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Copyright © 2008 by the Texas Heart® Institute, Houston Treating Acute “No-Reflow” with Intracoronary Adenosine in 4 Patients during Percutaneous Coronary Intervention | |||||||||
Abstract Angiographic evidence of impaired tissue perfusion, known as the “no-reflow” phenomenon, is a serious complication of percutaneous coronary intervention—one that is associated with increased mortality rates. Adenosine is an endogenous nucleoside that attenuates many of the mechanisms that are responsible for no-reflow. Herein, we report the cases of 4 patients who developed the no-reflow phenomenon after elective percutaneous coronary intervention to their native coronary arteries and saphenous vein grafts. In all 4 patients, and without adverse effects, small bolus doses of adenosine through the guiding catheter improved epicardial perfusion—measured by either Thrombolysis In Myocardial Infarction (TIMI) flow grade or corrected TIMI frame count—and tissue-level perfusion, graded according to myocardial blush. In view of adenosine's extremely short half-life in blood, the continuous administration of adenosine into the distal vascular bed throughout percutaneous coronary intervention may further improve outcomes by reversing or preventing the no-reflow phenomenon. Key words: Adenosine/administration & dosage/physiology/therapeutic use, angioplasty, transluminal, percutaneous coronary/adverse effects/methods, atherosclerosis/complications/therapy, cardiotonic agents/administration & dosage/therapeutic use, coronary vessels/drug effects, creatine kinase/blood, dose-response relationship, drug, graft occlusion, vascular/therapy, myocardial reperfusion/methods, treatment outcome, vasodilator agents/administration & dosage/therapeutic use | |||||||||
Percutaneous coronary intervention (PCI) is frequently used to treat atherosclerosis-induced stenosis in native coronary arteries and in degenerated saphenous vein grafts (SVGs). Although PCI has a high initial success rate, enzymatic evidence of myocardial cell necrosis occurs in 22% to 44% of patients after apparently uneventful PCI procedures.1,2 Microvascular obstruction (due in part to embolization of platelets and atheromatous débris) and intense vasoconstriction of the distal bed (secondary to the release of potent humoral mediators) are responsible for microinfarction after PCI.3–6 In some patients, vascular compromise manifests itself during the procedure as an abrupt decrease in epicardial blood flow—Thrombolysis In Myocardial Infarction (TIMI) grade 0 to 1—which is known as the “no-reflow” or “slow-reflow” phenomenon. The compromise occurs in the absence of apparent dissection, coronary spasm, thrombus formation, substantial residual stenosis, or distal-vessel cutoff that is suggestive of macroembolization. Adenosine attenuates mechanisms that are responsible for the no-reflow phenomenon.7 We describe here the cases of 4 patients in whom intracoronary adenosine reversed no-reflow during PCI of the native coronary vessels and SVGs, as measured by TIMI flow grade, corrected TIMI frame count (CTFC), and myocardial blush grade (MBG). | |||||||||
Case Reports Patient 1 In May 2004, a 62-year-old man presented with a 1-week history of exertional angina. He had long-standing coronary disease, having experienced at age 47 a non-ST-segment-elevation myocardial infarction (NSTEMI) in the inferior leads. At that time, coronary angiography revealed 3-vessel disease with relative sparing of the left anterior descending coronary artery (LAD), which had a 50% lesion at the apex. Five-vessel coronary artery bypass grafting was then performed, with internal mammary artery grafts to the right coronary artery (RCA) and 1st diagonal artery, and SVGs to a ramus intermedius and 2 obtuse marginal branches.For 15 years, the patient had remained asymptomatic, and scintigraphic stress studies performed every 2 to 3 years were negative for ischemia. In view of the longevity of the grafts and the severe disease that had been noted during surgery, the patient underwent repeat angiography 1 week after the current presentation. All grafts were patent. Severe (90%), smooth, focal luminal narrowing was identified in the proximal portion of the venous graft to the 3rd marginal branch and in the ostium of the graft to the ramus intermedius (Fig. 1A). No angiographic evidence of thrombus or disease