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For patients hospitalized for heart failure with reduced ejection fraction (HFrEF), guidelines recommend optimization of medical therapy prior to discharge. The degree to which changes in medical therapy occur during hospitalizations for HFrEF in North American clinical practice is unclear.The VICTORIA registry (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) enrolled patients hospitalized for worsening chronic HFrEF across 51 sites in the United States and Canada from February 2018-January 2019. In patients with complete medication data who were not receiving dialysis, use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB), angiotensin receptor neprilysin inhibitor (ARNI), beta-blocker, mineralocorticoid receptor antagonist (MRA), and sodium glucose cotransporter-2 inhibitors (SGLT2i) were assessed at admission and discharge.Of 1695 patients, the median (IQR) age was 69 (59-79) years, and 33% were women. Among eligible patients, 33%, 25% and 55% were not prescribed ACEI/ARB/ARNI, beta-blocker, and MRA at discharge, respectively; 99% were not prescribed SGLT2i. For each medication,50% of patients remained on stable subtarget doses or no medication during hospitalization. In-hospital rates of initiation/dose increase were 20% for ACEI/ARB, 4% for ARNI, 20% for beta-blocker, 22% for MRA, and1% for SGLT2i; corresponding rates of dose decrease/discontinuation were 11%, 2%, 9%, 5%, and1%, respectively. Overall, 17% and 28% of eligible patients were prescribed triple therapy prior to admission and at discharge, respectively. At both admission and discharge, 1% of patients were prescribed triple therapy at target doses. Across classes of medication, multiple factors were independently associated with higher likelihood of in-hospital initiation/dosing increase (eg, Canadian enrollment, white race, admission to intensive care units) and discontinuation/dosing decrease (eg, worse renal function, admission to intensive care units).In this contemporary North American registry of patients hospitalized for worsening chronic HFrEF, for each recommended medical therapy, the large majority of eligible patients remained on stable subtarget doses or without medication at admission and discharge. Although most patients had no alterations in medical therapy, hospitalization in Canada and multiple patient characteristics were associated with higher likelihood of favorable in-hospital medication changes.

Aims Vericiguat reduced the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization in patients with worsening HF with reduced ejection fraction (HFrEF) and a lower limit of baseline estimated glomerular filtration rate (eGFR) of 15 mL/min/1.73 m2. We evaluated the relationship between the efficacy of vericiguat and baseline and subsequent changes in renal function. Methods and results In VICTORIA, core laboratory serum creatinine was measured at baseline (n = 4956) and weeks 16, 32, and 48. Worsening renal function (WRF), defined as an increase ≥0.3 mg/dL in creatinine from baseline to week 16, was assessed via a Cox model with respect to subsequent primary events. Mean age was 69 years, 24% were female, and mean baseline eGFR was 61 mL/min/1.73 m2. During 48 weeks of treatment, the trajectories in eGFR and creatinine with vericiguat were similar to placebo (P = 0.50 and 0.18). The beneficial effects of vericiguat on the primary outcome were not influenced by baseline eGFR (interaction P = 0.48). WRF occurred in 15% of patients and was associated with worse outcomes (adjusted hazard ratio 1.28, 95% confidence interval 1.11–1.47; P, The left panel shows no differences in the change in creatinine (P = 0.18) between the vericiguat and placebo groups, as evaluated by the interaction between treatment and study visit in the model. The right panel shows a natural cubic spline plot showing that the treatment effect of vericiguat on the primary outcome was similar across the full range of estimated glomerular filtration rate (eGFR) (P = 0.23).

This trial sought to evaluate whether vericiguat, a novel oral soluble guanylate cyclase (sGC) stimulator, was superior to placebo, on a background of standard of care, in increasing the time to the first occurrence of the composite endpoints of cardiovascular (CV) death and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction (HFrEF). Deficiency in sGC-derived cyclic guanosine monophosphate (cGMP) causes both myocardial dysfunction and impaired endothelium-dependent vasomotor regulation that includes the myocardial microcirculation. Experimental studies have suggested multiple potential benefits of sGC stimulators including prevention, or even reversal, of left ventricular hypertrophy and fibrosis, as well as reduction of ventricular afterload through both systemic and pulmonary vasodilation. Hence, restoration of sufficient nitric oxide (NO)-sGC–cGMP signaling has been proposed as an important treatment target in HF. Vericiguat has been shown to directly stimulate sGC and enhance sGC sensitivity to endogenous NO. Available phase IIb data in HFrEF patients indicate vericiguat is safe and well-tolerated, and exploratory analyses indicate that it results in a dose-dependent, clinically significant reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP) at the highest tested dose. VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) is a randomized, placebo-controlled, parallel group, multicenter, double-blind, event-driven phase 3 trial of vericiguat in subjects with HFrEF. Approximately 4,872 subjects will be randomized to evaluate the efficacy and safety of vericiguat compared with placebo on a background of standard of care. After a screening phase of up to 30 days, eligible subjects will be treated until the required number of cardiovascular deaths is observed. The estimated median follow-up duration is approximately 18 months. All subjects will be followed until study completion to assess for the occurrence of endpoint events. VICTORIA will establish the efficacy and safety of vericiguat on cardiovascular death and HF hospitalization in patients with HFrEF. (A Randomized Parallel-Group, Placebo-Controlled, Double-Blind, Event-Driven, Multi-Center Pivotal Phase III Clinical Outcome Trial of Efficacy and Safety of the Oral sGC Stimulator Vericiguat in Subjects With Heart Failure With Reduced Ejection Fraction [HFrEF]—VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534)

Background In VICTORIA, vericiguat was more effective than placebo in addition to standard of care in reducing the composite outcome of CV death (CVD) or HF hospitalization (HFH). We describe baseline guideline-directed medical therapy (GDMT) and examine if the primary outcome was associated with differences in adherence to GDMT including dosing. Methods We used baseline data for 5 GDMT: ACEi, ARBs, ARNI, beta-blockers (BB), and MRAs. We defined adherence as: (1) basic adherence (yes/no); (2) indication-corrected adherence (basic adherence after accounting for indications, contraindications and tolerance); and (3) dose-corrected adherence (indication-corrected adherence + ≥50% of dose target). Associations of study treatment and the primary outcome by GDMT adherence was assessed with Cox proportional hazard regression and adjustment for the MAGGIC score. Results 5040 patients had relevant data available. Basic adherence was 87.4% for RAS inhibition (73.4% for ACEi or ARB, 14.5% for ARNI), 95.6% using indication-corrected and 40.9% for dose-corrected adherence. For BBs, 93.1% met basic and 96.2% indication-corrected adherence, 45.1% met dose-corrected adherence. For MRA, 70.3% met basic and 90% indication-corrected adherence, 82.6% dose-corrected adherence. For triple therapy (ACEi, ARB or ARNI + beta-blocker + MRA), basic adherence was 59.7%, and 86% using indication-corrected adherence and 80.3% with dose-corrected adherence. Using basic or dose corrected adherence, the treatment effect of vericiguat was consistent across GDMT with no treatment heterogeneity, with or without adjustment for variables (Fig). However, vericiguat appeared to be associated with a greater reduction in the primary outcome in those meeting ≥50% dose target for BB (HR 0.72, 95% CI 0.61-0.84) than those who did not (HR 1.01, 95% CI 0.88-1.15; p-interaction 0.001). Conclusions Patients in VICTORIA were well treated with GDMT and the efficacy of vericiguat was consistent across background GDMT therapy with very high indication-corrected adherence accounting for patient-level indications, contraindications, and tolerance.

