CHAPTER · CHAPTER 17 Rabin Chakraborty, Arindam Pande INTRODUCTION Percutaneous coronary intervention (PCI) ... 118 Section 3: Coronary Artery Disease Thus, no/slow reflow and coronary

Protection of Microcirculation during PCI

CHAPTER 17Rabin Chakraborty, Arindam Pande

INTRODUCTIONPercutaneous coronary intervention (PCI) during acute myocardial infarction (AMI) usually achieves normalized coronary epicardial flow; however, distal embolization is common and it impairs microcirculation.1,2 Poor myocardial reperfusion is associated with adverse outcomes including reduced left ventricular (LV) function and survival.3-5 Numerous adjunctive pharmacological measures as well as coronary devices have been developed in an attempt to decrease or prevent embolization during revascularization and therefore to improve clinical outcomes. The use of embolic protection devices to reduce adverse cardiac events in stable patients with saphenous vein graft lesions has been documented previously.6,7 Accordingly, embolic protection of saphenous vein grafts is considered class I therapy by the recent practice guidelines. Conversely, during acute myocardial infarction, the effect of adjunctive devices on clinical outcomes is unknown.8-10 Moreover, some devices such as the AngioJet device (Possis Medical, Inc., Minneapolis, MN, USA) have been shown to increase the adverse cardiac events.11 One explanation why clinical outcome data with adjunctive devices is currently unknown is that individual trials have been powered to study only the surrogate markers of clinical outcomes, such as the thrombolysis in myocardial infarction (TIMI) blush grade12 and ST-segment resolution.13

The rupture of an atherosclerotic plaque in an epicardial coronary artery does not always result in

complete thrombotic coronary occlusion and impending myocardial infarction; milder forms of plaque rupture may leave some residual blood flow and result in the washout of atherothrombotic debris into the coronary microcirculation and its subsequent embolization. Coronary microembolization became a focus of attention about a decade ago with the awareness that coronary microembolization and its sequelae are a frequent iatrogenic complication of percutaneous coronary interventions (PCIs).14,15 However, coronary microembolization was recognized much earlier as being the underlying pathophysiological event in sudden death of patients with unstable angina.16-19

NO-REFLOW/SLOW-FLOW PHENOMENONNo or slow reflow after successful PCI is an often-unexpected complication in 0.5–1% of patients,20,21 reflects an impairment of microcirculatory blood flow, and carries an adverse prognosis.22,23 Often, coronary microembolization is simplistically assumed to be the cause of no/slow reflow. Coronary microembolization can certainly contribute to no/slow reflow in the clinical scenario;24 however, a profound no-reflow phenomenon is also seen in animal experiments in which a perfectly normal epicardial coronary artery is occluded by an external device that is then released to restore blood flow. The area of no reflow is then confined to the area of infarcted myocardium and is characterized by obstructive capillary damage, i.e., it is a consequence and not a cause of infarction.25

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Thus, no/slow reflow and coronary microembolization should be viewed as distinct phenomena. Several vasodilator agents, such as nitroprusside, verapamil, and adenosine, have been shown to improve microcirculatory flow with varying degrees of success.25 The recognition that thromboxane A2 and serotonin are released from rupturing plaques26 may provide a potential new treatment option.

THERAPEUTIC OPTIONS FOR PROTECTING MICROCIRCULATION DURING PERCUTANEOUS CORONARY INTERVENTION

Statins

Statins not only stabilize a vulnerable atherosclerotic coronary plaque by reducing its lipid content, but their anti-inflammatory, pleiotropic action might also attenuate the inflammatory myocardial responses associated with coronary microembolization and microinfarction.27,28 In support of this notion, patients given statin therapy when undergoing PCI have a reduced incidence of periprocedural myocardial injury, as reflected by creatine kinase and troponin release, less inflammatory response, and better outcome. It is not clear for how long and at what dose statins must be given before PCI to protect against coronary microembolization.29 However, even statin loading just before PCI provides protection;24 the short-term effects of statin loading cannot be attributed to plaque stabilization but are a result of the anti-inflammatory actions of statins or activation of survival pathways.28 In fact, protection is also seen when statin treatment is initiated after PCI, when it cannot be related to plaque stabilization and prevention of microembolization as such but only to attenuation of its inflammatory consequences.30 Apart from any relation to coronary microembolization, higher doses of statins provide better protection.31,32 In addition, high levels of high-density lipoprotein cholesterol per se protect against PCI-related microinfarction.33

Protection Devices

The most direct evidence for the clinical importance of coronary microembolization is expected from studies of its prevention by use of protection devices during PCI. Distal protection devices are introduced downstream of the culprit lesion and entail the risk of causing microembolization during their introduction and of occluding side branches; a proximal protection device for occlusion and aspiration remains upstream of the culprit lesion and avoids such risks.34 The Saphenous vein graft Angioplasty Free of Emboli Randomized (SAFER) trial has

