Anuj Gupta

Safety and Efficacy of Drug-Eluting and Bare Metal Stents Comprehensive Meta-Analysis of Randomized Trials and Observational Studies

Background— The safety and efficacy of drug-eluting stents (DES) among more generalized “real-world” patients than those enrolled in pivotal randomized controlled trials (RCTs) are controversial. We sought to perform a meta-analysis of DES studies to estimate the relative impact of DES versus bare metal stents (BMS) on safety and efficacy end points, particularly for non–Food and Drug Administration–labeled indications. Methods and Results— Comparative DES versus BMS studies published or presented through February 2008 with ≥100 total patients and reporting mortality data with cumulative follow-up of ≥1 year were identified. Data were abstracted from studies comparing DES with BMS; original source data were used when available. Data from 9470 patients in 22 RCTs and from 182 901 patients in 34 observational studies were included. RCT and observational data were analyzed separately. In RCTs, DES (compared with BMS) were associated with no detectable differences in overall mortality (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.81 to 1.15; P=0.72) or myocardial infarction (HR, 0.95; 95% CI, 0.79 to 1.13; P=0.54), with a significant 55% reduction in target vessel revascularization (HR, 0.45; 95% CI, 0.37 to 0.54; P<0.0001); point estimates were slightly lower in off-label compared with on-label analyses. In observational studies, DES were associated with significant reductions in mortality (HR, 0.78; 95% CI, 0.71 to 0.86), myocardial infarction (HR, 0.87; 95% CI, 0.78 to 0.97), and target vessel revascularization (HR, 0.54; 95% CI, 0.48 to 0.61) compared with BMS. Conclusions— In RCTs, no significant differences were observed in the long-term rates of death or myocardial infarction after DES or BMS use for either off-label or on-label indications. In real-world nonrandomized observational studies with greater numbers of patients but the admitted potential for selection bias and residual confounding, DES use was associated with reduced death and myocardial infarction. Both RCTs and observational studies demonstrated marked and comparable reductions in target vessel revascularization with DES compared with BMS. These data in aggregate suggest that DES are safe and efficacious in both on-label and off-label use but highlight differences between RCT and observational data comparing DES and BMS.

Safety and efficacy of renal denervation as a novel treatment of ventricular tachycardia storm in patients with cardiomyopathy

BACKGROUND Modulation of the autonomic nervous system has been used to treat refractory ventricular tachycardia (VT). Renal artery denervation (RDN) is under investigation for the treatment of sympathetic-driven cardiovascular diseases. OBJECTIVE The purpose of this study was to report the largest case series to date using RDN as adjunctive therapy for refractory VT in patients with underlying cardiomyopathy. METHODS Four patients with cardiomyopathy (2 nonischemic, 2 ischemic) with recurrent VT despite maximized antiarrhythmic therapy and prior endocardial (n = 2) or endocardial/epicardial (n = 2) ablation underwent RDN ± repeat VT ablation. RDN was performed spirally along each main renal artery with either a nonirrigated (6 W at 50°C for 60 seconds) or an open irrigated ablation catheter (10-12 W for 30-60 seconds). Renal arteriography was performed before and after RDN. RESULTS RDN was well tolerated acutely and demonstrated no clinically significant complications during follow-up of 8.8 ± 2.6 months (range 5.0-11.0 months). No hemodynamic deterioration or worsening of renal function was observed. The number of VT episodes was decreased from 11.0 ± 4.2 (5.0-14.0) during the month before ablation to 0.3 ± 0.1 (0.2-0.4) per month after ablation. All VT episodes occurred in the first 4 months after ablation (2.6 ± 1.5 months). The responses to RDN were similar for ischemic and nonischemic patients. CONCLUSION This case series provides promising preliminary data on the safety and effectiveness of RDN as an adjunctive therapy in the treatment of patients with cardiomyopathy and VT resistant to standard interventions.

Angiographic Patterns of Drug-Eluting Stent Restenosis and One-Year Outcomes After Treatment With Repeated Percutaneous Coronary Intervention

Patterns of in-stent restenosis (ISR) after drug-eluting stent (DES) implantation and outcomes after treatment have not been studied systematically in all comers. We compared patterns of ISR and outcomes of repeated percutaneous coronary intervention in consecutive patients with DES-ISR. A total of 137 patients with 182 lesions underwent repeated percutaneous coronary intervention for DES-ISR at Columbia University Medical Center from August 2004 to April 2006. DES-ISR was treated with repeated DES placement in 84% of patients and balloon angioplasty in 16%. There was 1 stent thrombosis at 30 days, and at 1 year, major adverse cardiac events occurred in 10% of patients, driven primarily by an 8% rate of target-lesion revascularization. After exclusion of 12 patients with multiple ISR lesions, data were further analyzed from 125 patients with 152 DES-ISR lesions, of which 118 were originally treated with sirolimus-eluting stents and 34 were treated with paclitaxel-eluting stents (PES-ISR). Baseline features were well matched between the 2 groups, except that patients with PES-ISR were older. A focal pattern of ISR was observed in 69.5% of patients overall. However, patients originally treated with a PES had a significantly higher frequency of diffuse-intrastent ISR in comparison with sirolimus-eluting stent ISR (30.3% vs 13.6%, p = 0.03). In conclusion, the pattern of ISR in most DES-ISR in this unselected patient population was focal, with higher rates of diffuse intrastent restenosis seen with PES-ISR. Treatment with either repeated DES implantation or balloon angioplasty for DES-ISR was safe and associated with low overall rates of target-lesion revascularization and major adverse cardiac events at 1 year.