International audience; Aim: Describe the distinguishing features of heart failure (HF) patients with reduced ejection fraction (HFrEF) in the VICTORIA (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction) trial.Methods and results: Key background characteristics were evaluated in 5050 patients randomized in VICTORIA and categorized into three cohorts reflecting their index worsening HF event. Differences within the VICTORIA population were assessed and compared with PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and COMMANDER HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure). VICTORIA patients had increased risk of mortality and rehospitalization: New York Heart Association class (40% class III), atrial fibrillation (45%), diabetes (47%), hypertension (79%) and mean estimated glomerular filtration rate of 61.5 mL/min/1.73 m2 . Baseline standard of HF care was very good: 60% received triple therapy. Their N-terminal pro-B-type natriuretic peptide was 3377 pg/mL [interquartile range (IQR) 1992-6380]. Natriuretic peptides were 30% higher level in the 67% patients with HF hospitalization

Background Randomized controlled trials (RCT) often enroll patients with different demographics and outcomes than a broader non-RCT population. To provide context for the VICTORIA RCT, we designed a registry of patients with worsening heart failure (WHF) to characterize baseline characteristics, outcomes, and potential reasons for non-participation in a RCT. Methods 51 VICTORIA RCT sites were selected from Canada and the US. Eligible patients for the registry included those with chronic HF, currently or recently hospitalized for HF, and EF Results 2056 patients were enrolled in the registry, of whom 61% (n = 1256) were not eligible for the RCT, 37% (n = 766) were eligible but not enrolled, and 2% (n = 34) were enrolled in the RCT. Registry patients had a median age of 70, 33% were women, 63% were white, 48% had atrial fibrillation on ECG, and 59% had CAD. Median EF was 25%, median eGFR was 50 ml/min/1.73m2 and median NT-proBNP at discharge was 4376 pg/ml. The median MAGGIC risk score was 28 (23-32) indicating a 20.9% (13.4-29.2%) predicted 1-year mortality, similar to the all-cause mortality seen in the VICTORIA RCT (21.2%). Reasons for ineligibility in the RCT included long-acting nitrate use (23%), SBP Fig ). For eligible patients, reasons for non-participation in the RCT included lack of interest (28%), poor compliance (25%), inability to complete follow-up (23%), too sick (19%), unable to provide consent (17%), and distance from site (15%). Conclusions Patients with WHF in a contemporaneous registry exhibit high-risk features with many having modifiable reasons for exclusion from an RCT. Several reasons for non-participation in an RCT indicate opportunities for improving enrollment to ensure generalizability.

In December 2008, the US Food and Drug Administration (FDA) issued a guidance for industry requiring sponsors to demonstrate that a new antidiabetic therapy being developed to treat type 2 diabetes does not increase cardiovascular (CV) risk to an unacceptable extent. CV events reported during phase 2 and phase 3 trials should be prospectively and independently adjudicated. Before submission of a new drug application or biologics license application, sponsors should compare the incidence of major CV events occurring with the investigational agent versus the control group to show that the upper bound of the 2-sided 95% confidence interval (CI) for the estimated risk ratio is less than 1.8. If the CI includes 1.3, a postmarketing trial will be necessary to definitively show that the upper bound of the 95% CI for the estimated risk ratio is then less than 1.3. In 2012, the European Medicines Agency (EMA) issued an updated guideline on the clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus that detailed its CV safety assessment requirements. Although similar to the FDA guidance, the EMA guideline does not prospectively define any pre- or postapproval risk margins. This expert perspective, prepared by members of the Cardiac Safety Research Consortium, discusses clinical development strategies, operational issues, and statistical methodological issues to satisfy the FDA's CV safety requirements, and, where appropriate, the EMA guideline. Actual case examples, where applicable, are presented.

This trial sought to evaluate whether vericiguat, a novel oral soluble guanylate cyclase (sGC) stimulator, was superior to placebo, on a background of standard of care, in increasing the time to the first occurrence of the composite endpoints of cardiovascular (CV) death and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction (HFrEF). Deficiency in sGC-derived cyclic guanosine monophosphate (cGMP) causes both myocardial dysfunction and impaired endothelium-dependent vasomotor regulation that includes the myocardial microcirculation. Experimental studies have suggested multiple potential benefits of sGC stimulators including prevention, or even reversal, of left ventricular hypertrophy and fibrosis, as well as reduction of ventricular afterload through both systemic and pulmonary vasodilation. Hence, restoration of sufficient nitric oxide (NO)-sGC-cGMP signaling has been proposed as an important treatment target in HF. Vericiguat has been shown to directly stimulate sGC and enhance sGC sensitivity to endogenous NO. Available phase IIb data in HFrEF patients indicate vericiguat is safe and well-tolerated, and exploratory analyses indicate that it results in a dose-dependent, clinically significant reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at the highest tested dose. VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) is a randomized, placebo-controlled, parallel group, multicenter, double-blind, event-driven phase 3 trial of vericiguat in subjects with HFrEF. Approximately 4,872 subjects will be randomized to evaluate the efficacy and safety of vericiguat compared with placebo on a background of standard of care. After a screening phase of up to 30 days, eligible subjects will be treated until the required number of cardiovascular deaths is observed. The estimated median follow-up duration is approximately 18 months. All subjects will be followed until study completion to assess for the occurrence of endpoint events. VICTORIA will establish the efficacy and safety of vericiguat on cardiovascular death and HF hospitalization in patients with HFrEF. (A Randomized Parallel-Group, Placebo-Controlled, Double-Blind, Event-Driven, Multi-Center Pivotal Phase III Clinical Outcome Trial of Efficacy and Safety of the Oral sGC Stimulator Vericiguat in Subjects With Heart Failure With Reduced Ejection Fraction [HFrEF]-VerICiguaT Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534).

Endpoint selection is a critically important step in clinical trial design. It poses major challenges for investigators, regulators, and study sponsors, and it also has important clinical and practical implications for physicians and patients. Clinical outcomes of interest in heart failure trials include all-cause mortality, cause-specific mortality, relevant non-fatal morbidity (e.g., all-cause and cause-specific hospitalization), composites capturing both morbidity and mortality, safety, symptoms, functional capacity, and patient-reported outcomes. Each of these endpoints has strengths and weaknesses that create controversies regarding which is most appropriate in terms of clinical importance, sensitivity, reliability, and consistency. Not surprisingly, a lack of consensus exists within the scientific community regarding the optimal endpoint(s) for both acute and chronic heart failure trials. In an effort to address these issues, the Heart Failure Association of the European Society of Cardiology (HFA-ESC) convened a group of expert heart failure clinical investigators, biostatisticians, regulators, and pharmaceutical industry scientists (Nice, France, 12-13 February 2012) to evaluate the challenges of defining heart failure endpoints in clinical trials and to develop a consensus framework. This report summarizes the group's recommendations for achieving common views on heart failure endpoints in clinical trials.

The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue on the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17, 2016, represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions.

