Evidence suggests that troponin-only testing is the superior strategy to diagnose acute myocardial infarction (AMI).¹ Because of this, in February 2015, the Choosing Wisely^® campaign issued a recommendation to use troponin I or T to diagnose AMI, and not to test for myoglobin or creatine kinase-MB (CK-MB).² This recommendation was in line with guidelines from the American Heart Association and the American College of Cardiology, which recommended that myoglobin and CK-MB are not useful and offer no benefit for the diagnosis of acute coronary syndrome.³ Some institutions have developed interventions to promote troponin-only testing, reporting substantial cost savings and no negative consequences.^4,5

Despite these successes, it is likely that institutions vary with respect to the adoption of the Choosing Wisely^® troponin-only testing recommendation.⁶ Implementing this recommendation requires both promoting clinician behavior change and a strong institutional culture of high-value care.⁷ Understanding the variation across institutions of troponin-only testing could inform how to promote high-value care recommendations nationwide. We aimed to describe patterns of troponin, myoglobin, and CK-MB testing in a sample of academic teaching hospitals before and after the Choosing Wisely^® recommendation.

Troponin, myoglobin, and CK-MB ordering data were extracted from Vizient’s (formerly University HealthSystem Consortium, Chicago, IL) Clinical Database/Resource Manager (CDB/RM^®) for all patients with a principal discharge diagnosis of AMI at all hospitals reporting all 36 months from the fourth quarter of 2013 through the third quarter of 2016. This period includes time both before and after the Choosing Wisely^® recommendation, which was released in the first quarter of 2015. Vizient’s CDB/RM contains ordering data for 300 academic medical centers and their affiliated hospitals and includes the discharge diagnoses for patients cared for by these institutions. Only patients with a principal discharge diagnosis of AMI were included because the Choosing Wisely^® recommendation is specific with regard to troponin-only testing for the diagnosis of AMI. Patients with a principal diagnosis code for subcategories of myocardial ischemia (eg, stable angina, unstable angina) were not included because of the large number of diagnosis codes for these subcategories (more than 100 in the International Classification of Diseases, Ninth Revision and the International Classification of Diseases, Tenth Revision) and because the variation in their use across institutions within the dataset limited the utility of using these codes to consistently and accurately identify patients with myocardial ischemia. Moreover, the diagnosis of AMI encompasses the subcategories of myocardial ischemia.⁸

Hospital rates of ordering cardiac biomarkers (troponin-only or troponin and myoglobin/CK-MB) were determined overall for the entire study period and for each quarter of the study period based on the total patients with a discharge diagnosis of AMI. For each quarter of the 12 study quarters, all the hospitals were divided into tertiles based on their rate of troponin-only testing per discharge diagnosis of AMI. Hospitals were then classified into 3 groups based on their tertile ranking over the full 12 study quarters. The first group included hospitals whose rate of troponin-only testing placed them in the top tertile for each and all quarters throughout the study period. The second group included hospitals whose troponin-only testing rate placed them in the bottom tertile for each and all quarters throughout the study period. The third group included hospitals whose troponin-only testing rate each quarter led to either an increase or decrease in their tertile ranking throughout the study period. χ² tests were used to test for bivariate associations among hospitals based on their rate of troponin-only testing and hospital size (number of beds), their regional geographic location, the volume of AMI patients seen at the hospital, whether the primary physician during the hospitalization was a cardiologist or other provider, and the hospitals’ quality ratings. Quality rating was based on an internal Vizient rating and the “Best Hospitals for Cardiology and Heart Surgery Rankings” as published in the US News & World Report.⁹ The Vizient quality rating is based on a composite score that combines scores from the domains of quality (hospital quality incentive scores), safety (patient safety indicators), patient-centeredness (Hospital Consumer Assessment of Healthcare Providers and Systems Hospital Survey), and equity (distribution of care by race/ethnicity, gender, and age). Simple slopes were calculated to determine the rate of change in troponin-only testing for each study quarter, and Student t tests were used to compare the rates of change of these simple slopes across study quarters.

Pattern of Troponin-Only Testing by Hospital Size

Pattern of Troponin-Only Testing by Geographic Region

The rate of troponin-only testing also varied and was statistically significantly different when comparing the 3 groups of hospitals across geographic regions of the country (P < 0.0001). Of the hospitals in the top tertile of troponin-only testing throughout the study period, the majority were in the Midwest (n = 6) and Mid-Atlantic (n = 5) regions. However, the rate of troponin-only testing for AMI in this group was highest in hospitals in the West (86/100 patients) and/or Southeast (75/100 patients) regions, although this rate was based on a small number of hospitals in these geographic areas (n = 1 in the West, n = 2 in the Southeast). Of hospitals in the bottom tertile of troponin-only testing throughout the study period, the majority were in the Mid-Atlantic region (n = 10). Hospitals that increased their troponin-only testing during the study period were predominantly in the Midwest (n = 12) and Mid-Atlantic regions (n = 11; Table), with the hospitals in the Midwest having the highest rate of troponin-only testing in this group.

Pattern of Troponin-Only Testing by Volume of AMI Patients

Of the hospitals in the top tertile of troponin-only testing during the study period, the majority cared for ≥1500 AMI patients (n = 9), but interestingly, among these hospitals, those caring for a smaller volume of AMI patients all had higher rates of troponin-only testing per 100 patients (P < 0.0001; Table). There was no other obvious pattern of troponin-only testing based on the volume of AMI patients cared for in hospitals in either the bottom tertile of troponin-only testing or hospitals that improved troponin-only testing during the study period.

Pattern of Troponin-Only Testing by Physician Type

Of the hospitals in the top tertile of troponin-only testing throughout the study period, those where a cardiologist cared for patients with AMI had higher rates of troponin-only testing (71/100 patients) than did hospitals where patients were cared for by a noncardiologist (60/100 patients). However, of the hospitals that improved their troponin-only testing during the study period, higher rates of troponin-only testing were seen in hospitals where patients were cared for by a noncardiologist (48/100 patients) compared with patients cared for by a cardiologist (34/100 patients; Table). These differences in hospital rates of troponin-only testing during the study period based on physician type were statistically significant (P < 0.0001; Table).

Pattern of Troponin-Only Testing by Quality Rating

Hospitals that were in the top tertile of troponin-only testing and were rated highly by Vizient’s quality rating or recognized as a top hospital by the US News & World Report had higher rates of troponin-only testing per 100 patients than did hospitals in the top tertile that were not ranked highly by Vizient’s quality rating or recognized as a top hospital by the US News & World Report. However, the majority of hospitals in the top tertile of troponin-only testing were not rated highly by Vizient (n = 15) or recognized as a top hospital by the US News & World Report (n = 16). The large majority of hospitals in the bottom tertile of troponin-only testing were not recognized as high-quality hospitals by Vizient (n = 32) or the US News & World Report (n = 31). Of the hospitals that improved their troponin-only testing during the study period, the majority were not recognized as high-quality hospitals by Vizient (n = 33) or the US News & World Report (n = 36), but among this group, those hospitals recognized by Vizient as high quality (n = 5) had the highest rate of troponin-only testing (57/100 patients). The differences in the rate of troponin-only testing across the different groups of hospitals and quality ratings were statistically significant (P < 0.0001; Table).

The Effect of Choosing Wisely^® on Troponin-Only Testing

Disclosure 

No other individuals besides the authors contributed to this work. This project was not funded or supported by any external grant or agency. Dr. Prochaska’s institute received funding from the Agency for Research Healthcare and Quality for a K12 Career Development Grant (AHRQ K12 HS023007) outside the submitted work. Dr. Hohmann and Dr Modes have nothing to disclose. Dr. Arora receives financial compensation as a member of the Board of Directors for the American Board of Internal Medicine and has received grant funding from the ABIM Foundation. She also receives royalties from McGraw Hill.

Evidence suggests that troponin-only testing is the superior strategy to diagnose acute myocardial infarction (AMI).¹ Because of this, in February 2015, the Choosing Wisely^® campaign issued a recommendation to use troponin I or T to diagnose AMI, and not to test for myoglobin or creatine kinase-MB (CK-MB).² This recommendation was in line with guidelines from the American Heart Association and the American College of Cardiology, which recommended that myoglobin and CK-MB are not useful and offer no benefit for the diagnosis of acute coronary syndrome.³ Some institutions have developed interventions to promote troponin-only testing, reporting substantial cost savings and no negative consequences.^4,5

Despite these successes, it is likely that institutions vary with respect to the adoption of the Choosing Wisely^® troponin-only testing recommendation.⁶ Implementing this recommendation requires both promoting clinician behavior change and a strong institutional culture of high-value care.⁷ Understanding the variation across institutions of troponin-only testing could inform how to promote high-value care recommendations nationwide. We aimed to describe patterns of troponin, myoglobin, and CK-MB testing in a sample of academic teaching hospitals before and after the Choosing Wisely^® recommendation.

Troponin, myoglobin, and CK-MB ordering data were extracted from Vizient’s (formerly University HealthSystem Consortium, Chicago, IL) Clinical Database/Resource Manager (CDB/RM^®) for all patients with a principal discharge diagnosis of AMI at all hospitals reporting all 36 months from the fourth quarter of 2013 through the third quarter of 2016. This period includes time both before and after the Choosing Wisely^® recommendation, which was released in the first quarter of 2015. Vizient’s CDB/RM contains ordering data for 300 academic medical centers and their affiliated hospitals and includes the discharge diagnoses for patients cared for by these institutions. Only patients with a principal discharge diagnosis of AMI were included because the Choosing Wisely^® recommendation is specific with regard to troponin-only testing for the diagnosis of AMI. Patients with a principal diagnosis code for subcategories of myocardial ischemia (eg, stable angina, unstable angina) were not included because of the large number of diagnosis codes for these subcategories (more than 100 in the International Classification of Diseases, Ninth Revision and the International Classification of Diseases, Tenth Revision) and because the variation in their use across institutions within the dataset limited the utility of using these codes to consistently and accurately identify patients with myocardial ischemia. Moreover, the diagnosis of AMI encompasses the subcategories of myocardial ischemia.⁸

Hospital rates of ordering cardiac biomarkers (troponin-only or troponin and myoglobin/CK-MB) were determined overall for the entire study period and for each quarter of the study period based on the total patients with a discharge diagnosis of AMI. For each quarter of the 12 study quarters, all the hospitals were divided into tertiles based on their rate of troponin-only testing per discharge diagnosis of AMI. Hospitals were then classified into 3 groups based on their tertile ranking over the full 12 study quarters. The first group included hospitals whose rate of troponin-only testing placed them in the top tertile for each and all quarters throughout the study period. The second group included hospitals whose troponin-only testing rate placed them in the bottom tertile for each and all quarters throughout the study period. The third group included hospitals whose troponin-only testing rate each quarter led to either an increase or decrease in their tertile ranking throughout the study period. χ² tests were used to test for bivariate associations among hospitals based on their rate of troponin-only testing and hospital size (number of beds), their regional geographic location, the volume of AMI patients seen at the hospital, whether the primary physician during the hospitalization was a cardiologist or other provider, and the hospitals’ quality ratings. Quality rating was based on an internal Vizient rating and the “Best Hospitals for Cardiology and Heart Surgery Rankings” as published in the US News & World Report.⁹ The Vizient quality rating is based on a composite score that combines scores from the domains of quality (hospital quality incentive scores), safety (patient safety indicators), patient-centeredness (Hospital Consumer Assessment of Healthcare Providers and Systems Hospital Survey), and equity (distribution of care by race/ethnicity, gender, and age). Simple slopes were calculated to determine the rate of change in troponin-only testing for each study quarter, and Student t tests were used to compare the rates of change of these simple slopes across study quarters.

Pattern of Troponin-Only Testing by Hospital Size

Pattern of Troponin-Only Testing by Geographic Region

The rate of troponin-only testing also varied and was statistically significantly different when comparing the 3 groups of hospitals across geographic regions of the country (P < 0.0001). Of the hospitals in the top tertile of troponin-only testing throughout the study period, the majority were in the Midwest (n = 6) and Mid-Atlantic (n = 5) regions. However, the rate of troponin-only testing for AMI in this group was highest in hospitals in the West (86/100 patients) and/or Southeast (75/100 patients) regions, although this rate was based on a small number of hospitals in these geographic areas (n = 1 in the West, n = 2 in the Southeast). Of hospitals in the bottom tertile of troponin-only testing throughout the study period, the majority were in the Mid-Atlantic region (n = 10). Hospitals that increased their troponin-only testing during the study period were predominantly in the Midwest (n = 12) and Mid-Atlantic regions (n = 11; Table), with the hospitals in the Midwest having the highest rate of troponin-only testing in this group.

Pattern of Troponin-Only Testing by Volume of AMI Patients

Of the hospitals in the top tertile of troponin-only testing during the study period, the majority cared for ≥1500 AMI patients (n = 9), but interestingly, among these hospitals, those caring for a smaller volume of AMI patients all had higher rates of troponin-only testing per 100 patients (P < 0.0001; Table). There was no other obvious pattern of troponin-only testing based on the volume of AMI patients cared for in hospitals in either the bottom tertile of troponin-only testing or hospitals that improved troponin-only testing during the study period.

Pattern of Troponin-Only Testing by Physician Type

Of the hospitals in the top tertile of troponin-only testing throughout the study period, those where a cardiologist cared for patients with AMI had higher rates of troponin-only testing (71/100 patients) than did hospitals where patients were cared for by a noncardiologist (60/100 patients). However, of the hospitals that improved their troponin-only testing during the study period, higher rates of troponin-only testing were seen in hospitals where patients were cared for by a noncardiologist (48/100 patients) compared with patients cared for by a cardiologist (34/100 patients; Table). These differences in hospital rates of troponin-only testing during the study period based on physician type were statistically significant (P < 0.0001; Table).

Pattern of Troponin-Only Testing by Quality Rating

Hospitals that were in the top tertile of troponin-only testing and were rated highly by Vizient’s quality rating or recognized as a top hospital by the US News & World Report had higher rates of troponin-only testing per 100 patients than did hospitals in the top tertile that were not ranked highly by Vizient’s quality rating or recognized as a top hospital by the US News & World Report. However, the majority of hospitals in the top tertile of troponin-only testing were not rated highly by Vizient (n = 15) or recognized as a top hospital by the US News & World Report (n = 16). The large majority of hospitals in the bottom tertile of troponin-only testing were not recognized as high-quality hospitals by Vizient (n = 32) or the US News & World Report (n = 31). Of the hospitals that improved their troponin-only testing during the study period, the majority were not recognized as high-quality hospitals by Vizient (n = 33) or the US News & World Report (n = 36), but among this group, those hospitals recognized by Vizient as high quality (n = 5) had the highest rate of troponin-only testing (57/100 patients). The differences in the rate of troponin-only testing across the different groups of hospitals and quality ratings were statistically significant (P < 0.0001; Table).

The Effect of Choosing Wisely^® on Troponin-Only Testing

Disclosure 

No other individuals besides the authors contributed to this work. This project was not funded or supported by any external grant or agency. Dr. Prochaska’s institute received funding from the Agency for Research Healthcare and Quality for a K12 Career Development Grant (AHRQ K12 HS023007) outside the submitted work. Dr. Hohmann and Dr Modes have nothing to disclose. Dr. Arora receives financial compensation as a member of the Board of Directors for the American Board of Internal Medicine and has received grant funding from the ABIM Foundation. She also receives royalties from McGraw Hill.

Evidence suggests that troponin-only testing is the superior strategy to diagnose acute myocardial infarction (AMI).¹ Because of this, in February 2015, the Choosing Wisely^® campaign issued a recommendation to use troponin I or T to diagnose AMI, and not to test for myoglobin or creatine kinase-MB (CK-MB).² This recommendation was in line with guidelines from the American Heart Association and the American College of Cardiology, which recommended that myoglobin and CK-MB are not useful and offer no benefit for the diagnosis of acute coronary syndrome.³ Some institutions have developed interventions to promote troponin-only testing, reporting substantial cost savings and no negative consequences.^4,5

Despite these successes, it is likely that institutions vary with respect to the adoption of the Choosing Wisely^® troponin-only testing recommendation.⁶ Implementing this recommendation requires both promoting clinician behavior change and a strong institutional culture of high-value care.⁷ Understanding the variation across institutions of troponin-only testing could inform how to promote high-value care recommendations nationwide. We aimed to describe patterns of troponin, myoglobin, and CK-MB testing in a sample of academic teaching hospitals before and after the Choosing Wisely^® recommendation.

Troponin, myoglobin, and CK-MB ordering data were extracted from Vizient’s (formerly University HealthSystem Consortium, Chicago, IL) Clinical Database/Resource Manager (CDB/RM^®) for all patients with a principal discharge diagnosis of AMI at all hospitals reporting all 36 months from the fourth quarter of 2013 through the third quarter of 2016. This period includes time both before and after the Choosing Wisely^® recommendation, which was released in the first quarter of 2015. Vizient’s CDB/RM contains ordering data for 300 academic medical centers and their affiliated hospitals and includes the discharge diagnoses for patients cared for by these institutions. Only patients with a principal discharge diagnosis of AMI were included because the Choosing Wisely^® recommendation is specific with regard to troponin-only testing for the diagnosis of AMI. Patients with a principal diagnosis code for subcategories of myocardial ischemia (eg, stable angina, unstable angina) were not included because of the large number of diagnosis codes for these subcategories (more than 100 in the International Classification of Diseases, Ninth Revision and the International Classification of Diseases, Tenth Revision) and because the variation in their use across institutions within the dataset limited the utility of using these codes to consistently and accurately identify patients with myocardial ischemia. Moreover, the diagnosis of AMI encompasses the subcategories of myocardial ischemia.⁸

Hospital rates of ordering cardiac biomarkers (troponin-only or troponin and myoglobin/CK-MB) were determined overall for the entire study period and for each quarter of the study period based on the total patients with a discharge diagnosis of AMI. For each quarter of the 12 study quarters, all the hospitals were divided into tertiles based on their rate of troponin-only testing per discharge diagnosis of AMI. Hospitals were then classified into 3 groups based on their tertile ranking over the full 12 study quarters. The first group included hospitals whose rate of troponin-only testing placed them in the top tertile for each and all quarters throughout the study period. The second group included hospitals whose troponin-only testing rate placed them in the bottom tertile for each and all quarters throughout the study period. The third group included hospitals whose troponin-only testing rate each quarter led to either an increase or decrease in their tertile ranking throughout the study period. χ² tests were used to test for bivariate associations among hospitals based on their rate of troponin-only testing and hospital size (number of beds), their regional geographic location, the volume of AMI patients seen at the hospital, whether the primary physician during the hospitalization was a cardiologist or other provider, and the hospitals’ quality ratings. Quality rating was based on an internal Vizient rating and the “Best Hospitals for Cardiology and Heart Surgery Rankings” as published in the US News & World Report.⁹ The Vizient quality rating is based on a composite score that combines scores from the domains of quality (hospital quality incentive scores), safety (patient safety indicators), patient-centeredness (Hospital Consumer Assessment of Healthcare Providers and Systems Hospital Survey), and equity (distribution of care by race/ethnicity, gender, and age). Simple slopes were calculated to determine the rate of change in troponin-only testing for each study quarter, and Student t tests were used to compare the rates of change of these simple slopes across study quarters.

Pattern of Troponin-Only Testing by Hospital Size

Pattern of Troponin-Only Testing by Geographic Region

The rate of troponin-only testing also varied and was statistically significantly different when comparing the 3 groups of hospitals across geographic regions of the country (P < 0.0001). Of the hospitals in the top tertile of troponin-only testing throughout the study period, the majority were in the Midwest (n = 6) and Mid-Atlantic (n = 5) regions. However, the rate of troponin-only testing for AMI in this group was highest in hospitals in the West (86/100 patients) and/or Southeast (75/100 patients) regions, although this rate was based on a small number of hospitals in these geographic areas (n = 1 in the West, n = 2 in the Southeast). Of hospitals in the bottom tertile of troponin-only testing throughout the study period, the majority were in the Mid-Atlantic region (n = 10). Hospitals that increased their troponin-only testing during the study period were predominantly in the Midwest (n = 12) and Mid-Atlantic regions (n = 11; Table), with the hospitals in the Midwest having the highest rate of troponin-only testing in this group.

Pattern of Troponin-Only Testing by Volume of AMI Patients

Of the hospitals in the top tertile of troponin-only testing during the study period, the majority cared for ≥1500 AMI patients (n = 9), but interestingly, among these hospitals, those caring for a smaller volume of AMI patients all had higher rates of troponin-only testing per 100 patients (P < 0.0001; Table). There was no other obvious pattern of troponin-only testing based on the volume of AMI patients cared for in hospitals in either the bottom tertile of troponin-only testing or hospitals that improved troponin-only testing during the study period.

Pattern of Troponin-Only Testing by Physician Type

Of the hospitals in the top tertile of troponin-only testing throughout the study period, those where a cardiologist cared for patients with AMI had higher rates of troponin-only testing (71/100 patients) than did hospitals where patients were cared for by a noncardiologist (60/100 patients). However, of the hospitals that improved their troponin-only testing during the study period, higher rates of troponin-only testing were seen in hospitals where patients were cared for by a noncardiologist (48/100 patients) compared with patients cared for by a cardiologist (34/100 patients; Table). These differences in hospital rates of troponin-only testing during the study period based on physician type were statistically significant (P < 0.0001; Table).

Pattern of Troponin-Only Testing by Quality Rating

Hospitals that were in the top tertile of troponin-only testing and were rated highly by Vizient’s quality rating or recognized as a top hospital by the US News & World Report had higher rates of troponin-only testing per 100 patients than did hospitals in the top tertile that were not ranked highly by Vizient’s quality rating or recognized as a top hospital by the US News & World Report. However, the majority of hospitals in the top tertile of troponin-only testing were not rated highly by Vizient (n = 15) or recognized as a top hospital by the US News & World Report (n = 16). The large majority of hospitals in the bottom tertile of troponin-only testing were not recognized as high-quality hospitals by Vizient (n = 32) or the US News & World Report (n = 31). Of the hospitals that improved their troponin-only testing during the study period, the majority were not recognized as high-quality hospitals by Vizient (n = 33) or the US News & World Report (n = 36), but among this group, those hospitals recognized by Vizient as high quality (n = 5) had the highest rate of troponin-only testing (57/100 patients). The differences in the rate of troponin-only testing across the different groups of hospitals and quality ratings were statistically significant (P < 0.0001; Table).

The Effect of Choosing Wisely^® on Troponin-Only Testing

Disclosure 

No other individuals besides the authors contributed to this work. This project was not funded or supported by any external grant or agency. Dr. Prochaska’s institute received funding from the Agency for Research Healthcare and Quality for a K12 Career Development Grant (AHRQ K12 HS023007) outside the submitted work. Dr. Hohmann and Dr Modes have nothing to disclose. Dr. Arora receives financial compensation as a member of the Board of Directors for the American Board of Internal Medicine and has received grant funding from the ABIM Foundation. She also receives royalties from McGraw Hill.

Intravascular ultrasonography (IVUS) has been used for the past 20 years to measure atheromatous plaque in patients with coronary artery disease. The total volume of atherosclerosis in a coronary artery segment can be calculated using IVUS. A rotating transducer produces an image of a single, cross-sectional slice of the artery from which the atheroma area is calculated. A motorized device is used to withdraw the catheter, obtaining a series of cross-sectional slices at 1-mm intervals. The atheroma area for each slice is summated to obtain the total volume of atherosclerosis in the artery.

IVUS has demonstrated that statins slow the progression or even induce regression of coronary atherosclerosis in proportion to the degree of reduction in low-density lipoprotein cholesterol (LDL-C).^1–4 No LDL-C-lowering therapy other than statins has shown regression of atherosclerosis in a trial using IVUS. The lowest LDL-C achieved in prior trials using statins was about 60 mg/dL.^1,3 While this is very low, lower levels have not previously been explored.

Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors, a new class of drugs, are injectable, fully human monoclonal antibodies that inactivate the PCSK9 protein. PCSK9 inhibitors have been shown to lower LDL-C incrementally when added to statins, achieving very low LDL-C levels.^5,6 However, no data exist describing the effect of low LDL-C levels reached using PCSK9 inhibitors on the progression of atherosclerosis.

THE GLAGOV TRIAL

Based on information from reference 7.

RESULTS

LDL-C levels

Based on information from reference 7.

Total atheroma volume and percent of patients with atheroma regression

The secondary end point measuring the total atheroma volume in the coronaries showed no change in total volume of atherosclerotic plaque in the statin monotherapy group and a decrease in the statin plus evolocumab group.

Based on information from reference 7.

Patients with LDL-C < 70 mg/dL

A subgroup of patients had a baseline LDL-C below 70 mg/dL, the lowest level recommended by guideline. Patients in this subgroup who received statin monotherapy remained at a mean LDL-C of 70 mg/dL whereas patients on statin plus evolocumab achieved a mean LDL-C of 24 mg/dL with a mean 2-week post-dosing trough level of 15 mg/dL, an unbelievably low level of LDL-C. In this subgroup, 81% of patients receiving statin plus evolocumab had atheroma regression, compared with 48% of patients in the statin monotherapy group. The percent of patients with atheroma regression in this subgroup of patients with low LDL-C at baseline was twice that seen in the larger study population (33% vs 17%), revealing profound levels of regression in patients treated with dual therapy.

Limitations

Like all trials, this one has limitations. The population is very select: these are patients with clinically indicated angiogram, not a primary prevention population. Some study participants dropped out, which is always a limitation. And of course, this is a surrogate measure; it is a measure of disease activity, not a measure of morbidity and mortality. Morbidity and mortality data for this new class of drugs should be available in about a year, though this study suggests that those data will be favorable.

CONCLUSION

High LDL-C is universally accepted as a factor in the formation of arterial plaque and atherosclerosis. Statin therapy reduces LDL-C levels to slow or induce regression of coronary atherosclerosis in proportion to the magnitude of LDL-C reduction as measured by IVUS. However, the question of how far to reduce lipid levels has evolved over the last 4 decades. In the 1970s, a normal total cholesterol was < 300 mg/dL. More recent data that suggest optimal LDL-C levels for patients with coronary artery disease may be much lower than commonly achieved.

In this study, in patients with symptomatic coronary artery disease, treatment with statins and the addition of the PCSK9 inhibitor evolocumab achieved mean LDL-C levels of 36.6 mg/dL, produced atheroma regression with a mean change in PAV of about 1% (P < .001), induced regression in a greater percentage of patients, and showed incremental benefit for treatment of LDL-C down to as low as 20 mg/dL. The GLAGOV trial provides intriguing evidence that clinical benefits may extend to LDL-C levels as low as 20 mg/dL; however, the sample size of the trial was modest, providing limited power for safety assessments.

Since this presentation, the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial achieved a median LDL-C of 30 mg/dL and reduced risk of cardiovascular events in patients with atherosclerotic cardiovascular disease treated with evolocumab added to statin therapy.⁸ Additional large outcomes trials of PCSK9 inhibitors and their role in reducing LDL-C and regression of coronary atheroma and atherosclerosis are eagerly awaited.

Intravascular ultrasonography (IVUS) has been used for the past 20 years to measure atheromatous plaque in patients with coronary artery disease. The total volume of atherosclerosis in a coronary artery segment can be calculated using IVUS. A rotating transducer produces an image of a single, cross-sectional slice of the artery from which the atheroma area is calculated. A motorized device is used to withdraw the catheter, obtaining a series of cross-sectional slices at 1-mm intervals. The atheroma area for each slice is summated to obtain the total volume of atherosclerosis in the artery.

