A Case-Based Discussion of No-Reflow Treatment: Do We Need More?

In the last two decades, technology has advanced significantly to address the improvement of epicardial coronary flow (ECF). We are now in the era of no-reflow (NR) phenomenon. Once ECF is restored after primary percutaneous intervention (PCI), myocardial flow and perfusion can be impaired, called NR. Perfusion at the tissue level can be severely compromised even when the epicardial coronary artery appears to be fully patent by coronary angiography. In the absence of apparent dissection, spasm, thrombus, residual stenosis, or distal vessel cutoff, significant flow limitations are suggestive of microembolization.

There are many hypotheses about the mechanism of the NR phenomenon, but the exact mechanism is not yet known. Some of the proposed mechanisms include the following: 

1. Compromised blood flow to the myocardial bed leads to myocardial edema, and necrosis causes capillary compression, which further compromises blood flow in a vicious cycle.
2. Distal embolization of atheromatous and platelet-rich microthrombi reduces tissue perfusion.
3. Reperfusion injury: once flow is restored, free radicals cause damage to the myocardium. 

A number of drugs have been shown to improve NR experimentally and clinically, but none have been associated with conclusive improvements in clinical outcomes. Some of the common drugs include adenosine, glycoprotein (GP) IIb/IIIa inhibitors, nipride, and verapamil.

Adjunctive therapies, such as mechanical thrombectomy, have not shown much improvement in TIMI flow. Newer technology like laser atheterctomy seems promising, but no randomized trials have been formed in order to conclude any clinical benefit. Hemodynamic support via an intra-aortic balloon pump (IABP) or other mechanical circulatory devices has been successful in limited cases. Herein, we present a case-based approach in order to discuss the available treatment of NR and to review the clinical significance of ventricular unloading.

Case report  

A 43-year-old male with a past medical history of hypertension, hyperlipidemia, and diabetes, on diet control with obesity, and a smoker, presented to emergency department with chest pain for two hours. The initial electrocardiogram (EKG) showed significant ST segment elevation in lead aVR and anterior leads, and depression in inferior leads. His initial vitals were stable, except for significant chest pain. A ST-elevation myocardial infarction (STEMI) code was activated and the patient was brought to the cardiac catheterization laboratory for an emergent coronary angiogram.

Selective coronary angiogram via a right radial approach showed no significant stenosis of the right coronary artery. Selective left coronary angiography showed no significant stenosis of the left circumflex coronary system (Figure 1) and an acute occlusion of the left anterior descending coronary artery (LAD) from the ostium (Figure 2). A Runthrough coronary wire (Terumo) was negotiated to the LAD with some difficulty. Due to significant thrombus burden, laser atherectomy was performed, followed by angioplasty with a 2.0 x 20 mm and 2.5 x 40 mm compliant balloon. After angioplasty, flow in the LAD was TIMI-1 (Figure 3) and the patient continued to have significant chest pain with worsening of electrocardiographic ST-T segment changes. An intravenous nitroglycerine drip was initiated. The plan was to place an upfront Impella left ventricular assist device (Abiomed), for several reasons:

• Clinically unstable patient;
• Worsening EKG findings;
• Stabilization of hemodynamics during unforeseen complications;
• Buy additional time to pursue a possibly complex procedure;
• Upfront left ventricular unloading in case of cardiogenic shock, acute heart failure, and/or no reflow.

Left heart catheterization revealed a left ventricular end-diastolic pressure of 40 mmHg and the estimated left ventricular ejection fraction by ventriculography was 20-25%. An Impella CP (14 French sheath) was placed via the right common femoral artery, followed by percutaneous intervention of the proximal LAD with a 3.0 x 38 mm drug-eluting stent (DES). TIMI 1- to 2-grade flow was noted distal to the stent (Figure 4). An intracoronary injection of nipride with a micro catheter resulted in mild improvement in TIMI flow at the distal LAD, to TIMI 2. Another 2.5 x 23 mm DES was placed at the mid LAD with no significant improvement in distal flow and myocardial blush (Figure 5). Repeated intracoronary nipride and a GP IIb/IIIa inhibitor were administered. A final angiogram showed TIMI-2 flow distal to the mid LAD (Figure 6). At this point, the patient’s chest pain was completely resolved, along with some resolution of ST segments. 

Right heart catheterization at the end of the intervention showed a pulmonary capillary diastolic pressure of 27 mmHg with a Fick cardiac index of 1.9 L/min/m². The patient was transferred to the coronary care unit with Impella support and continuous hemodynamic monitoring with a Swan-Ganz catheter. The next day, the Impella was weaned successfully and the patient was initiated on goal-directed medical therapy. On day 4, he was successfully discharged out of the hospital.

