Highlights from the American Heart Association annual scientific sessions 2001: November 11 to 14, 2001☆☆☆

Study: 

Local Drug Delivery to Inhibit Coronary Artery Restenosis: Data from the ELUTES (EvaLUation of pacliTaxel Eluting Stent) Clinical Trial

Presenter: 

Dr Anthony H. Gershlick, Glenfield Hospital, Leicester, UK

Background: 

Several recent studies of drug-coated stents have described striking reductions in the development of in-stent intimal hyperplasia, thereby generating much enthusiasm as a potential treatment to eliminate restenosis. Although paclitaxel effectively inhibits smooth muscle cell proliferation, its optimal dose and safety as a stent coating remain uncertain.

Results: 

The ELUTES study was a double-blinded, randomized multicenter dose-finding and efficacy trial designed to evaluate the paclitaxel-coated V-Flex (Cook Inc, Bloomington, IN) slotted tube stent in de novo coronary artery lesions. Unlike previous paclitaxel-coated stent designs, the V-Flex stent has no polymer coating, and the drug is applied directly to the stent surface. One hundred ninety patients were randomized to 1 of 5 dose densities: 0 μg/mm2, 0.2 μg/mm2, 0.7 μg/mm2, 1.4 μg/mm2, and 2.7 μg/mm2. Major inclusion criteria included single de novo coronary lesions with a vessel diameter 2.75 mm to 3.5 mm and length less than 15 mm. All patients received aspirin and clopidogrel for 3 months after percutaneous coronary intervention. The primary end point was procedural and angiographic efficacy was at 6 months. Secondary safety analyses included major adverse coronary events (MACE) at 1 and 6 months. The study was designed to detect a reduction in the percent diameter stenosis from 35% to 20% with 80% power at an α level of .05.

There were no significant baseline differences in the clinical and angiographic characteristics among the patient groups. Immediate procedural success and 6-month angiographic follow-up were achieved in 99% and 91% of patients, respectively. Immediate postprocedural minimal luminal diameter (MLD) was similar among all groups. For all angiographic parameters, a clear dose-dependent response was observed. At 6 months, angiographic restenosis (>50% decrease in MLD) occurred in 21% of patients receiving the bare stent and 3% of patients treated with the 2.7 μg/mm2 stent (P = .055). Percent diameter stenosis was 34% with the control stent and 14% with the 2.7 μg/mm2 stent (P < .01). Late lumen loss was 0.73 mm for the control stent and 0.10 mm for the 2.7 μg/mm2 stent (P < .005). Event-free survival at both 30 days and 6 months also did not significantly differ between treatment groups. At 30 days, there was 1 death and 1 myocardial infarction among patients receiving the paclitaxel-coated stents. In addition, 1 patient in each group had subacute thrombosis, but no late in-stent thromboses were observed at 6-month follow-up. Target vessel (but not target lesion) revascularization occurred in 1 patient receiving the drug-coated stent.

Interpretation: 

Similar to TAXUS I, the ELUTES trial supports the efficacy of a paclitaxel-coated stent in reducing restenosis with no short-term adverse events. Unlike TAXUS I, however, the ELUTES study appears to have identified a minimally effective paclitaxel dose using a polymer-free stent. Although the most effective doses differ between the studies, this difference may reflect the methods used to calculate dose densities on the stent surface.

Amidst the enthusiasm of successive positive results, the early experience with drug-coated stents has also identified several important unanswered questions. Unresolved issues include identifying the most effective agent(s), determining the optimal duration of antiplatelet therapy, and identifying the best delivery platform (ie, polymer carrier or not). Moreover, the long-term certainty of preventing restenosis and maintaining safety is not established. Results from larger, randomized trials, including the PATENCY trial with the paclitaxel-coated V-Flex stent, are awaited.

Study: 

TAXUS I Six Month Final Results: Prospective, Randomized, Double-blind Comparison of NIRx Stents Coated with Paclitaxel in a Polymer Carrier in De-novo Coronary Lesions Compared with Uncoated Controls

Presenter: 

Dr Eberhard Grube, Herzzentrum Siegburg, Siegburg, Germany

Background: 

Although stents reduce the incidence of restenosis and the need for repeat revascularization compared with balloon angioplasty alone, restenosis still occurs in 20% to 40% of patients receiving a stent. Several recent studies have demonstrated striking reductions in the development of in-stent intimal hyperplasia with drug-coated stents. Paclitaxel is a chemotherapeutic agent that polymerizes microtubule formation, thereby inhibiting replication at the mitosis phase of the cell cycle.

Results: 

TAXUS I was a prospective, double-blinded, randomized multicenter trial evaluating the safety and efficacy of the paclitaxel-coated NIRx stent (Boston Scientific/Scimed Corp, Maple Grove, Minn) in de novo atherosclerotic coronary lesions. The NIRx stent is a polymer-based, slow-release, paclitaxel-eluting coronary stent with a drug density of 1.0 μ/mm2.

Sixty-one patients with established de novo coronary artery disease were randomized to either the paclitaxel-coated or bare NIR stent (31 NIRx, 30 bare NIR). The primary end point was 30-day major adverse cardiac events (MACE: death, Q-wave myocardial infarction, target vessel revascularization [TVR], and thrombosis). Secondary end points included 6-month clinical safety and efficacy, as well as 6-month quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) parameters.

Baseline clinical and angiographic characteristics did not significantly differ between the groups. Approximate average baseline lesion characteristics were: reference vessel diameter 3.0 mm, lesion length 12.0 mm, and percent diameter stenosis 60%. At 6 months, binary angiographic restenosis (>50% reduction in minimal lumen diameter, MLD) occurred in 10% of patients receiving the bare NIR stent versus none of the NIRx patients (P = .1124). Major adverse cardiac events occurred in none of the patients in either group at 30 days. At 6 months, cumulative MACE occurred in none of the NIRx patients and 7% of bare NIR patients, entirely attributable to TVR. No edge-effect stenosis was observed. Six-month QCA demonstrated use of the NIRx stent was associated with significantly greater MLD (2.19 ± 0.65 mm with the NIR stent, 2.61 ± 0.49 mm with the NIRx; P = .0072) and significantly decreased late lumen loss (0.71 ± 0.47 NIR stent, 0.36 ± 0.48 NIRx; P = .0073). Late loss index was 0.45 ± 0.29 mm with the NIR stent and 0.22 ± 0.28 mm with the NIRx stent (51% decrease, P = .0029). Intravascular ultrasound confirmed significant reductions in neointimal volume with no occurrence of stent malapposition.

