study is completed, it may be necessary to modify what we consider an ideal LDL cholesterol level. The TNT study is a large-scale (n ⫽ 8,600), double-blind, randomized trial designed to evaluate whether lowering LDL cholesterol levels ⬎100 mg/dl adds any further risk reduction for a major coronary event. Enrolled patients at high risk for CAD will be treated with atorvastatin 10 mg/day for a target LDL choesterol level of 100 mg/dl or with atorvastatin 80 mg/day for a target LDL cholesterol level of 75 mg/dl for an average of 5 years. Results from TNT are anticipated in 2003. It has become clear that the benefits of treatment with statins also extend beyond their lipid-lowering effects. The reduction in coronary ischemic events and mortality observed in clinical trials cannot be explained simply by a reduction in LDL cholesterol and a slight decrease in the extent of stenoses. These improved outcomes in patients who received medical therapy alone as well as in those who underwent PCTA, are likely attributable to factors considered to be pleiotropic effects of statins.18 In general, statins restore endothelial function, thereby increasing nitric oxide production, decreasing the adhesiveness of the endothelium, reestablishing proper vasomotor responses, and improving tissue perfusion. Importantly, statins help to stabilize rupture-prone plaques by reducing inflammatory activity and inhibiting the proliferation and migration of smooth muscle cells.19
These features appear to inhibit plaque growth, which likely plays a role in the ability of statins to improve outcomes and reduce restenosis after PCTA.1,20 Emerging evidence suggests that patients with elevated C-reactive protein levels, regardless of their lipid levels, may benefit from statin therapy.21
WHY IMPOSE A MORATORIUM? The positive aspects of a moratorium on PTCA in select patients with stable angina would be significant. Even with full use of multiple drug therapies, significant cost savings can be expected. Most drugs required for aggressive medical therapy have generic equivalents and represent only a fraction of procedural costs. Additionally, such polypharmacy is well within the capabilities of most primary care physicians, reducing the need for referral to specialists. In addition, to further reduce costs, specially trained nurse practitioners or physician assistants could manage longterm care of this group of patients, with appropriate physician supervision and oversight. This arrangement may be particularly suitable to outpatient clinics of major medical institutions, which see a large number of patients and provide sophisticated medical supervision. Because PTCA is often followed by the need for repeated procedures,22 the moratorium would also permit delay of the initial procedure, while a course of aggressive medical therapy is given, leading to a reduction in the total number of procedures performed. Despite the potential benefits of the proposed moratorium, some resistance to the idea is predictable. Interventional cardiologists, in particular, may reject the imposition of a moratorium as antithetical to their belief that “open is better.” Hospital administrators may consider a moratorium a threat to their precarious funding. In addition, turf and economic battles are inevitable among the other various clinician groups that will be affected. Furthermore, we can fully expect some patients to be resistant because of concerns that they are being denied their choice of treatment.
HOW WOULD A MORATORIUM BE INITIATED? Any change as drastic as a moratorium would first require an educational program for physicians, their patients, the general public, and health care institutions as well. Professional education is needed to counteract the common, but unfounded, belief among clinicians that more procedures on more patients will translate into longer life spans, and therefore costs should not be entered into consideration. Patient and public education programs must present the benefits of a moratorium in a clear and easily accessible manner. EDITORIAL
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WHERE WOULD A MORATORIUM TRIAL BE INITIATED? The moratorium could be initiated within the context of a prospective trial, initially at not-for-profit, governmental, and managed care organizations, such as selected academic medical centers and Veterans Administration hospitals. Because such institutions do not rely on financial proceeds from PTCAs, a moratorium trial could be initiated without significant dissent among staff and administrative personnel. After appropriate follow-up intervals, publications emanating from the results of these early moratorium trials could be used to further educate professionals in the community and to encourage other institutions to adopt the practice.
