Prevention of Cardiovascular Events after Percutaneous Coronary Intervention
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《新英格兰医药杂志》
Cardiologists agree that the best and safest percutaneous coronary intervention is the one that never becomes necessary. In this regard, new therapies that prevent restenosis and retard or reverse atherosclerosis are welcomed by noninvasive and interventional cardiologists alike. However, clinically important coronary stenoses and acute coronary syndromes will develop in many patients despite our best efforts at prevention. In such cases, interventionalists may fix the culprit lesion mechanically, but treatment should not end when patients leave the catheterization laboratory (Figure 1).
Figure 1. Cutaway View of a Coronary Artery Showing a Stent Implanted to Treat a Previously Flow-Limiting Stenosis.
The stent may elute a drug to prevent restenosis within the stent. Aspirin and clopidogrel are used to block platelet deposition, which contributes to acute and subacute stent thrombosis. Other strategies (statins, angiotensin-converting–enzyme inhibitors, diabetes and hypertension control, nutritional counseling, smoking cessation, exercise, and possible folate supplementation) are necessary to prevent new and progressive atherosclerotic lesions in other coronary-artery locations.
In this issue of the Journal, Lange et al. report that oral supplementation with a combination of folic acid and vitamins B6 and B12 after an initial intravenous bolus significantly increased the risk of restenosis among 636 patients who had received bare-metal stents.1 This finding directly contradicts the results of the Swiss Heart Study,2 in which folic acid supplementation was associated with a marked reduction in restenosis and target-vessel revascularization after percutaneous coronary intervention. Both trials targeted homocysteine, a moderate risk factor for coronary artery disease3 as well as for death, among patients with established coronary artery disease.4 The serum level of this amino acid can be lowered by dietary supplementation with folic acid and fortified grain products,5 but there is no proof that lowering homocysteine levels with vitamin supplementation lowers the risk of cardiovascular events. Now, however, the findings of Lange et al. raise the disturbing possibility that a therapy that has previously been considered safe may actually be harmful.
How can we reconcile the results of these two angioplasty studies? First, the two studies used different doses of vitamins. Lange et al. used an initial intravenous loading bolus and higher doses of all three agents, particularly vitamin B6, which could have a greater influence on the relative metabolism of homocysteine by the vitamin B6–dependent transsulfuration pathway than by the vitamin B12–dependent and folate-dependent remethylation pathways. Second, the patient populations in the two studies were quite different. Patients in the Swiss Heart Study were more likely to smoke (which is associated with a higher homocysteine level), to have diabetes, and to have had a prior myocardial infarction. These patients also had lower baseline homocysteine levels, and although vessel sizes were similar in the two populations, the patients studied by Lange et al. had shorter lesions.
Both studies were well-designed, randomized, double-blind, placebo-controlled trials, but Lange et al. obtained angiographic follow-up data for only 76 percent of the original study population, because 91 patients discontinued treatment and 62 patients did not undergo follow-up angiography. The detrimental effect of folic acid supplementation was most pronounced in patients without diabetes, in men, and in patients with a low homocysteine level at baseline. Another important difference between these two studies relates to the use of balloon angioplasty and stents. In the Swiss Heart Study, most of the benefit was observed in the patients who were treated with angioplasty alone, rather than in those who received stents (reduction in risk, 76 percent vs. 31 percent). Finally, more patients were treated with adjunctive medications, including statins and angiotensin-converting–enzyme (ACE) inhibitors, in the Swiss Heart Study.
On the basis of these differences and the potential for harm demonstrated in the current study, folic acid, vitamin B6, and vitamin B12 should not be routinely administered to patients receiving coronary stents in an effort to reduce the risk of restenosis. Folate therapy may be a reasonable means of secondary prevention in patients with high homocysteine levels after percutaneous coronary intervention, as suggested by some authorities, but the validity of this approach is not supported by current federal guidelines, owing to the absence of supporting clinical trials.6 Studies are needed to clarify the optimal dose, route, and timing of administration and the subgroups of patients who might benefit most from this treatment. In the meantime, the recent and widespread adoption of the use of drug-eluting stents, which lower the need for repeated target-vessel revascularization to about 5 percent, has made the consideration of folate therapy to prevent restenosis moot.
