James B. Hermiller

Transcatheter aortic-valve replacement with a self-expanding prosthesis.

BACKGROUND We compared transcatheter aortic-valve replacement (TAVR), using a self-expanding transcatheter aortic-valve bioprosthesis, with surgical aortic-valve replacement in patients with severe aortic stenosis and an increased risk of death during surgery. METHODS We recruited patients with severe aortic stenosis who were at increased surgical risk as determined by the heart team at each study center. Risk assessment included the Society of Thoracic Surgeons Predictor Risk of Mortality estimate and consideration of other key risk factors. Eligible patients were randomly assigned in a 1:1 ratio to TAVR with the self-expanding transcatheter valve (TAVR group) or to surgical aortic-valve replacement (surgical group). The primary end point was the rate of death from any cause at 1 year, evaluated with the use of both noninferiority and superiority testing. RESULTS A total of 795 patients underwent randomization at 45 centers in the United States. In the as-treated analysis, the rate of death from any cause at 1 year was significantly lower in the TAVR group than in the surgical group (14.2% vs. 19.1%), with an absolute reduction in risk of 4.9 percentage points (upper boundary of the 95% confidence interval, -0.4; P<0.001 for noninferiority; P = 0.04 for superiority). The results were similar in the intention-to-treat analysis. In a hierarchical testing procedure, TAVR was noninferior with respect to echocardiographic indexes of valve stenosis, functional status, and quality of life. Exploratory analyses suggested a reduction in the rate of major adverse cardiovascular and cerebrovascular events and no increase in the risk of stroke. CONCLUSIONS In patients with severe aortic stenosis who are at increased surgical risk, TAVR with a self-expanding transcatheter aortic-valve bioprosthesis was associated with a significantly higher rate of survival at 1 year than surgical aortic-valve replacement. (Funded by Medtronic; U.S. CoreValve High Risk Study ClinicalTrials.gov number, NCT01240902.).

A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study of Intravenous Adult Human Mesenchymal Stem Cells (Prochymal) After Acute Myocardial Infarction

OBJECTIVES Our aim was to investigate the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hMSCs) in patients with myocardial infarction (MI). BACKGROUND Bone marrow-derived hMSCs may ameliorate consequences of MI, and have the advantages of preparation ease, allogeneic use due to immunoprivilege, capacity to home to injured tissue, and extensive pre-clinical support. METHODS We performed a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n=53). The primary end point was incidence of treatment-emergent adverse events within 6 months. Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points. RESULTS Adverse event rates were similar between the hMSC-treated (5.3 per patient) and placebo-treated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes (p=0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 s (p=0.003) in the hMSC-treated patients. Global symptom score in all patients (p=0.027) and ejection fraction in the important subset of anterior MI patients were both significantly better in hMSCs versus placebo subjects. In the cardiac magnetic resonance imaging substudy, hMSC treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling. CONCLUSIONS Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. (Safety Study of Adult Mesenchymal Stem Cells [MSC] to Treat Acute Myocardial Infarction; NCT00114452).

Twelve or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents

BACKGROUND Dual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications, yet the benefits and risks of treatment beyond 1 year are uncertain. METHODS Patients were enrolled after they had undergone a coronary stent procedure in which a drug-eluting stent was placed. After 12 months of treatment with a thienopyridine drug (clopidogrel or prasugrel) and aspirin, patients were randomly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months; all patients continued receiving aspirin. The coprimary efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death, myocardial infarction, or stroke) during the period from 12 to 30 months. The primary safety end point was moderate or severe bleeding. RESULTS A total of 9961 patients were randomly assigned to continue thienopyridine treatment or to receive placebo. Continued treatment with thienopyridine, as compared with placebo, reduced the rates of stent thrombosis (0.4% vs. 1.4%; hazard ratio, 0.29 [95% confidence interval {CI}, 0.17 to 0.48]; P<0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%; hazard ratio, 0.71 [95% CI, 0.59 to 0.85]; P<0.001). The rate of myocardial infarction was lower with thienopyridine treatment than with placebo (2.1% vs. 4.1%; hazard ratio, 0.47; P<0.001). The rate of death from any cause was 2.0% in the group that continued thienopyridine therapy and 1.5% in the placebo group (hazard ratio, 1.36 [95% CI, 1.00 to 1.85]; P=0.05). The rate of moderate or severe bleeding was increased with continued thienopyridine treatment (2.5% vs. 1.6%, P=0.001). An elevated risk of stent thrombosis and myocardial infarction was observed in both groups during the 3 months after discontinuation of thienopyridine treatment. CONCLUSIONS Dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding. (Funded by a consortium of eight device and drug manufacturers and others; DAPT ClinicalTrials.gov number, NCT00977938.).