Importance Previous trial results have suggested that dipeptidyl peptidase 4 inhibitor (DPP4i) use might increase heart failure (HF) risk in type 2 diabetes mellitus (T2DM). The DPP4i sitagliptin has been shown to be noninferior to placebo with regard to primary and secondary composite atherosclerotic cardiovascular (CV) outcomes in the Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS). Objective To assess the association of sitagliptin use with hospitalization for HF (hHF) and related outcomes. Design, Setting, and Participants TECOS was a randomized, double-blind, placebo-controlled study evaluating the CV safety of sitagliptin vs placebo, each added to usual antihyperglycemic therapy and CV care among patients with T2DM and prevalent atherosclerotic vascular disease. The median follow-up was 2.9 years. The setting was 673 sites in 38 countries. Participants included 14 671 patients with T2DM and atherosclerotic vascular disease. The study dates were December 2008 through March 2015. Interventions Patients were randomized to sitagliptin vs placebo added to standard care. Main Outcomes and Measures Prespecified secondary analyses compared the effect on hHF, hHF or CV death, and hHF or all-cause death composite outcomes overall and in prespecified subgroups. Supportive analyses included total hHF events (first plus recurrent) and post-hHF death. Meta-analyses evaluated DPP4i effects on hHF and on hHF or CV death. Results Of 14 671 patients, 7332 were randomized to sitagliptin and 7339 to placebo. Hospitalization for HF occurred in 3.1% (n = 228) and 3.1% (n = 229) of the sitagliptin and placebo groups, respectively (unadjusted hazard ratio, 1.00; 95% CI, 0.83-1.19). There was also no difference in total hHF events between the sitagliptin (n = 345) and placebo (n = 347) groups (unadjusted hazard ratio, 1.00; 95% CI, 0.80-1.25). Post-hHF all-cause death was similar in the sitagliptin and placebo groups (29.8% vs 28.8%, respectively), as was CV death (22.4% vs 23.1%, respectively). No heterogeneity for the effect of sitagliptin on hHF was observed in subgroup analyses across 21 factors ( P > .10 for all interactions). Meta-analysis of the hHF results from the 3 reported DPP4i CV outcomes trials revealed moderate heterogeneity ( I2 = 44.9, P = .16). Conclusions and Relevance Sitagliptin use does not affect the risk for hHF in T2DM, both overall and among high-risk patient subgroups. Trial Registration clinicaltrials.gov Identifier:NCT00790205

Objectives The purpose of this study was to use intravascular ultrasound (IVUS) to investigate chronic arterial responses at the site of and adjacent to overlapping paclitaxel-eluting TAXUS stents (PES) compared with overlapping bare-metal stents (BMS). Background Increased paclitaxel dose in the PES-overlap region might be associated with arterial toxicity expressed as excessive expansive remodeling, incomplete stent apposition, or aneurysm formation. Methods In the TAXUS-V and -VI trials, 51 patients with overlapping stents (27 PES and 24 BMS) were imaged with serial IVUS immediately after procedure and at 9 months. The IVUS measurements included intimal hyperplasia (IH), peri-stent plaque plus media (PaM), and external elastic membrane (EEM) areas. Vascular responses were assessed at the proximal and distal single stent strut regions and the central overlap region. Results Compared with BMS, all 3 PES stent regions showed: 1) significantly decreased IH (proximal: 0.97 ± 1.06 mm2 vs. 3.12 ± 2.40 mm2, overlap: 0.74 ± 0.91 mm2 vs. 3.23 ± 1.75 mm2, distal: 0.88 ± 0.85 mm2 vs. 2.69 ± 1.49 mm2, all p l 0.05); and 2) increased PaM and EEM areas (Delta PaM; proximal: 0.96 ± 1.36 mm2 vs. −0.02 ± 1.48 mm2, overlap: 1.56 ± 1.88 mm2 vs. 0.29 ± 1.82 mm2, distal: 1.03 ± 1.81 mm2 vs. 0.11 ± 0.89 mm2, all p l 0.05). The IH and changes in EEM and PaM areas were not significantly different in both the BMS and PES groups comparing the single stent strut and overlap regions. Incomplete stent apposition did not occur at the site of overlapping PES in any patient. Conclusions Nine months after stent implantation, neointimal tissue growth was reduced and expansive remodeling was greater with PES compared with BMS—effects that were not exaggerated at the overlap region of PES.

Both quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) are currently used to assess in-stent restenosis. This study aimed to use standardized imaging and clinical follow-up to compare QCA parameters with several IVUS parameters to evaluate their strengths and weaknesses for detecting in-stent restenosis in a drug-eluting stent population. A subset of patients from the TAXUS IV, V, and VI studies was evaluated. The subset, which included 216 TAXUS-treated patients and 191 bare-metal stent-treated patients, had complete IVUS and QCA performed at baseline and follow-up. As expected, all QCA and IVUS parameters were consistent with less intimal hyperplasia in TAXUS patients than controls. The overall incidence of QCA binary restenosis was 14.0%, which was 9.3% in TAXUS-treated patients and 19% in bare-metal stent-treated patients (p = 0.0008). Regression analysis showed that QCA late lumen loss and percentage of diameter stenosis correlated only moderately with the various IVUS measures of neointimal hyperplasia for the combined group of patients (TAXUS + bare-metal stent), as well as for the TAXUS-treated and bare-metal stent-treated patients separately. However, in general, correlations within the control (bare-metal stent) group tended to be stronger than within the TAXUS group. The strongest correlation was between QCA percentage of diameter stenosis and IVUS percentage of intimal hyperplasia in the overall group and the control group. The strongest IVUS predictor of QCA binary restenosis at 9 months was maximum percentage of intimal hyperplasia, with an overall C = 0.91 and p

Aims The TAXUS® Express® stent has been shown to reduce angiographic restenosis, repeat revascularizations, and neointimal hyperplasia when compared with bare metal stent (BMS) control (TAXUS IV, V, and VI) in individual TAXUS trials. Since intravascular ultrasound (IVUS) methodology and core laboratory were consistent among all three TAXUS trials, an integrated analysis of 956 patients across all IVUS cohorts can be performed providing superior power. Methods and results In the TAXUS randomized trials, patients received an Express BMS or paclitaxel-eluting TAXUS Express stent. Volumetric analysis was performed on a selected subgroup at implantation and 9 months. Compared with BMS control, TAXUS increased 9-month lumen volumes (144 ± 79 vs. 179 ± 95 mm3; P < 0.0001) due to reduced neointimal volume (66 ± 49 vs. 27 ± 30 mm3; P < 0.0001). This corresponded to a 61% decrease in net lumen volume obstruction (31 ± 15 vs. 12 ± 12 mm3; P < 0.0001). Lumen loss was similar between groups for the proximal 5 mm outside the stent but was reduced in TAXUS at the distal edge ( P = 0.0056). Neointimal hyperplasia was significantly reduced in the double-strut region of overlapping TAXUS vs. BMS control and in high-risk patients with diabetes, long lesions, multiple stents, and multiple overlapping stents. Late-acquired incomplete stent apposition (ISA) was more common with moderate-release TAXUS stents. Importantly, there were no major adverse cardiac events or stent thromboses in any late-acquired ISA patient through 2 years. Univariate and multivariable analyses revealed that longer lesion length and previous myocardial infarction are risk factors for late-acquired ISA. Conclusion Integrated analysis of the TAXUS trials shows that the paclitaxel-eluting TAXUS Express stent effectively inhibits in-stent neointimal proliferation, even in high-risk and overlapping stent patients.

Polymer-Based, Paclitaxel-Eluting TAXUS Liberte Stent in De Novo Lesions: The Pivotal TAXUS ATLAS TrialMark A. Turco, John A. Ormiston, Jeffrey J. Popma, Lazar Mandinov, Charles D. O’Shaughnessy, T...

Objectives This study sought to study stent thrombosis with the paclitaxel-eluting Taxus stent. Background The incidence and timing of stent thrombosis after drug-eluting stent placement compared with bare-metal stent implantation remain unsettled, with consequent uncertainty about risk stratification and long-term recommendations for antiplatelet medications. Methods This study used a patient-based meta-analysis using the 4 principal TAXUS randomized trials (3,445 patients) with a follow-up duration of ≥1 year. Results Cumulative stent thrombosis occurred in 1.28% ± 0.31% in the Taxus group and 0.76% ± 0.23% in the bare-metal stent group at 3 years (hazard ratio 1.51 [95% confidence interval 0.73 to 3.14], p = 0.26). Hazard ratios (per 100 patients per 6 months) were similar between the Taxus stent group (0.59 [95% confidence interval 0.22 to 0.95]) and the bare-metal stent group (0.64 [95% confidence interval 0.26 to 1.02]) through 6 months during the prescribed clopidogrel period. However, from 6 months to 3 years there were more stent thromboses in the Taxus group (hazard ratio 0.19 [95% confidence interval 0.06 to 0.32] vs. 0.02 [95% confidence interval 0.00 to 0.07], p = 0.049). Of 8 patients with Taxus-related thrombosis after 6 months, 0 were taking clopidogrel and 2 were not taking aspirin consistently. No Taxus-related stent thrombosis occurred after 2 years (922 patients thus far followed up for 3 years). Independent correlates of stent thrombosis were nonuse of clopidogrel, male gender, smoking, and possibly use of multiple nonoverlapping stents. Conclusions Approximately 0.8% of Taxus patients have stent thrombosis in the first 6 months after stent implantation, similar to bare-metal stents. However, a modest increase in risk is present with Taxus stents beyond 6 months, possibly because of inadequate antiplatelet drug therapy.

