- Email: [email protected]
Initial experience with multivessel percutaneous coronary intervention during mechanical reperfusion for acute myocardial infarction
Initial Experience With Multivessel Percutaneous Coronary Intervention During Mechanical Reperfusion for Acute Myocardial Infarction Matthew T. Roe, MD, Fernando A. Cura, MD, Peter S. Joski, MS, Eulogio Garcia, MD, Victor Guetta, MD, Dean J. Kereiakes, MD, Felix Zijlstra, MD, Bruce R. Brodie, MD, Cindy L. Grines, MD, and Stephen G. Ellis, MD he optimal revascularization strategy for patients with acute myocardial infarction (AMI) found to T have multivessel coronary disease during acute angiography is unknown, but traditional options have included staged percutaneous revascularization after recanalization of the infarct-related artery (IRA) or urgent coronary artery bypass grafting. However, because outcomes of elective multivessel percutaneous coronary intervention (PCI) have improved with the use of stents and platelet glycoprotein IIb/IIIa inhibitors, simultaneous percutaneous revascularization of nonculprit arteries may be a useful therapeutic option for patients with AMI found to have multivessel disease during acute angiography.1,2 Therefore, to determine the feasibility and safety of nonculprit artery PCI during mechanical reperfusion, we analyzed patients with AMI who underwent simultaneous multivessel PCI compared with matched controls in whom PCI was limited to the IRA. •••
Inquiries were made to multiple international centers experienced with mechanical reperfusion for AMI to identify consecutive patients who underwent multivessel PCI during the initial acute procedure from June 1995 to June 1999. Patients who underwent multivessel PCI were defined as those who had simultaneous dilation of ⱖ1 lesion in a nonculprit artery during either primary PCI or rescue PCI. Patients who underwent PCI of branch vessels of the IRA or the left main coronary artery were excluded. Control cases were randomly selected from each site during the same time period and were defined as patients with multivessel disease (ⱖ1 coronary stenosis ⱖ50% in a nonculprit vessel) in whom PCI was limited to the IRA. Control cases were equally matched to index cases of multivessel PCI on the basis of age (⫾5 years) and Killip class, because these characteristics have been shown to be among the strongest predictors of 30-day mortality in patients with AMI undergoing mechanical reperfusion.3,4 From the Duke Clinical Research Institute, Durham, North Carolina; Cleveland Clinic Foundation, Cleveland, Ohio; Hospital Gregorio Maranon, Madrid, Spain; Chaim Sheba Medical Center, TelHashomer, Israel; Lindner Center and Ohio Heart Health Center, Cincinnati, Ohio; Ziekenhuis De Weezenlanden, Zwolle, The Netherlands; Moses Cone Hospital, Greensboro, North Carolina; and William Beaumont Hospital, Royal Oak, Michigan. Dr. Roe’s address is: Duke Clinical Research Institute, P.O. Box 17969, Durham, North Carolina 27715. E-mail: [email protected]. Manuscript received October 4, 2000; revised manuscript received and accepted February 14, 2001.
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©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 88 July 15, 2001
Cine angiograms were reviewed in a central core laboratory by 1 investigator (FAC) for all patients in whom films were available. Clinical end points through 6 months were reported by each investigator and included death, reinfarction, repeat PCI, bypass surgery, bleeding, and stroke. The prespecified primary end point was a composite of death, reinfarction, repeat PCI, or bypass surgery. Reinfarction was defined as recurrent chest pain associated with new ischemic electrocardiographic changes or re-elevation of serum cardiac markers. Repeat PCI and bypass surgery included any additional revascularization procedure that occurred within 6 months of acute PCI. Serious bleeding included any significant hemorrhage that required transfusion of blood products. Stroke was defined as any neurologic event considered to represent a hemorrhagic or nonhemorrhagic stroke by the investigator. Kaplan-Meier methods were used to estimate event rates through 6 months for the multivessel PCI and control groups. Event rates were analyzed separately in patients who underwent primary PCI and rescue PCI. Comparisons of 30-day event rates between the groups were performed using the 2-sided Fisher’s exact test given the relatively small sample size and number of events. Comparisons of 6-month event rates between the groups were performed using the log-rank test. Multivariable logistic regression (30day events) and Cox proportional-hazards analyses (6-month events) were performed to determine whether event rates differed among the multivessel PCI and control groups