Abstract
Advances in medical and interventional therapy over the last few decades have revolutionized the treatment of acute myocardial infarction. Despite the ability to restore epicardial coronary artery patency promptly through percutaneous coronary intervention, tissue level damage may continue. The reported 30-day mortality after all acute coronary syndromes is 2 to 3%, and around 5% following myocardial infarction. Post-infarct complications such as heart failure continue to be a major contributor to cardiovascular morbidity and mortality. Inadequate microvascular reperfusion leads to worse clinical outcomes and potentially strategies to reduce infarct size during periods of ischemia–reperfusion can improve outcomes. Many strategies have been tested, but no single strategy alone has shown a consistent result or benefit in large scale randomised clinical trials. Herein, we review the historical efforts, current strategies, and potential novel concepts that may improve myocardial protection and reduce infarct size.
Highlights
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Infarct size is directly related to prognosis post myocardial infarction.
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Infarct size can be an endpoint for assessment of efficacy of treatment strategies.
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Various combination therapies are attempted to reduce the infarct size.
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We review the various potential strategies to reduce the infarct size.
1
Introduction
Risk factor modification, in combination with prompt revascularization and optimal medical therapy, has led to a reduction in the morbidity and mortality associated with myocardial infarction (MI) . However, one-month mortality following an infarct is still in the order of 2.5 to 5% and post-infarct conditions (e.g. myocardial dysfunction and heart failure) continue to be major contributors of morbidity and mortality and impact on health care economics worldwide . Irrespective of strategies aimed at prompt revascularization of occluded epicardial arteries in the catheterization laboratory, thrombosis, embolization and release of harmful substances to the myocardium persist in the peri-infarct period. The associated reperfusion injury can result in further harm and adversely affect the long-term prognosis after MI by increasing the infarct size .
The microvascular status remains a strong prognostic marker . Infarct size correlates with left ventricular (LV) systolic dysfunction, presence of arrhythmias, morbidity, and mortality following an acute MI . The importance of infarct size and increase in LV volumes has been shown in acute ST-elevation MI (STEMI) treated with reperfusion therapy . Various strategies can be used to measure the infarct size such as bio-markers, technetium-99 m sestamibi single-photon emission computed tomography (SPECT) myocardial perfusion imaging, and cardiac magnetic resonance imaging (CMR) . Strategies to reduce infarct size during periods of ischemia–reperfusion can lead to improved LV function .
Herein, we review the currently available therapies for myocardial protection (i.e., for the prevention of injury associated with an acute MI and reperfusion), while highlighting novel and cost-effective strategies to reduce infarct size.
2
Pathogenesis
2.1
Ischemic cascade
The myocardial territory supplied by the infarct-related artery (IRA) undergoes biochemical changes at the cellular level. Myocardial cells enter a state of ischaemia, switching the metabolism to anaerobic form, which leads to accumulation of lactate, cellular acidosis, increased intracellular calcium, and production of reactive oxygen species (ROS), all contributing to apoptosis.
2.2
Microvascular obstruction
Microvascular obstruction (MVO) is the inability of a previously ischemic myocardium to be reperfused despite having achieved patency of the epicardial vessel supplying the region of myocardium .
The incidence of MVO can be as high as 67% in patients presenting with STEMI and treated with primary percutaneous coronary intervention (PPCI), despite achieving thrombolysis in myocardial infarction grade 3 (TIMI 3) flow in the epicardial coronary artery . MVO is associated with major adverse cardiac events (MACE) rates of 30% at 1 month and 60% at 12 months . MVO results from a combination of an inflammatory state, endothelial dysfunction, apoptotic cell death, and associated vasoconstriction in the myocardial bed .
2.3
Reperfusion injury
Reperfusion injury may occur during the restoration of flow in occluded coronary arteries. This injury is thought to be due to free radicals, calcium build-up, acidosis, inflammation and accumulation of neutrophils. All these changes lead to the opening of the mitochondrial permeability transition pore (MPTP) and cell death.
The reperfusion era has seen great strides in the therapeutic strategies leading to improved survival of patients presenting with an acute MI and there are continued efforts to reduce the reperfusion-associated injury.
2.4
No-reflow phenomenon
No-reflow phenomenon is defined as inadequate myocardial perfusion through a given segment of the coronary circulation without angiographic evidence of mechanical vessel obstruction . No-reflow is possibly due to MVO alongside other mechanisms such as myocardial stunning, ischaemia-reperfusion injury, autonomic dysfunction and microvascular constriction, free radical-induced myocardial injury as well as neutrophil and platelet micro-aggregates causing luminal obstruction of the microvasculature . No-reflow phenomenon has been linked to larger infarct size and poorer outcomes .