Interpretation: 

The persistent problems of intimal hyperplasia and clinical restenosis after stent implantation have been motivating factors in the design of stents with biocompatible coatings to serve as a matrix for adjunctive drug delivery. The rationale for the development of drug-eluting stents includes the following: first, local pharmacologic delivery maximizes the drug effect where it is required, allowing for controlled release and reduction in potential systemic toxicity. Second, as a combined, one-step method, drug-loaded stents may offer a savings benefit in time and cost. Finally, the potential for stents as drug delivery devices has broad applications in both de novo and restenotic coronary disease, in addition to peripheral vascular disease.

If proven effective, drug-coated stents have the potential to broaden the use of stents in a variety of clinical settings and reduce the number of bypass surgery procedures. Considering the encouraging results of these early trials of stents coated with antiproliferative agents (including sirolimus, actinomycin D, and c-myc antisense), the enthusiasm for developing these technologies is only tempered by concerns over their predicted cost. Still, until long-term outcomes in larger patient populations are available, clinicians must be cautious before adopting coated stents as the definitive treatment for coronary artery disease. In the case of paclitaxel, remaining issues include the long-term effects of a polymer carrier and the optimal paclitaxel dose, considering its narrow therapeutic window. Preclinical studies evaluating paclitaxel-coated stents have demonstrated dose-dependent inhibition of neointimal proliferation, although higher doses may be associated with medial toxicity and stent thrombosis. This latter finding, in addition to improper antiplatelet therapy, has been offered as a potential explanation for the trend toward higher rates of subacute thrombosis in the ASPECT trial. Forthcoming results from the TAXUS II, III (in-stent restenosis trial), and IV studies are awaited.

Study: 

PRESTO—Tranilast for Restenosis

Presenter: 

Dr David R. Holmes, Jr, Mayo Clinic, Rochester, Minn

Background: 

Coronary restenosis remains a substantial problem, occurring in approximately 30% to 40% of patients after balloon angioplasty and in 15% to 25% of patients after coronary artery stenting.

Tranilast is a potent oral antiproliferative agent that inhibits the growth and migration of vascular smooth muscle cells. It was originally developed in Japan by Kissei Pharmaceuticals and has been shown to be efficacious in preventing restenosis in animal studies and smaller clinical trials.

The Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial, sponsored by GlaxoSmithKline, was a randomized, placebo-controlled trial of tranilast to treat coronary restenosis after angioplasty. In this, the largest ever coronary intervention trial, patients were randomized to 1 of 5 treatment groups: 3 months of placebo, given twice daily; 1 month of tranilast (300 mg or 450 mg, twice daily) or 3 months of tranilast (300 mg or 450 mg, twice daily).

Treatment started within 4 to 8 hours after either urgent or elective percutaneous coronary intervention in any type of lesion. The primary end point was the occurrence of major adverse cardiac events (MACE) including death, MI or ischemia-driven target vessel revascularization at 9 months. Some patients were also prospectively assigned to follow-up angiogram at 9 months, and IVUS investigations were carried out in some patients.

Results: 

In this worldwide study, 11,500 patients (44% from the United States and 40% from western Europe) were enrolled over a 12-month period from 1999 to 2000. Approximately 85% of the patients received coronary stenting, and the average lesion length was 13 mm. Totally occluded vessels composed 6% of the lesions studied. The primary end point of the study was the composite of death, myocardial infarction, and ischemia-driven target vessel revascularization at the end of 9 months of follow-up.

This composite occurred in 358 (15.7%) of the patients assigned to placebo, 352 (15.4%) of the patients assigned to 1 month of 300 mg of tranilast, 351 (15.5%) of the patients assigned to 1 month of 450 mg of tranilast, 363 (16.0%) of the patients on 3 months of 300 mg of tranilast, and 364 (16.0%) of patients on 3 months of 450 mg of tranilast. The corresponding P values for the comparison of each of the treatment regimens to placebo were .815, .77, .815 and .765, respectively. Subgroup analyses failed to identify any group that had a benefit with tranilast over placebo treatment.

Interpretation: 

Tranilast, given orally in a dose of 300 mg or 450 mg for 1 or 3 months, is ineffective in reducing major adverse cardiac events after coronary intervention. In his discussion after Dr Holmes's presentation, Dr Patrick Serruys (Thoraxcenter, Rotterdam, The Netherlands) said careful reading of the results of the 4 small Japanese studies that led to the decision to conduct the $100 million PRESTO trial would have revealed that the trial data were not analyzed on a pure “intention-to-treat” basis. This may have led to some misinterpretation of the results of those early trials.

Study: 

Combined Use of Eptifibatide and Enoxaparin in Patients Undergoing Percutaneous Coronary Intervention: The Results of the CRUISE Trial

Presenter: 

Dr Deepak L Bhatt, Cleveland Clinic Foundation, Cleveland, Ohio

Study: 

Optimal Anticoagulation and Platelet Inhibition Are Achieved when Enoxaparin Is Combined with Small Molecule Glycoprotein IIb/IIIa Inhibition during Elective Percutaneous Coronary Intervention.

Presenter: 

Dr Mina Madan, Sunnybrook and Women's College Health Science Center, Toronto, Ontario, Canada

Background and results: 

The glycoprotein (Gp) IIb/IIIa inhibitors have been shown in several randomized clinical trials to reduce the ischemic complications of percutaneous coronary intervention. These agents are now used in the majority of coronary stent procedures performed in the United States. The trials that have established the effectiveness of the Gp IIb/IIIa inhibitors have combined the agent with unfractionated heparin.