WHEN SHOULD A TRIAL MORATORIUM BEGIN? With the tacit agreement that the idea of a moratorium is timely, these preliminary efforts could begin as soon as protocols are written and institutional review boards are solicited for approval. Until low-risk patients with chronic stable angina have received an adequate trial of medical and lifestyle interventions to control modifiable risk factors, a moratorium on the use of PTCA in these patients is an idea whose time has come. 1. Pitt B, Waters D, Brown WV, van Boven J, Schwartz L, Title LM, Eisenberg
D, Schurzinske L, McCormick LS. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999;341:70 – 76. 2. RITA-2 Trial Participants. Coronary angioplasty versus medical therapy for angina: the second Randomised Intervention Treatment of Angina (RITA-2) trial. Lancet 1997;350:461–468. 3. Blumenthal RS, Cohn G, Schulman SP. Medical therapy versus coronary angioplasty in stable coronary artery disease: a critical review of the literature. J Am Coll Cardiol 2000;36:668 –673. 4. Smith SC, Dove JT, Jacobs AK, Kennedy JW, Kereiakes D, Kern MJ, Kuntz RE, Popma JJ, Schaff HV, Williams DO. ACC/AHA guidelines for percutaneous coronary intervention (revision of the PTCA guidelines)— executive summary. Circulation 2001;103:3019 –3041. 5. American Heart Association. 2001 Heart and Stroke Statistical Update. Dallas, TX, American Heart Association, 2000. 6. Bucher HC, Hengstler P, Schindler C, Guyatt GH. Percutaneous transluminal coronary angioplasty versus medical treatment for non-acute coronary heart disease: meta-analysis of randomised controlled trials. Br Med J 2000;321:73–77. 7. Parisi AF, Folland ED, Hartigan P, Veterans Affairs ACME Investigators. A
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comparison of angioplasty with medical therapy in the treatment of single-vessel coronary artery disease. N Engl J Med 1992;326:10 –16. 8. Califf RM, Mark DB. Percutaneous intervention, surgery, and medical therapy: a perspective from the Duke Databank for Cardiovascular Diseases. Semin Thorac Cardiovasc Surg 1994;6:120 –128. 9. Mark DB, Nelson CL, Califf RM, Harrell FE Jr, Lee KL, Jones RH, Fortin DF, Stack RS, Glower DD, Smith LR. Continuing evolution of therapy for coronary artery disease: initial results from the era of coronary angioplasty. Circulation 1994;89:2015–2025. 10. Greenbaum AB, Califf RM, Jones RH, Gardner LH, Philips HR, Sketch MH Jr, Stack RS, Puma JA. Comparison of medicine alone, coronary angioplasty, and left internal mammary artery-coronary artery bypass for one-vessel proximal left anterior descending coronary artery disease. Am J Cardiol 2000;86:1322–1326. 11. National Institutes of Health. PCI plus intensive medical therapy will be superior to intensive medical therapy alone in reducing all cause mortality or nonfatal MI. Available at: http://clinicaltrials.gov/ct/gui/c/w2r/s. Accessed October 22, 2001. 12. Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM, Grunwald MA, Levy D, Lytle BW, O’Rourke RA, Schafer WP, Williams SV. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Management of Patients with Chronic Stable Angina). Circulation 1999;99:2829 –2848. 13. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol-lowering in 4444 patients with coronary heart disease (4S). Lancet 1994;344:1383–1389. 14. Sueta CA, Chowdurh M, Boccuzzi SJ, Smith SC Jr, Alexander CM, Londe A, Lulla A, Simpson RJ Jr. Analysis of the degree of undertreatment of hyperlipidemia and congestive heart failure secondary to coronary artery disease. Am J Cardiol 1999;83:1303–1307. 15. Qureshi AI, Suri MFK, Guterman LR, Hopkins LN. Ineffective secondary prevention in survivors of cardiovascular events in the US population: report from the third National Health and Nutrition Examination Survey. Arch Intern Med 2001;161:1621–1628. 16. Yarzebski J, Spencer F, Goldberg RJ, Lessard D, Gore JM. Temporal trends (1986 –1997) in cholesterol level assessment and management practices in patients with acute myocardial infarction. Arch Intern Med 2001;161:1521–1528. 17. LaRosa JC, for the TNT Steering Committee. Effect of lowering LDL-C beyond currently recommended minimum targets—the treating to new targets (TNT) study. In: XIII International Symposium on Drugs Affecting Lipid Metabolism. Abstract Book, Florence Italy, May 30-June 3, 1998, Houston: Giovanni Lorenzini Medical Foundation: 65. 18. Davignon J. Methods and endpoint issues in clinical development of lipidacting agents with pleiotropic effects. Am J Cardiol 1998;81:17F–24F. 19. Ganz P, Creager MA, Fang JC, McConell MV, Lee RT, Libby P, Selwyn AP. Pathogenetic mechanisms of atherosclerosis: effect of lipid lowering on the biology of atherosclerosis. Am J Med 1996;101(suppl 4A):10S–16S. 20. Mulder HJGH, Bal ET, Jukema JW, Zwinderman AH, Schalij MJ, van Bovan J, Bruschke AVG. Pravastatin reduces restenosis two years after percutaneous transluminal coronary angioplasty (REGRESS trial). Am J Cardiol 2000;86:742– 746. 21. Horne BD, Muhlestein JB, Carlquist JF, Bair TL, Madson TE, Hart NI, Anderson JL. Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease. J Am Coll Cardiol 2000;36:1774 –1780. 22. Nishiyama S, Iwase T, Ishiwata S, Komiyama N, Kobayashi T, Naruse Y, Yanagishita Y, Makuuchi H, Nakanishi S, Seki A. Comparison of long-term efficacy of medical treatment versus percutaneous transluminal coronary angioplasty (PTCA) in single-vessel disease. Jpn Heart J 1995;36:565–72.
