Management of Coronary Disease in the Era of Transcatheter Aortic Valve Replacement

M a n a g e m e n t o f C o ron a r y D i s e a s e in t h e E r a o f Tr a n s c a t h e t e r A o r t i c Val v e Replacement

Comprehensive Review of the Literature Anthony Poulin, MDa, Josep Rodés-Cabau, MDa, Jean-Michel Paradis, MDa,b,* KEYWORDS  Coronary artery disease  Aortic valve stenosis  Percutaneous coronary intervention  Transcatheter aortic valve replacement

KEY POINTS

INTRODUCTION Aortic valve stenosis is the most frequent valvular heart disease in the elderly population. Risk factors for aortic stenosis (AS) have been shown to be similar to those of atherosclerosis and coronary artery disease (CAD).1 Therefore, CAD and degenerative AS frequently coexist among elderly patients.2 In fact, more than 65% of patients with AS older than 80 years of age also have significant CAD.3 For many decades, surgical aortic valve replacement (SAVR) and coronary artery

bypass graft (CABG) were considered the standard treatment option for the management of concomitant CAD in the context of symptomatic severe AS. However, in recent years, transcatheter aortic valve replacement (TAVR) has significantly modified the treatment algorithm, especially for patients with severe AS deemed at high or extreme risk for open heart surgery. This article describes the latest knowledge in the management of CAD in the era of TAVR, a less invasive technique. It also identifies areas where uncertainty remains as part of

J. Rode´s-Cabau has received consulting fees from Edwards Lifesciences and St. Jude Medical. The other authors declare no conflict of interest. a Department of Cardiology, Interventional Cardiology Division, Quebec Heart and Lung Institute, 2725, Chemin Sainte-Foy, Que´bec, Quebec G1V 4G5, Canada; b Cardiovascular Research Foundation, 111 East 59th Street, New York, NY 10022, USA * Corresponding author. 2725, Chemin Sainte-Foy, Que´bec, Quebec G1V 4G5, Canada. E-mail address: [email protected] Intervent Cardiol Clin 4 (2015) 13–21 http://dx.doi.org/10.1016/j.iccl.2014.09.003 2211-7458/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.

interventional.theclinics.com

 The risks and benefits of performing transcatheter aortic valve replacement in the presence of unrevascularized CAD should be weighed against the risk/benefit ratio of doing a percutaneous coronary intervention.  Stenosis in proximal epicardial coronaries supplying a large myocardial territory should probably be revascularized.  Lesions located in small vessels, distal lesions, and chronic total occlusions should possibly be managed with medical therapy.  When an interventional approach is selected, the decision to implant a bare-metal stent or a drugeluting stent should be individualized.

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Poulin et al the day-to-day management of these complex and multifaceted patients.

ASSOCIATION BETWEEN AORTIC VALVE SCLEROSIS AND CONCOMITANT CORONARY ARTERY DISEASE The prevalence of CAD in patients undergoing SAVR grows higher with both age and presence of aortic valve calcification. Clinical factors associated with progression from aortic sclerosis to AS are age, male gender, lipoprotein (a), height, hypertension, present smoking, and level of low-density lipoprotein cholesterol.1 These factors are similar to those reported for CAD in the literature.3 In a cohort of 388 patients undergoing coronary angiography, patients with aortic valve calcification had a higher rate of CAD (90% vs 85%), indicating that aortic valve calcification can be used as a marker of CAD.4 This is supported by a study conducted by Katz and colleagues2 in 2006. In this study, computed tomography was used to assess the prevalence of aortic valve calcification among 6780 multiethnic patients. It established that a linear, graded relationship exists between the prevalence of metabolic syndrome components and aortic valve calcifications. These evidences indicate that aortic valve calcifications and CAD are different manifestations of the same systemic vascular atherosclerotic process.

ANGINA AND ITS IMPLICATIONS Multiple studies have shown that the relation between angina and CAD in patients with AS is clinically difficult to interpret. In patients undergoing SAVR, concomitant CAD is reported in up to one-third of patients.5 In AS patients with angina and normal coronary arteries, angina seems to be related to left ventricular hypertrophy combined with abnormally high systolic and diastolic wall tension.6 This creates diminished coronary flow reserve (CFR) and mismatch between oxygen demand and delivery. Because of the poor sensitivity and specificity of angina,1 guidelines have been developed recommending coronary angiography in patients with severe AS. The American College of Cardiology and American Heart Association 2014 guidelines on valvular heart disease recommend that patients with angina, evidence of myocardial ischemia, decreased left ventricular function, past history of CAD or two more risk factors for CAD, and functional mitral regurgitation undergo evaluation via coronary angiography.7 Specific subsets of the population, such as symptomatic men older than 35 years or asymptomatic men older than 45 years, women older than

55 years, and premenopausal women older than 35 years with risk factors, should also undergo coronary angiography before their surgery.