The low-molecular-weight heparins have several attractive properties in the PCI setting: a more predictable and stable dose response, resistance to inhibition by PF4, and greater anti-Xa:anti-IIa activity. Although the NICE 4 registry demonstrated that the low-molecular-weight heparin enoxaparin plus abciximab during PCI produced efficacy and safety outcomes similar to those reported for abciximab plus unfractionated heparin in previous clinical studies, the combination has not previously been evaluated in a prospective randomized fashion.

The Coronary Revascularization Using INTEGRILIN and Single bolus Enoxaparin (CRUISE) trial compared the safety and efficacy of eptifibatide (given as 2 180 μg/kg boluses 10 minutes apart with an infusion of 2 μg/kg/min) plus enoxaparin 0.75 μg/kg intravenous bolus (n = 129) with eptifibatide combined with unfractionated heparin 60 U/kg intravenous bolus (n = 132) in patients undergoing nonemergency percutaneous coronary intervention (PCI) with planned stent implantation. Patients with acute myocardial infarction were excluded.

The maximum median ACT level in the unfractionated heparin group was 274 s (241, 317). The bleeding index at 24 hours, defined as the change in hemoglobin plus the number of units of blood transfused, was similar for both groups (0.8 enoxaparin vs 1.1 unfractionated heparin; P = .14). The respective TIMI major bleeding rates were 2.5% vs 1.6%; P = .68. At 48 hours, the composite of death, MI or need for urgent target vessel revascularization had occurred in 8.5% of the enoxaparin-treated patients and 7.6% of the unfractionated heparin-treated patients (P = .82).

The Assessment of Combination Therapy In Obstructed Native coronary arteries (ACTION) trial randomized 200 patients undergoing percutaneous coronary intervention in a native coronary artery to 1 of 4 treatment groups, with 50 patients in each group; enoxaparin 0.75 mg intravenous bolus or unfractionated heparin 60 U/kg bolus combined with either eptifibatide (in the double bolus dosing outlined above) or tirofiban (10 μg/kg bolus and 0.15 μg/kg/min infusion).

At 30 days, no deaths, urgent target vessel revascularizations or major TIMI bleeding incidents were reported. For the enoxaparin versus unfractionated heparin comparison, MI occurred in 8% versus 14%, respectively (P = .18), with similar minor TIMI bleeding rates (2% in each group). For the eptifibatide versus tirofiban comparison, MI occurred in 7% versus 15%, respectively (P = .07), with minor TIMI bleeding rates of 3% and 1%, respectively.

Interpretation: 

In these small, randomized, yet underpowered studies, the combination of enoxaparin with a small molecule glycoprotein IIb/IIIa inhibitor did not result in any excess bleeding or access site complications. In addition, the combination did not result in any apparent loss of efficacy despite the inability to monitor levels of anticoagulation. These findings need to be confirmed in larger, ongoing randomized studies.

Study: 

Neurologic Events after Carotid Stenting with Distal Protection Using an Occlusion Balloon: Final Results from the CAFÉ-USA (Carotid Artery intervention Free of Emboli-USA) Trial

Presenter: 

Dr Roxana Mehran, Cardiovascular Research Foundation, Lenox Hill Heart and Vascular Institute, New York, NY

Background: 

Carotid artery stenting (CAS) is an emerging endovascular treatment for patients with obstructive carotid artery atherosclerotic disease. Despite advancements in percutaneous interventional techniques, the potential for stroke remains an important concern because clinically significant embolization of atherothrombotic debris occurs in approximately 5% of cases. The Guardwire system consists of a distal occlusion balloon mounted on a 0.014 inch guidewire that is inflated to permit “protected” angioplasty and stenting.

Results: 

The CAFÉ-USA multicenter registry was designed to prospectively evaluate the safety and efficacy of distal embolic protection using the Percusurge Guardwire system (Medtronic Inc, Minneapolis, Minn) in carotid artery percutaneous intervention. Two hundred twelve patients with either symptomatic (≥60% stenosis) or asymptomatic (≥70% stenosis) carotid artery stenosis underwent stenting with the self-expanding Wallstent (Boston Scientific/Scimed, Maple Grove, Minn). Additional inclusion criteria included a distal internal carotid artery with a diameter 4.0 to 6.0 mm and no significant distal disease or tortuosity. Major exclusion criteria included recent stroke or myocardial infarction and contralateral total carotid occlusion with significant vertebral artery disease. The primary end point included both technical success (<30% residual stenosis or evidence of embolic debris) and clinical success (angiographic success with absence of death or stroke at 30 days).

Patients' baseline angiographic and clinical characteristics were remarkable for 20% age >80 years, 74% prior stroke/TIA, 14% prior carotid endarterectomy, and 55% contralateral carotid artery disease. Seven patients received adjunctive treatment with glycoprotein (Gp) IIb/IIIa inhibition.

The Guardwire system was used successfully in 98% of patients with an average distal occlusion time of 11.9 ± 4.6 minutes. Technical success was achieved in 91% of patients with visual debris in 100% of cases. Intraprocedural nondisabling stroke occurred in 3 patients (1.4%), with 2 of the patients having intracranial hemorrhage. At 30 days, neurologic events occurred in 12 patients (5.7%), including neurologic death (2 patients, 1.0%), major stroke (2 patients, 1.0%), nondisabling stroke (10 patients, 4.8%), and transient ischemic attack (5 patients, 2.4%). Predictors of stroke included advanced age, prior stroke, symptomatic presentation, and use of Gp IIb/IIIa blockade.