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vailable evidence suggests that medical treatment of low-risk patients with stable coronary artery disease (CAD) may be at least equivalent in efficacy to percutaneous transluminal coronary angioplasty (PTCA) in reducing the occurrence of myocardial ischemic events.1 Despite extensive use of this procedure, the superiority of PTCA over medical therapy for prolongation of life has not been demonstrated.2 In fact, use of PTCA in patients with stable CAD without first attempting to modify risk factors is currently considered by some experts to be suboptimal therapy.3 Therefore, it is reasonable to suggest that a moratorium be declared on the use of PTCA in the treatment of chronic stable angina in low-risk patients until such patients undergo an aggressive program to control modifiable risk factors, particularly low-density lipoprotein (LDL) cholesterol levels, for a minimum of 6 weeks. This period of time will not unduly delay the effective use of invasive treatment, and, if patients are seen weekly, blood pressure and lipid levels can usually be controlled within this time frame. A moratorium on a procedure that occurs ⬎1,300 times every day in the United States alone may appear to be a draconian measure, but a review of the who, what, where, when, why, and how of this moratorium suggests it is appropriate, if not overdue.
WHO WOULD BE AFFECTED? Based on accumulated evidence, low-risk asymptomatic patients or those with mild to moderate angina would be the best candidates for a trial of aggressive medical treatment before intervention with PTCA.4 Low-risk patients include those with stable CAD, i.e., those with 1 or 2 major coronary arteries narrowed ⬎50% in diameter, no severe anginal symptoms, and relatively normal left ventricular function (ejection fraction ⱖ40%).1 Clearly, patients presenting with acute myocardial infarction or unstable angina pectoris should be excluded from the moratorium. In the United States, approximately 1.8 million cardiac catheterizations and at least 500,000 PTCA From Upstate Medical University, Syracuse, New York. Manuscript received August 29, 2001; revised manuscript received and accepted November 7, 2001. Address for reprints: David T. Nash, MD, Syracuse Preventive Cardiology, 600 East Genesee Street, Suite 204, Syracuse, New York 13202. E-mail: [email protected]. ©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 89 March 1, 2002
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procedures are performed yearly.5 The number of these procedures performed each year has steadily increased over the past decade. Although many PTCA procedures are performed to treat unstable angina or acute myocardial infarction, PTCA is also increasingly used as early intervention for patients with nonacute coronary disease.6 Although PTCA may provide more immediate symptom relief than medical therapy in these patients, its effects on long-term risk reduction and survival remain unproven.1,2,7 Patients who are asymptomatic may have little to gain from PTCA beyond what aggressive medical therapy with multiple drugs can offer. Duke University Medical Center has been collecting prospective observational data on survival outcomes of revascularization procedures since 1969.8 During the period from 1984 to 1990, 9,263 patients with symptomatic CAD were referred for cardiac catheterization.9 Of these, approximately 30% underwent PTCA, 37% had coronary bypass surgery, and the remaining 33% received medical therapy. Confirming earlier results,8,9 the effect of revascularization on survival was related to the extent of anatomic disease. For patients with 1-vessel CAD and less severe forms of 2-vessel CAD, there was no significant survival advantage for revascularization over medical therapy to 5 years. However, as would be expected, revascularization demonstrated survival benefit for the most severe forms of CAD. The second Randomized Intervention Treatment of Angina (RITA-2) trial2 demonstrated that PTCA reduces symptoms of angina in patients with CAD (n ⫽ 1,018) in whom either PTCA intervention or medical therapy would be appropriate. However, PTCA was associated with a greater risk of death or myocardial infarction than medical treatment (relative risk 1.92, 95% confidence interval 1.08 to 3.41; p ⫽ 0.02). Approximately 80% of patients in this trial had grade ⱕ2 angina and one-fifth were asymptomatic. A recent meta-analysis of PTCA and medical treatment in nonacute CAD found that PTCA was superior to medical treatment in reducing angina symptoms, but at the expense of an increased need for coronary artery bypass grafting.6 Again, medical therapy was not always ideally applied. Recently published results from the Atorvastatin VErsus Revascularization Treatment (AVERT) study1 0002-9149/02/$–see front matter PII S0002-9149(01)02298-6
