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J Am Coll Cardiol, 2004; 43:875-890, doi:10.1016/j.jacc.2003.12.024
© 2004 by the American College of Cardiology Foundation
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YEAR IN CARDIOLOGY SERIES

The year in interventional cardiology

William W. O'Neill, MD, FACC*,* and Simon R. Dixon, BHB, MBChB, FRACP*

* Division of Cardiology, William Beaumont Hospital, Royal Oak, Michigan, USA

* Reprint requests and correspondence: Dr. William W. O'Neill, Division of Cardiology, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, Michigan 48073, USA.
woneill{at}beaumont.edu

We are daunted by the challenge of attempting to summarize the important scientific observations in the field of interventional cardiology for the year 2003. Few other fields of clinical science evolve as quickly as this one. Not only are clinicians inundated with publications and peer review journals, but also late-breaking trials are presented at major meetings (Table 1). Internet web sites further disseminate early presentation of trials, and even pharmaceutical company yearly reports are used as a method for disseminating trial results. It would be pointless to simply abstract all sources of information in this review. Rather, we have chosen to highlight certain areas and studies that we believe will stand the test of time as important contributions in the field. In the end, we hope this review will provide non-interventionalists with a working knowledge of advances in the field. For interventionalists, we have attempted to collate trials and findings into major categories as a framework for more in-depth study. We believe 2003 will be remembered as the year of drug-eluting stents (DES) and mechanical reperfusion therapy for ST-segment elevation myocardial infarction (STEMI). For this reason, we have chosen to highlight these areas. In addition, adjunctive pharmacology, new devices, and important mechanistic studies will be summarized. Finally, we will point out the future trials that will be highlighted in the year 2004. We wish to acknowledge the brilliance and perseverance of the investigators who have made this review possible.


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  		Table 1 Glossary of Interventional Cardiology Trials in 2003

 

   Acute myocardial infarction (AMI)
Top
 Acute myocardial infarction...
Acute coronary syndromes (ACS)
 Drug-eluting stents
 Other coronary devices
 Contrast nephropathy
 Diabetes mellitus and pci
 Adjunctive pharmacotherapy
 Future advances
 References
 
The reperfusion wars of the last decade seem a distant memory. Numerous data, including a recent overview of 23 randomized trials, clearly support the superiority of catheter-based reperfusion over fibrinolytic therapy for the treatment of STEMI (1,2) (Fig. 1). A recent analysis of the National Registry of Myocardial Infarction trials has also demonstrated a mortality benefit with primary percutaneous coronary intervention (PCI) in STEMI patients who have contraindications to thrombolytic therapy (3). Accordingly, the focus of clinical research in AMI has been directed toward several key issues: 1) how to improve the availability of mechanical reperfusion in the community; 2) what is the optimal preprocedural therapy before primary PCI; and 3) what adjunctive therapies can be applied to enhance myocardial salvage (Table 2)?



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  		Figure 1 Short-term clinical outcomes in individuals treated with percutaneous transluminal coronary angioplasty (PTCA) or thrombolytic therapy, according to the type of thrombolytic agent used. Odds ratios and 95% confidence intervals are shown. (Reprinted from Keeley et al. [1], with permission from Lancet.)

 

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  		Table 2 Interventional Trials in Acute Myocardial Infarction

 
Expanding the benefit of mechanical reperfusion.   Two landmark studies published this year stole the spotlight: the DANish trial in Acute Myocardial Infarction (DANAMI-2) and PRimary Angioplasty in acute myocardial infarction patients from General community hospitals transported to percutaneous transluminal coronary angioplasty Units versus Emergency thrombolysis (PRAGUE-2) (4,5). The results of these trials have already had an important impact on clinical practice patterns in North America. Both studies were designed to evaluate the optimal reperfusion strategy for patients presenting to hospitals without invasive facilities. Patients were treated either on-site with fibrinolysis (tissue-type plasminogen activator [t-PA] in DANAMI-2 and streptokinase in PRAGUE-2) or transferred to an invasive center for emergency cardiac catheterization and coronary intervention, when indicated. In both trials, there was a dramatic reduction in the incidence of major adverse cardiac events (MACE) at 30 days in the invasive groups; in fact, the DANAMI-2 trial was halted early by the Data Safety and Monitoring Board because of the marked improvement in outcome in patients treated with mechanical reperfusion.

Therefore, these data validate the hypothesis that transfer for catheter-based reperfusion is superior to on-site fibrinolytic therapy, despite the additional time to treatment incurred during patient transfer. This benefit is partly explained by the fact that stenting, unlike thrombolysis, results in greater myocardial salvage, independent of the time to treatment (6). Additionally, primary PCI significantly reduces the risk of early re-infarction, which is associated with increased mortality after fibrinolytic therapy (7). In a recent meta-analysis of six randomized trials, patient transfer for PCI was associated with a 42% reduction in the composite end point (death/re-infarction/stroke), compared with a strategy of on-site thrombolysis (8). This was driven mainly by a reduction in the incidence of re-infarction (68% reduction) and stroke (56% reduction), but there was also a trend toward improved survival with PCI. Overall, these findings strongly support community-wide adoption of a transfer strategy for mechanical reperfusion. The challenge now is to overcome logistical obstacles and replicate these impressive results in routine clinical practice.