after adjusting for age, Killip class, and infarct location, given the important prognostic implications of these variables.3–5 A total of 79 cases of multivessel PCI were collected from 8 international centers and were equally matched to control cases. Baseline clinical characteristics of the 2 groups were similar (Table 1). Primary PCI was performed in 68 of 79 patients who underwent multivessel PCI (86%) and in 61 of 79 control patients (75%). The remaining patients underwent rescue PCI after treatment with intravenous fibrinolytic therapy failed to achieve sufficient reperfusion. The time to treatment from symptom onset to the first balloon inflation was ⬍6 hours in 60% of the patients in the multivessel PCI group and in 44% of patients in the control group. The indication for performing multivessel PCI was hemodynamic instability in 39% of patients, routine in 31%, other in 12%, persistent ischemia after PCI of the IRA in 10%, and unknown in 8%. 0002-9149/01/$–see front matter PII S0002-9149(01)01615-0
TABLE 1 Baseline Characteristics Multivessel PCI (n ⫽ 79)
TABLE 2 Procedural Characteristics Controls (n ⫽ 79)
Age (yrs)† (range) 64 (53–74) 63 (56–73) Men 77.2% 65.8% Systolic blood pressure 115 (90–130) 116 (90–131) (mm Hg)† (range) Heart rate 82 (70–98) 80 (70–96) (beats/min)† (range) Diabetes mellitus 37.2% 29.1% Current smoking 37.2% 24.1% Hypertension 53.8% 64.6% Prior stroke 5.2% 6.3% Prior congestive heart 7.7% 3.8% failure Prior AMI 35.9% 21.5% Prior PCI 17.5% 13.9% Prior bypass surgery 12.8% 10.1% Infarct location Anterior 45.6% 40.5% Inferior 38.0% 40.5% Lateral 5.0% 2.5% Indeterminate 11.4% 16.5% Killip class I 55.7% 57.0% II 8.9% 10.1% III 7.6% 5.1% IV 27.8% 27.8%
p Value* NS NS NS NS
NS 0.07 NS NS NS NS NS NS NS‡
NS†
IRA Left anterior descending Left circumflex Right coronary artery Bypass graft Intra-aortic balloon pump Glycoprotein IIb/IIIa inhibitor PCI of the IRA Angioplasty Stenting Unsuccessful PCI of the second vessel (n ⫽ 79) Angioplasty Stenting Unsuccessful PCI of the third vessel (n ⫽ 6) Angioplasty Stenting
Multivessel PCI (n ⫽ 79)
Controls (n ⫽ 79)
45.6%
44.3%
19.0% 29.1% 6.3% 39.7%
22.8% 26.6% 6.3% 43.0%
NS
59.5%
62.0%
NS
27.8% 70.9% 1.3%
53.1% 45.6% 1.3%
⬍0.001 ⬍0.001 NS
p Value* NS†
22.8% 72.1% 5.1%
33.3% 66.7%
*NS, p ⬎0.10; †across distributions of categories.
*NS, p ⬎0.10; †median (25th, 75th percentiles); ‡across the distribution of categories.
TABLE 3 Angiographic Core Laboratory Analysis
Coronary stents were used during PCI of the IRA in more patients in the multivessel PCI group (Table 2). Intra-aortic balloon pumps and glycoprotein IIb/ IIIa inhibitors were used in a similar proportion of patients from each group. Angiograms were available for core laboratory review from 58 patients in the multivessel PCI group and 63 patients in the control group (Table 3). Normal flow was reestablished in the IRA in similar proportions of patients in the multivessel PCI and control groups. Nonculprit vessel PCI was successful in most of the cases, but was unsuccessful in 2 patients with chronic total occlusions (3%). Analysis of clinical outcomes through 30 days showed that patients who underwent multivessel PCI had a nonsignificantly higher incidence of mortality in both the rescue PCI and primary PCI subgroups (Table 4). An increased risk of stroke was present in patients from the multivessel PCI group who underwent primary PCI. The frequency of the composite end point of death, reinfarction, re-PCI, or bypass surgery at 6 months was similar among the multivessel PCI and control patients in the rescue PCI and primary PCI subgroups (Table 5). Most repeat revascularization procedures occurred between 30 days and 6 months after acute PCI (Table 5). Indications for repeat PCI in the multivessel PCI group included restenosis of a nonculprit lesion (n ⫽ 5), restenosis of the IRA (n ⫽ 1), and recurrent ischemia caused by a noninfarct vessel lesion not treated during the initial procedure (n ⫽ 1). Indications for repeat PCI in the control group included restenosis of the IRA (n ⫽ 5), staged PCI of lesions in nonculprit
IRA Pre-PCI stenosis (%)* (range) Vessel diameter (mm)* (range) Final TIMI flow grade Grade 0 or 1 Grade 2 Grade 3 Dissection Distal embolization Side branch closure Noninfarct vessels Pre-PCI stenosis (%)* (range) Vessel diameter (mm)* (range) Lesion length (mm)* (range) Final TIMI flow grade Grade 0 or 1 Grade 2 Grade 3 Dissection Distal embolization Side-branch closure
Multivessel PCI (n ⫽ 58)
Controls (n ⫽ 63)
100 (88–100)
100 (89–100)
3.0 (2.6–3.3)
2.9 (2.6–3.4)
10.4% 5.2% 84.4% 3.4% 1.7% 1.7%
4.8% 15.9% 79.3% 12.7% 4.8% 1.6%
76 (67–95) 2.9 (2.6–3.2) 7.0 (5.0–9.4)
3.5% 0% 96.5% 8.8% 3.5% 1.8%
*Median (25th, 75th percentiles). TIMI ⫽ Thrombolysis In Myocardial Infarction.
