Abciximab-facilitated percutaneous coronary intervention and long-term survivala prospective single-center registry
Sorin J. Brenera,*,
Stephen G. Ellisa,
Jakob Schneidera,
Carolyn Apperson-Hansenb and
Eric J. Topola
a Department of Cardiology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk F-25, Cleveland,OH 44195, USA
b Department of Biostatistics, Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk F-25, Cleveland, OH 44195, USA
* Corresponding author. Tel.: +1-216-444-0732; fax: +1-216-444-8050
E-mail address: breners{at}ccf.org
Received 25 October 2002;
accepted 29 October 2002
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Abstract
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Aims To identify predictors of use of abciximab and evaluate the long-term survival after percutaneous coronary intervention with or without abciximab in a broad spectrum of patients.
Methods We prospectively evaluated, in a dedicated registry, the 4-year survival of patients undergoing percutaneous revascularization and the treatment with or without abciximab, using the Social Security Death Index.
Results Among 10,471 patients treated between 2/1/1995 and 12/31/2001, 5655 received abciximab and 4816 did not. Propensity score analysis (c-statistic 0.83) identified the following variables to be independently associated with abciximab use: later date of procedure, stent use, acute or recent infarction, increasing lesion complexity, vein graft intervention, hyperlipidemia, normal renal function, male gender and decreasing age. Procedural success was higher in the abciximab group, 93 vs. 89%,
. Unadjusted KaplanMeyer survival analysis demonstrated a strong trend for improved survival in the abciximab group at 4 years, 86.3 vs. 84.7%,
. In the 7533 patients with acute coronary syndromes (ACS), the respective values were 86.0 vs. 83.6%,
. Multivariate Cox proportional hazard analysis identified increasing age, significant left ventricular dysfunction or congestive heart failure, chronic renal insufficiency and diabetes mellitus as main predictors of mortality. Abciximab was independently associated with improved survival only in patients with ACS (adjusted HR 0.87, 95% confidence interval, 0.811.00,
). Abciximab use was associated with a higher rate of access site hematoma (2.8 vs. 1.5%) and blood product transfusion (6.8% vs. 4.8%),
for both.
Conclusion Abciximab use improves procedural success and is associated with lower 4-year mortality in patients with ACS, for whom it should be strongly considered. A lesser effect is seen in patients without high-risk characteristics.
List of Abbreviations: CABG=Coronary artery bypass grafting CCF=Cleveland Clinic Foundation CI=Confidence interval EPIC=Evaluation of c7E3 for the prevention of ischemic complications EPILOG=Evaluation of PTCA to improve long-term outcome by c7E3 glycoprotein receptor blockade EPISTENT=Evaluation of platelet IIb/IIIa inhibitor for stenting GP IIb/IIIa=Platelet glycoprotein IIb/IIIa receptor HR=Hazard ratio MI=Myocardial infarction PCI=Percutaneous coronary intervention RCT=Randomized clinical trial TIMI flow grade=Thrombolysis in myocardial infarction flow grade
Key Words: Abciximab Percutaneous coronary intervention Survival
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1. Introduction
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Inhibition of fibrinogen-mediated platelet aggregation with antagonists of the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor has profoundly reduced the incidence of major adverse cardiac events at 6 months after percutaneous coronary intervention (PCI).1 Abciximab,2 a monoclonalchimeric antibody directed against the GP IIb/IIIa receptor, was the first agent tested in patients undergoing PCI. A vast body of evidence was accumulated in a short period of time from numerous large clinical trials, demonstrating that abciximab reduces the incidence of death or myocardialinfarction (MI) by 3075% in the immediate period after PCI, as well as at 13 years following the procedure, independent of the device used for revascularization.39 Although there was consistent benefit in all subgroups of patients analyzed, it appeared that patients at higher risk for adverse events have the greatest reduction in ischemic events. This impressive benefit led to widespread use in the US, where today catheterization laboratories use GP IIb/IIIa blockade in over 65% ofpatients undergoing PCI. Nevertheless, it remained unclear whether the data accumulated in randomized clinical trials apply to patients with different baseline and procedural characteristics treated in routine practice. Thus, we compared the long-term survival of patients treated with and without abciximab since the commercial availability of the drug at a large tertiary institution, and identified the clinical and angiographic characteristics associated with its use.
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2. Methods
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The Cleveland Clinic Foundation (CCF) Interventional Registry prospectively collects demographic, procedural and outcome information on all patients undergoing PCI.
