NO-REFLOW

PHENOMENON

Dr.Surinder S Hansra
 Introduction

 “No-reflow”, used to describe microvascular obstruction and reduced myocardial flow after
opening an occluded artery, is a frequent occurrence in primary PCI.

 It occurs after reperfusion with a variable prevalence, ranging from 5% up to 50%.

Catheter Cardiovasc Interv 2008

 Data has clearly shown that patients with no-reflow exhibit a higher prevalence of
1) early postinfarction complications (arrhythmias, effusion, tamponade, early CHF)
2) left adverse ventricular remodeling
3) late repeat hospital stays for heart failure
4) mortality
 Prevalence of No-Reflow
100 patients without cardiogenic shock treated by primary PCI
Estimation derived from analysis of the CADILLAC trial (2004)
 Pathogenetic Components of No-Reflow

 Distal embolization
 Emboli originate from epicardial coronary thrombus and from fissured
atherosclerotic plaques
 Myocardial blood flow decreases irreversibly when microspheres obstruct more
than 50% of coronary capillaries.
 Large emboli (200 um diameter) can obstruct pre-arterioles, causing infarctlets.
 Angiographic evidence of distal embolization in patients treated with primary
PCI has been shown to occur in approximately 15% - 19%. JACC 2006

 Ischemia-related injury
 Changes in endothelial cells, after prolonged ischemia, are represented by
endothelial protrusions and endothelial gaps.
 Myocardial cell swelling associated with interstitial edema might cause
microvascular compression.
 Reperfusion-related injury
 Reintroduction of neutrophils in post-ischemic myocardium results in their
activation,and release of proteolytic enzymes, and pro-inflammatory mediators
(TNF-alpha, IL-1) that can directly cause tissue and endothelial damage.
 Neutrophils also form aggregates with platelets that plug capillaries.
 Vasoconstrictors released by damaged endothelial cells, neutrophils, and platelets
contribute to sustained vasoconstriction.
 Finally, the balance between NO and superoxide is tipped in favor of superoxide
within minutes of reperfusion of ischemic tissues, which leads to an exacerbation
of the inflammatory state.

 Individual predisposition of coronary microcirculation to injury

 Predisposition might be genetic and/or acquired.
 Diabetes has been associated with impaired microvascular reperfusion after PPCI
 Hypercholesterolemia in the animal model aggravates reperfusion injury.
Predictors of the Pathogenetic Components of No-Reflow
 Diagnosis of No-reflow
 Coronary angiography (Low sensitivity)
 TIMI flow grade 2 without a residual obstructive lesion.
 Corrected TIMI frame count (CTFC)
 Myocardial Blush Grade
 Together, angiographic no-reflow can be defined as a TIMI flow grade <3 or 3 with a MBG
0 to 1.

ECG
 Lack of STR <50% or 70% at 1 hr after primary PCI (70% sensitivity and 54% specificity)
 one-third of patients with TIMI flow grade 3 and MBG 2 to 3 do not exhibit STR
 Terminal T-wave inversion & AIVR only reflect IRA patency.

Noninvasive imaging techniques
 Neither blush grade nor ECG resolution provide a direct assessment of myocardial
perfusion.
 Myocardial contrast echo - In AMICI study, the extent of no-reflow at MCE was
demonstrated to be the best predictor of adverse LV remodeling after AMI, being superior
to STR and to MBG among patients exhibiting TIMI-3 flow.
 CMR - Studies performed by CMR have confirmed that no-reflow is a powerful predictor of
LV remodeling and of patient survival.
 Prevention and Treatment of No-Reflow
 Management of ischemia-related injury
 Reducing pain-onset-to-balloon time
 Reduce myocardial oxygen consumption
 Beneficial effects of carvedilol, fosinopril, and valsartan on coronary no-reflow
have been recently demonstrated.
 Management of individual susceptibility to microcirculatory Injury
 Optimal and prompt treatment of hyperglycemia The
DIGAMI study shows that periprocedural reduction of blood glucose was
associated with a reduction of infarct size.
 Statins are emerging as drugs potentially able to reduce reperfusion injury.
Chronic statin therapy in patients with or without hypercholesterolemia is
associated with lower prevalence of no-reflow and better functional recovery.
Eur Heart J
2006
 Induction of ischemic pre-conditioning by drugs and avoidance of substances
potentially blocking pre-conditioning like sulfonylureas and high doses of
alcohol.
 Management of distal embolization

 Direct stent implantation –

Avoids balloon-induced thrombus fragmentation and by entrapping the
atherothrombus under the stent struts.
However, only those with good distal visualization of the IRA after guidewire
passage through the culprit lesion, are suitable for direct stenting.

