Martin B. Leon

Updated standardized endpoint definitions for transcatheter aortic valve implantation: The Valve Academic Research Consortium-2 consensus document

OBJECTIVES The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI) clinical endpoints to make them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection. BACKGROUND A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous. METHODS AND RESULTS Two in-person meetings (held in September 2011 in Washington, DC, and in February 2012 in Rotterdam, The Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and noninterventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the US Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC-2 consensus manuscript was derived. This document provides an overview of risk assessment and patient stratification that need to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding complications, acute kidney injury, vascular complications, conduction disturbances and arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiographic recommendations are provided for the evaluation of prosthetic valve (dys)function. Definitions for the quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints. CONCLUSIONS This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of the study results, supplying an increasingly growing body of evidence with respect to TAVI and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavors of applying definitions to other transcatheter valve therapies (for example, mitral valve repair).

Transendocardial delivery of autologous Bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia

OBJECTIVES We tested the hypothesis that intramyocardial injection of autologous bone marrow (ABM) promotes collateral development in ischemic porcine myocardium. We also defined, in vitro, whether bone marrow (BM) cells secrete vascular endothelial growth factor (VEGF) and macrophage chemoattractant protein-1 (MCP-1). BACKGROUND The natural processes leading to collateral development are extremely complex, requiring multiple growth factors interacting in concert and in sequence. Because optimal angiogenesis may, therefore, require multiple angiogenic factors, we thought that injection of BM, which contains cells that secrete numerous angiogenic factors, might provide optimal therapeutic angiogenesis. METHODS Bone marrow was cultured four weeks in vitro. Conditioned medium was assayed for VEGF and MCP-1 and was added to cultured pig aortic endothelial cells (PAEC) to assess proliferation. Four weeks after left circumflex ameroid implantation, freshly aspirated ABM (n = 7) or heparinized saline (n = 7) was injected transendocardially into the ischemic zone (0.2 ml/injection at 12 sites). Echocardiography to assess myocardial thickening and microspheres to assess perfusion were performed at rest and during stress. RESULTS Vascular endothelial growth factor and MCP-1 concentrations increased in a time-related manner. The conditioned medium enhanced, in a dose-related manner, PAEC proliferation. Collateral flow (ischemic/normal zone X 100) improved in ABM-treated pigs (ABM: 98 +/- 14 vs. 83 +/- 12 at rest, p = 0.001; 89 +/- 18 vs. 78 +/- 12 during adenosine, p = 0.025; controls: 92 +/- 10 vs. 89 +/- 9 at rest, p = 0.49; 78 +/- 11 vs. 77 +/- 5 during adenosine, p = 0.75). Similarly, contractility increased in ABM-treated pigs (ABM: 83 +/- 21 vs. 60 +/- 32 at rest, p = 0.04; 91 +/- 44 vs. 36 +/- 43 during pacing, p = 0.056; controls: 69 +/- 48 vs. 64 +/- 46 at rest, p = 0.74; 65 +/- 56 vs. 37 +/- 56 during pacing, p = 0.23). CONCLUSIONS Bone marrow cells secrete angiogenic factors that induce endothelial cell proliferation and, when injected transendocardially, augment collateral perfusion and myocardial function in ischemic myocardium.

Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study.

OBJECTIVES We conducted a pilot study to evaluate the feasibility of transendocardial delivery of autologous bone marrow (ABM) strategy in patients with severe symptomatic chronic myocardial ischemia not amenable to conventional revascularization. BACKGROUND Transendocardial injection of ABM cells appears to enhance perfusion of ischemic porcine myocardium. METHODS Ten patients underwent transendocardial injection of freshly aspirated and filtered unfractionated ABM using left ventricular electromechanical guidance. Twelve injections of 0.2 ml each were successfully delivered into ischemic noninfarcted myocardium pre-identified by single-photon emission computed tomography perfusion imaging. RESULTS Autologous bone marrow injection was successful in all patients and was associated with no serious adverse effects; in particular, there was no arrhythmia, evidence of infection, myocardial inflammation, or increased scar formation. Two patients were readmitted for recurrent chest pain. At three months, Canadian Cardiovascular Society angina score significantly improved (3.1 +/- 0.3 vs. 2.0 +/- 0.94, p = 0.001), as well as stress-induced ischemia occurring within the injected territories (2.1 +/- 0.8 vs. 1.6 +/- 0.8, p < 0.001). Treadmill exercise duration, available in nine patients, increased, but the change was not significant (391 +/- 155 vs. 485 +/- 198, p = 0.11). CONCLUSIONS This study provides preliminary clinical data indicating feasibility of catheter-based transendocardial delivery of ABM to ischemic myocardium.