Late loss has been used as a reliable surrogate end point for evaluation and differentiation of short-term performance of drug-eluting stents. This study investigated the consistency between angiographic and intravascular ultrasound (IVUS) outcomes of late lumen loss (late loss) and neointimal growth to measure restenotic plaque load in TAXUS and bare metal stents. The randomized TAXUS II trial evaluates the polymer-based paclitaxel-eluting TAXUS stent in slow- and moderate-release formulations. Serial angiographic and IVUS analyses were available in 155 event-free patients (bare metal stent, 74; TAXUS stent, 81) after the procedure, at 6 months, and at 2 years. For this subanalysis, quantitative coronary angiographic (QCA) and IVUS measurements were used to derive late loss and neointimal volume. From after the procedure to 6 months, quantitative coronary angiography and IVUS showed matching results for the 2 groups with significant decreases in late loss and neointimal volume in the TAXUS versus the control group. From 6 months to 2 years, QCA and IVUS measurements also showed results similar to those in the control group, demonstrating neointimal compaction over time. However, in the TAXUS group, QCA late loss showed a nonsignificant decrease from 6 months to 2 years, whereas IVUS neointimal volume increased. In conclusion, although QCA and IVUS results were similar over the first 6 months, long-term assessment of changes in restenotic plaque load showed discrepant findings for the TAXUS. These findings suggest the need for critical reevaluation of current end points and the use of more precise techniques to detect lumen and stent boundaries.

Background— Intracoronary polymer-based stent delivery of paclitaxel has been shown to be effective in reducing restenosis in simple coronary lesions, but the evidence base for contemporary use in longer, more complex coronary stenoses is lacking. Methods and Results— TAXUS VI is a prospective, multicenter, double-blind, randomized trial assessing clinical and angiographic outcomes of the TAXUS Moderate Release paclitaxel-eluting stent in the treatment of long, complex coronary artery lesions. Four hundred forty-eight patients at 44 sites were randomized (1:1) between a drug-eluting TAXUS Express 2 and an uncoated Express 2 control stent. Per protocol, the 9-month follow-up included an angiographic reevaluation in all patients. The primary end point was the rate of target-vessel revascularization 9 months after the study procedure; secondary end points included the rate of target-lesion revascularization and binary restenosis at follow-up. Mean lesion length in the study was 20.6 mm, with a mean stent-covered length of 33.4 mm. Of all lesions, 55.6% were classified as complex lesions (type C of the AHA/ACC classification). At 9 months, target-vessel revascularization was 9.1% in the TAXUS group and 19.4% in the control group ( P =0.0027; relative reduction, 53%). Target-lesion revascularization was reduced from 18.9% to 6.8%, respectively ( P =0.0001). The incidence of major adverse cardiac events was similar in the 2 groups, 16.4% and 22.5% in TAXUS and control, respectively ( P =0.12), including comparable rates for acute myocardial infarction. Binary restenosis in the stented area was reduced from 32.9% in the control group to 9.1% in the TAXUS patients ( P Conclusions— The finding that the TAXUS Moderate Release stent system is safe and effective in the treatment of long, complex coronary artery lesions provides the evidence base for the more widespread use of drug-eluting stents in contemporary clinical practice.

We sought to assess the importance of Th1 cells for the development of cardiac allograft vasculopathy.Despite improvements in immunosuppressive regimens, chronic rejection still represents one of the leading causes of death beyond the first year after heart transplantation. Chronic rejection is characterized by the development of transplant vasculopathy. The exact mechanisms initiating and promoting this form of arteriosclerosis in the human setting remain unclear.In order to assess the role of T lymphocytes we characterized differentiated T-cell subsets in 32 transplant recipients early after transplantation using RT-PCR, flow cytometry and immunhistochemistry and matched these findings with endothelial function testing as an early clinical indicator of transplant vasculopathy.Allograft endothelial dysfunction (ED) was defined as a compromised coronary flow reserve to acetylcholine (CFVR2 in 8 of 32 transplant recipients). In these patients, mRNA transcript levels for the T-helper (Th)1 signature cytokines interferon (INF)-gamma (p0.0001) and interleukin (IL)-2 (p0.005) and STAT4 (Th1 transcription factor, p0,05) were significantly higher than in the remaining 24 patients with normal endothelial function. This correlated with a significant increase in circulating CD3(+)/IFN-gamma(+)-T-cells (28.6 +/- 4.4% vs 8.7 +/- 5.6%; p0.0001). In contrast, transcript levels for the Th2 signature cytokines (IL-4, IL-10) and STAT6 (Th2 transcription factor) did not differ significantly between the two groups.Peripheral expansion of circulating Th1 but not Th2 cells predicts coronary ED after cardiac transplantation. Therefore, quantification of circulating T cells might be a diagnostic tool to predict development of ED in patients after heart transplantation.

Background— Atherosclerosis is an inflammatory disease in which monocytes and macrophages have been suggested to play an essential role. The underlying signaling mechanisms are unknown thus far. We hypothesized that the human isoform of Toll-like receptor (hTLR)-4 is involved in monocyte activation of patients with accelerated forms of atherosclerosis. Methods and Results— Expression of hTLR4 on circulating monocytes from 30 controls, 20 patients with stable angina (SA), 40 patients with unstable angina (UA), and 28 patients with acute myocardial infarction (AMI) was compared with the use of flow-cytometry and reverse transcription–polymerase chain reaction. Regulation of interleukin (IL)-12 and B7-1 as downstream events of TLR4 activation was analyzed after lipopolysaccharide stimulation of monocytes. TLR4-transfected Chinese hamster ovary (CHO) cells were used to identify potential hTLR4 ligands in the serum of patients with UA or AMI. Circulating hTLR4 + /CD14 + monocytes were ≈2.5-fold increased above controls and patients with SA in the UA and AMI groups ( P P P P P Conclusions— UA and AMI are associated with enhanced expression and signaling events downstream of hTLR4 in circulating monocytes. These observations suggest hTLR4 activation as a signaling mechanism in immune-mediated progression of atherosclerosis.

Objectives We sought to evaluate the relationship between angiographic late loss and clinical outcomes in the drug-eluting stent era. Background The interrelationship between angiographic late loss, binary restenosis, and clinical recurrence (target lesion revascularization [TLR]) after coronary stent implantation has been incompletely evaluated. Methods Using the angiographic substudy of the TAXUS-IV trial, in which 1,314 patients with de novo coronary lesions were randomized to either the paclitaxel-eluting TAXUS stent or to its bare-metal equivalent, we defined the relationship between in-stent and analysis segment late loss, the shape of the late loss histogram (variance and skewedness), and nine-month TLR. Results Late loss by several measures was closely related to TLR (area under the receiver-operator curve >0.90). For individual vessels of the size in this study (2.8 ± 0.5 mm), the likelihood of TLR did not exceed 5% until analysis segment late loss was >0.5 mm, and did not exceed 10% until late loss was >0.65 mm. At greater late losses, the late loss TLR relationship was steep and nearly linear. For the overall patient cohort, the rate of TLR was related, however, not only to median late loss, but also to measures of its statistical distribution (TLR increased with lack of homogeneous biologic response [greater variance and greater right skewedness]). Similar relationships held for late loss measured within the confines of the stent itself. Conclusions Coronary stents result in large lumens with “room” to accommodate up to ∼0.5 to 0.65 mm of tissue (angiographic analysis segment late loss) before the likelihood of clinical restenosis (TLR) exceeds 5% to 10%. These data have important implications toward understanding the absolute and relative efficacy of drug-eluting stents.

