Despite significant advances in the treatment of acute myocardial infarction (AMI) with the introduction of efficient reperfusion strategies such as primary percutaneous coronary intervention (PCI) and improvement in medical therapy, coronary artery disease remains the leading cause of death in the United States, with a mortality rate of about 10% at 1 year for AMI patients.^1,2 In an attempt to further reduce adverse events following AMI, several novel adjuvant therapies have been pursued with great enthusiasm. Ischemic postconditioning, deferred stenting, and left ventricular (LV) unloading are some of the strategies that have generated a great amount of buzz in the field of interventional cardiology.

Ischemic Postconditioning

Myocardial reperfusion injury remains a major hurdle to improving outcomes with primary PCI. The phenomenon of paradoxical myocyte death induced by reperfusion of acutely ischemic myocardium was described by Jennings and colleagues in 1960.³ Studies in animal models of AMI suggest that reperfusion injury accounts for up to 50% of the final infarct size. Several therapeutic strategies have been shown to ameliorate myocardial reperfusion injury in animal models of ischemia/reperfusion.⁴ Ischemic postconditioning is one such strategy that has generated a great amount of interest.

The origins for the concept of ischemic postconditioning may have initially risen from the concept of ischemic preconditioning, which was originally proposed by Murry and colleagues.⁵ In this study, it was found that four 5-minute cycles of occlusion and reflow of the circumflex coronary artery rendered a protective effect on the canine myocardium and significantly reduced infarct size when performed prior to coronary occlusion. The concept of ischemic preconditioning also has a clinical basis because patients with severe coronary stenoses often develop or recruit collaterals, which may minimize ischemic injury and reduce the development of fatal ventricular arrhythmias following acute vessel occlusion. Indeed, patients without pre-existing severe stenoses who experience plaque rupture of a nonobstructive coronary lesion are unlikely to have pre-existing collaterals and are thus at higher risk of ischemic injury and fatal arrhythmia.⁶ Other animal studies of ischemic preconditioning also demonstrated a reduction in the accumulation of polymorphonuclear neutrophils and apoptosis.⁷ However, this intriguing phenomenon remained within the confines of the animal laboratory given several barriers, the most glaring of which was the fact that the preconditioning had to be done prior to the acute coronary event. Decades later, Zhao and colleagues introduced the concept of ischemic postconditioning, in which repetitive ischemia was applied during early reperfusion in the form of three cycles of alternating 30-second occlusion and 30-second reperfusion of the left anterior descending (LAD) coronary artery.⁸ This intervention at the onset of coronary reflow was associated with a significant reduction in infarct size. The protection was thought to be secondary to reduction in oxygen free radicals because there was a significant decrease in malondialdehyde, a product of lipid peroxidation.⁸ This provided a reasonably practical target for application in human studies.

Remote ischemic postconditioning involves the same occlusion-reperfusion cycles that have been described but is applied to areas such as an arm or leg to confer cardioprotection against reperfusion injury. In 1993, Przyklenk and colleagues performed four cycles of ischemia/reperfusion applied to the left circumflex artery and reduced infarct size when it preceded ischemia in the LAD territory. This was subsequently extended to remote non-cardiac tissue areas such as arm and leg. Several small studies using surrogate markers revealed a cardioprotective effect in the form of reduced infarct size. The mechanism of cardioprotection in these cases remains unclear but is thought to be secondary to paracrine effects.⁹ However, there have been no large studies with long-term clinical endpoints yet.

Since these early animal studies, several small studies in humans have confirmed the beneficial effects of ischemic postconditioning, both acutely and in long-term follow-up using surrogate markers.¹⁰ However, use of surrogate markers to predict clinical hard outcomes such as death, recurrent myocardial infarction, and heart failure (HF) exacerbation has repeatedly fallen short when major randomized trials are conducted. The most recent victim appears to be the cholesteryl ester transfer protein inhibitor drug class, for which the reduction of low-density lipoprotein cholesterol and increase in high-density lipoprotein cholesterol should improve clinical outcomes but instead had no effect or even placed patients at risk.

