Pretreatment with Intragraft Verapamil Prior to Percutaneous Coronary Intervention of Saphenous Vein Graft Lesions: Results of t

Author(s): 

Andrew D. Michaels, MD, *Mark Appleby, MD, Matthew H. Otten, BA, †Kent Dauterman, MD, Thomas A. Ports, MD, Tony M. Chou, MD, §C. Michael Gibson, MS, MD

Intracoronary calcium channel blockers have been administered during percutaneous coronary interventions (PCI) for the management of reduced coronary flow due to microvascular dysfunction.1–3 More recent studies have shown that intracoronary calcium antagonists may improve coronary and myocardial perfusion when given prophylactically prior to elective PCI,4,5 and in patients undergoing primary PCI for acute myocardial infarction.6 In addition to calcium channel blockers, other agents including abciximab,7 adenosine8 and the adenosine triphosphate-sensitive potassium channel opener nicorandil9 have been used to treat or prevent no-reflow.
No-reflow during PCI of degenerated saphenous vein grafts (SVGs) occurs in roughly 10–40% of cases. Intragraft adenosine8 and verapamil10 have been shown to be effective in treating no-reflow during PCI of SVGs, while nitroglycerin has no beneficial effect.10 No study, however, has assessed the efficacy of intragraft calcium antagonists in the prevention of no-reflow prior to SVG PCI. Accordingly, we randomized patients undergoing SVG PCI to receive intragraft verapamil or no verapamil prior to PCI in order to test the hypothesis that intragraft verapamil was effective in preventing no-reflow and improving graft and native coronary blood flow.

Methods

Patient selection. Patients enrolled in this study were candidates for PCI of an SVG. Patients with systolic blood pressure < 95 mmHg, heart rate < 50 beats per minute, and those on vasopressors were excluded. Patients with completely occluded SVGs on diagnostic angiography were also excluded. The study protocol was approved by the University of California at San Francisco Committee on Human Research, and informed written consent was obtained from all patients.

Study protocol. Eligible patients were randomized to receive 200 µg of intragraft verapamil through the guiding catheter or no verapamil prior to advancing the guidewire into the SVG. Coronary angiography was performed prior to and following PCI of the SVG. Cardiac enzymes (CK-MB or troponin I) were checked 6–12 hours post-PCI.

Angiographic definitions. No-reflow was defined as a decrease of at least one Thrombolysis in Myocardial Infarction (TIMI) flow grade during or after PCI. TIMI flow grade, TIMI frame count (TFC), and TIMI myocardial perfusion grade (TMPG) were assessed prior to and following PCI by an experienced, blinded angiographic reader.
The TIMI flow grade was used for the assessment of flow in the graft. TIMI flow in the vessel was classified as grade 0 (no flow); grade 1 (penetration without perfusion); grade 2 (partial perfusion); or grade 3 (complete perfusion). The TFC is the number of cineframes required for dye to travel from the ostium of a saphenous vein bypass graft to a standardized distal native coronary landmark.11
Angiographic assessment of myocardial perfusion was undertaken using the TIMI myocardial perfusion grading system. TMPG is a categorical angiographic method to assess the filling and clearance of contrast in the myocardium to assess tissue level perfusion.12 In TMPG 3, there is the normal diffuse ground glass appearance of myocardial blush. At the end of the washout phase, dye is only mildly persistent or gone. The washout phase is the time after the end of dye injection during which dye would normally be expected to clear from the epicardial vessels during opacification of the myocardium, followed by clearing from the myocardium. In TMPG 2, dye enters the myocardium, but accumulates and exits more slowly, so that at the end of the washout phase, dye in the myocardium is strongly persistent; however, dye totally clears by the next injection. In TMPG 1, the dye does not leave the myocardium and there is a stain on the next injection. In TMPG 0, dye does not enter the myocardium and there is minimal or no blush apparent during the injection and washout phases.

Statistical analysis. Data are presented as mean standard deviation unless otherwise noted. Differences between the experimental groups were noted by two-tailed student’s t-test, Chi-square, and exact Mann-Whitney rank test where appropriate. P-values < 0.05 were considered significant.
Results

Patient population. Twenty-two patients were enrolled in the VAPOR trial: twelve patients in the placebo arm and 10 patients in the verapamil arm. The mean age of the overall patient population was 72.2 ± 8.7 years, 86% were male and 23% were diabetic. There were no differences in demographic characteristics, incidence of acute coronary syndrome, or SVG age between the two groups (Table 1).

