Long-Term Outcomes of Coronary and Carotid Artery Disease Revascularization in the FRIENDS Study

Objectives The aim of this study is to assess long-term-outcomes of patients with concomitant CAD and COD treated with different revascularization strategies. Background Multisite artery disease is common and patients with combined disease have poor prognosis. The best therapeutic strategy for patients with concomitant carotid obstructive disease (COD) and coronary artery disease (CAD) remains controversial. Methods This observational registry enrolled, between January 2006 and December 2012, 1022 consecutive patients from high volume institutions with concomitant CAD and COD suitable for endovascular, surgical, or hybrid revascularization in both territories selected by consensus of a multidisciplinary team. Results The cumulative incidence of 5-year major cardiovascular events (MACCE) including cardiovascular death, myocardial infarction (MI), or stroke in the overall population was 12%. The incidence of 5-year MACCE was not statistically different in the surgical, endovascular, or hybrid patients group (10.1% vs. 13.0% vs. 13.2%, P = .257, respectively). However, the hybrid group exhibited rates of myocardial infarction, chronic kidney disease, and cumulative incidence of all clinical events higher than the surgical group. After propensity score matching, the incidence of 5-year MACCE was similar in the three groups (13.0% vs. 15.0% vs. 16.0%, p = .947, respectively). Conclusions An individualized revascularization approach of patients with combined CAD and COD yields very good results at long-term follow-up, despite the high risk of this multilevel population even when the baseline clinical features are equalized.


Introduction
Multisite artery disease (MSAD) is defined by the simultaneous presence of clinically relevant atherosclerotic lesions in at least two major vascular territories [1]. Patients with MSAD are regularly encountered in clinical practice and their prognosis is poorer than that of patients with just one territory affected [2][3][4][5]; however, recommendations for the treatment of such patients are inconsistent. Indeed, in general the treatment strategy is decided case by case within the context of a dedicated multidisciplinary team and most experts agree on focusing first on the symptomatic vascular territory. In particular, patients with coexisting coronary artery disease (CAD) and carotid obstructive disease (COD) represent a complex and high-risk population, in whom revascularization can be performed by surgical, endovascular, or hybrid strategies (the latest being a combined approach that includes both forms of treatment).
The absence of dedicated randomised trials or large registries designed to assess advantages, shortcomings, and longterm-outcomes of patients with concomitant CAD and COD treated with different revascularization strategies add further uncertainty on the management of this rapidly growing subset of high-risk patients [6].

