Drug-Eluting Stents in Primary PCI
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《新英格兰医药杂志》
To the Editor: In their report on stent use in primary percutaneous coronary intervention (PCI), Spaulding et al. (Sept. 14 issue) suggest that sirolimus-eluting stents are superior to conventional stents in patients with acute myocardial infarction.1 However, some methodologic issues should be addressed. First, despite the randomized design of the study, there were imbalances in most of the procedure-related factors (length and size of the stent and balloon inflation pressure). These imbalances imply the use of different strategies — not disclosed — that might have influenced the results.2 Likewise, the reasons for the poorer early angiographic results (luminal diameter and stenosis) in the sirolimus-stent group than in the uncoated-stent group remain elusive. Second, previous studies have demonstrated that late angiographic variables have a skewed distribution after the implantation of sirolimus-eluting stents.3,4 If this was the case in the study by Spaulding and colleagues, presenting the data as median values would have been helpful. Third, although the protocol required only 6 months of dual antiplatelet therapy, half the patients continued to receive this regimen at 1 year. Definitions of the criteria for the selection of candidates for this prolonged therapy would be appreciated. Finally, given the high rates of stent thrombosis (3.4% in the sirolimus-stent group and 3.6% in the uncoated-stent group), a further emphasis on the potential benefit of more aggressive or prolonged antithrombotic strategies in this challenging setting5 appears warranted.
Fernando Alfonso, M.D.
Hospital Universitario Clinico San Carlos
28040 Madrid, Spain
falf@hotmail.com
References
Spaulding C, Henry P, Teiger E, et al. Sirolimus-eluting versus uncoated stents in acute myocardial infarction. N Engl J Med 2006;355:1093-1104.
Alfonso F. Coronary-artery stenting in acute myocardial infarction. N Engl J Med 2000;342:1448-1448.
Alfonso F, Perez-Vizcayno MJ, Hernandez R, et al. A randomized comparison of sirolimus-eluting stent with balloon angioplasty in patients with in-stent restenosis: results of the Restenosis Intrastent: Balloon Angioplasty Versus Elective Sirolimus-Eluting Stenting (RIBS-II) trial. J Am Coll Cardiol 2006;47:2152-2160.
Mauri L, Orav EJ, O'Malley AJ, et al. Relationship of late loss in lumen diameter to coronary restenosis in sirolimus-eluting stents. Circulation 2005;111:321-327.
Park DW, Park SW, Park KH, et al. Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during long-term follow-up. Am J Cardiol 2006;98:352-356.
To the Editor: We disagree with the comparison in the editorial by Van de Werf1 of different measures of clinical restenosis in the control groups of the Trial to Assess the Use of the Cypher Stent in Acute Myocardial Infarction Treated with Balloon Angioplasty (TYPHOON), reported on by Spaulding et al., and the Paclitaxel-Eluting Stent versus Conventional Stent in Myocardial Infarction with ST-Segment Elevation (PASSION) trial, reported on by Laarman et al.2 The study population in the PASSION trial had a lower risk of restenosis, given the lower prevalence of diabetes and the larger diameter of the reference vessel and postprocedural minimal luminal diameter in this population than in that in the PASSION trial, a difference that explains the discrepancy between the findings in the PASSION trial and TYPHOON.1,2
Furthermore, TYPHOON was confounded not only by angiographic findings on follow-up but also by the results of routine noninvasive testing. The TYPHOON investigators should report the number of events driven by "routine" noninvasive testing and the restenosis rates among subjects who did not have angiographic follow-up or "routine" noninvasive testing.
Finally, it is interesting that none of the patients in the PASSION trial who discontinued clopidogrel prematurely had stent thrombosis, whereas all the patients with stent thrombosis were compliant with the medication regimen.2 Stent thrombosis is a complex medical problem, and it is time to shift the focus of research to the study of it. Restenosis is often a benign disease; stent thrombosis, however, is a potentially fatal one.3
Hani Jneid, M.D.
Andrew O. Maree, M.D.
Igor F. Palacios, M.D.
Massachusetts General Hospital
Boston, MA 02114
jneid.hani@mgh.harvard.edu
Drs. Jneid and Palacios report receiving a research grant from Pfizer.
References
Van de Werf F. Drug-eluting stents in acute myocardial infarction. N Engl J Med 2006;355:1169-1170.
Laarman GJ, Suttorp MJ, Dirksen MT, et al. Paclitaxel-eluting versus uncoated stents in primary percutaneous coronary intervention. N Engl J Med 2006;355:1105-1113.
Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126-2130.
To the Editor: Although the results of the TYPHOON and PASSION studies represent considerable advances in our understanding of the role of drug-eluting stents in acute myocardial infarction, we concur with Van de Werf that routine implantation of drug-eluting stents cannot be recommended for all patients undergoing primary PCI. In TYPHOON, the enrolled patients were carefully selected (35% of the screened population). This selectiveness is in keeping with protocol-mandated clinical and angiographic exclusion criteria and the low overall rates of death (2.2%) and myocardial infarction (1.3%) at 1 year. In the PASSION trial, less restrictive selection criteria allowed the recruitment of a broader patient population (60% of the screened population). Thus, patient selection may play a role in explaining the difference in findings between the two trials. Also, in both trials, enrollment was allowed only after coronary angiography to ensure selection of good stent candidates. This requirement may explain both the higher event rates reported in primary PCI studies in which randomization was performed before coronary angiograms were obtained1,2 and calls for future investigations to evaluate drug-eluting stents in a less selected population with acute myocardial infarction.
Marco Valgimigli, M.D., Ph.D.
Gianfranco Percoco, M.D.
University of Ferrara
44100 Ferrara, Italy
vlgmrc@unife.it
Leonardo Bolognese, M.D.
San Donato Hospital
52100 Arezzo, Italy
References
Valgimigli M, Percoco G, Malagutti P, et al. Tirofiban and sirolimus-eluting stent vs abciximab and bare-metal stent for acute myocardial infarction: a randomized trial. JAMA 2005;293:2109-2117.
Suryapranata H, De Luca G, van't Hof AW, et al. Is routine stenting for acute myocardial infarction superior to balloon angioplasty? A randomised comparison in a large cohort of unselected patients. Heart 2005;91:641-645.
Dr. Spaulding and colleagues reply: The imbalances in baseline characteristics between the two study groups noted by Alfonso were due solely to chance. A multiple logistic-regression analysis showed that these differences did not influence the results of our trial. The mean residual stenosis after the procedure was higher in patients receiving a sirolimus-eluting stent; it was also higher in both the study groups than in previous studies, probably because high-pressure balloon inflation and overexpansion were discouraged, in accordance with the trial protocol. Dual antiplatelet therapy was recommended for at least 6 months; however, the date of cessation was left to the investigator's discretion. The beneficial effect of prolonged dual antiplatelet therapy (for more than 6 months) after implantation of the drug-eluting stent has not been evaluated and therefore cannot be recommended.
We disagree with Valgimigli and colleagues; in routine practice, the choice of a stent is based on both clinical and angiographic features. Therefore, postangiographic randomization is not a study limitation. By their nature, well-designed randomized trials must select patients carefully. Although the extension of the results of TYPHOON to a broader population obviously must be confirmed by studies of data from large-scale registries, we believe that our conclusions can already be applied to patients with clinical and angiographic features similar to those of patients enrolled in our study.
We appreciate the comments of Jneid and colleagues about the effect of angiographic follow-up on the results of stent trials. Our study was carefully designed to minimize this bias. First, follow-up angiography was performed only in a subgroup of patients, and a significant difference in rates of target-vessel failure was also found among patients without angiographic follow-up (6.8% in the sirolimus-eluting stent group vs. 12.7% in the bare-metal stent group, P=0.03). Second, noninvasive testing for evidence of ischemia was recommended before follow-up angiography to avoid revascularization guided solely by angiographic findings. Third, target-vessel revascularization was adjudicated by an independent committee. Nevertheless, noninvasive testing is performed routinely at 6 months in most countries in Europe, and this practice may have increased the rate of repeated revascularization. Finally, we agree with Jneid and colleagues' analysis of the differences between TYPHOON and PASSION. In our opinion, the PASSION trial was underpowered, enrolled patients at lower risk for restenosis than those in TYPHOON, and used a less potent drug-eluting stent. The negative results of the PASSION trial are therefore not surprising.
Christian Spaulding, M.D.
Patrick Henry, M.D., Ph.D.
Emmanuel Teiger, M.D., Ph.D.
