Prophylactic Intragraft Injection of Nicardipine Prior to Saphenous Vein Graft Percutaneous Intervention for the Prevention of No-reflow: A Review and Comparison to Protection Devices

ABSTRACT: No-reflow is a failure to restore normal coronary flow despite appropriate treatment of coronary obstruction. It is most commonly seen during interventions in saphenous vein grafts and is associated with poor outcome. The cause of no-reflow is complex and multifactorial. Various mechanisms including vasospasm and distal embolization of debris released during the intervention have been explained as the cause of no-reflow. Treatment to prevent or reverse no-reflow includes, but is not limited to, protective devices and intracoronary vasodilators. Intracoronary nicardipine seems to be the best option in preventing no-reflow regarding its minimal systemic side effects, modest negative inotropic and chronotropic effects, duration of action and feasibility of use. The goal of this manuscript is to review the effects of prophylactic intragraft nicardipine injection for prevention of no-reflow during saphenous vein graft intervention.  

J INVASIVE CARDIOL 2011;23:202–206

Key words: complication; coronary intervention;
myocardial infarction; slow flow; vein graft intervention; stenting;
PCI; embolic protection; vasodilator; filter wires

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Definition and pathophysiology of no-reflow

Successful restoration of epicardial coronary artery patency does not necessarily normalize tissue perfusion.¹ Failure to restore normal coronary antegrade flow after appropriate treatment of coronary obstruction is defined as the no-reflow phenomenon in the absence of dissection, thrombus formation or vessel closure.^2,3 In this phenomenon, the flow to the previously ischemic myocardium is significantly reduced. The prevalence of this complication occurs in 0.6–5% of percutaneous coronary interventions (PCIs).^4,5 Patients undergoing PCI of saphenous vein grafts (SVGs), for acute myocardial infarction (MI) or during rotational atherectomy, have the highest incidence of no-reflow.⁶ This is one of the main reasons for lower thrombolysis in myocardial infarction (TIMI) 3 flow after PCI of SVGs in comparison to PCI of native vessels (70.2–80.7% as compared to 92–97.4%).⁷

The cause of no-reflow is complex and multifactorial. Various mechanisms like alfa-adrenergic vascular constriction, local increase in angiotension II receptor density, neutrophils activation and interaction with endothelium, distal embolization of plaque and/or thrombus and local release of vasoconstrictor substances have been thought to be among many causes of no-reflow.⁶

It has been shown that no-reflow phenomenon is associated with poor clinical outcomes.⁸ Patients with no-reflow have an increased prevalence of congestive heart failure early after MI with higher left ventricular end-diastolic volume.^9,10 Persistent no-reflow has been associated with increased mortality and future incidence of MI.^6,11

High-risk coronary lesion morphology and clinical presentation are risk factors for the occurrence of this complication.¹² Except for thrombus-containing lesions and degenerative SVGs, it can be difficult to predict the risk of no-reflow based on the angiographic appearance of a given coronary artery lesion.¹² Figure 1 shows an example of no-reflow occurring after angioplasty of a degenerative SVG lesion.

Regarding the consequences of no-reflow, prevention of this phenomenon may improve safety of PCI, particularly during SVG interventions that are at highest risk for this complication.⁶ Many studies have evaluated the administration of various medications or use of devices for prevention of no-reflow. Nicardipine has been found to have the best pharmacokinetic qualities for the prevention of no-reflow during SVG interventions, with the  largest volume of published literature in this regard. The use of protection devices is costly and time-consuming and carries the risk of device-related complications. This is the main reason why these devices are only used in the minority of patients undergoing SVG intervention.¹³ Furthermore, only 77% of cases had anatomic and lesion characteristics suitable for embolic protection device use.¹⁴

The focus of this review is to evaluate the use of nicardipine in the prevention of no-reflow during SVG interventions in comparison to other modalities. For this review, we briefly discuss advantages and disadvantages of currently available protection devices used during SVG PCI for the prevention of no-reflow and compare their effects to intragraft injection of nicardipine.