Interpretation: 

The CAFÉ-USA results add to a growing body of evidence supporting the safety and efficacy of carotid stenting, particularly for patients who are at high risk for surgical complications or who have anatomically unfavorable lesions for endarterectomy. This trial supports other studies demonstrating advanced age as a predictor of stroke, but it also proposes additional clinical and procedural characteristics that may increase complications. Distal protection devices appear to decrease the risk of cerebral microembolization during CAS,1 although the optimal method for distal protection (eg, balloon occlusion vs filter device) and the importance of operator experience will require further study. For example, in the CAFÉ-USA trial, successful Guardwire placement occurred in 93.4% of cases with a 1.9% incidence of stroke. For the second 106 patients, however, the distal occlusion balloon inflation time was significantly reduced, and the rates of procedural success and stroke were 95.3% and 0.9%, respectively (P = .82 for comparison of stroke among the 2 groups). Although not a prespecified end point, the association of stroke with Gp IIb/IIIa inhibition also promotes the need to refine appropriate anticoagulant and antiplatelet therapy.

Before carotid stenting is adopted as routine therapy for high-grade carotid stenoses, however, results from larger, randomized trials comparing CAS with carotid endarterectomy are necessary. Long-term clinical and economic outcomes remain uncertain. At present, the available data from single-center studies performed in a wide variety of clinical settings and operator experience have reported conflicting results.2 Forthcoming results from the large, multicenter randomized CREST trial comparing “protected” CAS to carotid endarterectomy are therefore eagerly awaited.

Study: 

The Heart Protection Study (HPS)

Presenter: 

Dr Rory Collins, Oxford University, Oxford, UK

Background: 

Many secondary prevention trials have proven a mortality benefit with the use of HMG CoA reductase inhibitors in patients with coronary heart disease (CHD) and elevated lipids. In addition, primary prevention trials have shown that this therapy reduces the risk of myocardial infarction (MI) and stroke (CVA) in patients with LDL cholesterol levels > 130 mg/dl. It remains unclear, however, whether patients with cardiovascular disease without elevations in LDL or total cholesterol levels, or patients at risk for cardiovascular disease with only mildly elevated lipids, would benefit from initiation of HMG CoA inhibitors. In addition, animal studies have shown that vitamins, particularly those with antioxidant properties, stabilize arterial plaques and therefore may reduce the risk for myocardial infarction and stroke. Complicating this argument, some authorities have suggested that vitamins may reduce the risk of some cancers. Clinical trials in humans, however, have led to conflicting results on the efficacy of various vitamin supplements in preventing cardiovascular events and malignancies. It remains uncertain whether the addition of vitamins to a frequently already-complicated medical regimen adds any benefit. The goal of HPS was to assess whether the HMG-CoA reductase inhibitor simvastatin and a combination of vitamins would reduce mortality in patients who did not have a clear current indication for their use. The primary end point of the study was all-cause mortality as well as mortality from cardiovascular events. Secondary end points include the incidence of new malignancies, as well as total cardiovascular events in the treatment groups compared with controls. Cardiovascular events included nonfatal MI or CHD death, fatal or non-fatal CVA, and need for revascularization.

Results: 

The trial was a 2 × 2 multicenter trial, double blinded and placebo controlled. Patients from 69 centers in the UK were enrolled from 1994 to 1997. Enrolled patients were randomized to 40 mg of simvastatin or placebo, and a combination of 600 mg of vitamin E, 250 mg of vitamin C, and 20 mg of beta-carotene or placebo. Eligible patients included those at increased risk for cardiovascular events but who at the time of recruitment were not being considered for lipid-lowering therapy. Groups at increased risk included those with a previous MI or known CAD, diabetes mellitus (DM), known or suspected peripheral vascular disease and men over the age of 65 years with hypertension. Candidates had to be between the ages of 40 and 80 and have a total cholesterol ≥135 mg/dL.

A total of 20,536 patients were enrolled in the trial with an average follow-up of 5.5 years. Overall there was about two thirds compliance with the treatment regimen over the 5 years of follow-up, with a significant number of subjects enrolled in the placebo group eventually receiving statin therapy on the basis of recommendations of their primary physicians.

There was no evidence of a significant decrease in the risk of all-cause mortality or CV death in those randomized to the combination vitamin regimen compared with placebo. In terms of the secondary end points of CV events or incidence of malignancy, there was also no benefit in patients taking the vitamin combination compared with controls. There was a 12% relative risk reduction in all-cause mortality as well as a 17% relative risk reduction in cardiovascular mortality in patients randomized to simvastatin compared with controls. Kaplan-Meier survival curves demonstrated that this reduction continued to increase and suggested that anticipated benefits would be even greater with time. In further subgroup analyses, there was a 24% relative risk reduction in cardiovascular events in those with known cardiovascular disease at enrollment, as well as a 27% relative risk reduction in strokes in the simvastatin arm. There was no difference in this observed benefit between men and women, and the reduction spanned all age groups. For diabetics with no known previous CHD, there was a similar relative risk reduction of 24% for both MI and stroke. In approximately 7000 patients with LDLs <130 mg/dL, a 24% relative risk reduction was seen for all CV events. This risk reduction persisted even in the smaller group of approximately 3000 patients with LDLs <100 mg/dL. The risk associated with simvastatin was low, with 0.8% showing a significant elevation in liver enzymes in the treatment arm compared with 0.6% in the placebo arm. Only 0.09% of patients in the treatment arm developed a greater than 10× elevation of CPK compared with 0.05% in the placebo arm. Both placebo and treatment arms reported a 5% incidence in myalgias.

The overall estimated risk reduction in CV events was approximately one third when taking into account the fact that many of the patients in the control arm were started on statin therapy by their primary physicians after enrollment in the trial, probably decreasing total events in the placebo group. Treatment with statins in this population will typically prevent “major vascular events” in about 100 of every 1000 patients with previous MI, 80 of every 1000 patients with diabetes and age >40 years, 70 in every 1000 patients with a history of previous CVA, and 70 in every 1000 patients with known peripheral vascular disease.