FRACTIONAL FLOW RESERVE CFR is the maximal increase in myocardial blood flow above its resting level for a given perfusion pressure when coronary vasculature is maximally dilated via pharmacologic agents.8 The reduction in the CFR might be the key factor explaining angina and ischemic symptoms in patients with severe AS and normal coronary arteries. Nevertheless, the reasons explaining the decline of CFR in patients with AS remain ambiguous. In the past, concentric left ventricular hypertrophy was thought to be the main mechanism underneath the regression of CFR in patients with AS. However, contemporary data indicate that high left ventricular workload may be the most important element. Indeed, both effective orifice area and transvalvular pressure gradient correlate better with diminished CFR than left ventricular mass. Furthermore, intramyocardial coronary microcirculation dysfunction caused by long-term pressure overload might also be involved in the reduction of CFR in patients with severe AS.9 Fractional flow reserve (FFR) expresses the maximal flow down a vessel in the presence of a stenosis compared with the maximal flow in the hypothetical absence of the stenosis. The FAME study demonstrated that for patients with multivessel CAD, measurement of FFR to guide percutaneous coronary interventions (PCIs) with implantation of drug-eluting stents reduces mortality by 4.5% at 2 years compared with angiography-guided PCI.10 In patients with severe AS and CAD, a recent case series of five patients first reported beneficial outcomes when FFR is used during routine coronary angiography before TAVR.11 Still, the safety and usefulness of the FFR in this population remain uncertain and require further studies.

OUTCOMES OF PATIENT WITH CORONARY ARTERY DISEASE AND SEVERE AORTIC STENOSIS Combined CABG and valve operations reduce the rates of perioperative myocardial infarction (MI), operative and late mortality, and morbidity compared with patients with valvular heart disease and significant CAD who do not undergo revascularization at the time of valve operation.12 American College of Cardiology and American Heart Association guidelines indicate, as a class 2a recommendation, that CABG or PCI is reasonable in patients

Aortic Stenosis and CAD undergoing valve repair or replacement with significant CAD (70% reduction in luminal diameter in major coronary arteries or 50% reduction in luminal diameter in the left main coronary artery).7 Yet, interventions conjoining surgical AVR and coronary artery bypass carry a higher rate of postoperative mortality than SAVR alone.12 In a retrospective study of 717 patients older than 70 years of age, operative mortality was 4.2% for AVR alone versus 8.8% for AVR with concomitant CABG. In another large observational study of 3923 patients at the Cleveland Clinic undergoing CABG1AVR or AVR alone, hospital mortality and long-term survival were poorer when CAD was present (43% vs 59% at 10 years).13 Nonetheless, after a propensity matching analysis to account for disparities in baseline comorbidities, survival at 10 years was similar in the two groups (55% for isolated AS vs 50% for AS1CAD), suggesting that the greater risk profile of individuals undergoing both AVR and CABG is responsible for the increased operative and long-term risk.

PERCUTANEOUS CORONARY INTERVENTIONS AND SEVERE AORTIC STENOSIS Because CABG and SAVR have been considered the standard of care in patients with severe AS and concomitant CAD, data concerning outcomes of PCI in this group of patients are limited. A large retrospective observational study published in 2012 included 254 patients with severe AS undergoing PCI. With propensity matching, they found 508 case-controls without AS undergoing PCI.14 In this study, 30-day mortality was similar in both groups (4.3% with AS vs 4.7% without AS). Two subgroups had a higher risk of 30-day mortality after PCI: those with a baseline ejection fraction less than or equal to 30% (15.4%) and those with a Society of Thoracic Surgeons (STS) score greater than or equal to 10% (10.4%). Multivariable analysis found several significant predictors of worse outcomes in patients with severe AS undergoing PCI: ejection fraction less than or equal to 30%, chronic kidney disease, diabetes mellitus, and chronic obstructive pulmonary disease. Before generalizing the conclusions of this study, some limitations are worth mentioning: it was a single-center observational study with only 22% of patients receiving a drug-eluting stent, making this largely a bare-metal stent study.