Materials and Methods
FRIENDS is an Italian, spontaneously generated, independent and no profit working group whose members are engaged at high volume Italian institutions and are committed to cardiovascular care and work with a shared intention under common coordination.
. . Patient Population and Data Collection. Between January 2006 and December 2012, 1022 consecutive patients with concomitant CAD and COD suitable for endovascular, surgical or hybrid revascularization in one or both territories have been enrolled in the FRIENDS registry. From January 2006 all consecutive patients who satisfied all inclusion and exclusion criteria were enrolled in our prospective registry. The database was designed to collect uniformly all individual dataset from each participating center. All patients included in this study gave informed consent to undergo the proposed treatment and complete the prespecified follow-up program. The ethical committees of each participating institution approved aims and methods of this study under the coordination of the University of Verona ethical committee (CESC no. 2246). Clinical follow-up was obtained prospectively by either clinical visit or telephone contact. The 30-day and 1year results of this research have previously been published [7][8][9]. Here we report the results of long-term clinical followup in the overall population. (ii) Diagnosis of concomitant CAD and COD with indication to revascularization. All patients, regardless of the treatment strategy applied, should show a significant concomitant vascular disease in both the territories. CAD and COD definitions were previously reported [1,10,11]. Briefly, CAD with indication to treatment was diagnosed by selected coronary angiography if a stenosis >70% was present in at least one of the major coronary branches or >50% in the left main; COD with indication to treatment was diagnosed in presence of a stenosis involving the internal carotid artery ≥70% in neurologically asymptomatic patients and ≥50% in neurologically symptomatic patients. When carotid artery stenting (CAS) was indicated, lesion severity was assessed also by selective angiography. Patients were considered symptomatic if an ipsilateral cerebrovascular event (including transient ischemic attack, amaurosis fugax, ischemic stroke, or retinal infarction) had occurred within the prior 6 months.
(ii) Lack of informed consent.
(iv) Impossibility to obtain follow-up information.
. . Revascularization Strategies and Techniques. Revascularization strategies and techniques have been previously published [7][8][9] and here briefly summarized. Each center appointed a committee of experts in cardiac and vascular medicine (cardiovascular team) that jointly evaluated each case to assess the best therapeutic indication in these specific patient settings [12]. A cardiovascular team includes cardiac and vascular surgeons and clinical and interventional cardiologists. Opinions of neurologists and radiologists were obtained as needed. Coronary and carotid interventions were mandated either by symptoms as well as by the indication consistent with current guidelines [11,[13][14][15]. Interventions were considered simultaneous when performed in the same procedure or within the same day. Staged interventions were intended as those performed within a range of 1 to 45 days from the first procedure. The sequence of intervention was established by the cardiovascular team considering the neurological and/or cardiovascular symptoms and the anatomical characteristics of the atherosclerotic lesions after diagnostic angiography. Coronary artery bypass grafting (CABG) was performed "on pump" in 70% of cases. Carotid endoarterectomy (CEA) was performed according to conventional techniques preferring local anesthesia when possible. According to standard clinical practice, percutaneous coronary interventions (PCI) was performed via a 6-or 7-F sheath in the femoral or radial artery. Stent placement during PCI followed nearly 100% of balloon dilatation and, in patients with multivessel CAD, the most complete degree of revascularization was attempted unless contraindicated by severe comorbidities or particularly unfavorable anatomy. The carotid artery stenting (CAS) procedures were performed via a 7-, 8-, or 9-F sheath in the femoral artery using different kinds of stents and distal protection devices according to individual clinical and anatomical characteristics as recommended by experts [16].
. . Antithrombotic Regimen. All patients treated by endovascular procedures received anticoagulation with unfractioned heparin and antiplatelet therapy with aspirin before catheterization. A loading dose of a thienopyridine Journal of Interventional Cardiology 3 was administered before percutaneous coronary intervention or CAS, and a dual antiplatelet therapy was advised for a minimum of 1 and maximum 12 months according to the clinical presentation and the type of stent implanted, as recommended by current guidelines [11,13]. In patients needing chronic oral anticoagulation the antithrombotic regimen was managed according to the CHA2DS2-VASc score [17]. In general, a peri-intervention short bridge with low-molecular weight heparin was associated with antiplatelet therapy maintained by one month only, followed by an association of warfarin and aspirin, or dual antiplatelet therapy thereafter.
For surgical candidates, CEA and CABG were performed under aspirin alone, and in patients needing chronic oral anticoagulation the same bridging strategy described before was implemented without association of a thienopyridine. In the hybrid group, patients undergoing percutaneous coronary intervention after CEA started the dual antiplatelet therapy 48 hours after surgery. Those undergoing CABG after CAS in a simultaneous approach were pretreated with aspirin and unfractioned heparin and received a bolus of the short-term IIb-IIIa glycoprotein inhibitor tirofiban during the procedure and the iv infusion was continued until 6 hours before cardiac surgery. If CABG followed CAS in a staged procedure, cardiac surgery was performed after 1 month of dual antiplatelet therapy, under aspirin alone, and 5 days after thienopyridine suspension.
. . Study Endpoints. Prespecified primary outcomes measure of the analysis was the 5-year incidence of major cardiac and cerebrovascular events (MACCE), including cardiovascular death, myocardial infarction (MI), or stroke, according to the three different revascularization strategies. Secondary endpoints were the 5-year incidence of the individual components of the primary endpoint, any death and chronic kidney disease (CKD) or need of hemodialysis. Endpoints definitions were previously reported [7][8][9]. In particular myocardial infarction included all spontaneous MI diagnosed by an increase in biomarker values above the upper limit of normal (creatine kinase-myocardial band fraction or, preferably, cardiac troponin), reinfarction (defined as recurrence of symptoms together with ST-segment elevation or new left bundle branch block and an increase in cardiac enzymes after stable or decreasing values), or periprocedural MI (diagnosed by elevation of cardiac biomarker values in patients with normal baseline values). After August 2012, all the MIs were reclassified, and the new one accounted according to the third universal definition of MI [18]. Chronic kidney disease was diagnosed according to the National Kidney Foundation criteria, based on the calculated glomerular filtration rate [19]. Events included in the endpoints were adjudicated by the same independent expert for all the centres to be assessed in a blinded way.
. . Statistical Methods. Continuous data are expressed as means and standard deviations. Categorical data are presented as absolute values and percentages. Differences between endovascular versus either the surgical and the A Cox regression, univariate first and then multivariate, was performed on primary end point including all baseline parameters stated in Table 2 and kind of treatment to establish the impact of each factor ( Table 4).
As the three subgroups differed significantly regarding many clinical variables, a propensity score analysis was additionally used to reduce confounding factors between categories. The scoring itself was produced by means of a logistic regression between treatment and all baseline clinical characteristics stated in Table 1; best neighbour method was then used to obtain a one to one, one hundred patients group per each of the three category of population. Efficacy of the process was then tested again and proved satisfactory as shown below.
The association between clinical and treatment variables and MACCE at 5-year follow-up was assessed by means of a Cox proportional hazards regression analysis.  A probability value of less than or equal to 5% was considered significant. SPSS (version 21, IBM Corporation, Somers, New York) and Excel (Microsoft, Redmond, Washington) were used for data analysis.