established protection by distal filter devices in patients with stable angina undergoing PCI of saphenous vein aortocoronary bypass grafts,35 and this together with the FIRE (FilterWire EX Randomized Evaluation) trial36-38 has led to a class 1A recommendation in European Society of Cardiology guidelines.39 However, in the aggregate, the existing data on distal protection devices, all of which apart from the SAFER trial were derived from patients with acute myocardial infarction, are disappointing, and this view is supported by meta-analyses and editorial comments.34,40-42 No protection is seen with the use of filter devices during PCI of native coronary vessels, and many studies revealed no protection, whether with biomarkers, imaging, or major cardiac events as end points, with the use of balloon occlusion/aspiration devices in either native or saphenous vein bypass vessels. In addition, no difference between the use of filter or distal balloon occlusion/aspiration devices in saphenous vein bypass grafts is apparent, which would be expected if small particles and/or soluble factors that are not trapped by filter devices were of major importance. Given the evidence that protection against coronary microembolization (for example, by statins) is beneficial, a satisfying explanation for the apparent lack of protection afforded by distal devices is not available; possibly, there is damage by the additional instrumentation and/or side-branch occlusion that offsets any protection. In the setting of acute myocardial infarction, the removal of thrombotic material and of thrombus-related soluble substances reduces thrombus burden,26 improves myocardial perfusion, and provides protection, again supporting the pathophysiological importance of coronary microembolization.43 Thromboaspiration before con ventional PCI is primarily practiced with angiographically visible thrombi but is also protective without prior visualization of thrombi.44,45 In initial studies, thromboaspiration shown protection when performed manually or with the use of automated devices, which are more effective but also larger. It is not clear why thromboaspiration offered protection, but distal protection fails to protect even when both strategies are used in patients with acute myocardial infarction and with the same end points. Prevention of formation of microemboli by thromboaspiration rather than their retrieval by distal protection devices once they are formed, as well as the iatrogenic induction of microembolization by advancement of the protection device distal to the culprit lesion, are potential explanations; in addition, a filter pore size of 80–100 m may still permit the embolization of smaller particles, which are nevertheless of considerable impact in animal studies. Though in later studies, benefit of thromboaspiration was also questionable, and accordingly level of recommendation was also lowered in all the major guidelines.46

Chapter 17: Protection of Microcirculation during PCI 119

Table 1 Antiplatelet and vasodilator agents in PCI

Patient characteristics Outcome

Coronary status, number of patients Target vessel, number of treated culprit lesions

Surrogate parameter

Acute coronary syndrome

Drug Stable NSTEMI Not at-tributable to NSTEMI or STEMI

STEMI Native, Yes vs No

Not attributable to native or SVG, Yes vs No

SVG, Yes vs No

Biomarker Imaging Clinical end point: MACE

Antiplatelet agents, yes vs no*

Abciximab 75 30 vs 45 ↓ ↓

Abciximab on top of alteplase

346 211 vs 125 ↓ (ECG)

Abciximab on top of heparin

1874 935 vs 939 ↓ ↓ ↓

Abciximab 2409 1583 vs 826 ↓ ↓ ↓

Tirofiban 172 114 vs 58 ↓ ↓ ↓

Antiplatelet agent vs antiplatelet agent

Prasugrel vs clopidogrel

13608 13608 ↓ ↓

55% 26%

Vasoactive agents, yes vs no

Adenosine 279 79 vs 200 ↓ (ECG)

Adenosine 1416 703 vs 713 ↓

Adenosine 30 15 vs 15 ↓ ↓

Edaravone 80 40 vs 40 ↓ ↓

Nicorandil 408 206 vs 202 ↓ ↓

Nitroprusside 120 60 vs 60 60 ∅ ↓

Nitroprusside or verapamil on top of nitroglycerin

135 42 vs 51 vs 42 ∅ ↓† ∅

Abbreviations: NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction; SVG, saphenous vein graft; MACE, major advers cardiac events; R, randomized study; ↓, decreased damage; ↑, increased damage; ∅ no change; TIMI, thrombolysis in myocardial infarction; EPILOG, evaluation of PTCA to improve long-term outcome with abciximab glycoprotein IIb/IIIa blockade; EPISTENT, evaluation of platelet IIb/IIIa inhibitor for stenting trial; TRION/TMI 38, trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel thrombolysis in myocardial infarction 38; AMISTAD-II, acute myocardial infarction study of adenosine-II*Clopidogrel is regarded as standard therapy with any PCI and therefore is not considered in this table. †only for verapamil

Antiplatelet Agents and Coronary Vasodilators

Of the many studies on the use of antiplatelet and vasodilator agents in PCI, only those should be considered in which the respective agent had objective signs of myocardial damage (biomarker, imaging) as an end point, because only with reduction of myocardial damage can the targeted thrombotic and/or vasoconstrictor mechanism be regarded as a cause rather than a consequence of

myocardial infarction (see above on the slow-reflow/no-reflow phenomenon). Clearly, there are a number of studies in which the use of antiplatelet agents in patients with stable angina or acute coronary syndromes and vasodilator agents in patients with acute coronary syndromes attenuated myocardial damage or reduced adverse events as shown in Table 1,47-59 which supports the contribution of thrombotic and vasoconstrictor mechanisms to the pathophysiology of coronary

Section 3: Coronary Artery Disease120

microembolization; however, it is unclear whether the respective agent actually prevented the formation of microemboli (possible with antiplatelet agents) or attenuated their consequences in the microcirculation (possible with coronary vasodilators).

CONCLUSIONCoronary microembolization is also a frequent complication during PCI. It may occur spontaneously as well, and possibly much more frequently than is recognized. The consequences of coronary microembolization are reduced coronary reserve, microinfarcts with inflammatory responses, and myocardial dysfunction. Statins, antiplatelet agents, and coronary vasodilators protect against coronary microembolization and its consequences. The use of distal protection devices has thus far been disappointing. Thromboaspiration reduced thrombus burden and conferred protection in patients with acute myocardial infarction; however, based on recent studies, this strategy is recommended for some special situations only (Class 2b), when there is huge thrombus burden preangioplasty or visible thrombus or slow flow post-stent deployment.

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