IVUS has demonstrated that statins slow the progression or even induce regression of coronary atherosclerosis in proportion to the degree of reduction in low-density lipoprotein cholesterol (LDL-C).^1–4 No LDL-C-lowering therapy other than statins has shown regression of atherosclerosis in a trial using IVUS. The lowest LDL-C achieved in prior trials using statins was about 60 mg/dL.^1,3 While this is very low, lower levels have not previously been explored.

Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors, a new class of drugs, are injectable, fully human monoclonal antibodies that inactivate the PCSK9 protein. PCSK9 inhibitors have been shown to lower LDL-C incrementally when added to statins, achieving very low LDL-C levels.^5,6 However, no data exist describing the effect of low LDL-C levels reached using PCSK9 inhibitors on the progression of atherosclerosis.

THE GLAGOV TRIAL

Based on information from reference 7.

RESULTS

LDL-C levels

Based on information from reference 7.

Total atheroma volume and percent of patients with atheroma regression

The secondary end point measuring the total atheroma volume in the coronaries showed no change in total volume of atherosclerotic plaque in the statin monotherapy group and a decrease in the statin plus evolocumab group.

Based on information from reference 7.

Patients with LDL-C < 70 mg/dL

A subgroup of patients had a baseline LDL-C below 70 mg/dL, the lowest level recommended by guideline. Patients in this subgroup who received statin monotherapy remained at a mean LDL-C of 70 mg/dL whereas patients on statin plus evolocumab achieved a mean LDL-C of 24 mg/dL with a mean 2-week post-dosing trough level of 15 mg/dL, an unbelievably low level of LDL-C. In this subgroup, 81% of patients receiving statin plus evolocumab had atheroma regression, compared with 48% of patients in the statin monotherapy group. The percent of patients with atheroma regression in this subgroup of patients with low LDL-C at baseline was twice that seen in the larger study population (33% vs 17%), revealing profound levels of regression in patients treated with dual therapy.

Limitations

Like all trials, this one has limitations. The population is very select: these are patients with clinically indicated angiogram, not a primary prevention population. Some study participants dropped out, which is always a limitation. And of course, this is a surrogate measure; it is a measure of disease activity, not a measure of morbidity and mortality. Morbidity and mortality data for this new class of drugs should be available in about a year, though this study suggests that those data will be favorable.

CONCLUSION

High LDL-C is universally accepted as a factor in the formation of arterial plaque and atherosclerosis. Statin therapy reduces LDL-C levels to slow or induce regression of coronary atherosclerosis in proportion to the magnitude of LDL-C reduction as measured by IVUS. However, the question of how far to reduce lipid levels has evolved over the last 4 decades. In the 1970s, a normal total cholesterol was < 300 mg/dL. More recent data that suggest optimal LDL-C levels for patients with coronary artery disease may be much lower than commonly achieved.

In this study, in patients with symptomatic coronary artery disease, treatment with statins and the addition of the PCSK9 inhibitor evolocumab achieved mean LDL-C levels of 36.6 mg/dL, produced atheroma regression with a mean change in PAV of about 1% (P < .001), induced regression in a greater percentage of patients, and showed incremental benefit for treatment of LDL-C down to as low as 20 mg/dL. The GLAGOV trial provides intriguing evidence that clinical benefits may extend to LDL-C levels as low as 20 mg/dL; however, the sample size of the trial was modest, providing limited power for safety assessments.

Since this presentation, the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial achieved a median LDL-C of 30 mg/dL and reduced risk of cardiovascular events in patients with atherosclerotic cardiovascular disease treated with evolocumab added to statin therapy.⁸ Additional large outcomes trials of PCSK9 inhibitors and their role in reducing LDL-C and regression of coronary atheroma and atherosclerosis are eagerly awaited.

Intravascular ultrasonography (IVUS) has been used for the past 20 years to measure atheromatous plaque in patients with coronary artery disease. The total volume of atherosclerosis in a coronary artery segment can be calculated using IVUS. A rotating transducer produces an image of a single, cross-sectional slice of the artery from which the atheroma area is calculated. A motorized device is used to withdraw the catheter, obtaining a series of cross-sectional slices at 1-mm intervals. The atheroma area for each slice is summated to obtain the total volume of atherosclerosis in the artery.

IVUS has demonstrated that statins slow the progression or even induce regression of coronary atherosclerosis in proportion to the degree of reduction in low-density lipoprotein cholesterol (LDL-C).^1–4 No LDL-C-lowering therapy other than statins has shown regression of atherosclerosis in a trial using IVUS. The lowest LDL-C achieved in prior trials using statins was about 60 mg/dL.^1,3 While this is very low, lower levels have not previously been explored.

Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors, a new class of drugs, are injectable, fully human monoclonal antibodies that inactivate the PCSK9 protein. PCSK9 inhibitors have been shown to lower LDL-C incrementally when added to statins, achieving very low LDL-C levels.^5,6 However, no data exist describing the effect of low LDL-C levels reached using PCSK9 inhibitors on the progression of atherosclerosis.

THE GLAGOV TRIAL

Based on information from reference 7.

RESULTS

LDL-C levels

Based on information from reference 7.

Total atheroma volume and percent of patients with atheroma regression

The secondary end point measuring the total atheroma volume in the coronaries showed no change in total volume of atherosclerotic plaque in the statin monotherapy group and a decrease in the statin plus evolocumab group.

Based on information from reference 7.

Patients with LDL-C < 70 mg/dL

A subgroup of patients had a baseline LDL-C below 70 mg/dL, the lowest level recommended by guideline. Patients in this subgroup who received statin monotherapy remained at a mean LDL-C of 70 mg/dL whereas patients on statin plus evolocumab achieved a mean LDL-C of 24 mg/dL with a mean 2-week post-dosing trough level of 15 mg/dL, an unbelievably low level of LDL-C. In this subgroup, 81% of patients receiving statin plus evolocumab had atheroma regression, compared with 48% of patients in the statin monotherapy group. The percent of patients with atheroma regression in this subgroup of patients with low LDL-C at baseline was twice that seen in the larger study population (33% vs 17%), revealing profound levels of regression in patients treated with dual therapy.

Limitations

Like all trials, this one has limitations. The population is very select: these are patients with clinically indicated angiogram, not a primary prevention population. Some study participants dropped out, which is always a limitation. And of course, this is a surrogate measure; it is a measure of disease activity, not a measure of morbidity and mortality. Morbidity and mortality data for this new class of drugs should be available in about a year, though this study suggests that those data will be favorable.

CONCLUSION

High LDL-C is universally accepted as a factor in the formation of arterial plaque and atherosclerosis. Statin therapy reduces LDL-C levels to slow or induce regression of coronary atherosclerosis in proportion to the magnitude of LDL-C reduction as measured by IVUS. However, the question of how far to reduce lipid levels has evolved over the last 4 decades. In the 1970s, a normal total cholesterol was < 300 mg/dL. More recent data that suggest optimal LDL-C levels for patients with coronary artery disease may be much lower than commonly achieved.

In this study, in patients with symptomatic coronary artery disease, treatment with statins and the addition of the PCSK9 inhibitor evolocumab achieved mean LDL-C levels of 36.6 mg/dL, produced atheroma regression with a mean change in PAV of about 1% (P < .001), induced regression in a greater percentage of patients, and showed incremental benefit for treatment of LDL-C down to as low as 20 mg/dL. The GLAGOV trial provides intriguing evidence that clinical benefits may extend to LDL-C levels as low as 20 mg/dL; however, the sample size of the trial was modest, providing limited power for safety assessments.

Since this presentation, the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial achieved a median LDL-C of 30 mg/dL and reduced risk of cardiovascular events in patients with atherosclerotic cardiovascular disease treated with evolocumab added to statin therapy.⁸ Additional large outcomes trials of PCSK9 inhibitors and their role in reducing LDL-C and regression of coronary atheroma and atherosclerosis are eagerly awaited.

Many clinical improvements in treating patients with acute ST-elevation myocardial infarction (STEMI) have been realized in the past 20 years, including angiotensin-converting enzyme inhibitors, antiplatelet agents, and reduced time to cardiac cauterization procedures for acute myocardial infaction.¹ Presumably, primary and secondary prevention measures have also resulted in changes in coronary artery disease (CAD) risk factors over the past 20 years. We sought to quantify mortality outcomes for patients treated in our catherization laboratory and to investigate trends in cardiovascular risk factors in patients during the same period.²

STEMI OUTCOMES

Data from our catherization laboratory database of 3,913 patients treated for STEMI at our tertiary care center from 1995 through 2014 were analyzed. To evaluate outcomes over time, patients were grouped based on years treated in 5-year increments resulting in 4 groups spanning 20 years.²

CARDIOVASCULAR RISK FACTORS

A reduction in mortality rates in patients treated for STEMI is to be expected over time, given the improvements in clinical practices and procedures and novel medications developed since 1996. But it is also possible that patients presenting with STEMI are healthier than in the past as a result of primary prevention efforts to minimize CAD risk factors and changes in CAD risk factors over time.

To determine whether CAD risk factors have changed over time, we analyzed the risk factors in the 3,913 patients treated for STEMI in our database. Risk factors included in the analysis were:

• Age
• Sex
• Diabetes mellitus
• Hypertension
• Smoking
• Hyperlipidemia
• Chronic renal impairment (serum creatinine greater than 1.5 mg/dL)
• Obesity (body mass index greater than 30 kg/m²).²

The prevalence of risk factors was determined in the entire cohort as well as in the 34% (n = 1,325) of patients previously diagnosed with CAD. The trend in risk factors in patients previously diagnosed with CAD could indicate the effectiveness of secondary prevention efforts compared with primary prevention in the broader patient population.

Based on data from reference 2.

Based on data from reference 2.

These data suggest that despite a better understanding of cardiovascular risk factors, the cardiovascular risk profiles of patients with acute STEMI have deteriorated over the past 20 years: patients are younger at presentation and more likely to be obese, to smoke, and to have hypertension and diabetes. These trends hold true in patients with and without a history of CAD, suggesting primary and secondary prevention efforts are ineffective.

To evaluate whether geographic or patient population characteristics could have biased our results, we analyzed mortality and risk factor data from the National (Nationwide) Inpatient Sample (NIS) for patients presenting with STEMI (N = 445,319), non-STEMI (N = 915,341), and stroke (N = 937,425) from 2003 to 2013.^4,5

Mortality rates

Consistent with the trend in our data, the 10-year NIS data showed a lower mortality rate in 2003 compared with 2013 in patients admitted with extreme-severity STEMI (22% vs 18%), non-STEMI (13% vs 8%), and stroke (15% vs 10%), as well as in patients with moderate-severity disease.⁴

Risk factors

Unfortunately, the prevalence of these relatively preventable CAD risk factors is moving in the wrong direction. The prevalence of smoking in patients presenting with non-STEMI, STEMI, or acute stroke is higher than in the past, contrary to the nationwide trend of decreasing rates of smoking.⁶ The increased rate of obesity evident in our data and the NSI data is consistent with rising obesity rates in the United States, which went from 30% to 37% in adults and from 14% to 17% in youth from 2000 to 2014.⁷ The percentage of adults with diabetes has increased tremendously in the United States, from 4.4% of adults in 1994 to 9.1% of adults in 2015.⁸ The rise in diabetes has led to increased rates of CAD, heart disease, and stroke in patients with diabetes.⁹

OPPORTUNITIES AHEAD

Despite improved STEMI outcomes, trends in cardiovascular risk profiles are deteriorating, emphasizing the critical need to educate people about primary and secondary prevention. Folsom et al¹⁰ conducted an analysis of a community-based sample to determine the prevalence of ideal cardiovascular health based on 4 ideal health behaviors (nonsmoking, low body mass index, adequate physical activity, healthy diet) and 3 ideal risk health factors (total cholesterol, blood pressure, and moderate glucose control).¹⁰ Each of the 7 behavior and risk factors was defined by ideal, intermediate, and poor characteristics. Very few study participants (0.1%) had ideal levels for all 7 healthy cardiovascular behaviors and risk factors, and over 82% had poor levels for all 7 behaviors and characteristics. The need to educate and improve cardiovascular health exists for both adults and youth. Measures of cardiovascular health in the United States indicate that 18% of adults age 50 or older and 46% of youth (ages 12 to 19) have 5 or more of the 7 health cardiovascular behaviors and risk factors at ideal levels.¹¹

Improvement in primary and secondary prevention measures may also present opportunities to contain or reduce the cost of care. Thus far, according to NIS registry data from 2003 to 2013, the mean adjusted cost of hospitalization for patients with STEMI increased about 14%, remained about the same for patients with non-STEMI, and increased about 3% for patients with stroke.⁴

CONCLUSION

Advances in clinical care have improved outcomes for patients with CAD during the past 2 decades. These gains have come despite a higher prevalence of CAD risk factors in patients. More emphasis on primary and secondary prevention to reduce CAD risk factors may further improve outcomes and possibly lower the cost of care. Aggressive encouragement of risk factor modification is necessary and should go beyond cardiologists to include primary care physicians, preventive clinics, secondary cardiovascular prevention, and population-based efforts.

Many clinical improvements in treating patients with acute ST-elevation myocardial infarction (STEMI) have been realized in the past 20 years, including angiotensin-converting enzyme inhibitors, antiplatelet agents, and reduced time to cardiac cauterization procedures for acute myocardial infaction.¹ Presumably, primary and secondary prevention measures have also resulted in changes in coronary artery disease (CAD) risk factors over the past 20 years. We sought to quantify mortality outcomes for patients treated in our catherization laboratory and to investigate trends in cardiovascular risk factors in patients during the same period.²

STEMI OUTCOMES

Data from our catherization laboratory database of 3,913 patients treated for STEMI at our tertiary care center from 1995 through 2014 were analyzed. To evaluate outcomes over time, patients were grouped based on years treated in 5-year increments resulting in 4 groups spanning 20 years.²

CARDIOVASCULAR RISK FACTORS

A reduction in mortality rates in patients treated for STEMI is to be expected over time, given the improvements in clinical practices and procedures and novel medications developed since 1996. But it is also possible that patients presenting with STEMI are healthier than in the past as a result of primary prevention efforts to minimize CAD risk factors and changes in CAD risk factors over time.

To determine whether CAD risk factors have changed over time, we analyzed the risk factors in the 3,913 patients treated for STEMI in our database. Risk factors included in the analysis were:

• Age
• Sex
• Diabetes mellitus
• Hypertension
• Smoking
• Hyperlipidemia
• Chronic renal impairment (serum creatinine greater than 1.5 mg/dL)
• Obesity (body mass index greater than 30 kg/m²).²

The prevalence of risk factors was determined in the entire cohort as well as in the 34% (n = 1,325) of patients previously diagnosed with CAD. The trend in risk factors in patients previously diagnosed with CAD could indicate the effectiveness of secondary prevention efforts compared with primary prevention in the broader patient population.

Based on data from reference 2.

Based on data from reference 2.

These data suggest that despite a better understanding of cardiovascular risk factors, the cardiovascular risk profiles of patients with acute STEMI have deteriorated over the past 20 years: patients are younger at presentation and more likely to be obese, to smoke, and to have hypertension and diabetes. These trends hold true in patients with and without a history of CAD, suggesting primary and secondary prevention efforts are ineffective.

To evaluate whether geographic or patient population characteristics could have biased our results, we analyzed mortality and risk factor data from the National (Nationwide) Inpatient Sample (NIS) for patients presenting with STEMI (N = 445,319), non-STEMI (N = 915,341), and stroke (N = 937,425) from 2003 to 2013.^4,5

Mortality rates

Consistent with the trend in our data, the 10-year NIS data showed a lower mortality rate in 2003 compared with 2013 in patients admitted with extreme-severity STEMI (22% vs 18%), non-STEMI (13% vs 8%), and stroke (15% vs 10%), as well as in patients with moderate-severity disease.⁴

Risk factors

Unfortunately, the prevalence of these relatively preventable CAD risk factors is moving in the wrong direction. The prevalence of smoking in patients presenting with non-STEMI, STEMI, or acute stroke is higher than in the past, contrary to the nationwide trend of decreasing rates of smoking.⁶ The increased rate of obesity evident in our data and the NSI data is consistent with rising obesity rates in the United States, which went from 30% to 37% in adults and from 14% to 17% in youth from 2000 to 2014.⁷ The percentage of adults with diabetes has increased tremendously in the United States, from 4.4% of adults in 1994 to 9.1% of adults in 2015.⁸ The rise in diabetes has led to increased rates of CAD, heart disease, and stroke in patients with diabetes.⁹

OPPORTUNITIES AHEAD

Despite improved STEMI outcomes, trends in cardiovascular risk profiles are deteriorating, emphasizing the critical need to educate people about primary and secondary prevention. Folsom et al¹⁰ conducted an analysis of a community-based sample to determine the prevalence of ideal cardiovascular health based on 4 ideal health behaviors (nonsmoking, low body mass index, adequate physical activity, healthy diet) and 3 ideal risk health factors (total cholesterol, blood pressure, and moderate glucose control).¹⁰ Each of the 7 behavior and risk factors was defined by ideal, intermediate, and poor characteristics. Very few study participants (0.1%) had ideal levels for all 7 healthy cardiovascular behaviors and risk factors, and over 82% had poor levels for all 7 behaviors and characteristics. The need to educate and improve cardiovascular health exists for both adults and youth. Measures of cardiovascular health in the United States indicate that 18% of adults age 50 or older and 46% of youth (ages 12 to 19) have 5 or more of the 7 health cardiovascular behaviors and risk factors at ideal levels.¹¹

Improvement in primary and secondary prevention measures may also present opportunities to contain or reduce the cost of care. Thus far, according to NIS registry data from 2003 to 2013, the mean adjusted cost of hospitalization for patients with STEMI increased about 14%, remained about the same for patients with non-STEMI, and increased about 3% for patients with stroke.⁴

CONCLUSION

Advances in clinical care have improved outcomes for patients with CAD during the past 2 decades. These gains have come despite a higher prevalence of CAD risk factors in patients. More emphasis on primary and secondary prevention to reduce CAD risk factors may further improve outcomes and possibly lower the cost of care. Aggressive encouragement of risk factor modification is necessary and should go beyond cardiologists to include primary care physicians, preventive clinics, secondary cardiovascular prevention, and population-based efforts.

Many clinical improvements in treating patients with acute ST-elevation myocardial infarction (STEMI) have been realized in the past 20 years, including angiotensin-converting enzyme inhibitors, antiplatelet agents, and reduced time to cardiac cauterization procedures for acute myocardial infaction.¹ Presumably, primary and secondary prevention measures have also resulted in changes in coronary artery disease (CAD) risk factors over the past 20 years. We sought to quantify mortality outcomes for patients treated in our catherization laboratory and to investigate trends in cardiovascular risk factors in patients during the same period.²

STEMI OUTCOMES

Data from our catherization laboratory database of 3,913 patients treated for STEMI at our tertiary care center from 1995 through 2014 were analyzed. To evaluate outcomes over time, patients were grouped based on years treated in 5-year increments resulting in 4 groups spanning 20 years.²

CARDIOVASCULAR RISK FACTORS

A reduction in mortality rates in patients treated for STEMI is to be expected over time, given the improvements in clinical practices and procedures and novel medications developed since 1996. But it is also possible that patients presenting with STEMI are healthier than in the past as a result of primary prevention efforts to minimize CAD risk factors and changes in CAD risk factors over time.

To determine whether CAD risk factors have changed over time, we analyzed the risk factors in the 3,913 patients treated for STEMI in our database. Risk factors included in the analysis were:

• Age
• Sex
• Diabetes mellitus
• Hypertension
• Smoking
• Hyperlipidemia
• Chronic renal impairment (serum creatinine greater than 1.5 mg/dL)
• Obesity (body mass index greater than 30 kg/m²).²

The prevalence of risk factors was determined in the entire cohort as well as in the 34% (n = 1,325) of patients previously diagnosed with CAD. The trend in risk factors in patients previously diagnosed with CAD could indicate the effectiveness of secondary prevention efforts compared with primary prevention in the broader patient population.

Based on data from reference 2.

Based on data from reference 2.

These data suggest that despite a better understanding of cardiovascular risk factors, the cardiovascular risk profiles of patients with acute STEMI have deteriorated over the past 20 years: patients are younger at presentation and more likely to be obese, to smoke, and to have hypertension and diabetes. These trends hold true in patients with and without a history of CAD, suggesting primary and secondary prevention efforts are ineffective.

To evaluate whether geographic or patient population characteristics could have biased our results, we analyzed mortality and risk factor data from the National (Nationwide) Inpatient Sample (NIS) for patients presenting with STEMI (N = 445,319), non-STEMI (N = 915,341), and stroke (N = 937,425) from 2003 to 2013.^4,5

Mortality rates

Consistent with the trend in our data, the 10-year NIS data showed a lower mortality rate in 2003 compared with 2013 in patients admitted with extreme-severity STEMI (22% vs 18%), non-STEMI (13% vs 8%), and stroke (15% vs 10%), as well as in patients with moderate-severity disease.⁴

Risk factors

Unfortunately, the prevalence of these relatively preventable CAD risk factors is moving in the wrong direction. The prevalence of smoking in patients presenting with non-STEMI, STEMI, or acute stroke is higher than in the past, contrary to the nationwide trend of decreasing rates of smoking.⁶ The increased rate of obesity evident in our data and the NSI data is consistent with rising obesity rates in the United States, which went from 30% to 37% in adults and from 14% to 17% in youth from 2000 to 2014.⁷ The percentage of adults with diabetes has increased tremendously in the United States, from 4.4% of adults in 1994 to 9.1% of adults in 2015.⁸ The rise in diabetes has led to increased rates of CAD, heart disease, and stroke in patients with diabetes.⁹

OPPORTUNITIES AHEAD

Despite improved STEMI outcomes, trends in cardiovascular risk profiles are deteriorating, emphasizing the critical need to educate people about primary and secondary prevention. Folsom et al¹⁰ conducted an analysis of a community-based sample to determine the prevalence of ideal cardiovascular health based on 4 ideal health behaviors (nonsmoking, low body mass index, adequate physical activity, healthy diet) and 3 ideal risk health factors (total cholesterol, blood pressure, and moderate glucose control).¹⁰ Each of the 7 behavior and risk factors was defined by ideal, intermediate, and poor characteristics. Very few study participants (0.1%) had ideal levels for all 7 healthy cardiovascular behaviors and risk factors, and over 82% had poor levels for all 7 behaviors and characteristics. The need to educate and improve cardiovascular health exists for both adults and youth. Measures of cardiovascular health in the United States indicate that 18% of adults age 50 or older and 46% of youth (ages 12 to 19) have 5 or more of the 7 health cardiovascular behaviors and risk factors at ideal levels.¹¹

Improvement in primary and secondary prevention measures may also present opportunities to contain or reduce the cost of care. Thus far, according to NIS registry data from 2003 to 2013, the mean adjusted cost of hospitalization for patients with STEMI increased about 14%, remained about the same for patients with non-STEMI, and increased about 3% for patients with stroke.⁴

CONCLUSION

Advances in clinical care have improved outcomes for patients with CAD during the past 2 decades. These gains have come despite a higher prevalence of CAD risk factors in patients. More emphasis on primary and secondary prevention to reduce CAD risk factors may further improve outcomes and possibly lower the cost of care. Aggressive encouragement of risk factor modification is necessary and should go beyond cardiologists to include primary care physicians, preventive clinics, secondary cardiovascular prevention, and population-based efforts.

Surgical aortic valve replacement (SAVR) started in the 1960s with a porcine aortic valve sutured to a stainless steel frame. The first human transcatheter aortic valve replacement (TAVR) procedure in the United States was in 2002. In the past 15 years, technological advances in heart valve design have made TAVR the preferred alternative in patients at high risk for surgical complications. This article outlines studies comparing balloon-expandable TAVR vs SAVR for patients at extreme, high, and intermediate surgical risk, and presents evidence that supports the expanded use of TAVR in patients at lower surgical risk.

TAVR: THE PREFERRED ALTERNATIVE TO SURGERY

Investigators next established TAVR outcomes as being noninferior to SAVR in high surgical risk patients (PARTNER trial cohort A) at 1 year.² A midterm follow-up of this study published in 2015 reported comparable rates of all-cause mortality at 5 years in high-risk patients undergoing TAVR vs SAVR, thus confirming the noninferiority of TAVR vs a surgical approach in high-risk patients for the longest duration of follow-up currently available.³

For patients, if the results of 2 different procedures are similar, they are typically going to choose the less invasive option. As a result, use of TAVR has increased: nearly 300,000 procedures have been performed worldwide, and approximately 75,000 were completed in 2016 alone. These numbers are projected to increase fourfold in the next 10 years. In the United States, almost one-third of Medicare-reported aortic valve replacements in 2015 were performed using TAVR.⁴

These data show that TAVR has become the preferred alternative to SAVR in inoperable and high-risk patients.

TAVR IN INTERMEDIATE-RISK PATIENTS

The US Food and Drug Administration (FDA) initially approved TAVR for patients judged to be ineligible for open-chest valve replacement cardiac surgery or at high risk for SAVR. This represents a small percentage of the total patient population needing aortic valve replacement. The Society of Thoracic Surgeons database of aortic valve disease cases during 2002 to 2010 (N = 141,905) shows that just 6.2% were ranked as high risk (ie, population eligible for TAVR in 2016). Most patients (79.9%) were low risk, and 13.9% were intermediate risk.⁵

A subanalysis of the transfemoral-access cohort provided additional support for TAVR. It showed that the rate of death and stroke in this cohort began to trend more favorably for TAVR. At 24 months, the difference in the primary end point was statistically significant in favor of TAVR (16.3% vs 20.0% for surgery; P = .04).¹

Based on these data, in August 2016, the FDA approved the Sapien valves for use in patients with aortic valve stenosis who are at intermediate risk of death or complications associated with open-heart surgery. If the differences in outcomes reported during the PARTNER S3i trial are extrapolated to the total number of valve replacement surgeries performed worldwide, the potential number of patients who may benefit from TAVR is substantial.

Although results with TAVR appear promising, there are important issues to address before it can be adopted in a wider patient population (ie, low-risk patients). These primarily focus on the following:

• Stroke
• Paravalvular leak
• Need for pacemaker replacement
• Valve durability
• Leaflet immobility or valve thrombosis.

Stroke

The incidence of stroke associated with TAVR is a concern, but it has decreased with the introduction of the Sapien 3 valve. In the PARTNER 2 trial, the 30-day stroke rate in intermediate-risk patients who received the Sapien 3 valve was 2.6%.¹ This compares with a 5.6% overall rate in the PARTNER 1A trials using the first Sapien valve.² The rate of stroke events is expected to decrease further as TAVR is expanded into healthier populations with better vasculature.

Paravalvular leak

Rates of moderate or severe paravalvular leak at 30 days have also decreased with the Sapien 3 valve and were 4.2% overall in the PARTNER S3i trial.⁶ These rates have ranged from 11.5% overall in the PARTNER 1A trial² to 4.2% in the PARTNER 2B trial¹ that used the Sapien XT valve for transfemoral-access TAVR.

New pacemakers

The percentage of TAVR procedures that result in a new requirement for a pacemaker increased to about 11% in 2014, up from 6.8% in 2012 to 2013.⁸ The requirement for a new pacemaker within 30 days following TAVR appeared to decrease again in the PARTER 2 trial, to 8.5%.¹ 

Durability

Evidence is emerging showing the limited durability of bioprosthetic aortic valve. Multiple studies have reportedly shown this, and this is true for all tissue valves, including those surgically inserted. A study assessing data from 357 patients showed that structural valve degeneration begins at 7 years post­operatively. By 10 years, only about 86% of valves were free from degeneration. At 12 years, that dropped to 69%.⁹

A study comparing TAVR vs SAVR showed that under identical loading conditions and with identical leaflet tissue properties, leaflets of valves placed via TAVR sustained higher stresses, strains, and fatigue damage.¹⁰

Overall, these results provide the possibility that TAVR valves may have reduced valve life compared with SAVR valves. Unknown durability may be an issue to consider when evaluating TAVR for implantation in intermediate- and low-risk patients.

