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Practical Approach to Diagnosis, Prevention, and Management of Coronary No-Reflow
How to cite this article: Nemani L. Practical Approach to Diagnosis, Prevention, and Management of Coronary No-Reflow. Indian J Cardiovasc Dis Women 2023;8:65-74.
Coronary no-reflow (NR) defined as inadequate myocardial perfusion despite restoration of coronary artery patency is a bane for an interventional cardiologist. It can complicate percutaneous coronary interventions especially in the setting of STEMI and dampens the potential benefits of PPCI. Broadly classified as Reperfusion NR and Interventional NR, mechanism is multifactorial. The basic underlying culprit is microvascular obstruction either secondary to distal embolization, intravascular plugging, or ischemic reperfusion injury. Coronary angiogram is an easy, readily available, and essential modality to diagnose no-reflow, but the gold standard is gadolinium-enhanced cardiovascular magnetic resonance imaging. Preventive strategies for NR should be integral part of prePCI planning especially in clinical scenario where NR is expected such as STEMI with delayed presentation and high thrombus burden, atherectomy, and SVG PCI. The cornerstone of treatment for NR is local vasodilators and antiplatelet therapy to ameliorate vasospasm and thromboembolism respectively, and different combinations of the two should be used in no specific order to achieve reversal of NR. NR phenomenon is associated with poor short-term and long-term prognosis and every attempt should be made to avoid or reverse it. Therapeutic hypothermia, hyperoxemic reperfusion therapy, targeted anti-inflammatory approach, and cellular approach appear proising but further research is mandatory.
Coronary no-reflow (NR) is defined as inadequate myocardial perfusion despite restoration of coronary artery patency in the absence of dissection or spasm. Angiographically, NR is thrombolysis in myocardial infarction (TIMI) flow Grade <3 and myocardial blush Grade (MBG) <3 manifesting as reduced or absent flow in the affected coronary vessel despite removal of primary obstruction. TIMI flow Grade 0–1 is referred as NR, and TIMI flow grade as slow flow. The different terms no flow/NR/low flow/slow flow/slow reflow apparently are expressions for the same abnormality and simply referred as NR.
NR complicates nearly 50% cases of STEMI, less frequent in NSTEMI. Incidence in elective cases is <1.5% with a higher occurrence of nearly 4% in saphenous venous graft interventions.
NR is broadly classified as reperfusion NR and interventional NR [Figure 1].
The mechanism of NR is multifactorial [Figure 2]. The basic underlying culprit is microvascular obstruction (MVO) secondary to distal embolization, intravascular plugging, or ischemic-reperfusion injury.[4-6]
Clinical scenario varies from asymptomatic state to hemodynamic compromise with life threatening arrhythmias. Reperfusion NR may be asymptomatic or present as ongoing chest pain and non-resolution of ST-segment elevation. Interventional NR classically with acute chest pain and ECG changes of ischemia which may over time. Acute ischemia presents as hemodynamic compromise prompting early initiation of strategies to reverse NR. Even in asymptomatic cases, every attempt should be made to correct NR, as it has poor outcome both short- and long-term.
PREDICTORS FOR NR
Certain clinical and angiographic factors predispose to Noreflow [Table 1].
|Predictors of individual susceptibility||Predictors of ischemic reperfusion injury||Angiographic predictors|
|• Age >65
• Female sex
• Atrial fibrillation
• Renal insufficiency
• Genetic- adenosine 2A receptor polymorphism (1976T>C)/ lysis resistance
|• Time to treatmentdelayed presentation
• Larger area of infarction (LAD occlusion)
• Mean platelet volume
• Oxidative stress
• Thromboxane A2 levels
• Vasoconstrictor ET-1 levels
• Inflammatory markersneutrophil count, CRP
|• High thrombus burden,
• Plaque composition
• SVG PCI,
• Long lesions (> 15 mm)
RISK SCORES FOR NR
|MELD SCORE [Model for end-stage liver disease-XI score]||MELD-XI score = 5.11×(total bilirubin, mg/dL) +11.76× (creatinine, mg/dL) +9.44
Bilirubin: Potent endogenous antioxidant, suppresses ROS production,inhibits oxidative stress that contribute to no-reflow.
High bilirubin levels-NR(Celik et al.)