Health-Related Quality of Life After Transcatheter Aortic Valve Replacement in Inoperable Patients With Severe Aortic Stenosis

Background— Transcatheter aortic valve replacement (TAVR) has been shown to improve survival compared with standard therapy in patients with severe aortic stenosis who cannot have surgery. The effects of TAVR on health-related quality of life have not been reported from a controlled study. Methods and Results— The Placement of Aortic Transcatheter Valves (PARTNER) trial randomized patients with symptomatic, severe aortic stenosis who were not candidates for surgical valve replacement to TAVR (n=179) or standard therapy (n=179). Health-related quality of life was assessed at baseline and at 1, 6, and 12 months with the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the 12-item Short Form-12 General Health Survey (SF-12). The primary end point was the KCCQ overall summary score (range, 0–100; higher=better). At baseline, mean KCCQ summary scores (35±20) and SF-12 physical summary scores (28±7) were markedly depressed. Although the KCCQ summary score improved from baseline in both groups, the extent of improvement was greater after TAVR compared with control at 1 month (mean between-group difference, 13 points; 95% confidence interval, 8–19; P<0.001) with larger benefits at 6 months (mean difference, 21 points; 95% confidence interval, 15–27; P<0.001) and 12 months (mean difference, 26 points; 95% confidence interval, 19–33; P<0.001). At 12 months, TAVR patients also reported higher SF-12 physical and mental health scores with mean differences compared with standard care of 5.7 and 6.4 points, respectively (P<0.001 for both comparisons). Conclusions— Among inoperable patients with severe aortic stenosis, compared with standard care, TAVR resulted in significant improvements in health-related quality of life that were maintained for at least 1 year. Clinical Trials Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00530894.

Five-Year Follow-Up After Sirolimus-Eluting Stent Implantation : Results of the SIRIUS (Sirolimus-Eluting Stent in De-Novo Native Coronary Lesions) Trial

OBJECTIVES The aim of this study was to examine the 5-year clinical safety and efficacy outcomes in patients enrolled in the SIRIUS (Sirolimus-Eluting Stent in De-Novo Native Coronary Lesions) trial. BACKGROUND The SIRIUS trial was a double-blinded randomized study that demonstrated that sirolimus-eluting stents (SES) significantly improved angiographic results (at 8 months) and clinical outcomes (at 9 and 12 months) compared with bare-metal stents (BMS). METHODS Patients (n = 1,058) with de novo native coronary artery lesions were randomized to either SES (n = 533) or control BMS (n = 525) and were followed for 5 years. RESULTS Between 1 and 5 years, additional clinical events were similarly distributed among the sirolimus and control groups. At 5 years, in sirolimus versus control patients, target lesion revascularization was 9.4% versus 24.2% (p < 0.001) and major adverse cardiovascular events and target vessel failure rates were 20.3% versus 33.5% and 22.5% versus 33.5%, respectively (p < 0.0001 for both). There were no significant differences in death, myocardial infarction, and nontarget lesion revascularization. No significant differences were observed in the cumulative incidence of stent thrombosis for sirolimus versus control patients with either protocol-derived (1.0% vs. 0.8%) or Academic Research Consortium definitions (3.9% vs. 4.2%). CONCLUSIONS In patients with noncomplex coronary artery disease, clinical outcomes 5 years after implantation of SES continue to demonstrate significant reduction in the need for repeat revascularization, with similar safety (death and myocardial infarction) compared with BMS, without evidence for either disproportionate late restenosis or late stent thrombosis.

Effect of Concomitant Coronary Artery Disease on Procedural and Late Outcomes of Transcatheter Aortic Valve Implantation

BACKGROUND Previous coronary artery bypass grafting increases predicted operative risk for conventional valve replacement, according to the Society of Thoracic Surgeons risk algorithm. Additionally, the presence of coronary artery disease (CAD) has been demonstrated to increase procedural risk with conventional aortic valve replacement. Significant coexisting CAD requires preemptive percutaneous coronary intervention (PCI) in patients under consideration for transcatheter aortic valve implantation (TAVI). This study examined the impact of previous coronary artery bypass grafting or PCI on procedural outcomes and overall survival in patients having TAVI. METHODS Two hundred and one high-risk patients were enrolled in two international feasibility studies from December 2005 to February 2008 for the treatment of aortic stenosis using TAVI. Thirty patients were excluded from analysis due to failure to successfully deploy the valve in the aortic annulus. Data were collected concurrently using an ad hoc database that included operative and long-term survival. Previous cardiovascular intervention prior to TAVI was used to identify the existence of concomitant CAD. Logistic regression along with Kaplan-Meier estimates were employed to establish the association between CAD and survival from TAVI. RESULTS Overall mortality after TAVI was significantly higher among the CAD group (35.7%) in contrast with the non-CAD patients (18.4%), p = 0.01. Logistic regression analysis found that patients who had CAD were 10.1 times more likely to die (95% confidence interval 2.1 to 174.8) within 30 days of the procedure than those who did not. Proportional hazards analysis established that the risk of dying at any point in time was 2.3 times higher among the patients with CAD (95% confidence interval 1.29 to 4.17). Kaplan-Meier survival curves demonstrate improved long-term survival among patients without CAD. CONCLUSIONS Coexisting coronary artery disease negatively impacts procedural outcomes and long-term survival in patients undergoing TAVI, and implies that risk assessment and anticipated outcomes might be inaccurate due to stratification as isolated aortic valve replacement rather than AVR+CABG. Comparison of procedural outcomes, based on operative approach without controlling for unequal distribution of CAD in the cohorts, are likely invalid.