Objectives The aim of this study was to use serial volumetric intravascular ultrasound (IVUS) to evaluate the effects of polymer-based, paclitaxel-eluting stents on in-stent neointima formation and late incomplete stent apposition. Background The TAXUS-IV trial demonstrated that the slow-release, polymer-based, paclitaxel-eluting stent reduces angiographic restenosis and the need for repeat revascularization procedures. Serial IVUS studies reveal details of the pattern of vascular responses provoked by stent implantation that provide insight into device safety and efficacy. Methods In the TAXUS-IV trial, patients were randomized to the slow-release, polymer-based, paclitaxel-eluting TAXUS stent or a bare-metal EXPRESS stent (Boston Scientific Corp., Natick, Massachusetts). As part of a formal substudy, complete volumetric IVUS data were available in 170 patients, including 88 TAXUS patients and 82 controls, at implantation and at nine-month follow-up. Results No baseline differences were present in the clinical characteristics or IVUS parameters between the control and TAXUS groups. At nine-month follow-up, IVUS lumen volumes were larger in the TAXUS group (123 ± 43 mm3vs. 104 ± 44 mm3, p = 0.005), due to a reduction in neointimal volume (18 ± 18 mm3vs. 41 ± 23 mm3, p Conclusions Polymer-based, paclitaxel-eluting TAXUS stents are effective in inhibiting neointimal tissue proliferation, and do not result in late incomplete stent apposition.

Background— The purpose of this study was to evaluate long-term vascular responses as long as 2 years after implantation of polymer-based, paclitaxel-eluting stents in contrast to uncoated stents. Methods and Results— TAXUS II is a randomized, double-blind trial comparing slow-release (SR) and moderate-release (MR) TAXUS stents with bare-metal control stents (BMSs). One hundred sixty-one event-free patients (SR, 43; MR, 41; and BMS, 77) underwent serial intravascular ultrasound (IVUS) analysis after the procedure and at 6 months and 2 years. At 2 years, neointimal responses continued to be significantly suppressed in the SR and MR groups when compared with the BMS group (BMS, 1.49±1.12 mm 2 ; SR, 0.94±0.76 mm 2 [ P =0.004]; and MR, 1.06±0.90 mm 2 [ P =0.02]). Between 6 months and 2 years, the BMS group showed compaction of the neointima (Δ, −0.22±1.05 mm 2 [ P =0.08]). In contrast, both the SR and MR groups exhibited an increase (Δ SR, 0.30±0.76 mm 2 ( P =0.01); MR, 0.41±0.94 mm 2 [ P =0.009]). Between 6 months and 2 years, the initial increase in plaque outside the stent regressed in the BMS and SR groups to levels comparable to those after the procedure, whereas expansive remodeling partially regressed in the MR group (Δ between after the procedure and 2 years BMS, −0.34±1.28 mm 2 [ P =0.05]; SR, −0.02±1.40 mm 2 [ P =0.93]; MR, 0.32±1.56 mm 2 [ P =0.27]). Conclusions— The 2-year follow-up demonstrates that neointimal suppression was dose independent and that this effect was still sustained at 2 years. However, the increase in area outside the stent seen at 6 months regressed to different extents in a dose-dependent manner at 2 years.

Background In patients with dilated cardiomyopathy (DCM), the heart enlarges, leading to a corresponding increase in ventricular wall stress. To reduce the stress, transventricular tension members (Myosplint, Myocor, Inc.) were implanted to change the left ventricle (LV) effective radius and to reduce the LV wall stress by 20%. We conducted this study to evaluate the intra- and peri-operative safety and feasibility of LV–shape change therapy. Methods In 7 patients, all diagnosed with DCM, Myosplints were implanted. New York Heart Association class ranged from III–IV, and LV end-diastolic diameter ranged from 70 to 102 mm. Mitral valve regurgitation was classified as mild in 3 and moderate in 4 cases. Four patients underwent mitral valve annuloplasty. Results We observed no significant device-related complications, such as thromboembolism, bleeding, device instability, or vascular damage, at 90 days. Early indications in a small patient population demonstrate some improvements in clinical parameters. Conclusions From this initial experience, one may conclude that placement of the Myosplint devices can be safely performed without early, significant adverse events. In patients with significant mitral valve incompetence, concomitant mitral valve repair is indicated to realize the full benefit of the procedure. This study also suggests that Myosplints can be safely implanted in combination with mitral valve repair. The long-term effect of each procedure on cardiac function and survival will require further evaluation.

Contains fulltext : 119127.pdf (Publisher’s version ) (Closed access) Thrombotic events (coronary thrombosis, venous thromboembolism, intraventricular thrombosis, intracranial and systemic thromboembolism) occur frequently in patients with heart failure. These events may be precipitated by several mechanisms including hypercoagulability through enhancement of procoagulant reactions, impairment of the protein C pathway, protease activated receptor (PAR) activation, adenosine-mediated thrombosis, or neurohormonal activation; stasis secondary to low cardiac output; and endothelial dysfunction from neurohormonal activation or systemic inflammation. Pathophysiologic evidence and analyses of retrospective data support the hypothesis that antithrombotic agents may improve outcomes in patients with heart failure. Warfarin has not been shown to reduce clinical events in patients with heart failure, although several of the completed randomized trials were underpowered, and the most recent was not placebo-controlled. Many unanswered questions remain that justify continued research in this area. This paper examines the conceptual framework, opportunities, and challenges of clinical investigative approaches with the newer anti-thrombotic agents in patients with heart failure. Critical questions are raised with regard to clinical trial designs that warrant consideration as the field progresses.

Background— Until recently, patients with heterozygous familial hypercholesterolemia (HeFH) were considered the best subjects for the assessment of changes in carotid intima-media thickness (cIMT) in randomized intervention trials. Our aims were to investigate whether contemporary statin-treated HeFH patients still show accelerated cIMT increase and to assess the impact of statin treatment, before and after random assignment, on atherosclerosis progression. Methods and Results— We retrospectively evaluated cIMT change, and prior statin treatment and postbaseline LDL-C change as predictors of cIMT change, in 1513 HeFH patients who were randomly assigned to the statin arms of the early ASAP and more recent RADIANCE 1, CAPTIVATE, and ENHANCE studies. In the 3 recent studies combined, mean cIMT increased at only 33%of the rate of the simvastatin-treated patients in the ASAP study (0.014 mm/2 years [95% confidence interval, −0.0003–0.028] versus 0.041 mm/2 years [95% confidence interval, 0.020–0.061]; P Conclusions— Over the years, intensification of statin therapy in HeFH patients has resulted in an impressive decrease in carotid atherosclerosis progression. In studies that assess other antiatherosclerotic modalities, statin therapy may still induce rapid changes in cIMT. For future cIMT studies, our analyses suggest that patient populations other than intensively pretreated HeFH patients should be selected and that the statin regimen should not be changed on study initiation.