2
Pathogenesis
2.1
Ischemic cascade
The myocardial territory supplied by the infarct-related artery (IRA) undergoes biochemical changes at the cellular level. Myocardial cells enter a state of ischaemia, switching the metabolism to anaerobic form, which leads to accumulation of lactate, cellular acidosis, increased intracellular calcium, and production of reactive oxygen species (ROS), all contributing to apoptosis.
2.2
Microvascular obstruction
Microvascular obstruction (MVO) is the inability of a previously ischemic myocardium to be reperfused despite having achieved patency of the epicardial vessel supplying the region of myocardium .
The incidence of MVO can be as high as 67% in patients presenting with STEMI and treated with primary percutaneous coronary intervention (PPCI), despite achieving thrombolysis in myocardial infarction grade 3 (TIMI 3) flow in the epicardial coronary artery . MVO is associated with major adverse cardiac events (MACE) rates of 30% at 1 month and 60% at 12 months . MVO results from a combination of an inflammatory state, endothelial dysfunction, apoptotic cell death, and associated vasoconstriction in the myocardial bed .
2.3
Reperfusion injury
Reperfusion injury may occur during the restoration of flow in occluded coronary arteries. This injury is thought to be due to free radicals, calcium build-up, acidosis, inflammation and accumulation of neutrophils. All these changes lead to the opening of the mitochondrial permeability transition pore (MPTP) and cell death.
The reperfusion era has seen great strides in the therapeutic strategies leading to improved survival of patients presenting with an acute MI and there are continued efforts to reduce the reperfusion-associated injury.
2.4
No-reflow phenomenon
No-reflow phenomenon is defined as inadequate myocardial perfusion through a given segment of the coronary circulation without angiographic evidence of mechanical vessel obstruction . No-reflow is possibly due to MVO alongside other mechanisms such as myocardial stunning, ischaemia-reperfusion injury, autonomic dysfunction and microvascular constriction, free radical-induced myocardial injury as well as neutrophil and platelet micro-aggregates causing luminal obstruction of the microvasculature . No-reflow phenomenon has been linked to larger infarct size and poorer outcomes .
3
Assessing infarct size
An electrocardiogram is the earliest and perhaps the easiest way to gain information regarding infarct size. Infarct size can be estimated from the extent of ST-segments deviations (elevation and depression) as well from the number of leads affected. ECG can be used to assess the efficacy of various reperfusion therapies. However, this is imprecise and has been shown not to correlate well with imaging studies . Attempts at quantifying final infarct size by using formulae to calculate the myocardium at risk, such as Aldrich score was employed in the thrombolytic era . Infarct size can be measured using biomarkers or imaging. Peak levels of creatine kinase isoenzyme MB (CK-MB) and troponin have been studied . Although biomarkers are useful in giving a rough estimate of the infarct size, their use is limited because of reperfusion affecting the enzyme kinetics and difficulty in determining peak values . There is a significant correlation between individual time-point, peak, and area-under time-concentration curve (AUC) of these biomarkers determined infarct size in comparison with SPECT. The AUC and peak levels of troponin I at 72 h have strong predictive correlation as compared to troponin T . It is important to note that it is less practical to generate AUC curves from troponins, as opposed to CK, as they are elevated for a longer time and hence a peak value of a troponin measured at a specific time can be a more useful in in daily practice . A single point measurement can be as useful in infarct size estimation as compared to a measurement derived from the area under the curve.
Imaging modalities such as Tc99 Sestamibi SPECT imaging and CMR have been widely studied . SPECT Sestamibi imaging has been used as endpoints in several randomized trials . It is good at detecting transmural infarcts. However, CMR with superior spatial resolution has improved ability to detect smaller, sub-endocardial infarcts and has emerged as the gold standard in assessing infarct size . CMR is also able to evaluate other useful parameters such as microvascular obstruction (MVO), salvaged myocardium, and myocardium at risk and predict ventricular dysfunction . In addition CMR indices have been shown to provide independent prognostic information . Echocardiographic assessment of global and regional left ventricular function can be used but these are indirect measurements and influenced by variety of factors . Advanced echocardiographic techniques such as global longitudinal strain by 2D speckle tracking and wall motion score index have been studied and shown to correlate with infarct size of CMR . These techniques may prove to be quick and easy methods to assess infarct size and predict prognosis at the bedside. The various methods commonly employed to assess infarct size has been summarized in Table 1 .