Immediate patient transfer for coronary intervention also appears to be beneficial for those patients who receive full-dose fibrinolytic therapy as the initial reperfusion strategy. Current clinical guidelines discourage routine coronary intervention immediately after thrombolysis because of historical (but outdated) studies, suggesting an excess risk in these patients (9–11). With this in mind, the results of the Streptokinase In Acute Myocardial infarction (SIAM-III) trial are timely (12). After full-dose reteplase, patients admitted to a community hospital were randomly assigned to immediate PCI (within 6 h) or delayed intervention (at 2 weeks). Immediate stenting was associated with a significant reduction in the composite clinical end point and improved left ventricular function at six months. More importantly, there was no clear "downside" to immediate intervention in terms of angiographic outcomes or major bleeding.

Optimizing preprocedural therapy.   Given the inherent time delay associated with patient transfer, there has been a resurgence of interest in combining pharmacologic and mechanical reperfusion strategies in patients with AMI, recently termed the "pharmacoinvasive approach" (13). The hypothesis is that antecedent pharmacologic therapy (typically a fibrinolytic agent either alone or with a glycoprotein [GP] IIb/IIIa inhibitor) will partially recanalize the infarct vessel before PCI, thus improving angiographic and clinical outcomes. Two studies evaluating this approach were presented in the latter half of the year. In the GRupo de Análisis de la Cardiopatia Isquémica Aguda (GRACIA-2) trial, patients were randomized to a strategy of primary PCI (with abciximab) or immediate tenecteplase plus enoxaparin, followed by early angiography (within 3 to 12 h) and intervention, if indicated (14). There was no difference in infarct size or left ventricular function (at 6 weeks); however, more patients had complete ST-segment resolution (>70%) at 6 h in the "facilitated" group. The incidence of major bleeding was similar in each group. In contrast, the Bavarian Reperfusion AlternatiVes Evaluation (BRAVE) trial compared combination therapy (half-dose reteplase and abciximab) with abciximab alone, followed by immediate PCI, in both treatment groups (15). Seventy-four percent of patients presented to a non-PCI center (mean transfer distance of 39 km). Initial Thrombolysis In Myocardial Infarction trial (TIMI) flow grade 3 was significantly higher in the combination therapy group (40% vs. 18%, p < 0.001); however, there was no difference in the incidence of TIMI flow grade 3 after PCI. The primary end point of the study—infarct size by single-photon emission computed tomographic imaging—was similar in both study groups. Moreover, there was a higher rate of complications, including major bleeding, in patients treated with reteplase plus abciximab. Overall, these data suggest that the pharmacoinvasive approach is not superior to primary PCI alone when mechanical intervention can be performed rapidly after hospital presentation. On the other hand, the facilitated approach with thrombolytic pre-treatment should be considered when a delay (>3 h) is anticipated before cardiac catheterization.

The optimal preprocedural therapy for patients in the catheterization laboratory remains controversial (16). Recently, Antoniucci et al. (17) found that abciximab decreased the primary end point (death, myocardial infarction, target vessel revascularization, stroke at one month) in 400 patients randomized to PCI with or without abciximab. In contrast, the larger Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial showed only a modest clinical benefit, so further trials will be required (18). Denigration or trumpeting of previous negative or positive adjunctive abciximab trials cannot resolve this controversy.

Other groups have investigated the role of early GP IIb/IIIa inhibition alone (without fibrinolytic therapy) to facilitate primary PCI outcomes. Two recent studies have addressed the issue of timing: the ONgoing Tirofiban in Myocardial infarction Evaluation (ON-TIME) and TIrofiban Given in the Emergency Room before Primary Angioplasty (TIGER-PA) (19,20). In both studies, patients were randomized to receive tirofiban early (ON-TIME started either in the ambulance or referral center; TIGER-PA started in the emergency room) or in the catheterization laboratory. Early tirofiban was associated with an improvement in initial angiographic outcomes, but there was no significant difference in final TIMI flow grade, corrected TIMI frame count, or blush score in either study. Thus, early administration of tirofiban before primary PCI is safe but appears to have only a modest benefit in terms of initial angiographic outcomes.

Adjunctive therapies and devices to enhance myocardial salvage.   The results of several studies evaluating new adjuncts to mechanical reperfusion were reported this year. The common goal in each of these studies was to test new pharmacologic agents or devices that might limit the extent of myocardial necrosis and thus preserve left ventricular function. Therapeutic targets included prevention of reperfusion injury or distal embolization and modulation of myocyte metabolism.

The COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial was performed to determine the effect of pexelizumab, a C5 complement inhibitor, on infarct size (21). Complement activation is an important mediator of inflammatory damage and is believed to contribute to reperfusion injury. In the active treatment arms, two dosing regimens were tested: bolus alone and bolus plus infusion. The primary end point—infarct size by creatine kinase area-under-the-curve analysis—was similar in each study group. However, there was an intriguing and statistically significant reduction in 90-day mortality in the pexelizumab bolus plus infusion group compared with the bolus alone or placebo group, suggesting that pexelizumab may be beneficial in this setting. A definitive mortality trial (Apex MI) will be conducted in patients with anterior wall infarction. Another pharmacologic agent, AmP579 (a mixed adenosine agonist), was studied in 311 patients undergoing primary PCI; however, there was no effect of the therapy on final infarct size in the AMP-579 Delivery for Myocardial Infarction REduction (ADMIRE) trial (22).

There has been renewed interest in protecting the ischemic myocardium via metabolic modulation, in particular, with glucose-insulin-potassium (GIK) treatment. This therapy has a number of beneficial effects at a cellular and biochemical level, including shift of myocardial metabolism from free fatty acids to glucose oxidation and increased glycolytic adenosine triphosphate synthesis. This therapy was investigated in a large, randomized trial conducted by the Zwolle group (23). A total of 940 patients with AMI were randomly assigned to either continuous GIK infusion for 8 to 12 h or no infusion. Overall, there was no difference in 30-day mortality (the primary end point) between study groups; however, there was an impressive improvement in survival with GIK in the 856 patients who presented without signs of heart failure (Killip class I) (1.2% vs. 4.2%, p < 0.01). Conversely, a higher mortality was seen in the GIK group in those with heart failure, possibly due to the high rate of GIK infusion. Further studies are currently being conducted to clarify the effects of GIK treatment in myocardial infarction.

Myocardial cooling is a newer and innovative approach to cardioprotection. Experimental studies have demonstrated that mild hypothermia reduces metabolic demand in the risk region and limits infarct size. Accordingly, the COOLing as an adjunctive therapy to percutaneous intervention in patients with acute Myocardial Infarction (COOL-MI) investigators sought to evaluate the effect of mild systemic hypothermia during myocardial infarction (24). A total of 395 patients with AMI were assigned to primary PCI with hypothermia or primary PCI alone. Hypothermia was induced using an endovascular cooling system with a target temperature of 33°C. Cooling was found to be safe and well tolerated. At the time of PCI, the median reduction in core temperature was approximately 1°C, which was less than anticipated. The final infarct size at 30 days was similar in both study groups; however, there was a significant reduction in infarct size in patients with an anterior infarction who were adequately cooled at the time of reperfusion. These findings suggest that the heart needs to be cooled to the target temperature (33°C) before reperfusion for hypothermia to provide optimal myocyte protection. Further studies are planned to confirm these findings.

Embolization of thrombus and atherosclerotic plaque is an important mechanism contributing to poor myocardial perfusion after infarct artery angioplasty. Several techniques are being studied to limit the effects of distal embolization, including the use of thrombectomy devices and distal protection systems. Two studies reported this year demonstrated that patients treated with adjunctive thrombectomy before stenting have a lower incidence of angiographic complications, such as no-reflow and distal embolization, and better myocardial perfusion after PCI than patients treated without thrombectomy (assessed by the degree of ST-segment resolution or TIMI myocardial perfusion grade) (25,26). Improved angiographic outcomes have also been reported with a filter-based distal protection system (27). Although larger trials are required to evaluate the effect of thrombectomy on clinical outcomes, these data suggest that preventing distal embolization is an important approach during mechanical reperfusion. Results of the randomized trial of AngioJet thrombectomy plus stent versus stent alone (AIMI) and Enhance Myocardial Efficacy and Removal by Aspiration of Liberated Debris (EMERALD) (GuardWire distal protection system) clinical trials will be presented in early 2004.

Clinical outcomes.   On another note, an important observational study was reported this year by the Zwolle group regarding the impact of circadian variations on the outcome of primary angioplasty (28). In this analysis of 1,702 consecutive patients, those treated during off-hours had a higher incidence of failed angioplasty (6.9% vs. 3.8%, p < 0.01) and worse clinical outcome than those treated during routine hours. The explanation for these findings is not clear; however, these data have important implications for interventionalists, especially with the growing enthusiasm for mechanical reperfusion as the primary therapeutic strategy in myocardial infarction.