567
suggest that aggressive lipid-lowering therapy in select patients with stable CAD may provide greater reduction in risk of ischemic events than PTCA. In this trial, 341 patients with stable angina pectoris, relatively normal left ventricular function (ejection fraction ⱖ40%), asymptomatic or mild to moderate angina, and an LDL cholesterol level of at least 115 mg/dl who were initially referred for PTCA were randomized to 1 of 2 groups: treatment with atorvastatin 80 mg/day or intervention with PTCA followed by usual care, including lipid-lowering therapy. Asymptomatic patients accounted for 18% of the atorvastatin group and 15% of the PTCA group. Over 18 months of follow-up, treatment with atorvastatin was associated with a 36% reduction in the incidence of ischemic events compared with PTCA. Fewer patients in the atorvastatin group experienced ischemic events than those in the PTCA group (22 of 164 [13%] vs 37 of 177 [21%]; p ⫽ 0.048); however, the difference between the 2 treatment groups was not considered statistically significant because performance of interim analyses mandated an adjustment of the significance level for the incidence of ischemic events down to 4.5% rather than the conventional 5%.1 Fewer angioplasty procedures, fewer coronary bypass procedures, and fewer hospitalizations for worsening angina accounted for the overall reduction in ischemic events in the AVERT study. In addition, the time to a first ischemic event was significantly longer with atorvastatin treatment than with PTCA intervention (p ⫽ 0.03). Whereas significantly more patients in the PTCA group than in the atorvastatin group reported an improvement in anginal symptoms, this improvement was offset by the reduction in ischemic event incidence and prolongation of the time to a first event observed with atorvastatin.1 Use of antianginal medications, including  blockers, nitrates, and calcium channel blockers, was similar between treatment groups at the beginning and end of the study, but more patients in the PTCA group than in the atorvastatin group initiated use or increased their doses of antianginal medications. Could this mean that the atorvastatin group required less aggressive antianginal therapy because of their statin use? A recent trial10 examined the comparative benefits on survival of PTCA, left internal mammary artery bypass grafting, and medical therapy (as determined by each patient’s primary care physician and cardiologist) in 1,188 patients who presented with proximal 1-vessel disease over a 9-year period. The median follow-up period was 5.7 years. Interventional therapies led to no statistically significant mortality benefit over medical therapy, although patients in the medical therapy group had more congestive heart failure, a greater history of acute myocardial infarction, and a longer duration of anginal symptoms. Because the medically treated patients did not uniformly receive 568 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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ideal medical therapy, the comparative data were stacked against the medical group. Yet these findings suggest that there would be no increased risk of mortality associated with implementing a trial of medical therapy as the initial treatment of mild angina during a moratorium on PTCA. An ongoing large-scale, multicenter, randomized controlled trial, the Clinical Outcomes Utilizing Revascularization and Aggressive drug Evaluation (COURAGE) trial, is comparing optimal catheterbased coronary revascularization plus intensive medical therapy versus intensive medical therapy alone. Patients eligible for inclusion will consist of all but very high-risk subjects, and will include those with chronic angina pectoris, uncomplicated myocardial infarction, and asymptomatic myocardial ischemia. The trial is expected to accrue ⬎3,000 patients and to be completed in 2005.11 Symptomatic patients are not the only patients referred for PTCA. Numerous asymptomatic patients undergo an exercise treadmill test as a routine examination for the evaluation of risk factors. Frequently, a positive test is followed by an angiogram and often an angioplasty (“the ocular-stenotic reflex,” i.e., if the artery is narrowed it should be treated). All these procedures are performed in an asymptomatic middleaged adult, with no likelihood of prolonging life!