| Method | Advantages | Disadvantages |
|---|---|---|
| ECG | Easily available. Available in an emergency. | It provides an indirect measure of infarct size that can be quantitative by utilization of various scores. |
| Biomarkers | Easily available. Available in an emergency | Need for repeated sampling for peak levels, affected by reperfusion. True troponin AUCs is not a practical approach. |
| Echocardiographic techniques | Easily available. Available in emergency | Operator dependent, not widely used outside the research setting. |
| Tc99 Sestamibi SPECT imaging | Can assess full thickness infarcts. Not available in an emergency | The low spatial resolution, hence misses sub-endocardial infarcts; need for radioactive tracer with limited shelf life and use of ionizing radiation. |
| Cardiac MRI | Current gold standard; high spatial resolution; can detect sub-endocardial infarcts better. not available in an emergency | Not widely available, cannot be used in patients with metal implants or those who have claustrophobia. Not available in the emergency setting. |
| Index of micro-circulatory resistance (IMR) | The numerical value for myocardial resistance Correlates with infarct size on CMR. Useful for prompt decision-making in the catheterisation laboratory. | Invasive technique Requires adenosine to induce hyperaemia. |
The index of microcirculatory resistance (IMR) was developed as an invasive measure of microvascular status, utilizing a pressure and temperature sensitive guidewire . In a recently published trial involving 283 STEMI patients, IMR greater than 40 was associated with larger infarct size on CMR . This may be a useful tool to risk stratify patients in the cardiac catheterization laboratory.
4
Therapies for infarct size reduction
There are various potential strategies for infarct size reduction [ Figure 1 ]. Efforts to minimize the myocardial damage can be started even before the patients’ presentation to hospital, and various mechanical and pharmacological agents can be tried during the hospital stay and continued even after discharge to have best clinical outcomes. These efforts for emerging therapies are ongoing, and large-scale randomized clinical trials are needed to investigate the clinical applicability of various strategies.
4.1
Mechanical interventions
4.1.1
Primary angioplasty and timing of stenting
Primary percutaneous coronary intervention (PPCI) is the current gold standard worldwide for the treatment for STEMI, with strong evidence supporting the benefits of PPCI over thrombolysis . When compared to fibrinolysis, PPCI leads to better ST segment elevation resolution, arterial patency, and reduced infarct size . However, PCI of an athero-thrombotic lesion during STEMI, can lead to distal embolization of debris, further augmenting MVO, infarct size, and other harmful sequelae . Therefore, various interventions can be used in an attempt to reduce this risk.
In order to minimize the damage associated with stenting, a strategy of delaying the stenting tested. There were initial results from a small study showing benefit in a delayed stenting strategy in patients with the patent infarct related artery . This was followed by the larger randomized DEFER-STEMI study (Randomized Trial of Deferred Stenting Versus Immediate Stenting to Prevent No- or Slow-Reflow in Acute ST-Segment Elevation Myocardial Infarction), which also supported a strategy of deferred stenting with lesser no-reflow/slow flow, fewer thrombotic events and increased myocardial salvage . However, the Danish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction: DEFER and the Mechanical Intervention Approach in Acute ST-Segment-Elevation Myocardial Infarction: The MIMI Study failed to show the benefit of such strategy . The Deferred versus conventional stent implantation in patients with ST-segment elevation myocardial infarction (DANAMI 3-DEFER) study was a large open-label randomized controlled trial that randomized patients to immediate and delayed stenting strategies. This study also failed to show any difference in the occurrence of death, heart failure, myocardial infarction, or repeat revascularization .
More recently, the INNOVATION Study (Impact of Immediate Stent Implantation Versus Deferred Stent Implantation on Infarct Size and Microvascular Perfusion in Patients With ST-Segment–Elevation Myocardial Infarction) randomized 114 patients to immediate stenting or deferred stenting. The overall infarct size and MVO were not significantly different between the groups . However, in anterior wall MI, deferred stenting strategy seemed to have beneficial effects on infarct size and MVO.
MVO assessed by CMR after MI has been shown to be related to ischaemic time (time between symptom onset and successful restoration of blood flow) as opposed to the mode of reperfusion therapy, highlighting the importance of early reperfusion in reducing MVO .
There is convincing evidence that early revascularization with primary PCI helps in infarct size reduction. A strategy of deferred stenting cannot be recommended at this stage.