Results
From January 2006 to December 2012, 1022 consecutive patients with combined CAD and COD were enrolled in the four hospitals being part of the FRIENDS study group. All clinical and procedural data were prospectively entered in the FRIENDS database and retrospectively analysed. Clinical diagnosis at admission are summarized in Table 1. Descriptions of type of treatment applied were previously published [9] and the comparison of unadjusted baseline clinical characteristics of the patients included in the three different treatment groups is summarized in Table 2.
Follow-up was completed in 92% of patients. Median follow-up was 62.1 months (interquartile range 20.9 months), with 554 of the patients (54.2%) being followed up for at least 5 years. Patients received OMT including statins at maximum tolerated dose, beta-blockers, and ACE inhibitors or angiotensin receptor inhibitors in the majority of cases (respectively, 81%, 74%, and 65%); only 12% of patients were treated with nitrates to control symptoms. The mean systolic blood pressure at follow-up was 134±15 mmHg with no significant difference between the 3 groups.
. . Unadjusted Comparison of All ree Strategies. Unadjusted comparison of primary and secondary endpoints for the 3 groups is reported in Table 3. The incidence of 5-year MACCE was not significantly different in the surgical, endovascular or hybrid patients group (10.1% vs. 13.0% vs. 13.2%, P = .257, respectively). However, the hybrid group exhibited rates of myocardial infarction and CKD/haemodialysis higher than the surgical group (hazard ratio 2.98, 95% confidence interval 1.12 to 7.95, and P = .02; and hazard ratio 2.54, 95% confidence interval 1.16 to 5.56, and P = .02; respectively). Also the cumulative incidence of all clinical events was higher in the hybrid group than in the surgical group (hazard ratio 1.9, 95% confidence interval 1.2 to 3.2, and P = .006). Although not statistically significant, the  Values are n (%) or mean ± SD. CAD=coronary artery disease; COD= carotid obstructive disease.
incidence of all clinical events was higher in the hybrid group also when compared with the endovascular group (hazard ratio = 0.7, 95% confidence interval 0.4 to 1.1). No other significant difference was detected among groups. Of note, patients undergoing a hybrid revascularization appeared at higher risk than the other two groups; in fact, they had higher rates of bilateral COD, multivessel CAD, acute coronary syndromes, symptomatic carotid stenosis, and lower left ventricle ejection fraction as shown in Table 2. The Kaplan-Meier curves for the 5-year primary and secondary endpoints are shown in Figure 1. Univariate and multivariable Cox regression analyses of potential factors affecting the primary end-point have been performed. At univariate model age, left ventricular ejection fraction and the presence of a diffused disease (bilateral COD and multivessel CAD) were significantly associated with the primary endpoint. Multivariable analysis confirmed only age and left ventricular ejection fraction ad independent predictors of the primary end-point.

. . Propensity-Adjusted
ree-Group Comparison for the Primary and Secondary Endpoints. After propensity score matching, three groups of 100 patients each were selected. The adequacy of the propensity score is confirmed in Table 5, showing that patients of the three groups had similar baseline characteristics. The incidence of clinical events at 5 years and the comparisons among groups in the propensity-matched population are shown in Table 6.
The incidence of 5-year MACCE was similar in the surgical, endovascular, or hybrid patients group (13.0% vs. 15.0% vs. 16.0%, p = .947, respectively). Similarly, no significant difference was detected among groups at the single events analysis. However, although not statistically significant, the incidence of myocardial infarction and CKD/hemodialysis was still higher in the hybrid group (11% and 14%, respectively) than in the surgical (7% and 6%, respectively) or endovascular group (4% and 6%, respectively). The Kaplan-Meier curves for the 5-year primary and secondary endpoints after propensity score matching are shown in Figure 2

