Pharmaceutical Interventions for the Management of No-Reflow

Percutaneous coronary intervention (PCI) for atherosclerotic coronary artery disease is an effective therapy for restoring vessel caliber and improving blood flow to ischemic myocardium. At least 1.25 million PCIs are performed annually in the United States, and it has been estimated that nearly 2 million procedures are performed annually worldwide.¹ The growth in the number of PCIs has occurred in tandem with technological refinements and advances in peri- and postprocedural medication, which have reduced procedural risk, improved success rates and dramatically changed the prognosis of patients with acute coronary syndromes.^2–8
The no-reflow and slow-reflow phenomena⁹ are poorly understood complications of PCI in which reduced coronary flow persists despite the intraprocedural removal of the occlusive lesion from the epicardial coronary artery or arteries. In as many as 2% of patients without acute myocardial infarction (AMI) who undergo PCI, restoration of normal anterograde myocardial blood flow (myocardial “blush”) is unsuccessful due to microcirculatory dysfunction and/or mechanical obstruction; this failure — slow- or no-reflow — occurs in the absence of postprocedural angiographic evidence of an encroaching luminal lesion (e.g., evolving dissection) or evidence of macroscopic distal embolization.^10–12 The no-reflow phenomenon is encountered most frequently among patients undergoing PCI of saphenous vein grafts (SVGs) and in patients with AMI who undergo thrombolysis or mechanical intervention. In these populations, the incidence of slow- or no-reflow may be greater than 30%.^12–14
The no-reflow phenomenon following PCI is associated with significant cardiac consequences due to myocardial ischemia caused by inadequate distal microvascular flow and poor myocardial perfusion. Despite widely patent epicardial vessel lumens, no-reflow can be associated with angina and ischemic ST-segment changes in these patients.¹⁰ Consequently, angiographic or contrast-enhanced echocardiographic demonstration of open epicardial vessels may not be a reliable indicator of successful myocardial reperfusion in AMI patients with no-reflow and residual perfusion defects in the risk area.¹⁵ No-reflow predicts a poor functional recovery and impaired ventricular remodeling, and its persistence — despite attempted treatment — is associated with a high incidence of ongoing or recurrent acute coronary syndrome (ACS) as well as increased short-term mortality.^11,13,15,16
Etiology of angiographic no-reflow. The exact pathophysiology underlying the no-reflow phenomenon is unknown, but is likely multifactorial. Potential mechanisms responsible for no-reflow include processes and mediators whose individual contribution to poor reperfusion may depend on the clinical or experimental setting, and ultimately on whether reperfusion is accomplished by thrombolysis or PCI (Table 1).^11,17 “Angiographic” no-reflow, the type most often encountered by interventionalists during angioplasty or stent deployment, is partly an expression of vascular reperfusion injury, one of the major types of reperfusion abnormalities (others include lethal reperfusion injury, myocardial stunning and reperfusion dysrhythmia).^11,12,18,19
Reperfusion injury is associated with extremely complex and interrelated phenomena, including production of oxygen free radicals, altered membrane permeability, capillary edema, modified calcium metabolism, complement activation, apoptosis and a degraded cellular ultrastructure facilitating progressive microvascular dysfunction despite removal of an upstream occlusion.^{9,11,17,19–21}
While reperfusion injury per se may contribute to angiographic no-reflow, additional mechanisms are related directly to the introduction of a percutaneous device into a diseased native vessel or degenerated vein graft. Angioplasty causes plaque rupture, which in turn yields particulate and plaque debris to be showered downstream within seconds of balloon deflation.²² Progressive microvascular impairment results from distal embolization of fragments, cholesterol crystals, microthrombi and other matter from dilated sites.^23,24 Additionally, complex homeostatic interactions between platelets and endothelial cells are disturbed by reperfusion. Stimulated by increased expression of endothelium-secreted cellular adhesion molecules or selectins from exposed postischemic coronary endothelial surfaces, occlusive platelet aggregates and leukocytes have direct involvement in the development of no-reflow in cardiac microvessels.²⁵