Leaflet immobility and valve thrombosis

In the past 2 years, the problem of potential subclinical valve leaflet thrombosis, on both surgically inserted and TAVR valves, has emerged.¹¹ The FDA is monitoring these complications because of their potential impact on the safety and efficacy of these valves.

This complication was first reported as an unexpected finding of reduced leaflet motion on 4-dimensional computed tomography, a sign suspicious for valve thrombosis, in a subgroup of patients evaluated 30 days after implantation.¹² A study from Denmark found a 7% incidence of valve thrombosis in TAVR valves. They reported that warfarin could prevent thrombosis.¹³

At the Heart Hospital Baylor Plano, our TAVR team has identified approximately 50 cases of thrombosis that caused partial valve occlusion. Administering warfarin for 3 months resolved the thrombosis in virtually all cases. In 1 case, a thrombosed valve was surgically explanted with good patient outcome. Pathological analysis confirmed that reduced leaflet motion seen on 4-dimensional CT was valve thrombosis, as suspected by imaging specialists.¹⁴

Although there are ample data supporting the use of TAVR in intermediate-risk patients, SAVR remains the most effective option in certain clinical situations: 

• Younger patients who will need valve replacement later in life
• Bicuspid valves with eccentric bulky calcification
• Aortopathy (aortic disease above the valve)
• Small calcified roots
• Severe calcification of left ventricular outflow tract
• Low-lying coronary arteries (typically, ≤ 6 mm from the aortic annulus)
• Severe septal bulging
• Severe mitral regurgitation and/or tricuspid regurgitation
• Conduction system disease that puts the patient at high risk for pacemaker implantation
• Valve replacement in valves with a diameter 20 mm or smaller.

Nevertheless, outcomes seem to support TAVR in intermediate-risk patients. At the Heart Hospital Baylor Plano, 30-day outcomes with the Sapien 3 valve have shown all-cause mortality of 1.1% and all-stroke mortality of 2.6% (1.0% for disabling stroke). Large registries of the Sapien 3 valve have reported similar outcomes at 30 days: mortality 1%, disabling stroke 2%, major vascular complications 2%, and moderate to severe paravalvular leak 2%.¹⁵

Overall, the rates of major vascular complications and of life-threatening bleeding are 2%, and the need for new pacemakers is 4%. Results from several trials support TAVR as an alternative to surgery in intermediate-risk patients. In patients who are candidates for transfemoral access, TAVR may provide additional clinical advantages. However, questions about long-term durability and new requirements for pacemakers are issues for TAVR use in intermediate- and low-risk patients. More data are needed to answer these questions. 

At the Heart Hospital Baylor Plano, the number of TAVR procedures from 2012 to 2015 increased from 49 cases to 215, while the number of SAVR procedures remained constant (166 in 2012 and 162 in 2015). During that time, outcomes improved dramatically: in-hospital mortality rates dropped from 2% to 0% and 30-day mortality dropped from 3% to 0%. There have been 227 consecutive SAVR patients with no in-hospital or 30-day mortality and 261 consecutive TAVR patients with no mortality.

These results support initiating clinical trials of TAVR in low-risk patients. In 2016, the FDA approved TAVR valves for 2 clinical trials in patients with aortic stenosis who are at low risk of surgical mortality. These large clinical trials, each with about 1,200 patients, are expected to provide data that will help determine whether TAVR is a safe and effective option for low-risk patients.

Surgical aortic valve replacement (SAVR) started in the 1960s with a porcine aortic valve sutured to a stainless steel frame. The first human transcatheter aortic valve replacement (TAVR) procedure in the United States was in 2002. In the past 15 years, technological advances in heart valve design have made TAVR the preferred alternative in patients at high risk for surgical complications. This article outlines studies comparing balloon-expandable TAVR vs SAVR for patients at extreme, high, and intermediate surgical risk, and presents evidence that supports the expanded use of TAVR in patients at lower surgical risk.

TAVR: THE PREFERRED ALTERNATIVE TO SURGERY

Investigators next established TAVR outcomes as being noninferior to SAVR in high surgical risk patients (PARTNER trial cohort A) at 1 year.² A midterm follow-up of this study published in 2015 reported comparable rates of all-cause mortality at 5 years in high-risk patients undergoing TAVR vs SAVR, thus confirming the noninferiority of TAVR vs a surgical approach in high-risk patients for the longest duration of follow-up currently available.³

For patients, if the results of 2 different procedures are similar, they are typically going to choose the less invasive option. As a result, use of TAVR has increased: nearly 300,000 procedures have been performed worldwide, and approximately 75,000 were completed in 2016 alone. These numbers are projected to increase fourfold in the next 10 years. In the United States, almost one-third of Medicare-reported aortic valve replacements in 2015 were performed using TAVR.⁴

These data show that TAVR has become the preferred alternative to SAVR in inoperable and high-risk patients.

TAVR IN INTERMEDIATE-RISK PATIENTS

The US Food and Drug Administration (FDA) initially approved TAVR for patients judged to be ineligible for open-chest valve replacement cardiac surgery or at high risk for SAVR. This represents a small percentage of the total patient population needing aortic valve replacement. The Society of Thoracic Surgeons database of aortic valve disease cases during 2002 to 2010 (N = 141,905) shows that just 6.2% were ranked as high risk (ie, population eligible for TAVR in 2016). Most patients (79.9%) were low risk, and 13.9% were intermediate risk.⁵

A subanalysis of the transfemoral-access cohort provided additional support for TAVR. It showed that the rate of death and stroke in this cohort began to trend more favorably for TAVR. At 24 months, the difference in the primary end point was statistically significant in favor of TAVR (16.3% vs 20.0% for surgery; P = .04).¹

Based on these data, in August 2016, the FDA approved the Sapien valves for use in patients with aortic valve stenosis who are at intermediate risk of death or complications associated with open-heart surgery. If the differences in outcomes reported during the PARTNER S3i trial are extrapolated to the total number of valve replacement surgeries performed worldwide, the potential number of patients who may benefit from TAVR is substantial.

Although results with TAVR appear promising, there are important issues to address before it can be adopted in a wider patient population (ie, low-risk patients). These primarily focus on the following:

• Stroke
• Paravalvular leak
• Need for pacemaker replacement
• Valve durability
• Leaflet immobility or valve thrombosis.

Stroke

The incidence of stroke associated with TAVR is a concern, but it has decreased with the introduction of the Sapien 3 valve. In the PARTNER 2 trial, the 30-day stroke rate in intermediate-risk patients who received the Sapien 3 valve was 2.6%.¹ This compares with a 5.6% overall rate in the PARTNER 1A trials using the first Sapien valve.² The rate of stroke events is expected to decrease further as TAVR is expanded into healthier populations with better vasculature.

Paravalvular leak

Rates of moderate or severe paravalvular leak at 30 days have also decreased with the Sapien 3 valve and were 4.2% overall in the PARTNER S3i trial.⁶ These rates have ranged from 11.5% overall in the PARTNER 1A trial² to 4.2% in the PARTNER 2B trial¹ that used the Sapien XT valve for transfemoral-access TAVR.

New pacemakers

The percentage of TAVR procedures that result in a new requirement for a pacemaker increased to about 11% in 2014, up from 6.8% in 2012 to 2013.⁸ The requirement for a new pacemaker within 30 days following TAVR appeared to decrease again in the PARTER 2 trial, to 8.5%.¹ 

Durability

Evidence is emerging showing the limited durability of bioprosthetic aortic valve. Multiple studies have reportedly shown this, and this is true for all tissue valves, including those surgically inserted. A study assessing data from 357 patients showed that structural valve degeneration begins at 7 years post­operatively. By 10 years, only about 86% of valves were free from degeneration. At 12 years, that dropped to 69%.⁹

A study comparing TAVR vs SAVR showed that under identical loading conditions and with identical leaflet tissue properties, leaflets of valves placed via TAVR sustained higher stresses, strains, and fatigue damage.¹⁰

Overall, these results provide the possibility that TAVR valves may have reduced valve life compared with SAVR valves. Unknown durability may be an issue to consider when evaluating TAVR for implantation in intermediate- and low-risk patients.

Leaflet immobility and valve thrombosis

In the past 2 years, the problem of potential subclinical valve leaflet thrombosis, on both surgically inserted and TAVR valves, has emerged.¹¹ The FDA is monitoring these complications because of their potential impact on the safety and efficacy of these valves.

This complication was first reported as an unexpected finding of reduced leaflet motion on 4-dimensional computed tomography, a sign suspicious for valve thrombosis, in a subgroup of patients evaluated 30 days after implantation.¹² A study from Denmark found a 7% incidence of valve thrombosis in TAVR valves. They reported that warfarin could prevent thrombosis.¹³

At the Heart Hospital Baylor Plano, our TAVR team has identified approximately 50 cases of thrombosis that caused partial valve occlusion. Administering warfarin for 3 months resolved the thrombosis in virtually all cases. In 1 case, a thrombosed valve was surgically explanted with good patient outcome. Pathological analysis confirmed that reduced leaflet motion seen on 4-dimensional CT was valve thrombosis, as suspected by imaging specialists.¹⁴

Although there are ample data supporting the use of TAVR in intermediate-risk patients, SAVR remains the most effective option in certain clinical situations: 

• Younger patients who will need valve replacement later in life
• Bicuspid valves with eccentric bulky calcification
• Aortopathy (aortic disease above the valve)
• Small calcified roots
• Severe calcification of left ventricular outflow tract
• Low-lying coronary arteries (typically, ≤ 6 mm from the aortic annulus)
• Severe septal bulging
• Severe mitral regurgitation and/or tricuspid regurgitation
• Conduction system disease that puts the patient at high risk for pacemaker implantation
• Valve replacement in valves with a diameter 20 mm or smaller.

Nevertheless, outcomes seem to support TAVR in intermediate-risk patients. At the Heart Hospital Baylor Plano, 30-day outcomes with the Sapien 3 valve have shown all-cause mortality of 1.1% and all-stroke mortality of 2.6% (1.0% for disabling stroke). Large registries of the Sapien 3 valve have reported similar outcomes at 30 days: mortality 1%, disabling stroke 2%, major vascular complications 2%, and moderate to severe paravalvular leak 2%.¹⁵

Overall, the rates of major vascular complications and of life-threatening bleeding are 2%, and the need for new pacemakers is 4%. Results from several trials support TAVR as an alternative to surgery in intermediate-risk patients. In patients who are candidates for transfemoral access, TAVR may provide additional clinical advantages. However, questions about long-term durability and new requirements for pacemakers are issues for TAVR use in intermediate- and low-risk patients. More data are needed to answer these questions. 

At the Heart Hospital Baylor Plano, the number of TAVR procedures from 2012 to 2015 increased from 49 cases to 215, while the number of SAVR procedures remained constant (166 in 2012 and 162 in 2015). During that time, outcomes improved dramatically: in-hospital mortality rates dropped from 2% to 0% and 30-day mortality dropped from 3% to 0%. There have been 227 consecutive SAVR patients with no in-hospital or 30-day mortality and 261 consecutive TAVR patients with no mortality.

These results support initiating clinical trials of TAVR in low-risk patients. In 2016, the FDA approved TAVR valves for 2 clinical trials in patients with aortic stenosis who are at low risk of surgical mortality. These large clinical trials, each with about 1,200 patients, are expected to provide data that will help determine whether TAVR is a safe and effective option for low-risk patients.

Surgical aortic valve replacement (SAVR) started in the 1960s with a porcine aortic valve sutured to a stainless steel frame. The first human transcatheter aortic valve replacement (TAVR) procedure in the United States was in 2002. In the past 15 years, technological advances in heart valve design have made TAVR the preferred alternative in patients at high risk for surgical complications. This article outlines studies comparing balloon-expandable TAVR vs SAVR for patients at extreme, high, and intermediate surgical risk, and presents evidence that supports the expanded use of TAVR in patients at lower surgical risk.

TAVR: THE PREFERRED ALTERNATIVE TO SURGERY

Investigators next established TAVR outcomes as being noninferior to SAVR in high surgical risk patients (PARTNER trial cohort A) at 1 year.² A midterm follow-up of this study published in 2015 reported comparable rates of all-cause mortality at 5 years in high-risk patients undergoing TAVR vs SAVR, thus confirming the noninferiority of TAVR vs a surgical approach in high-risk patients for the longest duration of follow-up currently available.³

For patients, if the results of 2 different procedures are similar, they are typically going to choose the less invasive option. As a result, use of TAVR has increased: nearly 300,000 procedures have been performed worldwide, and approximately 75,000 were completed in 2016 alone. These numbers are projected to increase fourfold in the next 10 years. In the United States, almost one-third of Medicare-reported aortic valve replacements in 2015 were performed using TAVR.⁴

These data show that TAVR has become the preferred alternative to SAVR in inoperable and high-risk patients.

TAVR IN INTERMEDIATE-RISK PATIENTS

The US Food and Drug Administration (FDA) initially approved TAVR for patients judged to be ineligible for open-chest valve replacement cardiac surgery or at high risk for SAVR. This represents a small percentage of the total patient population needing aortic valve replacement. The Society of Thoracic Surgeons database of aortic valve disease cases during 2002 to 2010 (N = 141,905) shows that just 6.2% were ranked as high risk (ie, population eligible for TAVR in 2016). Most patients (79.9%) were low risk, and 13.9% were intermediate risk.⁵

A subanalysis of the transfemoral-access cohort provided additional support for TAVR. It showed that the rate of death and stroke in this cohort began to trend more favorably for TAVR. At 24 months, the difference in the primary end point was statistically significant in favor of TAVR (16.3% vs 20.0% for surgery; P = .04).¹

Based on these data, in August 2016, the FDA approved the Sapien valves for use in patients with aortic valve stenosis who are at intermediate risk of death or complications associated with open-heart surgery. If the differences in outcomes reported during the PARTNER S3i trial are extrapolated to the total number of valve replacement surgeries performed worldwide, the potential number of patients who may benefit from TAVR is substantial.

Although results with TAVR appear promising, there are important issues to address before it can be adopted in a wider patient population (ie, low-risk patients). These primarily focus on the following:

• Stroke
• Paravalvular leak
• Need for pacemaker replacement
• Valve durability
• Leaflet immobility or valve thrombosis.

Stroke

The incidence of stroke associated with TAVR is a concern, but it has decreased with the introduction of the Sapien 3 valve. In the PARTNER 2 trial, the 30-day stroke rate in intermediate-risk patients who received the Sapien 3 valve was 2.6%.¹ This compares with a 5.6% overall rate in the PARTNER 1A trials using the first Sapien valve.² The rate of stroke events is expected to decrease further as TAVR is expanded into healthier populations with better vasculature.

Paravalvular leak

Rates of moderate or severe paravalvular leak at 30 days have also decreased with the Sapien 3 valve and were 4.2% overall in the PARTNER S3i trial.⁶ These rates have ranged from 11.5% overall in the PARTNER 1A trial² to 4.2% in the PARTNER 2B trial¹ that used the Sapien XT valve for transfemoral-access TAVR.

New pacemakers

The percentage of TAVR procedures that result in a new requirement for a pacemaker increased to about 11% in 2014, up from 6.8% in 2012 to 2013.⁸ The requirement for a new pacemaker within 30 days following TAVR appeared to decrease again in the PARTER 2 trial, to 8.5%.¹ 

Durability

Evidence is emerging showing the limited durability of bioprosthetic aortic valve. Multiple studies have reportedly shown this, and this is true for all tissue valves, including those surgically inserted. A study assessing data from 357 patients showed that structural valve degeneration begins at 7 years post­operatively. By 10 years, only about 86% of valves were free from degeneration. At 12 years, that dropped to 69%.⁹

A study comparing TAVR vs SAVR showed that under identical loading conditions and with identical leaflet tissue properties, leaflets of valves placed via TAVR sustained higher stresses, strains, and fatigue damage.¹⁰

Overall, these results provide the possibility that TAVR valves may have reduced valve life compared with SAVR valves. Unknown durability may be an issue to consider when evaluating TAVR for implantation in intermediate- and low-risk patients.

Leaflet immobility and valve thrombosis

In the past 2 years, the problem of potential subclinical valve leaflet thrombosis, on both surgically inserted and TAVR valves, has emerged.¹¹ The FDA is monitoring these complications because of their potential impact on the safety and efficacy of these valves.

This complication was first reported as an unexpected finding of reduced leaflet motion on 4-dimensional computed tomography, a sign suspicious for valve thrombosis, in a subgroup of patients evaluated 30 days after implantation.¹² A study from Denmark found a 7% incidence of valve thrombosis in TAVR valves. They reported that warfarin could prevent thrombosis.¹³

At the Heart Hospital Baylor Plano, our TAVR team has identified approximately 50 cases of thrombosis that caused partial valve occlusion. Administering warfarin for 3 months resolved the thrombosis in virtually all cases. In 1 case, a thrombosed valve was surgically explanted with good patient outcome. Pathological analysis confirmed that reduced leaflet motion seen on 4-dimensional CT was valve thrombosis, as suspected by imaging specialists.¹⁴

Although there are ample data supporting the use of TAVR in intermediate-risk patients, SAVR remains the most effective option in certain clinical situations: 

• Younger patients who will need valve replacement later in life
• Bicuspid valves with eccentric bulky calcification
• Aortopathy (aortic disease above the valve)
• Small calcified roots
• Severe calcification of left ventricular outflow tract
• Low-lying coronary arteries (typically, ≤ 6 mm from the aortic annulus)
• Severe septal bulging
• Severe mitral regurgitation and/or tricuspid regurgitation
• Conduction system disease that puts the patient at high risk for pacemaker implantation
• Valve replacement in valves with a diameter 20 mm or smaller.

Nevertheless, outcomes seem to support TAVR in intermediate-risk patients. At the Heart Hospital Baylor Plano, 30-day outcomes with the Sapien 3 valve have shown all-cause mortality of 1.1% and all-stroke mortality of 2.6% (1.0% for disabling stroke). Large registries of the Sapien 3 valve have reported similar outcomes at 30 days: mortality 1%, disabling stroke 2%, major vascular complications 2%, and moderate to severe paravalvular leak 2%.¹⁵

Overall, the rates of major vascular complications and of life-threatening bleeding are 2%, and the need for new pacemakers is 4%. Results from several trials support TAVR as an alternative to surgery in intermediate-risk patients. In patients who are candidates for transfemoral access, TAVR may provide additional clinical advantages. However, questions about long-term durability and new requirements for pacemakers are issues for TAVR use in intermediate- and low-risk patients. More data are needed to answer these questions. 

At the Heart Hospital Baylor Plano, the number of TAVR procedures from 2012 to 2015 increased from 49 cases to 215, while the number of SAVR procedures remained constant (166 in 2012 and 162 in 2015). During that time, outcomes improved dramatically: in-hospital mortality rates dropped from 2% to 0% and 30-day mortality dropped from 3% to 0%. There have been 227 consecutive SAVR patients with no in-hospital or 30-day mortality and 261 consecutive TAVR patients with no mortality.

These results support initiating clinical trials of TAVR in low-risk patients. In 2016, the FDA approved TAVR valves for 2 clinical trials in patients with aortic stenosis who are at low risk of surgical mortality. These large clinical trials, each with about 1,200 patients, are expected to provide data that will help determine whether TAVR is a safe and effective option for low-risk patients.

The evolution of coronary artery bypass grafting (CABG) has been a key component in significantly reducing the morbidity and mortality associated with occlusive coronary artery disease (CAD). Cleveland Clinic surgeons, through their technical interventions and innovations, have led the evolution in coronary revascularization starting in the 1960s and continuing today. This article provides a brief overview of the evolution and describes the issues associated with current CABG approaches.

EARLY WORK IN RECONSTRUCTIVE CORONARY ARTERY SURGERY

Results from the first large series of venous grafting for CAD were reported in 1970 by Favaloro and colleagues at Cleveland Clinic.¹ They showed the efficacy of grafting in treating CAD, with low associated morbidity and mortality, thus establishing this surgery as the treatment modality for CAD.

The technique of surgical myocardial revascularization was a culmination of developments that began years earlier with the Vineberg procedure, involving suturing of the mammary artery to the muscle rather than a vessel-to-vessel anastomosis. From this followed the coronary patch, end-to-end bypass, and then end-to-side bypass.

In the 1970s, the refinement of suturing the left internal mammary artery (LIMA) directly to the left anterior descending (LAD) artery using magnifying loops was pioneered and popularized at Cleveland Clinic. This later became the cornerstone of future coronary revascularizations.

As a direct result of the successful technical advances and excellent clinical outcomes, the volume of CABG procedures in the United States rose steadily during the 1980s and reached its peak in 1995. It then began a slow decline that continued until 2013, when the trend began to reverse. It was still rising through 2015.

WHY THE RENEWED INTEREST IN CABG?

A key component to continued use of CABG is that it appears to have a clinical edge over other treatments. This has been shown in several high-profile studies: SYNTAX,^2,3 FREEDOM,^4,5 BEST,⁶ and NOBLE.⁷ For example, in the SYNTAX trial, which compared CABG vs percutaneous coronary intervention (PCI), the conclusion from both the 1-year² and the 5-year³ results was that CABG should remain the standard of care for patients with complex lesions—those with an intermediate or high burden of CAD.

The 5-year outcomes showed that the rate of major adverse cardiac and cerebrovascular events favored CABG over PCI (26.9% vs 37.3%, respectively; P < .0001).³ All-cause mortality, although not statistically significant, also was better for CABG (11.4% vs 13.9%). This indicates that as the complexity and burden of disease increase, the benefit of CABG over PCI becomes more prominent. In short, the worse the disease, the better the results with CABG.

Why is CABG better?

One rationale is that CABG not only bypasses the culprit-lesion vessel, it also protects against future lesions. An elegant study published in 2010 showed that in most cases of acute myocardial infarction (MI), the culprit coronary lesion is in the first 7 cm of the LAD.⁸ With CABG, most distal anastomoses are beyond 7 cm and, thus, are beyond the location of the vast majority of potential future culprit lesions.

An important factor is the modern-day safety record of CABG. According to the Society of Thoracic
Surgeons Adult Cardiac Surgery Database,⁹ in 2016 the expected operative mortality for CABG was just over 2%. At the Cleveland Clinic, CABG mortality has consistently been below 1% despite the complexity of the cases and the higher percentage of reoperations performed at the Clinic. In addition, the low incidence of major complications after CABG has contributed to its endurance as an important therapeutic option for CAD over the decades.

IMPROVING LONG-TERM CABG OUTCOMES

Improving vein graft patency

The Achilles heel of CABG is the decline of patency of saphenous vein grafts. The occlusion rate of these veins is 6% to 8% at hospital discharge and approximately 10% at 1 year after CABG. By 10 years, half of the vein grafts are diseased or occluded, with progression of atherosclerotic disease over time.

There has been controversy about whether open harvesting of the saphenous vein is better than endoscopic vein harvesting for patency-related outcomes. This arose after the publication of an ad hoc analysis that gave poor marks to endoscopic vein-graft harvesting.¹⁰ Its major finding was that endoscopic vein harvesting had higher rates of vein-graft failure at 12 to 18 months than open vein harvesting (46.7% vs 38.0%, respectively; P < .001). At 3 years, endoscopic harvesting was associated with higher rates of death, MI, or repeat revascularization (20.2% vs 17.4%, P = .04).

A US Food and Drug Administration-sanctioned Society of Thoracic Surgeons observational study, however, reviewed outcomes from 235,394 patients who underwent CABG from 2003 through 2008 and found no significant increase in 5-year mortality rates with use of endoscopic vein-graft harvesting vs open harvesting.¹¹ This study showed that the less invasive endoscopic approach is still an option.

In 2015, Taggart and colleagues¹² reported on a pioneering procedure that wraps the saphenous vein graft with a stent. Initial results showed external stenting had the potential to improve vein-graft lumen and reduce intimal hyperplasia at 1 year postoperatively. Surgeons can expect more data on this technology in the future.

Arterial vs venous grafts

The 1986 report by Loop and colleagues from Cleveland Clinic showed that the patency of the mammary artery graft was superior to that of the saphenous vein and that patients receiving a mammary bypass had significantly better 10-year survival (82.6% vs 71.0%, respectively; P < .0001).¹³ The findings of this landmark study established the LIMA-to-LAD bypass as the technical standard for surgical coronary revascularization.

Single vs bilateral mammary artery grafts

In December 2016, results of the Arterial Revascularization Trial (ART) were published comparing single vs double mammary artery grafts.¹⁴ In this prospective randomized trial, the 5-year results showed no significant difference between these mammary grafts in terms of all-cause mortality, MI, or stroke. Bilateral mammary artery grafts, however, were associated with a higher risk of sternal wound complications (3.5% vs 1.9%, respectively; P = .005) and sternal reconstruction (1.9% vs 0.6%; P = .002).

Radial artery vs saphenous vein grafts

In the largest randomized study comparing these two graft options,¹⁶ the 1-year results showed no difference in graft patency; a follow-up analysis is in progress. In contrast, randomized studies from Canada¹⁷ and the United Kingdom¹⁸ suggest that there are potential benefits associated with use of radial artery grafts in terms of patency and clinical outcomes. In addition, observational data from centers experienced in radial artery grafting have demonstrated favorable outcomes. Radial arteries perform best when bypassing totally occluded or severely stenotic vessels in which there is no or little risk of competitive flow from the native circulation.

Right internal mammary vs radial artery grafts

A propensity-matched comparison study looking at multiple studies (N = 15,374 patients) concluded that use of the right internal mammary artery provides better outcomes.¹⁹ It was associated with a 25% risk reduction for late death and a 63% risk reduction for repeat vascularization, both statistically significant vs the radial artery rates. But there is a randomized study showing that the radial artery is as good as or better than the right internal mammary artery. At this point, it is not clear which artery is better as an adjunct for the LIMA-to-LAD bypass.

GUIDELINES FOR GRAFT SELECTION

In 2016, the Society of Thoracic Surgeons published guidelines that encouraged the use of arterial grafts, giving it a class IIa designation, meaning that the evidence indicates it is reasonable to consider.²⁰

The guidelines note the following:

• The internal mammary artery should be used to bypass the LAD when bypass of the LAD is indicated.
• As an adjunct to the left internal mammary artery, a second arterial graft (the right internal mammary artery or radial artery) should be considered in appropriate patients.
• Use of bilateral internal mammary arteries should be considered in patients who are not at high risk for sternal complications.

COMPARING SURGICAL APPROACHES

Traditional CABG performed via median sternotomy and with the use of cardiopulmonary bypass remains the technical standard in surgical coronary revascularization. However, technologies have allowed surgeons to use different and sometimes less invasive approaches that may have good outcomes in select patients with suitable risk profiles and favorable coronary anatomies.

On-pump vs off-pump CABG

The popularity of CABG without cardiopulmonary bypass (“off-pump”) peaked in 2002, when it constituted approximately 23% of CABG procedures and then declined to 17% by 2012.²¹ The ROOBY (Veterans Affairs Randomized On/Off Bypass) trial of 2,203 VA patients showed that at 1 year, those in the off-pump group had worse composite outcomes, poorer graft patency, and greater incidence of incomplete revascularization than the on-pump group.²² However, the use of off-pump CABG was vindicated in two other trials—CORONARY and GOPCABE—in which experienced surgeons in high-volume centers with high-risk patients had no difference in outcomes at 1 and 5 years.^23–25 The recommendation is to tailor the procedure to the patient rather than the patient to the procedure. The best option is always to do what is right for the patient. For example, patients with diseased ascending aortas or liver disease may benefit from an off-pump approach.

