“Pharmacologic” Distal Protection Using Prophylactic, Intragraft
Nicardipine to Prevent No-Reflow and Non-Q-Wave Myocardial In

No-reflow is a common complication during percutaneous coronary intervention in degenerated saphenous vein grafts (SVGs), and is associated with serious adverse clinical outcomes.^1–6 The important role of microvascular vasoconstriction as a predominant mechanism of no-reflow has been demonstrated by the successful reversal of no-reflow events using a variety of microvascular vasodilators (verapamil, diltiazem, adenosine, nitroprusside, etc.).^6–11 Nicardipine is a highly potent arteriolar vasodilator with a longer duration of action than either diltiazem or verapamil when given by intracoronary administration.^11–13 Nicardipine has relatively greater coronary vasoselectivity, greater microcirculatory vasodilating activity and is associated with minimal myocardial depression or atrioventricular nodal disruption.^14–16 Thus nicardipine has many attractive properties when considering the best agent to prevent or reverse no-reflow. In this report we describe the promising results with the use of intracoronary nicardipine prophylaxis with immediate direct stenting to prevent no-reflow without distal mechanical protection in SVG interventions. Methods Patient population. From November 2000 until September 2005, 68 consecutive patients with 83 degenerative SVG obstructive lesions were enrolled in a protocol to assess the safety and efficacy of prophylactic intragraft nicardipine (Cardene IV, ESP Pharma, Edison, New Jersey) and direct stenting without mechanical distal protection to prevent no-reflow and non-Q-wave myocardial infarction (MI) during elective SVG intervention. Informed consent for the procedure was obtained from all patients. During the time course of this registry, prophylactic nicardipine administration, combined with direct stenting, was adopted as routine practice between the two practitioners participating in this study. A description of the patient’s age, gender, SVG target site, graft age, etc., are summarized in Table 1. This single-center registry study was started prior to the availability of FDA-approved mechanical distal protection system(s). Protocol. Inclusion criteria required patients to have angina and/or other ischemic symptoms, with noninvasive studies and/or angiographic evidence suggesting hemodynamically significant obstructive lesion(s) (>50% diameter stenosis) in one or more saphenous vein bypass graft. Exclusion criteria included recent Q-wave or non-Q-wave MI (within 48 hours) and/or total occlusion of the SVG (Thrombolysis In Myocardial Infarction [TIMI] 0 flow). All patients received anticoagulation with weight-adjusted heparin (70 IU/kg). All patients received aspirin (81–325 mg/day) prior to the procedure and indefinitely after the procedure. Following stent placement, all patients received a loading dose of clopidogrel (300–600 mg) followed by clopidogrel (75 mg/day for 3–6 months) or ticlopidine (250 mg bid for 3–6 months). Engagement of the ostium of the affected SVG was performed using standard techniques. Angiography was performed in the single best view to document the SVG lesion(s). The target lesion(s) in the diseased SVG was crossed with a 0.0014 inch coronary guidewire. The stent was advanced to the distal portion of the guiding catheter. All patients then received 200–300 µg of intragraft nicardipine (10–15 µg/ml of normal saline) injected via the guiding catheter. Immediately following the nicardipine injection, the stent was advanced to the target site, positioned and deployed via direct stenting (83/83 lesions) with a single, prolonged balloon inflation (>/=2 minutes; mean 2.4 ± 0.8 minutes) at 14–19 atmospheres inflation pressure (mean 16.5 ± 2.7). Following complete balloon deflation, the balloon was carefully removed from the SVG. Coronary angiography was then performed in the same projection that was used prior to intervention. Postdilatation was performed in 3/83 (3.6%) of the SVGs. In each of these cases, a second bolus of nicardipine was given just prior to the balloon inflation to postdilate. Final angiography was performed after removal of the guidewire. ECGs and CPKs, and CPK MBs were obtained preprocedure and at 12–18 hours after the intervention. CPK-MB was measured in all patients with postprocedural chest pain, ECG changes and/or CPKs above the upper limit of normal (ULN) (i.e., ULN for CPK is 190 IU in our laboratory). Thirty-day follow-up data were obtained in 67/68 (98%) patients. Adverse clinical events included all no-reflow in the catheterization laboratory, Q-wave or non-Q-wave MI, target lesion revascularization, and death. These data