WHAT SHOULD AGGRESSIVE MEDICAL THERAPY INCLUDE? An aggressive medical therapy program would include strategies that facilitate achievement and maintenance of optimal control of modifiable risk factors.3 All low-risk CAD patients with stable angina would be treated with lipid-lowering drugs to achieve an LDL cholesterol level of ⱕ100 mg/dl, unless otherwise contraindicated. Where appropriate, patients would also receive adequate treatment with nitrates,  blockers, aspirin, calcium antagonists, and angiotensin-converting enzyme inhibitors.3,12 Control and modification of other risk factors, such as hypertension, obesity, diabetes, and cigarette smoking, would also be required. In addition, patient education about their condition and how to modify their risk factors would be an essential part of treatment.12 Patients who remain significantly symptomatic after 6 weeks of a vigorously implemented medical regimen would then be offered interventional therapy with PTCA where appropriate.
HOW AGGRESSIVE SHOULD LIPIDALTERING THERAPY BE? Certainly, at the present time, we are falling short of reaching the currently accepted goal of LDL cholesterol levels ⬍100 mg/dl in most patients with CAD, despite excellent evidence establishing the value of lowering LDL cholesterol to at least this level.13 A MARCH 1, 2002
recent chart review of 48,586 patients with CAD14 assessed the degree of undertreatment of hyperlipidemia. Results revealed that only 25% of patients were treated with the 1993 National Cholesterol Education Program Adult Treatment Panel II LDL cholesterol goal of ⱕ100 mg/dl.14 Recently published data from the Third National Health and Nutrition Examination Survey indicate ineffective modification of risk factors (including systemic hypertension, diabetes mellitus, cigarette smoking, alcohol use, and hypercholesterolemia) in the context of secondary prevention. Among 1,252 survivors of myocardial infarction and/or stroke, 46% of those with previously diagnosed hypercholesterolemia had total cholesterol levels ⬎240 mg/dl, and hypercholesterolemia was detected for the first time in an additional 13% of the study population. Most of these patients (⬎80%) had been evaluated by a medical professional within the previous 6 months.15 Thus, even in the acute setting, cholesterol levels are not routinely tested and, therefore, patients do not receive adequate therapy. Additional observational data (n ⫽ 5,204) suggest that only 24% of patients hospitalized for acute myocardial infarction have their cholesterol levels measured, and of those with levels ⱖ240 mg/dl, only approximately 37% receive lipid-lowering therapy.16 Furthermore, once the Treating to New Targets (TNT)17 study is completed, it may be necessary to modify what we consider an ideal LDL cholesterol level. The TNT study is a large-scale (n ⫽ 8,600), double-blind, randomized trial designed to evaluate whether lowering LDL cholesterol levels ⬎100 mg/dl adds any further risk reduction for a major coronary event. Enrolled patients at high risk for CAD will be treated with atorvastatin 10 mg/day for a target LDL choesterol level of 100 mg/dl or with atorvastatin 80 mg/day for a target LDL cholesterol level of 75 mg/dl for an average of 5 years. Results from TNT are anticipated in 2003. It has become clear that the benefits of treatment with statins also extend beyond their lipid-lowering effects. The reduction in coronary ischemic events and mortality observed in clinical trials cannot be explained simply by a reduction in LDL cholesterol and a slight decrease in the extent of stenoses. These improved outcomes in patients who received medical therapy alone as well as in those who underwent PCTA, are likely attributable to factors considered to be pleiotropic effects of statins.18 In general, statins restore endothelial function, thereby increasing nitric oxide production, decreasing the adhesiveness of the endothelium, reestablishing proper vasomotor responses, and improving tissue perfusion. Importantly, statins help to stabilize rupture-prone plaques by reducing inflammatory activity and inhibiting the proliferation and migration of smooth muscle cells.19
These features appear to inhibit plaque growth, which likely plays a role in the ability of statins to improve outcomes and reduce restenosis after PCTA.1,20 Emerging evidence suggests that patients with elevated C-reactive protein levels, regardless of their lipid levels, may benefit from statin therapy.21