Pharmacotherapy of no-reflow

Adenosine. Adenosine is an endogenous, short-acting nucleoside. It is a potent dilator of arteries and arterioles, and rapidly reverses the effects of numerous vasoconstrictors. It also carries an antiplatelet effect, which prevents thrombus formation, embolization, and restores endothelial function. The beneficial effect of adenosine has been established from observational studies. Intracoronary adenosine administration before guide wire insertion or multiple intermittent boluses with a micro catheter have been used in the past.

The exact dose of adenosine by various modes of administration varies widely and is not yet standardized. An intracoronary high dose of adenosine followed by continuous infusion for 2 hours (50mcg/kg/hr) has been shown to limit infarct size in a porcine model of acute myocardial infarction.¹ 

In one meta-analysis, Navarese et al showed no adjunctive benefit of adenosine in survival, myocardial reinfarction, and heart failure symptoms in acute coronary syndrome patients treated with PCI or thrombolysis.² A recent meta-analysis showed benefit to intracoronary adenosine in the prevention of heart failure, as well as in improvement of NR.³

GP IIb/IIIa inhibitors. Platelets and fibrin are important contributors to the pathogenesis of NR. GP IIb/IIIa inhibitors inhibit platelet aggregation and thus improve epicardial and myocardial flow. Though the exact etiology of thrombotic (platelet-rich thrombus) occlusion in NR is not yet established, GP IIb/IIIa inhibitors have been shown to improve TIMI flow of epicardial vessels and decrease thrombus burden. Kunichika et al found that GP IIb/IIIa inhibitors decreased NR as well as infarct size in a non-thrombotic model.⁴ In combination with thrombolysis, GP IIb/IIIa inhibitors have been shown to improve ST-segment and 30-day clinical outcomes in post-MI patients, as well as coronary flow reserve and myocardial blush in elective PCI. This finding suggests that GP IIb/IIIa inhibitors not only improve epicardial flow, but also increase microvascular reperfusion.

Nipride. Nipride relaxes vascular smooth muscles of the arteries and veins. The venodilator effect decreases venous return to the heart and thus decreases preload (left ventricular end-diastolic pressure g pulmonary capillary wedge pressure.) It also decreases afterload by arteriolar relaxation (systemic vascular resistance, arterial pressure, and mean pressure). Coronary vasodilation and myocardial smooth muscle relaxation are helpful in NR. Intracoronary administration with a micro catheter in small, multiple boluses, as much as blood pressure permits, is beneficial. Nipride has been shown to improve major adverse cardiac events (MACE) during primary PCI and seems to be a promising adjunctive therapy for NR during primary PCI.⁵ Hypotension limits administration of intracoronary nipride.

Verapamil. Verapamil is a smooth muscle dilator and thereby increases blood supply and oxygen to the myocardium. It has shown to be beneficial in an animal model of the no-reflow phenomenon.⁶ Administration of intracoronary verapamil can improve NR by improving microvascular spasm, supporting the hypothesis that NR is caused by acute microvascular dysfunction, perhaps due to a disorder in calcium homeostasis or microvascular spasm. High intracoronary dose administration is limited by hypotension and heart block.

Mechanical adjunctive measures in no reflow. In STEMI, routine manual thrombus aspiration did not improve cardiovascular death, recurrent MI, cardiogenic shock, or heart failure.⁷ In selected cases of high thrombus burden, a theoretical benefit to thrombectomy in improving thrombus burden and preventing microvascular plugging persists.

The AngioJet rheolytic thrombectomy device (Boston Scientific) can be used for completeness of thrombus removal and clinical benefit. A distal protective device with mechanical thrombectomy is used to reduce distal embolization. In randomized, controlled trials, the AngioJet has failed to show any clinical benefit in acute MI patients. 

The excimer coronary laser vaporizes large thrombus burden. Topaz et al have shown that coronary laser angioplasty is beneficial in patients with contraindication to thrombolysis or who failed to show benefit with thrombolysis.⁸

An intra-aortic balloon pump (IABP) increases coronary blood flow, decreases myocardial oxygen demand, and can mitigate the NR.

Left ventricular unloading improves coronary flow and reduces myocardial oxygen demand, and is well recognized in the literature. By virtue of this hypothesis, newer, very effective left ventricular unloading devices such as the Impella should be considered upfront in patients with elevated left ventricular end-diastolic pressure, low ejection fraction, and early cardiogenic shock, and with persistent symptoms, as with our patient.