2.1. Patient population
All patients with a valid Social Security number undergoing first PCI at our institution from2/1/1995 to 12/31/2001 were included if: (a) they did not participate in a clinical trial involvingGP IIb/IIIa antagonists; (b) they did not receive aGP IIb/IIIa antagonist other than abciximab; and(c) abciximab was administered immediatelybefore the beginning of the procedure. The use of abciximab was completely at the discretion ofthe operator and was not guided by algorithmsof treatment.
2.2. Definition of variables
The endpoints for which statistical analyses were performed were the use of abciximab and death of any cause, determined from the Social Security Death Index.
Acute MI was defined as ST-segment deviation and/or positive cardiac markers within 24h of PCI, while recent MI refers to MI at 17 days before PCI. Clinical shock was defined as severe hypotension (<90mmHg) and/or need for inotropic support.Dyslipidemia was defined as a total cholesterol >240mg/dl (>200mg/dl since 1/1/1999) and/or treatment with lipid-lowering agents. Diabetes mellitus was defined as hyperglycemia treated with diet, insulin or oral hypoglycemic agents. Hypertension was defined as blood pressure >180/100 (>140/90 since 1/1/1999) or treatment with antihypertensive therapy. Family history of early symptomatic coronary disease was defined as MI in first-degree relative before the age of 55. Procedural success was defined as <50% residual stenosis with Thrombolysis in Myocardial Infarction (TIMI) 3 flow in all treated lesions. Post-PCI non-Q-wave MIentailed elevation of CKMB above 30ng/ml (4x upper limit) and Q-wave MI referred to development of new diagnostic Q-waves with CKMBelevation.
2.3. Statistical analysis
The customary descriptive statistics were used to summarize the data. A propensity model was developed for the use of abciximab.10 Potential predictors for the model included patient history and procedure date, as well as pre- and procedural-clinical and angiographic information. Whenappropriate, transformations and interactions were also considered. To develop the propensity model, a directed, forward, stepwise multivariable logistic regression process was used, which was confirmed by bootstrapping techniques and assessment of goodness of fit. The propensity score generated from the model was used in the long-term mortality analysis to balance the inherent differences between the patients, who did and did not receive abciximab. In addition, a parsimonious model was developed from the propensity model to identify the clinically relevant characteristics of patients treated with abciximab. The following variables were entered in the model used to determine the propensity score for abciximab use: procedure date, age, gender, classical risk factors for coronary disease, acute MI, recent MI, unstableangina, severe heart failure, chronic renalinsufficiency, peripheral vascular disease, pre-treatment with heparin, signs of cardiogenic shock, extent of coronary disease, ejection fraction,mitral regurgitation, worst-lesion complexity,IABP pre-PCI, stent use, recent use of fibrinolytics, left anterior descending artery (LAD) PCI, graftPCI, bifurcation or ostial lesion and priorrevascularization.
The KaplanMeyer method was used to estimate long-term survival. In addition, a Cox proportional hazards model was developed. The variablesentered in the regression model were derived from bootstrap analysis (forcing in the model the use of abciximab and propensity score for its use) and included: procedure date, age, acute MI, diabetes mellitus, hypertension, smoking, history of early MI in family, dyslipidemia, prior MI or coronary artery bypass grafting (CABG), intraaortic counterpulsation, renal insufficiency, peripheral vascular disease, heart failure class, shock, heart rate, blood pressure, treatment with heparin or fibrinolytics before PCI, left ventricular ejection fraction (LVEF), severe mitral regurgitation, extent of coronary disease, proximal LAD PCI, stent implantation, graft PCI, statin therapy after PCI and MI after PCI. Bootstrapping techniques were used to confirm the Cox model.
Statistical testing was conducted using two-sided alternatives with a type I error level of 0.05, using the SAS®package.
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3. Results
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During the study period, 15,197 PCI procedures were performed. After excluding patients undergoing a second procedure, or receiving a GP IIb/IIIa inhibitor other than abciximab, 10,471 patients remained eligible for analysis. There were 5655 patients who did, and 4816 who did not, receive abciximab. The use of abciximab increased from 14% in 1995 to 87% in 2001. The patient characteristics are shown in Table 1. The most important differences between the groups were the two-fold higher rate of acute MI and the significant excess of intraaortic balloon counterpulsation and proximal LAD PCI in the abciximab group.