Also, several clinical scenarios are less favorable for a combined CABG-AVR: patients presenting with acute coronary syndrome, need for valve reoperation, or poor conduit vessels. In these circumstances, some authors have suggested that hybrid procedures with SAVR and PCI might be a good alternative. This approach separates a highrisk surgery into two potentially lower-risk interventions. Yet, an important challenge of this treatment option is the timing of PCI considering the need of dual antiplatelet therapy and the subsequesnt increased risk of bleeding during the SAVR. In 2005, Byrne and colleagues16 were the first to publish a retrospective study analyzing 26 consecutive patients who underwent PCI before valve surgery between 1997 and 2003. In this series, the mortality rate was 3.8%, which was considerably lower than the 22% predicted mortality rate calculated with the STS risk calculator. Despite the high rate of blood transfusion (85%), the interesting finding of this study was that the hybrid approach combining PCI before SAVR (at a median of 5 days) was shown to be feasible. The small sample size, the single center experience, the absence of case control matching, and that 21 of 26 surgeries were for mitral valve pathology constitute the main limitations of this study. In the largest study to date about the hybrid approach, a retrospective evaluation was done of 65 patients who underwent planned PCI followed by minimally invasive surgery within 60 days. There was also a control group of 52 patients who underwent conventional CABG and valve repair.17 The composite end point of 30-day mortality, renal failure, or stroke occurred in 1.5% in the hybrid group versus 30.8% in the control group. The median number of days between valve surgery and PCI was 24. Length of hospital stay and intensive care unit stay were less in the AVRPCI group. Finally, the number of transfusions was similar, 1.6 versus 1.9 packed red blood cell units, but dual antiplatelet therapy was given to only 35.4% of patients. While awaiting further confirmatory data, the studies published to date demonstrate the feasibility of combining SAVR with staged or singlesetting PCI. However, long-term outcomes of this approach still remain unclear and there is a lack of strong evidence concerning management of dual antiplatelet therapy and optimal timing for PCI before SAVR.

HYBRID PROCEDURES WITH SURGICAL AORTIC VALVE REPLACEMENT AND PERCUTANEOUS CORONARY INTERVENTIONS

TRANSCATHETER AORTIC VALVE REPLACEMENT ERA

Combined AVR and CABG is associated with a mortality rate almost double that of AVR alone.15

In 2000, Iung3 studied 5001 patients with moderate to severe valvular heart disease. In this study,

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Poulin et al a significant proportion (31.8%) of patient with severe single-valve disease did not undergo any surgical intervention. A prohibitive operative risk probably explains this high percentage of medically treated patients. Most frequent advocated reasons to explain this elevated surgical risk were old age (27.6%), chronic obstructive pulmonary disease (13.6%), renal failure (6.1%), and short life expectancy (19.3%). In the past decade, TAVR has emerged as an excellent alternative for patients with high or extreme surgical risks. The PARTNER trial, which included two parallel prospective, multicenter, randomized, active-treatment controlled clinical trials, contributed largely to the establishment of this less invasive technology.18 Studies and registries demonstrated that in patients undergoing TAVR, the prevalence of CAD ranges from 47.6% to 74.9%. Coronary angiography is consequently highly recommended as part of the pre-TAVR work-up even if the best management of CAD in the setting of TAVR has not yet been established.

TRANSCATHETER AORTIC VALVE REPLACEMENT AND PREVIOUS CORONARY ARTERY BYPASS GRAFT When undergoing SAVR, early and late mortality rates are higher among patients with previous CABG.19 Minha and colleagues20 studied the outcome of patients with previous CABG undergoing TAVR. In a cohort of 372 consecutive patients who underwent transfemoral or transapical TAVR, 122 (32.8%) had previous bypass graft. Although patients with previous CABG were younger and had a higher risk profile, TAVR was safe and did not confer a significant risk of adverse events in this subgroup of patients.

TRANSCATHETER AORTIC VALVE REPLACEMENT AND MYOCARDIAL INFARCTION In the literature, several studies have shown a rate of periprocedural MI during TAVR between 0% and 4.6%. However, authors have used different thresholds to define MI during TAVR. The recent Valve Academic Research Consortium-2 (VARC2) document suggests using a threshold of 15 times the upper reference limit for troponin or five times for creatine kinase MB (CK-MB) to define periprocedural MI (<72 h after the index procedure).21 As shown in the study by Zahn and colleagues,22 postintervention MI is an important risk factor associated with higher early and 1-year mortality rates following TAVR. Furthermore, in a study of 101 patients, TAVR was systematically associated with

some degree of myocardial injury. A higher degree of cardiac troponin T (cTNT) and CK-MB increase was identified as an independent predictor of cardiovascular mortality at follow-up and was correlated with less improvement in left ventricular ejection.23