Procedural characteristics. No episodes of hypotension or bradycardia were observed in the verapamil group. The SVG target vessel was most commonly the obtuse marginal branch in both groups, and least commonly supplied the left anterior descending or diagonal branch (Table 2). The left ventricular ejection fraction was mildly reduced in both groups. Glycoprotein IIb/IIIa receptor inhibitors were prescribed prior to SVG PCI in 21 out of 22 patients. Abciximab was given to 12 patients, tirofiban to 5 patients, and eptifibatide to 4 patients. Only 1 patient in each group did not receive a stent. Rotational atherectomy was performed in an anastomotic lesion in 1 patient in the verapamil group. A distal protection device (i.e., PercuSurge™, Medtronic AVE, Santa Rosa, California) was not used in any of these cases.
There was a trend toward a fewer number of stents per patient in the verapamil group (0.9 ± 0.3 stents) compared to the placebo group (1.3 ± 0.6 stents; p = 0.07). There was also a slight trend toward a shorter total stent length used in the verapamil group (19.6 ± 5.7 mm) compared to the placebo group (26.7 ± 13.4 mm; p = 0.17). Iohexol contrast (Omnipaque™, Nycomed Amersham Imaging, Princeton, New Jersey) was used in all cases. Total volume of contrast and procedural fluoroscopic time were not significantly different between groups.
One patient in the placebo group was enrolled with an acute myocardial infarction involving the SVG to the obtuse marginal branch. Excluding this patient, two patients in each group had a new elevation in cardiac enzymes 6–12 hours following PCI.

Angiographic results.No-reflow occurred in 33.3% of the placebo group, compared to none of the verapamil patients (p = 0.10; Table 3). Additional intragraft vasodilator medication was given to 25% of the placebo group during or following PCI, compared to none of the verapamil patients (p = 0.23). There was a significant improvement in the TIMI frame count in patients given intragraft verapamil compared to those given placebo prior to intervention (11.5 ± 38.9 versus 53.3 ± 22.4; p = 0.016). There was a trend toward an improvement in TMPG in patients treated with verapamil compared with controls (37% versus 16.7%; p = 0.14).

Discussion

The administration of intragraft verapamil was associated with a significant improvement in coronary flow as assessed by the TIMI frame count in patients undergoing PCI of an SVG. There were trends toward improved TIMI flow grade and the TMPG, categorical qualitative measures of coronary blood flow and perfusion, respectively. While the incidence of no-reflow was reduced in the verapamil group (0%) compared to placebo (33%; p = 0.10), there was no change in the post-PCI incidence of CK or troponin-I release in this pilot study. The improvement in myocardial perfusion grade is intriguing given the pathophysiologic link between impaired tissue level perfusion, post-PCI myocardial infarction, and adverse outcomes in patients undergoing coronary stenting.13
It is possible that vasodilator administration prior to PCI may be effective in preventing the no-reflow phenomenon. When compared with diltiazem or verapamil, the vasoselective dihydropyridine nicardipine offers a more potent and prolonged increase in coronary blood flow, with little risk of serious systemic adverse effects.14 The longer-acting vasodilators, such as verapamil and nicardipine,13 may be more promising for the prevention of no-reflow compared to the short-acting adenosine. In a retrospective analysis of SVG PCI, the administration of intragraft adenosine prior to PCI did not prevent no-reflow; however, adenosine was effective in the treatment of no-reflow in these cases.15 The half-life of adenosine in human blood is less than 1 second.15 Therefore, prophylactic administration of a very short-acting agent may not be effective to prevent no-reflow. By administering a longer-acting agent to the microvasculature prior to PCI, peri-procedural vasoconstriction may be prevented.
Verapamil may be acting in a number of ways to improve microvascular perfusion in patients undergoing SVG PCI. During these cases, there is a substantial incidence of distal embolization. Mechanisms of benefit by which a longer-acting coronary vasodilator such as verapamil may prevent the no-reflow phenomenon include effects on downstream microvascular perfusion, alpha-adrenergic neural reflexes, prevention of spasm, and reduction of thrombotic occlusions of microvessels.
Of the proposed mechanisms of no-reflow, two appear to be the most treatable and preventable: 1) macrodebris/thrombus distal embolization; and 2) microvascular vasoconstriction and endothelial dysfunction. The PercuSurge™ Guardwire device has been shown to reduce adverse clinical events in patients undergoing SVG PCI.16 This device is effective in trapping and removing embolic material during SVG PCI. Neither this device nor a filter-design distal protection device were used in any of the cases in this pilot study. It is unclear whether prophylactic intragraft vasodilator therapy would confer additional benefit in patients undergoing PCI with distal protection.
The main limitation of this study is the small sample size. The difference in the baseline TFC between the two groups is attributable to the limitations with the small sample size. This study was performed at a single center. This pilot study was not powered to detect differences in adverse clinical events. It is also unclear whether the results of this trial could be generalized to other coronary vasodilators.

Conclusion

In the population studied, the administration of 200 µg of intragraft verapamil prior to SVG PCI produced a significant improvement in coronary flow measured by the TIMI frame count. There were trends toward improvement in the TIMI flow grade, a decreased incidence of no-reflow, and improved myocardial perfusion at the tissue level. As an adjunct to or instead of mechanical distal protection devices, long-acting pharmacologic vasodilators may provide a role in preventing vasospasm associated with distal embolization during SVG PCI. A larger randomized trial is required to determine whether clinical events are improved using intragraft verapamil prior to SVG PCI.


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