3.1. Propensity score analysis for abciximab use
The model had a c-statistic of 0.83
. The average propensity scores were 0.70±0.22;comptd;;center;stack;;;;;6;;;;;width> . and 0.35±0.25 for the abciximab
and noabciximab
groups, respectively,
. There was no heterogeneity among deciles of scores with respect to ratio of expected vs.observed cases of abciximab administration. The three strongest predictors of abciximab use were acute MI (adjusted odd ratio (OR) 2.9, 95% confidence interval (CI) 2.33.7), recent MI (adjusted OR, 2.3 [2.02.7]) and stent use (OR, 2.0 [1.82.3]). There was an increased use of abciximabover the study period, adjusted OR, 1.8 (1.71.9) for each additional year. Other important factors associated with the choice of abciximab were high lesion complexity (ACC/AHA class), graft PCI and lack of chronic renal insufficiency.
3.2. In-hospital outcome
Procedural success was significantly higher in the abciximab group, 93 vs. 89%,
. In a model adjusting for variables associated with procedural success, abciximab use was independently predictive of procedural success (OR 1.5, 95% CI 1.21.7,
). The incidence of major ischemic complications within 7 days after PCI is shown in Table 2 Despite marked imbalances in baseline characteristics, including a two-fold higher rate of acute or recent MI, there were no significant differences in the incidence of early major ischemic events. The incidence of bleeding complications was higher in the abciximab group. Large hematoma (>5cm) was noted in 2.8 vs. 1.5%
and blood product transfusion occurred in 6.8 vs. 4.8%
.
3.3. Long-term survival
There were 1504 (14.3% of the study population) deaths. The unadjusted cumulative rates of survival in the two groups are shown in Fig. 1. There wasa strong trend toward improved 4-year survivalin the abciximab group, 86.3 vs. 84.7%,
, corresponding to 11% relative risk reduction (RRR).
The patients with acute MI
exhibited a striking survival advantage with abciximab, 82.8 vs. 66.0%,
. (Figs. 2;comptd;;center;stack;;;;;6;;;;;width> ) Similarly, among allpatients with an acute coronary syndrome (ACS)
, defined as acute or recent MI or unstable angina, abciximab increased 4-year survival from 83.6 to 86.0%,
, or 15% RRR. (Fig. 3;comptd;;center;stack;;;;;6;;;;;width> ) Among diabetic patients
, the cumulative 4-year survival was 79.1 and 76.7%, respectively,
, while in those receiving stents it was 86.7% vs. 85.0%, respectively,
.
In order to correct for the imbalances in clinical presentation, baseline characteristics and time of enrollment in registry, Cox proportional hazard model analysis was performed. The independent predictors of long-term mortality are shown inTable 3. Abciximab use was not independentlyassociated with mortality (hazard ratio (HR) 0.98 [0.91.1], [
]. In contrast, the same model applied to patients with ACS revealed an adjusted HR of 0.87 (0.81.0),
(Fig. 4;comptd;;center;stack;;;;;6;;;;;width> ), Supporting the fact that higher risk patients, identified by a higher propensity score for abciximab use, derive greater benefit from it, is the observation that among the 2249 patients with the highest quartile of propensity score (0.74±0.04), recipients ofabciximab had a significantly superior 3-yearsurvival compared with those not treated withabciximab, 90.3 vs. 86.3%,
(Fig. 5;comptd;;center;stack;;;;;6;;;;;width> ).

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Fig. 5 Unadjusted survival curves in patients in the highest quartile of propensity score for abciximab use.
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4. Discussion
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Our prospectively collected data and extended follow-up provide the single largest reportedexperience with abciximab-facilitated PCI outside of clinical trials. Unlike in randomized clinical trials (RCT), where the randomization processensures a balanced study population according to eligibility criteria, this study takes into account the selection process that influences the fact as to which patients will be treated with certain therapies, according to the expected benefit from theintervention and perceived risk of adverse events.
The key findings are that a bolus and 12-hinfusion of abciximab, begun immediately prior to PCI, are associated with an independent and significant survival advantage in patients with ACS. Over a 4-year period, two to three deaths were prevented for every 100 patients treated, translating into a significant benefit, considering the large numberof procedures performed over such a period. Thepatients at the highest risk derive the greatest benefit. We also investigated the propensity to administer abciximab and identified a model with excellent discriminating properties. The excess morbidity related to bleeding complications isnot negligible, resulting in an excess of twotransfusions per 100 patients treated.