was seen elsewhere in the grafts. The native vessels were small and diffusely diseased. Before PCI, an angiogram of the graft to the marginal branch had revealed TIMI grade-3 flow, a CTFC of 40 frames, and an MBG of 3. A 0.014-inch Balance Middle Weight wire (Abbott Vascular; Santa Clara, Calif; part of Abbott Laboratories, Inc.; Abbott Park, Ill) was easily advanced into the distal 3rd obtuse marginal branch. Primary stenting was performed with a 4.0 × 12-mm Driver® bare-metal stent (Medtronic, Inc.; Minneapolis, Minn), with balloon pressure at 14 atm for 50 sec. After deflation of the balloon, the patient developed chest pain that was associated with 1-mm ST-segment elevation; angiography showed severe no-reflow (TIMI flow, grade 1; CTFC, 124; and MBG, 0) (Fig. 1B). Five 20-μg bolus doses of adenosine were administered over 10 minutes through the guiding catheter. The patient's symptoms and electrocardiographic (ECG) changes resolved within 1 to 2 minutes after the last adenosine bolus, and a subsequent angiogram revealed TIMI grade-2 flow, a CTFC of 50, and an MBG of 2 (Fig. 1C). Percutaneous coronary intervention was then performed on the venous graft to the ramus intermedius. With use of the same guidewire, the lesion was predilated with a 2.0 × 15-mm Maverick® balloon (Boston Scientific Corporation; Maple Grove, Minn), which reduced the luminal narrowing from 90% to 50%. After balloon deflation, the patient developed recurrent chest pain and ECG changes that were associated with a decrease in TIMI flow from grade 3 to grade 1, a worsening of the CTFC from 30 to 56 frames, and a decrease in the MBG from 3 to 0. Five more 20-μg bolus doses of adenosine were administered through the guiding catheter, whereupon the TIMI flow grade and MBG became normal and the CTFC improved to 20. A 3.0 × 12-mm Driver stent (Medtronic) was placed, with a good angiographic result. The patient's condition remained stable during overnight hospitalization, with no ECG changes. Twelve hours after the procedure, the patient's creatine kinase (CK) level was 363 U/L (normal range, 55–170 U/L) and the CK-MB fraction was 18.7 ng/mL (normal range, 0.1–5 ng/mL). Over the next 4 years, the patient remained in stable condition, and nuclear stress tests showed no evidence of ischemia.
Patient 2 In June 2007, a 59-year-old man presented with a 1-month history of progressive exertional angina. He had undergone angiography 10 years earlier for chest pain, but no coronary disease was then detected. Calcium screening 3 years before the current presentation had revealed calcium in 3 coronary vessels, for a score of 64.5 Agatston units. Two years later, a nuclear stress test had revealed no ischemia. At the current presentation, coronary angiography showed a 95% focal stenosis of the proximal LAD, with involvement of the 1st diagonal branch (Fig. 2A). The circumflex and right coronary arteries were of unremarkable appearance. Pre-interventional angiography revealed TIMI grade-3 flow, a CTFC of 24 frames, and an MBG of 3. Percutaneous coronary intervention was performed with the use of a 0.014-inch ChoICE® Floppy guidewire (Boston Scientific) with predilation from a 3.5 × 15-mm Maverick balloon (Boston Scientific) at 10 atm for 8 sec. After balloon deflation, acute no-reflow was observed (TIMI flow, grade 0) without evidence of dissection or thrombi (Fig. 2B). Acute vasospasm was excluded because a 200-μg bolus of nitroglycerin failed to restore flow. A 60-μg bolus of adenosine, administered through the guiding catheter, restored TIMI grade-3 flow. A 3.3 × 23-mm Cypher® stent (Cordis Corporation, a Johnson & Johnson company; Miami Lakes, Fla) was deployed at 10 atm for 11 sec. Acute no-reflow phenomenon was again noted (TIMI flow, grade 0); this was treated with another 60-μg bolus of adenosine. Angiography then showed TIMI grade-3 flow, a CTFC of 20, and a normal MBG (Fig. 2C). The severe stenosis in the 1st diagonal branch was unchanged. The patient's condition remained stable. Serial CK measurements reached a peak of 229 U/L with an MB fraction of 9.8 ng/mL; the peak troponin I level was 1.02 ng/mL (normal, <0.30 ng/mL). Repeat angiography, performed 4 months after the procedure because of anterolateral ischemia that had been discovered upon a nuclear stress test, showed a patent stent and normal TIMI flow; persistence of the diagonal lesion accounted for the scintigraphic finding.