TRANSCATHETER AORTIC VALVE REPLACEMENT AND IMPACT OF CORONARY ARTERY DISEASE Studies regarding the management of CAD in patients undergoing TAVR have shown conflicting results. In 2010, Dewey and colleagues24 analyzed the effect of previous PCI or CABG on the survival of patients undergoing TAVR. The analysis included 201 patients who were enrolled in two international feasibility studies: 40 patients undergoing transapical aortic valve implantation and 161 patients undergoing transfemoral TAVR. After a logistic regression analysis, patients with established CAD had 10.1 times higher mortality rate at 30 days (13.1% vs 1.2%). Beside the fact that this trial represents the early TAVR experience, other limitations of this study include the simplistic definition of CAD, significant amount of patients (13%) have been excluded because of technical complications, and the differences in term of comorbidities and risk profiles between the two groups. It is therefore difficult to conclude if CAD itself is a predictor of poor outcomes following TAVR or only a marker of a higher risk profile among these patients. On the other hand, a single-center study of 136 patients undergoing TAVR between 2005 and 2007 showed no difference in mortality rate according to the extent of CAD, as evaluated by the Duke Myocardial Jeopardy Score.25 Notwithstanding the small size of the study and that 15 patients underwent revascularization with PCI before TAVR, there was no trend toward a higher rate of adverse events with the presence of CAD or norevascularized myocardium.

Transcatheter Aortic Valve Replacement and Selective Revascularization Strategy Other studies have provided more insight on the optimal management of CAD in patients with severe AS undergoing TAVR, exploring the avenue of selective revascularization strategy. Between 2006 and 2009, Gautier and colleagues26 enrolled 240 consecutive patients with high-risk severe symptomatic AS undergoing treatment with TAVR, SAVR, or medical therapy. In this article, CAD was defined either as a history of prior MI, coronary revascularization, or greater than or equal to 70% epicardial artery stenosis (50%

Aortic Stenosis and CAD for left main stenosis). Among the 83 patients with CAD who underwent TAVR, 16 (19%) were free of any residual significant coronary stenosis, 56 (67.4%) with greater than or equal to one coronary stenosis did not undergo revascularization, and 11 (13.2%) underwent PCI before TAVR with a mean delay of 6 weeks between the two interventions. Decision to proceed with PCI was driven by symptoms of angina or proximal vessel stenosis supplying a large area of myocardium. When comparing both groups (TAVR1CAD vs TAVR1no-CAD), there was no statistical difference in mortality at 30 days (90% vs 95%; P 5 .37) and 1 year (76% vs 71%; P 5 .28). This study reflects a trend toward less systematic revascularization before TAVR. According to this study, CAD had a limited impact on the outcomes of TAVR and should not restrict TAVR indications. In fact, with multivariable analysis, CAD had no influence on the outcomes of the patients undergoing TAVR (odds ratio, 1.0; 95% confidence interval, 0.67–1.50). However, it was an observational study with a heterogeneous population, which limits generalization of the results. In 2012, Gasparetto and colleagues27 assessed the outcome of TAVR in patients with CAD treated with a selective, clinically based revascularization strategy. This study included 191 patients referred for TAVR. CAD was present in 113 patients (59.2%): one-third had single-vessel disease, one-third had two-vessel disease, and one-third had three-vessel disease. PCI was performed based on clinical symptoms and for lesions involving proximal-to-mid coronary segments of major coronary branches. Among patients with CAD, PCI was performed in 34.5% of patients with a mean use of 2.0 stents per patient and bare-metal stents were used in 56.4% of cases. Anatomic complete revascularization was achieved in only 38 patients (33.6%). After TAVR, 30-day all-cause mortality was similar in patients with or without CAD (5.7% vs 2.9%; P 5 .32). Long-term mortality was also similar regardless of CAD status (15.1% vs 14.3%; P 5 .88). Incidence of MI was not statistically different in both groups (4.4% vs 0%; P 5 .08). This study also reaffirms that selective revascularization is safe and associated with similar outcomes compared with no-CAD patients undergoing TAVR.

Transcatheter Aortic Valve Replacement and Outcomes According to SYNTAX Score A study of 263 patients published by Van Mieghem and colleagues28 in 2013 assessed the impact of selective revascularization on the outcomes of consecutive patients undergoing TAVR. Among them, 124 patients (47%) had significant CAD,

