The Value of Percutaneous Coronary Intervention in Aortic Valve Stenosis with Coronary Artery Disease

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1 The American Journal of Medicine (2007) 120, 185.e7-185.e13 BRIEF OBSERVATION The Value of Percutaneous Coronary Intervention in Aortic Valve Stenosis with Coronary Artery Disease Ronny Alcalai, MD, a Nicola Viola, MD, b Morris Mosseri, MD, a Ronen Beeri, MD, a David Leibowitz, MD, a Chaim Lotan, MD, a Dan Gilon, MD, FACC a a Heart Institute and b Cardio-Thoracic Surgery Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. ABSTRACT OBJECTIVES: The study determines whether treatment of coronary disease by percutaneous coronary intervention (PCI) in the presence of severe aortic stenosis (AS) is feasible and defines which patients might benefit most. BACKGROUND: Severe symptomatic AS is considered a class I indication for aortic valve replacement (AVR). Many patients with AS have concomitant coronary artery disease (CAD), and the true reason for symptoms is often unclear. It is common practice to combine AVR with coronary artery bypass grafting. However, in some cases PCI alone might improve symptoms and allow surgery to be deferred. METHODS: We analyzed 38 consecutive patients who underwent PCI for CAD in the presence of significant AS between 1989 and Data included demographic factors, clinical features, angiographic, and echocardiographic information. Events during follow-up included PCI complications, improvement post-pci, AVR, and death. Statistical analysis was used to assess the impact of PCI on outcome and survival. RESULTS: The mean age of the study group was years, and the mean aortic valve area was ( ) cm 2. Reasons for choosing PCI over surgery were patients preference, high surgical risk, and cardiologist recommendation. Thirty-five patients (92.1%) reported symptomatic improvement after PCI, and no major PCI-related complications were recorded. Significant predictors for long-term event-free survival were good functional class (P.006) and single-vessel coronary disease (P.017). CONCLUSION: PCI in patients with severe AS and significant CAD is safe, offers relief of symptoms in most cases, and has good long-term outcome in a subset of patients who have mild CAD and good functional class. This therapeutic approach should be considered in such patients and in those with high surgical risk Elsevier Inc. All rights reserved. KEYWORDS: Aortic stenosis; Coronary artery disease; Percutaneous coronary intervention Requests for reprints should be addressed to Dan Gilon, MD, FACC, Heart Institute, Hadassah-Hebrew University Medical Center, PO Box 12000, Jerusalem, Israel. address: gilond@cc.huji.ac.il. Symptomatic aortic stenosis (AS) is associated with a poor prognosis and low survival rates unless corrected surgically. 1,2 Angina pectoris, congestive heart failure, and syncope are clinical manifestations of advanced AS and are considered a class I indication for aortic valve replacement (AVR). 3 A large number of patients with AS have concomitant coronary disease. 4 Although once thought of as a degenerative lesion, calcific AS has many features in common with coronary disease. 5 Both conditions are more common in men, older persons, and patients with hypercholesterolemia, and both derive in part from an active inflammatory process. 6 Angina pectoris or dyspnea may be caused by either AS or coronary artery disease (CAD). 7 Both present a diagnostic and therapeutic challenge. It remains unclear whether angina pectoris predicts the presence of CAD in patients with AS; 8 however, current guidelines recommend a diagnostic coronary angiography before surgery in symptomatic patients with AS. 9 When severe AS, or in some cases moderate AS, is associated with CAD, combined AVR and coronary artery bypass grafting (CABG) are rec /$ -see front matter 2007 Elsevier Inc. All rights reserved. doi: /j.amjmed

2 185.e8 The American Journal of Medicine, Vol 120, No 2, February 2007 ommended, 3 even though the symptoms might be a result of only 1 of the 2 causes. This recommendation is based on the high mortality rates of the combined disease and the possible contribution of both the symptoms. 