ABSTRACT: Saphenous vein graft angioplasty and stenting has been associated with a relatively high risk of no-reflow and myocardial necrosis. The injectable dihydropyridine calcium channel blocker, nicardipine, is a highly potent arteriolar vasodilator, could be valuable as a prophylactic treatment to prevent no-reflow during SVG interventions. We examined the use of prophylactic, intracoronary (intra-graft) nicardipine, without distal protection, as a means to prevent no-reflow and myocardial necrosis in two consecutive patients undergoing 3-vessel, saphenous vein graft intervention. Following IC nicardipine injection, six stents were placed via direct stenting in the six degenerated SVGs. The average graft age was 13.5 years. Clinical, electrocardiographic, enzymatic (CPK and CPK-MB, troponin) and quantitative coronary angiographic methods were used to assess the safety and efficacy of this treatment in these two high-risk cases. There were no clinical, enzymatic or electrocardiographic signs of ischemia or injury after the use of nicardipine IC injection combined with direct stenting in these cases. Angiograph-ically, TIMI flow was 2.33 ± 0.52 prior to intervention, and improved to 3.0 ± 0.0 after intervention. The mean (TIMI) myocardial blush scores from the 6 SVG distributions improved from 1.82 ± 0.41 prior to intervention, to 2.67 ± 0.52 after intervention. The CPK peaks were 79 IU and 105 IU, respectively, in the two cases (upper limit normal = 190 IU). In summary, the dihydropyridine calcium channel blocker, nicardipine, may provide effective prophylaxis for no-reflow and myocardial necrosis, without the routine use of distal embolic protection devices, in SVG stent interventions. A larger prospective study is warranted to expand upon this preliminary observation.

       No-reflow, or slow-reflow, is a common complication during percutaneous coronary intervention in saphenous vein graft (SVG) angioplasty or stenting. No-reflow after SVG intervention is often associated with serious adverse clinical outcomes.^1–3 The important role of microvascular vasoconstriction as a predominant mechanism of no-reflow has been demonstrated by the successful reversal of no-reflow using a variety of microvascular vasodilators (verapamil, diltiazem, adenosine, nitroprusside, etc.).^4–11
       Nicardipine is a highly potent arteriolar vasodilator, with a longer duration of action than either diltiazem or verapamil when given by intracoronary administration.^10–12 Nicardipine has relatively greater coronary vasoselectivity, greater microcirculatory vasodilating activity, and is associated with minimal myocardial depression or AV nodal disruption.^12–16 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 to prevent no-reflow without distal protection in two “high-risk” cases of triple-vein graft intervention, using a direct stenting technique.

Methods
       Case 1. This was the case of an 80-year-old male with severe three-vessel coronary artery disease who presented with progressive angina. Non-invasive testing with a stress Myoview nuclear scan demonstrated multi-focal ischemia in the inferior and postero-lateral distributions. The patient had a history of bypass surgery in 1991, with reverse saphenous vein grafts (SVGs) placed to the obtuse marginal (OM), right (RCA), and diagonal coronary arteries. In 2003 he underwent stent placement for progressive disease in his “protected” left main coronary artery supplying the left anterior descending coronary artery.
       The patient was admitted in October 2004 for diagnostic coronary arteriography and possible intervention. His diagnostic study demonstrated patency of his left main stent. He had new and progressive disease in the proximal portion of the SVGs to the obtuse marginal and diagonal branches. There was moderately severe disease in the mid-portion of the SVG to the distal right coronary artery (RCA) (Figure 1). The ejection fraction was measured to be 68%.

Figure 1

Angiographic example of the usefulness and efficacy of intracoronary nicardipine in preventing "no-reflow" during multivessel saphenous vein bypass graft (SVG) intervention. Panels A, C and E show the pre-treatment appearance of the OM, RCA and diagonal SVGs, respectively. The final angiographic results for the SVGs to OM, RCA and diagonal SVGs are shown in panels B, D and F, respectively. The highlighted oval in panel D shows the potent myocardial blush following the direct stenting of the RCA SVG after nicardipine prophylaxis.