which was defined as greater than 50% stenosis of an epicardial artery on the coronary angiogram. Medtronic Corevalve (Medtronic Inc, Minneapolis, MN, USA) was used in 245 patients (93.2%). Three treatment options were possible: (1) staged PCI before TAVR, (2) PCI concomitant with TAVR, or (3) no PCI. The treatment strategy and completeness of revascularization were chosen by the heart team. Decision to proceed with revascularization was based on previous infarction zone, viable myocardium at risk, and technical complexity. In patients without previous CABG, the SYNTAX score (SS) was calculated before and after TAVR. In patients with previous CABG (27%), completeness of revascularization was evaluated by assessing native coronaries and their respective grafts. Patients with CAD and without previous CABG had a median preprocedure SS of 9.00 (2.38–15.63) and a median postprocedure SS of 5.00 (0.13–9.88). Staged PCI was done in 20 patients (16%) and concomitant PCI in 25 patients (20%). Overall, 99 patients (38%) had incomplete revascularization after TAVR and complete revascularization was only achieved in 20% of patients with incomplete revascularization at baseline. Revascularization status did not affect 30-day mortality (6.5% vs 6.5%; P 5 .99), bleeding complication rate (10.1% vs 5.6%; P 5 .19), or composite safety end point (23.3% vs 20.5%; P 5 .59). This demonstrates the feasibility of a heart-team–based selective revascularization in CAD before TAVR. The small sample size and its single-center design represent the major limitations of this study. A recent study by Stefanini and colleagues29 assessed clinical outcomes of patients undergoing TAVR when assessed with the SS. Between 2007 and 2012, 445 patients with symptomatic severe AS undergoing TAVR were included in a prospective registry. Patients were divided into three groups: (1) 158 without CAD (35.5%), (2) 207 with low SS (<22), and (3) 80 with high SS (>22). CAD was defined as greater than 50% epicardial artery diameter stenosis in vessels greater than or equal to 1.5 mm in diameter. Among patients with CAD, stenosis of greater than or equal to 70% of the diameter of the proximal coronary artery segments was completely revascularized by either staged or concomitant PCI. When PCI was performed, residual SS (rSS) was assessed. Notably, patients with high SS at baseline had higher rSS compared with those with low SS (21.2 vs 4.0; P 5 .001). Primary end point was a composite of cardiovascular death, stroke, or MI. At 30 days, the occurrence of the composite primary end points was similar in all groups (no CAD, 7.0%; low SS, 7.2%; high SS, 10.0%; P 5 .54). At 1 year, presence of CAD

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Poulin et al was associated with higher cardiovascular mortality (no CAD, 8.6%; low SS, 13.6%; high SS, 20.4%; P 5 .029) but the rate of stroke and MI was similar in all three groups. However, the group with high SS had higher prevalence of reduced ventricular ejection fraction. After multivariable analysis, decreased left ventricular ejection fraction was the only independent predictor of the primary end point (hazard ratio, 1.29; 95% confidence interval, 1.11–1.51). This study demonstrates that more severe and complex CAD is associated with poorer prognosis following TAVR and that high rSS is associated with worst outcomes. However, this was a single-center retrospective observational study. Also, the assessment of the SS can be challenging and less reproducible for less experienced readers. Khawaja and colleagues30 published a retrospective study of 271 patients who underwent TAVR with the Edwards bioprothesis. In this study, the authors defined CAD as a coronary stenosis greater than or equal to 70% or greater than or equal to 50% if in the left main stem or a vein graft. Ninety-three patients (34.3%) had a documented CAD. A secondary analysis was done using SS to assess the impact of CAD complexity on outcomes following TAVR. Compared with patients in the low or intermediate SS groups, those in the high SS group had a higher rate of mortality at 30 days and at 12 months. Receiver operating characteristic analysis demonstrated that SS greater than nine at the time of TAVR was the optimal cut-off, with an independent association with mortality (hazard ratio, 1.95; 95% confidence interval, 1.21–3.13; P 5 .006). These findings are similar to those from the study of Stefanini and colleagues,29 reinforcing the concept that patients with higher SS have poorer outcomes following TAVR.

TRANSCATHETER AORTIC VALVE REPLACEMENT AND CONCOMITANT PERCUTANEOUS CORONARY INTERVENTIONS Despite several studies looking at this clinical dilemma, the optimal timing for revascularization is still not known in patients undergoing TAVR. The following section reviews the existing data on the three different PCI timing strategies: before, concomitant, and after TAVR.

Percutaneous Coronary Interventions Before Transcatheter Aortic Valve Replacement The benefits of this approach are the possible reduction of the procedural risk of TAVR and the diminished future need for revascularization postTAVR. In the context of an ongoing prospective registry including 191 patients (PUREVALVE

Registry), PCI was performed before TAVR in 39 patients.27 CAD was defined as any coronary stenosis of at least 50% or any previous percutaneous or surgical coronary revascularization. Chronic total occlusions and lesions in small vessels (<2.5 mm) were not considered for revascularization. TAVR was performed at least 2 weeks after PCI and the median time between the two procedures was 27 days. Mortality rates at 30 days were comparable between CAD and noCAD patients (5.7% vs 2.9%; P 5 .32). However, there were five MI in the CAD group versus none in no-CAD group. This study thus suggests that selective, clinically driven revascularization before TAVR can lead to similar outcomes following the procedure compared with those seen in the noCAD patients. In another study of 55 high-risk patients who underwent PCI before TAVR with the Medtronic Corevalve system, 30-day mortality and VARC defined combined safety end point were similar between the PCI and non-PCI group,31 suggesting again that PCI before TAVR is safe and effective.

