Methods

The design and results of HORIZONS-AMI have been described in detail. In brief, HORIZONS-AMI was a prospective, open-label, multicenter, dual-arm, 2 × 2 factorial, randomized trial in patients with STEMI presenting <12 hours after symptom onset undergoing primary percutaneous coronary intervention (PCI). A first randomization was performed in 3,602 patients to the direct thrombin inhibitor bivalirudin alone versus heparin plus a glycoprotein IIb/IIIa inhibitor (1:1 randomization), and then, a second randomization was performed in 3,006 patients to the TAXUS Express paclitaxel-eluting stent versus an equivalent Express bare metal stent (3:1 randomization; Boston Scientific, Natick, Massachusetts). Clinical follow-up was performed at 30 days, 6 months, 1 year, and then annually for 3 years.

Of the 3,602 patients in HORIZONS-AMI, patients with LAD culprit lesions treated with primary PCI were included in the present substudy. Two independent cardiologists (NK, SJB) who were blinded to the clinical data categorized patients into 2 groups on the basis of coronary angiography as follows: (1) patients with an LAD wrapping around LV apex (wrap-around LAD) and (2) patients with an LAD not wrapping around LV apex (non–wrap-around LAD). Wrap-around LAD was defined as an LAD reaching beyond the LV apex to supply the apical inferior aspect of the heart; non–wrap-around LAD was defined as an LAD terminating at or before the LV apex ( Figure 1 ). Patients who did not obtain Thrombolysis in Myocardial Infarction (TIMI) flow grade >1 during the PCI procedure were excluded from the present study. In addition, all angiograms were reviewed in detail at an independent core laboratory (Cardiovascular Research Foundation, New York, New York) without knowledge of treatment assignment. Specifically, qualitative and quantitative coronary angiography analyses were performed for TIMI flow grade and myocardial blush grade (MBG) at baseline, before stent, and after intervention (final) using standard definitions. MBG was assessed according to the semiquantitative densitometric method that evaluates the maximal intensity of contrast penetrating the infarct zone in comparison to unaffected territories.

Examples of anatomic left anterior descending artery categorization. Left : An LAD wrapping around the LV apex (wrap-around LAD). Right : An LAD not wrapping around the LV apex (non–wrap-around LAD).

The ratio of the peak creatine kinase-MB value within 48 hours from the STEMI onset/local laboratory upper limit of normal was used because multiple commercially available assays for creatine kinase-MB were used in the present multicenter study. LV mural thrombi detected by echocardiography, left ventriculography, cardiac magnetic resonance imaging, or cardiac computed tomography were reported by each site. Adverse clinical events including death, reinfarction, stroke, and stent thrombosis were adjudicated by a Clinical Events Committee blinded to patient allocation. Severe heart failure, defined as the New York Heart Association classes III or IV, was site reported but not centrally adjudicated. Diagnosis of stent thrombosis was based on the Academic Research Consortium criteria. Major adverse cardiac events (MACE) were defined as death, stroke, or culprit lesion–related definite or probable stent thrombosis.

Baseline characteristics and clinical outcomes were analyzed on a patient level, whereas angiographic characteristics were analyzed on a lesion level. Categorical variables are summarized as frequencies and compared between groups using the chi-square or Fisher’s exact test. Continuous variables are displayed as median and interquartile range and compared using the Wilcoxon rank-sum statistics. Time-to-event outcomes including MACE, death, stroke, and stent thrombosis are summarized as Kaplan–Meier estimates of cumulative incidence and compared between groups with the log-rank test. Because the onset date of heart failure was not available, heart failure was evaluated as a binary variable (i.e., not time dependent). Cox proportional hazards regression models were conducted to determine the independent predictors for MACE, death, stroke, and stent thrombosis. Candidates for independent predictors for Cox proportional hazard models included wrap-around LAD, age, diabetes mellitus, history of myocardial infarction, dysrhythmia, 3-vessel disease with left main disease, proximal LAD culprit lesion location, final TIMI flow grade <3, total length of implanted stents, final lesion minimum lumen diameter, paclitaxel-eluting stent use, bivalirudin use, clopidogrel 600-mg loading dose, and statin use at discharge. To determine the independent predictors for severe heart failure, multiple logistic regression analysis was conducted including wrap-around LAD, age, diabetes mellitus, history of myocardial infarction, and proximal LAD culprit lesion location. Intraobserver and interobserver variability for the diagnosis of a wrap-around LAD was measured with the κ test of concordance. Statistical significance was set at p <0.05. Statistical analyses were performed using SAS version 9.1.3 (SAS Institute, Cary, North Carolina).

Results

Of the 3,602 patients enrolled in HORIZONS-AMI, 193 patients were treated medically and 64 patients had bypass surgery or delayed PCI. Thus, primary PCI was performed in 3,345 patients. Of them, 1,276 patients with a culprit lesion in the LAD were enrolled in the present substudy and categorized as wrap-around LAD or non–wrap-around LAD. Because of poor quality of angiograms or postprocedure TIMI flow grade 0 to 1, in which it was not possible to assess termination of the LAD, 181 patients (14.2%) could not be classified. Of the remaining 1,095 patients, 871 patients (79.5%) had a wrap-around LAD, and 224 patients (20.5%) had a non–wrap-around LAD. Interobserver (NK vs SJB) and intraobserver (NK, baseline vs 4 months later) variabilities in classification were 0.84 and 0.84, respectively.