Cost-Effectiveness of Transcatheter Aortic Valve Replacement Compared With Surgical Aortic Valve Replacement in High-Risk Patients With Severe Aortic Stenosis : Results of the PARTNER (Placement of Aortic Transcatheter Valves) Trial (Cohort A)

OBJECTIVES The aim of this study was to evaluate the cost-effectiveness of transcatheter aortic valve replacement (TAVR) compared with surgical aortic valve replacement (AVR) for patients with severe aortic stenosis and high surgical risk. BACKGROUND TAVR is an alternative to AVR for patients with severe aortic stenosis and high surgical risk. METHODS We performed a formal economic analysis based on cost, quality of life, and survival data collected in the PARTNER A (Placement of Aortic Transcatheter Valves) trial in which patients with severe aortic stenosis and high surgical risk were randomized to TAVR or AVR. Cumulative 12-month costs (assessed from a U.S. societal perspective) and quality-adjusted life-years (QALYs) were compared separately for the transfemoral (TF) and transapical (TA) cohorts. RESULTS Although 12-month costs and QALYs were similar for TAVR and AVR in the overall population, there were important differences when results were stratified by access site. In the TF cohort, total 12-month costs were slightly lower with TAVR and QALYs were slightly higher such that TF-TAVR was economically dominant compared with AVR in the base case and economically attractive (incremental cost-effectiveness ratio <

Incidence, management, and outcome of coronary artery perforation during percutaneous coronary intervention

50,000/QALY) in 70.9% of bootstrap replicates. In the TA cohort, 12-month costs remained substantially higher with TAVR, whereas QALYs tended to be lower such that TA-TAVR was economically dominated by AVR in the base case and economically attractive in only 7.1% of replicates. CONCLUSIONS In the PARTNER trial, TAVR was an economically attractive strategy compared with AVR for patients suitable for TF access. Future studies are necessary to determine whether improved experience and outcomes with TA-TAVR can improve its cost-effectiveness relative to AVR.

Clinical outcome following percutaneous coronary interventions in patients with chronic renal failure

We have analyzed the incidence, management, and outcome of 84 cases of coronary artery perforation in patients who underwent percutaneous coronary intervention at our institution. This complication was more frequent in female patients and in patients who underwent lesion modification with atheroablative devices. A total of 8 patients (9.5%) died after the procedure. They were usually older and had a higher incidence of cardiac tamponade; a larger percentage of these patients underwent emergency surgery than those who survived.

The future of transcatheter mitral valve interventions: competitive or complementary role of repair vs. replacement?

The clinical outcome of patients with chronic renal failure (CRF) who undergo percutaneous coronary intervention (PCI) has not been systematically evaluated in a large cohort of patients. We retrospectively analyzed the in‐hospital and 1‐year clinical outcomes of 10,076 consecutive patients who underwent PCI between January 1994 and December 1997. A total of 95 patients (0.9%) had end‐stage renal disease (ESRD) on dialysis, 786 patients (7.8%) had CRF, and 9,125 patients (90.6%) had normal renal function. Despite an angiographic success rate of 97% in all three groups, in‐hospital mortality was significantly higher among patients with renal disease, whether they were on dialysis or not, when compared to patients without renal dysfunction (6.8% vs. 4.2% vs. 0.9%; P < 0.0001). At 1‐year follow‐up, mortality rate was 48.8% for ESRD, 25.7% for patients with CRF, and 5.5%, for patients without renal dysfunction (P < 0.0001). By multivariate analysis, high left ventricular ejection fraction and creatinine clearance were associated with decreased late mortality (OR = 0.84 and 0.95; P < 0.0001), whereas ESRD (OR = 3.65; P = 0.0002), non–Q‐wave myocardial infarction (OR = 2.21; P < 0.0001), diabetes mellitus (OR = 1.99; P < 0.0001), and CRF (OR = 1.74; P = 0.003) were independent correlates of increased late mortality. Therefore, PCI in patients with impaired renal function, whether on dialysis or not, is associated with poor in‐hospital and 1‐year survival. Cathet Cardiovasc Intervent 2002;55:66–72.