The TAXUS(R) database was used to perform an integrated analysis across several large phase II and III trials to assess outcomes of polymer-based paclitaxel-eluting TAXUS stents in diabetic patients.While drug-eluting stents have reduced the risk for restenosis, diabetic patients remain at higher risk.This post hoc analysis of clinical and angiographic outcomes combined individual patient data from four randomized, multicentre, controlled clinical trials (TAXUS II, IV, V, and VI) representing outcomes across two paclitaxel release formulations and stent platforms.Breslow-Day analysis indicated homogeneous odds ratios across dose formulations and stent platforms, thus clinical data (9 months) were pooled from 3445 patients, including 814 diabetic patients. The randomized quantitative coronary angiography subset (n=2863) included 469 diabetic patients requiring oral medications only and 216 insulin-treated. Among patients receiving bare metal stents (BMS), those with diabetes had worse clinical and angiographic outcomes than non-diabetic patients. Target lesion revascularization rates were decreased in TAXUS patients relative to BMS controls by 59% (p=0.0001) among diabetic patients requiring oral medications, by 66% (p=0.006) among insulin-treated. Insulin-treated patients showed a significant TAXUS benefit for in-stent and in-segment percent diameter stenosis (p=0.0001, p=0.001, respectively) and late loss (p=0.001); a similar TAXUS benefit was seen in diabetic patients treated with oral medications (p0.0001). Binary restenosis in-segment was significantly decreased 65% in both diabetic subsets (p=0.0001).This post hoc analysis of data from four combined randomized TAXUS trials suggests the TAXUS benefit observed in non-diabetic patients is carried over into the high-risk diabetic population.

Objective Studies measuring progression of carotid artery intima-media thickness (cIMT) have been used to estimate the effect of lipid-modifying therapies cardiovascular event risk. The likelihood that future cIMT clinical trials will detect a true treatment effect is estimated by leveraging results from prior studies. The present analyses assess the impact of between- and within-study variability based on currently published data from prior clinical studies on the likelihood that ongoing or future cIMT trials will detect the true treatment effect of lipid-modifying therapies. Methods Published data from six contemporary cIMT studies (ASAP, ARBITER 2, RADIANCE 1, RADIANCE 2, ENHANCE, and METEOR) including data from a total of 3563 patients were examined. Bayesian and frequentist methods were used to assess the impact of between study variability on the likelihood of detecting true treatment effects on 1-year cIMT progression/regression and to provide a sample size estimate that would specifically compensate for the effect of between-study variability. Results In addition to the well-described within-study variability, there is considerable between-study variability associated with the measurement of annualized change in cIMT. Accounting for the additional between-study variability decreases the power for existing study designs. In order to account for the added between-study variability, it is likely that future cIMT studies would require a large increase in sample size in order to provide substantial probability (≥90%) to have 90% power of detecting a true treatment effect. Limitation Analyses are based on study level data. Future meta-analyses incorporating patient-level data would be useful for confirmation. Conclusion Due to substantial within- and between-study variability in the measure of 1-year change of cIMT, as well as uncertainty about progression rates in contemporary populations, future study designs evaluating the effect of new lipid-modifying therapies on atherosclerotic disease progression are likely to be challenged by large sample sizes in order to demonstrate a true treatment effect.

Aims This study sought to investigate the 2-year outcomes of patients treated with the paclitaxel-eluting TAXUS® stent (PES) or vascular brachytherapy (VBT), the previous ‘gold standard therapy’, for bare metal stent in-stent restenosis (ISR). Methods and results In the TAXUS V-ISR trial, 396 patients with bare metal stent ISR referred for percutaneous coronary intervention were prospectively randomized to either PES or beta source VBT. The present analysis reports 24-month clinical outcomes from that study. Between 9 and 24 months, ischaemia-driven target lesion revascularization tended to be required less frequently with assignment to PES compared to VBT (5.3 vs. 10.3%, P = .07). As a result, ischaemia-driven target lesion revascularization at 24 months was significantly reduced with PES compared with VBT (10.1 vs. 21.6%, P = 0.003), as was ischaemia-driven target vessel revascularization (18.1 vs. 27.5%, P = .03). There were no significant differences between the two groups with regard to death, myocardial infarction, or target vessel thrombosis either between 12 and 24 months, or cumulative to 24 months. Conclusion Freedom from clinical restenosis at 2 years is significantly enhanced after PES placement compared with VBT for bare metal stent ISR, with similar rates of death, myocardial infarction, and target vessel thrombosis.

Background A recent non-blinded, observational landmark study from uncontrolled registry data by Eisenstein et al. suggested that thienopyridine (T) use beyond 1 year may reduce death and MI in patients who have received drug-eluting stents (DES). We performed a similar examination of slow-release paclitaxel-eluting stents (PES) in the prospective, randomized, double-blind TAXUS DES trials. Methods Using data from the TAXUS II-SR, IV and V trials, a landmark analysis was performed on the 2,523 patients who were free of death, MI and stent thrombosis (ST) through 1 year. Patients were divided according to stent type (PES vs bare metal stent [BMS]) and thienopyridine usage at a 1-year landmark point: PES T+ (N=578), PES T− (N=683), BMS T+ (N=574), and BMS T− (N=688). Subsequent events (ST, death, MI) were tabulated for the next 3 years in TAXUS II-SR and IV, and for 1 year in TAXUS V. Results Thienopyridine and aspirin usage were well matched between BMS and PES patients at all time-points. T+ patients at 12 months had no ST events through 4 years, while T− patients had 6 ST events (0.57%; p=0.045, log-rank). This difference was not significant for BMS T+/T− (0.0% versus 0.22%, p=0.49), and borderline significant for PES T+/T− (0.0% versus 0.92%, p=0.056). There was no corresponding difference in death at either 2 or 4 years, but there was a borderline reduction in MI at 2 years for PES T+/T− (0.35% versus 1.49%, p=0.08; interaction term p=0.09 between stent type and thienopyridine use), which disappeared at 4 years (2.79% versus 3.42%, p=0.565; interaction term p=0.35). Conclusions Thienopyridine use at 1 year was associated with fewer subsequent late ST events overall, which was more pronounced for PES than BMS. While there was a borderline reduction in MI at 2 years, no sustained impact on death or MI at 4 years was demonstrated. These data will be updated with one additional year of follow-up in all 2,523 patients at the time of presentation.

Background : The TAXUS Liberté (TL) 38 mm stent, the longest drug-eluting stent, was designed with more uniform drug distribution, thinner struts and increased flexibility and conformability for use specifically in very long lesions. Long lesions have been identified as a risk factor for instent restenosis, stent thrombosis and incomplete apposition. Thus, TAXUS ATLAS Long Lesion (LL) assesses the performance of the TL 38 mm stent vs the TAXUS Express (TE) stent. Methods : TAXUS ATLAS LL is a prospective, non-randomized trial enrolling 150 pts from 24 global sites. Pts undergoing single TL stent implantation of a de novo lesion visually estimated to be 26 – 34 mm in length, with a reference vessel diameter of 2.7 – 4.0 mm, were enrolled. A subset of patients underwent IVUS at 9m. The TE Control consists of a lesion-matched cohort derived from TAXUS IV and TAXUS V. The primary endpoint is non-inferiority of 9m % diameter stenosis (%DS) of the analysis segment as determined by quanitative coronary angiography (QCA). Results : Baseline pt characteristics were well-matched between the TL and TE arms. However, the TL pts presented with longer and more complex lesions (by QCA). Procedure time was significantly shorter for TL, and the use of multiple stents was significantly less in TL vs TE. Compared to TE, TL demonstrated non-inferiority for 9m %DS, analysis segment (pre-specified non-inferiority margin = 6.89%, difference = −0.93%, upper 1-sided 95% Confidence Interval = 3.19%, p=0.0010); thus, the primary endpoint objective was met. The cardiac death or MI rate was significantly lower for TL, while other clinical and angiographic parameters were similar between the groups. There were no stent thromboses for TL. The incidence of early or late incomplete apposition was low and comparable between TL and TE. Conclusions : The TL 38 mm stent, the longest drug-eluting stent, demonstrated similar efficacy in reducing stenosis but an enhanced safety profile in very long lesions vs TE.