were collected for in-hospital events and out to a 30-day follow up. Complete follow up of procedural details and 30-day adverse events (defined as above) were obtained in 67/68 patients (98% follow up) by core lab film review, phone interview, clinic visit(s) and/or chart review. Data collection. The data collection included pre- and postoperative ECG, CPKs with CPK-MB fractions and quantitative coronary angiography (QCA). Angiographic data were collected by digital film review in our medical center’s QCA core laboratory using standard operating procedures and CMS Medis software. Pre- and postprocedural measurements of minimum lumen diameter (MLD), reference diameter, percent (%) diameter stenosis, and TIMI flow were collected for all 83 SVG interventions. In patients with normal (TIMI 3) flow prior to stent placement, no-reflow was defined as impaired antegrade coronary blood flow with a TIMI grade of 2 or lower, without angiographic evidence of vessel obstruction. For patients with (baseline) TIMI 2 flow, no-reflow was defined as any decrement in blood flow after stent placement (i.e., TIMI 1 or 0 flow), or TIMI 2 flow with chest pain and/or ischemic ECG changes. Any patient with TIMI 0 or 1 flow after stent placement was classified as having suffered a no-reflow event. Myocardial infarction was defined as the occurrence of an elevated CPK-MB fraction >3 times the ULN^17,18 for our laboratory. CPK-MB was measured in all patients with postprocedural chest pain, ECG changes and/or CPKs above the ULN. All patients with evidence of enzymatic MI underwent serial ECGs to assess whether the MI was a Q-wave or non-Q-wave MI. Statistics. Data are presented as mean ± standard deviation. Cost analysis was performed comparing the actual cost per case in the current series versus the projected cost with distal protection based upon pricing of distal protection devices at our institution. The angiographic, clinical and CPK elevation data from the SAFER (PercuSurge™), and PRIDE^17,18 trials using distal protection systems in SVG stenting were compared to the results in the current study. Since this represents a nonrandomized historical comparison, no statistics were used to evaluate the relative outcomes versus historical data. Results The clinical, angiographic and laboratory data for the 68 patients are summarized in Table 1. The average graft age was 11.9 ± 6.6 years (range 4–18 years). Angiographic signs of thrombus, defined as filling defect(s) consistent with thrombus and not plaque, were observed in 26/83 vessels (31%) prior to stenting. Successful stent placement was accomplished in 83/83 lesions (100%). The mean preintervention MLD and percent (%) diameter stenosis were 1.12 ± 0.48 mm and 67 ± 12%, respectively. The mean MLD and % diameter stenosis improved to 3.03 ± 0.75 mm and 12 ± 2% after stent intervention. The TIMI flow (mean) was 2.25 ± 0.79 prior to intervention, and 2.84 ± 0.69 after intervention. There were an average of 1.48 ± 0.89 stents placed per patient (range 1–6 stents). The average lesion length treated was 18.8 ± 12.4 mm, with a mean stent length of 23.7 ± 10.1 mm/lesion and 31 ± 13.6 mm stents placed per patient. Twelve patients had SVG intervention in 2 SVGs, and 3 patients had stents placed in 3 separate SVGs. Six patients had intervention in 1 or more native vessel lesion(s) in addition to the SVG intervention. In multivessel or multilesion SVG stenting, an intragraft bolus of nicardipine was given prior to direct stenting of each lesion/vessel. The postprocedural (12–18 hours postprocedure) total CPK levels were elevated to >2 times the ULN in 2/68 (2.6%) patients, and to >3 times the ULN in 1/68 patient (1.5%). CPK-MB was elevated to >3 times the ULN in 3/68 patients (4.4%), and >8 times normal in 0/68 cases. Among the 68 patients, the mean peak postprocedure CPK value was 107 ± 65 (ULN = 190). No patient had prolonged chest pain or ECG evidence of Q-wave MI. The mean cost of the nicardipine used was $89/patient. The average length of stay was 2.7 ± 0.8 days, with 63/68 patients discharged on the day following the SVG intervention. Angiographic images from 2 of the SVG interventions are shown in Figure 1. In neither of these cases did the patient experience chest discomfort, ECG changes or CPK elevation postintervention. In both cases, flow improved from TIMI 2 to TIMI 3 after the intervention. We have previously published the results with the first 2 patients undergoing 3 SVG stent procedures using nicardipine prophylaxis in one setting with excellent outcomes and no CPK elevation.