Assistance Publique–H?pitaux de Paris
75014 Paris, France
christian.spaulding@cch.ap-hop-paris.fr
Dr. Laarman replies: We agree with Jneid and colleagues that research should focus on the mechanisms and predictive risks of thrombosis associated with the use of drug-eluting stents. An important element of this research would be to obtain complete, long-term clinical follow-up data in different subgroups of patients. In our study, only one case of late stent thrombosis was documented at 1 year of follow-up. As we stated in the Discussion section of our article, this incidence is low, given the thrombotic environment at the time of stent placement, the potential for suboptimal stent deployment in the setting of PCI for acute myocardial infarction, and decreased flow in vessels that supply infarcted myocardium. On the one hand, however, our definition of stent thrombosis was conservative, since angiographic documentation was required, which might have led to underestimation of the incidence of stent thrombosis. On the other hand, inclusion of sudden death in the definition of stent thrombosis in this particular subgroup might overestimate the occurrence of stent thrombosis, since sudden death after myocardial infarction may be caused by arrhythmias that are not related to abrupt stent occlusion.
We have planned a careful and complete long-term clinical follow-up of patients in the PASSION trial in which we will use alternative and more liberal definitions of stent thrombosis in order to establish the true incidence of stent thrombosis after PCI for acute myocardial infarction with the use of paclitaxel-eluting stents.
Gerrit J. Laarman, M.D., Ph.D.
Onze Lieve Vrouwe Gasthuis
1217 NJ Amsterdam, the Netherlands
g.j.laarman@olvg.nl
Dr. Van de Werf replies: Jneid et al. believe that the higher prevalence of diabetes and the smaller size of the target vessels may explain the higher rates of repeated revascularization with the use of uncoated stents in TYPHOON, as compared with the PASSION trial. Although these differences in baseline characteristics may indeed have played a role, it is equally possible that the use of a variety of types of uncoated stents in TYPHOON contributed to the differences. Comparisons of baseline risk factors, treatments, and outcomes in different trials always remain speculative. The use of only two types of uncoated stents in the PASSION trial at least simplifies the comparison with drug-eluting stents, since the polymer and the drug are the only difference between the two treatment groups. I concur with Jneid et al. that angiographic follow-up in a significant proportion of the patients may have triggered additional revascularizations in TYPHOON, as I also indicated in my editorial. I cannot agree more with Jneid et al. that restenosis is a relatively benign clinical event, as compared with (late) stent thrombosis, and that future studies should focus on stent thrombosis and will therefore require longer follow-up.
Valgimigli et al. point out that the screening of patients was more stringent in TYPHOON than in the PASSION trial, but that in both trials, patients underwent randomization after coronary angiography in order to select ideal candidates for stent implantation. Valgimigli et al. believe that this selectivity can explain the lower event rates in these two studies than in most primary PCI trials in which randomization occurred before angiography. I agree. As mentioned in my editorial, we now need trials in which patients who have acute myocardial infarction with ST-segment elevation are randomly assigned to a drug-eluting or an uncoated stent, preferably before catheterization, with a clinical follow-up of several years and careful monitoring of thienopyridine therapy.
Frans Van de Werf, M.D., Ph.D.
University of Leuven
3000 Leuven, Belgium
Fernando Alfonso, M.D.
Hospital Universitario Clinico San Carlos
28040 Madrid, Spain
falf@hotmail.com
References
Spaulding C, Henry P, Teiger E, et al. Sirolimus-eluting versus uncoated stents in acute myocardial infarction. N Engl J Med 2006;355:1093-1104.
Alfonso F. Coronary-artery stenting in acute myocardial infarction. N Engl J Med 2000;342:1448-1448.
Alfonso F, Perez-Vizcayno MJ, Hernandez R, et al. A randomized comparison of sirolimus-eluting stent with balloon angioplasty in patients with in-stent restenosis: results of the Restenosis Intrastent: Balloon Angioplasty Versus Elective Sirolimus-Eluting Stenting (RIBS-II) trial. J Am Coll Cardiol 2006;47:2152-2160.
Mauri L, Orav EJ, O'Malley AJ, et al. Relationship of late loss in lumen diameter to coronary restenosis in sirolimus-eluting stents. Circulation 2005;111:321-327.
Park DW, Park SW, Park KH, et al. Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during long-term follow-up. Am J Cardiol 2006;98:352-356.