Robotic CABG

This procedure has advantages and disadvantages. The advantages are primarily related to the minimally invasive approach:

• There is no surgeon hand tremor
• It is less invasive
• It provides better cosmetic results
• It is expected to result in less pain, fewer transfusions, fewer complications, and shorter length of hospital stay, although those have not been proven.

Disadvantages include the following:

• Compromised completeness of revascularization—with some “difficult” vessels left unbypassed
• Longer operative times
• Higher cost
• Concern about graft patency with inexperienced surgeons
• Higher-than-expected mortality in some reports.

In 2013, a study of 500 patients treated with robotic totally endoscopic CABG showed that this procedure could be safe and effective, although the best outcomes were achieved in patients with less severe disease requiring fewer bypasses.²⁶ In other words, it is more appropriate for LIMA-to-LAD suturing and less complex anatomy, and it is best performed with cardiopulmonary bypass with the heart arrested.

Hybrid revascularization

This procedure is a combination of minimally invasive CABG (MIDCAB or robotic CABG) to revascularize the LAD and PCI to treat the remaining vessels in multivessel CAD. The CABG and PCI can be concurrent or staged. The hybrid approach has the attraction of being less invasive and uses the technical standard LIMA-to-LAD approach, but it has the obvious limitation of not incorporating additional arterial grafting and the possibility of a compromised technical outcome in less experienced hands.

A collaborative task force from several cardiovascular medical societies developed evidence-based guidelines to address the hybrid coronary revascularization approach. They give it a class IIa recommendation, indicating that it is a reasonable approach to treating patients in whom there are limitations and challenges to traditional CABG. For other patients, they gave it a class IIb recommendation, indicating that it may be reasonable to use as an alternative to multivessel PCI or CABG.²⁷

THE EVOLUTION CONTINUES: CABG VS PCI

As CABG and PCI continue to evolve, surgical approaches to CAD are becoming more sophisticated with the use of more arterial conduits, less invasive surgical approaches, and development of new types of stents for PCI; however, expect the debate to continue regarding which approach to CAD is best. This is not a battle between surgical and nonsurgical specialties. Rather, the goal should be an amicable, collaborative heart-care team. After all, the most important question is, as always, which therapy is best for the individual patient.

The evolution of coronary artery bypass grafting (CABG) has been a key component in significantly reducing the morbidity and mortality associated with occlusive coronary artery disease (CAD). Cleveland Clinic surgeons, through their technical interventions and innovations, have led the evolution in coronary revascularization starting in the 1960s and continuing today. This article provides a brief overview of the evolution and describes the issues associated with current CABG approaches.

EARLY WORK IN RECONSTRUCTIVE CORONARY ARTERY SURGERY

Results from the first large series of venous grafting for CAD were reported in 1970 by Favaloro and colleagues at Cleveland Clinic.¹ They showed the efficacy of grafting in treating CAD, with low associated morbidity and mortality, thus establishing this surgery as the treatment modality for CAD.

The technique of surgical myocardial revascularization was a culmination of developments that began years earlier with the Vineberg procedure, involving suturing of the mammary artery to the muscle rather than a vessel-to-vessel anastomosis. From this followed the coronary patch, end-to-end bypass, and then end-to-side bypass.

In the 1970s, the refinement of suturing the left internal mammary artery (LIMA) directly to the left anterior descending (LAD) artery using magnifying loops was pioneered and popularized at Cleveland Clinic. This later became the cornerstone of future coronary revascularizations.

As a direct result of the successful technical advances and excellent clinical outcomes, the volume of CABG procedures in the United States rose steadily during the 1980s and reached its peak in 1995. It then began a slow decline that continued until 2013, when the trend began to reverse. It was still rising through 2015.

WHY THE RENEWED INTEREST IN CABG?

A key component to continued use of CABG is that it appears to have a clinical edge over other treatments. This has been shown in several high-profile studies: SYNTAX,^2,3 FREEDOM,^4,5 BEST,⁶ and NOBLE.⁷ For example, in the SYNTAX trial, which compared CABG vs percutaneous coronary intervention (PCI), the conclusion from both the 1-year² and the 5-year³ results was that CABG should remain the standard of care for patients with complex lesions—those with an intermediate or high burden of CAD.

The 5-year outcomes showed that the rate of major adverse cardiac and cerebrovascular events favored CABG over PCI (26.9% vs 37.3%, respectively; P < .0001).³ All-cause mortality, although not statistically significant, also was better for CABG (11.4% vs 13.9%). This indicates that as the complexity and burden of disease increase, the benefit of CABG over PCI becomes more prominent. In short, the worse the disease, the better the results with CABG.

Why is CABG better?

One rationale is that CABG not only bypasses the culprit-lesion vessel, it also protects against future lesions. An elegant study published in 2010 showed that in most cases of acute myocardial infarction (MI), the culprit coronary lesion is in the first 7 cm of the LAD.⁸ With CABG, most distal anastomoses are beyond 7 cm and, thus, are beyond the location of the vast majority of potential future culprit lesions.

An important factor is the modern-day safety record of CABG. According to the Society of Thoracic
Surgeons Adult Cardiac Surgery Database,⁹ in 2016 the expected operative mortality for CABG was just over 2%. At the Cleveland Clinic, CABG mortality has consistently been below 1% despite the complexity of the cases and the higher percentage of reoperations performed at the Clinic. In addition, the low incidence of major complications after CABG has contributed to its endurance as an important therapeutic option for CAD over the decades.

IMPROVING LONG-TERM CABG OUTCOMES

Improving vein graft patency

The Achilles heel of CABG is the decline of patency of saphenous vein grafts. The occlusion rate of these veins is 6% to 8% at hospital discharge and approximately 10% at 1 year after CABG. By 10 years, half of the vein grafts are diseased or occluded, with progression of atherosclerotic disease over time.

There has been controversy about whether open harvesting of the saphenous vein is better than endoscopic vein harvesting for patency-related outcomes. This arose after the publication of an ad hoc analysis that gave poor marks to endoscopic vein-graft harvesting.¹⁰ Its major finding was that endoscopic vein harvesting had higher rates of vein-graft failure at 12 to 18 months than open vein harvesting (46.7% vs 38.0%, respectively; P < .001). At 3 years, endoscopic harvesting was associated with higher rates of death, MI, or repeat revascularization (20.2% vs 17.4%, P = .04).

A US Food and Drug Administration-sanctioned Society of Thoracic Surgeons observational study, however, reviewed outcomes from 235,394 patients who underwent CABG from 2003 through 2008 and found no significant increase in 5-year mortality rates with use of endoscopic vein-graft harvesting vs open harvesting.¹¹ This study showed that the less invasive endoscopic approach is still an option.

In 2015, Taggart and colleagues¹² reported on a pioneering procedure that wraps the saphenous vein graft with a stent. Initial results showed external stenting had the potential to improve vein-graft lumen and reduce intimal hyperplasia at 1 year postoperatively. Surgeons can expect more data on this technology in the future.

Arterial vs venous grafts

The 1986 report by Loop and colleagues from Cleveland Clinic showed that the patency of the mammary artery graft was superior to that of the saphenous vein and that patients receiving a mammary bypass had significantly better 10-year survival (82.6% vs 71.0%, respectively; P < .0001).¹³ The findings of this landmark study established the LIMA-to-LAD bypass as the technical standard for surgical coronary revascularization.

Single vs bilateral mammary artery grafts

In December 2016, results of the Arterial Revascularization Trial (ART) were published comparing single vs double mammary artery grafts.¹⁴ In this prospective randomized trial, the 5-year results showed no significant difference between these mammary grafts in terms of all-cause mortality, MI, or stroke. Bilateral mammary artery grafts, however, were associated with a higher risk of sternal wound complications (3.5% vs 1.9%, respectively; P = .005) and sternal reconstruction (1.9% vs 0.6%; P = .002).

Radial artery vs saphenous vein grafts

In the largest randomized study comparing these two graft options,¹⁶ the 1-year results showed no difference in graft patency; a follow-up analysis is in progress. In contrast, randomized studies from Canada¹⁷ and the United Kingdom¹⁸ suggest that there are potential benefits associated with use of radial artery grafts in terms of patency and clinical outcomes. In addition, observational data from centers experienced in radial artery grafting have demonstrated favorable outcomes. Radial arteries perform best when bypassing totally occluded or severely stenotic vessels in which there is no or little risk of competitive flow from the native circulation.

Right internal mammary vs radial artery grafts

A propensity-matched comparison study looking at multiple studies (N = 15,374 patients) concluded that use of the right internal mammary artery provides better outcomes.¹⁹ It was associated with a 25% risk reduction for late death and a 63% risk reduction for repeat vascularization, both statistically significant vs the radial artery rates. But there is a randomized study showing that the radial artery is as good as or better than the right internal mammary artery. At this point, it is not clear which artery is better as an adjunct for the LIMA-to-LAD bypass.

GUIDELINES FOR GRAFT SELECTION

In 2016, the Society of Thoracic Surgeons published guidelines that encouraged the use of arterial grafts, giving it a class IIa designation, meaning that the evidence indicates it is reasonable to consider.²⁰

The guidelines note the following:

• The internal mammary artery should be used to bypass the LAD when bypass of the LAD is indicated.
• As an adjunct to the left internal mammary artery, a second arterial graft (the right internal mammary artery or radial artery) should be considered in appropriate patients.
• Use of bilateral internal mammary arteries should be considered in patients who are not at high risk for sternal complications.

COMPARING SURGICAL APPROACHES

Traditional CABG performed via median sternotomy and with the use of cardiopulmonary bypass remains the technical standard in surgical coronary revascularization. However, technologies have allowed surgeons to use different and sometimes less invasive approaches that may have good outcomes in select patients with suitable risk profiles and favorable coronary anatomies.

On-pump vs off-pump CABG

The popularity of CABG without cardiopulmonary bypass (“off-pump”) peaked in 2002, when it constituted approximately 23% of CABG procedures and then declined to 17% by 2012.²¹ The ROOBY (Veterans Affairs Randomized On/Off Bypass) trial of 2,203 VA patients showed that at 1 year, those in the off-pump group had worse composite outcomes, poorer graft patency, and greater incidence of incomplete revascularization than the on-pump group.²² However, the use of off-pump CABG was vindicated in two other trials—CORONARY and GOPCABE—in which experienced surgeons in high-volume centers with high-risk patients had no difference in outcomes at 1 and 5 years.^23–25 The recommendation is to tailor the procedure to the patient rather than the patient to the procedure. The best option is always to do what is right for the patient. For example, patients with diseased ascending aortas or liver disease may benefit from an off-pump approach.

Robotic CABG

This procedure has advantages and disadvantages. The advantages are primarily related to the minimally invasive approach:

• There is no surgeon hand tremor
• It is less invasive
• It provides better cosmetic results
• It is expected to result in less pain, fewer transfusions, fewer complications, and shorter length of hospital stay, although those have not been proven.

Disadvantages include the following:

• Compromised completeness of revascularization—with some “difficult” vessels left unbypassed
• Longer operative times
• Higher cost
• Concern about graft patency with inexperienced surgeons
• Higher-than-expected mortality in some reports.

In 2013, a study of 500 patients treated with robotic totally endoscopic CABG showed that this procedure could be safe and effective, although the best outcomes were achieved in patients with less severe disease requiring fewer bypasses.²⁶ In other words, it is more appropriate for LIMA-to-LAD suturing and less complex anatomy, and it is best performed with cardiopulmonary bypass with the heart arrested.

Hybrid revascularization

This procedure is a combination of minimally invasive CABG (MIDCAB or robotic CABG) to revascularize the LAD and PCI to treat the remaining vessels in multivessel CAD. The CABG and PCI can be concurrent or staged. The hybrid approach has the attraction of being less invasive and uses the technical standard LIMA-to-LAD approach, but it has the obvious limitation of not incorporating additional arterial grafting and the possibility of a compromised technical outcome in less experienced hands.

A collaborative task force from several cardiovascular medical societies developed evidence-based guidelines to address the hybrid coronary revascularization approach. They give it a class IIa recommendation, indicating that it is a reasonable approach to treating patients in whom there are limitations and challenges to traditional CABG. For other patients, they gave it a class IIb recommendation, indicating that it may be reasonable to use as an alternative to multivessel PCI or CABG.²⁷

THE EVOLUTION CONTINUES: CABG VS PCI

As CABG and PCI continue to evolve, surgical approaches to CAD are becoming more sophisticated with the use of more arterial conduits, less invasive surgical approaches, and development of new types of stents for PCI; however, expect the debate to continue regarding which approach to CAD is best. This is not a battle between surgical and nonsurgical specialties. Rather, the goal should be an amicable, collaborative heart-care team. After all, the most important question is, as always, which therapy is best for the individual patient.

The evolution of coronary artery bypass grafting (CABG) has been a key component in significantly reducing the morbidity and mortality associated with occlusive coronary artery disease (CAD). Cleveland Clinic surgeons, through their technical interventions and innovations, have led the evolution in coronary revascularization starting in the 1960s and continuing today. This article provides a brief overview of the evolution and describes the issues associated with current CABG approaches.

EARLY WORK IN RECONSTRUCTIVE CORONARY ARTERY SURGERY

Results from the first large series of venous grafting for CAD were reported in 1970 by Favaloro and colleagues at Cleveland Clinic.¹ They showed the efficacy of grafting in treating CAD, with low associated morbidity and mortality, thus establishing this surgery as the treatment modality for CAD.

The technique of surgical myocardial revascularization was a culmination of developments that began years earlier with the Vineberg procedure, involving suturing of the mammary artery to the muscle rather than a vessel-to-vessel anastomosis. From this followed the coronary patch, end-to-end bypass, and then end-to-side bypass.

In the 1970s, the refinement of suturing the left internal mammary artery (LIMA) directly to the left anterior descending (LAD) artery using magnifying loops was pioneered and popularized at Cleveland Clinic. This later became the cornerstone of future coronary revascularizations.

As a direct result of the successful technical advances and excellent clinical outcomes, the volume of CABG procedures in the United States rose steadily during the 1980s and reached its peak in 1995. It then began a slow decline that continued until 2013, when the trend began to reverse. It was still rising through 2015.

WHY THE RENEWED INTEREST IN CABG?

A key component to continued use of CABG is that it appears to have a clinical edge over other treatments. This has been shown in several high-profile studies: SYNTAX,^2,3 FREEDOM,^4,5 BEST,⁶ and NOBLE.⁷ For example, in the SYNTAX trial, which compared CABG vs percutaneous coronary intervention (PCI), the conclusion from both the 1-year² and the 5-year³ results was that CABG should remain the standard of care for patients with complex lesions—those with an intermediate or high burden of CAD.

The 5-year outcomes showed that the rate of major adverse cardiac and cerebrovascular events favored CABG over PCI (26.9% vs 37.3%, respectively; P < .0001).³ All-cause mortality, although not statistically significant, also was better for CABG (11.4% vs 13.9%). This indicates that as the complexity and burden of disease increase, the benefit of CABG over PCI becomes more prominent. In short, the worse the disease, the better the results with CABG.

Why is CABG better?

One rationale is that CABG not only bypasses the culprit-lesion vessel, it also protects against future lesions. An elegant study published in 2010 showed that in most cases of acute myocardial infarction (MI), the culprit coronary lesion is in the first 7 cm of the LAD.⁸ With CABG, most distal anastomoses are beyond 7 cm and, thus, are beyond the location of the vast majority of potential future culprit lesions.

An important factor is the modern-day safety record of CABG. According to the Society of Thoracic
Surgeons Adult Cardiac Surgery Database,⁹ in 2016 the expected operative mortality for CABG was just over 2%. At the Cleveland Clinic, CABG mortality has consistently been below 1% despite the complexity of the cases and the higher percentage of reoperations performed at the Clinic. In addition, the low incidence of major complications after CABG has contributed to its endurance as an important therapeutic option for CAD over the decades.

IMPROVING LONG-TERM CABG OUTCOMES

Improving vein graft patency

The Achilles heel of CABG is the decline of patency of saphenous vein grafts. The occlusion rate of these veins is 6% to 8% at hospital discharge and approximately 10% at 1 year after CABG. By 10 years, half of the vein grafts are diseased or occluded, with progression of atherosclerotic disease over time.

There has been controversy about whether open harvesting of the saphenous vein is better than endoscopic vein harvesting for patency-related outcomes. This arose after the publication of an ad hoc analysis that gave poor marks to endoscopic vein-graft harvesting.¹⁰ Its major finding was that endoscopic vein harvesting had higher rates of vein-graft failure at 12 to 18 months than open vein harvesting (46.7% vs 38.0%, respectively; P < .001). At 3 years, endoscopic harvesting was associated with higher rates of death, MI, or repeat revascularization (20.2% vs 17.4%, P = .04).

A US Food and Drug Administration-sanctioned Society of Thoracic Surgeons observational study, however, reviewed outcomes from 235,394 patients who underwent CABG from 2003 through 2008 and found no significant increase in 5-year mortality rates with use of endoscopic vein-graft harvesting vs open harvesting.¹¹ This study showed that the less invasive endoscopic approach is still an option.

In 2015, Taggart and colleagues¹² reported on a pioneering procedure that wraps the saphenous vein graft with a stent. Initial results showed external stenting had the potential to improve vein-graft lumen and reduce intimal hyperplasia at 1 year postoperatively. Surgeons can expect more data on this technology in the future.

Arterial vs venous grafts

The 1986 report by Loop and colleagues from Cleveland Clinic showed that the patency of the mammary artery graft was superior to that of the saphenous vein and that patients receiving a mammary bypass had significantly better 10-year survival (82.6% vs 71.0%, respectively; P < .0001).¹³ The findings of this landmark study established the LIMA-to-LAD bypass as the technical standard for surgical coronary revascularization.

Single vs bilateral mammary artery grafts

In December 2016, results of the Arterial Revascularization Trial (ART) were published comparing single vs double mammary artery grafts.¹⁴ In this prospective randomized trial, the 5-year results showed no significant difference between these mammary grafts in terms of all-cause mortality, MI, or stroke. Bilateral mammary artery grafts, however, were associated with a higher risk of sternal wound complications (3.5% vs 1.9%, respectively; P = .005) and sternal reconstruction (1.9% vs 0.6%; P = .002).

Radial artery vs saphenous vein grafts

In the largest randomized study comparing these two graft options,¹⁶ the 1-year results showed no difference in graft patency; a follow-up analysis is in progress. In contrast, randomized studies from Canada¹⁷ and the United Kingdom¹⁸ suggest that there are potential benefits associated with use of radial artery grafts in terms of patency and clinical outcomes. In addition, observational data from centers experienced in radial artery grafting have demonstrated favorable outcomes. Radial arteries perform best when bypassing totally occluded or severely stenotic vessels in which there is no or little risk of competitive flow from the native circulation.

Right internal mammary vs radial artery grafts

A propensity-matched comparison study looking at multiple studies (N = 15,374 patients) concluded that use of the right internal mammary artery provides better outcomes.¹⁹ It was associated with a 25% risk reduction for late death and a 63% risk reduction for repeat vascularization, both statistically significant vs the radial artery rates. But there is a randomized study showing that the radial artery is as good as or better than the right internal mammary artery. At this point, it is not clear which artery is better as an adjunct for the LIMA-to-LAD bypass.

GUIDELINES FOR GRAFT SELECTION

In 2016, the Society of Thoracic Surgeons published guidelines that encouraged the use of arterial grafts, giving it a class IIa designation, meaning that the evidence indicates it is reasonable to consider.²⁰

The guidelines note the following:

• The internal mammary artery should be used to bypass the LAD when bypass of the LAD is indicated.
• As an adjunct to the left internal mammary artery, a second arterial graft (the right internal mammary artery or radial artery) should be considered in appropriate patients.
• Use of bilateral internal mammary arteries should be considered in patients who are not at high risk for sternal complications.

COMPARING SURGICAL APPROACHES

Traditional CABG performed via median sternotomy and with the use of cardiopulmonary bypass remains the technical standard in surgical coronary revascularization. However, technologies have allowed surgeons to use different and sometimes less invasive approaches that may have good outcomes in select patients with suitable risk profiles and favorable coronary anatomies.

On-pump vs off-pump CABG

The popularity of CABG without cardiopulmonary bypass (“off-pump”) peaked in 2002, when it constituted approximately 23% of CABG procedures and then declined to 17% by 2012.²¹ The ROOBY (Veterans Affairs Randomized On/Off Bypass) trial of 2,203 VA patients showed that at 1 year, those in the off-pump group had worse composite outcomes, poorer graft patency, and greater incidence of incomplete revascularization than the on-pump group.²² However, the use of off-pump CABG was vindicated in two other trials—CORONARY and GOPCABE—in which experienced surgeons in high-volume centers with high-risk patients had no difference in outcomes at 1 and 5 years.^23–25 The recommendation is to tailor the procedure to the patient rather than the patient to the procedure. The best option is always to do what is right for the patient. For example, patients with diseased ascending aortas or liver disease may benefit from an off-pump approach.

Robotic CABG

This procedure has advantages and disadvantages. The advantages are primarily related to the minimally invasive approach:

• There is no surgeon hand tremor
• It is less invasive
• It provides better cosmetic results
• It is expected to result in less pain, fewer transfusions, fewer complications, and shorter length of hospital stay, although those have not been proven.

Disadvantages include the following:

• Compromised completeness of revascularization—with some “difficult” vessels left unbypassed
• Longer operative times
• Higher cost
• Concern about graft patency with inexperienced surgeons
• Higher-than-expected mortality in some reports.

In 2013, a study of 500 patients treated with robotic totally endoscopic CABG showed that this procedure could be safe and effective, although the best outcomes were achieved in patients with less severe disease requiring fewer bypasses.²⁶ In other words, it is more appropriate for LIMA-to-LAD suturing and less complex anatomy, and it is best performed with cardiopulmonary bypass with the heart arrested.

Hybrid revascularization

This procedure is a combination of minimally invasive CABG (MIDCAB or robotic CABG) to revascularize the LAD and PCI to treat the remaining vessels in multivessel CAD. The CABG and PCI can be concurrent or staged. The hybrid approach has the attraction of being less invasive and uses the technical standard LIMA-to-LAD approach, but it has the obvious limitation of not incorporating additional arterial grafting and the possibility of a compromised technical outcome in less experienced hands.

A collaborative task force from several cardiovascular medical societies developed evidence-based guidelines to address the hybrid coronary revascularization approach. They give it a class IIa recommendation, indicating that it is a reasonable approach to treating patients in whom there are limitations and challenges to traditional CABG. For other patients, they gave it a class IIb recommendation, indicating that it may be reasonable to use as an alternative to multivessel PCI or CABG.²⁷

THE EVOLUTION CONTINUES: CABG VS PCI

As CABG and PCI continue to evolve, surgical approaches to CAD are becoming more sophisticated with the use of more arterial conduits, less invasive surgical approaches, and development of new types of stents for PCI; however, expect the debate to continue regarding which approach to CAD is best. This is not a battle between surgical and nonsurgical specialties. Rather, the goal should be an amicable, collaborative heart-care team. After all, the most important question is, as always, which therapy is best for the individual patient.

The development of a new generation of drug-eluting stents (DES) has had a dramatic impact on the number of stents used for percutaneous transluminal coronary angioplasty for the treatment of coronary artery disease (CAD). But even second- and third-generation DES fall short when compared with coronary artery bypass grafting (CABG) with regards to the need for repeat reavascularization. CABG is advantageous because it bypasses the entire disease segment of the vessel. Thus for multivessel complex CAD, it is still considered the best choice. Nevertheless, most patients prefer the less-invasive option of stents, so practitioners need to provide the best stent available.

There are 3 primary criteria for DES selection:

• Efficacy for a broad range of patients and lesion complexities that primarily provides consistency in improving measures of angiographic and clinical efficacy
• Safety as determined by the following:
  • Enable healing and promote endothelialization
  • Permit functional endothelium
  • Obtaining complete apposition
  • Reduction or elimination of late and very late stent thrombosis
  • Minimizing the need for long-term dual antiplatelet therapy

• Performance provided by reliable delivery capabilities to the lesion site.

GREAT EXPECTATIONS

New DES must be shown to be superior to previous generation stents. Although preclinical endothelialization and other mechanistic surrogates are good enough to claim an improvement, the traditional method is to compare clinical outcomes with the new stent versus the existing stent in a randomized clinical trial.

PROBLEMS WITH DURABLE POLYMER STENTS

Complications with durable polymer DES have included increased local inflammation and neoatherosclerosis. There are reports of subacute stent thrombosis due to lack of adequate expansion and stent apposition. Also reported was late thrombosis, resulting in increased rates of myocardial infarction and death.

These issues motivated engineers to improve and iterate the DES technology. One important technological change is the decrease in strut thickness from 140 µm to as low as 60 µm. The thickness of the polymer coating also has been reduced. The polymer became thinner, more biocompatible, and in some stents, only abluminal. Further developments were to substitute the durable polymer with a biodegradable polymer and perhaps even design a polymer-free stent.

BIORESORBABLE POLYMERS EMERGE

The time course for resorption of bioresorbable polymers ranges from 2 to 15 months, but they all degrade, which should improve long-term outcomes. A meta-analysis of data from the LEADERS trial and ISAR-TEST 3 and 4 found that the bioresorbable polymer stents were associated with significantly lower rates of target-lesion revascularization (P = .029) and stent thrombosis (P = .015) than durable polymer DES at 4 years after implantation.¹ Those results led to the notion that stents with a biodegradable polymer would result in lower rates of stent thrombosis than durable polymer stents; however, that was not the case when stents with biodegradable polymers were compared with second-generation DES.

In the COMPARE II trial,² the rates of stent thrombosis and target-lesion revascularization were not statistically different for the thick-strut biodegradable polymer biolimus-eluting stent (Nobori) compared with the second-generation thin-strut permanent-polymer stents (Xience). In the CENTURY II trial,³ a third-generation biodegradable sirolimus-eluting stent (Ultimaster) had stent thrombosis rates similar to those of a durable polymer everolimus-eluting stent (Xience) 300 days after insertion (4.36% vs 5.27%, respectively). Target-lesion revascularization rates were also about the same for the stents. In the EVOLVE II trial comparing the thin-strut biodegradable everolimus-eluting stent (Synergy) vs the thin-strut permanent-polymer everolimus-eluting stent (Promus), the 12-month target lesion failure rates for the stents were essentially the same.⁴

Another approach was to use biodegradable scaffolds that will be eliminating from the vessel wall once it “completes the job.” The main bioresorbable materials used were polylactic acid or biodegradable metal-like magnesium. These materials pose a technological challenge. While the biodegradable scaffolds are completely eliminated overtime, they still need to equate the performance of best-in-class drug-eluting stent with respect to efficacy and safety. After the Absorb everolimus-eluting BVS system (Absorb BVS) was launched in Europe, initial studies showed scaffold-related thrombosis rates as high as 3.4%.^5–7 That compares with 0.4% for second-generation DES—a troubling result for a new technology.

Rates of restenosis and stent thrombosis are similar for bioresorbable stents and standard durable polymer stents. But what are the potential added benefits of bioresorbable stents? And will they improve patient outcomes?