vessels (n ⫽ 2), and recurrent ischemia caused by a nonculprit lesion (n ⫽ 1). A trend for a higher adjusted likelihood of mortality was present at 30 days in the multivessel PCI group (odds ratio [OR] 2.72, 95% confidence interval [CI] BRIEF REPORTS
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acute angiography after fibrinolysis, enhanced noninfarct zone function and the absence of multivessel Rescue PCI Primary PCI disease in the noninfarct territory were significant predictors of improved survival.7 Similarly, multivesControls Multivessel Controls Multivessel sel disease predicted an increased risk of mortality and Outcome (n ⫽ 18) (n ⫽ 11) (n ⫽ 61) (n ⫽ 68) reduced global left ventricular function after AMI, so Death* 16.7% 18.2% 11.5% 22.1% simultaneous revascularization of severe lesions in Reinfarction 0% 0% 0% 5.9% nonculprit vessels may improve acute left ventricular Coronary artery 5.6% 0% 0% 2.9% bypass mechanical function and outcomes.8,9 Multivessel PCI surgery may also contribute to cost savings by reducing the Repeat PCI 0% 0% 3.3% 2.9% need for staged revascularization procedures. The poComposite 22.2% 18.2% 14.8% 25.0% tential benefits of multivessel PCI may be mitigated, Serious 5.6% 9.1% 4.9% 8.8% bleeding however, by an increased risk of procedural compliStroke† 0% 0% 0% 10.3% cations and nephrotoxicity from a larger contrast load. Patients with multivessel disease and AMI compli*p ⬎0.10; †p ⫽ 0.01. cated by cardiogenic shock may derive selective benefit from simultaneous nonculprit artery PCI. After TABLE 5 Six-Month Clinical Outcomes the onset of shock, coronary perfuRescue PCI Primary PCI sion pressure decreases to both the infarct and noninfarct zones, and Controls Multivessel Controls Multivessel global myocardial dysfunction reOutcome (n ⫽ 18) (n ⫽ 11) p Value* (n ⫽ 61) (n ⫽ 68) p Value sults. Recanalization of the IRA may Death 16.7% 18.2% NS 16.4% 25.0% NS not improve cardiac output and left Reinfarction 0% 0% 1.6% 8.8% 0.07 ventricular function significantly in Coronary artery 11.2% 9.1% NS 0% 4.4% 0.10 bypass patients with cardiogenic shock if sesurgery vere lesions of nonculprit vessels Repeat PCI 0% 9.1% NS 11.5% 8.8% 0.63 that compromise flow to the noninComposite 27.8% 27.3% NS 27.9% 35.3% NS farct zone are untreated.7,10 Patients Serious 5.6% 9.1% NS 4.9% 8.8% NS bleeding in cardiogenic shock found to have Stroke 5.6% 0% NS 0% 10.3% 0.01 multivessel disease during acute angiography often undergo emergency *NS, p ⬎0.10. bypass surgery, but delays associated with surgical revascularization may limit myocardial salvage.11 Multivessel PCI with coronary stents and glycoprotein 0.90 to 8.22, p ⫽ 0.08). The likelihood of the composite end point at 30 days, however, was not signif- IIb/IIIa inhibitors therefore may be an alternative icantly higher in the multivessel PCI group (OR 1.98, treatment strategy for patients with AMI complicated 95% CI 0.78 to 5.02, p ⫽ 0.15). The risks of mortality by cardiogenic shock who are found to have multives(hazard ratio 1.60, 95% CI 0.79 to 3.25, p ⫽ 0.19) and sel disease during acute angiography. Multiple limitations were present in this analysis. the composite end point (hazard ratio 1.40, 95% CI 0.80 to 2.47, p ⫽ 0.24) at 6 months were higher for the The small sample size limited the statistical comparmultivessel PCI group, but no significant difference ison of event rates, so this study had limited power to detect a true treatment difference. We were unable to was present. verify whether investigators included all consecutive ••• Simultaneous nonculprit vessel PCI for patients cases of multivessel PCI for AMI, so a selection bias undergoing mechanical reperfusion for AMI has not for high-risk characteristics may have influenced the been closely studied because percutaneous revascular- outcomes of the multivessel PCI group and may not ization has traditionally been restricted to the IRA to have been accounted for in this case-control study. limit procedural complications. An early study of pa- The high frequency of stroke in the multivessel PCI tients found to have multivessel disease during pri- patients who underwent primary PCI supports this mary angioplasty showed favorable survival rates with conclusion, because there was no clear pathophysioa strategy of staged percutaneous revascularization logic explanation for an increased risk of stroke in this after acute recanalization of the IRA.6 Our results cohort. Finally, we were unable to collect all angiorepresent the first published experience with simulta- grams, so the success rate and procedural complicaneous nonculprit artery PCI and show that multivessel tions of multivessel PCI were not completely evaluPCI may be associated with an increased risk of ad- ated. verse outcomes among patients with AMI treated with This exploratory analysis shows that multivessel mechanical reperfusion. Simultaneous nonculprit artery PCI may have po- PCI during mechanical reperfusion for AMI can tential benefits not uncovered in this retrospective, be accomplished with good procedural success but exploratory analysis. Among patients who underwent may be associated with an increased risk of adverse TABLE 4 Thirty-day Clinical Outcomes
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clinical outcomes compared with PCI restricted to the IRA. Prospective, randomized trials are needed to determine the optimal revascularization strategy for patients with AMI who are found to have multivessel disease during acute angiography. 1. Kornowski R, Mehran R, Satler LF, Pichard AD, Kent KM, Greenberg A, Mintz GS, Hong MK, Leon MB. Procedural results and late clinical outcomes following multivessel coronary stenting. J Am Coll Cardiol 1999;33:420 – 426. 2. Moussa I, Reimers B, Moses J, Di Mario C, Di Francesco L, Massimo F, Colombo A. Long-term angiographic and clinical outcome of patients undergoing multivessel coronary stenting. Circulation 1997;96:3873–3879. 3. Hannan EL, Racz MJ, Arani DT, Ryan TJ, Walford G, McCallister BD. Shortand long-term mortality for patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2000;36:1194 –1201. 4. DeGeare VS, Stone GW, Grines L, Brodie BR, Cox DA, Garcia E, Wharton TP, Boura JA, O’Neill WW, Grines CL. Angiographic and clinical characteristics associated with increased in-hospital mortality in elderly patients with acute myocardial infarction undergoing percutaneous intervention (a pooled analysis of the Primary Angioplasty in Myocardial Infarction trials). Am J Cardiol 2000;86: 30 –34.
