"Pharmacologic" Distal Protection Using Prophylactic, Intragraft Nicardipine to Prevent No-Reflow and Non-Q-Wave Myocardial Infarction during Elective Saphenous Vein Graft Intervention

Tim A. Fischell, MD; Raviprasad G. Subraya, MD; Kamal Ashraf, MD; Benjamin Perry, MD; Scott Haller, MS

Disclosures

J Invasive Cardiol. 2007;19(2):58-62. 

In This Article

Discussion

No-reflow is a frequent and morbid complication after percutaneous intervention in degenerated coronary SVGs.[1,2,3,4,5] 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.[1,2,3,4,5] 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.[6,7,8,9,10] 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,[6,7,8,9,10,16,19,20] 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.[12,13,14,15,16] Nicardipine is highly vasoselective. Unlike diltiazem and verapamil, nicardipine is associated with very modest negative chronotropic and inotropic effects.[12,13,14,15] 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 (<30% stenosis) coronary arteries.[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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