Prevention of no-reflow in vein grafts using protection devices. Considering distal embolization as one of the mechanisms for no-reflow, several  protection devices have been introduced to allow the capture of the materials released during PCI.¹⁵ There are two types of protective devices. One is based on a balloon occlusive system, which occludes a part of the vessel during the PCI, and later the thrombotic materials, which are released during the procedure, will be aspirated before coronary flow is released. The other one is a non-occlusive, filter-based system with tiny pores that trap the released materials, preventing distal embolization.¹⁶ Occlusive devices are divided into distal or proximal occlusive systems.

Distal Protection Devices

Distal occlusive devices have been studied in multiple trials and have been shown to reduce major adverse coronary events (Table 1). The main limitation of a distal occlusive system is related to the technical complexity of this procedure, leading to possible errors and increases in the procedural time and the occurrence of ischemia during balloon occlusion.

Distal filter devices have distinct advantages over occlusive balloons in which distal coronary flow is not compromised during SVG stenting and they are technically less challenging to use. This is one of the main reasons why distal occlusive devices have fallen out of favor. Comparisons of distal occlusion devices and distal filter devices have been performed in several trials. MACE rates were found to be similar with both systems^19,20 (Table 1). Currently, the FilterWire (Boston Scientific Corp., Natick, Massachusetts) is one of the most commonly used distal filter systems for SVG intervention.¹

In 2005, Swaminathan et al studied the influence of vessel diameter on the efficacy of  distal protection devices during PCI of SVGs.²¹ They studied the outcomes of 572 patients in vessel size tertiles who had undergone PCI of SVGs using either the GuardWire (Medtronic, Inc., Minneapolis, Minnesota) occlusive devices or FilterWire EX. They concluded that the 30-day MACE rates were relatively independent of vessel size using the GuardWire, but increased steadily with vessel size with the FilterWire EX. MACE rates were reduced by 71% with the FilterWire EX compared with the GuardWire in the smallest tertile.

Spider FX (ev3, Inc., Plymouth, Minnesota) is another type of  distal filter that can be used in SVG interventions as a filter-based  embolic protection device. In a multicenter, prospective, randomized trial, 383 patients undergoing SVG intervention were randomized to the Spider/Spider RX device versus 364 patients to the FilterWire EX or GuardWire protection devices. All patients had between 50–100% SVG stenosis. The primary endpoint of this trial was the combined rates of death, MI, emergent coronary artery bypass graft surgery (CABG) or target vessel revascularization (TVR) within 30 days of the procedure. They found that the Spider FX filter device was non-inferior to the control group. The result of this trial was presented at the Transcatheter Cardiovascular Therapeutics meeting in October 2005.

The Rubicon filter (Rubicon Medical Corp., Salt Lake City, Utah) is another type of distal protection device that is being used in Europe. This device was used in 42 patients (45% SVGs) with a 4.5% MACE rate at 30 days. A larger, randomized U.S. pivotal trial, RULE SVG, is currently evaluating the Rubicon filter against the FilterWire in SVGs treated with a Taxus Liberté stent (Boston Scientific).

The Interceptor PLUS Coronary Filter System (Medtronic Vascular, Santa Rosa, California) is one of the recently developed distal protection devices. Kereiakes et al in 2008, in a multicenter, randomized non-inferiority trial, evaluated the safety and efficacy of this device compared with the approved devices.²² They concluded that compared to GuardWire and FilterWire EZ, the Interceptor PLUS Coronary Filter System was not inferior in terms of safety and efficacy at 30 days (Table 1).

Distal filter devices have their own disadvantages. First of all, smaller particles can pass through the filter wire. Furthermore, this filter may not be able to seal the distal coronary vessel completely, leading to the passage of significant amounts of debris into the distal coronary bed. Due to the bulky filter, the passage of a filter across a lesion can be difficult or impossible. It also requires an appropriate zone for filter deployment, which cannot be too small or too large. In the very distal lesions, deployment of these filters can be impossible. Finally, these filters can be trapped in the stent after or during the procedure, which can lead to significant dissection, morbidity and need for urgent CABG for device retrieval.¹⁷ It is important to notice that in the native coronary arteries, several randomized trials have failed to show a reduction in no-reflow or infarct size during PCI using distal protection devices.^23–25 Due to the results of these negative trials, there is no FDA-approved  indication for the use of distal protection in the native coronary arteries at this time.¹⁷