5. Lee KL, Woodlief LH, Topol EJ, Weaver WD, Betriu A, Col J, Simoons M,
Aylward P, Van de Werf F, Califf RM. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction: results from an international trial of 41,021 patients. Circulation 1995;91:1659 –1668. 6. Kahn JK, Rutherford BD, McConahay DR, Johnson WL, Giorgi LV, Shimshak TM, Ligon RW, Hartzler GO. Results of primary angioplasty for acute myocardial infarction in patients with multivessel coronary artery disease. J Am Coll Cardiol 1990;16:1089 –1096. 7. Grines CL, Topol EJ, Califf RM, Stack RS, George BS, Kereiakes D, Boswick JM, Kline E, O’Neill WW. Prognostic implications and predictors of enhanced regional wall motion of the noninfarct zone after thrombolysis and angioplasty therapy of acute myocardial infarction. Circulation 1989;80:245–253. 8. Kahn JL, O’Keefe JH Jr, Rutherford BD, McConahay DR, Johnson WL, Giorgi LV, Shimshak TM, Ligon RW, Hartzler GO. Timing and mechanism of in-hospital and late death after primary coronary angioplasty during acute myocardial infarction. Am J Cardiol 1990;66:1045–1048. 9. Muller DW, Topol EJ, Ellis SG, Sigmon KN, Califf RM. Multivessel coronary artery disease: a key predictor of short-term prognosis after reperfusion therapy for acute myocardial infarction. Am Heart J 1991;121:1042–1049. 10. Santoro GM, Buonamici P. Reperfusion therapy in cardiogenic shock complicating acute myocardial infarction. Am Heart J 1999;138:126 –131. 11. Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley JD, Buller CE, Jacobs AK, Slater JN, Col J, McKinlay SM, LeJemtel TH. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. N Engl J Med 1999;341:625– 634.
Effect of Pravastatin in Mildly Hypercholesterolemic Young Men on Serum Matrix Metalloproteinases Anne Kalela, MSc, Reijo Laaksonen, MD, PhD, Terho Lehtima ¨ ki, MD, PhD, Tommi A. Koivu, BM, Matti Ho ¨ yhtya ¨ , PhD, Tuula Janatuinen, MD, Perttu Po ¨ lla ¨ nen, MSc, Risto Vesalainen, MD, PhD, Pekka Saikku, MD, PhD, Juhani Knuuti, MD, PhD, and Seppo T. Nikkari, MD, PhD linical trials have demonstrated the efficacy of hydroxymethylglutaryl coenzyme A reductase inC hibitors (statins) in lowering elevated levels of total and low-density lipoprotein (LDL) cholesterol and decreasing the risk for clinical coronary events.1,2 Statins have been suggested to have benefits beyond lipid lowering. They have been shown to stabilize atherosclerotic plaques either by decreasing inflammation or promoting repair, or both.3 The anti-inflammatory effects comprise reduction of monocyte adhesion to endothelium4 and decrease of macrophage infiltrates.5,6 Statins have also been shown to inhibit matrix metalloproteinase (MMP-9) secretion by macrophages in vitro.7 Circulating levels of MMP-9 are influenced by a recently found polymorphism in the promoter region of the MMP-9 gene, where a cytosine From the Department of Medical Biochemistry, University of Tampere Medical School, Tampere; Department of Internal Medicine, Tampere University Hospital, Tampere; Department of Clinical Pharmacology, University of Helsinki, Helsinki; Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Centre for Laboratory Medicine, Tampere University Hospital and University of Tampere Medical School, Tampere; Diabor Ltd, Oulu; Turku PET Center, University of Turku, Turku; and National Public Health Institute, Oulu, Finland. The study was supported by grants from the Medical Research Fund of the Tampere University Hospital, Tampere, the Finnish Foundation for Cardiovascular Research, Helsinki, and Ida Montin Foundation, Helsinki, Finland. Dr. Nikkari’s address is: Department of Medical Biochemistry, University of Tampere Medical School, FIN-33014 University of Tampere, Finland. E-mail: [email protected]. Manuscript received November 17, 2000; revised manuscript received and accepted February 8, 2001. ©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 88 July 15, 2001
(C) to thymidine (T) transition at position 1562 results in higher promoter activity.8 This genetic variation has been shown to be associated with severity of angiographically assessed coronary artery disease. An association between progression of coronary artery disease and matrix metalloproteinase-3 (stromelysin-1) promoter polymorphism has also been reported.9 In the present study, we investigated the effect of pravastatin on serum MMP-9 concentration in clinically healthy men. We also studied the effect of C to 1562-T polymorphism on serum MMP-9 concentrations. •••
The study was a randomized, double-blind and placebo-controlled trial with 2 treatment groups: pravastatin (40 mg/day for 6 months, n ⫽ 24) and placebo (n ⫽ 26). The mean age of the subjects was 35 ⫾ 4 years. At baseline, serum total cholesterol levels were normal or mildly elevated (mean 5.5 ⫾ 0.8 mmol/L; 212 ⫾ 31 mg/dl). Participants did not receive any other drug therapy or antioxidants, and they were instructed to adhere to their normal diet during the study. All subjects had normal electrocardiograms at rest. Blood samples for biochemical analyses were collected after an overnight fast before and after the treatment period. Samples were stored at ⫺70°C until analyzed. Plasma triglycerides, total cholesterol, and high-density lipoprotein (HDL) cholesterol were analyzed colorimetrically using a Cobas Integra 700 au0002-9149/01/$–see front matter PII S0002-9149(01)01616-2