   Acute coronary syndromes (ACS)
Top
 Acute myocardial infarction...
 Acute coronary syndromes (ACS)
Drug-eluting stents
 Other coronary devices
 Contrast nephropathy
 Diabetes mellitus and pci
 Adjunctive pharmacotherapy
 Future advances
 References
 
A large body of evidence supports an early invasive approach in intermediate- or high-risk patients with ACS (non-STEMI/unstable angina). Data from the FRagmin during InStability in Coronary artery disease (FRISC-II) Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS), TIMI-18, and Randomized Intervention Treatment of Angina (RITA-3) trials clearly demonstrate improved clinical outcomes with routine early cardiac catheterization and revascularization, compared with a conservative strategy, especially in those patients with ST-segment depression or positive biomarkers (29–31). More recently, ST-segment elevation in lead aVR has also been identified as a high-risk feature in non-STEMI patients (32). Coupled with advances in adjunctive pharmacologic therapy and stent technology, the interventional community has rapidly adopted early intervention as the "standard-of-care" approach.

One of the key questions that emerged from these studies was the optimal timing for intervention. For many years it has been recognized that PCI in patients with ACS is associated with an increased risk of periprocedural complications, such as distal embolization, no-reflow, and myocardial infarction. Because of this hazard, it has been suggested that "plaque passivation" with antiplatelet and antithrombotic treatment before coronary intervention might improve angiographic and clinical outcomes. This hypothesis was formally tested in the Intracoronary Stenting and Antithrombotic Regimen (ISAR-COOL) trial (33). A total of 410 patients with unstable angina and ST-segment depression or elevated troponin T levels were randomized to early intervention (within 6 h of presentation) or to a "cooling-off" strategy with antithrombotic pretreatment for three to five days before intervention. All patients received aspirin, clopidogrel (600-mg loading dose), intravenous unfractionated heparin, and intravenous tirofiban. At 30 days, the primary end point (a composite of death or large myocardial infarction) was 11.6% in those receiving prolonged antithrombotic treatment and 5.9% in the early intervention group (relative risk 1.96, 95% confidence interval [CI] 1.01 to 3.82; p = 0.04). This difference was driven mainly by an increased incidence of myocardial infarction before catheterization in the prolonged antithrombotic group. Thus, early intervention with optimal antiplatelet therapy seems to be preferable to delayed intervention after several days and, notably, is not associated with an early procedural hazard. These data have important implications for the management of intermediate- and high-risk patients with ACS. Early intervention seems justified, both in terms of safety and clinical efficacy and, moreover, is likely to result in significant cost savings to hospitals and payors worldwide. Further data from the ongoing Medicine vs. Angioplasty for Thrombolytic Exclusions (MATE-2) trial are expected in 2005.


   Drug-eluting stents
Top
 Acute myocardial infarction...
 Acute coronary syndromes (ACS)
 Drug-eluting stents
Other coronary devices
 Contrast nephropathy
 Diabetes mellitus and pci
 Adjunctive pharmacotherapy
 Future advances
 References
 
After the initial euphoria created by the first-in-man experience (34) and the RAndomized study with the sirolimus-eluting Bx VELocity balloon-expandable stent (RAVEL) study (35), larger trials in more complex lesion subsets were required to validate sirolimus-eluting stents as a breakthrough. These larger trials were published in the year 2003. The Sirolimus-coated Bx velocity balloon-expandable stent in the treatment of patients with de novo artery lesions (SIRIUS) trial (36) was the first large U.S. experience with the Cypher (Johnson & Johnson, Warren, New Jersey) stent, and this trial was quickly followed by the large European experience (37). In addition, the Medtronic ABT-578–eluting stent had preliminary results presented in 2003. Finally, the Guidant everolimus-eluting stent had preliminary safety data presented (38) (Table 3). These trials demonstrate that rapamycin and rapamycin analogues dramatically decrease fibrointimal hyperplasia in de novo coronary lesions. Whether different stent designs, different polymers, or different rapamycin compounds provide superior outcomes will remain to be determined by future randomized, comparative trials. In addition, the Johnson & Johnson program has further evaluated the efficacy of the Cypher stent in complex in-stent restenosis (39,40). These two studies treated a total of 41 patients. One repeat angioplasty and two deaths occurred at follow-up. As a result of these pilot trials, a larger multicenter, randomized trial of the Cypher stent versus vascular brachytherapy for in-stent restenosis (SISR trial) is being conducted in the U.S.


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  		Table 3 Drug-Eluting Stent Trials: Sirolimus/Everolimus

 
In 2003, the results in anatomic subgroups excluded from the initial randomized trials were reported. Saia et al. (41) reported on 89 patients with STEMI who were treated with Cypher stents. In-hospital mortality was 6.2%. No early or late stent thromboses were observed, and no patients presented with clinical or angiographic restenosis. Lemos et al. (42) reported on 198 patients with ACS who were treated with Cypher stents. The 30-day MACE (6.1% vs. 6.6%) and stent thrombosis (0.5% vs. 1.7%) were similar for Cypher and historical control patients. These two reports suggest that treatment of thrombus-laden culprit lesions may be safe. Further expanding indications for DES use may include unprotected left main stenosis (43) and bifurcation lesions (44). Larger data sets will be required to assess the safety and efficacy in these complex lesion subsets.