Concomitant Percutaneous Coronary Interventions and Transcatheter Aortic Valve Replacement To optimize resource use, to enhance patient convenience, and to use only one arterial access site, some authors have proposed the performance of PCI and TAVR in the same setting. Wenaweser and colleagues32 studied 256 consecutive patients included into the Bern TAVI registry who underwent TAVR to address safety and feasibility of PCI in those patients. In patients with CAD, myocardium at risk was assessed using Duke Myocardial Jeopardy Score. CAD was defined as an angiographic stenosis of greater than 50% of at least one coronary artery and affected 165 patients. Of those, 23 patients underwent staged PCI and 46 patients underwent concomitant PCI and TAVR. Of the remaining 108 patients, 53 had complete revascularization previously and 55 had incomplete revascularization. Clinical outcomes at 30 days in terms of death (5.6% vs 10.2%; P 5 .24), major stroke (4.1% vs 3.4%; P 5 1.00), and VARC combined safety end point (31.0% vs 23.7%) were similar between TAVR and TAVR 1 PCI groups. These results demonstrated the feasibility and safety of PCI either before TAVR or combined with TAVR in a single-day procedure. However, limited numbers of patients and selection bias were the main factors limiting generalization of these results. However, another study suggests that PCI concomitant with TAVR may be associated with

Aortic Stenosis and CAD worse early and late clinical outcomes.33 In fact, in a study of 411 patients undergoing TAVR, 65 of them (16%) had planned staged PCI or synchronous PCI. For 95% of patients undergoing PCI, a single coronary artery was treated, with 71% of patients receiving bare-metal stents. Mortality at 30 days was higher (15% vs 5%; P 5 .01) in the PCI1TAVR group compared with the TAVRalone group. Nevertheless, this study was performed in only one institution, the design of the trial was observational, and the number of patients undergoing PCI and TAVR was limited.

Percutaneous Coronary Interventions After Transcatheter Aortic Valve Replacement Few studies and case reports regarding PCI after TAVR have been published. In fact, this strategy poses unique procedural risks and technical challenges, mainly because of the possible interference between the prosthetic valve and the future cannulation of the coronary arteries. Potential dislodgment of the valve and risk of early stent thrombosis are other possible disadvantages of this approach. To our knowledge, only one main study by Pasic and colleagues34 studied the performance of PCI after TAVR. This study included 419 patients who underwent TA-TAVR. Only 46 patients (11%) had PCI after TAVR and technical success was achieved in 100% of patients. Although this demonstrated the feasibility of PCI after TAVR, it was a single-center study with very restricted selection criteria for lesions amenable to straightforward PCI. This might have overestimated the success rate of this approach.

UPCOMING STUDIES PARTNER 2A and Surgical Replacement and Transcatheter Aortic Valve Implantation (SURTAVI) are two large, randomized, controlled trials that aim to compare the outcomes of patients who require surgical AVR with or without CABG and TAVR with or without PCI.

PARTNER 2A Trial The PARTNER 2A trial is a phase 3, prospective, multicenter, randomized trial of 2000 patients undergoing AVR that are deemed at intermediate surgical risk. The aim of this study is to compare safety and efficacy of SAVR versus TAVR with the Edwards SAPIEN XT THV (Edwards Lifesciences, Irvine, CA, USA) in this group of patients. The heart team has to agree (a priori) on a treatment strategy for concomitant CAD and if the decision is made to revascularize, the patients will either undergo PCI and TAVR or CABG and SAVR.

Complex CAD, defined as unprotected left main coronary artery or SS greater than 32, constitutes the major exclusion criteria of this study.

SURTAVI Trial The Medtronic Corevalve SURTAVI trial is a prospective randomized trial that will compare safety and efficacy of TAVR using the Medtronic CoreValve System versus SAVR in patients with severe, symptomatic AS deemed at intermediate surgical risk (STS score 3% and 10%). This randomized trial will include up to 2500 patients who will be followed through 5 years. Each patient will first undergo a heart team evaluation that will assess the need for revascularization of significant CAD. Patients with planned revascularization will then be randomized either to PCI and TAVR or CABG and SAVR. Patients with an SS greater than 22 and those with a left main lesion will be excluded from this trial.