Creatinine: Marker of renal impairment. Independent marker for NR in STEMI patients undergoing PCI. NR in renal dysfunction attributed to ROS and endothelial dysfunction
|• Independent predictor of NR during Primary PCI
• Highly predictive power for no-reflow
• May be useful in early risk stratification of patients with STEMI[15,16]
|• Both renal insufficiency and NR are manifestations of oxidative stress[13,14]|
[Renal function, Congestive heart failure, Hypertension, Diabetes, Age, peripheral Vascular disease, Stroke and female Sex
|1 point each
2 for Stroke and Age ≥75 years
2 points for renal function (eGFR) ≤ 60 mL/min/1.73 m2 using the MDRD formula)
|• High CHA2DS2-VASc score (≥3)-independent predictor of no-reflow (80.9% sensitivity and 74.6% specificity).
• The R2-CHA2DS2-VASc score-relatively poor predictive value for no-reflow. Score ≥3–52.6% sensitivity and 73.1% specificity for no-reflow.
|Novel Biomarker: Malat1
[Metastasis-Associated Lung Adeno-Carcinoma Transcript 1]
Long Non-Coding Rnas (Lnc Rnas)Are Transcripts With ≥200 Nucleotides. Recognised For Their Role In Many Biological Processes (Malat1)Conserved Lnc Rna, Biomarker In Lung Malignancy. Recently Identified For Its Role In Regulation Of Many Pathophysiological Processes Related To Vascular Disease
|Mi RNAs namely miR-30e and miR-126[23,24]biomarkers for predicting NR in STEMI patients
Elevated HPSE and EDN-1[25-27]are associated with no-reflow in STEMI
|• MALAT1 regulates the expression of miR-155
• Expression of MALAT1 is significantly increased and that of miR-30e, miR-126 and miR-155 suppressed in the patients with NR
DIAGNOSIS OF NR
Resolution of ST elevation following revascularization is highly specific (91%) for reestablishment of myocardial perfusion but less sensitive (77%).[29,30] ST resolution should be more than 70% at 60 min after PCI, anything less is a sign of NR.
Serial measures of cardiac biomarkers, namely, troponins, creatinine kinase MB, and serum myoglobin are useful for the assessment of patency in the infarct artery. They are estimated at baseline and then either 60 or 90 min after completion of reperfusion therapy. Greater increase in these markers over time from baseline indicates successful reopening of the occluded epicardial vessel, and also establishment of micro vascular tissue reperfusion.
Myocardial contrast echo
Easy, readily available, and essential modality of diagnosing NR in the catheterization laboratory.
TIMI flow grade – Only TIMI 3 flow indicates successful reperfusion, a flow <3 is considered as NR.
MBG – MBG allows further risk stratification in patients with TIMI 3 flow, with a MBG score of 0–1 indicates NR.
Corrected TIMI frame count – Another method to evaluate epicardial flow. Low frame counts after PPCI indicates favorable reperfusion.
Myocardial perfusion grade (TMPG)-In TIMI 3 flow, TMPG is a technique to assess myocardial perfusion or “blush” on a coronary angiogram. A TMPG score of 0/1 indicates impairment of microvascular flow, whereas a TMPG grade 2/3 implies salvaged myocardium.
Although coronary angiogram is the most frequently done procedure for NR, it is not accurate. A measure of flow parameters and resistance parameters is a more accurate invasive technique for diagnosis of NR.
Coronary flow reserve (CFR)
A CFR value <2.0 indicates presence of MVO with nearly 80% sensitivity. NR is characterized by typical flow pattern of systolic flow reversal (retrograde) and rapid diastolic flow deceleration.
Microvascular resistance index (IMR)
IMR = distal coronary pressure X mean transit time of a bolus at maximum hyperemia. It is an independent measure of microcirculatory flow
Angiography-derived IMR (IMR Angio)
Latest addition to the armamentarium. IMR angio can predict and IMR more than 40 units and the presence of large MVOs on cardiac magnetic resonance imaging (MRI) with good accuracy.
This new technology combines real-time microvascular assessment with the ability to administer intracoronary drugs.
The procedure involves transient balloon occlusion of the coronary, infusion of a crystalloid at fixed incremental dose rates, and simultaneous measurement of distal and proximal pressures
Microvascular resistance is derived from the flow and pressure quotient. The procedure is still experimental with initial encouraging results.
The gold standard for NR diagnosis is gadolinium-enhanced cardiovascular magnetic resonance imaging.
MVO appears as dark hypointense areas surrounded by hyperintense necrotic myocardium on T-weighted images in delayed gadolinium enhancement images (10–15 min), or as low signal images in early (1–3 min) images
First-pass perfusion (FPP) method: FPP is another technique which is also contrast dependent. It can detect even small areas of MVO. However, it is not as specific as DGE. A perfusion defect appears as absence of contract-enhancement in the affected myocardium.