The comparison of RCTs with routine clinical practice further emphasizes the striking differences between the cohorts, as demonstrated by their event rate in Table 4. Recently, Topol et al. presented the long-term outcome of nearly 6000 patients enrolled in the EPI-trials.11 There was a substantial and consistent reduction in mortality in the three trials at 3 years, which in aggregate was statistically significant, and clinically relevant, 6.4% for placebo vs. 5.0% for abciximab, HR 0.78 (0.630.98),
. The 3-year mortality rate in our study was at least two-fold of that reported in the EPI-trials and by 4 years the absolute reduction in mortality was nearly doubled. Our data corroborate the observation9,11,12 that only 7% ofpatients who subsequently died had a peri-procedural infarction, although this event was a significant independent predictor of late mortality. We did not show a nominal reduction in the incidence of moderate to large MIs after PCI (>4x upper limit of normal at our institution), as demonstrated in numerous RCTs. This finding needs to becautiously interpreted in view of the marked differences in baseline characteristics and acuitybetween the two groups. Because the long-term beneficial effect of abciximab cannot be solely explained by higher procedural success, alternative mechanisms may be playing a role. Abciximabreduces the inflammatory response followingPCI,13 thus promoting a more favorable response to arterial injury and less platelet and leukocyte deposition. Blockade of additional integrins (vitronectin and MAC-1) may prevent smooth muscle and leukocyte migration, which play an integral role in plaque growth and subsequent rupture.1416 The salutary effect of abciximab on the inflammatory response following reperfusion in acute MI17 may explain the marked benefit observed in this group and the dissociation between peri-procedural MI and late death.
Our results match well with the recent reports from the National Cardiovascular Data Registry. Among 100,292 patients treated between 1998 and 2000, the average age was 64 years, 10% had acute MI and 62% had ACS. The in-hospital mortalitywas 1.4% and emergency CABG occurred in 1.9%.18 The rate of use of GP IIb/IIIa inhibitors was not reported. In contrast, these data challenge the recent observations from the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial19 with respect to lack of beneficial effect of abciximab, whilesupporting previous observations regarding themarked benefit of abciximab in patients with acute MI.2023
Furthermore, this report addresses the roles of RCTs and large registries in implementing therapeutic paradigms. The former identifies beneficial interventions in relatively homogenous populations at lower risk, while the latter tests the paradigmin more heterogeneous populations, at higher risk. As the risk of cardiovascular death increases, it becomes increasingly more difficult to single out the beneficial role of one intervention applied for a short time, particularly with longer follow-up. These data conform to the findings of beneficial effect of abciximab in PCI and underscore themany confounding influences inherent to clinical registries.
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5. Limitations
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As always in observational studies, numerousfactors, which are not measured or recorded (such as better paradigms of therapy overtime), regardless of PCI outcome, affect the allocation of treatment and may confound our analyses. There is no information on the cause of death in these patients, and thus we may overestimate the contribution of coronary disease to death in this population. There was no reliable and consistent collection of data on the long-term incidence of MI or repeated revascularization, use of other medications, and we did not evaluate and compare the effect of other GP IIb/IIIa inhibitors on outcome because of very short follow-up. Finally, treatment with abciximab is associated with more frequent bleeding complications whose exact contribution to adverse outcome could not be evaluated in this study.
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6. Conclusions
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Despite these limitations, we conclude that initiation of abciximab immediately before PCI isassociated with increased procedural success and improved survival in patients with ACS. The data highlight the difference between large registries and RCTs in defining clinical benefit because of the heterogeneity of the population studied and the multitude of factors affecting long-term survival.
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Acknowledgments
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This research was supported in part by a research grant from Eli Lilly & Co., Indianapolis, IN.