ACTIVATION Trial The Percutaneous Coronary Intervention Prior to Transcatheter Aortic Valve Implantation (ACTIVATION), a randomized controlled trial, will randomize 310 patients with severe AS and at least one lesion of greater than or equal to 70% severity in a major epicardial vessel to undergo PCI and TAVR versus TAVR alone. The main purpose of this European trial is to assess the impact of coronary revascularization by PCI for obstructive CAD before TAVR. Until upcoming studies provide further insight on the optimal management of CAD in patients undergoing TAVR, we suggest that the heart team should use an individualized (case by case) approach to guide PCI before TAVR. Although there is no clear cut-off, the SS should be calculated for each patient. Distal lesions, lesions located in small vessels, chronic total occlusions, or complex lesions that require a large iodine load in patients with severe renal failure should probably be treated medically. If a PCI is planned, the heart team should decide if a balloon aortic valvuloplasty should be performed before the coronary intervention to mitigate the risk of the PCI in the setting of severe AS. Finally, the decision to implant a bare-metal stent or a drug-eluting stent should also be individualized and should integrate the possible impact of the use of antiplatelet agents on bleeding after TAVR and also the overall bleeding risk of the patient.

SUMMARY For many years, SAVR and CABG have been considered the mainstay of treatment of patients

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Poulin et al with symptomatic severe AS and significant CAD. In the era of TAVR, the optimal management of CAD is currently being reanalyzed. Nevertheless, robust data are scarce and many questions remain unanswered. Future studies are needed to rigorously evaluate the impact of CAD on outcomes after TAVR, but also to establish evidence-based revascularization strategies. The risks and benefits of performing TAVR in the presence of unrevascularized CAD should be weighed against the risk/ benefit ratio of doing a PCI. Stenosis in proximal epicardial coronaries supplying a large myocardial territory should probably be revascularized. However, lesions located in small vessels, distal lesions, and chronic total occlusions should possibly be managed with medical therapy. When an interventional approach is selected, the decision to implant a bare-metal stent or a drugeluting stent should be individualized. While awaiting more definitive data, the heart team concept for decision-making remains essential to correctly managing these complex and multifaceted patients with severe AS and coronary disease.

REFERENCES 1. Rapp AH, Hillis LD, Lange RA, et al. Prevalence of coronary artery disease in patients with aortic stenosis with and without angina pectoris. Am J Cardiol 2001;87(10):1216–7. A7. 2. Katz R, Wong ND, Kronmal R, et al. Features of the metabolic syndrome and diabetes mellitus as predictors of aortic valve calcification in the MultiEthnic Study of Atherosclerosis. Circulation 2006; 113(17):2113–9. 3. Iung B. Interface between valve disease and ischaemic heart disease. Heart 2000;84(3):347–52. 4. Adler Y, Vaturi M, Herz I, et al. Nonobstructive aortic valve calcification: a window to significant coronary artery disease. Atherosclerosis 2002;161(1):193–7. 5. Shaikh AH, Hanif B, Hasan K, et al. Coronary artery disease in patients undergoing valve replacement at a tertiary care cardiac centre. J Pak Med Assoc 2011;61(4):340–2. 6. Julius BK, Spillmann M, Vassalli G, et al. Angina pectoris in patients with aortic stenosis and normal coronary arteries. Mechanisms and pathophysiological concepts. Circulation 1997;95(4):892–8. 7. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ ACC Guideline for the Management of Patients With Valvular Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63(22):2438–88. 8. Garcia D, Camici PG, Durand LG, et al. Impairment of coronary flow reserve in aortic stenosis. J Appl Physiol (1985) 2009;106(1):113–21.