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Inquiries were made to multiple international centers experienced with mechanical reperfusion for AMI to identify consecutive patients who underwent multivessel PCI during the initial acute procedure from June 1995 to June 1999. Patients who underwent multivessel PCI were defined as those who had simultaneous dilation of ⱖ1 lesion in a nonculprit artery during either primary PCI or rescue PCI. Patients who underwent PCI of branch vessels of the IRA or the left main coronary artery were excluded. Control cases were randomly selected from each site during the same time period and were defined as patients with multivessel disease (ⱖ1 coronary stenosis ⱖ50% in a nonculprit vessel) in whom PCI was limited to the IRA. Control cases were equally matched to index cases of multivessel PCI on the basis of age (⫾5 years) and Killip class, because these characteristics have been shown to be among the strongest predictors of 30-day mortality in patients with AMI undergoing mechanical reperfusion.3,4 From the Duke Clinical Research Institute, Durham, North Carolina; Cleveland Clinic Foundation, Cleveland, Ohio; Hospital Gregorio Maranon, Madrid, Spain; Chaim Sheba Medical Center, TelHashomer, Israel; Lindner Center and Ohio Heart Health Center, Cincinnati, Ohio; Ziekenhuis De Weezenlanden, Zwolle, The Netherlands; Moses Cone Hospital, Greensboro, North Carolina; and William Beaumont Hospital, Royal Oak, Michigan. Dr. Roe’s address is: Duke Clinical Research Institute, P.O. Box 17969, Durham, North Carolina 27715. E-mail: [email protected]. Manuscript received October 4, 2000; revised manuscript received and accepted February 14, 2001.
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©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 88 July 15, 2001
Cine angiograms were reviewed in a central core laboratory by 1 investigator (FAC) for all patients in whom films were available. Clinical end points through 6 months were reported by each investigator and included death, reinfarction, repeat PCI, bypass surgery, bleeding, and stroke. The prespecified primary end point was a composite of death, reinfarction, repeat PCI, or bypass surgery. Reinfarction was defined as recurrent chest pain associated with new ischemic electrocardiographic changes or re-elevation of serum cardiac markers. Repeat PCI and bypass surgery included any additional revascularization procedure that occurred within 6 months of acute PCI. Serious bleeding included any significant hemorrhage that required transfusion of blood products. Stroke was defined as any neurologic event considered to represent a hemorrhagic or nonhemorrhagic stroke by the investigator. Kaplan-Meier methods were used to estimate event rates through 6 months for the multivessel PCI and control groups. Event rates were analyzed separately in patients who underwent primary PCI and rescue PCI. Comparisons of 30-day event rates between the groups were performed using the 2-sided Fisher’s exact test given the relatively small sample size and number of events. Comparisons of 6-month event rates between the groups were performed using the log-rank test. Multivariable logistic regression (30day events) and Cox proportional-hazards analyses (6-month events) were performed to determine whether event rates differed among the multivessel PCI and control groups after adjusting for age, Killip class, and infarct location, given the important prognostic implications of these variables.3–5 A total of 79 cases of multivessel PCI were collected from 8 international centers and were equally matched to control cases. Baseline clinical characteristics of the 2 groups were similar (Table 1). Primary PCI was performed in 68 of 79 patients who underwent multivessel PCI (86%) and in 61 of 79 control patients (75%). The remaining patients underwent rescue PCI after treatment with intravenous fibrinolytic therapy failed to achieve sufficient reperfusion. The time to treatment from symptom onset to the first balloon inflation was ⬍6 hours in 60% of the patients in the multivessel PCI group and in 44% of patients in the control group. The indication for performing multivessel PCI was hemodynamic instability in 39% of patients, routine in 31%, other in 12%, persistent ischemia after PCI of the IRA in 10%, and unknown in 8%. 0002-9149/01/$–see front matter PII S0002-9149(01)01615-0
TABLE 1 Baseline Characteristics Multivessel PCI (n ⫽ 79)
TABLE 2 Procedural Characteristics Controls (n ⫽ 79)
Age (yrs)† (range) 64 (53–74) 63 (56–73) Men 77.2% 65.8% Systolic blood pressure 115 (90–130) 116 (90–131) (mm Hg)† (range) Heart rate 82 (70–98) 80 (70–96) (beats/min)† (range) Diabetes mellitus 37.2% 29.1% Current smoking 37.2% 24.1% Hypertension 53.8% 64.6% Prior stroke 5.2% 6.3% Prior congestive heart 7.7% 3.8% failure Prior AMI 35.9% 21.5% Prior PCI 17.5% 13.9% Prior bypass surgery 12.8% 10.1% Infarct location Anterior 45.6% 40.5% Inferior 38.0% 40.5% Lateral 5.0% 2.5% Indeterminate 11.4% 16.5% Killip class I 55.7% 57.0% II 8.9% 10.1% III 7.6% 5.1% IV 27.8% 27.8%
p Value* NS NS NS NS
NS 0.07 NS NS NS NS NS NS NS‡
NS†
IRA Left anterior descending Left circumflex Right coronary artery Bypass graft Intra-aortic balloon pump Glycoprotein IIb/IIIa inhibitor PCI of the IRA Angioplasty Stenting Unsuccessful PCI of the second vessel (n ⫽ 79) Angioplasty Stenting Unsuccessful PCI of the third vessel (n ⫽ 6) Angioplasty Stenting
Multivessel PCI (n ⫽ 79)
Controls (n ⫽ 79)
45.6%
44.3%
19.0% 29.1% 6.3% 39.7%
22.8% 26.6% 6.3% 43.0%
NS
59.5%
62.0%
NS
27.8% 70.9% 1.3%
53.1% 45.6% 1.3%
⬍0.001 ⬍0.001 NS
p Value* NS†
22.8% 72.1% 5.1%
33.3% 66.7%
*NS, p ⬎0.10; †across distributions of categories.