Patient 3 In October 2007, a 64-year-old man with insulin-dependent diabetes mellitus presented with an acute coronary syndrome (ACS). His condition stabilized after the administration of intravenous nitroglycerin and heparin. His troponin I level increased to 0.78 ng/mL 24 hours after his admission to the hospital. Coronary angiography was deferred for 48 hours because of his stable condition and because he had been receiving warfarin for paroxysmal atrial fibrillation. Three years earlier, he had undergone placement of a 3.5 × 18-mm Driver bare-metal stent (Medtronic) to the distal RCA and angioplasty to the posterolateral branch; mild-to-moderate disease (40%–60%) was also noted in the left main and circumflex vessels. Angiography performed during his current admission revealed a severe stenosis in the proximal RCA, along with a filling defect (Fig. 3A). The TIMI flow was grade 2, the CTFC was 44 frames, and the MBG was 2. The distal RCA stent had a 30% stenosis; there was no significant change in the left system. Percutaneous coronary intervention was performed with the use of a 0.014-inch WHISPER wire and a 4.0 × 20-mm VOYAGER™ RX dilatation catheter (Abbott Vascular). After the wire was positioned in the distal RCA, the TIMI flow decreased to grade 1 and the CTFC increased to 80 (Fig. 3B). The administration of two 18-μg boli of adenosine through the guiding catheter resulted in TIMI grade-2 flow, a CTFC of 52, and an MBG of 2 (Fig. 3C). Balloon dilation at 8 atm for 60 sec resulted in TIMI grade-3 flow and a CTFC of 22 (Fig. 3D). A 5.0 × 20-mm Liberté® stent (Boston Scientific) was deployed at 13 atm for 60 sec. Acute no-reflow was again noted, with TIMI grade-1 flow and a CTFC of 80 (Fig. 3E). After the administration of another two 18-μg boli of adenosine, TIMI flow and MBG were each restored to grade 3 and the CTFC to 38 (Fig. 3F). The patient's condition remained stable, and his troponin I levels increased from 0.4 to 2.3 ng/mL 48 hours after the procedure.
Patient 4 In March 2008, a 79-year-old man presented with a 1-week history of exertional angina. Nine months earlier, he had undergone stenting of the 1st marginal branch of the circumflex artery after a NSTEMI (peak troponin level, 4.9 ng/mL). A normal RCA and a 30% stenosis of the 1st diagonal branch were noted at that time. Results of an adenosine nuclear stress test 3 months before the current presentation were normal. At the current presentation, coronary angiography showed an eccentric 60% lesion at the origin of the LAD, and a long 95% stenosis in the mid-LAD. The TIMI flow and MBG were normal, and the CTFC was 36 frames (Fig. 4A). The circumflex stent was patent, and the dominant RCA was angiographically normal. A 0.014-inch HI-TORQUE WHISPER hydrocoat wire (Abbott Vascular) was positioned in the distal vessel, and a 3.0 × 20-mm Maverick balloon (Boston Scientific) was inflated in the mid-LAD lesion at 6 atm for 30 sec. This intervention reduced that stenosis to 30% (Fig. 4B). A 3.0 × 18-mm Cypher stent (Cordis) was deployed at 12 atm; however, a subsequent angiogram revealed that the stent was undersized (Fig. 4C). The proximal lesion was investigated by use of intravascular ultrasonography and a 2.9F Eagle Eye® Gold (Volcano Corporation; San Diego, Calif), which showed a maximal luminal diameter of 3.5 mm and an eccentric mixed plaque that produced an 80% area narrowing. The lesion was subsequently treated with a 3.5 × 8-mm Cypher stent (Cordis). An angiogram revealed TIMI grade-3 flow and a CTFC of 36. A 3.5-mm balloon was then advanced into the stent in the mid-LAD, and 2 inflations at 14 atm were performed. After the 2nd inflation, no-reflow occurred, with a TIMI flow grade of 0 (Fig. 4D). Intracoronary nitroglycerin (200 μg) followed by 2 boli (200 μg each) of nitroprusside did not improve perfusion. Over the next 4 minutes, the patient received 3 boli of adenosine (30, 60 and 60 μg), which resulted in normal TIMI flow, a normal MBG, and a CTFC of 34 (Fig. 4E). Levels of cardiac enzymes, which were normal before the procedure, increased to peak values 18 hours after PCI (CK, 190 U/L; CK-MB, 24.7 ng/mL; troponin I, 4.8 ng/mL). The patient's condition remained stable, and he was discharged from the hospital 48 hours after having been admitted.