10 In recent years percutaneous coronary interventions (PCIs) have become a primary treatment for symptomatic CAD and have replaced CABG in large subgroups of patients. Currently, there are no data available regarding the indications for and results of PCI in the presence of moderate or severe AS. We hypothesized that in patients with significant AS and CAD, and angina pectoris or dyspnea, PCI alone might improve symptoms, thereby distinguishing between the 2 pathologies and delaying the need for AVR. The objective of this study was to determine the clinical outcome of patients with significant AS who underwent PCI in our institution. CLINICAL SIGNIFICANCE Degenerative aortic stenosis is a common finding in the growing elderly population, and, therefore, a major clinical problem in daily practice. Patients with significant aortic stenosis who present with angina pectoris often have coexisting coronary artery disease. Percutaneous coronary intervention is safe for patients with aortic stenosis and coronary artery disease. by the Gorlin equation. CAD was defined as single vessel disease or multivessel disease when stenosis of greater than 70% was present in the major epicardial coronary arteries or their branches. Patients after CABG were defined as single vessel disease or multivessel disease according to the patency of the graft and native arteries. Follow-up Data were retrieved from the clinical records and completed by direct contact with the patient or physician. Clinical follow-up data included in-hospital major adverse events (myocardial infarction, cerebrovascular accident, or death), improvement of symptoms, need for repeat revascularization with PCI, and need and time of AVR (with or without CABG). Mortality information was based on patients files and the Population Registry of the Ministry of Interior. METHODS Patients The study group was comprised of all patients who underwent PCI in the presence of significant AS at the Hadassah Hebrew University Medical Center between 1989 and All patients had symptoms of angina or dyspnea. Significant valvular AS was defined as an aortic valve area (AVA) of 1.2 cm 2 or less (which is the accepted cutoff for the definition of moderate to severe AS), 3 documented by 2-dimensional and Doppler echo within 6 months before or after PCI. Clinical Data Data were collected from patients files and the computerized database of the cardiac catheterization and echocardiography laboratories. Demographic and clinical details assessed included age at time of PCI, gender, medical history, and cardiovascular risk factors. Functional class at the time of PCI, according to the New York Heart Association classification, was determined from the patients files or by direct contact with the patients or their physicians. Functional class I was defined for patients who were asymptomatic before presenting with acute chest pain or congestive heart failure. Echocardiographic data included left ventricular size and function, presence of other valvular defects, and presence of pulmonary hypertension. AS severity was defined by measurement of AVA and pressure gradients in 2-dimensional Doppler echocardiography. Catheterization data included maximal and mean pressure gradients across the aortic valve and AVA calculation Statistical Analysis Chi-square test was used to assess the association between reasons for performing PCI and patients characteristics. To determine the long-term outcome after PCI we assessed event-free survival time, which was defined as the time from PCI to AVR or death. Censoring was at the date of last follow-up or May Event-free survival analysis, according to patients characteristics, was performed using the Kaplan-Meier 11 method. Differences in the survival curves were assessed with the log-rank test. Continuous variables as age and AV area were divided into 2 subgroups: age 70 years or 70 years (a commonly accepted threshold for definition of elderly) and AVA 0.9 cm 2 or 0.9 cm 2, the threshold for definition of severe AS. 12 We defined 2 groups of patients according to the eventfree survival time: long-term survivors, more than 30 months from PCI to first event (AVR or death), and shortterm survivors, 30 months or less. The cutoff of 30 months represents a significant period of follow-up that was chosen before analysis of the data. The Fisher exact test was used to assess the association between the event-free period (long vs short survivors) and the patients characteristics. Patients with less than 1 year of follow-up without an event were excluded from this analysis. RESULTS We identified 38 patients with significant AS who underwent PCI for CAD. All patients had symptoms of angina or dyspnea. None of the patients in the study group were asymptomatic or presented with syncope. Mean age was 71