Interpretation: 

The implications for patient care from this study are vast, as discussed by Dr Salim Yusuf (McMaster University, Hamilton, Ontario) after Dr Collins' presentation of the data. First, the resounding negative results in terms of any benefit from vitamin supplement supports the results of other large primary prevention studies, such as the HOPE trial. On the basis of the results of these trials, there is no evidence to suggest that vitamin therapy is beneficial in preventing cardiovascular disease or malignancy in a population with a relatively good nutritional status. In addition, this study demonstrates that the reduction of mortality and CV events with simvastatin extends to patients with baseline LDL <100 mg/dL. This CV event reduction includes a dramatic reduction in the risk of atherosclerotic strokes.

On the basis of this study, some authorities suggest caregivers may choose to initiate statin therapy in patients at high risk for CV disease without checking cholesterol levels. This is based on the premise that there is no longer a lower limit of LDL at which statin therapy should be initiated. However, this practice would likely miss a number of patients with very high LDL levels for whom 40 mg of simvastatin or its equivalent may not be adequate to lower the LDL levels to current target levels. This trial did not answer which of these strategies is better from a cost-effectiveness standpoint. Because this therapy has been demonstrated to be very safe, probably safer than over-the-counter aspirin, medical providers should have a low threshold to start statin therapy in most patients aged 40 to 80 years who have a significant risk for cardiovascular disease. What remains unclear is whether higher doses may provide additional benefit and what extra risk, if any, higher doses would have for our patients.

Study: 

E2F Decoy-Gene Therapy in Bypass Grafts. PREVENT II: The Project of Ex-Vivo Vein Graft Engineering Via Transfection

Presenter: 

Dr Eberhard Grube, Heart-Center Sieburg, Sieburg, Germany

Background: 

Coronary and peripheral bypass graft failure remain significant problems in postsurgical patients. An estimated 15% to 20% of grafts fail at 1 year, 30% to 40% fail at 5 years, and ≥40% fail at 10 years. Neointimal hyperplasia and subsequent accelerated atherosclerosis are felt to be responsible factors in a process that ultimately results in graft occlusion. This neointimal hyperplasia is mediated by smooth muscle cells that migrate from the media layer of the vessel wall into the intima in response to vessel injury (such as being exposed to arterial pressures post bypass). E2F is a cell cycle transcription factor that plays a role in vascular growth by up-regulating numerous cell cycle genes, which mediate this process. The E2F decoy is an oligonucleotide that binds and inactivates this transcription factor. Preclinical studies have shown that this decoy can inhibit neointimal hyperplasia in autologous vein graft animal models. These same studies also suggested that there was concomitant medial thickening, suggesting an arterialization of the vessel wall.

A phase I/II study of this therapy, published in the Lancet in October 1999, demonstrated the safety and feasibility of the oligonucleotide as a therapeutic agent in patients undergoing autologous peripheral arterial bypass surgery.1 This led to the present phase IIb study.

The PREVENT II trial was a randomized, double-blind, placebo-controlled phase IIb trial looking at the safety and feasibility of this oligonucleotide in preventing human autologous vein graft failure after coronary artery bypass surgery. This study randomized 200 patients to the E2F decoy treatment or placebo. The E2F decoy transfection occurs via a nondistending pressure-mediated device (6 pounds/square inch for 10 minutes). The graft is harvested in the usual manner and undergoes the transfection process before its use. The inclusion criteria were patients undergoing nonelective CABG who required at least 2 grafts. The primary end point was the safety and feasibility of the drug. Secondary end points were graft failure, predefined as ≥75% stenosis at 1 year as measured by quantitative coronary angiography, and vascular wall volume as measured by intravascular ultrasound (IVUS).

Results: 

The study was carried out at The Heart Center in Siegburg, Germany. The study population was 84% male, 100% white with a mean age of 68 years in the placebo group and 65 years in the treated group (P not significant). One hundred one patients were randomized to the E2F decoy and 99 to the placebo. The majority of patients received 2 or 3 grafts. At 1 year, patients were evaluated for primary and secondary end points. There was no difference in the composite of major adverse cardiac events between the groups at 1 year. There was also no difference in all-cause death, myocardial infarction, percutaneous intervention, repeat bypass, or need for bypass revision. There were also no significant differences when perioperative adverse events were specifically addressed. Secondary end points were assessed via angiography and IVUS. Quantitative angiography was performed 12 months after enrollment in 136 patients (61 placebo, 75 E2F decoy-treated) who received a total of 309 grafts. Graft failure at 1 year was detected in 38% of control patients and 27% of E2F decoy-treated patients (P = .03). Sixty-five cases were analyzed in the IVUS substudy. Vascular wall volume was reduced in the E2F decoy group compared with those receiving placebo (78.6 ± 45.6 mm3/cm compared with 114.8 ± 78.3 mm3/cm, P = .031). The IVUS findings are suggestive of positive vascular remodeling in the treated grafts.

Interpretation: 

This well-done phase IIb trial is an excellent example of the movement of ideas from the bench to bedside. It is the first randomized, double-blind, placebo-controlled trial of genetic manipulation of human autologous coronary artery vein bypass grafts. It confirms the safety and feasibility of the E2F decoy for treating autologous human vein grafts used in coronary artery bypass surgery. Furthermore, the secondary end points favor increased patency and positive vascular remodeling in the treated group. Although very encouraging, the impact of this therapy on hard clinical end points will require further assessment in an adequately powered phase III study. Phase III trials of both peripheral and coronary autologous bypass grafts are planned.

Study: 

Cost Effectiveness of Eptifibatide in Patients Undergoing Planned Coronary Stenting: Results from the ESPRIT Trial

Presenter: 

Dr David J. Cohen, Beth Israel Deaconess Medical Center, Boston, Mass

Background: 

Glycoprotein IIb/IIIa (Gp IIb/IIIa) antagonists have been shown to reduce adverse outcomes after elective percutaneous coronary intervention (PCI) but concerns over cost have limited their adoption by many catheterization laboratories. A formal cost-effectiveness evaluation of eptifibatide was planned in conjunction with the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial. The purpose of this study was 2-fold: first, to examine the economic impact of eptifibatide in patients undergoing planned coronary intervention from the hospital and medical care system perspectives, and second, to evaluate the overall cost-effectiveness of eptifibatide from the societal perspective (cost per year of life saved).