*NS, p ⬎0.10; †median (25th, 75th percentiles); ‡across the distribution of categories.
TABLE 3 Angiographic Core Laboratory Analysis
Coronary stents were used during PCI of the IRA in more patients in the multivessel PCI group (Table 2). Intra-aortic balloon pumps and glycoprotein IIb/ IIIa inhibitors were used in a similar proportion of patients from each group. Angiograms were available for core laboratory review from 58 patients in the multivessel PCI group and 63 patients in the control group (Table 3). Normal flow was reestablished in the IRA in similar proportions of patients in the multivessel PCI and control groups. Nonculprit vessel PCI was successful in most of the cases, but was unsuccessful in 2 patients with chronic total occlusions (3%). Analysis of clinical outcomes through 30 days showed that patients who underwent multivessel PCI had a nonsignificantly higher incidence of mortality in both the rescue PCI and primary PCI subgroups (Table 4). An increased risk of stroke was present in patients from the multivessel PCI group who underwent primary PCI. The frequency of the composite end point of death, reinfarction, re-PCI, or bypass surgery at 6 months was similar among the multivessel PCI and control patients in the rescue PCI and primary PCI subgroups (Table 5). Most repeat revascularization procedures occurred between 30 days and 6 months after acute PCI (Table 5). Indications for repeat PCI in the multivessel PCI group included restenosis of a nonculprit lesion (n ⫽ 5), restenosis of the IRA (n ⫽ 1), and recurrent ischemia caused by a noninfarct vessel lesion not treated during the initial procedure (n ⫽ 1). Indications for repeat PCI in the control group included restenosis of the IRA (n ⫽ 5), staged PCI of lesions in nonculprit
IRA Pre-PCI stenosis (%)* (range) Vessel diameter (mm)* (range) Final TIMI flow grade Grade 0 or 1 Grade 2 Grade 3 Dissection Distal embolization Side branch closure Noninfarct vessels Pre-PCI stenosis (%)* (range) Vessel diameter (mm)* (range) Lesion length (mm)* (range) Final TIMI flow grade Grade 0 or 1 Grade 2 Grade 3 Dissection Distal embolization Side-branch closure
Multivessel PCI (n ⫽ 58)
Controls (n ⫽ 63)
100 (88–100)
100 (89–100)
3.0 (2.6–3.3)
2.9 (2.6–3.4)
10.4% 5.2% 84.4% 3.4% 1.7% 1.7%
4.8% 15.9% 79.3% 12.7% 4.8% 1.6%
76 (67–95) 2.9 (2.6–3.2) 7.0 (5.0–9.4)
3.5% 0% 96.5% 8.8% 3.5% 1.8%
*Median (25th, 75th percentiles). TIMI ⫽ Thrombolysis In Myocardial Infarction.