¹⁷ Since no equivalent prospectively evaluable SVG intervention patients (at our institution) were available as controls, we elected to compare the results from this registry with contemporary published data in similar patients using similar endpoints from randomized clinical trials utilizing mechanical distal protection devices^17,18 (Figure 2). There were no additional major adverse cardiac events (MACE) observed from hospital discharge to 30-day follow up in the 67 patients who underwent 30-day follow up. One of the 68 patients was lost to follow up. The total MACE at 30 days was 4.4%, with no deaths, MI or repeat target lesion revascularization from hospital discharge to 30 days. Discussion No-reflow is a frequent and morbid complication after percutaneous intervention in degenerated coronary SVGs.^1–5 Historically, this complication occurs in 15–30% of SVG interventions and is associated with significant myocardial necrosis, prolonged hospital stay and a relatively high mortality rate.^1–5 In recent years, many operators have adopted the use of distal mechanical protection devices based on clinical trial data showing that these devices help to reduce the incidence of no-reflow events following SVG intervention.^17,18 Most of the prior research examining the use of calcium channel-blockers in the setting of no-reflow has focused on the reversal of this complication once it has occurred. However, in a recently published prospective, small, randomized study, Michaels et al demonstrated the feasibility of preventing no-reflow by premedication with the prophylactic administration of a calcium channel-blocker (verapamil), prior to stenting in SVG interventions.¹⁹ In this randomized trial, no-reflow occurred in 33.3% of the placebo group, compared to none of the verapamil patients. Similarly, our group has published encouraging data using prophylactic intragraft nicardipine in triple-vessel SVG interventions.¹⁶ There is a large body of clinical evidence demonstrating the effectiveness of arteriolar vasodilators such as diltiazem, verapamil, adenosine and nitroprusside in reversing no-reflow.^6–10 These data suggest that no-reflow is complex and may be caused predominantly by microvascular spasm and not directly by mechanical obstruction from macroscopic debris. This concept is further strengthened by an important recent study showing a marked increase in the highly potent, soluble vasoconstricting substances serotonin and endothelin after elective stenting of degenerated SVGs.²⁰ These observations may explain why mechanical distal protection, particularly with porous filters, is not completely effective in preventing no-reflow (i.e., the chemical substances released from activated platelets and/or endothelial cells will not be stopped by filters). Given the increasing evidence that microvascular spasm plays a central role in the no-reflow phenomenon,^{6–10,16,19,20} it is logical to consider the use of a relatively long-acting and potent arteriolar vasodilator just prior to stenting in order to facilitate reflow after balloon deflation. Nicardipine may be the best single agent for this application for a number of reasons. First, intracoronary nicardipine has been demonstrated to be highly effective in increasing coronary blood flow, while producing minimal systemic side effects.^12–16 Nicardipine is highly vasoselective. Unlike diltiazem and verapamil, nicardipine is associated with very modest negative chronotropic and inotropic effects.^12–15 Finally, unlike adenosine or nitroprusside, nicardipine has a relatively long duration of action following intracoronary administration (5–7 minutes). Fugit and colleagues demonstrated the potential advantages of nicardipine in an important study. In this investigation, intracoronary nicardipine (200 µg), diltiazem (10,000 µg) and verapamil (200 µg) were serially administered in a randomized, double-blind fashion to 9 patients who had minimally diseased (10 Doppler flow wire data demonstrated that nicardipine caused a substantially greater increase in coronary blood flow velocity and a longer duration of effect (5–7 minutes) than the other calcium channel-blockers.¹⁰ Huang and Savage recently published a series showing a high level of efficacy using nicardipine to reverse, rather than prevent, no-reflow.²² Slow- or no-reflow was reversed to TIMI 3 flow in 98% of native coronary artery events and in 100% of SVG events with no-reflow (23/23 cases).²¹ In addition to prophylactic arteriolar vasodilatation using nicardipine, we also employed prolonged balloon inflation during direct stenting. In theory, prolonged balloon inflation with direct stenting and avoidance of pre- and postdilatation could help to seal friable (SVG) plaque behind the stent struts and to minimize distal macroembolic embolization following balloon deflation. The ongoing arteriolar vasodilating effects from the nicardipine, combined with endogenous vasodilators from prolonged ischemia, should allow rapid washout of debris, platelets and vasoactive substances such as serotonin, endothelin and thromboxane.