The ESPRIT trial included patients undergoing PCI with planned use of one or more FDA-approved coronary artery stents. Patients were excluded if they had any of the following: Gp IIb/IIIa antagonist administration in the previous 30 days, myocardial infarction (MI) in the previous 24 hours, contraindications to Gp IIb/IIIa administration (recent stroke, bleeding diathesis, or thrombocytopenia), or renal failure defined as a serum creatinine >4.0 mg/dL. Two thousand sixty-four patients were randomized to receive either eptifibatide at a dose of 180 μg/kg bolus, followed by an infusion of 2 μg/kg/min, and a second bolus of 180 μg/kg, or placebo. Patients were randomized in the cardiac catheterization laboratory after the decision was made to proceed with PCI. All patients received aspirin and a thienopyridine (either ticlopidine or clopidogrel) on the day of randomization. Eptifibatide treatment was associated with a 40% relative risk reduction in the incidence of death or MI at 30 days, and a 37% relative reduction in death or MI at 1 year.

The cost-effectiveness study prospectively collected procedural and hospital resource utilization data on all 2064 patients beginning with the index hospitalization and up to 1 year of follow-up. The costs of eptifibatide and catheterization laboratory supplies were assigned on the basis of average acquisition costs in the United States. Costs associated with length of hospital stay, repeat procedures, MI, and vascular complications were based on a regression model developed separately in 3241 patients undergoing PCI in the United States (model R 2 = 0.68). The analysis was based on intention-to-treat and the primary end points were total medical care costs for the index hospitalization and the lifetime incremental cost-effectiveness ratio (cost per year of life saved).

Results: 

There were no significant differences between the eptifibatide and placebo groups with respect to age, sex distribution, and cardiovascular risk factors. Eptifibatide was associated with a nonsignificant reduction in procedure duration (86 minutes vs 89 minutes, P = .18) and a significant reduction in the number of stents used (1.3 vs 1.4 for eptifibatide, P = .01), as well as the incidence of periprocedural MI (5.4% vs 9.0%, P = .002). The net in-hospital cost per patient was calculated as the cost of eptifibatide ($495) minus the cost offset resulting from eptifibatide treatment (cost savings of $169 from lower procedure duration and $61 from reduced ischemic complications; cost increases of $15 for increased length of stay and $18 for increased vascular access site complications) for a net cost increment of $291 per patient. There was no significant difference between eptifibatide and placebo in resource utilization between hospital discharge and 30 days ($221 for eptifibatide vs $204 for placebo, P not significant).

Between 30 days and 6 months after the index procedure, eptifibatide was associated with a statistically nonsignificant cost savings of $111, based on reductions in repeat PCI, coronary artery bypass grafting (CABG), and rehospitalizations ($1155 for eptifibatide vs $1267 for placebo, P = .60). A similar trend was seen between 6 months and 1 year ($745 eptifibatide vs $788 placebo, P = .72). One year after the index procedure, a cumulative cost offset of 71% was seen with eptifibatide such that the net cost per patient was reduced from $495 to $146. This was based on the cost reductions from eptifibatide treatment seen during the index hospitalization and after 30 days, 6 months, and 1 year of follow-up.

The 1-year results from the main ESPRIT trial indicated a significant reduction in MI (7.2% vs 10.7%, P = .004) and a nonsignificant reduction in death (1.4% vs 2.0%, P = .28) associated with eptifibatide treatment. To calculate the cost per year of life saved with eptifibatide therapy, the investigators used both the observed 1-year mortality results from the ESPRIT trial and a long-term survival model developed from the Duke Cardiovascular Databank to project survival beyond the first year.

The ESPRIT-projected life expectancy estimates from the Duke Databank model showed a difference in life expectancy of 0.16 years in favor of eptifibatide (life expectancy 18.86 years with eptifibatide vs 18.70 years with placebo). This was discounted to 0.10 years. Using the 1-year cost difference of $146 per patient, eptifibatide treatment showed a cost-effectiveness ratio of $1407 per year of life saved. The first of 2 sensitivity analyses was performed assuming that only large MIs (those with CK-MB elevation greater than 5 times the upper limit of normal) affected survival. The life expectancy difference between eptifibatide and placebo was narrowed to 0.086 years, and eptifibatide therapy resulted in $1699 per year of life saved. The second sensitivity analysis assumed no effect of MI on survival, and the life expectancy difference was further reduced to 0.064 years, with a cost-effectiveness of $2274 per year of life saved. A comparison with other accepted therapies showed that eptifibatide for planned coronary stenting showed a societal cost that was more than aspirin for secondary prevention but less than statin use for secondary prevention.

Interpretation: 

This well-executed study demonstrates a very favorable cost-effectiveness ratio associated with eptifibatide therapy for planned coronary stenting that is more favorable than other benchmark therapies such as CABG for 3-vessel coronary artery disease, treatment of severe hypertension, and implantation of cardioverter-defibrillators for survivors of sudden death. Eptifibatide reduced ischemic complications of PCI by 40% with a decrease in net health care system costs from $495 to $146 per patient over the first year of follow-up. This cost-effectiveness was maintained at <$3000 per year of life saved over a wide range of assumptions, suggesting that cost alone should not preclude the use of eptifibatide for patients undergoing PCI. A direct comparison of eptifibatide with the other commercially available Gp IIb/IIIa antagonists would be required to determine which agent results in the greatest clinical benefit at the lowest cost.