Discussion
Multisite artery disease is a severe manifestation of atherosclerosis that involves simultaneously different vascular territories and therefore the function of multiple organs with a consequent negative impact on the quality of life and survival of affected patients. During the last decades, diagnosis of concomitant atherosclerotic disease in different  vascular beds continued to increase because of the prolonged life expectancy, and nowadays patients affected by MSAD represent a daily challenge. The appropriate treatment approach to this disseminated form of atherosclerosis, often associated with several comorbidities, is neither obvious nor easy. Due to the lack of randomized trials and dedicated guidelines, treatment strategies are not standardised and largely depend on expert's consensus, local standards, and habits. Immediate and long-term results even in the best circumstances are strongly dependent on the baseline clinical characteristics that are largely variable in such a complex population.
The FRIENDS study provides a unique opportunity to assess the long-term clinical outcome of a large cohort of patients with MSAD treated according to the best available standards of care and in agreement with the most recent and robust recommendations. The principal observations derived from this study can be summarized as follows.
The long-term incidence of MACCE, ranging between 10.1% and 13.2% at 5 years, is remarkably low despite the    [21] showing an incidence of MACCE of 10% in the surgical group and 12% in the endovascular group after treatment of isolated COD at a median follow-up of 7.4 years. However, it should be remembered that the capture of adverse events may be very different between registries and clinical trials; therefore these results are not fully comparable. Compared to the expected natural clinical evolution of patients included in our study, the low global event rates suggest an effective protective effect of the revascularization techniques and the medical therapy applied thereafter.
Further analysis of the global results indicates that independently of the revascularization strategy, all patients derived similar benefits despite the evident differences in the baseline risk profile. Noteworthy, only age at enrollment and left ventricular ejection fraction, but not the kind of treatment, were independently associated with the primary end-point at multivariate analysis. Indeed, although patients selected for a hybrid strategy were at a higher clinical risk, the long-term outcome is equalized compared to the immediate and one-year results previously reported [7][8][9], confirming the long-term benefits of surgery, in particular CABG in reducing MI and mortality in patients with diffuse CAD. Although some unfavorable outcomes in the highest-risk subgroups persist at 5 years, in particular in terms of MI and worsening of the renal function, these do not attain statistical significance supporting the appropriateness of the initial therapeutic choice.
A prespecified accurate propensity analysis was performed in order to better understand the prognostic impact of the revascularization strategies, regardless of the clinical presentation. As expected, when the baseline clinical features were equalized, the clinical outcomes of the three treatment strategies appear fairly equivalent. In support of this interpretation, most MACCEs occur after three years of treatment, as they were not directly related to the treatment technique but rather to aging and its unavoidable consequences (Figures 1 and 2).
The correct management of patients with multi-level vascular disease is particularly challenging and should be tailored according to a comprehensive medical evaluation and local experience rather than focusing on a determined form of intervention [22]. In the vast majority of cases the "leading organ" is the heart, whereas asymptomatic carotid stenoses are often an incidental finding during routine duplex 8 Journal of Interventional Cardiology ultrasonography as part of the global patient evaluation [23,24]. Similarly, even after effective treatment of the COD, the survival of patients with vascular disease is dictated by cardiac events and renal function, and therefore the treatment of CAD may be more determinant in the long-term survival of these patients. Patients with bilateral severe COD undergoing CABG have an augmented risk of perioperative stroke irrespective of the neurological symptoms, and preventive carotid revascularization is encouraged [22,25]. Our data confirmed that there are no differences between surgical and endovascular carotid treatment in terms of risk of stroke even in a high risk and old population as this. A thoughtful treatment strategy suited to each single case is mandatory in these complex clinical settings, and in addition to our previous reports focused on the immediate and 1-year clinical outcome, the present data provide information on the longterm outcome. These are important results that should be weighed in the decision-making process.
However, this is a multicenter experience and the individual treatment strategy was chosen according to the institutional expertise that derives from consolidated methods applied in high-volume centers committed to the treatment of MSAD with a dedicated multidisciplinary team. Such circumstances can impact clinical outcomes and may not be comparable to experiences obtained elsewhere. As already said, the study results are observational and influenced by the different clinical presentation of each treatment group.
In conclusion, surgical, endovascular, and hybrid treatment of CAD and associated COD yield good and similar long-term clinical results at 5 years follow-up provided that the best-suited revascularization strategy is discussed in a multidisciplinary context, chosen according to the clinical characteristics of each single case and performed with expertise. The lowest all-cause mortality rate was observed in the surgical group; a very low stroke rate was observed in all groups; and a higher myocardial infarction risk was observed among patients who received a hybrid treatment.
Five-year outcome, however, was similar among the three groups and compare favorably to the natural history of the disease analyzed in large observational registries [5,21,26].

Data Availability
The data used to support the findings of this study are restricted by the University of Verona ethical committee in order to protect patient privacy. Data are available from Prof. Flavio Ribichini for researchers who meet the criteria for access to confidential data.

Additional Points
Limitations. This is a multicentre experience conducted in high-volume centres dedicated to the treatment of multilevel vessel disease with a dedicated multidisciplinary team. Such circumstances have the potential to impact clinical outcomes and may not be comparable to different experiences obtained in other institutions. Furthermore, the study is an observational report without randomization.