Finally, vasoconstriction develops in response to soluble, potent vasoactive substances contained in effluent released from target sites during PCI, or elaborated following local activation of platelet- or endothelium-derived factors within the arteriolar bed. This has emerged as a critically important mechanism for no-reflow, with good evidence to suggest that intense microvascular spasm plays a key role in most cases of angiographic no-reflow, particularly in elective SVG PCI.^26,27
Pertinent management of angiographic no-reflow. Various strategies target abnormalities that directly or indirectly contribute to the no-reflow phenomenon and cell death. Nonpharmaceutical approaches to reduce the risk of microemboli include the use of distal protection devices to sequester effluent material subsequent to balloon deflation,^28,29 angioscopy to assess prospectively the presence of unfavorable intracoronary (IC) morphology and possibly identify patients most likely to warrant distal protection,³⁰ and the continuing technical refinement of catheters. Soluble, highly potent vasoactive factors released by interventions in degenerated grafts may elude containment and therefore represent a considerable challenge to mechanical distal protection.^26,31 Whether angiographic no-reflow is susceptible to an advanced medical device technology solution is unclear.¹¹
In contrast, pharmacologic adjuncts to PCI capable of impeding platelet aggregation or directly reducing microvascular spasm have attracted great interest, given the importance of both processes in the development of no-reflow pathophysiology, and the current availability of several medications for clinical use. A range of pharmacologic adjuncts have been evaluated to limit no-reflow, including adenosine, diltiazem, nicardipine, verapamil, nitroprusside, glycoprotein antiplatelet medications, soluble factor antagonists, anti-endothelins and others. Most await large-scale, randomized, controlled trials to confirm their roles and define optimal regimens (Table 2).
Adenosine. Adenosine is a primordial cell-signal mediator with activities implemented through interaction with specific receptors.³² Adenosine inhibits platelet activation, impedes platelet aggregation, and is a potent arteriolar dilator that has been shown to reduce the incidence of no-reflow following PCI in native vessels, and reverse — but not prevent—no-reflow in degenerated SVGs.^33,34 IC adenosine has an extremely short half-life and duration of action, and thus requires repetitive dosing during PCI.
In a prospective, randomized, placebo-controlled trial to study the effect of IC injection of adenosine, verapamil or placebo in a mixed population with ACS, adenosine administered after PCI significantly improved coronary flow and wall motion index as assessed by thrombolysis in myocardial infarction (TIMI) frame count (TFC), even when flow was visually established to be normal or near normal.³⁵ In two series, multiple rapid bolus administrations of adenosine via a guiding catheter safely reversed no-reflow to baseline or TIMI 3 flow in more than 90% of patients receiving high-dose regimens, with one study documenting the consistent onset of improvement within a mean of 3–5 minutes following initial injection.^34,36
Glycoprotein IIb/IIIa inhibitors. Interference with platelet aggregation through glycoprotein (GP) IIb/IIIa receptor inhibition is a theoretically attractive method for management of no-reflow that awaits confirmation by randomized study. Tirofiban reduced no-reflow in a canine non-thrombotic coronary occlusion model, and was more effective than aspirin or clopidogrel in attenuating no-reflow in a swine infarction/reperfusion model, but reports in human subjects are scant and inconclusive.^37–39
Clinical reports suggest that abciximab improves epicardial flow and microvascular perfusion as an adjunct to reduced-dose thrombolysis⁴⁰ and after primary PCI.⁴¹ In a subset of 101 patients with SVGs undergoing high-risk PCI, adjunctive abciximab bolus and infusion were associated with an 87% reduction in distal embolization compared with placebo (2% vs. 18%, p = 0.017), with a trend toward reduction in early large non-Q-wave AMI (2% vs .12%, p = 0.165).⁴²
Nitroprusside. Sodium nitroprusside has profound vasodilating properties. Initial studies of nitroprusside encompassing angioplasty, stent deployment or rotational atherectomy on either SVGs or native vessels demonstrated highly significant, rapid and safe improvement of no-reflow by a variety of criteria.⁴³ No significant hypotension or other adverse clinical events were reported. In a small study,⁴⁴ IC bolus injection of nitroprusside as an adjunct to primary PCI improved angiographic TIMI flow by at least 1 grade in 9 of 11 patients (82%; p = 0.007). Treatment was uniformly safe.