WHY IMPOSE A MORATORIUM? The positive aspects of a moratorium on PTCA in select patients with stable angina would be significant. Even with full use of multiple drug therapies, significant cost savings can be expected. Most drugs required for aggressive medical therapy have generic equivalents and represent only a fraction of procedural costs. Additionally, such polypharmacy is well within the capabilities of most primary care physicians, reducing the need for referral to specialists. In addition, to further reduce costs, specially trained nurse practitioners or physician assistants could manage longterm care of this group of patients, with appropriate physician supervision and oversight. This arrangement may be particularly suitable to outpatient clinics of major medical institutions, which see a large number of patients and provide sophisticated medical supervision. Because PTCA is often followed by the need for repeated procedures,22 the moratorium would also permit delay of the initial procedure, while a course of aggressive medical therapy is given, leading to a reduction in the total number of procedures performed. Despite the potential benefits of the proposed moratorium, some resistance to the idea is predictable. Interventional cardiologists, in particular, may reject the imposition of a moratorium as antithetical to their belief that “open is better.” Hospital administrators may consider a moratorium a threat to their precarious funding. In addition, turf and economic battles are inevitable among the other various clinician groups that will be affected. Furthermore, we can fully expect some patients to be resistant because of concerns that they are being denied their choice of treatment.
HOW WOULD A MORATORIUM BE INITIATED? Any change as drastic as a moratorium would first require an educational program for physicians, their patients, the general public, and health care institutions as well. Professional education is needed to counteract the common, but unfounded, belief among clinicians that more procedures on more patients will translate into longer life spans, and therefore costs should not be entered into consideration. Patient and public education programs must present the benefits of a moratorium in a clear and easily accessible manner. EDITORIAL
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WHERE WOULD A MORATORIUM TRIAL BE INITIATED? The moratorium could be initiated within the context of a prospective trial, initially at not-for-profit, governmental, and managed care organizations, such as selected academic medical centers and Veterans Administration hospitals. Because such institutions do not rely on financial proceeds from PTCAs, a moratorium trial could be initiated without significant dissent among staff and administrative personnel. After appropriate follow-up intervals, publications emanating from the results of these early moratorium trials could be used to further educate professionals in the community and to encourage other institutions to adopt the practice.
WHEN SHOULD A TRIAL MORATORIUM BEGIN? With the tacit agreement that the idea of a moratorium is timely, these preliminary efforts could begin as soon as protocols are written and institutional review boards are solicited for approval. Until low-risk patients with chronic stable angina have received an adequate trial of medical and lifestyle interventions to control modifiable risk factors, a moratorium on the use of PTCA in these patients is an idea whose time has come. 1. Pitt B, Waters D, Brown WV, van Boven J, Schwartz L, Title LM, Eisenberg
D, Schurzinske L, McCormick LS. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999;341:70 – 76. 2. RITA-2 Trial Participants. Coronary angioplasty versus medical therapy for angina: the second Randomised Intervention Treatment of Angina (RITA-2) trial. Lancet 1997;350:461–468. 3. Blumenthal RS, Cohn G, Schulman SP. Medical therapy versus coronary angioplasty in stable coronary artery disease: a critical review of the literature. J Am Coll Cardiol 2000;36:668 –673. 4. Smith SC, Dove JT, Jacobs AK, Kennedy JW, Kereiakes D, Kern MJ, Kuntz RE, Popma JJ, Schaff HV, Williams DO. ACC/AHA guidelines for percutaneous coronary intervention (revision of the PTCA guidelines)— executive summary. Circulation 2001;103:3019 –3041. 5. American Heart Association. 2001 Heart and Stroke Statistical Update. Dallas, TX, American Heart Association, 2000. 6. Bucher HC, Hengstler P, Schindler C, Guyatt GH. Percutaneous transluminal coronary angioplasty versus medical treatment for non-acute coronary heart disease: meta-analysis of randomised controlled trials. Br Med J 2000;321:73–77. 7. Parisi AF, Folland ED, Hartigan P, Veterans Affairs ACME Investigators. A