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References
|
---|
- Kong DF, Califf RM, Miller DP et al. Clinical outcomesof therapeutic agents that block the platelet glycoprotein IIb/IIIa integrin in ischemic heart disease. Circulation. 1998;98:28292835.[Abstract/Free Full Text]
- Coller BS. Platelet GPIIb/IIIa antagonists: the first anti-integrin receptor therapeutics. J Clin Investig. 1997;100:S57S60.[Medline]
- The EPIC Investigators. Use of monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med. 1994;330:956961.[Abstract/Free Full Text]
- The EPILOG Investigators. Platelet glycoprotein IIb/IIIareceptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med. 1997;336:16891696.[Abstract/Free Full Text]
- The CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet. 1997;349:14291435.[CrossRef][Medline]
- The EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein IIb/IIIa blockade. Lancet. 1998;352:8792.[Medline]
- Lincoff AM, Tcheng JE, Califf RM et al. Sustained suppression of ischemic complications of coronary intervention by platelet GP IIb/IIIa blockade with abciximab: one-year outcome in the EPILOG trial. Evaluation in PTCA to improve long-term outcome with abciximab GP IIb/IIIa blockade. Circulation. 1999;99:19511958.[Abstract/Free Full Text]
- Topol EJ, Ferguson JJ, Weisman HF et alfor the EPIC Investigator Group. Long-term protection from myocardial ischemic events in a randomized trial of brief integrin beta3 blockade with percutaneous coronary intervention. Evaluation of platelet IIb/IIIa inhibition for prevention of ischemic complication. JAMA. 1997;278:479484.[Abstract]
- Topol EJ, Mark DB, Lincoff AM et alfor the EPISTENT Investigators. Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicentre randomised trial. Evaluation of platelet IIb/IIIa inhibitor for stenting. Lancet. 1999;354:20192024.[CrossRef][Medline]
- Blackstone EH. Comparing apples and oranges. J Thorac Cardiovasc Surg. 2002;123:815.[Free Full Text]
- Topol EJ, Lincoff AM, Kereiakes DJ et al. Multi-year follow-up of abciximab therapy in three randomized, placebo-controlled trials of percuatenous coronary revascularization. Am J Med. 2002;113:106.
- Anderson KM, Califf RM, Stone GW et al. Long-term mortality benefit with abciximab in patients undergoing percutaneous coronary intervention. J Am Coll Cardiol. 2001;37:20592065.[CrossRef][Medline]
- Lincoff AMMD, Kereiakes DJMD, Mascelli MAP et al. Abciximab suppresses the rise in levels of circulatinginflammatory markers after percutaneous coronary revascularization. Circulation. 2001;104:163167.[Abstract/Free Full Text]
- Tam SH, Sassoli PM, Jordan RE et al. Abciximab (ReoPro, chimeric 7E3 Fab) demonstrates equivalent affinity and functional blockade of glycoprotein IIb/IIIa and alpha(v)beta3 integrins. Circulation. 1998;98:10851091.[Abstract/Free Full Text]
- Thompson RD, Wakelin MW, Larbi KY et al. Divergent effects of platelet-endothelial cell adhesion molecule-1 andbeta 3 integrin blockade on leukocyte transmigrationin vivo. J Immunol. 2000;165:426434.[Abstract/Free Full Text]
- Kaul DK, Tsai HM, Liu XD et al. Monoclonal antibodies to alphaVbeta3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor. [see comments]Blood. 2000;95:368374.[Abstract/Free Full Text]
- Neumann FJ, Zohlnhofer D, Fakhoury L et al. Effect of glycoprotein IIb/IIIa receptor blockade on platelet-leukocyte interaction and surface expression of the leukocyte integrin Mac-1 in acute myocardial infarction. J Am Coll Cardiol. 1999;34:14201426.[CrossRef][Medline]
- Anderson HV, Shaw RE, Brindis RG et al. A contemporary overview of percutaneous coronary interventions. The American College of CardiologyNational Cardiovascular Data Registry (ACCNCDR). J Am Coll Cardiol. 2002;39:10961103.[CrossRef][Medline]
- Stone GW, Grines CL, Cox DA et al. Comparison ofangioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med. 2002;346:957966.[Abstract/Free Full Text]
- Neumann FJ, Blasini R, Schmitt C et al. Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction. Circulation. 1998;98:26952701.[Abstract/Free Full Text]
- Brener SJ, Barr LA, Burchenal JE et al. Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. ReoPro and Primary PTCA Organization andRandomized Trial (RAPPORT) Investigators. Circulation. 1998;98:734741.[Abstract/Free Full Text]
- Montalescot G, Barragan P, Wittenberg O et al. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med. 2001;344:18951903.[Abstract/Free Full Text]
- Lefkovits J, Ivanhoe RJ, Califf RM et al. Effects of platelet glycoprotein IIb/IIIa receptor blockade by a chimeric monoclonal antibody (abciximab) on acute and six-monthoutcomes after percutaneous transluminal coronary angioplasty for acute myocardial infarction. EPIC investigators. Am J Cardiol. 1996;77:10451051.[CrossRef][Medline]