vessels (n ⫽ 2), and recurrent ischemia caused by a nonculprit lesion (n ⫽ 1). A trend for a higher adjusted likelihood of mortality was present at 30 days in the multivessel PCI group (odds ratio [OR] 2.72, 95% confidence interval [CI] BRIEF REPORTS
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acute angiography after fibrinolysis, enhanced noninfarct zone function and the absence of multivessel Rescue PCI Primary PCI disease in the noninfarct territory were significant predictors of improved survival.7 Similarly, multivesControls Multivessel Controls Multivessel sel disease predicted an increased risk of mortality and Outcome (n ⫽ 18) (n ⫽ 11) (n ⫽ 61) (n ⫽ 68) reduced global left ventricular function after AMI, so Death* 16.7% 18.2% 11.5% 22.1% simultaneous revascularization of severe lesions in Reinfarction 0% 0% 0% 5.9% nonculprit vessels may improve acute left ventricular Coronary artery 5.6% 0% 0% 2.9% bypass mechanical function and outcomes.8,9 Multivessel PCI surgery may also contribute to cost savings by reducing the Repeat PCI 0% 0% 3.3% 2.9% need for staged revascularization procedures. The poComposite 22.2% 18.2% 14.8% 25.0% tential benefits of multivessel PCI may be mitigated, Serious 5.6% 9.1% 4.9% 8.8% bleeding however, by an increased risk of procedural compliStroke† 0% 0% 0% 10.3% cations and nephrotoxicity from a larger contrast load. Patients with multivessel disease and AMI compli*p ⬎0.10; †p ⫽ 0.01. cated by cardiogenic shock may derive selective benefit from simultaneous nonculprit artery PCI. After TABLE 5 Six-Month Clinical Outcomes the onset of shock, coronary perfuRescue PCI Primary PCI sion pressure decreases to both the infarct and noninfarct zones, and Controls Multivessel Controls Multivessel global myocardial dysfunction reOutcome (n ⫽ 18) (n ⫽ 11) p Value* (n ⫽ 61) (n ⫽ 68) p Value sults. Recanalization of the IRA may Death 16.7% 18.2% NS 16.4% 25.0% NS not improve cardiac output and left Reinfarction 0% 0% 1.6% 8.8% 0.07 ventricular function significantly in Coronary artery 11.2% 9.1% NS 0% 4.4% 0.10 bypass patients with cardiogenic shock if sesurgery vere lesions of nonculprit vessels Repeat PCI 0% 9.1% NS 11.5% 8.8% 0.63 that compromise flow to the noninComposite 27.8% 27.3% NS 27.9% 35.3% NS farct zone are untreated.7,10 Patients Serious 5.6% 9.1% NS 4.9% 8.8% NS bleeding in cardiogenic shock found to have Stroke 5.6% 0% NS 0% 10.3% 0.01 multivessel disease during acute angiography often undergo emergency *NS, p ⬎0.10. bypass surgery, but delays associated with surgical revascularization may limit myocardial salvage.11 Multivessel PCI with coronary stents and glycoprotein 0.90 to 8.22, p ⫽ 0.08). The likelihood of the composite end point at 30 days, however, was not signif- IIb/IIIa inhibitors therefore may be an alternative icantly higher in the multivessel PCI group (OR 1.98, treatment strategy for patients with AMI complicated 95% CI 0.78 to 5.02, p ⫽ 0.15). The risks of mortality by cardiogenic shock who are found to have multives(hazard ratio 1.60, 95% CI 0.79 to 3.25, p ⫽ 0.19) and sel disease during acute angiography. Multiple limitations were present in this analysis. the composite end point (hazard ratio 1.40, 95% CI 0.80 to 2.47, p ⫽ 0.24) at 6 months were higher for the The small sample size limited the statistical comparmultivessel PCI group, but no significant difference ison of event rates, so this study had limited power to detect a true treatment difference. We were unable to was present. verify whether investigators included all consecutive ••• Simultaneous nonculprit vessel PCI for patients cases of multivessel PCI for AMI, so a selection bias undergoing mechanical reperfusion for AMI has not for high-risk characteristics may have influenced the been closely studied because percutaneous revascular- outcomes of the multivessel PCI group and may not ization has traditionally been restricted to the IRA to have been accounted for in this case-control study. limit procedural complications. An early study of pa- The high frequency of stroke in the multivessel PCI tients found to have multivessel disease during pri- patients who underwent primary PCI supports this mary angioplasty showed favorable survival rates with conclusion, because there was no clear pathophysioa strategy of staged percutaneous revascularization logic explanation for an increased risk of stroke in this after acute recanalization of the IRA.6 Our results cohort. Finally, we were unable to collect all angiorepresent the first published experience with simulta- grams, so the success rate and procedural complicaneous nonculprit artery PCI and show that multivessel tions of multivessel PCI were not completely evaluPCI may be associated with an increased risk of ad- ated. verse outcomes among patients with AMI treated with This exploratory analysis shows that multivessel mechanical reperfusion. Simultaneous nonculprit artery PCI may have po- PCI during mechanical reperfusion for AMI can tential benefits not uncovered in this retrospective, be accomplished with good procedural success but exploratory analysis. Among patients who underwent may be associated with an increased risk of adverse TABLE 4 Thirty-day Clinical Outcomes
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clinical outcomes compared with PCI restricted to the IRA. Prospective, randomized trials are needed to determine the optimal revascularization strategy for patients with AMI who are found to have multivessel disease during acute angiography. 1. Kornowski R, Mehran R, Satler LF, Pichard AD, Kent KM, Greenberg A, Mintz GS, Hong MK, Leon MB. Procedural results and late clinical outcomes following multivessel coronary stenting. J Am Coll Cardiol 1999;33:420 – 426. 2. Moussa I, Reimers B, Moses J, Di Mario C, Di Francesco L, Massimo F, Colombo A. Long-term angiographic and clinical outcome of patients undergoing multivessel coronary stenting. Circulation 1997;96:3873–3879. 3. Hannan EL, Racz MJ, Arani DT, Ryan TJ, Walford G, McCallister BD. Shortand long-term mortality for patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2000;36:1194 –1201. 4. DeGeare VS, Stone GW, Grines L, Brodie BR, Cox DA, Garcia E, Wharton TP, Boura JA, O’Neill WW, Grines CL. Angiographic and clinical characteristics associated with increased in-hospital mortality in elderly patients with acute myocardial infarction undergoing percutaneous intervention (a pooled analysis of the Primary Angioplasty in Myocardial Infarction trials). Am J Cardiol 2000;86: 30 –34.