²⁰ The current study describes the promising effectiveness of prophylactic, intracoronary administration of nicardipine prior to direct stenting, without adjunctive distal (mechanical) protection, as a method to minimize the incidence of no-reflow in SVG interventions. This consecutive series of 83 elective SVG interventions represents a “real-world” experience in elective SVG intervention. The inclusion criteria in this registry were extremely broad. Only SVGs with total occlusion or patients with ongoing MI were excluded from this consecutive cohort. The lesion length, graft age, patient’s age, lesion length and number of vessels treated would, if anything, suggest a higher risk of MACE in the current study as compared to prior trials evaluating the safety and efficacy of mechanical distal protection in SVG intervention (Table 1).^17,18 The 4.4% 30-day MACE and 4.4% incidence of >3 times CPK-MB elevation with prophylactic intragraft nicardipine in the current study compares favorably with data from the SAFER trial.¹⁷ The PRIDE trial looked at results with three different mechanical distal protection systems. In that study, the incidence of MI after elective SVG intervention in patients similar to those treated in our study was 11.9% for the FilterWire™ (Boston Scientific Corp., Natick, Massachusetts) subgroup, 11.3% for the GuardWire™ (PercuSurge, Inc., Sunnyvale, California) subgroup and 7.6% for the TriActiv™ (Kensey Nash Corp., Exton, Pennsylvania) subgroup. In the FilterWire subgroup, there was a 7.1% incidence of >8-fold CPK-MB increase compared to 0/68 (0%) cases in the current study. Although no statistical test was used to compare these results, it appears that the use of “pharmacologic” distal protection in our study resulted in much better outcomes than the control group in SAFER, and at least as well as the distal (mechanical) protection groups in both the SAFER and PRIDE studies.^17,18 The excellent results using prophylactic nicardipine are particularly relevant for the treatment of the 25–30% of lesions in which mechanical distal protection may not be anatomically feasible (e.g., too distal for filters). Unlike mechanical distal protection, this “pharmacologic” distal protection technique can be used in all SVG interventions, with or without adjunctive use of filters. In addition, there may also be trauma and initiation of no-reflow by the passage of the distal protection device across a severe stenosis. Prophylactic nicardipine may help to prevent these events. Finally, the pharmacologic technique used in this series allows a time-efficient and cost-effective intervention, compared to the routine use of distal (mechanical) protection devices. The total cost to our institution for the no-reflow prophylaxis in our 83 SVG interventions using nicardipine ($89/vial) was $7,387. In contrast, the total (projected) cost using a FilterWire would have been $107,651 ($1,189/graft), based upon current pricing of this device at our institution. Study limitations. This was a single-center, nonrandomized registry. Historical control data were used to examine the potential efficacy of prophylactic nicardipine to prevent slow-reflow and/or myonecrosis in these SVG interventions. Other operators at other centers may not necessarily reproduce the results obtained by the operators using this technique at our center. The films were read by the local angiographic core lab, and not by an outside laboratory. The technical staff read the films without input from the primary operators. Conclusions We conclude that prophylactic intragraft administration of nicardipine followed by immediate direct stenting appears to be a safe and effective means of performing elective SVG revascularization. The incidence of no-reflow and/or myonecrosis after SVG stenting with this technique appears at least as low, if not lower, than contemporary historical control data using mechanical distal protection. This approach may provide a simple time- and cost-effective alternative or adjunct to mechanical distal protection for elective SVG interventions. This technique is particularly relevant in the one-third of SVG interventions in which the anatomy precludes the use of distal mechanical protection. Ultimately, it would be useful to conduct a randomized trial comparing premedication with nicardipine to placebo, with or without the use of mechanical distal protection.

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