       After angiographic review, it was elected to proceed with multiple bypass graft, direct stent intervention using prophylactic intracoronary administration of nicardipine. The patient was medicated with 70 IU/kg of intravenous heparin. Intravenous eptifibitide was administered. The activated clotting time (ACT) was 231 seconds after heparin administration.
       The obtuse marginal (OM) SVG was engaged with a 7 French (Fr) left coronary bypass graft guiding catheter (Cordis, Corporation, Miami Lakes, Florida). A Cordis 0.0014 inch ATW wire was used to cross the OM SVG lesion. Cardene IV (25 mg in 10 ml vial; ESP Pharma, Edison, New Jersey) was mixed in normal saline to achieve a final nicardipine concentration of 10 mg/ml (2.5 mg mixed in 250 ml normal saline). Just prior to direct stenting of the SVG lesion, 300 micrograms of nicardipine were injected down the SVG (IC) via the guiding catheter. Immediately after the nicardipine injection, a 3.5 mm diameter x 18 mm length Cypher™ drug-eluting stent (Cordis Corp.) was advanced across the lesion. The balloon was inflated for 2 minutes at 18 atmospheres. Following pre-medication with a second dose of 300 mg of IC nicardipine, the stent was post-dilated using a 3.75 mm diameter balloon at 17 atmospheres. Final angiography demonstrated an excellent result, with brisk antegrade coronary blood flow.
       The diagonal SVG was engaged with a 7 Fr left coronary bypass graft guiding catheter (Cordis Corp.). Three-hundred micrograms of nicardipine were injected down the SVG via the guiding catheter, just prior to direct stenting. A 3.5 mm diameter x 28 mm length Cypher drug-eluting stent was advanced across the lesion. The balloon was inflated for 2 minutes at 17 atmospheres. Final angiography demonstrated an excellent result, with normal antegrade coronary blood flow.
       The RCA SVG was engaged with a 7 Fr multi-purpose guiding catheter (Cordis Corp.). Intracoronary nicardipine (300 mg) was injected down the SVG via the guiding catheter, just prior to direct stenting. A 4.0 mm diameter x 28 mm length Hepacoat™ stent (Cordis Corp.) was advanced across the lesion. The balloon was inflated for 2 minutes at 17 atmospheres. Final angiography demonstrated an excellent result, with normal coronary blood flow.
       Case 2. This was the case of an 83-year-old male with severe three-vessel coronary disease. The patient had undergone bypass surgery in 1989, with reverse saphenous vein grafts (SVGs) placed to the left anterior descending (LAD), obtuse marginal (OM), and right (RCA) coronary arteries. He presented with progressive chest pain and evidence of non-Q-wave myocardial infarction. His troponin level at the time of presentation was 278 ng/ml, falling to 121 ng/ml on the day prior to intervention (< 0.2 ng/ml is normal limit). His CPK peak, at the time of admission, was 827 IU with 11.2% MB fraction.
       Diagnostic coronary arteriography was performed three days after

Figure 2

Angiographic example of the usefulness and efficacy of intracoronary nicardipine in preventing "no-reflow" during multivessel saphenous vein bypass graft (SVG) intervention. Panels A, C and E show the pre-treatment appearance of the OM, RCA and LAD SVGs, respectively. The final angiographic results for the SVGs to OM, RCA and LAD SVGs are shown in panels B, D and F, respectively.