Value of Drug-Eluting Stents in Cardiac Transplant Recipients

Transplant allograft vasculopathy (TAV) was a leading cause of death in cardiac transplant recipients after the first year of transplantation. Whether drug-eluting stents (DESs) performed better than bare-metal stents (BMSs) for the treatment of patients with discrete epicardial stenosis was unknown. The aim was to determine the safety and efficacy of DESs compared with BMSs in the treatment of patients with TAV. Outcomes of 32 patients sequentially treated using DESs for TAV were retrospectively reviewed and compared with a historic cohort of 35 patients treated sequentially with BMSs for TAV. Patients treated with DESs were also compared with age- and gender-matched cardiac transplant controls to determine differences in survival. After adjustment for baseline risk factors, there was no difference in 1-year survival between patients treated with DESs or BMSs for TAV. Restenosis rates at 1 year were 49% in lesions treated using BMSs and 19% in those treated using DESs. Compared with an age- and gender-matched control group of cardiac transplant patients who did not have discrete obstructive epicardial TAV, patients who required treatment with DESs for epicardial obstructive disease had significantly worse survival. In conclusion, treatment of patients with TAV with DESs did not seem to alter the natural deleterious history of this disease process.

Differential Expression of Matrix Metalloproteinases and Tissue Inhibitors and Extracellular Matrix Remodeling in Aortic Regurgitant Hearts

Objectives: Myocardial fibrosis in experimental aortic regurgitation (AR) features abnormal fibronectin with normal collagen content, but the relevant degradative processes have not been assessed. Methods: To elucidate these degradative processes, mRNA (Northern) and protein levels (Western) of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), as well as MMP activity (zymography), were measured in cardiac fibroblasts (CF) from New Zealand white rabbits with experimental AR paired with normals (NL). Collagen and fibronectin were quantified by immunohistochemical staining. Results: In AR CF versus NL CF, MMP-2 and -14 mRNA and protein were increased (both p < 0.005), while TIMPs 1–3 were slightly decreased (p < 0.05–0.005; TIMP-4 undetectable). Gelatinase activity in AR CF was 1.7 times that in NL CF (p < 0.005); fibronectinase activity was unaffected. The Jun N-terminal kinase (JNK) inhibitor SP600125 suppressed MMP-2 protein (0.4-fold, p < 0.05) and mRNA (0.7-fold, p < 0.005) in AR CF; MMP-2 levels in NL CF were unaffected. AR MMP-9 mRNA, protein and activity were low and indistinguishable from NL. In left ventricular tissue, fibronectin was increased 1.9-fold (AR vs. NL, p < 0.05). Total AR collagen was indistinguishable from NL, but the collagen III to collagen I isoform ratio decreased (0.4-fold, p < 0.05). Conclusions: Collagen is relatively deficient in AR fibrosis, due at least in part to upregulated MMPs and downregulated TIMPs; fibronectinase is unaltered. JNK-dependent regulation may stimulate both MMP-2 and fibronectin expression in AR, providing a potential therapeutic target.

Implications of Public Reporting of Risk-Adjusted Mortality Following Percutaneous Coronary Intervention: Misperceptions and Potential Consequences for High-Risk Patients Including Nonsurgical Patients

Assessment of clinical outcomes such as 30-day mortality following coronary revascularization procedures has historically been used to spur quality improvement programs. Public reporting of risk-adjusted outcomes is already mandated in several states, and proposals to further expand public reporting have been put forward as a means of increasing transparency and potentially incentivizing high quality care. However, for public reporting of outcomes to be considered a useful surrogate of procedural quality of care, several prerequisites must be met. First, the reporting measure must be truly representative of the quality of the procedure itself, rather than be dominated by other underlying factors, such as the overall level of illness of a patient. Second, to foster comparisons among physicians and institutions, the metric requires accurate ascertainment of and adjustment for differences in patient risk profiles. This is particularly relevant for high-risk clinical patient scenarios. Finally, the potential deleterious consequences of public reporting of a quality metric should be considered prior to expanding the use of public reporting more broadly. In this viewpoint, the authors review in particular the characterization of high-risk patients currently treated by percutaneous coronary interventional procedures, assessing the adequacy of clinical risk models used in this population. They then expand upon the limitations of 30-day mortality as a quality metric for percutaneous coronary intervention, addressing the strengths and limitations of this metric, as well as offering suggestions to enhance its future use in public reporting.