Until recently, interventional cardiologists were preoccupied with the problem of restenosis after percutaneous coronary intervention. Vessel recoil and the healing response to the injury caused by balloon inflation at the site of a coronary lesion resulted in the need for repeated procedures in 30 to 40 percent of patients who had undergone balloon angioplasty. This problem was partially redressed by the introduction of bare-metal stents 10 years ago and has been virtually eliminated by the introduction of sirolimus- and paclitaxel-eluting stents.7,8 It is likely that even if folic acid has a small beneficial effect on the risk of restenosis after stenting in some patients, it will be clinically unimportant in the small subgroup of patients in whom stenosis recurs after the implantation of a drug-eluting stent.
Smoking cessation, lipid modification, blood-pressure control, dietary intervention to control diabetes and reduce obesity, and exercise are all well-established prophylactic treatments for cardiovascular disease. Studies have indicated that patients with hyperlipidemia, patients with diabetes, and those who continue to smoke after percutaneous coronary intervention are at increased risk for additional cardiac events, including death.9,10 Patients scheduled to undergo cardiac catheterization and percutaneous coronary intervention represent an ideal audience for lifestyle education and risk-factor modification. It is incumbent on all physicians who care for patients with cardiovascular disease to use this opportunity to initiate an effective prevention program. This strategy is unfortunately still underused, as illustrated by the fact that only 40 percent of the patients in the study by Lange et al. were taking statin medications at the time of their procedure and that this percentage did not increase substantially during the follow-up period.
Although the short-term effect of statins on restenosis is unclear, the benefit of these agents as a means of secondary prevention is compelling.11 Other medications also decrease the risk of cardiovascular events after percutaneous coronary intervention. Clopidogrel, combined with aspirin, is given as standard therapy for 3 to 6 months after stent placement to reduce the risk of acute and subacute thrombosis and has additional benefit in patients for up to 12 months after percutaneous coronary intervention.12,13 Tissue-specific ACE inhibitors and beta-blockers reduce vascular events among patients with coronary artery disease and those who have had a myocardial infarction. In the future, calcium-channel blockers, novel agents to treat dyslipidemia, and antiinflammatory agents may also prove beneficial.
As restenosis becomes less of a problem after percutaneous coronary intervention, we need to refocus on the underlying disease process in order to treat vulnerable plaques and atherosclerosis and prevent subsequent cardiac events and new and progressive atherosclerotic lesions. Data now exist to recommend the use of aspirin, clopidogrel, statins, ACE inhibitors, control of diabetes and hypertension, nutritional counseling, smoking cessation, and exercise for all patients who have received an intracoronary stent. Pending the completion of clinical trials, some physicians may recommend folate (and vitamins B6 and B12) therapy to patients with hyperhomocysteinemia.
All physicians who care for patients with cardiovascular disease should remain cognizant that atherosclerosis is a chronic progressive disease. Although percutaneous coronary intervention can dramatically improve a patient's clinical condition in the short term, both the physician and the patient must remain focused on the long-term consequences of subsequent disease progression and use all available strategies to attenuate it. Interventional cardiologists, in particular, should be at the forefront of cardiovascular prevention, redoubling efforts to intercept the disease process itself after the culprit lesion has been successfully stented.
Dr. Herrmann reports having received lecture fees and grant support from Boston Scientific, Johnson & Johnson, and Pfizer.
I am indebted to Drs. John W. Hirshfeld, Jr., and Daniel J. Rader for thoughtful comments on a draft of this editorial.
Source Information
From the University of Pennsylvania, Philadelphia.
References
Lange H, Suryapranata H, De Luca G, et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 2004;350:2673-2681.
Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001;345:1593-1600.
Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002;288:2015-2023.
Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997;337:230-236.
Jacques PF, Selhub J, Bostom AG, Wilson PWF, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999;340:1449-1454.
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report. Circulation 2002;106:3143-3421.
Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773-1780.
Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221-231.
Abizaid A, Kornowski R, Mintz GS, et al. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation. J Am Coll Cardiol 1998;32:584-589.
Hasdai D, Garratt KN, Grill DE, Lerman A, Holmes DR Jr. Effect of smoking status on the long-term outcome after successful percutaneous coronary revascularization. N Engl J Med 1997;336:755-761.