To the Editor: We disagree with the comparison in the editorial by Van de Werf1 of different measures of clinical restenosis in the control groups of the Trial to Assess the Use of the Cypher Stent in Acute Myocardial Infarction Treated with Balloon Angioplasty (TYPHOON), reported on by Spaulding et al., and the Paclitaxel-Eluting Stent versus Conventional Stent in Myocardial Infarction with ST-Segment Elevation (PASSION) trial, reported on by Laarman et al.2 The study population in the PASSION trial had a lower risk of restenosis, given the lower prevalence of diabetes and the larger diameter of the reference vessel and postprocedural minimal luminal diameter in this population than in that in the PASSION trial, a difference that explains the discrepancy between the findings in the PASSION trial and TYPHOON.1,2
Furthermore, TYPHOON was confounded not only by angiographic findings on follow-up but also by the results of routine noninvasive testing. The TYPHOON investigators should report the number of events driven by "routine" noninvasive testing and the restenosis rates among subjects who did not have angiographic follow-up or "routine" noninvasive testing.
Finally, it is interesting that none of the patients in the PASSION trial who discontinued clopidogrel prematurely had stent thrombosis, whereas all the patients with stent thrombosis were compliant with the medication regimen.2 Stent thrombosis is a complex medical problem, and it is time to shift the focus of research to the study of it. Restenosis is often a benign disease; stent thrombosis, however, is a potentially fatal one.3
Hani Jneid, M.D.
Andrew O. Maree, M.D.
Igor F. Palacios, M.D.
Massachusetts General Hospital
Boston, MA 02114
jneid.hani@mgh.harvard.edu
Drs. Jneid and Palacios report receiving a research grant from Pfizer.
References
Van de Werf F. Drug-eluting stents in acute myocardial infarction. N Engl J Med 2006;355:1169-1170.
Laarman GJ, Suttorp MJ, Dirksen MT, et al. Paclitaxel-eluting versus uncoated stents in primary percutaneous coronary intervention. N Engl J Med 2006;355:1105-1113.
Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126-2130.
To the Editor: Although the results of the TYPHOON and PASSION studies represent considerable advances in our understanding of the role of drug-eluting stents in acute myocardial infarction, we concur with Van de Werf that routine implantation of drug-eluting stents cannot be recommended for all patients undergoing primary PCI. In TYPHOON, the enrolled patients were carefully selected (35% of the screened population). This selectiveness is in keeping with protocol-mandated clinical and angiographic exclusion criteria and the low overall rates of death (2.2%) and myocardial infarction (1.3%) at 1 year. In the PASSION trial, less restrictive selection criteria allowed the recruitment of a broader patient population (60% of the screened population). Thus, patient selection may play a role in explaining the difference in findings between the two trials. Also, in both trials, enrollment was allowed only after coronary angiography to ensure selection of good stent candidates. This requirement may explain both the higher event rates reported in primary PCI studies in which randomization was performed before coronary angiograms were obtained1,2 and calls for future investigations to evaluate drug-eluting stents in a less selected population with acute myocardial infarction.
Marco Valgimigli, M.D., Ph.D.
Gianfranco Percoco, M.D.
University of Ferrara
44100 Ferrara, Italy
vlgmrc@unife.it
Leonardo Bolognese, M.D.
San Donato Hospital
52100 Arezzo, Italy
References
Valgimigli M, Percoco G, Malagutti P, et al. Tirofiban and sirolimus-eluting stent vs abciximab and bare-metal stent for acute myocardial infarction: a randomized trial. JAMA 2005;293:2109-2117.
Suryapranata H, De Luca G, van't Hof AW, et al. Is routine stenting for acute myocardial infarction superior to balloon angioplasty? A randomised comparison in a large cohort of unselected patients. Heart 2005;91:641-645.
Dr. Spaulding and colleagues reply: The imbalances in baseline characteristics between the two study groups noted by Alfonso were due solely to chance. A multiple logistic-regression analysis showed that these differences did not influence the results of our trial. The mean residual stenosis after the procedure was higher in patients receiving a sirolimus-eluting stent; it was also higher in both the study groups than in previous studies, probably because high-pressure balloon inflation and overexpansion were discouraged, in accordance with the trial protocol. Dual antiplatelet therapy was recommended for at least 6 months; however, the date of cessation was left to the investigator's discretion. The beneficial effect of prolonged dual antiplatelet therapy (for more than 6 months) after implantation of the drug-eluting stent has not been evaluated and therefore cannot be recommended.
We disagree with Valgimigli and colleagues; in routine practice, the choice of a stent is based on both clinical and angiographic features. Therefore, postangiographic randomization is not a study limitation. By their nature, well-designed randomized trials must select patients carefully. Although the extension of the results of TYPHOON to a broader population obviously must be confirmed by studies of data from large-scale registries, we believe that our conclusions can already be applied to patients with clinical and angiographic features similar to those of patients enrolled in our study.