Positron emission tomography (cardiac PET) and (SPECT) single-photon emission computed tomography for detection of NR have been described in experimental models, but not implemented practically.[47,48]
PREVENTION OF NR
NR is a challenging complication following PCI. Multiple therapies have been suggested, though none is 100% effective and doubtful impact on associated adverse cardiovascular outcome [Table 3].[49,50] As there are no ideal guidelines for the management of NR, first and foremost effort should be to prevent NR.
|Reducing the time to reperfusion from the onset of symptoms is the foremost method to salvage the myocardium and reduce no-reflow|
A. Pharmacological therapy
1. Beta-blockers (Metoprolol, Carvedilol and Nebivolol)
2. ACE-inhibitors and ARBS
|Early use has shown to protect coronary microcirculation and reduce NR due to its anti-inflammatory role in pre-clinical studies
Favorable results have been observed especially with fosinopril and valsartan.
Guidelines recommend early initiation of these drugs in acute MI unless
|3. Statins||High dose before PCI improved angiographic MVO in the STATIN STEMI.
Nearly 50% of reduction in CV events at 30 days was observed in the
SECURE-PCI study. Studies showed that patient who were already on
statins at index event experienced lesser rates of NR
B. Procedural tips to reduce No-reflow in the Cath lab
||1. Direct stenting and avoidance of high-pressure post-dilation especially in STEMI.
2. Short burr runs of <20 s; low burr speed of 140,000–150,000 rpm), and avoidance of decelerations more than 5000 rpm during atherectomy
3. Use of distal protection device (Percusurge and filter wire Ex device) have been proven to reduce no-reflow during elective SVG angioplasty
4. Deferred stenting in selected cases with high thrombus burden during which patient receives supportive treatment
5. Ischemic preconditioning pre and post though theoretically favor reduction of no-reflow, have not been proven so in randomized trials
Strategies for prevention of NR should be incorporated in pre-PCI planning especially in clinical scenario where NR is expected such as STEMI with delayed presentation and high thrombus burden, atherectomy, and SVG PCI.
TREATMENT OF NR
The cornerstone of treatment for NR is local vasodilators and antiplatelet therapy to ameliorate vasospasm and thromboembolism, respectively. Intracoronary vasodilator and GP IIb/IIIa inhibitor are Class IIA recommendations for NR according to the 2021 ACC/AHA PCI guidelines.
Pharmacological vasodilatation [Table 4]
When sudden cessation of flow is seen in target artery during PCI; dissection, acute stent thrombosis, plaque prolapse, and vasospasm should be excluded ideally with imaging if the clinical scenario permits. If NR is confirmed by the presence of patent vessel, intracoronary vasodilators should be administered liberally ensuring an optimal activated clotting time and mechanical hemodynamic support if needed.
|MEDICATION||DOSE||MECHANISM OF ACTION||ADVANTAGE/DISADVANTAGE||EVIDENCE|
|Adenosine||50–200 µg bolus IC
70 µg/kg/min IV
|- Dilatation of coronary microvasculature (A2 receptors mediated Smooth muscle relaxation)
- Platelet Inhibition
- Ischemic preconditioning
-Angiogenesis and Anti-apoptotic
|Side effects-Atrioventricular blocks, Hypotension, Dyspnoea, Bronchospasm and flushing
Advantage-very short half-life (<8 s)
|REOPEN-AMI: MVO improved, peak Troponin levels reduced.
Reduction in major
Favourable LV remodelling at 1 year
|Calcium channel blockers:
|100–250 µg bolus IC
50–200 µg bolus IC
|Block L-type calcium channels
- Smooth muscle relaxation
- Reduce myocardial
- Minimize damage mediated by oxygen free radicals
Effective in the treatment of NR
|Randomized trials and RECOVER-AM trial-CCB’s effective in prevention and treatment of NR, doubtful effect on improvement in outcome|
|Epinephrine||50–200 µg bolus IC||inotropic and chronotropic properties
- Alpha vasoconstriction corrects hypotension and improves coronary perfusion
- Coronary vasodilation
(Beta-2 receptor agonist)
- MC was sinus tachycardia Occasional SVT and non-sustained VT
More common with guide catheter directed therapy than local delivery of medication
|According to Skelding et al.; both TIMI flow and TIMI frame count improved.