5. Lee KL, Woodlief LH, Topol EJ, Weaver WD, Betriu A, Col J, Simoons M,
Aylward P, Van de Werf F, Califf RM. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction: results from an international trial of 41,021 patients. Circulation 1995;91:1659 –1668. 6. Kahn JK, Rutherford BD, McConahay DR, Johnson WL, Giorgi LV, Shimshak TM, Ligon RW, Hartzler GO. Results of primary angioplasty for acute myocardial infarction in patients with multivessel coronary artery disease. J Am Coll Cardiol 1990;16:1089 –1096. 7. Grines CL, Topol EJ, Califf RM, Stack RS, George BS, Kereiakes D, Boswick JM, Kline E, O’Neill WW. Prognostic implications and predictors of enhanced regional wall motion of the noninfarct zone after thrombolysis and angioplasty therapy of acute myocardial infarction. Circulation 1989;80:245–253. 8. Kahn JL, O’Keefe JH Jr, Rutherford BD, McConahay DR, Johnson WL, Giorgi LV, Shimshak TM, Ligon RW, Hartzler GO. Timing and mechanism of in-hospital and late death after primary coronary angioplasty during acute myocardial infarction. Am J Cardiol 1990;66:1045–1048. 9. Muller DW, Topol EJ, Ellis SG, Sigmon KN, Califf RM. Multivessel coronary artery disease: a key predictor of short-term prognosis after reperfusion therapy for acute myocardial infarction. Am Heart J 1991;121:1042–1049. 10. Santoro GM, Buonamici P. Reperfusion therapy in cardiogenic shock complicating acute myocardial infarction. Am Heart J 1999;138:126 –131. 11. Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley JD, Buller CE, Jacobs AK, Slater JN, Col J, McKinlay SM, LeJemtel TH. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. N Engl J Med 1999;341:625– 634.
Effect of Pravastatin in Mildly Hypercholesterolemic Young Men on Serum Matrix Metalloproteinases Anne Kalela, MSc, Reijo Laaksonen, MD, PhD, Terho Lehtima ¨ ki, MD, PhD, Tommi A. Koivu, BM, Matti Ho ¨ yhtya ¨ , PhD, Tuula Janatuinen, MD, Perttu Po ¨ lla ¨ nen, MSc, Risto Vesalainen, MD, PhD, Pekka Saikku, MD, PhD, Juhani Knuuti, MD, PhD, and Seppo T. Nikkari, MD, PhD linical trials have demonstrated the efficacy of hydroxymethylglutaryl coenzyme A reductase inC hibitors (statins) in lowering elevated levels of total and low-density lipoprotein (LDL) cholesterol and decreasing the risk for clinical coronary events.1,2 Statins have been suggested to have benefits beyond lipid lowering. They have been shown to stabilize atherosclerotic plaques either by decreasing inflammation or promoting repair, or both.3 The anti-inflammatory effects comprise reduction of monocyte adhesion to endothelium4 and decrease of macrophage infiltrates.5,6 Statins have also been shown to inhibit matrix metalloproteinase (MMP-9) secretion by macrophages in vitro.7 Circulating levels of MMP-9 are influenced by a recently found polymorphism in the promoter region of the MMP-9 gene, where a cytosine From the Department of Medical Biochemistry, University of Tampere Medical School, Tampere; Department of Internal Medicine, Tampere University Hospital, Tampere; Department of Clinical Pharmacology, University of Helsinki, Helsinki; Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Centre for Laboratory Medicine, Tampere University Hospital and University of Tampere Medical School, Tampere; Diabor Ltd, Oulu; Turku PET Center, University of Turku, Turku; and National Public Health Institute, Oulu, Finland. The study was supported by grants from the Medical Research Fund of the Tampere University Hospital, Tampere, the Finnish Foundation for Cardiovascular Research, Helsinki, and Ida Montin Foundation, Helsinki, Finland. Dr. Nikkari’s address is: Department of Medical Biochemistry, University of Tampere Medical School, FIN-33014 University of Tampere, Finland. E-mail: [email protected]. Manuscript received November 17, 2000; revised manuscript received and accepted February 8, 2001. ©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 88 July 15, 2001
(C) to thymidine (T) transition at position 1562 results in higher promoter activity.8 This genetic variation has been shown to be associated with severity of angiographically assessed coronary artery disease. An association between progression of coronary artery disease and matrix metalloproteinase-3 (stromelysin-1) promoter polymorphism has also been reported.9 In the present study, we investigated the effect of pravastatin on serum MMP-9 concentration in clinically healthy men. We also studied the effect of C to 1562-T polymorphism on serum MMP-9 concentrations. •••
The study was a randomized, double-blind and placebo-controlled trial with 2 treatment groups: pravastatin (40 mg/day for 6 months, n ⫽ 24) and placebo (n ⫽ 26). The mean age of the subjects was 35 ⫾ 4 years. At baseline, serum total cholesterol levels were normal or mildly elevated (mean 5.5 ⫾ 0.8 mmol/L; 212 ⫾ 31 mg/dl). Participants did not receive any other drug therapy or antioxidants, and they were instructed to adhere to their normal diet during the study. All subjects had normal electrocardiograms at rest. Blood samples for biochemical analyses were collected after an overnight fast before and after the treatment period. Samples were stored at ⫺70°C until analyzed. Plasma triglycerides, total cholesterol, and high-density lipoprotein (HDL) cholesterol were analyzed colorimetrically using a Cobas Integra 700 au0002-9149/01/$–see front matter PII S0002-9149(01)01616-2
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