Verapamil. A retrospective study demonstrated that IC verapamil improved TIMI flow grade in 89% of no-reflow patients following PCI and markedly improved TFC (from 91 ± 56 to 38 ± 21 frames, p < 0.001).¹⁰ Pretreatment verapamil administered to 10 patients undergoing PCI of saphenous vein grafts was associated with a nonsignificantly reduced incidence of no-reflow vs. no pretreatment. Flow rate in the vessel as assessed by TFC was significantly faster in pretreated patients (p = 0.016), suggestive of increased perfusion and reduced downstream resistance.45 In a prospective investigation, intragraft verapamil for no-reflow associated with angioscopy, extraction atherectomy, balloon angioplasty or stent implantation in degenerated SVG lesions resulted in significant improvement in flow in all instances (TIMI flow grade 1.4 ± 0.8 before, to 2.8 ± 0.5 after verapamil, p < 0.001). TIMI 3 flow was reestablished in 88% of episodes. In contrast, intragraft nitroglycerin alone had no relevant effects on TIMI flow.⁴⁶ IC verapamil reversed no-reflow in a consecutive series of 212 direct or rescue stent deployment for infarction. Twenty-three (10.8%) patients developed no-reflow. Verapamil reduced TFC from 56 ± 9 frames to 24 ± 4, a significant change versus controls (p < 0.001). TIMI flow grade 3 was restored in 65% of instances. Verapamil was associated with intermittent atrioventricular block in 3 patients.⁴⁷ Finally, in a randomized, comparative, placebo-controlled study of IC verapamil, adenosine or placebo administered immediately after PCI, both verapamil and adenosine significantly improved coronary flow, although 18% of patients receiving verapamil developed heart block.³⁵ Diltiazem. A retrospective series of 24 case reports indicated that IC diltiazem may be effective in reversing no-reflow associated with PCI of native arteries or grafts. Fifteen of the 24 patients in this series were severely symptomatic due to TIMI flow grade 0 or 1, requiring support with aramine, atropine or temporary pacing, and showed no improvement with IC nitroglycerin. Administration of IC diltiazem boluses led to prompt clinical and angiographic improvement in flow grade in most patients and was well tolerated.⁴⁸
Nicardipine. Nicardipine possesses a number of attributes suggesting particular utility for reversal and/or prevention of no-reflow.⁴⁹ It is a dihydropyridine calcium-channel antagonist with relatively selective coronary vascular effects, producing a marked increase in coronary blood flow in vascular smooth muscle with minimal direct myocardial depressant activity.^50,51 In a comparative study with IC diltiazem or verapamil, IC nicardipine achieved significantly more prolonged coronary vasodilation and a significantly greater mean increase over baseline coronary flow velocity than either nondihydropyridine.⁵²
In a retrospective study, IC nicardipine successfully reversed no-reflow associated with PCI of native vessels or grafts and restored TIMI 3 flow in 71/72 patients.⁵³ TIMI flow grade pre- and post-treatment was 1.65 ± 0.53 and 2.97 ± 0.24, respectively (p < 0.001), while frame counts decreased from 57 ± 40 at the time of no-reflow to 15 ± 12 after nicardipine (p < 0.001). More recently, prophylactic intragraft nicardipine followed immediately by direct stenting of SVGs without mechanical distal protection in a series of 68 elective patients dramatically reduced the incidence of no-reflow. Transient no-reflow was observed in 2/83 graft interventions (2.4%), an incidence comparable to elective interventions in native vessels. The overall rate of 30-day major adverse cardiac events in this study was at least as low as historical data from trials evaluating different mechanical distal protection systems, suggesting a potential pharmacologic alternative or adjunct to mechanical distal protection.³¹