MACCE at 30 days and 1 year improved
(Darwish et al.)
|Nitroprusside||50–200 µg bolus IC||Nitric oxide donor
|Systemic hypotension||Inferior to CCB’s and Adenosine|
|Nicorandil||Bolus of 2 mg IC
Followed by infusion of
|Activation of ATP-sensitive potassium channels and nitric oxide donor
- Neutrophil activation
- Inhibition of ROS
|No randomized trials, only small studies-proved effective in NR|
|Nitroglycerine (NTG): It is primarily a venodilator and minimal effect on arterial tone. Must be metabolized to nitric oxide to be effective which the microvascular arterioles are incapable to. Intracoronary NTG failed to show benefit in no-reflow|
Adenosine regimen: 6 mg (One ampule or 2 mL) added to 10 cc of saline, further diluted 10-fold (add 1 cc of the solution to 10 cc saline); second dilution (again 1 cc of the solution to another 10-cc saline) to achieve final concentration of 60 µg/10 mL. To be given intracoronary injection, dose may be repeated to a maximum of 120 µg
Epinephrine regimen: 1 mg (One ampule or 1 mL) added to 10 cc saline, then diluted 10-fold (add 1 cc of solution to 10 cc saline) to achieve final concentration of 10 µg/mL. 100 µg is injected intracoronary over 5 min. Dose may be repeated up to 3 times to reach a maximum dose of 400 µg
Intracoronary administration of these agents using a microcatheter or over-the-wire balloon ensure safe and effective delivery to the microcirculation with minimal adverse effects. A dedicated dual-lumen or thrombectomy catheter can also serve the purposes without losing wire position. An aspiration catheter or a pierced balloon inflated at the culprit lesion is other easily available options.
Multiple boluses of medications as mentioned above can be tried if NR persists and patient is hemodynamically stable. Different vasodilators should be tried if one does not work.
The PLEIO study demonstrated ticagrelor to be superior to clopidogrel in restoration of coronary microcirculation and reducing NR, also shown in a meta-analysis by Dai et al. However, no difference was observed in sub analysis of PLATO trial, ATLANTIC trial, or REDUCE-MVI trial. Trial Platelet Inhibition to Target Reperfusion Injury trial is an ongoing trial of Cardiac MRI too evaluate the efficacy of pre-procedural Cangrelor to reduce MVO and size of myocardial infarction.
Glycoprotein IIB/IIIA inhibitors
Potent antiplatelet agents appear promising for prevention and treatment of NR [Table 5]. However, none of the randomized trials have shown their benefit in NR. The latest ESC guidelines recommend them for use in NR or thrombotic complication (Class IIa, C).
|Abciximab||Bolus of 0.25 mg/kg iv followed by infusion of 0.125 µg/kg/min (max 10 µg/min) for 12 h||IC administration reduces NR and infarct size-CICERO trial and INFUSE-AMI
No benefit in terms of death, re-infarction or heart failure-AIDA-STEMI
|Eptifibatide||Bolus of 180 µg/kg, repeat 180 µg/kg bolus after 10 min, followed by infusion of 2 µg/kg/min for 18 h.
If CrCl < 50 mL/min, reduce infusion by 50%
|TIMI flow grading improvement in PROTECT TIMI trial|
|Tirofiban||25 µg/kg iv stat over 3 min, followed by infusion of 0.15 µg/kg/min for 18 h.
If CrCl < 30 mL/min, reduce infusion by 50%
|Prehospital intravenous infusion achieved better STR and MBG following PCI-ON TIME-2 trial|
In a recent study, combined use of GP 2B/3A inhibitors along with aspiration and balloon inflation, in STEMI cases resulted in reduced NR.
Though this treatment looks promising, further strong evidence is needed for their use in NR in PPCI.
In STEMI patients, low dose intracoronary alteplase during primary PCI did not reduce MVO in the T-TIME trial, a randomized trial
According to a meta-analysis by Alyamani et al., intracoronary thrombolysis was safe and effective
In the DISSOLUTION trial. manual aspiration followed by Urokinase in STEMI patients with large thrombus burden, showed greater prevalence of TIMI 3 flow, better ST-segment resolution, and favorable MACE at 6 months
Adjunct intracoronary streptokinase improved infarct size and LVEF in STEMI patients in another small randomized study.
From these studies, the use of these agents could be beneficial in selected cases. The dose of the agent varied from 1/3rd to 1/6th of the systemic dose in these studies. Results of two on-going trials evaluating the efficacy of reduced doses of either alteplase (STRIVE trial) or Tenecteplase (RESTORE-MI) are awaited.
Initial results with manual thrombectomy were promising in the TAPAS study, subsequent trials were all negative results (TASTE and TOTAL trial). According to the latest guidelines, routine aspiration thrombectomy in primary PCI is contraindicated. Manual aspiration thrombectomy is reasonable in primary PCI for high thrombus burden (class IIb, level of evidence C). No benefit of rheolytic thrombectomy (ANGIOJET/XSIZER) in primary PCI.