3 Alcalai et al Coronary Intervention in Aortic Stenosis 185.e9 Table 1 Patients Characteristics According to the Reason for Performing Percutaneous Coronary Intervention Subgroups Characteristic Total Cardiologist s Preference Patients Preference High Surgical Risk Reason Not Known P value Total Age (y) Sex Male Female Origin Ashkenazi Jews Sephardic Jews Arabs Functional class I-II III-IV Unknown Aortic valve area 0.9 cm cm Unknown Coronary disease severity Single vessel Multivessel Left ventricular function Good Moderate, poor years (range 45 85), and 24 patients (62.5%) were males. Mean AVA of the study population was ( ) cm 2. Six patients (16%) had critical AS of 0.6 cm 2 or less at the time of PCI. Functional class data were available in 35 of 38 patients. Valve gradients were used to define AS severity in 7 patients in whom AV area measurements were unavailable. Reasons for choosing PCI over surgery included patients refusal to undergo surgery in 9 (defined as PCI against medical advice), high surgical risk or bridge to noncardiac surgery in 6, and cardiologist s recommendation in 17. For the purposes of analysis, the 2 last reasons were combined into one and defined as PCI performed according to medical advice. In 6 patients the specific reasons were not stated. The demographic and clinical data in these different subgroups are summarized in Table 1. No major complications were recorded during or after PCI in any of the 38 patients. Thirty-five patients (92.1%) reported significant clinical improvement, defined as decline in the severity and frequency of symptoms and improvement by at least one functional class. The mean follow-up of the study group from PCI to event (AVR or death) or censored was 25.3 months (range 1-108). One patient was lost to follow-up a few months after PCI without recording of event; this patient was excluded from the long-term outcome analysis. Eighteen patients (48.6%) underwent AVR within a mean period of 24 months (range 1-66 months) after PCI. Sixteen patients died during the study period; 6 of them died after AVR. Three patients died within 6 months after PCI, one of respiratory failure secondary to morbid obesity. The other 2 were lost to follow-up, and the reason for death is not known. Seven patients died within a mean period of 52.3 months (range ) after PCI, without undergoing AVR. Six of them were older than 75 years, and 1 refused to undergo surgery. The results of the Kaplan-Meier event-free survival analysis according to patients characteristics are summarized in Table 2. There is a clear trend for better long-term outcome for patients with good functional class, with single vessel coronary disease, and who underwent PCI according to medical advice, but none of the variables reached statistical significance (Figures 1-3). Patients with a good functional class had a lower event rate during the years immediately after PCI with merging of the survival curves after 5 years (Figure 2). Patients who refused surgery and preferred to undergo PCI against medical advice had a remarkably higher event rate during the first year because of early need for AVR (Figure 3). This did not reach statistical significance probably because of the relatively small number of patients. Advanced age and AS severity were not associated with poor clinical outcome (need for AVR or death). Sixteen patients were in the short-term event-free survival group ( 30 months from PCI). Eleven patients underwent AVR, 4 patients died, and 1 patient had uneventful follow-up. Fourteen patients were in the long-term eventfree survival group ( 30 months), 7 patients underwent AVR, 6 patients died, and 1 patient had uneventful follow

4 185.e10 The American Journal of Medicine, Vol 120, No 2, February 2007 Table 2 Event-free Survival Analysis According to Patients Characteristics (Kaplan-Meier) Characteristic No. of Patients Mean Survival (mo) Median Survival (mo) P Value (log-rank) Total Age (y) Sex Male Female Origin Ashkenazi Jews Sephardic Jews Arabs *Functional class I-II III-IV *Aortic valve area 0.9 cm cm Coronary disease severity Single vessel Multivessel Left ventricular function Good Moderate, poor *Reason for PCI According to medical advice Against medical advice PCI percutaneous coronary intervention. Missing data for analysis: functional class in 2 patients, aortic valve area in 6 patients, and reason for PCI in 5 patients. Statistically significant values are shown in bold. up. Seven patients who had less than 1 year of follow-up without events were excluded from this analysis. Statistically significant predictors for long-term eventfree survival were single vessel coronary disease (P.017) and good functional class (P.006). As in the Kaplan- Meier analysis, there was a trend for better outcome for patients who underwent PCI according to medical advice, but this did not reach statistical significance (P.16). Age, gender, AS severity, and left ventricular function were not predictors of long-term survival (Table 3). Six patients were denied surgery because of high risk or acute unstable condition. The mean age of this group was 75.1 years, and 5 of them were aged more than 70 years Cumulative Event Free Survival p = Functional Class: I - II: III - IV: Cumulative Survival p = CAD severity: Single vessel: Multi vessel: time of follow-up (months) Figure 1 Event-free survival curves according to functional class. time of follow-up (months) Figure 2 Event-free survival curves according to coronary artery severity. CAD coronary artery disease.