Bioresorbable stents certainly appeal to patients who do not want a permanent, rigid, metallic implant. Also appealing are the proposed benefits of restoration of vasomotion, late luminal enlargement, preservation of CABG targets, and relief of angina. Whether bioresorbable stents improve these outcomes has not been established. Currently, there is no long-term evidence of reduced rates of adverse events, although in 1 study, optical coherence tomography images recorded 10 years after implantation of the first bioresorbable stents showed a pristine vessel with no signs of the struts.⁸

Several facts are known about the Absorb BVS:

• Preclinical evidence shows complete resorption and return of vascular function, but this takes 3 to 4 years.
• Imaging data at 5 years from the Absorb cohort B trial show complete resorption of struts, lumen preservation, return of function, and plaque regression.⁹
• In ABSORB III, the pivotal US trial, the stent was within the primary end point showing noninferiority in safety and effectiveness compared with Xience in the first year.¹⁰
• Absorb clinical trials in Japan and China confirmed ABSORB III results.
• Meta-analysis (> 3,300 patients) confirmed safety and effectiveness of Absorb.¹¹
• Real-world Absorb clinical evidence continues to show improving outcomes with optimized implant techniques.
• Absorb stent was approved by the US Food and Drug Administration (FDA) in July 2016; more than 150,000 have been implanted worldwide.

The increased rates of target-lesion revascularization and stent thrombosis were likely attributable to inserting the stents into small-diameter vessels that are probably too small for the Absorb BVS. When small vessels (< 2.25 mm) are eliminated from the analysis, the rates were as follows.

Results for vessels > 2.25 mm:

• Target-lesion revascularization: 6.7 % vs 5.5%
• Stent thrombosis: 0.9% vs 0.6%.
• Results for small vessels (< 2.25 mm):
• Target-lesion revascularization: 12.9% vs 8.3%
• Stent thrombosis: 4.6% vs 1.5%.

The lesson is that the Absorb BVS should not be placed in arteries smaller than 2.25 mm in diameter.

Another concern was uncovered in July 2016 when results were published from the ABSORB II trial on vasomotor reactivity at 3 years.¹³ This clinical trial randomized 501 patients in a 2:1 ratio to the Absorb BVS or the Xience DES at 46 sites outside the United States. Assessment for changes in mean lumen diameter between pre- and post-nitrate administration showed no differences between the groups; thus, the Absorb BVS did not achieve a level of superior vasomotor reactivity. There was vasomotor reactivity probably because the surrogate marker was angiographic follow-up and not intravascular ultrasound or tomography.

Further, the coprimary end point of angiographic late luminal loss at 3 years did not meet its noninferiority standard. The Absorb BVS was expected to have lower rates of late lumen loss because the struts are gone and there is less new intimal formation; however, at 3 years, that was not the case.

The rate of acute stent thrombosis also was alarming: 8 cases for Absorb BVS versus none for Xience. This caused alarm, raising the question of why it was happening in these patients 2 to 3 years after implantation.

Animal studies investigating the association of thicker struts and increased thrombogenicity have reported that the 157-µm BVS had much more platelet buildup and thrombogenicity than a 120-µm biomatrix stent. The 74-µm Synergy stent had even lower rates of thrombosis. The reason for increased thrombogenicity with thicker struts requires further study.

Also, an analysis of the secondary cardiac end points at 3 years in ABSORB II found no clinical patient-oriented differences between the Absorb BVS and the Xience stent (20.8% vs 24.0%, respectively; P = .44). However, rates of device-oriented clinical end points were significantly higher for Absorb BVS (10.4% vs 4.9%; P = .043).¹³

Clearly, the results for Absorb BVS in this study were not positive. One explanation is suboptimal implantation techniques that did not appose the polymer to the wall. A few years ago, focus shifted to an optimal technique for scaffold deployment, which included predilation, appropriate sizing of the scaffold to the size of the vessel, and postdilation with the intention of embedding the polymer in the vessel wall. Multiple studies have reported fewer incidents of stent thrombosis with the implementation of this protocol.¹⁴

Further studies have continued to report increased rates of late scaffold thrombosis in follow-ups of 30 days to 3 years. This resulted in an advisory letter from the FDA focused on appropriate clinical use of the device and withdrawal of ABSORB from commercial use in Europe and Australia.

BIORESORBABLE SCAFFOLDS PIPELINE

This is questionable because one has to believe in the vulnerable plaque theory, which assumes potential eruption of plaques. The Absorb can actually seal a thin cap atheroma and necrotic core over time. It seems that this technology can cause some late lumen enlargement and seal an existing plaque, which may have implications for the future.

SUMMARY

This is the current state of the Absorb BVS:

• More than 150,000 implanted globally
• Received FDA approval in July 2016
• Should not be used in small vessels (ie, lumen diameter < 2.25 mm)
• Thrombosis rates 2 to 3 years after implantation are of concern
• Focusing on appropriate surgical implantation technique can improve outcomes.

Overall, use of bioresorbable stent technology is intriguing. While there is ongoing patient preference for bioresorbable technology, clinical trial results raise the question of whether bioresorbable scaffolds are inferior to best-in-class DES. Improving the scaffold technology and the implantation techniques may equate the short-term outcome of the bioresorbable scaffolds with metallic stents with the hope that over time (when the scaffold is gone), the advantage will be with the bioresorbable scaffolds. Meanwhile, the technology is still seeking its best clinical utility, and a matching performance to the best-in-class DES.

Time will tell whether 5 to 10 years after implantation, BRS technology will outperform durable metallic stents.

The development of a new generation of drug-eluting stents (DES) has had a dramatic impact on the number of stents used for percutaneous transluminal coronary angioplasty for the treatment of coronary artery disease (CAD). But even second- and third-generation DES fall short when compared with coronary artery bypass grafting (CABG) with regards to the need for repeat reavascularization. CABG is advantageous because it bypasses the entire disease segment of the vessel. Thus for multivessel complex CAD, it is still considered the best choice. Nevertheless, most patients prefer the less-invasive option of stents, so practitioners need to provide the best stent available.

There are 3 primary criteria for DES selection:

• Efficacy for a broad range of patients and lesion complexities that primarily provides consistency in improving measures of angiographic and clinical efficacy
• Safety as determined by the following:
  • Enable healing and promote endothelialization
  • Permit functional endothelium
  • Obtaining complete apposition
  • Reduction or elimination of late and very late stent thrombosis
  • Minimizing the need for long-term dual antiplatelet therapy

• Performance provided by reliable delivery capabilities to the lesion site.

GREAT EXPECTATIONS

New DES must be shown to be superior to previous generation stents. Although preclinical endothelialization and other mechanistic surrogates are good enough to claim an improvement, the traditional method is to compare clinical outcomes with the new stent versus the existing stent in a randomized clinical trial.

PROBLEMS WITH DURABLE POLYMER STENTS

Complications with durable polymer DES have included increased local inflammation and neoatherosclerosis. There are reports of subacute stent thrombosis due to lack of adequate expansion and stent apposition. Also reported was late thrombosis, resulting in increased rates of myocardial infarction and death.

These issues motivated engineers to improve and iterate the DES technology. One important technological change is the decrease in strut thickness from 140 µm to as low as 60 µm. The thickness of the polymer coating also has been reduced. The polymer became thinner, more biocompatible, and in some stents, only abluminal. Further developments were to substitute the durable polymer with a biodegradable polymer and perhaps even design a polymer-free stent.

BIORESORBABLE POLYMERS EMERGE

The time course for resorption of bioresorbable polymers ranges from 2 to 15 months, but they all degrade, which should improve long-term outcomes. A meta-analysis of data from the LEADERS trial and ISAR-TEST 3 and 4 found that the bioresorbable polymer stents were associated with significantly lower rates of target-lesion revascularization (P = .029) and stent thrombosis (P = .015) than durable polymer DES at 4 years after implantation.¹ Those results led to the notion that stents with a biodegradable polymer would result in lower rates of stent thrombosis than durable polymer stents; however, that was not the case when stents with biodegradable polymers were compared with second-generation DES.

In the COMPARE II trial,² the rates of stent thrombosis and target-lesion revascularization were not statistically different for the thick-strut biodegradable polymer biolimus-eluting stent (Nobori) compared with the second-generation thin-strut permanent-polymer stents (Xience). In the CENTURY II trial,³ a third-generation biodegradable sirolimus-eluting stent (Ultimaster) had stent thrombosis rates similar to those of a durable polymer everolimus-eluting stent (Xience) 300 days after insertion (4.36% vs 5.27%, respectively). Target-lesion revascularization rates were also about the same for the stents. In the EVOLVE II trial comparing the thin-strut biodegradable everolimus-eluting stent (Synergy) vs the thin-strut permanent-polymer everolimus-eluting stent (Promus), the 12-month target lesion failure rates for the stents were essentially the same.⁴

Another approach was to use biodegradable scaffolds that will be eliminating from the vessel wall once it “completes the job.” The main bioresorbable materials used were polylactic acid or biodegradable metal-like magnesium. These materials pose a technological challenge. While the biodegradable scaffolds are completely eliminated overtime, they still need to equate the performance of best-in-class drug-eluting stent with respect to efficacy and safety. After the Absorb everolimus-eluting BVS system (Absorb BVS) was launched in Europe, initial studies showed scaffold-related thrombosis rates as high as 3.4%.^5–7 That compares with 0.4% for second-generation DES—a troubling result for a new technology.

Rates of restenosis and stent thrombosis are similar for bioresorbable stents and standard durable polymer stents. But what are the potential added benefits of bioresorbable stents? And will they improve patient outcomes?

Bioresorbable stents certainly appeal to patients who do not want a permanent, rigid, metallic implant. Also appealing are the proposed benefits of restoration of vasomotion, late luminal enlargement, preservation of CABG targets, and relief of angina. Whether bioresorbable stents improve these outcomes has not been established. Currently, there is no long-term evidence of reduced rates of adverse events, although in 1 study, optical coherence tomography images recorded 10 years after implantation of the first bioresorbable stents showed a pristine vessel with no signs of the struts.⁸

Several facts are known about the Absorb BVS:

• Preclinical evidence shows complete resorption and return of vascular function, but this takes 3 to 4 years.
• Imaging data at 5 years from the Absorb cohort B trial show complete resorption of struts, lumen preservation, return of function, and plaque regression.⁹
• In ABSORB III, the pivotal US trial, the stent was within the primary end point showing noninferiority in safety and effectiveness compared with Xience in the first year.¹⁰
• Absorb clinical trials in Japan and China confirmed ABSORB III results.
• Meta-analysis (> 3,300 patients) confirmed safety and effectiveness of Absorb.¹¹
• Real-world Absorb clinical evidence continues to show improving outcomes with optimized implant techniques.
• Absorb stent was approved by the US Food and Drug Administration (FDA) in July 2016; more than 150,000 have been implanted worldwide.

The increased rates of target-lesion revascularization and stent thrombosis were likely attributable to inserting the stents into small-diameter vessels that are probably too small for the Absorb BVS. When small vessels (< 2.25 mm) are eliminated from the analysis, the rates were as follows.

Results for vessels > 2.25 mm:

• Target-lesion revascularization: 6.7 % vs 5.5%
• Stent thrombosis: 0.9% vs 0.6%.
• Results for small vessels (< 2.25 mm):
• Target-lesion revascularization: 12.9% vs 8.3%
• Stent thrombosis: 4.6% vs 1.5%.

The lesson is that the Absorb BVS should not be placed in arteries smaller than 2.25 mm in diameter.

Another concern was uncovered in July 2016 when results were published from the ABSORB II trial on vasomotor reactivity at 3 years.¹³ This clinical trial randomized 501 patients in a 2:1 ratio to the Absorb BVS or the Xience DES at 46 sites outside the United States. Assessment for changes in mean lumen diameter between pre- and post-nitrate administration showed no differences between the groups; thus, the Absorb BVS did not achieve a level of superior vasomotor reactivity. There was vasomotor reactivity probably because the surrogate marker was angiographic follow-up and not intravascular ultrasound or tomography.

Further, the coprimary end point of angiographic late luminal loss at 3 years did not meet its noninferiority standard. The Absorb BVS was expected to have lower rates of late lumen loss because the struts are gone and there is less new intimal formation; however, at 3 years, that was not the case.

The rate of acute stent thrombosis also was alarming: 8 cases for Absorb BVS versus none for Xience. This caused alarm, raising the question of why it was happening in these patients 2 to 3 years after implantation.

Animal studies investigating the association of thicker struts and increased thrombogenicity have reported that the 157-µm BVS had much more platelet buildup and thrombogenicity than a 120-µm biomatrix stent. The 74-µm Synergy stent had even lower rates of thrombosis. The reason for increased thrombogenicity with thicker struts requires further study.

Also, an analysis of the secondary cardiac end points at 3 years in ABSORB II found no clinical patient-oriented differences between the Absorb BVS and the Xience stent (20.8% vs 24.0%, respectively; P = .44). However, rates of device-oriented clinical end points were significantly higher for Absorb BVS (10.4% vs 4.9%; P = .043).¹³

Clearly, the results for Absorb BVS in this study were not positive. One explanation is suboptimal implantation techniques that did not appose the polymer to the wall. A few years ago, focus shifted to an optimal technique for scaffold deployment, which included predilation, appropriate sizing of the scaffold to the size of the vessel, and postdilation with the intention of embedding the polymer in the vessel wall. Multiple studies have reported fewer incidents of stent thrombosis with the implementation of this protocol.¹⁴

Further studies have continued to report increased rates of late scaffold thrombosis in follow-ups of 30 days to 3 years. This resulted in an advisory letter from the FDA focused on appropriate clinical use of the device and withdrawal of ABSORB from commercial use in Europe and Australia.

BIORESORBABLE SCAFFOLDS PIPELINE

This is questionable because one has to believe in the vulnerable plaque theory, which assumes potential eruption of plaques. The Absorb can actually seal a thin cap atheroma and necrotic core over time. It seems that this technology can cause some late lumen enlargement and seal an existing plaque, which may have implications for the future.

SUMMARY

This is the current state of the Absorb BVS:

• More than 150,000 implanted globally
• Received FDA approval in July 2016
• Should not be used in small vessels (ie, lumen diameter < 2.25 mm)
• Thrombosis rates 2 to 3 years after implantation are of concern
• Focusing on appropriate surgical implantation technique can improve outcomes.

Overall, use of bioresorbable stent technology is intriguing. While there is ongoing patient preference for bioresorbable technology, clinical trial results raise the question of whether bioresorbable scaffolds are inferior to best-in-class DES. Improving the scaffold technology and the implantation techniques may equate the short-term outcome of the bioresorbable scaffolds with metallic stents with the hope that over time (when the scaffold is gone), the advantage will be with the bioresorbable scaffolds. Meanwhile, the technology is still seeking its best clinical utility, and a matching performance to the best-in-class DES.

Time will tell whether 5 to 10 years after implantation, BRS technology will outperform durable metallic stents.

The development of a new generation of drug-eluting stents (DES) has had a dramatic impact on the number of stents used for percutaneous transluminal coronary angioplasty for the treatment of coronary artery disease (CAD). But even second- and third-generation DES fall short when compared with coronary artery bypass grafting (CABG) with regards to the need for repeat reavascularization. CABG is advantageous because it bypasses the entire disease segment of the vessel. Thus for multivessel complex CAD, it is still considered the best choice. Nevertheless, most patients prefer the less-invasive option of stents, so practitioners need to provide the best stent available.

There are 3 primary criteria for DES selection:

• Efficacy for a broad range of patients and lesion complexities that primarily provides consistency in improving measures of angiographic and clinical efficacy
• Safety as determined by the following:
  • Enable healing and promote endothelialization
  • Permit functional endothelium
  • Obtaining complete apposition
  • Reduction or elimination of late and very late stent thrombosis
  • Minimizing the need for long-term dual antiplatelet therapy

• Performance provided by reliable delivery capabilities to the lesion site.

GREAT EXPECTATIONS

New DES must be shown to be superior to previous generation stents. Although preclinical endothelialization and other mechanistic surrogates are good enough to claim an improvement, the traditional method is to compare clinical outcomes with the new stent versus the existing stent in a randomized clinical trial.

PROBLEMS WITH DURABLE POLYMER STENTS

Complications with durable polymer DES have included increased local inflammation and neoatherosclerosis. There are reports of subacute stent thrombosis due to lack of adequate expansion and stent apposition. Also reported was late thrombosis, resulting in increased rates of myocardial infarction and death.

These issues motivated engineers to improve and iterate the DES technology. One important technological change is the decrease in strut thickness from 140 µm to as low as 60 µm. The thickness of the polymer coating also has been reduced. The polymer became thinner, more biocompatible, and in some stents, only abluminal. Further developments were to substitute the durable polymer with a biodegradable polymer and perhaps even design a polymer-free stent.

BIORESORBABLE POLYMERS EMERGE

The time course for resorption of bioresorbable polymers ranges from 2 to 15 months, but they all degrade, which should improve long-term outcomes. A meta-analysis of data from the LEADERS trial and ISAR-TEST 3 and 4 found that the bioresorbable polymer stents were associated with significantly lower rates of target-lesion revascularization (P = .029) and stent thrombosis (P = .015) than durable polymer DES at 4 years after implantation.¹ Those results led to the notion that stents with a biodegradable polymer would result in lower rates of stent thrombosis than durable polymer stents; however, that was not the case when stents with biodegradable polymers were compared with second-generation DES.

In the COMPARE II trial,² the rates of stent thrombosis and target-lesion revascularization were not statistically different for the thick-strut biodegradable polymer biolimus-eluting stent (Nobori) compared with the second-generation thin-strut permanent-polymer stents (Xience). In the CENTURY II trial,³ a third-generation biodegradable sirolimus-eluting stent (Ultimaster) had stent thrombosis rates similar to those of a durable polymer everolimus-eluting stent (Xience) 300 days after insertion (4.36% vs 5.27%, respectively). Target-lesion revascularization rates were also about the same for the stents. In the EVOLVE II trial comparing the thin-strut biodegradable everolimus-eluting stent (Synergy) vs the thin-strut permanent-polymer everolimus-eluting stent (Promus), the 12-month target lesion failure rates for the stents were essentially the same.⁴

Another approach was to use biodegradable scaffolds that will be eliminating from the vessel wall once it “completes the job.” The main bioresorbable materials used were polylactic acid or biodegradable metal-like magnesium. These materials pose a technological challenge. While the biodegradable scaffolds are completely eliminated overtime, they still need to equate the performance of best-in-class drug-eluting stent with respect to efficacy and safety. After the Absorb everolimus-eluting BVS system (Absorb BVS) was launched in Europe, initial studies showed scaffold-related thrombosis rates as high as 3.4%.^5–7 That compares with 0.4% for second-generation DES—a troubling result for a new technology.

Rates of restenosis and stent thrombosis are similar for bioresorbable stents and standard durable polymer stents. But what are the potential added benefits of bioresorbable stents? And will they improve patient outcomes?

Bioresorbable stents certainly appeal to patients who do not want a permanent, rigid, metallic implant. Also appealing are the proposed benefits of restoration of vasomotion, late luminal enlargement, preservation of CABG targets, and relief of angina. Whether bioresorbable stents improve these outcomes has not been established. Currently, there is no long-term evidence of reduced rates of adverse events, although in 1 study, optical coherence tomography images recorded 10 years after implantation of the first bioresorbable stents showed a pristine vessel with no signs of the struts.⁸

Several facts are known about the Absorb BVS:

• Preclinical evidence shows complete resorption and return of vascular function, but this takes 3 to 4 years.
• Imaging data at 5 years from the Absorb cohort B trial show complete resorption of struts, lumen preservation, return of function, and plaque regression.⁹
• In ABSORB III, the pivotal US trial, the stent was within the primary end point showing noninferiority in safety and effectiveness compared with Xience in the first year.¹⁰
• Absorb clinical trials in Japan and China confirmed ABSORB III results.
• Meta-analysis (> 3,300 patients) confirmed safety and effectiveness of Absorb.¹¹
• Real-world Absorb clinical evidence continues to show improving outcomes with optimized implant techniques.
• Absorb stent was approved by the US Food and Drug Administration (FDA) in July 2016; more than 150,000 have been implanted worldwide.

The increased rates of target-lesion revascularization and stent thrombosis were likely attributable to inserting the stents into small-diameter vessels that are probably too small for the Absorb BVS. When small vessels (< 2.25 mm) are eliminated from the analysis, the rates were as follows.

Results for vessels > 2.25 mm:

• Target-lesion revascularization: 6.7 % vs 5.5%
• Stent thrombosis: 0.9% vs 0.6%.
• Results for small vessels (< 2.25 mm):
• Target-lesion revascularization: 12.9% vs 8.3%
• Stent thrombosis: 4.6% vs 1.5%.

The lesson is that the Absorb BVS should not be placed in arteries smaller than 2.25 mm in diameter.

Another concern was uncovered in July 2016 when results were published from the ABSORB II trial on vasomotor reactivity at 3 years.¹³ This clinical trial randomized 501 patients in a 2:1 ratio to the Absorb BVS or the Xience DES at 46 sites outside the United States. Assessment for changes in mean lumen diameter between pre- and post-nitrate administration showed no differences between the groups; thus, the Absorb BVS did not achieve a level of superior vasomotor reactivity. There was vasomotor reactivity probably because the surrogate marker was angiographic follow-up and not intravascular ultrasound or tomography.

Further, the coprimary end point of angiographic late luminal loss at 3 years did not meet its noninferiority standard. The Absorb BVS was expected to have lower rates of late lumen loss because the struts are gone and there is less new intimal formation; however, at 3 years, that was not the case.

The rate of acute stent thrombosis also was alarming: 8 cases for Absorb BVS versus none for Xience. This caused alarm, raising the question of why it was happening in these patients 2 to 3 years after implantation.

Animal studies investigating the association of thicker struts and increased thrombogenicity have reported that the 157-µm BVS had much more platelet buildup and thrombogenicity than a 120-µm biomatrix stent. The 74-µm Synergy stent had even lower rates of thrombosis. The reason for increased thrombogenicity with thicker struts requires further study.

Also, an analysis of the secondary cardiac end points at 3 years in ABSORB II found no clinical patient-oriented differences between the Absorb BVS and the Xience stent (20.8% vs 24.0%, respectively; P = .44). However, rates of device-oriented clinical end points were significantly higher for Absorb BVS (10.4% vs 4.9%; P = .043).¹³

Clearly, the results for Absorb BVS in this study were not positive. One explanation is suboptimal implantation techniques that did not appose the polymer to the wall. A few years ago, focus shifted to an optimal technique for scaffold deployment, which included predilation, appropriate sizing of the scaffold to the size of the vessel, and postdilation with the intention of embedding the polymer in the vessel wall. Multiple studies have reported fewer incidents of stent thrombosis with the implementation of this protocol.¹⁴

Further studies have continued to report increased rates of late scaffold thrombosis in follow-ups of 30 days to 3 years. This resulted in an advisory letter from the FDA focused on appropriate clinical use of the device and withdrawal of ABSORB from commercial use in Europe and Australia.

BIORESORBABLE SCAFFOLDS PIPELINE

This is questionable because one has to believe in the vulnerable plaque theory, which assumes potential eruption of plaques. The Absorb can actually seal a thin cap atheroma and necrotic core over time. It seems that this technology can cause some late lumen enlargement and seal an existing plaque, which may have implications for the future.

SUMMARY

This is the current state of the Absorb BVS:

• More than 150,000 implanted globally
• Received FDA approval in July 2016
• Should not be used in small vessels (ie, lumen diameter < 2.25 mm)
• Thrombosis rates 2 to 3 years after implantation are of concern
• Focusing on appropriate surgical implantation technique can improve outcomes.

Overall, use of bioresorbable stent technology is intriguing. While there is ongoing patient preference for bioresorbable technology, clinical trial results raise the question of whether bioresorbable scaffolds are inferior to best-in-class DES. Improving the scaffold technology and the implantation techniques may equate the short-term outcome of the bioresorbable scaffolds with metallic stents with the hope that over time (when the scaffold is gone), the advantage will be with the bioresorbable scaffolds. Meanwhile, the technology is still seeking its best clinical utility, and a matching performance to the best-in-class DES.

Time will tell whether 5 to 10 years after implantation, BRS technology will outperform durable metallic stents.

In the years since the introduction of robotically assisted mitral valve surgery, surgeons have looked for ways to improve techniques and procedures. A study from Cleveland Clinic presented at the American Association for Thoracic Surgery in 2016 assessed efficacy and safety outcomes associated with 1,000 consecutive robotically assisted mitral valve surgeries at Cleveland Clinic.1 The purpose of the study was to assess the clinical outcomes from these cases and analyze whether the outcomes changed over time as surgeons became more competent with robotic techniques. This analysis was also designed to identify procedural processes that improved outcomes during the trial.

STUDY METHODS

Nearly all cases (96%) were classified as degenerative mitral valve disease (N = 960). Of those, most had posterior leaflet prolapse (68%), about one-third (29%) had bileaflet prolapse, and only 3% had anterior leaflet involvement.

All surgeries were performed through right port incisions and used femoral cannulation for peripheral bypass. The aorta was occluded with either a Chitwood transthoracic clamp or a balloon.

STUDY RESULTS

It is important to remember that with femoral artery perfusion, the blood flow is opposite to the normal direction; thus, it goes up the aorta into the head vessels, which presents its own risks and challenges. Also, during retrograde perfusion, there is a risk of dislodging atherosclerotic plaque leading to brain embolus and stroke.

In these 1,000 cases, 997 were planned mitral valve repairs, 2 were mitral valve replacements, and 1 was resection of a mitral valve fibroelastoma. Results for the mitral valve repairs were excellent, with postoperative mitral regurgitation occurring in less than 1% of patients.

A primary point of interest was to identify procedural improvements that occurred during the course of the study. The areas evaluated in robotically assisted mitral valve surgery were the efficacy of the procedure in time, transfusion rates, stroke risk, how many mitral valve replacements occurred, and how many required conversion to sternotomy. These were assessed to determine whether surgical experience resulted in improvement.

Results showed that those efficiencies improved during the study. Cardiopulmonary bypass time decreased from about 140 minutes to 130 minutes. Cross-clamp time improved more dramatically from about 110 minutes to 90 minutes. And the percentage of cases requiring postoperative or intraoperative blood transfusion improved from about 24% to 10%.

PATIENT SELECTION CRITERIA: ALGORITHM

ALGORITHM IMPACT

What was the effect of this algorithm? In the 500 cases after its implementation, the stroke rate decreased by more than half—from 10 incidents before to 4 incidents after—and mitral replacements dropped from 4 to 0. The rate of conversion from robotic repair to conventional sternotomy in this patient series also improved, although this likely reflects surgical experience more than the algorithm. The conversion rate initially increased as surgeons gained experience with the robotic techniques. It rose to 4% during the first 300 to 400 cases, then dropped to 2% at the 500-case mark. It leveled off for the next 300 cases before dropping to 0 toward the end of the series.

Other metrics improved as well, which were attributed to a combination of surgical experience with robotic assistance and use of the patient-selection algorithm. The stroke risk declined to 0.8%, ischemic and cardiopulmonary bypass times declined, and the transfusion rate declined. No mitral replacements were done in the last 500 cases, and the conversion to conventional sternotomy rate declined to 1%.

In conclusion, this Cleveland Clinic study showed that a combination of a focused preoperative assessment using the patient-selection algorithm and increased surgical experience with robotic techniques enhanced clinical outcomes and improved procedural efficiency associated with robotically assisted mitral valve surgery.

In the years since the introduction of robotically assisted mitral valve surgery, surgeons have looked for ways to improve techniques and procedures. A study from Cleveland Clinic presented at the American Association for Thoracic Surgery in 2016 assessed efficacy and safety outcomes associated with 1,000 consecutive robotically assisted mitral valve surgeries at Cleveland Clinic.1 The purpose of the study was to assess the clinical outcomes from these cases and analyze whether the outcomes changed over time as surgeons became more competent with robotic techniques. This analysis was also designed to identify procedural processes that improved outcomes during the trial.