Pressure-controlled intermittent coronary sinus occlusion (PICSO)
PICSO is a device to transiently occlude flow in the coronary sinus, which increases the cardiac venous pressure and improve microcirculatory perfusion. Use of PICSO before deploying the stent in patients with IMR more than 40 showed lesser infarct extension at 6 months in the Ox AMIPICSO trial.
Therapeutic hypothermia (TH)
It proved beneficial in reducing NR and myocardial damage in acute myocardial infarction in animal studies. However, the same benefit has not been shown in human trials. There are multiple reasons predicted to why the effective TH in animal study could not be seen in human trials-
Methods to cool the entire body even with the most effective cooling device take too long thus prolonging the ischemic time which counteracts its benefit. Target temperature could not be reached before reperfusion
Systemic hypothermia had many side effects – shivering in nearly all patients and even serious atrial arrhythmias in many
Hypothermia is effective when initiated before reperfusion, it is anticipated that in the studies conducted nearly 30% already have reperfusion and thus reperfusion injury before cooling is started.
TH appears to be a promising technique and further trials are necessary overcoming the above limitations. Results of the on-going EURO-ICE trial (European Intracoronary Cooling Evaluation in Patients with ST-Elevation Myocardial Infarction), a prospective, randomized, and controlled trial evaluating the efficacy of hypothermia in humans is awaited. This is the largest study of hypothermia in humans where selective intracoronary hypothermia has been used during PPCI.
Selective Intracoronary Hypothermia
The occlusion site is first crossed with a regular guidewire and an OTW balloon inflated at the site of the occlusion.
A pressure/temperature wire (Pressure Wire™ X; Abbott, St. Paul, MN, United States of America) is placed into the distal coronary, and the guidewire is removed. Two infusion pumps are attached to the lumen of balloon-one filled with saline at room temperature (solution A) and the other with saline 4°C (solution B).
Solution A is infused for 7–10 min at a flow rate of 15– 30 mL/min (to maintain distal coronary at 6–8°C below body temperature) – occlusion phase
The OTW Balloon is deflated, and solution B infused for another 7–10 min-reperfusion phase. Flow rate adjusted to maintain the temperature in distal coronary 4–6°C below body temperature
The OTW balloon is removed, and stent deployed over the Pressure Wire X
Hyperoxemic reperfusion (HR)
HR therapy is a treatment in which supersaturated oxygen is administered to a patient with STEMI following PCI to reduce myocardial damage. The procedure uses a device to remove arterial blood from a person, supersaturates it with oxygen and then reintroduce the highly oxygenated blood into the person’s affected coronary artery after stent deployment.
TherOx Downstream® System (TherOx Inc. of Irvine, CA) was approved in April 2019, for administration of super saturated oxygen therapy (SSO2 Therapy) following PCI to the left anterior descending coronary artery within 6 h of acute anterior wall MI
In IC-HOT study, the same administered for a duration of about 60 min proved safe with similar beneficial results.
Targeted anti-inflammatory approach and cellular approach for prevention and treatment of NR are presently in experimental stages. These include interventions that activate intracellular cardio protective signaling pathways directed at halting reperfusion injury. They have shown to reduce ischemic injury and improve myocardial perfusion following PCI and hold great promise. These techniques need refinement and further research is recommended before implementing them.
SIGNIFICANCE OF NR
NR phenomenon is associated with poor outcome immediately and in the long run. It underscores the benefits of PCI and is a nightmare for an interventional cardiologist. In-hospital course is complicated by life-threatening arrhythmias, heart failure and re-MI and hospitalization is prolonged. NR causes negative remodeling of the LV resulting in LV dilatation and heart failure leading to repeated hospitalizations and high 30-day mortality. Five-year survival is also low with high mortality (18.2% vs. 9.5%) in patients with NR compared to those with normal flow.
NR is an undesirable event that can complicate percutaneous coronary interventions especially in the setting of STEMI which could disheartens any interventional cardiologist. Prevention is better than cure hold true in this respect as, no available treatment is 100% effective. Different combinations of pharmacological vasodilation and antiplatelet therapy should be used in no specific order to achieve reversal of NR. Further research is mandatory to identify techniques to treat no-reflow that could benefit the outcome in these patients.
Declaration of patient consent
Patient’s consent not required as there are no patients in this study.
Conflicts of interest
There are no conflicts of interest.
Financial support and sponsorship
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