5 Alcalai et al Coronary Intervention in Aortic Stenosis 185.e11 Cumulative Survival time of follow-up(months) p = Reason for performing PCI: According to medical advice Against medical advice Figure 3 Event-free survival curves according to reason for performing PCI. PCI percutaneous coronary intervention. These high-risk patients underwent successful PCI. Two of them were sent to AVR surgery within 1 and 4 months after recovery from the acute state, and 3 of them had long event-free survival periods of 32, 57, and 60 months. Among 7 patients who underwent surgery 30 months or more after PCI, no deterioration of left ventricular function (documented by repeated echo) was noted during the time from PCI to AVR. None of these patients died in the perioperative period despite the delay of surgery DISCUSSION AS and CAD are 2 common diseases that may have similar clinical manifestations and often coexist. 6,10 An important clinical question in these patients is which of the 2 pathologies is the cause for the patients symptoms, mainly when they present with angina or dyspnea. Traditionally, the recommended therapeutic approach is combined AVR with CABG. PCI in patients with significant AS is generally used only in rare cases. The main reasons for refraining from PCI are the limited ability of the left ventricle to raise cardiac output if necessary during PCI, given the mechanical obstruction by AS, and the fact that many of these patients would eventually need AVR surgery in any event. The enormous progress in PCI techniques in the last decade has made PCI feasible in patients who were previously considered as too risky. Some of these relatively contraindicated conditions included acute myocardial infarction, left main disease, and severe AS. In the modern PCI era, procedures are shorter and have larger safety margins than in the past. This progress raises the question of whether combined surgery is necessary for all patients with both significant AS and CAD, or whether an alternative approach by PCI could be used. PCI alone, with postponement of AVR until AS severity by itself justifies surgery later on, might be a satisfactory solution to their CADrelated symptoms. Table 3 Comparison Between Long- and Short-term Survival Groups According to Patients Characteristics Characteristic Short-term Survivors ( 30 mo) Long-term Survivors ( 30 mo) P Value (2-sided Fisher Exact Test) No Age (y) Sex Male Female 7 4 *Functional class Good (I-II) Poor (III-IV) 13 4 *Aortic valve area 0.9 cm cm CAD severity Single vessel Multivessel 8 1 Left ventricular function Good Moderate and poor 4 4 *Reason for PCI According to medical advice Against medical advice 4 1 CAD coronary artery disease; PCI percutaneous coronary intervention. *Missing data for analysis: functional class in 2 patients, aortic valve area in 6 patients, and reason for PCI for in 5 patients. Statistically significant values are shown in bold.