admission. This study demonstrated severe obstructive disease in the ostial/proximal portion of the SVG to the LAD, with evidence of intraluminal thrombus. There was also severe obstruction in the proximal portions of the SVGs to the obtuse marginal and right coronary arteries (Figure 2). There was moderate hypokinesis of the anterolateral wall segment. The ejection fraction was 47%.
       After angiographic review, it was elected to proceed with multiple bypass graft, direct stent intervention using prophylactic intracoronary administration of nicardipine.
       The patient was medicated with 70 IU/kg of intravenous heparin. Intravenous eptifibitide was administered. The activated clotting time (ACT) was 274 seconds after heparin administration. The left anterior descending (LAD) SVG was engaged with a 7 Fr left coronary bypass graft guiding catheter (Cordis Corp.). Intragraft nicardipine (200 micrograms; mixed as 10 mg/ml in normal saline) was injected down the SVG via the guiding catheter, just prior to direct stenting. A 4.5 mm diameter x 18 mm length Hepacoat stent was advanced across the lesion. The stent delivery balloon was inflated for 2 minutes at 16 atmospheres. Final angiography demonstrated an excellent result, with normal coronary blood flow.
       The obtuse marginal SVG was engaged with the same 7 Fr left coronary bypass graft guiding catheter (Cordis Corp.). Nicardipine (200 mg) was injected down the SVG (IC) via the guiding catheter, just prior to direct stenting. A 5.0 mm diameter x 18 mm length Hepacoat stent was directly advanced across the lesion. The balloon was inflated for 2 minutes at 16 atmospheres. Final angiography demonstrated an excellent result, with normal coronary blood flow.
       The RCA SVG was engaged with a 7 Fr multi-purpose guiding catheter (Cordis Corp.). Nicardipine (300 mg) was injected down the SVG via the guiding catheter, just prior to direct stenting. A 5.0 mm diameter x 18 mm length Hepacoat stent was advanced across the lesion. The balloon was inflated for 2 minutes at 17 atmospheres. Final angiography demonstrated an excellent result.

       Data collection. The data collection included pre- and postoperative ECGs, CPKs with CPK MB fractions, troponin levels, and quantitative coronary angiography (QCA). Angiographic data were collected by digital film review in the Borgess QCA core laboratory using standard operating procedures. Pre- and post-procedural measurements of minimum lumen diameter (MLD), reference diameter, percent (%) diameter stenosis, TIMI flow, and TIMI myocardial blush scores were collected for all six SVG interventions. Myocardial blush scores were determined using standard definitions. Grade 0 = Failure of dye to enter the microvasculature; Grade 1 = Dye slowly enters but fails to exit the microvasculature; Grade 2 = Delayed entry and exit from the microvasculature (i.e., dye is strongly persistent after three cardiac cycles of the washout phase); Grade 3 = Normal entry and exit from the microvasculature (i.e., dye is gone or is mildly/moderately persistent after three cardiac cycles of the washout phase and noticeably diminishes in intensity during the washout phase), similar to that in an uninvolved artery.
       This paper is intended to be a descriptive case study, and not a controlled clinical trial. Therefore, no statistics were applied to compare the pre-intervention and post-intervention data.

Results
       The core laboratory angiographic data are presented in Table 1. All six lesions in the six saphenous vein grafts were treated successfully. The mean pre-intervention MLD and % diameter stenosis were 1.14 ± 0.44 mm and 64 ± 11%, respectively. The mean MLD and % diameter stenosis improved to 3.43 ± 0.83 mm and 10 ± 2% after stent intervention. The TIMI flow (mean) was 2.33 ± 0.52 prior to intervention, and 3.0 ± 0.0 after intervention. The TIMI perfusion (blush) scores (mean) were 1.83 ± 0.41 prior to intervention and 2.67±52 after intervention.
       The baseline CPK level was normal in patient 1 (68 IU), and moderately elevated at admission for patient 2 (827 CPK, 11.2% MB). The CPK peaks were 57 IU (2.5% MB fraction) and 105 (4% MB fraction) IU at 12 hours post-procedure for patients 1 and 2, respectively. The upper limit of normal for CPK is 190 IU, with < 4.1% MB fraction, in our laboratory. Patient 1 had troponin levels < 0.2 ng/ml prior to and 12 hours post-procedure (normal < 0.2 ng/ml). Patient 2 had elevated troponins of 278 ng/ml two days prior to stenting, and 121 ng/ml on the day prior to intervention. The troponin dropped to 21 ng/ml 12 hours after the stent intervention. Both of the patients’ ECGs were unchanged 12 hours post-intervention, compared to the pre-intervention ECGs.
       Angiographic images from the six interventions are shown in Figures 1 and 2. Neither patient had any chest discomfort, bleeding, or other in-hospital complications after their multi-vessel intervention. The total time for the three-vessel interventions were 37 minutes for patient 1, and 56 minutes for patient 2. Both patients were discharged on the morning following their intervention. There were no major adverse cardiac events for either patient at 30-day follow-up.