The results of the DANAMI 3 - iPOST (Third Danish Study of Optimal Acute Treatment of STEMI Patients) trial,¹¹ presented by Dr. Thomas Engstrøm at the ACC Annual Scientific Session in Chicago in April 2016, were heavily anticipated for several reasons. It was not only the largest study to date, with 1,234 patients, but also the first study to assess the effect of ischemic postconditioning on long-term clinical outcomes as opposed to using only surrogate markers. Additionally, ischemic postconditioning as a concept is simple to perform during primary PCI and could be readily adopted. The 1,234 ST-segment elevation myocardial infarction (STEMI) patients who underwent PCI within 12 hours of symptom onset were randomly assigned to either standard PCI or ischemic postconditioning prior to implantation of the stent. In the intervention arm, within 60 seconds of reperfusion, 4 cycles of balloon inflation for 30 seconds followed by reperfusion lasting for 30 seconds were performed. After a median follow-up of 39 months, there was no difference in the primary composite endpoint of all-cause mortality and HF hospitalizations with ischemic postconditioning compared with PCI alone (10.5 vs. 11.2% respectively, hazard ratio [HR] 0.93; confidence interval [CI] 0.66-1.30, p = 0.66). There was no difference in the primary endpoint and secondary endpoints including HF hospitalization, cardiovascular mortality, recurrent myocardial infarction, or target vessel revascularization (TVR) by PCI or coronary artery bypass grafting on sub-group analysis. There was, however, a statistically significant difference found in LV ejection fraction (LVEF) at 18 months; the ischemic postconditioning arm fared slightly better than the standard PCI arm (52.7 vs. 50.8%; p < 0.05) with LVEF > 45% being more common as well (80 vs. 72%; p = 0.015).¹¹ Thus, although ischemic postconditioning does not improve hard clinical endpoints, such as mortality, or reduce HF hospitalization, the potential benefit to LVEF by potentially reducing ischemic reperfusion injury may keep ischemic postconditioning alive.

Deferred Stenting

No-reflow, defined as an acute reduction in myocardial blood flow despite a patent epicardial coronary artery,¹² can be a frustrating and devastating outcome following primary PCI. Microvascular obstruction secondary to distal embolization of thrombus and plaque, vessel spasm, and thrombus propagation is thought to be the mechanism causing no-reflow, with the incidence of no-reflow estimated to be around 10% of primary PCI.^13,14 No-reflow following primary PCI is associated with worse clinical outcomes and often requires aggressive pharmacotherapy with glycoprotein IIb/IIIa inhibitors, which increase the risk of bleeding associated with PCI. The greatest benefit with pharmacological treatment appears to lie with use of vasodilator drugs such as intracoronary adenosine and calcium channel blockade.¹⁵

Although the purpose of primary PCI is to restore blood flow to the vessel, the placement of a coronary stent following restoration of flow with either balloon angioplasty or aspiration thrombectomy can result in no-reflow. This is thought to result from the "cheese-grater effect," where thrombus and components of the pro-thrombogenic ruptured plaque pass through the stent cells after stent balloon deflation and embolize downstream to the microvasculature. Delayed stenting after establishing good flow in the occluded artery was a potential means to avoid this complication. After restoring Thrombolysis in Myocardial Infarction 3 flow with balloon angioplasty or aspiration thrombectomy, the intereventionalist would initiate continued aggressive anticoagulation and antiplatelet therapy and delay stenting. The patient would then return to the cardiac catheterization laboratory at a later date, which enables time for reduction of lesion thrombus burden and lesion stabilization/organization. Thus, the risk of distal thrombus embolization leading to no-reflow and microvascular obstruction is significantly reduced. Several smaller studies and registries were conducted to assess the impact of deferred stenting in the setting of primary PCI on myocardial salvage, incidence of no-reflow, and development of microvascular obstruction in patients with STEMI. Microvascular obstruction, visualized on cardiac magnetic resonance (CMR) imaging, is another popular surrogate marker used in these trials. It is based on the simple concept that the microvascular obstruction prevents gadolinium to enter the downstream myocardium, thereby causing a signal defect within the surrounding bright infarct on late gadolinium-enhancement CMR T1 imaging. Most of these trials have indicated a benefit using surrogate markers such as CMR along with electrocardiographic and angiographic studies.¹⁶ A proof-of-concept trial in 2014 by Carrick and colleagues is one such study that demonstrated reduction in no-reflow with increase in myocardial salvage in the deferred stenting group when compared with conventional PCI with immediate stenting.¹⁴ However, these trials using surrogate markers have to be interpreted with caution. Several studies suggested that late microvascular obstruction is associated with poor prognosis after AMI,¹⁷ but a meta-analysis published in 2014 assessing the prognostic value of several CMR predictors demonstrated that there is insufficient evidence to support the use of microvascular obstruction for prognostication after AMI.¹⁸