We appreciate the comments of Jneid and colleagues about the effect of angiographic follow-up on the results of stent trials. Our study was carefully designed to minimize this bias. First, follow-up angiography was performed only in a subgroup of patients, and a significant difference in rates of target-vessel failure was also found among patients without angiographic follow-up (6.8% in the sirolimus-eluting stent group vs. 12.7% in the bare-metal stent group, P=0.03). Second, noninvasive testing for evidence of ischemia was recommended before follow-up angiography to avoid revascularization guided solely by angiographic findings. Third, target-vessel revascularization was adjudicated by an independent committee. Nevertheless, noninvasive testing is performed routinely at 6 months in most countries in Europe, and this practice may have increased the rate of repeated revascularization. Finally, we agree with Jneid and colleagues' analysis of the differences between TYPHOON and PASSION. In our opinion, the PASSION trial was underpowered, enrolled patients at lower risk for restenosis than those in TYPHOON, and used a less potent drug-eluting stent. The negative results of the PASSION trial are therefore not surprising.
Christian Spaulding, M.D.
Patrick Henry, M.D., Ph.D.
Emmanuel Teiger, M.D., Ph.D.
Assistance Publique–H?pitaux de Paris
75014 Paris, France
christian.spaulding@cch.ap-hop-paris.fr
Dr. Laarman replies: We agree with Jneid and colleagues that research should focus on the mechanisms and predictive risks of thrombosis associated with the use of drug-eluting stents. An important element of this research would be to obtain complete, long-term clinical follow-up data in different subgroups of patients. In our study, only one case of late stent thrombosis was documented at 1 year of follow-up. As we stated in the Discussion section of our article, this incidence is low, given the thrombotic environment at the time of stent placement, the potential for suboptimal stent deployment in the setting of PCI for acute myocardial infarction, and decreased flow in vessels that supply infarcted myocardium. On the one hand, however, our definition of stent thrombosis was conservative, since angiographic documentation was required, which might have led to underestimation of the incidence of stent thrombosis. On the other hand, inclusion of sudden death in the definition of stent thrombosis in this particular subgroup might overestimate the occurrence of stent thrombosis, since sudden death after myocardial infarction may be caused by arrhythmias that are not related to abrupt stent occlusion.
We have planned a careful and complete long-term clinical follow-up of patients in the PASSION trial in which we will use alternative and more liberal definitions of stent thrombosis in order to establish the true incidence of stent thrombosis after PCI for acute myocardial infarction with the use of paclitaxel-eluting stents.
Gerrit J. Laarman, M.D., Ph.D.
Onze Lieve Vrouwe Gasthuis
1217 NJ Amsterdam, the Netherlands
g.j.laarman@olvg.nl
Dr. Van de Werf replies: Jneid et al. believe that the higher prevalence of diabetes and the smaller size of the target vessels may explain the higher rates of repeated revascularization with the use of uncoated stents in TYPHOON, as compared with the PASSION trial. Although these differences in baseline characteristics may indeed have played a role, it is equally possible that the use of a variety of types of uncoated stents in TYPHOON contributed to the differences. Comparisons of baseline risk factors, treatments, and outcomes in different trials always remain speculative. The use of only two types of uncoated stents in the PASSION trial at least simplifies the comparison with drug-eluting stents, since the polymer and the drug are the only difference between the two treatment groups. I concur with Jneid et al. that angiographic follow-up in a significant proportion of the patients may have triggered additional revascularizations in TYPHOON, as I also indicated in my editorial. I cannot agree more with Jneid et al. that restenosis is a relatively benign clinical event, as compared with (late) stent thrombosis, and that future studies should focus on stent thrombosis and will therefore require longer follow-up.
Valgimigli et al. point out that the screening of patients was more stringent in TYPHOON than in the PASSION trial, but that in both trials, patients underwent randomization after coronary angiography in order to select ideal candidates for stent implantation. Valgimigli et al. believe that this selectivity can explain the lower event rates in these two studies than in most primary PCI trials in which randomization occurred before angiography. I agree. As mentioned in my editorial, we now need trials in which patients who have acute myocardial infarction with ST-segment elevation are randomly assigned to a drug-eluting or an uncoated stent, preferably before catheterization, with a clinical follow-up of several years and careful monitoring of thienopyridine therapy.
Frans Van de Werf, M.D., Ph.D.
University of Leuven
3000 Leuven, Belgium