Predictors of no-reflow^9,10: 

1. Age > 65; 
2. Elevated blood glucose;
3. Long lesion;
4. Higher reperfusion time;
5. Low TIMI flow grade prior to primary PCI;
6. Presence of collateral circulation;
7. Higher thrombus burden prior to PCI;
8. IABP placement prior to PCI.

Prognostic significance of no reflow

NR is associated with poor clinical outcomes, potentially leading to ventricular arrhythmia, cardiac death, congestive heart failure, and myocardial reinfarction. During PCI, NR results in increased mortality and morbidity. Therefore, effective treatment of NR improves clinical outcomes. For the last few decades, treatment of NR has been mostly pharmacotherapy-based, without much success. Despite maximum pharmacological therapy if refractory NR persists, aggressive thrombectomy, laser atherectomy with percutaneous cardiopulmonary support with IABP, and/or the Impella should be considered in individualized cases. Clinical evidence of risks and benefits varies significantly within these treatment classes.

Conclusion

The prognostic importance of NR during PCI parallels its close relationship to mortality and morbidity. Effective available treatment — case-based thrombus aspiration, upfront aggressive pharmacotherapy, laser atherectomy, and effective ventricular unloading in a timely fashion — must be sought to improve outcomes. There are no randomized, controlled trials large enough to demonstrate hard clinical endpoint benefits from a single pharmacological or mechanical agent in treating the NR phenomenon. A high-quality randomized trial is needed to reveal the most effective treatment to ameliorate the adverse effects of NR.

References

1. Yetgin T, Uitterdijk A, Te Lintel Hekkert M, Merkus D, Krabbendam-Peters I, van Beusekom HM, et al. Limitation of infarct size and no-reflow by intracoronary adenosine depends critically on dose and duration. JACC Cardiovasc Interv. 2015 Dec 28; 8(15): 1990-1999.
2. Navarese EP, Buffon A, Andreotti F, Gurbel PA, Kozinski M, Kubica A, et al. Adenosine improves post-procedural coronary flow but not clinical outcomes in patients with acute coronary syndrome: a meta-analysis of randomized trials. Atherosclerosis. 2012 May; 222(1): 1-7.
3. Bulluck H, Sirker A, Loke YK, Garcia-Dorado D, Hausenloy DJ. Clinical benefit of adenosine as an adjunct to reperfusion in ST-elevation myocardial infarction patients: An updated meta-analysis of randomized controlled trials. Int J Cardiol. 2016 Jan 1; 202: 228-237.
4. Kunichika H, Ben-Yehuda O, Lafitte S, Kunichika N, Peters B, DeMaria AN. Effects of glycoprotein IIb/IIIa inhibition on microvascular flow after coronary reperfusion. A quantitative myocardial contrast echocardiography study. J Am Coll Cardiol. 2004 Jan 21; 43(2): 276-283.
5. Zhao S, Qi G, Tian W, Chen L, Sun Y. Effect of intracoronary nitroprusside in preventing no reflow phenomenon during primary percutaneous coronary intervention: a meta-analysis. J Interv Cardiol. 2014 Aug; 27(4): 356-364.
6. Bolling SF, Schirmer WJ, Gott VL, Flaherty JT, Bulkley BH, Gardner TJ. Enhanced myocardial protection with verapamil prior to postischemic reflow. Surgery. 1983 Aug; 94(2): 283-290.
7. Jolly SS, Cairns JA, Yusuf S, Rokoss MJ, Gao P, Meeks B, et al; TOTAL Investigators. Outcomes after thrombus aspiration for ST elevation myocardial infarction: 1-year follow-up of the prospective randomised TOTAL trial. Lancet. 2016 Jan 9; 387(10014): 127-135. doi: 10.1016/S0140-6736(15)00448-1.
8. Topaz O, Shah R, Mohanty PK, McQueen RA, Janin Y, Bernardo NL. Application of excimer laser angioplasty in acute myocardial infarction. Lasers Surg Med. 2001; 29(2): 185-192.
9. Wang CH, Chen YD, Yang XC, Wang LF, Wang HS, Sun ZJ, Liu HB. A no-reflow prediction model in patients with ST-elevation acute myocardial infarction and primary drug-eluting stenting. Scand Cardiovasc J. 2011 Apr; 45(2): 98-104.
10. Zhou H, He X, Zhuang S, et al. Clinical and procedural predictors of no-reflow in patients with acute myocardial infarction after primary percutaneous coronary intervention. World J Emerg Med. 2014; 5(2): 96-102.