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comparison of angioplasty with medical therapy in the treatment of single-vessel coronary artery disease. N Engl J Med 1992;326:10 –16. 8. Califf RM, Mark DB. Percutaneous intervention, surgery, and medical therapy: a perspective from the Duke Databank for Cardiovascular Diseases. Semin Thorac Cardiovasc Surg 1994;6:120 –128. 9. Mark DB, Nelson CL, Califf RM, Harrell FE Jr, Lee KL, Jones RH, Fortin DF, Stack RS, Glower DD, Smith LR. Continuing evolution of therapy for coronary artery disease: initial results from the era of coronary angioplasty. Circulation 1994;89:2015–2025. 10. Greenbaum AB, Califf RM, Jones RH, Gardner LH, Philips HR, Sketch MH Jr, Stack RS, Puma JA. Comparison of medicine alone, coronary angioplasty, and left internal mammary artery-coronary artery bypass for one-vessel proximal left anterior descending coronary artery disease. Am J Cardiol 2000;86:1322–1326. 11. National Institutes of Health. PCI plus intensive medical therapy will be superior to intensive medical therapy alone in reducing all cause mortality or nonfatal MI. Available at: http://clinicaltrials.gov/ct/gui/c/w2r/s. Accessed October 22, 2001. 12. Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM, Grunwald MA, Levy D, Lytle BW, O’Rourke RA, Schafer WP, Williams SV. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Management of Patients with Chronic Stable Angina). Circulation 1999;99:2829 –2848. 13. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol-lowering in 4444 patients with coronary heart disease (4S). Lancet 1994;344:1383–1389. 14. Sueta CA, Chowdurh M, Boccuzzi SJ, Smith SC Jr, Alexander CM, Londe A, Lulla A, Simpson RJ Jr. Analysis of the degree of undertreatment of hyperlipidemia and congestive heart failure secondary to coronary artery disease. Am J Cardiol 1999;83:1303–1307. 15. Qureshi AI, Suri MFK, Guterman LR, Hopkins LN. Ineffective secondary prevention in survivors of cardiovascular events in the US population: report from the third National Health and Nutrition Examination Survey. Arch Intern Med 2001;161:1621–1628. 16. Yarzebski J, Spencer F, Goldberg RJ, Lessard D, Gore JM. Temporal trends (1986 –1997) in cholesterol level assessment and management practices in patients with acute myocardial infarction. Arch Intern Med 2001;161:1521–1528. 17. LaRosa JC, for the TNT Steering Committee. Effect of lowering LDL-C beyond currently recommended minimum targets—the treating to new targets (TNT) study. In: XIII International Symposium on Drugs Affecting Lipid Metabolism. Abstract Book, Florence Italy, May 30-June 3, 1998, Houston: Giovanni Lorenzini Medical Foundation: 65. 18. Davignon J. Methods and endpoint issues in clinical development of lipidacting agents with pleiotropic effects. Am J Cardiol 1998;81:17F–24F. 19. Ganz P, Creager MA, Fang JC, McConell MV, Lee RT, Libby P, Selwyn AP. Pathogenetic mechanisms of atherosclerosis: effect of lipid lowering on the biology of atherosclerosis. Am J Med 1996;101(suppl 4A):10S–16S. 20. Mulder HJGH, Bal ET, Jukema JW, Zwinderman AH, Schalij MJ, van Bovan J, Bruschke AVG. Pravastatin reduces restenosis two years after percutaneous transluminal coronary angioplasty (REGRESS trial). Am J Cardiol 2000;86:742– 746. 21. Horne BD, Muhlestein JB, Carlquist JF, Bair TL, Madson TE, Hart NI, Anderson JL. Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease. J Am Coll Cardiol 2000;36:1774 –1780. 22. Nishiyama S, Iwase T, Ishiwata S, Komiyama N, Kobayashi T, Naruse Y, Yanagishita Y, Makuuchi H, Nakanishi S, Seki A. Comparison of long-term efficacy of medical treatment versus percutaneous transluminal coronary angioplasty (PTCA) in single-vessel disease. Jpn Heart J 1995;36:565–72.
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