Proximal Protection Devices

Proximal occlusive devices have also been used to prevent no-reflow. With this system, complete flow will be ceased proximal to the target lesion using an occlusive balloon before stent deployment. This will allow complete aspiration of particles of all sizes after PCI or stenting of the lesion before restoring flow with proximal balloon deflation. In a non-inferiority trial by Mauri el al²⁶ in 2007, it was shown that the primary composite endpoint of death, MI or TVR at 30 days by intention-to-treat analysis was not significantly different in the control group (distal protection when possible) versus the test patients (Proxis proximal protection device) (10.0% vs 9.2% respectively). They concluded that outcomes of PCI of SVGs are the same using either proximal embolic protection compared to distal embolic protection devices²⁶ (Table 1).

One of the advantages of using proximal occlusion devices is the fact that no bulky device needs to cross the lesion. Furthermore, lesions with a poor distal landing zone for filter wires can be easily treated with a proximal protection device. The major disadvantage of this device is similar to that of a distal occlusive device where there is a complete cessation of coronary flow that can lead to ischemia and intolerance. Furthermore, this system is technically challenging, costly and requires larger 8 French sheaths. Finally, near-ostial or ostial lesions cannot be treated with this device.¹⁷ Similar to distal protection devices, proximal protection has not been shown to be beneficial in the setting of an ST-segment elevation MI or acute total SVG occlusion.⁷

Despite the use of protection devices, significant no-reflow can occur during SVG intervention. The no-reflow phenomenon might be predominately caused by microvascular spasm and not directly by mechanical obstruction from distal embolization.²⁷ This concept has been reiterated by a study performed by Salloum et al in 2005,²⁸ which showed an immediate increase in vasoactive factors including vasoconstrictive, thrombotic and inflammatory factors after PCI of SVGs. Fischell et al stated that these observations might explain why mechanical distal protection, particularly with porous filters, is not the best way to prevent no-reflow.²⁷

Based on these limitations, protection devices are used only in a minority of patients undergoing SVG interventions.¹³ Furthermore, as mentioned earlier, despite the use of protection devices, significant risk of no-reflow persists during SVG intervention. For these reasons, pharmacological prevention has been developed and successfully used for the prevention of no-reflow during SVG interventions.

Prevention of no-reflow in vein grafts using vasodilators. Many vasodilators have been studied for prevention of no-reflow in the setting of SVG intervention. The most commonly used vasodilators are nitroprusside, adenosine, verapamil, diltiazem and nicardipine.^29–34

Intracoronary nicardipine has been shown to be the most potent vasodilator used for no-reflow prevention. Intragraft administration of nicardipine can cause longer vasodilation with a lower risk of serious systemic side effects compared to intracoronary diltiazem or verapamil infusion.^27,33 In 2000, Fugit el al³³ compared the effects of intracoronary nicardipine, diltiazem and verapamil on coronary blood flow, heart rate and blood pressure. In a randomized, double-blinded study of 9 patients, nicardipine (200 µg), diltiazem (1 mg) and verapamil (200 µg) were serially administered in minimally diseased (< 30% stenosis) left anterior descending or left circumflex arteries. Epicardial coronary artery diameter was determined by quantitative coronary angiography, and coronary blood flow velocity was measured by Doppler flow in each patient before and after administration of each medication. They showed that nicardipine was more potent in inducing coronary vasodilation with longer duration of action (5–7 minutes) than verapamil or diltiazem, and was associated with less systemic side effects. Nicardipine also has greater coronary vasoselectivity with minimal myocardial depressant activity.^35,36

In 2006, Huang et al conducted a retrospective analysis of 72 consecutive patients who had received intracoronary nicardipine to reverse no-reflow during PCI. In 71 patients (98.6%), no-reflow was successfully reversed with restoration of TIMI 3 flow. There were no adverse hemodynamic or chronotropic effects.³⁷