STUDY METHODS

Nearly all cases (96%) were classified as degenerative mitral valve disease (N = 960). Of those, most had posterior leaflet prolapse (68%), about one-third (29%) had bileaflet prolapse, and only 3% had anterior leaflet involvement.

All surgeries were performed through right port incisions and used femoral cannulation for peripheral bypass. The aorta was occluded with either a Chitwood transthoracic clamp or a balloon.

STUDY RESULTS

It is important to remember that with femoral artery perfusion, the blood flow is opposite to the normal direction; thus, it goes up the aorta into the head vessels, which presents its own risks and challenges. Also, during retrograde perfusion, there is a risk of dislodging atherosclerotic plaque leading to brain embolus and stroke.

In these 1,000 cases, 997 were planned mitral valve repairs, 2 were mitral valve replacements, and 1 was resection of a mitral valve fibroelastoma. Results for the mitral valve repairs were excellent, with postoperative mitral regurgitation occurring in less than 1% of patients.

A primary point of interest was to identify procedural improvements that occurred during the course of the study. The areas evaluated in robotically assisted mitral valve surgery were the efficacy of the procedure in time, transfusion rates, stroke risk, how many mitral valve replacements occurred, and how many required conversion to sternotomy. These were assessed to determine whether surgical experience resulted in improvement.

Results showed that those efficiencies improved during the study. Cardiopulmonary bypass time decreased from about 140 minutes to 130 minutes. Cross-clamp time improved more dramatically from about 110 minutes to 90 minutes. And the percentage of cases requiring postoperative or intraoperative blood transfusion improved from about 24% to 10%.

PATIENT SELECTION CRITERIA: ALGORITHM

ALGORITHM IMPACT

What was the effect of this algorithm? In the 500 cases after its implementation, the stroke rate decreased by more than half—from 10 incidents before to 4 incidents after—and mitral replacements dropped from 4 to 0. The rate of conversion from robotic repair to conventional sternotomy in this patient series also improved, although this likely reflects surgical experience more than the algorithm. The conversion rate initially increased as surgeons gained experience with the robotic techniques. It rose to 4% during the first 300 to 400 cases, then dropped to 2% at the 500-case mark. It leveled off for the next 300 cases before dropping to 0 toward the end of the series.

Other metrics improved as well, which were attributed to a combination of surgical experience with robotic assistance and use of the patient-selection algorithm. The stroke risk declined to 0.8%, ischemic and cardiopulmonary bypass times declined, and the transfusion rate declined. No mitral replacements were done in the last 500 cases, and the conversion to conventional sternotomy rate declined to 1%.

In conclusion, this Cleveland Clinic study showed that a combination of a focused preoperative assessment using the patient-selection algorithm and increased surgical experience with robotic techniques enhanced clinical outcomes and improved procedural efficiency associated with robotically assisted mitral valve surgery.

In the years since the introduction of robotically assisted mitral valve surgery, surgeons have looked for ways to improve techniques and procedures. A study from Cleveland Clinic presented at the American Association for Thoracic Surgery in 2016 assessed efficacy and safety outcomes associated with 1,000 consecutive robotically assisted mitral valve surgeries at Cleveland Clinic.1 The purpose of the study was to assess the clinical outcomes from these cases and analyze whether the outcomes changed over time as surgeons became more competent with robotic techniques. This analysis was also designed to identify procedural processes that improved outcomes during the trial.

STUDY METHODS

Nearly all cases (96%) were classified as degenerative mitral valve disease (N = 960). Of those, most had posterior leaflet prolapse (68%), about one-third (29%) had bileaflet prolapse, and only 3% had anterior leaflet involvement.

All surgeries were performed through right port incisions and used femoral cannulation for peripheral bypass. The aorta was occluded with either a Chitwood transthoracic clamp or a balloon.

STUDY RESULTS

It is important to remember that with femoral artery perfusion, the blood flow is opposite to the normal direction; thus, it goes up the aorta into the head vessels, which presents its own risks and challenges. Also, during retrograde perfusion, there is a risk of dislodging atherosclerotic plaque leading to brain embolus and stroke.

In these 1,000 cases, 997 were planned mitral valve repairs, 2 were mitral valve replacements, and 1 was resection of a mitral valve fibroelastoma. Results for the mitral valve repairs were excellent, with postoperative mitral regurgitation occurring in less than 1% of patients.

A primary point of interest was to identify procedural improvements that occurred during the course of the study. The areas evaluated in robotically assisted mitral valve surgery were the efficacy of the procedure in time, transfusion rates, stroke risk, how many mitral valve replacements occurred, and how many required conversion to sternotomy. These were assessed to determine whether surgical experience resulted in improvement.

Results showed that those efficiencies improved during the study. Cardiopulmonary bypass time decreased from about 140 minutes to 130 minutes. Cross-clamp time improved more dramatically from about 110 minutes to 90 minutes. And the percentage of cases requiring postoperative or intraoperative blood transfusion improved from about 24% to 10%.

PATIENT SELECTION CRITERIA: ALGORITHM

ALGORITHM IMPACT

What was the effect of this algorithm? In the 500 cases after its implementation, the stroke rate decreased by more than half—from 10 incidents before to 4 incidents after—and mitral replacements dropped from 4 to 0. The rate of conversion from robotic repair to conventional sternotomy in this patient series also improved, although this likely reflects surgical experience more than the algorithm. The conversion rate initially increased as surgeons gained experience with the robotic techniques. It rose to 4% during the first 300 to 400 cases, then dropped to 2% at the 500-case mark. It leveled off for the next 300 cases before dropping to 0 toward the end of the series.

Other metrics improved as well, which were attributed to a combination of surgical experience with robotic assistance and use of the patient-selection algorithm. The stroke risk declined to 0.8%, ischemic and cardiopulmonary bypass times declined, and the transfusion rate declined. No mitral replacements were done in the last 500 cases, and the conversion to conventional sternotomy rate declined to 1%.

In conclusion, this Cleveland Clinic study showed that a combination of a focused preoperative assessment using the patient-selection algorithm and increased surgical experience with robotic techniques enhanced clinical outcomes and improved procedural efficiency associated with robotically assisted mitral valve surgery.

In 2015, Cleveland Clinic cardiac and vascular surgeons performed more than 1,000 open or endovascular operations involving the thoracic aorta, the most of any US medical center. Cardioaortic operations account for a large volume of the procedures performed annually in the Department of Thoracic and Cardiovascular Surgery at Cleveland Clinic. Of the approximately 4,000 cardiac procedures performed per year at Cleveland Clinic, nearly 1 in 5 includes thoracic aorta replacement.

Providing optimal care to patients with thoracic aortic disease requires a multidisciplinary approach beginning in the preoperative phase and extending through the life of patients and their families. In the Aortic Center at Cleveland Clinic Heart & Vascular Institute, cardiovascular medicine and imaging specialists, geneticists, and cardioaortic and vascular surgeons work in unison to provide the highest quality care. This involves active analysis of outcomes to continuously improve the quality of care provided.

This paper examines trends in the treatment of thoracic aortic disease, describes the different types of therapeutic procedures, and explores details about their safety and efficacy by summarizing the key research findings on cardioaortic procedures published from our Center during the last 2 years.

SEGMENTAL PERSPECTIVE

1. Modified Bentall procedure with a mechanical composite valve graft (CVG)

2. Modified Bentall procedure with a biologic CVG

3. Homograft, or allograft, root replacement with a human cadaveric aorta

4. Valve-preserving aortic root replacement with a prosthetic graft but which leaves the patient’s native aortic valve intact with or without accompanying repair of that valve.

A Cleveland Clinic study published in 2016 analyzed 957 elective aortic root replacement procedures performed from 1995 through 2014.¹ The number of procedures in this study were evenly distributed across these 4 aortic root replacement strategies.

The perioperative mortality rate was 0.73% and the stroke rate was 1.4%. For 3 of the 4 procedure types, 15-year survival rates were excellent: above 80% for mechanical CVG, allografts, and valve-preservation surgery. The survival rate for biologic CVG was lower (57%), reflecting the difference in population, as these were typically older patients.

This study also demonstrated the durability of these operations, with a reoperation rate of approximately 15% at 15 years. Reoperation rates for patients having undergone these operations should be considered in the light of competing risk of death from other causes. As such, the risk of reoperation after mechanical CVG, biologic CVG, and valve-preserving procedures were similar, ranging from 5% to 15%. Allografts had the highest reoperation rates (approximately 30% at 15 years) because they used to be the biologic root replacement of choice for younger patients but have since been found to wear out at a similar rate as other bioprostheses.2 As a result, they are now used less frequently for elective indications.

Cleveland Clinic practitioners now perform more than 80 valve-preserving root replacement operations per year, approximately 700 overall.

Clinical implications

For patients presenting with aortic root aneurysm, consider the following:

• Valve-preserving aortic root replacement is preferred for patients with root aneurysm and a tricuspid aortic valve without valve stenosis.
• Valve-preserving aortic root replacement with either remodeling or reimplantation is also preferred for patients with a bicuspid aortic valve with a dilated annulus or root aneurysm, but without aortic-associated aortic valve stenosis
• Mechanical CVG is preferred for younger patients with root aneurysm and aortic valve stenosis (usually a bicuspid or unicuspid aortic valve); biomechanical CVG is preferred for older patients with root aneurysm and associated aortic valve stenosis.
• Allografts are now reserved primarily for patients with endocarditis and for older patients with a small aortic root.

The condition of the patient at presentation has become the strongest predictor of surgical risk. An improved understanding of these associations can improve our prediction of risks and the decision about when to operate. Patients needing aortic replacement can present with a broad spectrum of pathologies. For example, a patient who presents with acute type A dissection is quite different from a patient with an enlarging ascending aneurysm who had a previous aortic valve replacement for bicuspid aortic valve stenosis as a young adult. Further, both are different from the elderly patient with the complex constellation of coronary disease, multivalve disease, atrial fibrillation, and an ascending aneurysm—an increasingly common presentation.

Guidelines supporting the decision to replace the aorta in patients with chronic asymptomatic aortic disease are limited by a lack of data on surgical risk and long-term effectiveness.

A study from the Society of Thoracic Surgeons database assessed outcomes in patients who had surgical replacement of the ascending aorta, with or without root repair.³ The operative mortality (either in-hospital or within 30 days of surgery) was 8.3% and ranged from 3.5% for elective surgery to 9.1% for urgent surgery, and 21.5% for emergencies. End-stage kidney disease and reoperation were also shown to be independent predictors of risk in that study.

Outcomes at Cleveland Clinic for elective ascending aortic procedures are much better than these national averages. Outcomes data are important to patients when making a decision about prophylactic surgery. In a study analyzing 1,889 patients undergoing elective ascending replacement at Cleveland Clinic between 2006 and 2010, the operative mortality was only 0.5% for those undergoing isolated ascending replacement and 2% for those requiring a multicomponent operation. In the multicomponent group, 87% included aortic valve replacement, 29% coronary bypass, and 25% underwent more than 2 different combined procedures.⁴

Patient risk factors

A comparison of patient risk factors for the 2 groups showed that the isolated replacement group had larger aortic diameters, more extensive disease with dilated descending aortas, and were more frequently undergoing a reoperation than the multicomponent group.

To further define the risks, we conducted a propensity-matching study of 197 pairs of these patients, comparing 62 variables including aortic morphology data gathered from 3-dimensional analysis of computed tomography scans. Results showed no differences in survival rates between the groups during 4 years of follow-up.⁴ A comparison of the risk of other perioperative complications—death, stroke, need for dialysis, respiratory failure, and bleeding—also showed no differences between the groups.

Does adding ascending aortic replacement to other cardiac procedures increase the surgical risk?

To answer this question, we collected data on Cleveland Clinic patients between 2006 and 2011 who had aortic surgery in combination with cardiac surgery (N = 1,677) and compared them against a similar cohort who only had cardiac surgery (N = 12,617).⁵ The objectives were to determine the risk of adding aortic surgery to an elective cardiac operation. A second objective was to determine the impact of circulatory arrest on outcomes.

Comparison 1. We identified 1,284 matched pairs from the 2 groups. Data showed a slightly higher risk of stroke in patients who had cardioaortic surgery (2.4%) compared with those who had cardiac surgery alone (1.7%); however, the mortality rate was not significantly different between the groups.

Does circulatory arrest affect the stroke rate?

From the matched pairs of patients who underwent cardioaortic surgery, we identified a subset of patients who had circulatory arrest and compared them with those who did not have circulatory arrest. The circulatory arrest group had worse outcomes. Mortality rates were 4.1% vs 1.0%, respectively, and stroke rates were 3.9% vs 0.9%. 

This raised the question of whether circulatory arrest was the cause of the worse outcomes or a marker of patients with more advanced disease.

The decision to use circulatory arrest is primarily based on 2 factors:

• Patient-specific factors, such as those with advanced aortic disease in whom circulatory arrest is unavoidable.
• Surgeon preference/technical decision. For example, in a patient with a bicuspid valve, the surgeon may choose to use a brief period of circulatory arrest instead of clamping the proximal arch.

Comparison 2. To further define the impact of circulatory arrest, we grouped the patients who underwent cardioaortic surgery (N = 1,677) into those who had circulatory arrest (n = 728) or no arrest (n = 949). From those groups, we identified 324 matched pairs of patients and compared the outcomes.

Our results showed no differences associated with the use of circulatory arrest in rates of mortality (1.2% with and 0.6% without) or stroke (1.5% for both groups) when comparing patients with similar disease characteristics. These results suggest that the need for circulatory arrest was probably not the culprit but more likely a marker of patients with more complex disease. It is their more advanced disease that puts them at higher risk.

Comparison 3. To determine whether circulatory arrest has an overall impact on cardiac surgery, we took the population of matched cardioaortic patients from comparison 2 regardless of whether they had circulatory arrest and compared them to the larger group of 12,617 cardiac surgery-alone patients. Again, results indicated that the addition of aortic surgery had no real impact on outcomes. Both groups had similarly low risks for both mortality (0.9% with aortic replacement vs 0.5% without) and stroke (1.4% with aortic replacement vs 1.1% without).

Clinical implications

This multistepped comparison study found that adding ascending aortic replacement to cardiac surgery had essentially no impact on mortality or stroke. These data provide evidence indicating that cardiac surgeons should be more proactive in deciding whether to add ascending aorta replacement to cardiac surgery when treating a patient with a dilated ascending aorta. It must be noted, however, that patients with more advanced aortic disease are a higher risk population. All of these findings highlight the importance of managing thoracic aortic disease within an experienced multidisciplinary center.

These findings provided important evidence supporting the need to be more proactive in the decision to perform aortic replacement. Furthermore, the data prompted the American Heart Association and the American College of Cardiology to publish a clarification statement providing more detail to its thoracic aorta and aortic valve guidelines. This update indicates that in patients with a bicuspid aortic valve, it is reasonable to recommend surgery when the aorta is 5 cm instead of waiting until 5.5 cm in high-volume centers that have demonstrated excellent surgical outcomes. This clarification statement was based on Cleveland Clinic outcomes showing a mortality rate of 0.25% and a stroke rate of 0.75% in a population that included patients undergoing emergency aortic dissection surgery.⁶

This study also analyzed data on patients treated with expectant care with optimal medical management and imaging surveillance (ie, to monitor the dilated aorta). Results from this subset showed that the probability of needing an aortic intervention is about 60% during the next 10 years once the aorta is within the 4.5 cm to 5 cm range.

Another study addressing the correlation between risk and aortic size examined 771 patients with a dilated ascending aorta (≥ 4 cm) and a tricuspid aortic valve.⁷ This study confirmed the use of patient height as an important factor for indexing maximum aortic size to patient body size for predicting risk of late complications. Specifically, this study suggested that the risk of complications from aortic aneurysm rises when the maximum aortic area-to-height ratio exceeds 10. This serves as a follow-up to previously published data demonstrating the value of aortic cross-sectional area-to-height ratio as a predictor of risk in patients with bicuspid valves.⁸ In general, the results of all 3 studies suggest that we should be more proactive in operating on patients with a dilated ascending aorta to prevent later risk of rupture or dissection when the surgical risk is low.

When making decisions about patients who need aortic replacement, it is important to assess many patient details: their aortic disease, their other nonaortic comorbidities, and the institution’s outcomes. This decision is best made by a dedicated cardioaortic specialist at a dedicated center of excellence.

WHAT IS COMING?

Minimally invasive and endovascular surgery

More ascending aortic surgeries are being done using minimally invasive approaches. At Cleveland Clinic, about 40% of isolated ascending aortic operations are performed through a mini-sternotomy J incision approach. A Cleveland Clinic study published in 2017 evaluated outcomes from this less-invasive technique for proximal aortic surgery compared with full median sternotomy.⁹ Results showed it was an effective approach with fewer complications, shorter hospital stays, and lower costs.

Stent grafts

The role for stent-graft devices has continued to expand.¹⁰ At Cleveland Clinic, we have performed more than 40 ascending aortic stent-graft procedures, one of the largest numbers in the world. Having this stent-graft option has enabled us to provide treatment for the patients at exceedingly high risk who previously had few or no options. Industry partners are working to develop dedicated devices for these indications, and we are working with them to bring new device trials to this underserved population of patients. 

In 2015, Cleveland Clinic cardiac and vascular surgeons performed more than 1,000 open or endovascular operations involving the thoracic aorta, the most of any US medical center. Cardioaortic operations account for a large volume of the procedures performed annually in the Department of Thoracic and Cardiovascular Surgery at Cleveland Clinic. Of the approximately 4,000 cardiac procedures performed per year at Cleveland Clinic, nearly 1 in 5 includes thoracic aorta replacement.

Providing optimal care to patients with thoracic aortic disease requires a multidisciplinary approach beginning in the preoperative phase and extending through the life of patients and their families. In the Aortic Center at Cleveland Clinic Heart & Vascular Institute, cardiovascular medicine and imaging specialists, geneticists, and cardioaortic and vascular surgeons work in unison to provide the highest quality care. This involves active analysis of outcomes to continuously improve the quality of care provided.

This paper examines trends in the treatment of thoracic aortic disease, describes the different types of therapeutic procedures, and explores details about their safety and efficacy by summarizing the key research findings on cardioaortic procedures published from our Center during the last 2 years.

SEGMENTAL PERSPECTIVE

1. Modified Bentall procedure with a mechanical composite valve graft (CVG)

2. Modified Bentall procedure with a biologic CVG

3. Homograft, or allograft, root replacement with a human cadaveric aorta

4. Valve-preserving aortic root replacement with a prosthetic graft but which leaves the patient’s native aortic valve intact with or without accompanying repair of that valve.

A Cleveland Clinic study published in 2016 analyzed 957 elective aortic root replacement procedures performed from 1995 through 2014.¹ The number of procedures in this study were evenly distributed across these 4 aortic root replacement strategies.

The perioperative mortality rate was 0.73% and the stroke rate was 1.4%. For 3 of the 4 procedure types, 15-year survival rates were excellent: above 80% for mechanical CVG, allografts, and valve-preservation surgery. The survival rate for biologic CVG was lower (57%), reflecting the difference in population, as these were typically older patients.

This study also demonstrated the durability of these operations, with a reoperation rate of approximately 15% at 15 years. Reoperation rates for patients having undergone these operations should be considered in the light of competing risk of death from other causes. As such, the risk of reoperation after mechanical CVG, biologic CVG, and valve-preserving procedures were similar, ranging from 5% to 15%. Allografts had the highest reoperation rates (approximately 30% at 15 years) because they used to be the biologic root replacement of choice for younger patients but have since been found to wear out at a similar rate as other bioprostheses.2 As a result, they are now used less frequently for elective indications.

Cleveland Clinic practitioners now perform more than 80 valve-preserving root replacement operations per year, approximately 700 overall.

Clinical implications

For patients presenting with aortic root aneurysm, consider the following:

• Valve-preserving aortic root replacement is preferred for patients with root aneurysm and a tricuspid aortic valve without valve stenosis.
• Valve-preserving aortic root replacement with either remodeling or reimplantation is also preferred for patients with a bicuspid aortic valve with a dilated annulus or root aneurysm, but without aortic-associated aortic valve stenosis
• Mechanical CVG is preferred for younger patients with root aneurysm and aortic valve stenosis (usually a bicuspid or unicuspid aortic valve); biomechanical CVG is preferred for older patients with root aneurysm and associated aortic valve stenosis.
• Allografts are now reserved primarily for patients with endocarditis and for older patients with a small aortic root.

The condition of the patient at presentation has become the strongest predictor of surgical risk. An improved understanding of these associations can improve our prediction of risks and the decision about when to operate. Patients needing aortic replacement can present with a broad spectrum of pathologies. For example, a patient who presents with acute type A dissection is quite different from a patient with an enlarging ascending aneurysm who had a previous aortic valve replacement for bicuspid aortic valve stenosis as a young adult. Further, both are different from the elderly patient with the complex constellation of coronary disease, multivalve disease, atrial fibrillation, and an ascending aneurysm—an increasingly common presentation.

Guidelines supporting the decision to replace the aorta in patients with chronic asymptomatic aortic disease are limited by a lack of data on surgical risk and long-term effectiveness.

A study from the Society of Thoracic Surgeons database assessed outcomes in patients who had surgical replacement of the ascending aorta, with or without root repair.³ The operative mortality (either in-hospital or within 30 days of surgery) was 8.3% and ranged from 3.5% for elective surgery to 9.1% for urgent surgery, and 21.5% for emergencies. End-stage kidney disease and reoperation were also shown to be independent predictors of risk in that study.

Outcomes at Cleveland Clinic for elective ascending aortic procedures are much better than these national averages. Outcomes data are important to patients when making a decision about prophylactic surgery. In a study analyzing 1,889 patients undergoing elective ascending replacement at Cleveland Clinic between 2006 and 2010, the operative mortality was only 0.5% for those undergoing isolated ascending replacement and 2% for those requiring a multicomponent operation. In the multicomponent group, 87% included aortic valve replacement, 29% coronary bypass, and 25% underwent more than 2 different combined procedures.⁴

Patient risk factors

A comparison of patient risk factors for the 2 groups showed that the isolated replacement group had larger aortic diameters, more extensive disease with dilated descending aortas, and were more frequently undergoing a reoperation than the multicomponent group.

To further define the risks, we conducted a propensity-matching study of 197 pairs of these patients, comparing 62 variables including aortic morphology data gathered from 3-dimensional analysis of computed tomography scans. Results showed no differences in survival rates between the groups during 4 years of follow-up.⁴ A comparison of the risk of other perioperative complications—death, stroke, need for dialysis, respiratory failure, and bleeding—also showed no differences between the groups.

Does adding ascending aortic replacement to other cardiac procedures increase the surgical risk?

To answer this question, we collected data on Cleveland Clinic patients between 2006 and 2011 who had aortic surgery in combination with cardiac surgery (N = 1,677) and compared them against a similar cohort who only had cardiac surgery (N = 12,617).⁵ The objectives were to determine the risk of adding aortic surgery to an elective cardiac operation. A second objective was to determine the impact of circulatory arrest on outcomes.

Comparison 1. We identified 1,284 matched pairs from the 2 groups. Data showed a slightly higher risk of stroke in patients who had cardioaortic surgery (2.4%) compared with those who had cardiac surgery alone (1.7%); however, the mortality rate was not significantly different between the groups.

Does circulatory arrest affect the stroke rate?

From the matched pairs of patients who underwent cardioaortic surgery, we identified a subset of patients who had circulatory arrest and compared them with those who did not have circulatory arrest. The circulatory arrest group had worse outcomes. Mortality rates were 4.1% vs 1.0%, respectively, and stroke rates were 3.9% vs 0.9%. 

This raised the question of whether circulatory arrest was the cause of the worse outcomes or a marker of patients with more advanced disease.

The decision to use circulatory arrest is primarily based on 2 factors:

• Patient-specific factors, such as those with advanced aortic disease in whom circulatory arrest is unavoidable.
• Surgeon preference/technical decision. For example, in a patient with a bicuspid valve, the surgeon may choose to use a brief period of circulatory arrest instead of clamping the proximal arch.

Comparison 2. To further define the impact of circulatory arrest, we grouped the patients who underwent cardioaortic surgery (N = 1,677) into those who had circulatory arrest (n = 728) or no arrest (n = 949). From those groups, we identified 324 matched pairs of patients and compared the outcomes.

Our results showed no differences associated with the use of circulatory arrest in rates of mortality (1.2% with and 0.6% without) or stroke (1.5% for both groups) when comparing patients with similar disease characteristics. These results suggest that the need for circulatory arrest was probably not the culprit but more likely a marker of patients with more complex disease. It is their more advanced disease that puts them at higher risk.

Comparison 3. To determine whether circulatory arrest has an overall impact on cardiac surgery, we took the population of matched cardioaortic patients from comparison 2 regardless of whether they had circulatory arrest and compared them to the larger group of 12,617 cardiac surgery-alone patients. Again, results indicated that the addition of aortic surgery had no real impact on outcomes. Both groups had similarly low risks for both mortality (0.9% with aortic replacement vs 0.5% without) and stroke (1.4% with aortic replacement vs 1.1% without).

Clinical implications

This multistepped comparison study found that adding ascending aortic replacement to cardiac surgery had essentially no impact on mortality or stroke. These data provide evidence indicating that cardiac surgeons should be more proactive in deciding whether to add ascending aorta replacement to cardiac surgery when treating a patient with a dilated ascending aorta. It must be noted, however, that patients with more advanced aortic disease are a higher risk population. All of these findings highlight the importance of managing thoracic aortic disease within an experienced multidisciplinary center.

These findings provided important evidence supporting the need to be more proactive in the decision to perform aortic replacement. Furthermore, the data prompted the American Heart Association and the American College of Cardiology to publish a clarification statement providing more detail to its thoracic aorta and aortic valve guidelines. This update indicates that in patients with a bicuspid aortic valve, it is reasonable to recommend surgery when the aorta is 5 cm instead of waiting until 5.5 cm in high-volume centers that have demonstrated excellent surgical outcomes. This clarification statement was based on Cleveland Clinic outcomes showing a mortality rate of 0.25% and a stroke rate of 0.75% in a population that included patients undergoing emergency aortic dissection surgery.⁶

This study also analyzed data on patients treated with expectant care with optimal medical management and imaging surveillance (ie, to monitor the dilated aorta). Results from this subset showed that the probability of needing an aortic intervention is about 60% during the next 10 years once the aorta is within the 4.5 cm to 5 cm range.

Another study addressing the correlation between risk and aortic size examined 771 patients with a dilated ascending aorta (≥ 4 cm) and a tricuspid aortic valve.⁷ This study confirmed the use of patient height as an important factor for indexing maximum aortic size to patient body size for predicting risk of late complications. Specifically, this study suggested that the risk of complications from aortic aneurysm rises when the maximum aortic area-to-height ratio exceeds 10. This serves as a follow-up to previously published data demonstrating the value of aortic cross-sectional area-to-height ratio as a predictor of risk in patients with bicuspid valves.⁸ In general, the results of all 3 studies suggest that we should be more proactive in operating on patients with a dilated ascending aorta to prevent later risk of rupture or dissection when the surgical risk is low.

When making decisions about patients who need aortic replacement, it is important to assess many patient details: their aortic disease, their other nonaortic comorbidities, and the institution’s outcomes. This decision is best made by a dedicated cardioaortic specialist at a dedicated center of excellence.

WHAT IS COMING?