DANAMI 3 - DEFER (Danish Study of Optimal Acute Treatment of Patients With ST-elevation Myocardial Infarction) is the first study powered to investigate the clinical outcomes of deferred stenting when compared with standard PCI in the randomized setting.¹⁶ It is the largest clinical trial on deferred stenting and addresses clinical outcomes including but not limited to mortality, hospitalizations for HF, recurrent myocardial infarction, TVR, and LVEF. The 1,215 patients who presented with STEMI were randomly assigned to conventional PCI versus deferred stent implantation. In the intervention arm, repeat coronary angiography was done about 48 hours (at least 24 hours) after the index procedure with the intention to implant a stent. After a median follow-up of 42 months, deferred stenting did not improve the composite primary endpoint of all-cause mortality, hospitalization for HF, reinfarction, and any unplanned TVR compared with immediate stenting (HR 0.99; p = 0.92; CI 0.75-1.29). There was no statistical difference among the constituents of the composite endpoint except for TVR. A higher TVR was found in the deferred stenting group when compared with traditional PCI (HR 1.70, p = 0.0342, CI 1.04-2.92). Deferred stenting was, however, associated with a slightly better LVEF when evaluated in two-thirds of the patients 18 months after treatment (60 vs. 57%, p = 0.042). The number of patients with an LVEF ≤ 45% was also favorable to the deferred stent group (13 vs. 18%, p = 0.05). Although 2 of the 27 procedure-related complications in the deferred stenting group were associated with the additional procedure, there were no significant differences between the two groups when procedure-related adverse events were examined (5% [28 events] for conventional PCI vs. 4% (27 events) for deferred stenting; p = 0.94]. These included periprocedural myocardial infarction, bleeding requiring surgery or transfusion, contrast-induced nephropathy, and stroke. There was no statistical difference between the two arms among any of the subgroups.

DANAMI 3 - DEFER does not justify the routine use of deferred stenting in the treatment of STEMI, but it does raise some interesting questions. Given the slight numerical superiority of LVEF after 1.5 years in the deferred stenting group, it remains to be seen whether this translates to long-term improved clinical outcomes. Also, the higher TVR rate in the deferred stenting arm mostly secondary to occurrence of re-occlusion or worsening of the culprit lesion before the scheduled PCI raises the concern for potential life-threatening implications for patients. This TVR rate could inflate further in certain high-risk groups and cannot be taken lightly. The discrepancy between the outcomes when compared with previous trials may be overcome by selecting patients who are high risk for no-reflow in the future studies as opposed to unselected STEMI patients. As mentioned, this trial once again reminds us that benefit demonstrated using surrogate markers does not necessarily translate to improved clinical outcomes. The currently ongoing PRIMACY (Primary Reperfusion Secondary Stenting Trial) is a randomized clinical trial that will compare clinical outcomes similar to DANAMI 3 - DEFER in patients treated with stent implantation either immediately or 4-7 days after the index procedure when combined with adjunctive anticoagulation. It remains to be seen whether this would rekindle interest in the matter or if it would prove to be the final nail in the coffin for deferred stenting.