The year 2003 also brought forth the first systematic reports of restenosis after Cypher stent implantation. Colombo et al. (45) reported that 11 of 368 consecutive patients had in-stent or in-segment restenosis. The pattern of restenosis was focal, and all lesions were intra-stent. Similarly, Lemos et al. (46) reported that after detailed, systematic ultrasound analysis, restenosis after Cypher stent implantation was predominately related to vessel trauma outside the stented segment. These studies and analysis of the E-SIRIUS trial suggest that stent implantation with generous coverage of lesion margins, has almost entirely eliminated in-segment restenosis. Importantly, a diffuse proliferative pattern was not encountered in any of the reported trials.

A second major alternative to the rapamycin-coated stent was reported in 2003 (Table 4). The year 2003 initially brought enthusiasm for a simple painting of paclitaxel on the Supra G stent (Cook Inc., Bloomington, Indiana). The ASian Paclitaxel-Eluting stent Clinical Trial (ASPECT) had clinical, angiographic, and intravascular ultrasound findings reported (47,48). Unfortunately, these trials could not be replicated in the U.S. pivotal trial sponsored by Guidant Corp. (Randomized Comparison of Paclitaxel-coated versus Metallic Stents for Treatment of Coronary Lesions [DELIVER] trial) (49). In contradistinction, the prospective, multicenter, randomized trial of the polymer-based paclitaxel-eluting stent in patients with de novo lesions (TAXUS) program from Boston Scientific, where paclitaxel is eluted from a polymer matrix, has been quite successful, and the results were presented in 2003. The TAXUS program from Boston Scientific generated reports on the TAXUS I, TAXUS II, and TAXUS III trials (50–52). Importantly, TAXUS IV, a randomized paclitaxel U.S. trial, was presented in September 2003 and led to a Food and Drug Administration (FDA) advisory panel recommendation for approval in November 2003 (53). Thus, it is likely that U.S. clinicians will have two types of DES available for general use in 2004. With the likelihood that two competitive DES systems will be on the market in the U.S., the year 2004 will bring enormous marketing efforts to the forefront. Advocates of either system will attempt to point out differences in late loss index, differences in subgroups such as diabetics, differences in late stent malposition, and differences in stent deliverability. Many of these comparisons must await formalized comparative trials, such as the ongoing European randomized trial of Cypher versus TAXUS stent (REALITY) trial. For now, U.S. patients and physicians will have two safe and extremely effective stent systems for prevention of in-stent restenosis.


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  		Table 4 Drug-Eluting Stent Trials: Paclitaxel

 

   Other coronary devices
Top
 Acute myocardial infarction...
 Acute coronary syndromes (ACS)
 Drug-eluting stents
 Other coronary devices
Contrast nephropathy
 Diabetes mellitus and pci
 Adjunctive pharmacotherapy
 Future advances
 References
 
Although the year has been dominated by interest in DES technology, the results of several clinical trials evaluating new coronary devices have also been reported (Table 5). Notably, these studies have all addressed new approaches in the treatment of saphenous vein graft (SVG) disease, which remains a significant challenge in clinical practice. Specifically, these new devices were designed to reduce the risk of either distal embolic complications or late restenosis.


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  		Table 5 Trials of Other Coronary Devices

 
Distal embolic protection.   The importance of distal protection during SVG intervention is well established. In the Saphenous vein graft Angioplasty Free of Emboli Randomized (SAFER) trial, there was a 50% relative reduction in the incidence of MACE in patients treated with the GuardWire balloon occlusion and aspiration system, thus setting a new standard in the treatment of vein graft disease (54). However, there are a number of disadvantages with balloon occlusion systems, including relative complexity of use and procedural ischemia. On the other hand, filters are somewhat easier to use, as they are designed to capture embolic particles while maintaining continuous flow.

The results of two randomized trials investigating filter devices in vein graft intervention were reported this year. The FilterWire EX Randomized Evaluation (FIRE) trial evaluated the efficacy of the Boston Scientific FilterWire EX system, compared with the approved GuardWire balloon occlusion and aspiration system (55). The FilterWire EX device consists of a 0.014-inch guide wire that has an oval-shaped loop at the distal end, supporting a porous membrane filter. The primary end point of this non-inferiority trial (MACE at 30 days) occurred in 9.9% of FilterWire EX patients and 11.6% of GuardWire patients (difference –1.7% [95% CI –6.4% to 3.1%], p = 0.53 for superiority, p = 0.0008 for non-inferiority). This was the first study to demonstrate that distal embolic protection with a filter system provides a level of protection equivalent to that of the GuardWire balloon occlusion system. Based on these results, the FilterWire Ex System was approved by the FDA for use in SVG intervention.