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Discussion Percutaneous coronary intervention is the procedure most widely used to treat various clinical syndromes that are associated with atherosclerotic stenosis of native coronary arteries and degenerated SVGs. Due to advances in equipment technology and to newer and more potent pharmacologic agents, PCI currently has a success rate of greater than 95%. Nonetheless, studies1,2 have shown that 22% to 44% of procedures that are categorized as successful and uncomplicated result in varying degrees of myocardial cell necrosis.1,2 Significant elevations of cardiac enzymes occur regardless of whether the procedure is elective or emergent (for an ACS).1,2 Furthermore, post-procedural elevations of CK-MB and troponin significantly increase the risk of early and late death and of recurrent infarction; increasing levels of these enzymes are associated with a parallel increase in death.8,9 Investigation by magnetic resonance imaging has confirmed that these elevations are due to microinfarction that is secondary to distal embolization.10 Percutaneous coronary intervention in the presence of ACS has validated the importance of optimizing epicardial blood flow after the procedure by use of the TIMI grade system and CTFC to measure the flow.11 Recent studies have underscored the importance of evaluating flow throughout the entire vascular bed via the measurement of microcirculatory flow, and of using MBG as a measure of tissue perfusion.7,11,12 Tissue perfusion correlates poorly with epicardial blood flow and is an independent multivariate predictor of early and late death in ACS patients who are undergoing emergency PCI.11 The occurrence of acute no-reflow or slow-reflow phenomenon during PCI manifests itself as a sudden decrease in flow (to TIMI grade 0–1), a condition that is usually associated with clinical and ECG evidence of ischemia. This phenomenon is associated most frequently with PCI of SVGs and with PCI after STEMIs.7,12,13 The pathogenesis of no-reflow is multifactorial and secondary to obstruction of the microvascular bed that is distal to the culprit lesion.4,7,12 The importance of microembolism of atheromatous and platelet débris in the occurrence of no-reflow phenomenon is supported by the retrieval of cellular and noncellular material of varying sizes from embolic protection devices.1 Mechanical obstruction is likely to be more prevalent in the presence of a large thrombus burden (as in STEMI) or of friable plaque (as in SVGs). The failure of protection devices to reduce infarct size after PCI in STEMI, along with the approximate 10% incidence of major adverse cardiac events after SVG intervention, highlights the importance of humoral mediators in no-reflow.13–15 Cardiac catheterization induces platelet activation, which is amplified in the presence of thrombolytic agents and angioplasty.16 Stent insertion increases the local release of serotonin more than does angioplasty alone, and angioplasty in ACS triggers the release of the potent vasoconstrictor endothelin-1.5,6 Ischemia and reperfusion also activate the sympathetic nervous and renin–angiotensin systems, which further contribute to the intense vasoconstriction in the reperfused bed.11 Adenosine is an endogenous nucleoside that activates extracellular receptors, which produce physiologic effects that inhibit the formation of thromboemboli and reverse the intense vasoconstriction that occurs after PCI.7,12 As a potent dilator of both arteries and arterioles, adenosine also rapidly reverses the effects of numerous vasoconstrictors in the coronary circulation during PCI.12 Thrombus formation and embolization are inhibited by adenosine's antiplatelet effects and its ability to restore the profibrinolytic activity of endothelial cells. The importance of adenosine as an antithrombotic agent is supported by the experimental observation that endogenous adenosine inhibits the formation of thromboemboli during low-flow ischemia.17 Evidence supports the concept that prophylactic boli or infusions of adenosine reduce enzymatic evidence of myonecrosis after elective PCI. For example, a 50-μg bolus of intracoronary adenosine before guidewire insertion reduced enzymatic myonecrosis after elective PCI.18 Similar findings were observed in the pilot ADELINE trial when adenosine was infused into the guiding catheter 10 minutes before the procedure.19 In a trial that focused on anterior STEMI, a 4-mg intracoronary bolus of adenosine before angioplasty significantly reduced no-reflow, in accordance with an evaluation of TIMI flow 30 minutes after the procedure.20 In a small retrospective study, multiple doses of intracoronary adenosine (24–48 μg) that were administered throughout PCI significantly reduced no-reflow in anterior and inferior STEMI.21 Gibson22 reported the case of a patient who experienced anterior STEMI and closed microvasculature after angioplasty (MBG, 0): multiple doses of adenosine that were infused via the balloon catheter markedly improved the patient's CTFC and restored tissue perfusion. Recently, a 5- to 10-minute selective infusion of a high dose of adenosine (60 mg) significantly improved the CTFC and MBG in STEMI patients who experienced abnormal tissue perfusion, as evidenced by persistent ST-segment