The purpose of this study was to use intravascular ultrasound (IVUS) to investigate chronic arterial responses at the site of and adjacent to overlapping paclitaxel-eluting TAXUS stents (PES) compared with overlapping bare-metal stents (BMS).Increased paclitaxel dose in the PES-overlap region might be associated with arterial toxicity expressed as excessive expansive remodeling, incomplete stent apposition, or aneurysm formation.In the TAXUS-V and -VI trials, 51 patients with overlapping stents (27 PES and 24 BMS) were imaged with serial IVUS immediately after procedure and at 9 months. The IVUS measurements included intimal hyperplasia (IH), peri-stent plaque plus media (PM), and external elastic membrane (EEM) areas. Vascular responses were assessed at the proximal and distal single stent strut regions and the central overlap region.Compared with BMS, all 3 PES stent regions showed: 1) significantly decreased IH (proximal: 0.97 +/- 1.06 mm(2) vs. 3.12 +/- 2.40 mm(2), overlap: 0.74 +/- 0.91 mm(2) vs. 3.23 +/- 1.75 mm(2), distal: 0.88 +/- 0.85 mm(2) vs. 2.69 +/- 1.49 mm(2), all p0.05); and 2) increased PM and EEM areas (Delta PM, proximal: 0.96 +/- 1.36 mm(2) vs. -0.02 +/- 1.48 mm(2), overlap: 1.56 +/- 1.88 mm(2) vs. 0.29 +/- 1.82 mm(2), distal: 1.03 +/- 1.81 mm(2) vs. 0.11 +/- 0.89 mm(2), all p0.05). The IH and changes in EEM and PM areas were not significantly different in both the BMS and PES groups comparing the single stent strut and overlap regions. Incomplete stent apposition did not occur at the site of overlapping PES in any patient.Nine months after stent implantation, neointimal tissue growth was reduced and expansive remodeling was greater with PES compared with BMS--effects that were not exaggerated at the overlap region of PES.

Aims: To provide insight on the patients with long lesions that received multiple, overlapping stents by reporting clinical outcomes, together with a detailed angiographic and intravascular ultrasound analysis of the overlap zone. Methods and results: TAXUS VI is a prospective, multicentre, double-blind, trial, specifically designed to assess outcomes of paclitaxel-eluting stents in longer lesions by randomising 446 patients (1:1) between a drug-eluting TAXUS™ Express 2 Moderate Release (MR) and an uncoated Express 2 control stent. Multiple overlapping stents were implanted in 124 patients (27.8%) and are the subject of this report. Clinical, angiographic and IVUS outcomes at nine months were compared in the overlap group for patients receiving the TAXUS™ Express 2 MR stent and the uncoated Express 2 stent. In the overlap group, mean lesion length was 25.1 mm with a mean stent length of 43.6 mm. At nine months, TVR was reduced by 94% from 25.0% to 1.6% in the TAXUS patients compared with control (p=

Background— Drug-eluting stents compared with bare metal stents (BMS) may increase late stent thrombosis (ST), although an accompanying increase in the rates of death and myocardial infarction (MI) has not been observed. We hypothesized that the prevention of restenosis-related adverse events by drug-eluting stents might offset some or all of the excess risk from ST. Methods and Results— We analyzed a pooled patient-level database from 4 prospective, double-blind trials in which 3445 patients were randomized to paclitaxel-eluting stents or BMS. The occurrence of death or MI within 7 days of ST or target lesion revascularization was assessed. With a median follow-up of 3.2 years, ST occurred in 34 patients (1.0%), 31 (91.1%) of whom sustained death or MI within 7 days. Target lesion revascularization was performed in 425 patients (12.3%), 15 (3.5%) of whom died or had MI within 7 days. ST occurred in 14 BMS and 20 paclitaxel-eluting stent patients, resulting in 12 and 19 deaths or MIs within 7 days, respectively. Target lesion revascularization was performed in 290 BMS and 135 paclitaxel-eluting stent patients, resulting in 11 and 4 deaths or MI events within 7 days, respectively. In total, 23 patients in both the BMS and paclitaxel-eluting stents groups died or had an MI event within 7 days of either ST or target lesion revascularization. Conclusions— ST, although infrequent, results in a high incident rate of death and MI, whereas the more frequent occurrence of target lesion revascularization is associated with a finite but lower rate of death and MI. The marked reduction in restenosis with drug-eluting stents compared with BMS may counterbalance the potential excess risk from late ST with drug-eluting stents.

The goal of this research was to assess non-inferiority of the next-generation TAXUS Liberté stent (Boston Scientific Corp., Natick, Massachusetts) versus the TAXUS Express stent (Boston Scientific Corp.).The introduction of drug-eluting stents (DES) has shifted clinical practice towards more complex lesion subsets, prompting the need for more deliverable DES. TAXUS Liberté was designed to combine the established polymer-based, paclitaxel-elution TAXUS technology with the more advanced Liberté stent platform.The TAXUS ATLAS study is a global, prospective, single-arm trial evaluating outcomes in de novo coronary lesions visually estimated to be 10 to 28 mm in length in vessels 2.5 to 4.0 mm in diameter. The control group is an entry-criteria-matched population of TAXUS Express patients from the TAXUS IV and V trials. The primary end point is non-inferiority of TAXUS Liberté versus TAXUS Express for 9-month target vessel revascularization.Despite similar inclusion criteria, quantitative coronary angiography-determined baseline lesion characteristics were significantly more complex for TAXUS Liberté than TAXUS Express. The primary non-inferiority end point was met with the 1-sided 95% confidence bound of 2.98% less than the pre-specified non-inferiority margin of 3% (p = 0.0487).Despite the treatment of more complex lesions with TAXUS Liberté, the primary end point was met, demonstrating that TAXUS Liberté is non-inferior to TAXUS Express. The successful transfer of the proven TAXUS technology to the more advanced TAXUS Liberté platform was demonstrated. (TAXUS ATLAS: TAXUS Liberté-SR Stent for the Treatment of De Novo Coronary Artery Lesions; http://www.clinicaltrials.gov/ct/show/NCT00371709?order=1; NCT00371709).

Restenosis remains a problem following percutaneous coronary intervention in patients with coronary artery disease. Drug-eluting stents (DES), which combine mechanical and pharmacologic properties, have been shown to prevent or reduce neointimal growth after deployment. This review describes the TAXUS paclitaxel-eluting stent clinical trial expansion program (TAXUS® Express®, Boston Scientific, Natick, MA). This program comprises the largest data set of randomized controlled trials (RCTs) of DES to date, with over 6,200 patients enrolled since 2000. The program includes treatment of de novo lesions, as well as higher-risk lesion and patient populations. In this review, we discuss the results from the TAXUS family of randomized clinical trials, and compare the findings with data from TAXUS registries. The data from the randomized clinical trials suggest that the paclitaxel-eluting stent provides consistent and durable benefits across multiple lesion and patient types. Evidence from peri-and postapproval registries, where patient populations are more heterogeneous than those eligible and included in the RCTs, corroborate these findings, with overall low rates of cardiac events, including reinterventions.