 Thrombectomy devices and distal filters -

 The REMEDIA trial, which was the first randomized trial to assess the role of
simple manual aspiration catheter, had promising results.
The benefit was particularly evident in the subset of patients with higher
thrombus burden and with total IRA occlusion.
 A recent meta-analysis showed that thrombectomy was associated with a
significant improvement of reperfusion as assessed by STR and MBG, whereas
distal protection was not. Int J
Cardiol 2008
 ATTEMPT Study
Meta-analysis of 11 randomised trials

Adjuntive Manual Thrombectomy (1815 pts.)

European Heart Journal (2009) 30, 2193–2203

ATTEMPT Study
MACE rates
 ATTEMPT Study
Non-manual thrombectomy
(X-sizer, Angiojet & TVAC)
 Adjunctive Thrombectomy for AMI
A Bayesian Meta-Analysis of 16 Aspiration thrombectomy RCTs
Circ Cardiovasc Interv 2010

There was no evidence for a decrease in 30-day

post-MI death, death, recurrent MI, or stroke.
Moreover, aspiration thrombectomy
devices did not lead to substantially better results.
Further data on long-term clinical effects of
thrombectomy are needed to justify a liberal use
of these costly devices in primary PCI.
The superiority of aspiration devices remains
controversial.
 Management of reperfusion-related
 Glycoprotein IIb/IIIa antagonists -
injury
 Abciximab has been found to improve myocardial perfusion when started during
PPCI and infused for 12 h thereafter.
 The effects of peptidic glycoprotein IIb/IIIa antagonists on no-reflow and long-term
mortality still need to be tested in large randomized trials.
 A small randomized study of abciximab versus tirofiban for patients undergoing
PPCI, demonstrated similar rates of final TIMI flow grade 3, adverse cardiac
remodeling, and clinical events at 1 month. Am J Cardiol 2004
 IC abciximab has been proven to be superior to IV abciximab in patients treated by
primary PPCI. Circulation 2008
 Adenosine -
 In a randomized trial, IC administration of adenosine before complete vessel
reopening resulted in a lower rate of no-reflow. Circulation 2000
 IC administration of high dose of adenosine (60 mg) was found to reduce the rate of
incomplete STR after PPCI. Catheter Cardiovasc Interv 2008
 IV adenosine has been tested in 2 large randomized trials (AMISTAD I and II),
showing a reduction of incomplete STR with a 3-h infusion of adenosine, but in-
hospital and 6-month clinical outcome were similar to the placebo group
 IC administration of nitroprusside, compared with control, failed to improve cTFC and rate of complete
STR. Conversely, 2 small registries showed an improvement of final TIMI flow grade after administration
of IC nitroprusside given in the attempt to reverse no-reflow Am J Cardiol 2005, 2007
 Nicorandil - IV infusion of nicorandil for 24 h after PPCI resulted in better angiographic, functional, and
clinical outcome as compared with placebo in 2 randomized studies

JACC 1999, Am
Heart J 2004
 ANP has been tested recently in a large-scale randomized trial. The J-WIND trial, showed that ANP
treatment was associated with a reduction of 14.7% in infarct size, an increase in LVEF by 5% in 6 to 12
months, and an improved myocardial perfusion. In the same trial the authors randomized patients to
IV nicorandil or placebo but failed to show any reduction in the infarct size or improvement in LVEF in
the nicorandil group. However, oral nicorandil prescribed during the follow-up improved LVEF.
Lancet 2007
 Verapamil – IC verapamil has been shown to be associated with better microvascular function as assessed
by MCE. Accordingly, intracoronary verapamil has been successfully used to reverse no-reflow after
PPCI. Catheter Cardiovasc Interv 2002
 Selective ET-1 or TxA2 antagonism might represent novel therapeutic approaches
 Conclusion

 The understanding of the prevailing pathogenic mechanism of no-reflow in the individual

patient is probably important in the selection of the most appropriate therapeutic approach.

 Patients with a high thrombus score are more likely to benefit from thrombus aspiration,
whereas those at high risk of reperfusion injury are more likely to benefit from
pharmacotherapy.

 New drugs such as ET-1 or TxA2 antagonists and the combination of old drugs such as
adenosine, nitroprusside, and nicorandil should be tested in large controlled randomized trials
in patients at high risk of reperfusion injury.

 Finally, optimal and prompt risk factor control and induction of preconditioning represent
additional therapeutic options that, again, should be tested in large controlled randomized
trials.