Baseline clinical features, in patients with versus without a wrap-around LAD, are provided in Table 1 . The prevalence of hypertension, Killip class ≥II, and major dysrhythmia were higher in patients with a wrap-around LAD than in those with a non–wrap-around LAD. LV mural thrombi tended to be more frequently observed in patients with a wrap-around LAD than in those with a non–wrap-around LAD; as a result, there was a similar trend in the frequency of warfarin use at discharge.

Angiographic lesion findings are provided in Table 2 . Preprocedural lesion length and postprocedure stent length were longer in lesions with versus without a wrap-around LAD. Preprocedural and postprocedural TIMI flow grade and postprocedural MBG were comparable between the 2 groups. Angiographic LV ejection fraction was significantly lower in patients with a wrap-around LAD than in those with a non–wrap-around LAD.

Long-term outcomes through 3 years are provided in Table 3 and Figure 2 . The Kaplan–Meier estimate cumulative incidence of MACE (p = 0.002), death (p = 0.052), stroke (p = 0.12), and stent thrombosis (p = 0.047) were greater in patients with a wrap-around LAD than in those with a non–wrap-around LAD. The frequency of heart failure was significantly higher in patients with a wrap-around LAD than in those with a non–wrap-around LAD (p = 0.03).

Time-to-event curves through 3 years. Time-to-event curves through 3 years are shown for major adverse cardiac events (death, stroke, and culprit lesion–related definite or probable stent thrombosis) (top) , death (middle) , and stent thrombosis (bottom) according to wrap-around LAD (solid lines) versus non–wrap-around LAD (dotted lines) . Incidence of MACE (12.7% vs 5.4%, hazard ratio [HR] 2.45, p = 0.002), death (6.6% vs 3.2%, HR 2.14, p = 0.052), and stroke (1.9% vs 0.5%, HR 4.31, p = 0.12) was higher in patients with a wrap-around LAD versus those without a wrap-around LAD. Event rates represent the Kaplan–Meier estimates; p values are based on the log-rank test. CI = confidence interval.

Multivariate Cox proportional hazard analysis showed that a wrap-around LAD independently and significantly predicted MACE ( Table 4 ). Multivariate logistic regression analysis also indicated that a wrap-around LAD significantly predicted severe heart failure ( Table 5 ) and independent of lesion location in the LAD (proximal vs mid vessel).

Table 4

Cox proportional hazards analysis for predictors of adverse cardiac events at 3 years

Variable	Univariable Analysis			Multivariable Analysis
	Hazard Ratio	95% Confidence Interval	p Value	Hazard Ratio	95% Confidence Interval	p Value
To predict MACE
Wrap-around LAD	2.50	1.44–4.33	0.001	2.18	1.16–4.09	0.02
Age (10-year increase)	1.04	1.03–1.04	<0.0001	1.17	0.99–1.38	0.07
Diabetes mellitus	1.64	1.33–2.02	<0.0001
History of myocardial infarction	1.76	1.39–2.22	<0.0001	2.11	1.23–3.63	0.007
Major dysrhythmia	1.73	1.15–2.61	0.009	2.43	1.28–4.65	0.007
3 Vessel with left main disease	2.40	1.48–3.89	0.0004
Final TIMI flow grade 3	0.57	0.45, 0.72	<0.0001
Proximal LAD culprit lesion	1.26	0.97–1.63	0.09
Paclitaxel-eluting stent use	1.01	0.80-1.27	0.93
Bivalirudin use	0.87	0.73-1.04	0.14
Final lesion minimum lumen diameter (1-mm increase)	0.73	0.64–0.85	<0.0001
Statin use at discharge	0.45	0.32–0.62	<0.0001	0.36	0.19–0.68	0.002
To predict death
Wrap-around LAD	2.31	1.11–4.80	0.02	1.68	0.71–3.97	0.24
Age (10-year increase)	1.08	1.07–1.09	<0.0001	1.74	1.33–2.28	<0.0001
Major cardiac rhythm or rate disturbance	2.36	1.48–3.75	0.0003	3.83	1.74–8.39	0.001
3 Vessel with left main disease	3.64	2.16–6.12	<0.0001
Final TIMI flow grade 3	0.47	0.35 – 0.62	<0.0001
Statin use at discharge	0.31	0.20–0.46	<0.0001	0.39	0.16–0.93	0.04
To predict stroke
Wrap-around LAD	2.37	0.55–10.21	0.25	4.11	0.54–31.00	0.17
Age (10-year increase)	1.04	1.02–1.06	0.0004
History of myocardial infarction	2.02	1.13–3.63	0.02	3.76	1.23–11.54	0.02
To predict stent thrombosis
Wrap-around LAD	2.35	1.01–5.46	0.047	2.35	0.93–5.93	0.07
History of myocardial infarction	1.36	0.88–2.08	0.16	2.32	1.09–4.94	0.03
Total length of implanted stents	1.01	1.00–1.02	0.003
Final lesion minimum lumen diameter (1-mm increase)	0.80	0.62–1.03	0.08
Clopidogrel 600 mg loading dose	0.70	0.53–0.94	0.02	0.54	0.31–0.93	0.03

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