6 185.e12 The American Journal of Medicine, Vol 120, No 2, February 2007 In recent years, medical centers with high PCI volume have acquired experience in performing PCI in patients with moderate and severe AS. Initially it was performed only in patients who refused surgery or had comorbidities that rendered them inoperable. Later on, PCI was performed in selected patients with AS on the basis of cardiologists preferences. Reasons for the performance of PCI were usually multifactorial and took into account the severity of AS, other clinical manifestations, surgical risk, PCI feasibility, and others. To the best of our knowledge, no data are available in the literature to determine whether the approach of performing PCI in patients with significant AS is justified. In this retrospective study we demonstrate that PCI is feasible, safe, and may offer immediate symptomatic relief even in the presence of severe and critical AS. The clinical improvement achieved by PCI in a significant proportion of these patients demonstrates the important contribution of coronary disease to their clinical symptoms. In approximately half of the patients, PCI was associated with longterm, surgery- and death-free survival, for up to 5 years. The clinical predictors for long-term event-free survival in our study were good functional class before PCI and single vessel coronary disease. No other characteristic, including the degree of AS severity, proved to be a significant predictor for outcome. We were able to define 2 subgroups of patients who might particularly benefit from percutaneous treatment of coronary lesions in the presence of moderate to severe or severe AS. One group includes the low-risk patients who have milder coronary disease and good functional class. In this group of patients, relief of symptoms and postponement of surgery for more than 2.5 years were achieved, without deterioration of left ventricle function or increased surgical risk. Because these patients progressed from symptomatic to asymptomatic AS, it justified avoiding surgery. The other group includes the high-risk patients who are considered poor surgical candidates with expected high rates of morbidity and mortality. PCI may offer such patients symptomatic improvement and in some cases may stabilize critically ill patients and serve as a bridge to surgery. The option for the hybrid procedure, first PCI and then AVR surgery alone, seems attractive and represents an excellent alternative to conventional CABG/valve surgery in some high-risk patients, as recently published by Byrne et al. 13 In recent years, it is being increasingly recognized that degenerative AS is an inflammatory, atheromatous, and potentially modifiable disease. 14 New studies suggest that medical therapies may soon be available to slow its progression and reduce the need for surgery, especially in patients who would become asymptomatic after PCI. The degree of AS severity, as defined by AV area, was not found to be a predictor for major events during followup. This finding suggests that our ability to predict the progression rate of valve stenosis in a particular patient is limited, and predictors for progression need to be better defined. 15 A potential explanation for this finding is that 2-dimensional echo alone may have a limited ability to precisely assess the severity of the aortic valve disease. The 3-dimensional valve shape provides additional information beyond the planimetered orifice area in determining the impact of valvular AS on patient hemodynamics. 16 Aortic valve morphology determined by 3-dimensional echo may better estimate the degree of valve stenosis and its hemodynamic consequences, and may better predict progression. Other variables such as amount of valvular calcification and cholesterol levels might also be taken into consideration when deciding whether to perform PCI or surgery. These variables, previously shown to be associated with aortic valve stenosis prognosis, 17,18 were not available in this retrospective study. Our study has 2 main limitations: First, it is a retrospective analysis and may be subject to selection bias. It nevertheless potentially identifies a subgroup of patients who may have significant immediate and long-term symptomatic improvement before or without concomitant AVR. The second limitation is the relatively small number of patients in the study group, which may explain the fact that some of the subgroup analyses did not reach statistical significance. Our study addresses an important clinical problem growing in importance, given the aging of the population. We demonstrate that many patients with significant AS who underwent PCI according to medical advice have excellent short- and long-term outcomes and show that with appropriate clinical assessment we can identify patients who could benefit most from PCI, despite the co-presence of severe AS. Further studies in larger cohorts are necessary to try and identify additional subgroups of patients with AS and CAD who may benefit from PCI before or even instead of AVR. References 1. Frank S, Johnson A, Ross J. Natural history of valvular aortic stenosis. Br Heart J.1973;35: Braunwald E. On the natural history of severe aortic stenosis. JAm Coll Cardiol. 1990;15: ACC/AHA guidelines for the management of patients with valvular heart disease. A report of the American College of Cardiology/American Heart Association. Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). 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