Mechanical Unloading of LV to Reduce Infarct Size

Mechanical support in the setting of STEMI has long been an area of active research. Although recent studies have not supported the routine use of intra-aortic balloon pump for shock in the setting of AMI to reduce afterload and improve coronary blood flow,¹⁹ interventionalists obviously continue to utilize mechanical support in "patients who need it." Many therapies have been studied to reduce myocardial injury in the setting of AMI, but recent data raise the question whether mechanical unloading of the ventricle prior to PCI may reduce myocardial injury. Although the concept of ventricular unloading is not new,²⁰ ventricular unloading with an intra-aortic balloon pump is minimal compared with LV assist devices (LVAD). There are multiple options to provide hemodynamic support in patients with AMI and cardiogenic shock, including peripheral and central venoarterial extracorporeal membrane oxygenation, TandemHeart device (peripheral LVAD) (CardiacAssist, Inc; Pittsburg, PA), Impella CP or 2.5 device (ABIOMED, Inc; Danvers, MA), or multiple different LVAD options for surgical placement. Preclinical research suggests unloading the ventricle may significantly improve hemodynamics and decrease infarct size. In a study of percutaneous left atrial to femoral artery bypass with a TandemHeart device for ventricular unloading in a porcine AMI model,²¹ the 4 animals that underwent 120 minutes of mid-LAD occlusion were placed on a TandemHeart device for 30 minutes of additional occlusion time and had continued support during reperfusion. These animals had a 42% reduction in infarct size by cardiac enzymes and histological analysis compared with animals that experience only 120 minutes of ischemia followed by reperfusion alone. Analysis of the data revealed that mechanical unloading before reperfusion activates signaling pathways that protect against reperfusion injury in the non-infarct zone during AMI without any difference in the infarct zone.21 These findings suggest that reducing LV wall stress with a delay in reperfusion reduces myocardial damage after ischemia. Total circulatory support with a LVAD has also been shown to significantly decrease infarct size compared with partial circulatory support.²² Venoarterial extracorporeal membrane oxygenation in a porcine model of AMI increased coronary blood flow and reduced intracardiac pressures.²³ However, peripheral and central venoarterial extracorporeal membrane oxygenation can be limited by LV distension due to increased LV pressures, resulting in pulmonary edema. LV venting remains an important technique to unload the LV in these patients when extracorporeal membrane oxygenation is utilized for hemodynamic support.²⁴ Finally, intracorporeal axial flow catheters, such as Impella, have been shown to significantly reduce infarct size in both sheep and porcine AMI models.^25,26 LV unloading with Impella 30 or 60 min prior to reperfusion reduced infarct size, increased cardioprotective signaling, and improved mitochondrial integrity.²⁶ Thus, Impella serves as an important option to interventional cardiologists to provide ventricular unloading in patients with cardiogenic shock due to AMI or other etiologies such as decompensated HF or recurrent ventricular tachycardia.

In a retrospective analysis, the USpella Registry found that patients who received Impella prior to revascularization for cardiogenic shock had significantly improved survival compared with patients who had Impella placed following revascularization (30 day survival was 57.4 vs 38.2%, respectively, p = 0.004).²⁷ Although multivariate analysis demonstrated that placement of an Impella prior to PCI was independently associated with improved survival, this study is retrospective and clearly suffers from selection bias. Placement of ventricular support devices is clearly not without risk and carries potential for complications, especially vascular complications. A heart team approach may help physicians determine the best device given the clinical scenario. Furthermore, these devices add significant cost and have yet to show a clear clinical benefit.²⁸ It is important to recognize that many patients have dramatic clinical and hemodynamic improvement immediately following restoration of coronary flow following PCI, and it is difficult to determine which patients presenting with AMI will develop cardiogenic shock.

Conclusion

As has been illustrated numerous times, mice are not men. It is critical not to rush the push for bench to bedside without performing careful and appropriately powered randomized studies that have meaningful clinical outcomes. As seen by ischemic postconditioning and deferred stenting, it is essential to assess the value of ventricular unloading prior to PCI in patients with AMI presenting in cardiogenic shock by conducting an adequately powered randomized controlled trial. Although ventricular unloading to decrease reperfusion injury is appealing and has strong preclinical support, it is critical that a well-designed clinical trial validate these findings in humans before we switch from "door to balloon" to "door to support device" in patients with AMI.

References

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Keywords: Adenosine, Angioplasty, Balloon, Coronary, Arrhythmias, Cardiac, Cholesterol Ester Transfer Proteins, Cholesterol, LDL, Cholesterol, HDL, Coronary Angiography, Coronary Artery Bypass, Coronary Artery Disease, Coronary Stenosis, Electrocardiography, Extracorporeal Membrane Oxygenation, Heart Failure, Ischemic Postconditioning, Ischemic Preconditioning, Lipoproteins, HDL, Magnetic Resonance Spectroscopy, Myocardial Infarction, Percutaneous Coronary Intervention, Pulmonary Edema, Shock, Cardiogenic, Stents, Stroke, Tachycardia, Ventricular, Thrombectomy, Thrombosis, Vasodilator Agents

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