Cellular response of human cardiac fibroblasts to mechanically simulated aortic regurgitation.

Myocardial fibrosis has been identified in biopsy specimens from catheterization and valve replacement surgery in patients with severe chronic aortic regurgitation (AR). While characterization of these extracellular matrix (ECM) alterations has been incomplete in humans, fibrosis also has been identified in chronic severe experimentally created AR, in which ECM composition features abnormal fibronectin/glycoprotein production, with normal collagen content. Virtually identical ECM variations have been induced when normal rabbit cardiac fibroblasts (CF) are subjected in culture to cyclic mechanical strain mimicking that found in the left ventricle (LV) in severe AR. To determine whether the changes seen experimentally can be extrapolated to humans, we exposed normal human CF in culture to the mechanical strain employed in the experimental model to simulate severe AR (n = 3 replications from 1 patient). CF were isolated from epicardial biopsy distant from diseased coronary arteries in a 38-year-old man with normal LV function and without prior myocardial infarction who was undergoing elective coronary artery bypass grafting. Gelatin Sepharose affinity chromatography (GSAC) and Western analysis were used to compare fibronectin expression in strained versus nonstrained normal human CF in tissue culture; Western analysis was used to compare type I collagen production. In AR-strained CF, fibronectin synthesis nominally increased [av 38% (Western) and 45% (GSAC)] relative to control; type I collagen synthesis was virtually unchanged. These results simulate those found experimentally and suggest that human CF, like rabbit CF, manifest abnormal compositional distribution of ECM proteins in AR.

CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis

Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non–foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1&agr; and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1&agr; via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1&agr;/VEGF-A pathway.

Very Late Pathological Responses to Cobalt–Chromium Everolimus‐Eluting, Stainless Steel Sirolimus‐Eluting, and Cobalt–Chromium Bare Metal Stents in Humans

Background The “very late” clinical outcomes for durable polymer drug‐eluting stents and bare metal stents (BMSs) have been shown to be dissimilar in clinical studies. Conceptually, the long‐term vascular compatibility of BMSs is still regarded to be superior to drug‐eluting stents; however, no pathologic study to date has specifically addressed this issue. We evaluated the very late (≥1 year) pathologic responses to durable polymer drug‐eluting stents (cobalt–chromium [CoCr] everolimus‐eluting stents [EESs] and stainless steel sirolimus‐eluting stents [SS‐SESs]) versus BMSs (CoCr‐BMSs). Methods and Results From the CVPath stent registry, we studied a total of 119 lesions (40 CoCr‐EESs, 44 SS‐SESs, 35 CoCr‐BMSs) from 92 autopsy cases with a duration ranging from 1 to 5 years. Sections of stented coronary segments were pathologically analyzed. Inflammation score and the percentage of struts with giant cells were lowest in CoCr‐EESs (median inflammation score: 0.6; median percentage of struts with giant cells: 3.8%) followed by CoCr‐BMSs (median inflammation score: 1.3 [P<0.01]; median percentage of struts with giant cells: 8.9% [P=0.02]) and SS‐SESs (median inflammation score: 1.7 [P<0.01]; median percentage of struts with giant cells: 15.3% [P<0.01]). Polymer delamination was observed exclusively in SS‐SESs and was associated with increased inflammatory and giant cell reactions. The prevalence of neoatherosclerosis with CoCr‐EESs (50%) was significantly less than with SS‐SESs (77%, P=0.02) but significantly greater than with CoCr‐BMSs (20%, P<0.01). Conclusions CoCr‐EESs, SS‐SESs, and BMSs each demonstrated distinct vascular responses. CoCr‐EESs demonstrated the least inflammation, near‐equivalent healing to BMSs, and lower neointimal formation. These results challenge the belief that BMSs have superior biocompatibility compared with some polymeric coated drug‐eluting stents and may have implications for future stent design.

Reasons and implications of agreements and disagreements between coronary flow reserve, fractional flow reserve, and myocardial perfusion imaging

Information on coronary physiology and myocardial blood flow (MBF) in patients with suspected angina is increasingly important to inform treatment decisions. A number of different techniques including myocardial perfusion imaging (MPI), noninvasive estimation of MBF, and coronary flow reserve (CFR), as well as invasive methods for CFR and fractional flow reserve (FFR) are now readily available. However, despite their incorporation into contemporary guidelines, these techniques are still poorly understood and their interpretation to guide revascularization decisions is often inconsistent. In particular, these inconsistencies arise when there are discrepancies between the various techniques. The purpose of this article is therefore to review the basic principles, techniques, and clinical value of MPI, FFR, and CFR—with particular focus on interpreting their agreements and disagreements.