1. Late-breaking clinical trials; 2. Acute myocardial infarction, adjunctive therapy studies: 1. Enhancing recovery in coronary heart disease patients (ENRICHD) study; 2. Sertraline for major depression after acute coronary syndromes—the SADHART trial 

Study: 

Feasibility of Point-of-care Echo by Non-cardiologist Physicians to Assess Left Ventricular Function, Pericardial Effusion, Mitral Regurgitation, and Aortic Valvular Thickening

Presenter: 

Dr John H. Alexander, Duke Clinical Research Institute, Durham, NC

Background: 

Echocardiography has become a mainstay in the diagnosis and management of patients with cardiac disease. With high-end standard echocardiographic systems costing upwards of $200,000 per unit, however, the widespread use of this imaging modality represents a substantial cost to the health care system. Recently, medical imaging companies (Agilent, Sonosite) have introduced miniaturized echocardiographic systems approximately the size of a laptop computer. Although these systems have significantly fewer imaging features than standard systems, they are substantially cheaper (Agilent's OptiGo device retails for $12,000) and more portable. Although the portability and economical cost of these machines make them potentially attractive alternatives to standard echocardiographic systems as screening tools, there are few data available regarding their accuracy in the hands of physicians without prior echo training.

Results: 

Sixteen medical residents and 4 cardiology fellows without prior echo experience underwent a 3-hour training course on the operation of the OptiGo device and recognition of 4 specific sonographic findings: LV dysfunction, aortic valve thickening, pericardial effusion, and mitral regurgitation. Inpatients and outpatients referred to the echo laboratory for transthoracic echo were approached for this study. Each enrolled subject underwent a brief (5 minute) history and physical by a trainee followed by point-of-care (POC) echo examination. LV ejection fraction (EF) was classified as <55% or ≥55% and pericardial effusion, mitral regurgitation (MR), and aortic valve thickening as < or ≥ moderate. Each patient's standard echo was interpreted twice on these same findings to determine interobserver agreement. History and physical and POC echo agreement coupled with standard echo was compared with standard echo's interobserver agreement coupled with the McNemar test. Kappa statistics were also calculated to correct for chance agreement for some diagnoses.

Five hundred thirty-seven patients were enrolled over 7 months. Three patients were excluded for >72 hour separation between standard and POC echo examinations and 1 patient was excluded because he was younger than 18 years and not able to give informed consent as a minor. The mean age was 59 years and the mean weight was 183 pounds. In this group, 53% were male, 15% had COPD, 79% were positionable on one side, 68% were intermediate bed inpatients, and 10% were ICU patients. The average POC examination lasted 8.5 minutes. By standard echo, 42% had LVEF <55%, 15.8% had moderate or severe MR, 6.8% had moderate or severe aortic valve thickening, and 2.4% had moderate or large pericardial effusion. Agreement rates (κ) for POC echo and standard echo for LV dysfunction, effusion, MR, and aortic valve thickening were 75% (0.51), 98% (0.51), 79% (0.31), and 92% (0.32), respectively. These compared with the agreement rates (κ) of history and physical of 69% (0.35), 97% (0), 80% (0.23), and 92% (0.30) and the standard echo interobserver agreements (κ) 83% (0.63), 97% (0.53), 92% (0.68), and 95% (0.62), respectively, for these same 4 diagnoses.

Interpretation: 

This study demonstrates that it is feasible to briefly train physicians without prior sonographic experience to perform POC echo examinations to answer some basic clinical questions. Although POC echo was not as good as standard echo for all diagnoses, it was significantly better than history and physical examination for recognition of LV dysfunction and pericardial effusion. As one of a series of timely investigations into this new technology, this study adds to the small but growing literature on the application and limitations of POC echo devices.

Study: 

The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study

Presenter: 

Dr Eric A. Rose, Columbia University, New York, NY

Background: 

The human and economic toll of heart failure (HF) is astounding. More than 5 million Americans are affected, and the 1-year mortality rate in those with advanced disease approaches 50%. Many patients with severe ventricular dysfunction and unrelieved symptoms become refractory to medical therapy. Cardiac transplantation remains a treatment option in a select few, although donor heart supply limitations and strict eligibility criteria limit this strategy's overall impact on this public health problem. For almost 40 years, there has been an intense interest in developing mechanical circulatory support devices as an alternative to cardiac transplantation for those with advanced disease. In selected patients, these devices have improved abnormalities in hemodynamics, functional capacity, and nutritional status in their current use as bridges to transplantation.

The REMATCH trial was designed to investigate the use of an implantable left-ventricular assist device (HeartMate VE, Thoratec Corporation, Pleasanton, Calif) as an alternative to medical therapy in patients with advanced heart failure who were ineligible for cardiac transplantation.

Results: 

This prospective, randomized trial was conducted at 20 transplantation centers in the United States. One hundred twenty-nine patients were randomized to receive either the HeartMate VE left-ventricular assist device (LVAD) or optimal medical therapy (according to guidelines established by the trial's medical committee). The primary endpoint was all-cause mortality. Baseline characteristics were similar between the 2 groups, and reflected the marked severity of illness in the study population. All patients had New York Heart Association (NYHA) class IV symptoms, with a mean ejection fraction of 17% in each group. Cardiac index was ≤2 L/min/m2 in each group, and more than two thirds of patients were receiving intravenous inotropic therapy at enrollment. Patients well enough to undergo exercise testing had a mean peak oxygen consumption of <10 mL/kg/min. The most common reason for transplant ineligibility was advanced age.

Kaplan-Meier survival analysis revealed a 48% reduction in the risk of death from any cause in the group receiving the LVAD versus those receiving medical therapy (RR = 0.52; 95% CI 0.34-0.78; P = .001). The survival rates at 1 year in the LVAD and medical groups were 52% and 25%, respectively (P = .002). Corresponding rates at 2 years were 23% and 8% (P = .09). Median survival was 408 days in the LVAD group and 150 days in the medical therapy group. Pump failure was the cause of death in the majority (n = 50, 82%) of patients in the medical therapy group. The most common causes of death in the LVAD group were sepsis (n = 17, 41%) and device failure (n = 7, 17%).