One-Year Clinical Results With the Slow-Release, Polymer-Based, Paclitaxel-Eluting TAXUS Stent: The TAXUS-IV Trial

Background—The safety and efficacy of the slow-release, polymer-based, paclitaxel-eluting stent after implantation in a broad cross section of de novo coronary lesions at 1 year are unknown. Methods and Results—In the TAXUS-IV trial, 1314 patients with single de novo coronary lesions 10 to 28 mm in length, with reference-vessel diameter 2.5 to 3.75 mm, coverable by a single study stent, were prospectively randomized to the slow-release, polymer-based, paclitaxel-eluting TAXUS stent or an identical-appearing bare-metal EXPRESS stent. By actuarial analysis, the TAXUS stent compared with the bare-metal stent reduced the 12-month rates of target-lesion revascularization by 73% (4.4% versus 15.1%, P <0.0001), target-vessel revascularization by 62% (7.1% versus 17.1%, P <0.0001), target-vessel failure by 52% (10.0% versus 19.4%, P <0.0001), and composite major adverse cardiac events by 49% (10.8% versus 20.0%, P <0.0001). The 1-year rates of cardiac death (1.4% versus 1.3%), myocardial infarction (3.5% versus 4.7%), and subacute thrombosis (0.6% versus 0.8%) were similar between the paclitaxel-eluting and control stents, respectively. Between 9 and 12 months, there were significantly fewer myocardial infarctions (0% versus 1.1%, P =0.007), target-vessel revascularizations (2.4% versus 5.8%, P =0.002), and major adverse cardiac events (2.4% versus 6.3%, P =0.0009) in the paclitaxel-eluting stent than in the control stent group, respectively. Conclusions—The relative efficacy reported at 9 months for the polymer-based, paclitaxel-eluting TAXUS stent compared with the EXPRESS stent is preserved and continues to increase at 1 year, with no safety concerns apparent.

Percutaneous Mitral Repair With the MitraClip System : Safety and Midterm Durability in the Initial EVEREST (Endovascular Valve Edge-to-Edge REpair Study) Cohort

OBJECTIVES We undertook a prospective multicenter single-arm study to evaluate the feasibility, safety, and efficacy of the MitraClip system (Evalve Inc., Menlo Park, California). BACKGROUND Mitral valve repair for mitral regurgitation (MR) has been performed by the use of a surgically created double orifice. Percutaneous repair based on this surgical approach has been developed by use of the Evalve MitraClip device to secure the mitral leaflets. METHODS Patients with 3 to 4+ MR were selected in accordance with the American Heart Association/American College of Cardiology guidelines for intervention and a core echocardiographic laboratory. RESULTS A total of 107 patients were treated. Ten (9%) had a major adverse event, including 1 nonprocedural death. Freedom from clip embolization was 100%. Partial clip detachment occurred in 10 (9%) patients. Overall, 79 of 107 (74%) patients achieved acute procedural success, and 51 (64%) were discharged with MR of < or =1+. Thirty-two patients (30%) had mitral valve surgery during the 3.2 years after clip procedures. When repair was planned, 84% (21 of 25) were successful. Thus, surgical options were preserved. A total of 50 of 76 (66%) successfully treated patients were free from death, mitral valve surgery, or MR >2+ at 12 months (primary efficacy end point). Kaplan-Meier freedom from death was 95.9%, 94.0%, and 90.1%, and Kaplan-Meier freedom from surgery was 88.5%, 83.2%, and 76.3% at 1, 2, and 3 years, respectively. The 23 patients with functional MR had similar acute results and durability. CONCLUSIONS Percutaneous repair with the MitraClip system can be accomplished with low rates of morbidity and mortality and with acute MR reduction to < 2+ in the majority of patients, and with sustained freedom from death, surgery, or recurrent MR in a substantial proportion (EVEREST I; NCT00209339. EVEREST II; NCT00209274).

Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery

OBJECTIVES This study sought to evaluate the safety and efficacy of the CoreValve transcatheter heart valve (THV) for the treatment of severe aortic stenosis in patients at extreme risk for surgery. BACKGROUND Untreated severe aortic stenosis is a progressive disease with a poor prognosis. Transcatheter aortic valve replacement (TAVR) with a self-expanding bioprosthesis is a potentially effective therapy. METHODS We performed a prospective, multicenter, nonrandomized investigation evaluating the safety and efficacy of self-expanding TAVR in patients with symptomatic severe aortic stenosis with prohibitive risks for surgery. The primary endpoint was a composite of all-cause mortality or major stroke at 12 months, which was compared with a pre-specified objective performance goal (OPG). RESULTS A total of 41 sites in the United States recruited 506 patients, of whom 489 underwent attempted treatment with the CoreValve THV. The rate of all-cause mortality or major stroke at 12 months was 26.0% (upper 2-sided 95% confidence bound: 29.9%) versus 43.0% with the OPG (p < 0.0001). Individual 30-day and 12-month events included all-cause mortality (8.4% and 24.3%, respectively) and major stroke (2.3% and 4.3%, respectively). Procedural events at 30 days included life-threatening/disabling bleeding (12.7%), major vascular complications (8.2%), and need for permanent pacemaker placement (21.6%). The frequency of moderate or severe paravalvular aortic regurgitation was lower 12 months after self-expanding TAVR (4.2%) than at discharge (10.7%; p = 0.004 for paired analysis). CONCLUSIONS TAVR with a self-expanding bioprosthesis was safe and effective in patients with symptomatic severe aortic stenosis at prohibitive risk for surgical valve replacement. (Safety and Efficacy Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902).

Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial

BACKGROUND Recombinant fibroblast growth factor-2 (rFGF-2) improves perfusion in models of myocardial and hindlimb ischaemia. We investigated whether one or two doses of intra-arterial rFGF-2 improves exercise capacity in patients with moderate-to-severe intermittent claudication. METHODS 190 patients with intermittent claudication caused by infra-inguinal atherosclerosis were randomly assigned (1:1:1) bilateral intra-arterial infusions of placebo on days 1 and 30 (n=63); rFGF-2 (30 microg/kg) on day 1 and placebo on day 30 (single-dose, n=66); or rFGF-2 (30 microg/kg) on days 1 and 30 (double-dose, n=61). Primary outcome was 90-day change in peak walking time. Secondary outcomes included ankle-brachial pressure index and safety. The main analysis was per protocol. FINDINGS Before 90 days, six patients had undergone peripheral revascularisation and were excluded, and ten withdrew or had missing data. 174 were therefore assessed for primary outcome. Peak walking time at 90 days was increased by 0.60 min with placebo, by 1.77 min with single-dose, and by 1.54 min with double-dose. By ANOVA, the difference between groups was p=0.075. In a secondary intention-to-treat analysis, in which all 190 patients were included, the difference was p=0.034. Pairwise comparison showed a significant difference between placebo and single-dose (p=0.026) but placebo and double-dose did not differ by much (p=0.45). Serious adverse events were similar in all groups. INTERPRETATION Intra-arterial rFGF-2 resulted in a significant increase in peak walking time at 90 days; repeat infusion at 30 days was no better than one infusion. The findings of TRAFFIC provide evidence of clinical therapeutic angiogenesis by intra-arterial infusion of an angiogenic protein.

Randomized Comparison of Distal Protection With a Filter-Based Catheter and a Balloon Occlusion and Aspiration System During Percutaneous Intervention of Diseased Saphenous Vein Aorto-Coronary Bypass Grafts

Background—The high rate of periprocedural complications resulting from atherothrombotic embolization after percutaneous intervention in diseased saphenous vein grafts is reduced by distal microcirculatory protection using a balloon occlusion and aspiration system. Whether filter-based catheters, which offer the inherent advantages of maintained perfusion and ease of use, are as effective for this purpose has not been established. Methods and Results—A total of 651 patients undergoing percutaneous intervention of 682 saphenous vein graft lesions were prospectively randomized to distal protection with the filter-based FilterWire EX versus the GuardWire balloon occlusion and aspiration system. Device success was 95.5% and 97.2% with the FilterWire EX and GuardWire, respectively (P =0.25). Postprocedural measures of epicardial flow and angiographic complications were similar between the 2 groups, although bailout IIb/IIIa inhibitors were required slightly less frequently in the FilterWire EX group (0% versus 1.5%, P =0.03). The primary end point, the composite incidence of death, myocardial infarction, or target vessel revascularization at 30 days, occurred in 9.9% of FilterWire EX patients and 11.6% of GuardWire patients (difference [95% CI]=−1.7% [−6.4%, 3.1%]; P for superiority=0.53, P for noninferiority=0.0008). Conclusions—Distal protection with the FilterWire EX may be safely used as an adjunct to percutaneous intervention of diseased saphenous vein grafts and, compared with distal protection with the GuardWire balloon occlusion and aspiration system, results in similar rates of major adverse cardiac events at 30 days.

Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study

BACKGROUND Dual antiplatelet therapy (DAPT) cessation increases the risk of adverse events after percutaneous coronary intervention (PCI). Whether risk changes over time, depends on the underlying reason for DAPT cessation, or both is unknown. We assessed associations between different modes of DAPT cessation and cardiovascular risk after PCI. METHODS The PARIS (patterns of non-adherence to anti-platelet regimens in stented patients) registry is a prospective observational study of patients undergoing PCI with stent implantation in 15 clinical sites in the USA and Europe between July 1, 2009, and Dec 2, 2010. Adult patients (aged 18 years or older) undergoing successful stent implantation in one or more native coronary artery and discharged on DAPT were eligible for enrolment. Patients were followed up at months 1, 6, 12, and 24 after implantation. Prespecified categories for DAPT cessation included physician-recommended discontinuation, brief interruption (for surgery), or disruption (non-compliance or because of bleeding). All adverse events and episodes of DAPT cessation were independently adjudicated. Using Cox models with time-varying covariates, we examined the effect of DAPT cessation on major adverse events (MACE [composite of cardiac death, definite or probable stent thrombosis, myocardial infarction, or target-lesion revascularisation]). Incidence rates for DAPT cessation and adverse events were calculated as Kaplan-Meier estimates of time to the first event. This study is registered with ClinicalTrials.gov, number NCT00998127. FINDINGS We enrolled 5031 patients undergoing PCI, including 5018 in the final study population. Over 2 years, the overall incidence of any DAPT cessation was 57·3%. Rate of any discontinuation was 40·8%, of interruption was 10·5%, and of disruption was 14·4%. The corresponding overall 2 year MACE rate was 11·5%, most of which (74%) occurred while patients were taking DAPT. Compared with those on DAPT, the adjusted hazard ratio (HR) for MACE due to interruption was 1·41 (95% CI 0·94-2·12; p=0·10) and to disruption was 1·50 (1·14-1.97; p=0·004). Within 7 days, 8-30 days, and more than 30 days after disruption, adjusted HRs were 7·04 (3·31-14·95), 2·17 (0·97-4·88), and 1·3 (0·97-1·76), respectively. By contrast with patients who remained on DAPT, those who discontinued had lower MACE risk (0·63 [0·46-0·86]). Results were similar after excluding patients receiving bare metal stents and using an alternative MACE definition that did not include target lesion revascularisation. INTERPRETATION In a real-world setting, for patients undergoing PCI and discharged on DAPT, cardiac events after DAPT cessation depend on the clinical circumstance and reason for cessation and attenuates over time. While most events after PCI occur in patients on DAPT, early risk for events due to disruption is substantial irrespective of stent type. FUNDING Bristol-Myers Squibb and Sanofi-Aventis.

Randomized Comparison of Everolimus-Eluting and Paclitaxel-Eluting Stents : Two-Year Clinical Follow-Up From the Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions (SPIRIT) III Trial

Background— In the prospective randomized Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Artery Lesions (SPIRIT) III trial, an everolimus-eluting stent (EES) compared with a widely used paclitaxel-eluting stent (PES) resulted in a statistically significant reduction in angiographic in-segment late loss at 8 months and noninferior rates of target vessel failure (cardiac death, myocardial infarction, or target vessel revascularization) at 1 year. The safety and efficacy of EES after 1 year have not been reported. Methods and Results— A total of 1002 patients with up to 2 de novo native coronary artery lesions (reference vessel diameter, 2.5 to 3.75 mm; lesion length ≤28 mm) were randomized 2:1 to EES versus PES. Antiplatelet therapy consisted of aspirin indefinitely and a thienopyridine for ≥6 months. Between 1 and 2 years, patients treated with EES compared with PES tended to have fewer episodes of protocol-defined stent thrombosis (0.2% versus 1.0%; P=0.10) and myocardial infarctions (0.5% versus 1.7%; P=0.12), with similar rates of cardiac death (0.3% versus 0.3%; P=1.0) and target vessel revascularization (2.9% versus 3.0%; P=1.0). As a result, at the completion of the 2-year follow-up, treatment with EES compared with PES resulted in a significant 32% reduction in target vessel failure (10.7% versus 15.4%; hazard ratio, 0.68; 95% confidence interval, 0.48 to 0.98; P=0.04) and a 45% reduction in major adverse cardiac events (cardiac death, myocardial infarction, or target lesion revascularization; 7.3% versus 12.8%; hazard ratio, 0.55; 95% confidence interval, 0.36 to 0.83; P=0.004). Among the 360 patients who discontinued clopidogrel or ticlopidine after 6 months, stent thrombosis subsequently developed in 0.4% of EES patients versus 2.6% of PES patients (P=0.10). Conclusions— Patients treated with EES rather than PES experienced significantly improved event-free survival at a 2-year follow-up in the SPIRIT III trial, with continued divergence of the hazard curves for target vessel failure and major adverse cardiac events between 1 and 2 years evident. The encouraging trends toward fewer stent thrombosis episodes after 6 months in EES-treated patients who discontinued a thienopyridine and after 1 year in all patients treated with EES rather than PES deserve further study.