Minimally invasive and endovascular surgery

More ascending aortic surgeries are being done using minimally invasive approaches. At Cleveland Clinic, about 40% of isolated ascending aortic operations are performed through a mini-sternotomy J incision approach. A Cleveland Clinic study published in 2017 evaluated outcomes from this less-invasive technique for proximal aortic surgery compared with full median sternotomy.⁹ Results showed it was an effective approach with fewer complications, shorter hospital stays, and lower costs.

Stent grafts

The role for stent-graft devices has continued to expand.¹⁰ At Cleveland Clinic, we have performed more than 40 ascending aortic stent-graft procedures, one of the largest numbers in the world. Having this stent-graft option has enabled us to provide treatment for the patients at exceedingly high risk who previously had few or no options. Industry partners are working to develop dedicated devices for these indications, and we are working with them to bring new device trials to this underserved population of patients. 

In 2015, Cleveland Clinic cardiac and vascular surgeons performed more than 1,000 open or endovascular operations involving the thoracic aorta, the most of any US medical center. Cardioaortic operations account for a large volume of the procedures performed annually in the Department of Thoracic and Cardiovascular Surgery at Cleveland Clinic. Of the approximately 4,000 cardiac procedures performed per year at Cleveland Clinic, nearly 1 in 5 includes thoracic aorta replacement.

Providing optimal care to patients with thoracic aortic disease requires a multidisciplinary approach beginning in the preoperative phase and extending through the life of patients and their families. In the Aortic Center at Cleveland Clinic Heart & Vascular Institute, cardiovascular medicine and imaging specialists, geneticists, and cardioaortic and vascular surgeons work in unison to provide the highest quality care. This involves active analysis of outcomes to continuously improve the quality of care provided.

This paper examines trends in the treatment of thoracic aortic disease, describes the different types of therapeutic procedures, and explores details about their safety and efficacy by summarizing the key research findings on cardioaortic procedures published from our Center during the last 2 years.

SEGMENTAL PERSPECTIVE

1. Modified Bentall procedure with a mechanical composite valve graft (CVG)

2. Modified Bentall procedure with a biologic CVG

3. Homograft, or allograft, root replacement with a human cadaveric aorta

4. Valve-preserving aortic root replacement with a prosthetic graft but which leaves the patient’s native aortic valve intact with or without accompanying repair of that valve.

A Cleveland Clinic study published in 2016 analyzed 957 elective aortic root replacement procedures performed from 1995 through 2014.¹ The number of procedures in this study were evenly distributed across these 4 aortic root replacement strategies.

The perioperative mortality rate was 0.73% and the stroke rate was 1.4%. For 3 of the 4 procedure types, 15-year survival rates were excellent: above 80% for mechanical CVG, allografts, and valve-preservation surgery. The survival rate for biologic CVG was lower (57%), reflecting the difference in population, as these were typically older patients.

This study also demonstrated the durability of these operations, with a reoperation rate of approximately 15% at 15 years. Reoperation rates for patients having undergone these operations should be considered in the light of competing risk of death from other causes. As such, the risk of reoperation after mechanical CVG, biologic CVG, and valve-preserving procedures were similar, ranging from 5% to 15%. Allografts had the highest reoperation rates (approximately 30% at 15 years) because they used to be the biologic root replacement of choice for younger patients but have since been found to wear out at a similar rate as other bioprostheses.2 As a result, they are now used less frequently for elective indications.

Cleveland Clinic practitioners now perform more than 80 valve-preserving root replacement operations per year, approximately 700 overall.

Clinical implications

For patients presenting with aortic root aneurysm, consider the following:

• Valve-preserving aortic root replacement is preferred for patients with root aneurysm and a tricuspid aortic valve without valve stenosis.
• Valve-preserving aortic root replacement with either remodeling or reimplantation is also preferred for patients with a bicuspid aortic valve with a dilated annulus or root aneurysm, but without aortic-associated aortic valve stenosis
• Mechanical CVG is preferred for younger patients with root aneurysm and aortic valve stenosis (usually a bicuspid or unicuspid aortic valve); biomechanical CVG is preferred for older patients with root aneurysm and associated aortic valve stenosis.
• Allografts are now reserved primarily for patients with endocarditis and for older patients with a small aortic root.

The condition of the patient at presentation has become the strongest predictor of surgical risk. An improved understanding of these associations can improve our prediction of risks and the decision about when to operate. Patients needing aortic replacement can present with a broad spectrum of pathologies. For example, a patient who presents with acute type A dissection is quite different from a patient with an enlarging ascending aneurysm who had a previous aortic valve replacement for bicuspid aortic valve stenosis as a young adult. Further, both are different from the elderly patient with the complex constellation of coronary disease, multivalve disease, atrial fibrillation, and an ascending aneurysm—an increasingly common presentation.

Guidelines supporting the decision to replace the aorta in patients with chronic asymptomatic aortic disease are limited by a lack of data on surgical risk and long-term effectiveness.

A study from the Society of Thoracic Surgeons database assessed outcomes in patients who had surgical replacement of the ascending aorta, with or without root repair.³ The operative mortality (either in-hospital or within 30 days of surgery) was 8.3% and ranged from 3.5% for elective surgery to 9.1% for urgent surgery, and 21.5% for emergencies. End-stage kidney disease and reoperation were also shown to be independent predictors of risk in that study.

Outcomes at Cleveland Clinic for elective ascending aortic procedures are much better than these national averages. Outcomes data are important to patients when making a decision about prophylactic surgery. In a study analyzing 1,889 patients undergoing elective ascending replacement at Cleveland Clinic between 2006 and 2010, the operative mortality was only 0.5% for those undergoing isolated ascending replacement and 2% for those requiring a multicomponent operation. In the multicomponent group, 87% included aortic valve replacement, 29% coronary bypass, and 25% underwent more than 2 different combined procedures.⁴

Patient risk factors

A comparison of patient risk factors for the 2 groups showed that the isolated replacement group had larger aortic diameters, more extensive disease with dilated descending aortas, and were more frequently undergoing a reoperation than the multicomponent group.

To further define the risks, we conducted a propensity-matching study of 197 pairs of these patients, comparing 62 variables including aortic morphology data gathered from 3-dimensional analysis of computed tomography scans. Results showed no differences in survival rates between the groups during 4 years of follow-up.⁴ A comparison of the risk of other perioperative complications—death, stroke, need for dialysis, respiratory failure, and bleeding—also showed no differences between the groups.

Does adding ascending aortic replacement to other cardiac procedures increase the surgical risk?

To answer this question, we collected data on Cleveland Clinic patients between 2006 and 2011 who had aortic surgery in combination with cardiac surgery (N = 1,677) and compared them against a similar cohort who only had cardiac surgery (N = 12,617).⁵ The objectives were to determine the risk of adding aortic surgery to an elective cardiac operation. A second objective was to determine the impact of circulatory arrest on outcomes.

Comparison 1. We identified 1,284 matched pairs from the 2 groups. Data showed a slightly higher risk of stroke in patients who had cardioaortic surgery (2.4%) compared with those who had cardiac surgery alone (1.7%); however, the mortality rate was not significantly different between the groups.

Does circulatory arrest affect the stroke rate?

From the matched pairs of patients who underwent cardioaortic surgery, we identified a subset of patients who had circulatory arrest and compared them with those who did not have circulatory arrest. The circulatory arrest group had worse outcomes. Mortality rates were 4.1% vs 1.0%, respectively, and stroke rates were 3.9% vs 0.9%. 

This raised the question of whether circulatory arrest was the cause of the worse outcomes or a marker of patients with more advanced disease.

The decision to use circulatory arrest is primarily based on 2 factors:

• Patient-specific factors, such as those with advanced aortic disease in whom circulatory arrest is unavoidable.
• Surgeon preference/technical decision. For example, in a patient with a bicuspid valve, the surgeon may choose to use a brief period of circulatory arrest instead of clamping the proximal arch.

Comparison 2. To further define the impact of circulatory arrest, we grouped the patients who underwent cardioaortic surgery (N = 1,677) into those who had circulatory arrest (n = 728) or no arrest (n = 949). From those groups, we identified 324 matched pairs of patients and compared the outcomes.

Our results showed no differences associated with the use of circulatory arrest in rates of mortality (1.2% with and 0.6% without) or stroke (1.5% for both groups) when comparing patients with similar disease characteristics. These results suggest that the need for circulatory arrest was probably not the culprit but more likely a marker of patients with more complex disease. It is their more advanced disease that puts them at higher risk.

Comparison 3. To determine whether circulatory arrest has an overall impact on cardiac surgery, we took the population of matched cardioaortic patients from comparison 2 regardless of whether they had circulatory arrest and compared them to the larger group of 12,617 cardiac surgery-alone patients. Again, results indicated that the addition of aortic surgery had no real impact on outcomes. Both groups had similarly low risks for both mortality (0.9% with aortic replacement vs 0.5% without) and stroke (1.4% with aortic replacement vs 1.1% without).

Clinical implications

This multistepped comparison study found that adding ascending aortic replacement to cardiac surgery had essentially no impact on mortality or stroke. These data provide evidence indicating that cardiac surgeons should be more proactive in deciding whether to add ascending aorta replacement to cardiac surgery when treating a patient with a dilated ascending aorta. It must be noted, however, that patients with more advanced aortic disease are a higher risk population. All of these findings highlight the importance of managing thoracic aortic disease within an experienced multidisciplinary center.

These findings provided important evidence supporting the need to be more proactive in the decision to perform aortic replacement. Furthermore, the data prompted the American Heart Association and the American College of Cardiology to publish a clarification statement providing more detail to its thoracic aorta and aortic valve guidelines. This update indicates that in patients with a bicuspid aortic valve, it is reasonable to recommend surgery when the aorta is 5 cm instead of waiting until 5.5 cm in high-volume centers that have demonstrated excellent surgical outcomes. This clarification statement was based on Cleveland Clinic outcomes showing a mortality rate of 0.25% and a stroke rate of 0.75% in a population that included patients undergoing emergency aortic dissection surgery.⁶

This study also analyzed data on patients treated with expectant care with optimal medical management and imaging surveillance (ie, to monitor the dilated aorta). Results from this subset showed that the probability of needing an aortic intervention is about 60% during the next 10 years once the aorta is within the 4.5 cm to 5 cm range.

Another study addressing the correlation between risk and aortic size examined 771 patients with a dilated ascending aorta (≥ 4 cm) and a tricuspid aortic valve.⁷ This study confirmed the use of patient height as an important factor for indexing maximum aortic size to patient body size for predicting risk of late complications. Specifically, this study suggested that the risk of complications from aortic aneurysm rises when the maximum aortic area-to-height ratio exceeds 10. This serves as a follow-up to previously published data demonstrating the value of aortic cross-sectional area-to-height ratio as a predictor of risk in patients with bicuspid valves.⁸ In general, the results of all 3 studies suggest that we should be more proactive in operating on patients with a dilated ascending aorta to prevent later risk of rupture or dissection when the surgical risk is low.

When making decisions about patients who need aortic replacement, it is important to assess many patient details: their aortic disease, their other nonaortic comorbidities, and the institution’s outcomes. This decision is best made by a dedicated cardioaortic specialist at a dedicated center of excellence.

WHAT IS COMING?

Minimally invasive and endovascular surgery

More ascending aortic surgeries are being done using minimally invasive approaches. At Cleveland Clinic, about 40% of isolated ascending aortic operations are performed through a mini-sternotomy J incision approach. A Cleveland Clinic study published in 2017 evaluated outcomes from this less-invasive technique for proximal aortic surgery compared with full median sternotomy.⁹ Results showed it was an effective approach with fewer complications, shorter hospital stays, and lower costs.

Stent grafts

The role for stent-graft devices has continued to expand.¹⁰ At Cleveland Clinic, we have performed more than 40 ascending aortic stent-graft procedures, one of the largest numbers in the world. Having this stent-graft option has enabled us to provide treatment for the patients at exceedingly high risk who previously had few or no options. Industry partners are working to develop dedicated devices for these indications, and we are working with them to bring new device trials to this underserved population of patients. 

Adverse events (AEs) from systemic treatment of cancer have a negative impact on patient quality of life (QoL). The extent of this impact is difficult to ascertain, particularly in patients undergoing palliative treatment because of variations in QoL resulting from antitumor effect.¹ Patient-reported outcomes (PROs) are the best tool for elicitation of patient preferences, therefore helping cancer patients, oncologists, and health care managers to make better choices. Indeed, analysis of self-reported QoL during cancer chemotherapy provides new insights that are missed by other efficacy outcomes,² although patient-reported AEs correlate well with AEs reported by clinicians.³ Self-reported symptoms provide better control during cancer treatment.⁴ However, there are other instruments to measure the impact of treatments on QoL that are based on preferences of members of the general public. Use of that strategy has been strongly debated. The most obvious problem is the difficulty that persons from the general public may have in putting themselves in the patient position.⁵ In addition, there is evidence that compared with the general public, patients adapt to their illness^5,6 and then tend to downplay severity when rating values of health states.⁷ Therefore, a systematic discrepancy is observed between actual patients and the general public. It is not clear if it reflects the inability of members of the general public to fully grasp the relative severity of health problems or to the adaptation process of patients. This fact may obscure a negative impact on QoL which, in turn, could be detected using the general public as a surrogate. A combination of both approaches has been recommended for rating QoL when the ultimate purpose is making decisions on resource allocation.⁵ This debate is prolonging in time and it is far from over.^8,9

Based on this background, this study investigates the impact of AEs on QoL of cancer patients from the perspective of cancer patients who had experienced the AEs of interest (ex post population) and the perspective of members of the general public. The second group comprised participants imagining themselves as hypothetical cancer patients experiencing the AEs (ex ante population). Previous studies with this dual approach allowing for comparisons between these two populations are small or centered on a few AEs.¹⁰ Therefore, a large and comprehensive study on the impact of AEs on QoL is lacking. Supported by previous literature, the investigational hypothesis was that ex post impact would be significantly lower than that imagined in an ex ante setting. The secondary objective is to study the potential use of the EuroQol (EQ-5D) instrument for health-related QoL in the measurement of the impact of AEs in cancer patients. This generic instrument is based on interviews with members of the general public. We tried to investigate to what extent those values relate to the cancer patients’ evaluation of their own health during treatment. The ultimate goal of the study is to assist in increasing the utility that patients derive from the benefits associated with cancer treatment.
 

Methods

Selection of AEs

Five AEs related to systemic treatment of cancer – alopecia, acneiform rash, oxaliplatin-associated peripheral neuropathy, diarrhea, and vomiting – were selected for the study. Investigators set up different relevant cut-off points for severity, resulting in 10 toxic events that were ad hoc defined as the variables for the study (Table 1). We used the Common Terminology Criteria for Adverse Events (CTCAE, version 4) to classify alopecia, acneiform rash, diarrhea, and vomiting. For oxaliplatin-associated peripheral neuropathy, we adapted Misset’s oxaliplatin-specific scale¹¹ (range, grade 1-4; Table 1) in which grade 1 (neurotoxicity [NTX] 1) = paresthesias only with cold lasting a few days; grade 2 [NTX2] = paresthesias with and without cold that may last months; and grade 4 [NTX3] = paresthesias with functional consequence).

Participants

Two populations were included in the study: cancer patients who had experienced a particular AE and received treatment at the medical oncology departments of Hospital Santa Tecla and Hospital del Vendrell in Tarragona, Spain; and participants from the general public who received care at the Primary Health Care Center-Llevant in the same city.



Cancer patients. These participants had to be 18 years or older and had to have experienced 1 of the 10 toxic events in the 5 years before inclusion in the study; the treatment setting could be either curative attempt (adjuvant, neoadjuvant) or palliative, and patients with ongoing treatment should have received almost 3 months of treatment. Patients were excluded if they had an ECOG PS grade of 3 or more (Eastern Cooperative Oncology Group Performance Status; range, 0-5, where 0 = fully active, 3 = capable of limited self-care; confined to bed or chair more than 50% of waking hours, and 5 = dead). A particular patient with cancer could be included because of more than 1 study toxic event (eg, alopecia and severe vomiting or NTX1 and NTX2) but had to complete separate questionnaires for the different toxic events.

General public group. Participants in this group were selected from the records of general practitioner consultations at the aforementioned primary health care center. They had to be 18 years or older and could not have a history of cancer or symptomatic/severe chronic diseases (eg, they could have hypertension or diabetes without chronic target organ involvement, or they could be patients with either acute nonserious illness or nonserious injuries).
 

Survey procedures

Cancer patients. Participants in this group filled in 2 questionnaires provided by a medical oncologist in a face-to-face interview: the 5-dimension, 5-level EuroQol (EQ-5D-5L) questionnaire in reference to the days when patients were suffering the toxic event; and a visual analog scale (VAS) answering the question: How do you feel that this AE has impacted on your QoL the days you have experienced it?

VAS scores ranged from 0 (the poorest QoL, the highest impact) to 100 (the better QoL, the lower impact). The EQ-5D-5L has 5 dimensions (Mobility, Self-care, Daily life activities/social performance, Discomfort/pain, and Anxiety/depression) with 5 level response options each (No problem at all, Light problem, Moderate problem, Severe problem, Extreme problem/unable).¹² The combination of 5 answers is converted to a single score, which is different for different countries; in the validated version for Spanish population, the score ranges from -0.654 (the worst health state) to 1.000 (the best health state). Patients were asked to make an effort to separate and encapsulate the impact of every adverse event and separate it from others they may have experienced during the same period. Table 2 summarizes survey procedures.

General public group. Two internal medicine residents who administered the questionnaire to the participants of the public group were well trained to carefully explain what each of the 10 the toxic events meant. Some details on these explanations are shown in Table 1, and the full set of explanations is shown in Appendix 1 (online only). Participants in the general public group were asked in a face-to-face interview to imagine they were cancer patients and envision how these toxic events would impact on their QoL if they were undergoing systemic treatment of cancer. They were asked to rate the imagined impact with the VAS (1 VAS/every toxic event = 10 VAS/participant). Then, they were presented with 10 cards, each with the name of 1 of the 10 toxic events (Appendix 2 [online only]), to show them the order of the impact on QoL based on their scores (respecting ties). The participants were asked if they agreed with the order, and if they did not, they were invited to change the scores. Therefore, results in the general public group also show the rank-order of the study toxic events.
 

Statistical analysis

We calculated the sample size as follows:

Primary outcomes were VAS score in cancer patients and VAS score in the general public. Primary analyses were comparison between VAS in both populations. Secondary outcomes were EQ-5D-5L score in cancer patients, and intra-participant rank-order in the general public group. Secondary analyses were correlation between VAS score and EQ-5D-5L in cancer patients and descriptive analysis of rank-ordered data in the general public group.

It was planned to compare means of quantitative variables with the Mann-Whitney U test and to assess correlation between quantitative variables with the Spearman rho test. All tests for contrast were nonparametric because a normal distribution was not expected from quoted scores with some ceiling or floor effect. A hierarchical generalized cluster analysis was planned to study clusters of variables grouped by VAS score in the public group.
 

Ethics

The study was conducted in accordance with the Declaration of Helsinki version Fortaleza 2013 and was approved by the institutional review board of the participant institutions. All of the patients provided written informed consent before study entry. Data of the participants of the general public were anonymous, so those participants were asked to provide only oral assent, with the permission of the review board.
 

Results

Between December 1, 2013 and January 31, 2015, a total of 250 participants of the general public and 139 cancer patients were included in the study. Four participants of the general public had incompletely filled the questionnaire and were excluded from the study, resulting in 246 participants with complete data available. There were no losses in the patient group, of whom 79 (57%) were currently on treatment and 118 (85%) had received the treatment in the previous 2 years. The total number of study toxic events in the 139 cancer patients was 200 (20 by each of the 10 study toxicity variables). Of those, 42 patients (30%) experienced (and were included in the study for) more than 1 toxic event.

Of the 139 patients, 91 (65%) received the treatment with curative intent. The most frequent diagnosis was colorectal cancer in 77 patients (55%), followed by breast cancer (13 patients, 9.4%), and lung cancer (11 patients, 7.9%). Systemic treatment of cancer was one of these options: chemotherapy alone, anti-EGFR [epidermal growth factor receptor] alone, chemotherapy plus anti-EGFR, or chemotherapy plus other biologics. The chemotherapy regimen most frequently administered was mFOLFOX6 [modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin] which, alone or in combination, was administered to 51 patients (37%). An anti-EGFR agent was administered to 22 patients (16%): cetuximab (15 patients), panitumumab (4 patients), erlotinib (2 patients) and afatinib (1 patient). The baseline characteristics of the patients and participants in the study are shown in Table 3.

Discussion

The findings in this study show that impact on QoL imagined by members of the general public is higher than that declared by cancer patients who have experienced the AEs. It is worth noting that that result was observed for all 10 toxic events, thus confirming the investigational hypothesis of the study. However, the graph shows a strong parallel between the 2 groups, which means that both populations similarly perceive upward and downward variations in the impact resulting from the different toxic events (Figure).

Three previous studies have addressed the comparison of the impact of different AEs in these 2 populations and findings from all 3 showed the same systematic difference between patients and the general public participants. The first, Calhoun and colleagues used time to trade-off (TTO, a measure of the QoL a person or groups is experiencing) to compare therapies for ovarian cancer in patients and the general population (n = 39 for each group). The results showed that cancer patients valued more the health status associated with toxicity than did the general public participants.¹³ The design of the second study, by Havrilesky and colleagues, was similar to that of the present study, and they compared toxic events one by one, using VAS and TTO in 13 ovarian cancer patients and 37 women of the general public.¹⁴ The investigators found the same results as we did on the parallel of the 2 groups and also a very similar order of the toxic events. Indeed, alopecia was the less bothersome, whereas both motor neuropathy and severe vomiting were among the worst toxic events. Therefore, our results correlate perfectly with theirs. Best and colleagues found that health states values associated with oxaliplatin-related peripheral neuropathy were lower in the general public population compared with those of cancer patients.¹⁵ Besides adaptive behavior of the patients, all these results may be explained by an established awareness cancer patients have of the dual outcome of cancer treatments (AEs and benefits from the treatment).⁹ This awareness is absent in the general public participants, who can only envision the negative outcomes and who do not realize the importance of the benefits.⁹ Findings from previous studies conducted in several tumor types such as breast cancer^16-18 non–small-cell lung cancer,¹⁹ thyroid cancer,²⁰ and renal cancer²¹ have shown that patients are willing to trade-off AEs for treatment benefits.

Alopecia has been considered as one of the most distressing and troublesome AEs of cancer therapy.²² However, in the present study, alopecia was rated inside the range of mild toxic events as it is in the study by Havrilesky and colleagues.¹⁴ Our results show that alopecia was placed as the first less damaging toxic event when assessed with the EQ-5D-5L, the second less damaging when assessed with a rank-order system, and the third less damaging when assessed the VAS. This could be related to current fashion trends that promote shaving one’s hair, which minimizes the social stigma of alopecia and its association with cancer treatment.

The other esthetic event we analyzed was acneiform rash associated with anti-EGFR agents. Our results show that severe rash was rated as clearly worse than alopecia by the 2 populations, irrespective of the measuring instrument (VAS, EQ-5D-5L, or ordinal assessment). To our knowledge, the present study is the first to demonstrate the relative impact of total alopecia and severe rash on patient QoL. This result is even more significant considering that we included grade 2 acneiform rash inside the Severe Rash toxic event. Our results show that the worst AEs for both populations were severe vomiting and neurotoxicity with functional impairment. The high impact of severe vomiting, the quintessentially chemotherapy-induced AE, was to be expected because it is strongly supported by a number of previous reports,^14,23 as is also true for peripheral motor neuropathy.^14,15,24

EQ-5D is a powerful instrument for measuring health status²⁵ and is widely used to describe and evaluate patient health.²⁶ Our results from the 5 dimensions represented by a single score were well correlated with the results of the VAS. However, whereas median VAS scores were evenly distributed in the 0-100 range of the VAS, median EQ-5D-5L scores were distributed mainly in the 0.5-1.0 range (full range, -0.654-1.000, for Spanish population).

The final single score of the original EQ-5D is based on responses from the general public, and we have shown that its use is a valid option when the objective is the evaluation of AEs in patients with cancer. Management of AEs is of the utmost importance in this era of personalized cancer medicine. Basch and colleagues recently reported that an intensive web-based follow-up of AEs during chemotherapy improved overall survival compared with standard follow-up.²⁷ The results of our study show that patients have strongly defined preferences regarding AEs. Therefore, therapeutic strategies with a personalized approach in managing AEs would be associated with increased effectiveness.

There are some limitations in the present study. First, we modified slightly the EQ-5D-5L questionnaire by asking patients to recall and rate the days they experienced the adverse event instead of asking for “today’s feelings.” It is not known how this modification affects internal validity of this study. Second, we asked patients to isolate the toxic event to rate it independently from the other toxic events. We believe that this request may have been difficult for some patients to do because they might have experienced more than 1 toxic event concurrently. Third, using VAS to assess health status may be a weakness because it has been considered to be too straightforward an instrument. Likewise, there are some strengths of the study: it was performed in a face-to-face manner; it displayed cardinal and ordinal results for participants in the public group; and the results are the same as those in a previous study.¹⁴

In conclusion, patients with cancer who have experienced AEs perceive a lower impact on their QoL compared with that envisioned by participants from the general public. The EQ-5D-5L is a useful tool for evaluating cancer-therapy–related AEs. The impact of alopecia on QoL was notably low and even lower than that of severe rash. Further investigation on this issue should focus on patients’ and oncologists’ shared choices, which increasingly will be driven by patient preferences.
 

The Oncologic Association Dr Amadeu Pelegrí (AODAP), a charitable organization led by cancer patients and based in Salou, Spain, provided the financial support needed to conduct this study (www.aodapelegri.com).

Adverse events (AEs) from systemic treatment of cancer have a negative impact on patient quality of life (QoL). The extent of this impact is difficult to ascertain, particularly in patients undergoing palliative treatment because of variations in QoL resulting from antitumor effect.¹ Patient-reported outcomes (PROs) are the best tool for elicitation of patient preferences, therefore helping cancer patients, oncologists, and health care managers to make better choices. Indeed, analysis of self-reported QoL during cancer chemotherapy provides new insights that are missed by other efficacy outcomes,² although patient-reported AEs correlate well with AEs reported by clinicians.³ Self-reported symptoms provide better control during cancer treatment.⁴ However, there are other instruments to measure the impact of treatments on QoL that are based on preferences of members of the general public. Use of that strategy has been strongly debated. The most obvious problem is the difficulty that persons from the general public may have in putting themselves in the patient position.⁵ In addition, there is evidence that compared with the general public, patients adapt to their illness^5,6 and then tend to downplay severity when rating values of health states.⁷ Therefore, a systematic discrepancy is observed between actual patients and the general public. It is not clear if it reflects the inability of members of the general public to fully grasp the relative severity of health problems or to the adaptation process of patients. This fact may obscure a negative impact on QoL which, in turn, could be detected using the general public as a surrogate. A combination of both approaches has been recommended for rating QoL when the ultimate purpose is making decisions on resource allocation.⁵ This debate is prolonging in time and it is far from over.^8,9

Based on this background, this study investigates the impact of AEs on QoL of cancer patients from the perspective of cancer patients who had experienced the AEs of interest (ex post population) and the perspective of members of the general public. The second group comprised participants imagining themselves as hypothetical cancer patients experiencing the AEs (ex ante population). Previous studies with this dual approach allowing for comparisons between these two populations are small or centered on a few AEs.¹⁰ Therefore, a large and comprehensive study on the impact of AEs on QoL is lacking. Supported by previous literature, the investigational hypothesis was that ex post impact would be significantly lower than that imagined in an ex ante setting. The secondary objective is to study the potential use of the EuroQol (EQ-5D) instrument for health-related QoL in the measurement of the impact of AEs in cancer patients. This generic instrument is based on interviews with members of the general public. We tried to investigate to what extent those values relate to the cancer patients’ evaluation of their own health during treatment. The ultimate goal of the study is to assist in increasing the utility that patients derive from the benefits associated with cancer treatment.
 