Quality-of-life assessments were obtained at baseline and at 1 year in surviving patients. Patients in the LVAD arm had significant improvements in the physical function and emotional role subscales of the SF-36, the Beck Depression Inventory, and NYHA class. The median number of days spent in and out of the hospital was greater among patients in the LVAD group. Patients in the LVAD arm had higher rates of serious adverse events (RR = 2.35; 95% CI 1.86-2.95). Within 3 months of device implantation, the probability of infection was 28% (95% CI 15%-38%). The probability of device failure at 24 months was 35%. Within 6 months, patients in the LVAD group had a 42% incidence of bleeding. Patients in the LVAD group were more likely to have neurologic dysfunction, defined as stroke, TIA, or toxic encephalopathy, compared with those in the medical therapy arm (RR = 4.35; 95% CI 1.31-14.50).

Interpretation: 

The REMATCH trial is the first randomized study to test the hypothesis that the use of a mechanical circulatory assist device is a legitimate alternative to medical therapy among patients with advanced heart failure. The results of this extremely important trial demonstrate that the use of an implantable LVAD significantly improves survival and quality of life compared with the best medical therapy in patients with end-stage heart failure who are not eligible for cardiac transplantation. Despite the significant mortality reduction, however, almost 80% of patients in the LVAD group were dead at 2 years, and serious adverse events were more common in those receiving LVADs than in medically treated patients.

The performance of this trial is an important step in determining the proper care of these gravely ill patients, and it serves as a benchmark by which newer devices should be judged. The continued evolution of completely implantable systems capable of biventricular support will likely improve outcomes and reduce morbidity further in this growing population and may ultimately supplant cardiac transplantation as the preferred treatment for end-stage heart failure.

Study: 

Neurodevelopmental Outcomes after Congenital Heart Surgery: Results from an Institutional Registry

Presenter: 

Dr Joseph M. Forbess, Children's Hospital of Boston, Boston, Mass

Background: 

Recent studies in adults have shown a decline in cognitive function in patients after a successful cardiopulmonary bypass (CPB). This decline was noticed even in patients who had no documented perioperative central nervous system (CNS) events, and the cognitive decline persisted even years after the surgery. Little is known about whether a similar cognitive decline occurs in children who undergo repair or palliation of congenital heart defects (CHD) in early childhood. Because of the dramatic growth of the brain during the first year of life, it is certain that results of adult studies in this area cannot and should not be extrapolated to infants and toddlers. The ongoing growth and differentiation of the CNS cells may render children more or less vulnerable to ischemic injury than adults.

This investigation is part of an institutional effort to examine the neurodevelopment of 5-year-old children after repair or palliation of CHD. In this study, 694 children from New England and the New York area who had cardiac surgery at Children's Hospital of Boston were asked to participate. A total of 258 (37%) families failed to reply, and 176 (25%) refused enrollment. Of the remaining 260, an additional 17 (2.4%) were ineligible because of either Down syndrome or Williams syndrome, which would affect neurodevelopment regardless of other factors. The remaining 243 children underwent formal neurodevelopment testing.

A battery of neuropsychologic tests were performed on these children between 1998 and 2001, including the Wechsler Preschool and Primary Scale of Intelligence Revised (WPPSI-R), the Wide Range Assessment of Visual-Motor Abilities (WRAVMA), and the Wide Range Assessment of Memory and Learning (WRAML). Children were categorized into 12 groups on the basis of anatomic diagnosis. Nine groups underwent biventricular repair and 3 groups underwent single ventricular palliation.

Results: 

In the sample as a whole, mean Full-scale (FSIQ), Verbal (VIQ), and Performance (PIQ) scores were in the normal range (96.5 ± 16.1, 97.7 ± 15, and 96.0 ± 17.2, respectively, with the normal mean of 100). Mean FSIQ in the single ventricle group was 91.5 ± 16.4. Mean FSIQ in the biventricular repair group was 97.7 ± 15.7. In regression analysis, children with single ventricles (n = 37) scored lower than children with 2 ventricles (n = 189) on FSIQ (P = .03), PIQ (P = .02), verbal memory (verbal learning, P = .05, story memory, P = .04), visual memory (design memory, P = .04), and the composite score on a test of visual-motor abilities (P = .02). When corrected for socioeconomic status, as determined by the Hollingshead Four Factor Index, lower FSIQ scores were predicted by a diagnosis of velocardial facial syndrome (P = .0001), younger age at first surgery (P = .02), the diagnosis of hypoplastic left heart syndrome (HLHS, P = .03), cumulative duration (minutes) of CPB (P = .02), and cumulative duration of hypothermic circulatory arrest (HCA, P = .0001). Those with cumulative HCA less than 33 minutes had normal visual-motor and memory scores, whereas those with cumulative HCA >33 minutes had significantly lower visual-motor composite scores (P = .0002) and memory and learning scores (P = .0017). Those children who required CPB had a mean FSIQ of 95.9, whereas those who did not require CPB had a mean FSIQ of 101.7 (P > .05). Performance and verbal IQ were also not statistically different between these 2 groups.

In conclusion, the average scores obtained on a multitude of neurodevelopment tests showed no significant decline in cognitive levels at 5 years of age compared with the normal population of children on whom these tests were validated. Risk factors for decreased levels of cognition at 5 years of age include younger age at first surgery, cumulative CPB and HCA times, velocardial facial syndrome, and single ventricle repair (the last potentially explained by cumulative CPB and HCA times as these children frequently require 3 cardiac surgeries before the fifth birthday).

Interpretation: 

This trial was the first large-scale evaluation of neuropsychologic outcomes in children requiring cardiac surgery during the first year of life. The results suggest that, as a whole, children who undergo a biventricular repair in early childhood do not have decreased FSIQ scores at 5 years of age unless the surgery is required at a very early age or they have an associated velcocardial facial syndrome. Sampling bias could, however, confound these results. A relatively small percentage of the total population eligible for enrollment actually completed the battery of tests, and those who did not respond or refused enrollment could have a significant effect on the total FSIQ scores of the children who underwent surgery. This potentially limits our interpretation of these results. Nonetheless, this is the first of hopefully many large trials evaluating the long-term neurodevelopment of these children, paving the way for further long-term analysis. Potential further experiments on animal models may allow us to limit the effect of more prolonged HCA and CPB on long-term cognitive scores.