Schomig A, Mehilli J, Holle H, et al. Statin treatment following coronary artery stenting and one-year survival. J Am Coll Cardiol 2002;40:854-861.
Mehta SR, Yusuf S, Peters RJG, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527-533.
Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411-2420.(Howard C. Herrmann, M.D.)
Figure 1. Cutaway View of a Coronary Artery Showing a Stent Implanted to Treat a Previously Flow-Limiting Stenosis.
The stent may elute a drug to prevent restenosis within the stent. Aspirin and clopidogrel are used to block platelet deposition, which contributes to acute and subacute stent thrombosis. Other strategies (statins, angiotensin-converting–enzyme inhibitors, diabetes and hypertension control, nutritional counseling, smoking cessation, exercise, and possible folate supplementation) are necessary to prevent new and progressive atherosclerotic lesions in other coronary-artery locations.
In this issue of the Journal, Lange et al. report that oral supplementation with a combination of folic acid and vitamins B6 and B12 after an initial intravenous bolus significantly increased the risk of restenosis among 636 patients who had received bare-metal stents.1 This finding directly contradicts the results of the Swiss Heart Study,2 in which folic acid supplementation was associated with a marked reduction in restenosis and target-vessel revascularization after percutaneous coronary intervention. Both trials targeted homocysteine, a moderate risk factor for coronary artery disease3 as well as for death, among patients with established coronary artery disease.4 The serum level of this amino acid can be lowered by dietary supplementation with folic acid and fortified grain products,5 but there is no proof that lowering homocysteine levels with vitamin supplementation lowers the risk of cardiovascular events. Now, however, the findings of Lange et al. raise the disturbing possibility that a therapy that has previously been considered safe may actually be harmful.
How can we reconcile the results of these two angioplasty studies? First, the two studies used different doses of vitamins. Lange et al. used an initial intravenous loading bolus and higher doses of all three agents, particularly vitamin B6, which could have a greater influence on the relative metabolism of homocysteine by the vitamin B6–dependent transsulfuration pathway than by the vitamin B12–dependent and folate-dependent remethylation pathways. Second, the patient populations in the two studies were quite different. Patients in the Swiss Heart Study were more likely to smoke (which is associated with a higher homocysteine level), to have diabetes, and to have had a prior myocardial infarction. These patients also had lower baseline homocysteine levels, and although vessel sizes were similar in the two populations, the patients studied by Lange et al. had shorter lesions.
Both studies were well-designed, randomized, double-blind, placebo-controlled trials, but Lange et al. obtained angiographic follow-up data for only 76 percent of the original study population, because 91 patients discontinued treatment and 62 patients did not undergo follow-up angiography. The detrimental effect of folic acid supplementation was most pronounced in patients without diabetes, in men, and in patients with a low homocysteine level at baseline. Another important difference between these two studies relates to the use of balloon angioplasty and stents. In the Swiss Heart Study, most of the benefit was observed in the patients who were treated with angioplasty alone, rather than in those who received stents (reduction in risk, 76 percent vs. 31 percent). Finally, more patients were treated with adjunctive medications, including statins and angiotensin-converting–enzyme (ACE) inhibitors, in the Swiss Heart Study.
On the basis of these differences and the potential for harm demonstrated in the current study, folic acid, vitamin B6, and vitamin B12 should not be routinely administered to patients receiving coronary stents in an effort to reduce the risk of restenosis. Folate therapy may be a reasonable means of secondary prevention in patients with high homocysteine levels after percutaneous coronary intervention, as suggested by some authorities, but the validity of this approach is not supported by current federal guidelines, owing to the absence of supporting clinical trials.6 Studies are needed to clarify the optimal dose, route, and timing of administration and the subgroups of patients who might benefit most from this treatment. In the meantime, the recent and widespread adoption of the use of drug-eluting stents, which lower the need for repeated target-vessel revascularization to about 5 percent, has made the consideration of folate therapy to prevent restenosis moot.