Methods

Selection of AEs

Five AEs related to systemic treatment of cancer – alopecia, acneiform rash, oxaliplatin-associated peripheral neuropathy, diarrhea, and vomiting – were selected for the study. Investigators set up different relevant cut-off points for severity, resulting in 10 toxic events that were ad hoc defined as the variables for the study (Table 1). We used the Common Terminology Criteria for Adverse Events (CTCAE, version 4) to classify alopecia, acneiform rash, diarrhea, and vomiting. For oxaliplatin-associated peripheral neuropathy, we adapted Misset’s oxaliplatin-specific scale¹¹ (range, grade 1-4; Table 1) in which grade 1 (neurotoxicity [NTX] 1) = paresthesias only with cold lasting a few days; grade 2 [NTX2] = paresthesias with and without cold that may last months; and grade 4 [NTX3] = paresthesias with functional consequence).

Participants

Two populations were included in the study: cancer patients who had experienced a particular AE and received treatment at the medical oncology departments of Hospital Santa Tecla and Hospital del Vendrell in Tarragona, Spain; and participants from the general public who received care at the Primary Health Care Center-Llevant in the same city.



Cancer patients. These participants had to be 18 years or older and had to have experienced 1 of the 10 toxic events in the 5 years before inclusion in the study; the treatment setting could be either curative attempt (adjuvant, neoadjuvant) or palliative, and patients with ongoing treatment should have received almost 3 months of treatment. Patients were excluded if they had an ECOG PS grade of 3 or more (Eastern Cooperative Oncology Group Performance Status; range, 0-5, where 0 = fully active, 3 = capable of limited self-care; confined to bed or chair more than 50% of waking hours, and 5 = dead). A particular patient with cancer could be included because of more than 1 study toxic event (eg, alopecia and severe vomiting or NTX1 and NTX2) but had to complete separate questionnaires for the different toxic events.

General public group. Participants in this group were selected from the records of general practitioner consultations at the aforementioned primary health care center. They had to be 18 years or older and could not have a history of cancer or symptomatic/severe chronic diseases (eg, they could have hypertension or diabetes without chronic target organ involvement, or they could be patients with either acute nonserious illness or nonserious injuries).
 

Survey procedures

Cancer patients. Participants in this group filled in 2 questionnaires provided by a medical oncologist in a face-to-face interview: the 5-dimension, 5-level EuroQol (EQ-5D-5L) questionnaire in reference to the days when patients were suffering the toxic event; and a visual analog scale (VAS) answering the question: How do you feel that this AE has impacted on your QoL the days you have experienced it?

VAS scores ranged from 0 (the poorest QoL, the highest impact) to 100 (the better QoL, the lower impact). The EQ-5D-5L has 5 dimensions (Mobility, Self-care, Daily life activities/social performance, Discomfort/pain, and Anxiety/depression) with 5 level response options each (No problem at all, Light problem, Moderate problem, Severe problem, Extreme problem/unable).¹² The combination of 5 answers is converted to a single score, which is different for different countries; in the validated version for Spanish population, the score ranges from -0.654 (the worst health state) to 1.000 (the best health state). Patients were asked to make an effort to separate and encapsulate the impact of every adverse event and separate it from others they may have experienced during the same period. Table 2 summarizes survey procedures.

General public group. Two internal medicine residents who administered the questionnaire to the participants of the public group were well trained to carefully explain what each of the 10 the toxic events meant. Some details on these explanations are shown in Table 1, and the full set of explanations is shown in Appendix 1 (online only). Participants in the general public group were asked in a face-to-face interview to imagine they were cancer patients and envision how these toxic events would impact on their QoL if they were undergoing systemic treatment of cancer. They were asked to rate the imagined impact with the VAS (1 VAS/every toxic event = 10 VAS/participant). Then, they were presented with 10 cards, each with the name of 1 of the 10 toxic events (Appendix 2 [online only]), to show them the order of the impact on QoL based on their scores (respecting ties). The participants were asked if they agreed with the order, and if they did not, they were invited to change the scores. Therefore, results in the general public group also show the rank-order of the study toxic events.
 

Statistical analysis

We calculated the sample size as follows:

Primary outcomes were VAS score in cancer patients and VAS score in the general public. Primary analyses were comparison between VAS in both populations. Secondary outcomes were EQ-5D-5L score in cancer patients, and intra-participant rank-order in the general public group. Secondary analyses were correlation between VAS score and EQ-5D-5L in cancer patients and descriptive analysis of rank-ordered data in the general public group.

It was planned to compare means of quantitative variables with the Mann-Whitney U test and to assess correlation between quantitative variables with the Spearman rho test. All tests for contrast were nonparametric because a normal distribution was not expected from quoted scores with some ceiling or floor effect. A hierarchical generalized cluster analysis was planned to study clusters of variables grouped by VAS score in the public group.
 

Ethics

The study was conducted in accordance with the Declaration of Helsinki version Fortaleza 2013 and was approved by the institutional review board of the participant institutions. All of the patients provided written informed consent before study entry. Data of the participants of the general public were anonymous, so those participants were asked to provide only oral assent, with the permission of the review board.
 

Results

Between December 1, 2013 and January 31, 2015, a total of 250 participants of the general public and 139 cancer patients were included in the study. Four participants of the general public had incompletely filled the questionnaire and were excluded from the study, resulting in 246 participants with complete data available. There were no losses in the patient group, of whom 79 (57%) were currently on treatment and 118 (85%) had received the treatment in the previous 2 years. The total number of study toxic events in the 139 cancer patients was 200 (20 by each of the 10 study toxicity variables). Of those, 42 patients (30%) experienced (and were included in the study for) more than 1 toxic event.

Of the 139 patients, 91 (65%) received the treatment with curative intent. The most frequent diagnosis was colorectal cancer in 77 patients (55%), followed by breast cancer (13 patients, 9.4%), and lung cancer (11 patients, 7.9%). Systemic treatment of cancer was one of these options: chemotherapy alone, anti-EGFR [epidermal growth factor receptor] alone, chemotherapy plus anti-EGFR, or chemotherapy plus other biologics. The chemotherapy regimen most frequently administered was mFOLFOX6 [modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin] which, alone or in combination, was administered to 51 patients (37%). An anti-EGFR agent was administered to 22 patients (16%): cetuximab (15 patients), panitumumab (4 patients), erlotinib (2 patients) and afatinib (1 patient). The baseline characteristics of the patients and participants in the study are shown in Table 3.

Discussion

The findings in this study show that impact on QoL imagined by members of the general public is higher than that declared by cancer patients who have experienced the AEs. It is worth noting that that result was observed for all 10 toxic events, thus confirming the investigational hypothesis of the study. However, the graph shows a strong parallel between the 2 groups, which means that both populations similarly perceive upward and downward variations in the impact resulting from the different toxic events (Figure).

Three previous studies have addressed the comparison of the impact of different AEs in these 2 populations and findings from all 3 showed the same systematic difference between patients and the general public participants. The first, Calhoun and colleagues used time to trade-off (TTO, a measure of the QoL a person or groups is experiencing) to compare therapies for ovarian cancer in patients and the general population (n = 39 for each group). The results showed that cancer patients valued more the health status associated with toxicity than did the general public participants.¹³ The design of the second study, by Havrilesky and colleagues, was similar to that of the present study, and they compared toxic events one by one, using VAS and TTO in 13 ovarian cancer patients and 37 women of the general public.¹⁴ The investigators found the same results as we did on the parallel of the 2 groups and also a very similar order of the toxic events. Indeed, alopecia was the less bothersome, whereas both motor neuropathy and severe vomiting were among the worst toxic events. Therefore, our results correlate perfectly with theirs. Best and colleagues found that health states values associated with oxaliplatin-related peripheral neuropathy were lower in the general public population compared with those of cancer patients.¹⁵ Besides adaptive behavior of the patients, all these results may be explained by an established awareness cancer patients have of the dual outcome of cancer treatments (AEs and benefits from the treatment).⁹ This awareness is absent in the general public participants, who can only envision the negative outcomes and who do not realize the importance of the benefits.⁹ Findings from previous studies conducted in several tumor types such as breast cancer^16-18 non–small-cell lung cancer,¹⁹ thyroid cancer,²⁰ and renal cancer²¹ have shown that patients are willing to trade-off AEs for treatment benefits.

Alopecia has been considered as one of the most distressing and troublesome AEs of cancer therapy.²² However, in the present study, alopecia was rated inside the range of mild toxic events as it is in the study by Havrilesky and colleagues.¹⁴ Our results show that alopecia was placed as the first less damaging toxic event when assessed with the EQ-5D-5L, the second less damaging when assessed with a rank-order system, and the third less damaging when assessed the VAS. This could be related to current fashion trends that promote shaving one’s hair, which minimizes the social stigma of alopecia and its association with cancer treatment.

The other esthetic event we analyzed was acneiform rash associated with anti-EGFR agents. Our results show that severe rash was rated as clearly worse than alopecia by the 2 populations, irrespective of the measuring instrument (VAS, EQ-5D-5L, or ordinal assessment). To our knowledge, the present study is the first to demonstrate the relative impact of total alopecia and severe rash on patient QoL. This result is even more significant considering that we included grade 2 acneiform rash inside the Severe Rash toxic event. Our results show that the worst AEs for both populations were severe vomiting and neurotoxicity with functional impairment. The high impact of severe vomiting, the quintessentially chemotherapy-induced AE, was to be expected because it is strongly supported by a number of previous reports,^14,23 as is also true for peripheral motor neuropathy.^14,15,24

EQ-5D is a powerful instrument for measuring health status²⁵ and is widely used to describe and evaluate patient health.²⁶ Our results from the 5 dimensions represented by a single score were well correlated with the results of the VAS. However, whereas median VAS scores were evenly distributed in the 0-100 range of the VAS, median EQ-5D-5L scores were distributed mainly in the 0.5-1.0 range (full range, -0.654-1.000, for Spanish population).

The final single score of the original EQ-5D is based on responses from the general public, and we have shown that its use is a valid option when the objective is the evaluation of AEs in patients with cancer. Management of AEs is of the utmost importance in this era of personalized cancer medicine. Basch and colleagues recently reported that an intensive web-based follow-up of AEs during chemotherapy improved overall survival compared with standard follow-up.²⁷ The results of our study show that patients have strongly defined preferences regarding AEs. Therefore, therapeutic strategies with a personalized approach in managing AEs would be associated with increased effectiveness.

There are some limitations in the present study. First, we modified slightly the EQ-5D-5L questionnaire by asking patients to recall and rate the days they experienced the adverse event instead of asking for “today’s feelings.” It is not known how this modification affects internal validity of this study. Second, we asked patients to isolate the toxic event to rate it independently from the other toxic events. We believe that this request may have been difficult for some patients to do because they might have experienced more than 1 toxic event concurrently. Third, using VAS to assess health status may be a weakness because it has been considered to be too straightforward an instrument. Likewise, there are some strengths of the study: it was performed in a face-to-face manner; it displayed cardinal and ordinal results for participants in the public group; and the results are the same as those in a previous study.¹⁴

In conclusion, patients with cancer who have experienced AEs perceive a lower impact on their QoL compared with that envisioned by participants from the general public. The EQ-5D-5L is a useful tool for evaluating cancer-therapy–related AEs. The impact of alopecia on QoL was notably low and even lower than that of severe rash. Further investigation on this issue should focus on patients’ and oncologists’ shared choices, which increasingly will be driven by patient preferences.
 

The Oncologic Association Dr Amadeu Pelegrí (AODAP), a charitable organization led by cancer patients and based in Salou, Spain, provided the financial support needed to conduct this study (www.aodapelegri.com).

Adverse events (AEs) from systemic treatment of cancer have a negative impact on patient quality of life (QoL). The extent of this impact is difficult to ascertain, particularly in patients undergoing palliative treatment because of variations in QoL resulting from antitumor effect.¹ Patient-reported outcomes (PROs) are the best tool for elicitation of patient preferences, therefore helping cancer patients, oncologists, and health care managers to make better choices. Indeed, analysis of self-reported QoL during cancer chemotherapy provides new insights that are missed by other efficacy outcomes,² although patient-reported AEs correlate well with AEs reported by clinicians.³ Self-reported symptoms provide better control during cancer treatment.⁴ However, there are other instruments to measure the impact of treatments on QoL that are based on preferences of members of the general public. Use of that strategy has been strongly debated. The most obvious problem is the difficulty that persons from the general public may have in putting themselves in the patient position.⁵ In addition, there is evidence that compared with the general public, patients adapt to their illness^5,6 and then tend to downplay severity when rating values of health states.⁷ Therefore, a systematic discrepancy is observed between actual patients and the general public. It is not clear if it reflects the inability of members of the general public to fully grasp the relative severity of health problems or to the adaptation process of patients. This fact may obscure a negative impact on QoL which, in turn, could be detected using the general public as a surrogate. A combination of both approaches has been recommended for rating QoL when the ultimate purpose is making decisions on resource allocation.⁵ This debate is prolonging in time and it is far from over.^8,9

Based on this background, this study investigates the impact of AEs on QoL of cancer patients from the perspective of cancer patients who had experienced the AEs of interest (ex post population) and the perspective of members of the general public. The second group comprised participants imagining themselves as hypothetical cancer patients experiencing the AEs (ex ante population). Previous studies with this dual approach allowing for comparisons between these two populations are small or centered on a few AEs.¹⁰ Therefore, a large and comprehensive study on the impact of AEs on QoL is lacking. Supported by previous literature, the investigational hypothesis was that ex post impact would be significantly lower than that imagined in an ex ante setting. The secondary objective is to study the potential use of the EuroQol (EQ-5D) instrument for health-related QoL in the measurement of the impact of AEs in cancer patients. This generic instrument is based on interviews with members of the general public. We tried to investigate to what extent those values relate to the cancer patients’ evaluation of their own health during treatment. The ultimate goal of the study is to assist in increasing the utility that patients derive from the benefits associated with cancer treatment.
 

Methods

Selection of AEs

Five AEs related to systemic treatment of cancer – alopecia, acneiform rash, oxaliplatin-associated peripheral neuropathy, diarrhea, and vomiting – were selected for the study. Investigators set up different relevant cut-off points for severity, resulting in 10 toxic events that were ad hoc defined as the variables for the study (Table 1). We used the Common Terminology Criteria for Adverse Events (CTCAE, version 4) to classify alopecia, acneiform rash, diarrhea, and vomiting. For oxaliplatin-associated peripheral neuropathy, we adapted Misset’s oxaliplatin-specific scale¹¹ (range, grade 1-4; Table 1) in which grade 1 (neurotoxicity [NTX] 1) = paresthesias only with cold lasting a few days; grade 2 [NTX2] = paresthesias with and without cold that may last months; and grade 4 [NTX3] = paresthesias with functional consequence).

Participants

Two populations were included in the study: cancer patients who had experienced a particular AE and received treatment at the medical oncology departments of Hospital Santa Tecla and Hospital del Vendrell in Tarragona, Spain; and participants from the general public who received care at the Primary Health Care Center-Llevant in the same city.



Cancer patients. These participants had to be 18 years or older and had to have experienced 1 of the 10 toxic events in the 5 years before inclusion in the study; the treatment setting could be either curative attempt (adjuvant, neoadjuvant) or palliative, and patients with ongoing treatment should have received almost 3 months of treatment. Patients were excluded if they had an ECOG PS grade of 3 or more (Eastern Cooperative Oncology Group Performance Status; range, 0-5, where 0 = fully active, 3 = capable of limited self-care; confined to bed or chair more than 50% of waking hours, and 5 = dead). A particular patient with cancer could be included because of more than 1 study toxic event (eg, alopecia and severe vomiting or NTX1 and NTX2) but had to complete separate questionnaires for the different toxic events.

General public group. Participants in this group were selected from the records of general practitioner consultations at the aforementioned primary health care center. They had to be 18 years or older and could not have a history of cancer or symptomatic/severe chronic diseases (eg, they could have hypertension or diabetes without chronic target organ involvement, or they could be patients with either acute nonserious illness or nonserious injuries).
 

Survey procedures

Cancer patients. Participants in this group filled in 2 questionnaires provided by a medical oncologist in a face-to-face interview: the 5-dimension, 5-level EuroQol (EQ-5D-5L) questionnaire in reference to the days when patients were suffering the toxic event; and a visual analog scale (VAS) answering the question: How do you feel that this AE has impacted on your QoL the days you have experienced it?

VAS scores ranged from 0 (the poorest QoL, the highest impact) to 100 (the better QoL, the lower impact). The EQ-5D-5L has 5 dimensions (Mobility, Self-care, Daily life activities/social performance, Discomfort/pain, and Anxiety/depression) with 5 level response options each (No problem at all, Light problem, Moderate problem, Severe problem, Extreme problem/unable).¹² The combination of 5 answers is converted to a single score, which is different for different countries; in the validated version for Spanish population, the score ranges from -0.654 (the worst health state) to 1.000 (the best health state). Patients were asked to make an effort to separate and encapsulate the impact of every adverse event and separate it from others they may have experienced during the same period. Table 2 summarizes survey procedures.

General public group. Two internal medicine residents who administered the questionnaire to the participants of the public group were well trained to carefully explain what each of the 10 the toxic events meant. Some details on these explanations are shown in Table 1, and the full set of explanations is shown in Appendix 1 (online only). Participants in the general public group were asked in a face-to-face interview to imagine they were cancer patients and envision how these toxic events would impact on their QoL if they were undergoing systemic treatment of cancer. They were asked to rate the imagined impact with the VAS (1 VAS/every toxic event = 10 VAS/participant). Then, they were presented with 10 cards, each with the name of 1 of the 10 toxic events (Appendix 2 [online only]), to show them the order of the impact on QoL based on their scores (respecting ties). The participants were asked if they agreed with the order, and if they did not, they were invited to change the scores. Therefore, results in the general public group also show the rank-order of the study toxic events.
 

Statistical analysis

We calculated the sample size as follows:

Primary outcomes were VAS score in cancer patients and VAS score in the general public. Primary analyses were comparison between VAS in both populations. Secondary outcomes were EQ-5D-5L score in cancer patients, and intra-participant rank-order in the general public group. Secondary analyses were correlation between VAS score and EQ-5D-5L in cancer patients and descriptive analysis of rank-ordered data in the general public group.

It was planned to compare means of quantitative variables with the Mann-Whitney U test and to assess correlation between quantitative variables with the Spearman rho test. All tests for contrast were nonparametric because a normal distribution was not expected from quoted scores with some ceiling or floor effect. A hierarchical generalized cluster analysis was planned to study clusters of variables grouped by VAS score in the public group.
 

Ethics

The study was conducted in accordance with the Declaration of Helsinki version Fortaleza 2013 and was approved by the institutional review board of the participant institutions. All of the patients provided written informed consent before study entry. Data of the participants of the general public were anonymous, so those participants were asked to provide only oral assent, with the permission of the review board.
 

Results

Between December 1, 2013 and January 31, 2015, a total of 250 participants of the general public and 139 cancer patients were included in the study. Four participants of the general public had incompletely filled the questionnaire and were excluded from the study, resulting in 246 participants with complete data available. There were no losses in the patient group, of whom 79 (57%) were currently on treatment and 118 (85%) had received the treatment in the previous 2 years. The total number of study toxic events in the 139 cancer patients was 200 (20 by each of the 10 study toxicity variables). Of those, 42 patients (30%) experienced (and were included in the study for) more than 1 toxic event.

Of the 139 patients, 91 (65%) received the treatment with curative intent. The most frequent diagnosis was colorectal cancer in 77 patients (55%), followed by breast cancer (13 patients, 9.4%), and lung cancer (11 patients, 7.9%). Systemic treatment of cancer was one of these options: chemotherapy alone, anti-EGFR [epidermal growth factor receptor] alone, chemotherapy plus anti-EGFR, or chemotherapy plus other biologics. The chemotherapy regimen most frequently administered was mFOLFOX6 [modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin] which, alone or in combination, was administered to 51 patients (37%). An anti-EGFR agent was administered to 22 patients (16%): cetuximab (15 patients), panitumumab (4 patients), erlotinib (2 patients) and afatinib (1 patient). The baseline characteristics of the patients and participants in the study are shown in Table 3.

Discussion

The findings in this study show that impact on QoL imagined by members of the general public is higher than that declared by cancer patients who have experienced the AEs. It is worth noting that that result was observed for all 10 toxic events, thus confirming the investigational hypothesis of the study. However, the graph shows a strong parallel between the 2 groups, which means that both populations similarly perceive upward and downward variations in the impact resulting from the different toxic events (Figure).

Three previous studies have addressed the comparison of the impact of different AEs in these 2 populations and findings from all 3 showed the same systematic difference between patients and the general public participants. The first, Calhoun and colleagues used time to trade-off (TTO, a measure of the QoL a person or groups is experiencing) to compare therapies for ovarian cancer in patients and the general population (n = 39 for each group). The results showed that cancer patients valued more the health status associated with toxicity than did the general public participants.¹³ The design of the second study, by Havrilesky and colleagues, was similar to that of the present study, and they compared toxic events one by one, using VAS and TTO in 13 ovarian cancer patients and 37 women of the general public.¹⁴ The investigators found the same results as we did on the parallel of the 2 groups and also a very similar order of the toxic events. Indeed, alopecia was the less bothersome, whereas both motor neuropathy and severe vomiting were among the worst toxic events. Therefore, our results correlate perfectly with theirs. Best and colleagues found that health states values associated with oxaliplatin-related peripheral neuropathy were lower in the general public population compared with those of cancer patients.¹⁵ Besides adaptive behavior of the patients, all these results may be explained by an established awareness cancer patients have of the dual outcome of cancer treatments (AEs and benefits from the treatment).⁹ This awareness is absent in the general public participants, who can only envision the negative outcomes and who do not realize the importance of the benefits.⁹ Findings from previous studies conducted in several tumor types such as breast cancer^16-18 non–small-cell lung cancer,¹⁹ thyroid cancer,²⁰ and renal cancer²¹ have shown that patients are willing to trade-off AEs for treatment benefits.

Alopecia has been considered as one of the most distressing and troublesome AEs of cancer therapy.²² However, in the present study, alopecia was rated inside the range of mild toxic events as it is in the study by Havrilesky and colleagues.¹⁴ Our results show that alopecia was placed as the first less damaging toxic event when assessed with the EQ-5D-5L, the second less damaging when assessed with a rank-order system, and the third less damaging when assessed the VAS. This could be related to current fashion trends that promote shaving one’s hair, which minimizes the social stigma of alopecia and its association with cancer treatment.

The other esthetic event we analyzed was acneiform rash associated with anti-EGFR agents. Our results show that severe rash was rated as clearly worse than alopecia by the 2 populations, irrespective of the measuring instrument (VAS, EQ-5D-5L, or ordinal assessment). To our knowledge, the present study is the first to demonstrate the relative impact of total alopecia and severe rash on patient QoL. This result is even more significant considering that we included grade 2 acneiform rash inside the Severe Rash toxic event. Our results show that the worst AEs for both populations were severe vomiting and neurotoxicity with functional impairment. The high impact of severe vomiting, the quintessentially chemotherapy-induced AE, was to be expected because it is strongly supported by a number of previous reports,^14,23 as is also true for peripheral motor neuropathy.^14,15,24

EQ-5D is a powerful instrument for measuring health status²⁵ and is widely used to describe and evaluate patient health.²⁶ Our results from the 5 dimensions represented by a single score were well correlated with the results of the VAS. However, whereas median VAS scores were evenly distributed in the 0-100 range of the VAS, median EQ-5D-5L scores were distributed mainly in the 0.5-1.0 range (full range, -0.654-1.000, for Spanish population).

The final single score of the original EQ-5D is based on responses from the general public, and we have shown that its use is a valid option when the objective is the evaluation of AEs in patients with cancer. Management of AEs is of the utmost importance in this era of personalized cancer medicine. Basch and colleagues recently reported that an intensive web-based follow-up of AEs during chemotherapy improved overall survival compared with standard follow-up.²⁷ The results of our study show that patients have strongly defined preferences regarding AEs. Therefore, therapeutic strategies with a personalized approach in managing AEs would be associated with increased effectiveness.

There are some limitations in the present study. First, we modified slightly the EQ-5D-5L questionnaire by asking patients to recall and rate the days they experienced the adverse event instead of asking for “today’s feelings.” It is not known how this modification affects internal validity of this study. Second, we asked patients to isolate the toxic event to rate it independently from the other toxic events. We believe that this request may have been difficult for some patients to do because they might have experienced more than 1 toxic event concurrently. Third, using VAS to assess health status may be a weakness because it has been considered to be too straightforward an instrument. Likewise, there are some strengths of the study: it was performed in a face-to-face manner; it displayed cardinal and ordinal results for participants in the public group; and the results are the same as those in a previous study.¹⁴

In conclusion, patients with cancer who have experienced AEs perceive a lower impact on their QoL compared with that envisioned by participants from the general public. The EQ-5D-5L is a useful tool for evaluating cancer-therapy–related AEs. The impact of alopecia on QoL was notably low and even lower than that of severe rash. Further investigation on this issue should focus on patients’ and oncologists’ shared choices, which increasingly will be driven by patient preferences.
 

The Oncologic Association Dr Amadeu Pelegrí (AODAP), a charitable organization led by cancer patients and based in Salou, Spain, provided the financial support needed to conduct this study (www.aodapelegri.com).

Supplement Editor:
Maan A. Fares, MD

Contents

Introduction: Challenges and advances in cardiovascular disease
Maan A. Fares

Cardiac amyloidosis: An update on diagnosis and treatment
Joseph P. Donnelly and Mazen Hanna

Management of coronary chronic total occlusion
Jaikirshan Khatri, Mouin Abdallah, and Stephen Ellis

Update on the management of venous thromboembolism
John R. Bartholomew

Cardiac implantable electronic device infection
Cameron T. Lambert and Khaldoun G. Tarakji

Lung transplant: Candidates for referral and the waiting list
Kenneth R. McCurry and Marie M. Budev

Supplement Editor:
Maan A. Fares, MD

Contents

Introduction: Challenges and advances in cardiovascular disease
Maan A. Fares

Cardiac amyloidosis: An update on diagnosis and treatment
Joseph P. Donnelly and Mazen Hanna

Management of coronary chronic total occlusion
Jaikirshan Khatri, Mouin Abdallah, and Stephen Ellis

Update on the management of venous thromboembolism
John R. Bartholomew

Cardiac implantable electronic device infection
Cameron T. Lambert and Khaldoun G. Tarakji

Lung transplant: Candidates for referral and the waiting list
Kenneth R. McCurry and Marie M. Budev

Supplement Editor:
Maan A. Fares, MD

Contents

Introduction: Challenges and advances in cardiovascular disease
Maan A. Fares

Cardiac amyloidosis: An update on diagnosis and treatment
Joseph P. Donnelly and Mazen Hanna

Management of coronary chronic total occlusion
Jaikirshan Khatri, Mouin Abdallah, and Stephen Ellis

Update on the management of venous thromboembolism
John R. Bartholomew

Cardiac implantable electronic device infection
Cameron T. Lambert and Khaldoun G. Tarakji

Lung transplant: Candidates for referral and the waiting list
Kenneth R. McCurry and Marie M. Budev