This study sought to study stent thrombosis with the paclitaxel-eluting Taxus stent.The incidence and timing of stent thrombosis after drug-eluting stent placement compared with bare-metal stent implantation remain unsettled, with consequent uncertainty about risk stratification and long-term recommendations for antiplatelet medications.This study used a patient-based meta-analysis using the 4 principal TAXUS randomized trials (3,445 patients) with a follow-up duration ofor =1 year.Cumulative stent thrombosis occurred in 1.28% +/- 0.31% in the Taxus group and 0.76% +/- 0.23% in the bare-metal stent group at 3 years (hazard ratio 1.51 [95% confidence interval 0.73 to 3.14], p = 0.26). Hazard ratios (per 100 patients per 6 months) were similar between the Taxus stent group (0.59 [95% confidence interval 0.22 to 0.95]) and the bare-metal stent group (0.64 [95% confidence interval 0.26 to 1.02]) through 6 months during the prescribed clopidogrel period. However, from 6 months to 3 years there were more stent thromboses in the Taxus group (hazard ratio 0.19 [95% confidence interval 0.06 to 0.32] vs. 0.02 [95% confidence interval 0.00 to 0.07], p = 0.049). Of 8 patients with Taxus-related thrombosis after 6 months, 0 were taking clopidogrel and 2 were not taking aspirin consistently. No Taxus-related stent thrombosis occurred after 2 years (922 patients thus far followed up for 3 years). Independent correlates of stent thrombosis were nonuse of clopidogrel, male gender, smoking, and possibly use of multiple nonoverlapping stents.Approximately 0.8% of Taxus patients have stent thrombosis in the first 6 months after stent implantation, similar to bare-metal stents. However, a modest increase in risk is present with Taxus stents beyond 6 months, possibly because of inadequate antiplatelet drug therapy.

Background Changes in the treatment of coronary artery disease both surgically and percutaneously have rendered the major randomized trials historical. Furthermore, the restrictive criteria of previous trials excluded most patients treated in daily practice. Although coronary surgery is still considered the current, evidence-based, gold-standard treatment of left main (LM) and 3-vessel coronary disease, the added benefit of drug-eluting stents has further expanded the use of percutaneous coronary intervention (PCI) beyond less complex populations in daily practice. Study Design The 1500-patient, prospective, multicenter, multinational (European and North American), randomized SYNTAX study with nested registries will enroll “all-comers.” Consecutive patients with de novo 3-vessel disease (3VD) and/or LM disease will be screened for eligibility by the Heart Team (composed of an interventionalist, a cardiac surgeon, and the study coordinator) at each site and then allocated to either (1) the randomized cohort, if comparable revascularization can be achieved by either PCI or coronary artery bypass surgery (CABG), or (2) to one of the nested registries for CABG-ineligible patients (PCI registry) or for PCI-ineligible patients (CABG registry). Randomized patients will be stratified based on LM disease and diabetes by site. The primary end point for the randomized comparison is noninferiority of major adverse cardiac and cerebral events between the 2 groups at 1 year. To adequately project the expected enrollment rate per site, a run-in phase was mandated for each site interested in participating in the trial. Both cardiothoracic and interventional cardiology departments within the same institution were asked to complete a questionnaire regarding their frequency of treatment of LM and 3VD over a retrospective 3-month period. Implications By replacing most traditional inclusion and exclusion criteria with the real-world decision between the cardiothoracic surgeon and the interventionalist, this study will define the roles of CABG and PCI using drug-eluting stents in the contemporary management of LM and 3VD. Results of the run-in phase were used by the steering committee to determine eligibility and to project enrollment for each site.

ContextCompared with bare metal stents, drug-eluting stents reduce restenosis in noncomplex lesions. The utility of drug-eluting stents has not been evaluated in more difficult stenoses.ObjectiveTo investigate the safety and efficacy of the polymer-based, slow-release paclitaxel-eluting stent in a patient population with more complex lesions than previously studied.Design, Setting, and PatientsProspective, placebo-controlled, double-blind, multicenter randomized trial conducted from February 2003 to March 2004 at 66 academic and community-based institutions with 1156 patients who underwent stent implantation in a single coronary artery stenosis (vessel diameter, 2.25-4.0 mm; lesion length, 10-46 mm), including 664 patients (57.4%) with complex or previously unstudied lesions (requiring 2.25-mm, 4.0-mm, and/or multiple stents) and 9-month clinical and angiographic follow-up.InterventionsPatients were randomly assigned to receive 1 or more bare metal stents (n = 579) or identical-appearing paclitaxel-eluting stents (n = 577).Main Outcome MeasureIschemia-driven target vessel revascularization at 9 months.ResultsBaseline characteristics were well matched. Diabetes was present in 31% of patients. The mean (SD) reference vessel diameter was 2.69 (0.57) mm, the reference lesion length was 17.2 (9.2) mm, and 78% of lesions were type B2/C. A mean (SD) of 1.38 (0.58) stents (total mean [SD] length, 28.4 [13.1] mm) were implanted per lesion; 33% of lesions required multiple stents. Stents that were 2.25 mm and 4.0 mm in diameter were used in 18% and 17% of lesions, respectively. Compared with bare metal stents, paclitaxel-eluting stents reduced the 9-month rate of target lesion revascularization from 15.7% to 8.6% (P

BACKGROUND Long-term success of cardiac transplantation is limited by various forms of graft rejection. The specific mechanisms initiating and controlling these highly specialized immune processes remain unclear so far. METHODS To investigate the role of innate immunity in the development of allograft rejection, we assessed toll-like receptor (TLR)4 expression and typical downstream effects of TLR signaling (B7-1, interleukin [IL]-12, tumor necrosis factor [TNF]-alpha) in circulating CD14+ monocytes in 38 transplant recipients 1 to 3 years and in 10 transplant recipients 6 to 10 years after transplantation and compared them with 20 healthy controls using reverse transcription polymerase chain reaction, flow cytometry, and enzyme-linked immunoadsorbent assay. The results were matched with endothelial function testing as an early clinical indicator of transplant vasculopathy early after transplantation. RESULTS Allograft endothelial dysfunction (ED) was defined as a compromised coronary flow reserve (CFVR) to acetylcholine (CFVR

We sought to determine whether different stages of coronary artery disease (CAD) are associated with distinct differentiation patterns of activated T cells.Atherosclerosis is an inflammatory disease. However, little is known about specific inflammatory cell activation in atherosclerosis, for example, the T-helper (Th)1/Th2-balance.We studied 18 patients with stable angina (SA), 28 patients with acute coronary syndrome (ACS) (16 with unstable angina pectoris and 12 with ST-segment elevation myocardial infarction), 19 patients with unheralded myocardial infarction (UH), and 16 control patients. Cytokine patterns and transcription factor signaling pathways of circulating T cells were characterized using reverse transcription polymerase chain reaction and flow cytometry.Although interferon (IFN)-gamma(+)/CD3(+) T cells were approximately 2-fold greater in patients with SA or UH than in control subjects, there was a massive expansion of Th1 cells in patients with ACS (p0.001). This increase was paralleled by significantly increased mRNA transcript levels for signal-transducer-and-activator-4 (ACS 1.17 +/- 0.14 relative units [RU]; control patients 0.44 +/- 0.09 RU; SA 0.67 +/- 0.12 RU; UH 0.61 +/- 0.17 RU), interleukin-2 (ACS 1.55 +/- 0.51 RU; control patients 0.21 +/- 0.09 RU; SA 0.54 +/- 0.18 RU; UH 0.45 +/- 0.16 RU), and IFN-gamma in ACS (1.27 +/- 0.39 RU; control patients 0.35 +/- 0.09 RU; SA 0.58 +/- 0.11 RU; UH 0.53 +/- 0.24 RU; p0.002). Th2 and Th0 cells were not different across patient subsets. The burden of CAD was identical between SA (1.4 +/- 0.2 diseased vessels, 68 +/- 13% diameter stenosis) and ACS (1.4 +/- 0.2 diseased vessels, 64 +/- 17% diameter stenosis) but significantly greater in patients with UH (2.5 +/- 0.5 diseased vessels, 95 +/- 7% diameter stenosis; p0.05).Patients with UH have a greater burden of obstructive CAD than SA but no greater T-cell activation. Patients with ACS have the same extent of CAD than SA but significantly greater activation of Th1 cells that may contribute to the increasing instability. Differences in circulating Th1 cells might indicate different pathogenic components, leading to ACS and UH.