Until recently, interventional cardiologists were preoccupied with the problem of restenosis after percutaneous coronary intervention. Vessel recoil and the healing response to the injury caused by balloon inflation at the site of a coronary lesion resulted in the need for repeated procedures in 30 to 40 percent of patients who had undergone balloon angioplasty. This problem was partially redressed by the introduction of bare-metal stents 10 years ago and has been virtually eliminated by the introduction of sirolimus- and paclitaxel-eluting stents.7,8 It is likely that even if folic acid has a small beneficial effect on the risk of restenosis after stenting in some patients, it will be clinically unimportant in the small subgroup of patients in whom stenosis recurs after the implantation of a drug-eluting stent.
Smoking cessation, lipid modification, blood-pressure control, dietary intervention to control diabetes and reduce obesity, and exercise are all well-established prophylactic treatments for cardiovascular disease. Studies have indicated that patients with hyperlipidemia, patients with diabetes, and those who continue to smoke after percutaneous coronary intervention are at increased risk for additional cardiac events, including death.9,10 Patients scheduled to undergo cardiac catheterization and percutaneous coronary intervention represent an ideal audience for lifestyle education and risk-factor modification. It is incumbent on all physicians who care for patients with cardiovascular disease to use this opportunity to initiate an effective prevention program. This strategy is unfortunately still underused, as illustrated by the fact that only 40 percent of the patients in the study by Lange et al. were taking statin medications at the time of their procedure and that this percentage did not increase substantially during the follow-up period.
Although the short-term effect of statins on restenosis is unclear, the benefit of these agents as a means of secondary prevention is compelling.11 Other medications also decrease the risk of cardiovascular events after percutaneous coronary intervention. Clopidogrel, combined with aspirin, is given as standard therapy for 3 to 6 months after stent placement to reduce the risk of acute and subacute thrombosis and has additional benefit in patients for up to 12 months after percutaneous coronary intervention.12,13 Tissue-specific ACE inhibitors and beta-blockers reduce vascular events among patients with coronary artery disease and those who have had a myocardial infarction. In the future, calcium-channel blockers, novel agents to treat dyslipidemia, and antiinflammatory agents may also prove beneficial.
As restenosis becomes less of a problem after percutaneous coronary intervention, we need to refocus on the underlying disease process in order to treat vulnerable plaques and atherosclerosis and prevent subsequent cardiac events and new and progressive atherosclerotic lesions. Data now exist to recommend the use of aspirin, clopidogrel, statins, ACE inhibitors, control of diabetes and hypertension, nutritional counseling, smoking cessation, and exercise for all patients who have received an intracoronary stent. Pending the completion of clinical trials, some physicians may recommend folate (and vitamins B6 and B12) therapy to patients with hyperhomocysteinemia.
All physicians who care for patients with cardiovascular disease should remain cognizant that atherosclerosis is a chronic progressive disease. Although percutaneous coronary intervention can dramatically improve a patient's clinical condition in the short term, both the physician and the patient must remain focused on the long-term consequences of subsequent disease progression and use all available strategies to attenuate it. Interventional cardiologists, in particular, should be at the forefront of cardiovascular prevention, redoubling efforts to intercept the disease process itself after the culprit lesion has been successfully stented.
Dr. Herrmann reports having received lecture fees and grant support from Boston Scientific, Johnson & Johnson, and Pfizer.
I am indebted to Drs. John W. Hirshfeld, Jr., and Daniel J. Rader for thoughtful comments on a draft of this editorial.
Source Information
From the University of Pennsylvania, Philadelphia.
References
Lange H, Suryapranata H, De Luca G, et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 2004;350:2673-2681.
Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001;345:1593-1600.
Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002;288:2015-2023.
Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997;337:230-236.
Jacques PF, Selhub J, Bostom AG, Wilson PWF, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999;340:1449-1454.
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): final report. Circulation 2002;106:3143-3421.
Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773-1780.
Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221-231.
Abizaid A, Kornowski R, Mintz GS, et al. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation. J Am Coll Cardiol 1998;32:584-589.
Hasdai D, Garratt KN, Grill DE, Lerman A, Holmes DR Jr. Effect of smoking status on the long-term outcome after successful percutaneous coronary revascularization. N Engl J Med 1997;336:755-761.
Schomig A, Mehilli J, Holle H, et al. Statin treatment following coronary artery stenting and one-year survival. J Am Coll Cardiol 2002;40:854-861.
Mehta SR, Yusuf S, Peters RJG, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527-533.
Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411-2420.(Howard C. Herrmann, M.D.)