elevation after successful stent deployment.23 Intracoronary and intravenous infusions of adenosine produced striking myocardial salvage in experimental models of regional ischemia, and this was associated with preservation of microcirculatory flow and vasodilatory reserve. The clinical AMISTAD trials confirmed these experimental observations.7,12 Although blood flow was not evaluated in the AMISTAD trials, it seems plausible that the beneficial effects were partly mediated through preservation of tissue perfusion. Intracoronary adenosine also effectively prevented no-reflow after rotational atherectomy, which has a high propensity to cause vasospasm and microembolization.24 Before the routine use of embolic protection devices, numerous agents—including adenosine—were evaluated in the treatment of no-reflow after PCI in stenotic SVGs. After a small pilot study, Fischell and co-authors25 reported that repeated 18-μg, high-velocity boli of adenosine (mean dose, 216 μg per event) reversed no-reflow in most of the patients. These observations were reproduced in another retrospective study,26 wherein high doses of adenosine (70–120 μg) reversed no-reflow in 91% of the patients. In the VAPOR trial,27 pretreatment with intragraft verapamil prevented no-reflow but did not reduce necrosis or improve tissue perfusion. Other studies28 showed that verapamil improved established no-reflow in SVGs but failed to prevent significant myocyte necrosis in approximately 30% of patients. A randomized study29 compared the effects of intracoronary adenosine and verapamil on TIMI flow count in the presence of ACS after PCI. Although both agents produced a significant and equivalent increase in coronary blood flow, the numerous cardioprotective effects of adenosine (in addition to vasodilation) would be expected to improve outcomes. Moreover, while no hemodynamic effects were observed with adenosine, verapamil was associated with complete heart block in approximately 10% of patients and also with a decrease in systolic blood pressure in most patients. Nitroprusside reversed no-reflow in 75% of a heterogeneous group of patients who underwent PCI.30 Although nitroprusside is a potent arteriolar vasodilator through its action as a direct nitric oxide donor, its beneficial effects may be reduced in the presence of diffuse vascular disease and a dysfunctional endothelium. In our patients, repeated bolus doses of adenosine safely and effectively reversed no-reflow in native coronary vessels and in degenerated SVGs, with improvement in epicardial blood flow as measured by TIMI flow grade and CTFC and in tissue-level perfusion as evaluated by MBG. Furthermore, we noted only minimal increases in cardiac enzymes, and all 4 patients were asymptomatic after the procedure. The frequent occurrence of no-reflow in SVG interventions is highlighted by the fact that, in our Patient 1, neither SVG lesion had any angiographic features of a high-risk lesion—each was smooth and discrete, without evidence of thrombi or diffuse graft disease. In contrast with the no-reflow that occurs in native vessels, our patient required multiple doses of adenosine over a longer time period (as was documented by Fischell and colleagues in their patients25). A limitation of our report is that it was not a randomized study, and it is conceivable that all no-reflow may resolve spontaneously. The cases of our patients show that adenosine is useful in reversing no-reflow after interventions to native arteries or SVGs. It is likely, however, that adenosine's full therapeutic potential is compromised due to its extremely short half-life in blood (approximately 1 sec) and because of dilutional effects that are associated with either guiding-catheter administration or infusion into a branch vessel with selective injections via a balloon catheter. Prophylactic and continuous infusion of adenosine throughout the procedure may optimize the cardioprotective effects of the nucleoside. In this regard, we have recently developed polymers to which adenosine can be covalently bonded. These adenosine-containing polymers can be coated onto metallic devices (for example, guidewires) by using standard techniques, such as electropolymerization plating. In vitro studies have confirmed the release of pharmacologic amounts of adenosine over 60 minutes from wires coated with adenosine-containing polymers. Moreover, when a vascular bed was constricted with potent vasoconstrictors to mimic no-reflow, wires coated with adenosine-containing polymers caused potent regional vasodilation when they were inserted into the artery that supplied the bed.* In summary, we found that intracoronary adenosine was effective and safe in reversing acute no-reflow in native vessels and SVGs. Future technological innovations that would enable the continuous administration of adenosine into the distal vascular bed during PCI may further improve post-PCI outcomes in various clinical syndromes. | |||||||||
Footnotes *Unpublished data; Forman and Jackson, 2007–2008. Address for reprints: Edwin K. Jackson, PhD, Center for Clinical Pharmacology, University of Pittsburgh School of Medicine, 100 Technology Drive, Suite 450, Pittsburgh, PA 15219. E-mail: edj/at/pitt.edu | |||||||||
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