The TRAP trial, which is the only superiority designed filter study, compared the efficacy of stenting with or without the TRAP vascular filtration system (56). The trial was started before any protection devices were commercially available in the U.S., but had difficulty with patient enrollment once the GuardWire System was approved for clinical use. This ultimately led to early termination of the study after 360 of 460 planned patients had been randomized. The primary end point of the study—30-day MACE—was not significantly different in either treatment group; however, there was trend toward a lower incidence of MI in the TRAP group, with a relative reduction similar to that seen in the SAFER trial (Fig. 2). Several non-inferiority trials with other filter systems are currently in progress and will compare the investigational device to either the FilterWire System or GuardWire device.



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  		Figure 2 Incidence of major adverse cardiac events (MACE) and myocardial infarction (MI) at 30 days in the Saphenous vein graft Angioplasty Free of Emboli Randomized (SAFER) and TRAP vascular filtration system (TRAP) randomized trials.

 
Thrombolysis/thrombectomy.   Because most SVG lesions contain a significant thrombus burden, several devices have been designed to reduce and/or remove thrombus before stent implantation, in the hope that this will lessen the risk of embolic complications. Coronary ultrasound thrombolysis uses an acolysis probe to deliver low-frequency ultrasound at the treatment site, which will lyse or liquefy thrombus to subcapillary size. Initial results suggested this device would be a promising mechanical adjunct in SVG intervention. In the multicenter Acolysis during Treatment of Lesions Affecting Saphenous vein bypass grafts (ATLAS) trial, patients with ACS undergoing SVG lesion treatment were randomized to receive either acolysis or abciximab (57). However, the Data and Safety Monitoring Committee stopped the trial prematurely, after 181 patients were enrolled, because of a higher incidence of adverse events in the acolysis arm. At 30 days, the cumulative incidence of MACE was 25% in the acolysis group and 12.4% in the abciximab group, mainly due to a higher rate of MI in the acolysis group. Use of the X-Sizer (ev3, Plymouth, Minnesota) thrombectomy device was studied in the X-SIZER for TReatment of thrombus and Atherosclerosis in Coronary intervention Trial (X-TRACT) (58). Two-thirds of patients had a SVG lesion. Overall, the incidence of periprocedural MI was similar in device and control patients, and there was no major clinical benefit with thrombectomy at one-year follow-up. However, the rate of large infarction (creatine kinase-MB fraction >8 x upper limits of normal or new Q waves) was reduced with the X-SIZER device, especially in patients with visible thrombus. These data suggest that adjunctive thrombectomy with the X-SIZER device reduces the extent but not the occurrence of periprocedural myonecrosis.

Covered stents.   Two randomized trials (Randomized Evaluation of polytetrafluoroethylene COVERed stent in Saphenous vein grafts [RECOVERS] and STents IN Grafts [STING]) have evaluated the role of a polytetrafluoroethylene-covered stent in SVG intervention (59,60). The JoStent coronary stent graft (Jomed, Sweden), which was used in both studies, has a sandwich-like design with a polytetrafluoroethylene membrane between two stainless-steel stents. It was proposed that the membrane would entrap debris and plaque during stent implantation, thus reducing embolic complications, and also reduce neointimal proliferation through the stent mesh. At six months, the incidence of binary restenosis (the primary end point in both trials) was similar between the polytetrafluoroethylene stent graft and conventional bare-metal stent groups. Moreover, in the RECOVERS trial, there was a higher incidence of in-hospital and late myocardial infarction in the polytetrafluoroethylene stent group, whereas the STING trial demonstrated a trend toward a higher rate of late occlusion in the stent graft group (16% vs. 7%, p = 0.069). These studies therefore indicate that routine use of the JoStent in SVG lesions does not confer any additional benefit over bare-metal stents. Other coronary stent grafts, with easier deployment techniques, are presently under clinical investigation and may have a more favorable outcome given the significant differences in stent design.


   Contrast nephropathy
Top
 Acute myocardial infarction...
 Acute coronary syndromes (ACS)
 Drug-eluting stents
 Other coronary devices
 Contrast nephropathy
Diabetes mellitus and pci
 Adjunctive pharmacotherapy
 Future advances
 References
 
The year 2003 brought mixed results in efforts to reduce contrast nephropathy after PCI. Gruberg et al. (61) re-emphasized the adverse prognostic impact that impaired renal function has on in-hospital and one-year survival. They analyzed in-hospital and one-year mortality in 1,265 patients undergoing PCI of SVG lesions. Patients with a creatinine clearance <30 ml/min had a 7.1% versus 0.3% in-hospital and 7.1% versus 36.7% one-year (p < 0.01) mortality compared with patients with a creatinine clearance ≥70 ml/min. Similarly, Qureshi et al. (62) found that impaired renal function was associated with a twofold increase in the risk of death in a large institutional data base. Aspelin et al. (63) randomized 129 patients with impaired renal function (serum creatinine of 1.5 to 3.1 mg/dl) to direct arteriography with iodixanol or iohexol. Fewer patients (3% vs. 26%, p = 0.002) had contrast nephropathy with iodixanol (serum creatinine increase of 0.5 mg/dl vs. baseline). Conversely, Stone et al. (64) found in the prospective, randomized, placebo-controlled, multicenter trial evaluating fenoldopam mesylate for the prevention of Contrast-induced nephropathy (CONTRAST trial ) that there was no impact of the type of contrast agent used on radiocontrast-induced nephropathy. More importantly, the CONTRAST trial conclusively demonstrated that fenoldopam pretreatment had no benefit in prevention of RCIN, with 28% versus 24% (p = NS) of active treatment versus control treated patients developing serum creatinine increases ≥0.5 mg/dl. Marenzi et al. (65) randomized 114 patients with creatinine >2 mg/dl to control versus postprocedural hemofiltration. The incidence of RCIN (increase of serum creatinine ≥25% of baseline) was reduced from 52% to 9% (p < 0.001). In addition, hospital mortality was reduced (2% vs. 14%, p = 0.001). The main criticism of this trial is that the contrast dose in both patient groups appeared to be excessive (258 ml).