In 2007, Fischell et al reported some promising results with the use of intracoronary nicardipine to prevent no-reflow without distal mechanical protection in SVG intervention.²⁷ They evaluated 83 SVG interventions involving 68 consecutive patients. The average graft age was 11.9 ± 6.6 years. The average lesion length treated was 18.8 ± 12.4 mm. There were angiographic signs of thrombus in 26 grafts (31%) prior to stenting. All 83 SVG lesions underwent successful stent placement. All patients received 200–300 µg of intragraft nicardipine (10–15 µg/ml of normal saline) injected via the guiding catheter immediately prior to stenting. The total CPK levels were elevated to > 2 times the upper limits of normal in 2 patients and > 3 times in 1 patient 12–18 hours after the procedure. CPK-MB was elevated to > 3 times the upper limit of normal in 3 patients. No patient had > 8 times normal elevation in CPK-MB levels or prolonged chest pain or electrocardiographic evidence of Q-wave MI. The total MACE rate at 30 days was 4.4%, with no deaths, MI or repeat TLR from hospital discharge out to 30 days. The results were compared to published data involving similar patients and similar endpoints from randomized clinical trials utilizing mechanical distal protection devices (SAFER and PRIDE trials). The SAFER trial (Saphenous vein graft Angioplasty Free of Emboli Randomized), a multicenter U.S. study, included 801 patients who were undergoing SVG intervention.¹⁸ In this trial, 406 patients were randomly assigned to stent placement with a distal protection device, and 395 were assigned to stent placement over a conventional 0.014 inch angioplasty guidewire (control group). They noticed a 42% relative reduction in MACE (a composite of death, MI, emergency CABG or TLR by 30 days). The authors concluded that this risk reduction was driven by MI (8.6% vs. 14.7%; p = 0.008) and the no-reflow phenomenon (3% vs. 9%; p = 0.02).

The PRIDE trial (Protection During Saphenous Vein Graft Intervention to Prevent Distal Embolization) was a prospective study of 631 patients with SVG lesions who were randomized to embolic protection with the TriActiv System or to a control group (GuardWire System or FilterWire EX). The incidence of MACE at 30 days was 11.2% for the TriActiv group and 10.1% for the control group.¹⁹

In the Fischell et al study, no statistical test was used to compare their findings with the SAFER and PRIDE trials, but authors concluded that using pharmacologic protection resulted in much better outcomes compared to those of the control group in the SAFER trial and at least as good as distal mechanical protection devices used in the SAFER and PRIDE trials.²⁷

Conclusion

Despite the beneficial effect of protection devices for prevention of no-reflow during SVG intervention, the use of these devices is technically challenging and has many major limitations leading to longer procedure times, higher cost and greater contrast use. This has led to low utilization rates of these devices among interventional cardiologists performing SVG interventions. Furthermore, despite the uses of these devices, no-reflow can still occur in significant numbers of patients. Nicardipine has been successfully used for this propose with great success and a low side-effect profile. Preliminary studies have shown similar efficacy in comparison to protection devices. A combination of intragraft administration of nicardipine together with the use of protection devices has not been studied but appears to be logical, with significant potential to reduce the occurrence of no-reflow compared to each preventive measure alone. Due to the low cost and significant safety profile of prophylactic intracoronary nicardipine administration, we strongly recommend the routine use of this drug during all SVG interventions with or without the use of a protection device. Table 2 summarizes the advantages and disadvantages of the different methods for prevention of no reflow during SVG intervention.

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From the ¹Division of Cardiology, The Southern Arizona VA Health Care System, Tucson, Arizona and the ²Division of Cardiology, University of Arizona Sarver Heart Center, Tucson, Arizona.
The authors report no conflicts of interest regarding the content herein.
Manuscript submitted February 1, 2011, provisional acceptance given February 7, 2011, final version accepted March 3, 2011.
Address for correspondence: M. Reza Movahed, MD, PhD, FACP, FACC, FSCAI, Professor of Medicine, The Southern Arizona VA Health Care System and University of Arizona Sarver Heart Center, 1501 North Campbell Avenue, Tucson, AZ 85724. Email: rmova@aol.com