Nicorandil. Nicorandil has specific vasodilating effects mediated through effects on adenosine triphosphate-sensitive potassium channels and may impede the formation of radical oxygen species.^54,55 Intravenous infusion showed benefit compared with placebo in reducing the incidence of no-reflow in 33 patients undergoing PCI for AMI.⁵⁵ IC administration of nicorandil in combination with adenosine for no-reflow was associated with statistically significant improvements compared with adenosine alone. Improvements were demonstrated for TIMI flow grade (2.0 ± 0.9 vs. 2.6 ± 0.6, p = 0.024) and change in TFC before and after PCI (45.2 ± 24.5 vs. 63.6 ± 23.2, p = 0.014).56 IC nicorandil was more effective than IC verapamil in preventing no-reflow in 61 patients (63 lesions) undergoing rotational atherectomy. No- or slow-reflow was observed in 11/63 (17.5%) lesions among verapamil-treated subjects, compared with 1/37 (2.7%) lesions in the nicorandil group (p = 0.03).⁵⁷
Endothelin antagonists. The potent vasoconstricting and proliferative properties of the endothelins (ETs), a family of three 21-amino acid peptides (ET-1, ET-2 and ET-3), were discovered in the 1980s.⁵⁸ ET-1 is physiologically most significant⁵⁹ and exerts a wide spectrum of biologic actions (Figure 1). Intravenous administration causes rapid and transient vasodilatation followed by a sustained increase in blood pressure.⁵⁸ The pressor response is secondary to increased total peripheral resistance with no change in heart rate or cardiac output. It is blocked by the administration of ETAR antagonists. In addition to its direct vasoconstrictor effect, ET-1 amplifies the contractile response to other vasoactive agents including norepinephrine and serotonin. In a similar manner, these agents can potentiate the vasoconstrictor response to ET-1. Thus, ET-1 plays an important role in regulating vascular reactivity. In healthy individuals, administration of a mixed ETAR-ETBR antagonist causes increased forearm blood flow and a small decrease in blood pressure, providing further evidence that ET-1 is involved in regulating vascular tonus.
Coronary artery and cerebral arterial vasospasm have the same physiologic effect on their destination vascular beds, myocardial ischemia and cerebral ischemia, resulting in cellular hypoxia and death. No-reflow through the myocardium after angiographic patency is reestablished has been successfully treated, while cerebrovascular arteries pose a different challenge, but no less of a threat to the integrity of the matrix.
Successful treatment of cerebral vasospasm remains elusive to this day, particularly in light of the mixed results of the Clazosentan to Overcome Neurological iSChemia and Infarct OccUrring after Subarachnoid hemorrhage (CONSCIOUS-1) study. Although clazosentan, an endothelin receptor antagonist, reduced the relative risk of angiographic vasospasm by 65% in patients treated with the highest dose, there was only a small reduction in the number of delayed neurological deteriorations, and no effect on clinical outcome at 3 months.⁶⁰

Conclusion

The emergence of no-reflow as a frequent complication of PCI, particularly when the intervention involves a degenerated vein graft, suggests that improving the integrity of microvascular flow should be as much a focus of reperfusion therapy as opening the culprit vessel. The restoration of patency in large-caliber vessels should not be confused with restoration of microvascular flow. The challenge facing interventional cardiology is to identify adjunctive methods to optimize robust reflow into the myocardium.
The no-reflow phenomenon reflects the structural, neurohumoral and metabolic tumult associated with cardiac ischemia and its reversal. Many mechanisms are implicated in the development of no-reflow, and optimal therapy is unclear. It remains to be determined whether individual agents or combinations of medications or devices addressing specific targets will provide clinically relevant benefits. For selected patients undergoing PCI, GP IIb/IIIa antagonists, distal protection and vasodilating drugs may be reasonable adjuncts to maximize periprocedural microvascular integrity. For patients in whom the no-reflow syndrome develops, prompt administration of a vasodilating medication such as adenosine, nitroprusside, verapamil or nicardipine may represent the most potent and practical therapeutic intervention to reperfuse myocardium.

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