The benefit of acetylcysteine has been extended to urgent procedures by the use of an intravenous formulation administrated as an intravenous bolus in the RApid Protocol for the Prevention of contrast-Induced renal Dysfunction (RAPPID) study (66). The incidence of RCIN was reduced from 21% to 5% (p = 0.045) in this randomized trial of 80 patients. Finally, an intriguing pilot study employing a 2:1 dilution of gadolinium and iohexol was reported by Sarkis et al. (67). In total, these studies suggest that acetylcysteine or hemofiltration may ameliorate the problem of RCIN. It appears that more effective, easier to use methods of renal protection still need to be developed.


   Diabetes mellitus and pci
Top
 Acute myocardial infarction...
 Acute coronary syndromes (ACS)
 Drug-eluting stents
 Other coronary devices
 Contrast nephropathy
 Diabetes mellitus and pci
Adjunctive pharmacotherapy
 Future advances
 References
 
With the looming epidemic of diabetes and coronary artery disease, the year 2003 brought further study into diabetic patients undergoing PCI. Marso et al. (68) reviewed the Mid America Heart experience with PCI from 1980 to 1999. They found that diabetic patients had an almost twofold increased risk of in-hospital death after elective or urgent PCI. Outcomes appear to be improving for elective but not for urgent cases. Muhlstein et al. (69) found an excessive risk in undiagnosed diabetics who had only mild elevations of fasting glucose levels. Similarly, Corpus et al. (70) found that mild elevations of hemoglobin A1c were associated with increased risk of death and target vessel revascularization in undiagnosed "prediabetic" patients. These two studies demonstrate that impaired glucose tolerance is common and often unrecognized in PCI patients, and this has definite adverse consequences. Mazeika et al. (71) demonstrated that poor glycemic control increased the risk of restenosis in diabetic patients. Recognition of occult diabetes and optimal glycemic control is critical, since Takagi et al. (72) demonstrated that pioglitazone decreases intimal proliferation in diabetic patients. As Piatti et al. (73) suggest, insulin resistance plays a role in restenosis in diabetics. In aggregate, these studies are a continued call to action for aggressive screening for occult diabetic patients and aggressive glycemic control after PCI.


   Adjunctive pharmacotherapy
Top
 Acute myocardial infarction...
 Acute coronary syndromes (ACS)
 Drug-eluting stents
 Other coronary devices
 Contrast nephropathy
 Diabetes mellitus and pci
 Adjunctive pharmacotherapy
Future advances
 References
 
Clopidogrel has become a mainstay agent to limit subacute thrombosis after stent implantation. In 2003, an alternative method to decrease stent thrombosis was presented with two studies evaluating heparin-coated stents (74,75). Mehran et al. (74) randomized 200 patients to treatment with a heparin-coated stent and aspirin alone or aspirin and clopidogrel. No difference in the incidence of subacute thrombosis was observed between the groups. This stent may be particularly useful in patients who cannot take clopidogrel or in whom antiplatelet therapy must be stopped quickly (i.e., urgent noncardiac surgery). The most important advance concerning clopidogrel was the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) trial (76) (Table 6). In this study, 2,195 elective PCI patients were randomized to a 600-mg oral loading dose of clopidogrel or abciximab therapy. No difference in MACE occurred. This study suggests that when elective PCI patients can be loaded with 600 mg clopidogrel, there may not be a need for intravenous GP receptor blockade.


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  		Table 6 Trials of Adjunctive Pharmacotherapy

 
The pharmacokinetics of oral loading of clopidogrel received intense scrutiny in 2003. Although oral loading of 600 mg in elective cases led to excellent outcomes in the ISAR-REACT trial, a 75-mg loading dose appears insufficient (77). In fact, Mueller et al. (78) found that ticlopidine (500-mg bolus and 250 mg twice daily) resulted in a lower mortality than clopidogrel (75-mg bolus and 75 mg/day) in a randomized trial of 700 patients. Grubel et al. (77) found that great patient variability occurs with respect to platelet inhibition after 300 mg oral loading dose. Muller et al. (79) reported that statin therapy did not alter platelet inhibition after a 600-mg oral loading dose of clopidogrel. In aggregate, these studies suggest that a clear dose-response curve exists for oral loading of clopidogrel. A loading dose of 75 mg is clearly inadequate. Based on the ISAR-REACT trial, a new standard loading dose of 600 mg orally at least 2 h before planned intervention appears necessary.