9. Bartel T, Yang Y, Muller S, et al. Noninvasive assessment of microvascular function in arterial hypertension by transthoracic Doppler harmonic echocardiography. J Am Coll Cardiol 2002;39(12): 2012–8. 10. Pijls NH, Fearon WF, Tonino PA, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study. J Am Coll Cardiol 2010;56(3):177–84. 11. Stahli BE, Maier W, Corti R, et al. Fractional flow reserve evaluation in patients considered for transfemoral transcatheter aortic valve implantation: a case series. Cardiology 2012;123(4):234–9. 12. Tjang YS, van Hees Y, Korfer R, et al. Predictors of mortality after aortic valve replacement. Eur J Cardiothorac Surg 2007;32(3):469–74. 13. Beach JM, Mihaljevic T, Svensson LG, et al. Coronary artery disease and outcomes of aortic valve replacement for severe aortic stenosis. J Am Coll Cardiol 2013;61(8):837–48. 14. Goel SS, Agarwal S, Tuzcu EM, et al. Percutaneous coronary intervention in patients with severe aortic stenosis: implications for transcatheter aortic valve replacement. Circulation 2012;125(8):1005–13. 15. Pibarot P, Dumesnil JG. Improving assessment of aortic stenosis. J Am Coll Cardiol 2012;60(3): 169–80. 16. Byrne JG, Leacche M, Unic D, et al. Staged initial percutaneous coronary intervention followed by valve surgery (“hybrid approach”) for patients with complex coronary and valve disease. J Am Coll Cardiol 2005;45(1):14–8. 17. Santana O, Funk M, Zamora C, et al. Staged percutaneous coronary intervention and minimally invasive valve surgery: results of a hybrid approach to concomitant coronary and valvular disease. J Thorac Cardiovasc Surg 2012;144(3):634–9. 18. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363(17):1597–607. 19. Fighali SF, Avendano A, Elayda MA, et al. Early and late mortality of patients undergoing aortic valve replacement after previous coronary artery bypass graft surgery. Circulation 1995;92(9 Suppl): Ii163–8. 20. Minha S, Magalhaes MA, Barbash IM, et al. Impact of previous coronary artery bypass grafting on patients undergoing transcatheter aortic valve implantation for aortic stenosis. Am J Cardiol 2014; 113(7):1222–7. 21. Kappetein AP, Head SJ, Genereux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic

Aortic Stenosis and CAD

22.

23.

24.

25.

26.

27.

28.

Research Consortium-2 consensus document. J Am Coll Cardiol 2012;60(15):1438–54. Zahn R, Gerckens U, Linke A, et al. Predictors of one-year mortality after transcatheter aortic valve implantation for severe symptomatic aortic stenosis. Am J Cardiol 2013;112(2):272–9. Rodes-Cabau J, Gutierrez M, Bagur R, et al. Incidence, predictive factors, and prognostic value of myocardial injury following uncomplicated transcatheter aortic valve implantation. J Am Coll Cardiol 2011;57(20):1988–99. Dewey TM, Brown DL, Herbert MA, et al. Effect of concomitant coronary artery disease on procedural and late outcomes of transcatheter aortic valve implantation. Ann Thorac Surg 2010;89(3):758–67 [discussion: 767]. Masson JB, Lee M, Boone RH, et al. Impact of coronary artery disease on outcomes after transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2010;76(2):165–73. Gautier M, Pepin M, Himbert D, et al. Impact of coronary artery disease on indications for transcatheter aortic valve implantation and on procedural outcomes. EuroIntervention 2011;7(5):549–55. Gasparetto V, Fraccaro C, Tarantini G, et al. Safety and effectiveness of a selective strategy for coronary artery revascularization before transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2013;81(2):376–83. Van Mieghem NM, van der Boon RM, Faqiri E, et al. Complete revascularization is not a prerequisite for success in current transcatheter aortic valve

29.

30.

31.

32.

33.

34.

implantation practice. JACC Cardiovasc Interv 2013;6(8):867–75. Stefanini GG, Stortecky S, Cao D, et al. Coronary artery disease severity and aortic stenosis: clinical outcomes according to SYNTAX score in patients undergoing transcatheter aortic valve implantation. Eur Heart J 2014. [Epub ahead of print]. Khawaja MZ, Asrress KN, Haran H, et al. The effect of coronary artery disease defined by quantitative coronary angiography and SYNTAX score upon outcome after transcatheter aortic valve implantation (TAVI) using the Edwards bioprosthesis. EuroIntervention 2014. [Epub ahead of print]. Abdel-Wahab M, Mostafa AE, Geist V, et al. Comparison of outcomes in patients having isolated transcatheter aortic valve implantation versus combined with preprocedural percutaneous coronary intervention. Am J Cardiol 2012;109(4):581–6. Wenaweser P, Pilgrim T, Guerios E, et al. Impact of coronary artery disease and percutaneous coronary intervention on outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation. EuroIntervention 2011;7(5):541–8. Griese DP, Reents W, Toth A, et al. Concomitant coronary intervention is associated with poorer early and late clinical outcomes in selected elderly patients receiving transcatheter aortic valve implantation. Eur J Cardiothorac Surg 2014;46(1):e1–7. Pasic M, Dreysse S, Unbehaun A, et al. Combined elective percutaneous coronary intervention and transapical transcatheter aortic valve implantation. Interact Cardiovasc Thorac Surg 2012;14(4):463–8.

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