Discussion
       This report describes the potential effectiveness of prophylactic intracoronary administration of nicardipine prior to direct stenting, as a method to reduce the incidence of no-reflow in saphenous vein graft interventions. Both patients could be considered to be at very high risk of no-reflow due to the graft age, their presentation with acute coronary syndromes, and the sequential stenting of three severely diseased SVGs in one procedure.
       Given the increasing evidence that microvascular spasm plays a central role in the no-reflow phenomenon,^4–11 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 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 vaso-selective. Unlike diltiazem and verapamil, nicardipine is associated with very modest negative chronotropic and inotropic effects.^12–16 Finally, nicardipine has a relatively long duration of action following intracoronary administration (5–7 minutes). This allows ongoing vasodilatation during prolonged balloon inflations using direct stenting. In theory, this could help to seal friable (SVG) plaque behind the stent struts, and thereby minimize distal embolization following balloon deflation. Relatively high-pressure stent deployment was utilized in these cases to achieve optimal stent expansion. This approach is based upon our prior evaluation of stent delivery balloon compliance curves.¹⁷
       The advantages of nicardipine are best illustrated in an important study by Fugit and colleagues. In this study, intracoronary nicardipine (200 mg), diltiazem (10,000 mg), and verapamil (200 mg) were serially administered in a randomized double-blind fashion to 9 patients who had minimally diseased (< 30% stenosis) coronary arteries.¹¹ Two patients receiving intracoronary diltiazem had a transient episode of type 1 second-degree AV block. Doppler flow-wire data demonstrated that nicardipine caused a substantially greater increase in coronary blood flow velocity and a longer duration of effect (5–6 minutes) than the other calcium channel blockers. These data suggest that nicardipine should be the preferred calcium channel blocker for the prophylaxis or treatment of no-reflow.¹¹
       Most of the prior research examining the use of calcium channel blockers in the setting of the no-reflow has focused on the reversal of this complication once it has occurred. However, in a recently published prospective, randomized study, Michaels et al. demonstrated the possibility of preventing no-reflow by pre-medication with the prophylactic administration of a calcium channel blocker (verapamil) prior to stenting in saphenous vein graft interventions.¹⁸ In this randomized trial, no-reflow occurred in 33.3% of the placebo group, compared to none of the verapamil patients. Similar, encouraging data have been published showing a reduction of non-Q-wave myocardial infarction using prophylactic administration of intracoronary diltiazem prior to treatment with directional atherectomy in native vessels.¹⁹
       The results reported in this case study are encouraging, and suggest that prophylactic administration of nicardipine prior to direct stenting may be associated with a low incidence of no-reflow. Our group is completing data collection from a consecutive series of more than 70 SVG stent interventions using prophylactic intracoronary nicardipine to prevent no reflow.
       Importantly, this technique can allow a time-efficient and potentially cost-effective intervention when compared to the routine use of distal protection devices. The ability to perform complex, three-vessel SVG intervention in less than 45 minutes attests to the efficiency of this approach. In addition, a minimum of three separate distal filters would have had be used in each of the cases presented if one follows FDA labeling instructions. In our laboratory, the three Filterwires™ required (Boston Scientific, Natick, Massachusetts) would cost $3,891/case. In contrast, the one vial of Cardene IV used in each of the cases presented in this study cost only $89/vial at our medical center.
       It should be noted that this technique does not preclude the use of distal protection. It is possible that the use of prophylactic intracoronary nicardipine, combined with distal protection, may provide the most effective method for reducing the incidence of the morbid and mortal complications of no-reflow. The results observed in these case studies should be reconfirmed in a larger case series and ultimately in a randomized trial comparing premedication with nicardipine to placebo, with or without the use of distal protection.

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