A second major advance in PCI pharmacotherapy occurred with the publication of the Randomized Evaluation of Percutaneous coronary intervention Linking Angiomax to reduced Clinical Events (REPLACE-2) trial (80). In this trial, 6,010 patients undergoing PCI were randomized to treatment with bivalirudin and clopidogrel or heparin plus GP receptor blocker and clopidogrel treatment. A higher risk of bleeding was seen in the GP IIb/IIIa group, whereas a slight increased risk of post-PCI creatine kinase elevation occurred in the bivalirudin group. This trial suggests that, at least in low-risk patients, bivalirudin and clopidogrel may be an effective alternative to GP IIb/IIIa as an antiplatelet regimen.

The use of GP IIb/IIIa came under further scrutiny with the publication of the New York State experience (81). In this large community database, GP IIb/IIIa appeared to increase adverse outcomes. However, as Klein and Calvin (82) point out, extrapolation of outcomes from tightly monitored clinical trials to the "real world" may not be appropriate. In addition, high-dose heparin therapy may have been the problem in the New York experience. In this vein, the Coronary Revascularization Using Integrilin and Single-bolus Enoxaparin (CRUISE) trial suggests that judicious dosing of either heparin or enoxaparin will result in low rates of bleeding complications in patients undergoing PCI with concomitant GP IIb/IIIa therapy (83). Furthermore, the National Investigators Collaborating on Enoxaparin-3 (NICE-3) trial also found that combined therapy with enoxaparin and GP IIb/IIIa was associated with a low bleeding risk in 628 patients undergoing PCI (84). In summary, optimal antiplatelet therapy (oral or intravenous) and optimal antithrombotic therapy (heparin, enoxaparin, and bivalirudin) have been extensively tested. No doubt, the year 2004 will bring numerous further studies with these combinations.

Cilostazol, a platelet-aggregation inhibitor, appears to be a beneficial adjunct for patients who are treated with a bare-metal stent during coronary revascularization. In the multicenter Cilostazol for REStenosis Trial (CREST), patients assigned to cilostazol therapy had a significant reduction in angiographic restenosis at six months (85). Importantly, a benefit was also seen in diabetics and those with small vessels. This is the first oral agent that has been shown to successfully reduce restenosis after stent implantation.


   Future advances
Top
 Acute myocardial infarction...
 Acute coronary syndromes (ACS)
 Drug-eluting stents
 Other coronary devices
 Contrast nephropathy
 Diabetes mellitus and pci
 Adjunctive pharmacotherapy
 Future advances
References
 
Numerous studies have attempted to delineate procedural risk after PCI (62,86,87). These studies suggest that advances in computerized databases may play a major role in future outcome research. The year 2003 also ushered in the dawn of new diagnostic imaging modalities (88–90). These studies suggest that multi-slice computed tomography and cardiac magnetic resonance imaging will emerge as alternatives to invasive coronary angiography. If this occurs, a revolution in screening for coronary artery disease, assessment of coronary progression and regression, and studies of restenosis and bypass graft patency will occur. In addition, the year 2003 brought the dawn of alternatives to radiography as a prerequisite for therapeutic intervention. Faddis et al. (91) have demonstrated that catheters, designed to be manipulated by magnetic fields, will allow interventions (both coronary and intracavitary) to occur with minimal x-ray exposure. Finally, cell transplantation is emerging as a promising approach to cardiac repair in acute and chronic ischemic heart disease (92,93).

The year 2004 will bring a variety of new clinical trials in AMI, ACS, DES implantation, and vein graft interventions (Table 7). We anticipate as difficult a task in 2004 as we have had in 2003 in summarizing advances in this rapidly evolving field.


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  		Table 7 Upcoming Interventional Cardiology Trials in 2004

 


   Footnotes
 
Dr. O'Neill is a consultant to the following corporations: Guidant, Medtronic, Johnson & Johnson, Cordis, and Boston Scientific. Dr. O'Neill has equity in the TherOx Corporation and the Radiant Corporation. William Beaumont Hospital Division of Cardiology has received research funding support from the following corporations: Guidant, Medtronic, Johnson & Johnson, TherOx, Radiant, Pfizer, and Aventis.


   References
Top
 Acute myocardial infarction...
 Acute coronary syndromes (ACS)
 Drug-eluting stents
 Other coronary devices
 Contrast nephropathy
 Diabetes mellitus and pci
 Adjunctive pharmacotherapy
 Future advances
 References
 

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