4.1.2
Distal protection devices
Embolic protection devices (EPD) are intended to capture and remove debris generated during the various interventional procedures, with the ultimate aim of reducing myocardial damage. Various EPDs have been used in an attempt to reduce adverse distal embolization . In contrast to their benefit in vein graft interventions, the evidence regarding the utility of these devices in preserving myocardium viability during STEMI has been disappointing [ Table 2 ].
| Trial (year) | Number | Device | Findings |
|---|---|---|---|
| EMERALD (2005) | 501 | Guard wire plus | No reduction in infarct size. |
| MICADO (2007) | 154 | Guide wire | Better TIMI perfusion grade |
| ASPARAGUS (2007) | 341 | Guide wire plus | No reduction in infarct size |
| PREMIAR (2007) | 140 | Spider X | No benefit on myocardial perfusion/ejection fraction. |
| PROMISE (2005) | 200 | Filter wire-EX | No improvement in perfusion |
| UPFLOW (2007) | 100 | Filter wire-EX | No improvement in perfusion |
| DEDICATION (2008) | 626 | Filter wire-EZ & Spider X | No improvement in perfusion |
| PREPARE (2009) | 284 | Proxis embolic protection system | Rapid ST segment resolution. No difference in myocardial reperfusion. |
4.1.3
Thrombectomy
Thrombectomy during acute MI has shown conflicting results. There is some evidence that manual thrombectomy can reduce infarct size and preserve microvascular integrity as assessed by CMR . On the other hand, a meta-analysis suggested that it may be associated with harm . The Intracoronary Abciximab and Aspiration Thrombectomy in Patients with Large Anterior Myocardial Infarction (INFUSE-AMI) trial showed no benefit in infarct size reduction . Initially, there was much enthusiasm with the publication of the TAPAS (Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction Study) trial that showed benefits of using routine thrombus aspiration, not only in improving reperfusion as assessed by TIMI blush grade, but also in reducing mortality . It led to changes in guideline recommendation in favor of mechanical thrombectomy. Later, the larger TASTE (Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia) trial showed no improvement in both 30-day and 1-year mortality with routine aspiration thrombectomy . Finally, TOTAL (Trial of Routine Aspiration Thrombectomy with PCI versus PCI Alone in Patients with STEMI) trial proved that routine manual thrombectomy in STEMI patients did not improve clinical outcomes . A sub-study of TOTAL demonstrated that routine thrombectomy during PPCI has no beneficial impact on myocardial blush grade or post-PCI TIMI flow grade. There was reduced distal embolization associated with thrombectomy group in comparison to PCI alone group .
TAPAS trial was a relatively small single centre trial with the very high use of GP2b3a inhibitors. It was underpowered to detect differences in the secondary endpoints. Some of the differences between the three trials are summarized in Table 3 .
| Characteristic | TAPAS | TASTE | TOTAL |
|---|---|---|---|
| Number of patients randomized | 1071 | 7244 | 10,732 |
| Study design | Single-centre RCT | Swedish multicentre RCT | Multi-national multicentre RCT |
| Direct stenting | 62% | 15% | 17% |
| GP2b3a use | 92% | 17% | 40% |
| Primary end point | Post-procedural myocardial blush grade of 0 or 1 | All-cause mortality at 30 days | CV death, recurrent MI, cardiogenic shock or NYHA IV heart failure at 180 days |
| Secondary endpoints | TIMI flow grade of 3, complete resolution of ST-segment elevation, the absence of persistent ST-segment deviation, TVR, reinfarction, death & MACE at 30 days | 30-day rates of hospitalization for recurrent MI, stent thrombosis, TVR, TLR, and the composite of all-cause mortality or recurrent MI and during index admission, complications of PCI, stroke, heart failure, and length of stay in the hospital | Stent thrombosis or TVR within 180 days and cardiovascular death within 180, safety outcome of stroke within 30 days |
| Reperfusion | Improved | Not reported | Improved |
| Stroke at 30 days | Not reported | No difference | Increased |
| 1-year mortality | Reduced | No difference | No difference |
| 1-year recurrent MI, Stent thrombosis, TVR | No difference | No difference | No difference |
The contradictory findings between TAPAS and the other two trials may be due to some of the differences such as the use of GP2b3a inhibitors, direct stenting and use of balloon predilatation. TASTE and TOTAL trials were conducted in different eras with significant differences in anti-thrombotic pharmacotherapies, increased use of radial access for PCI and improved stent technology. Ultimately, the discrepancy between the trials underscore the importance of performing clinical trials with sufficient power, once smaller trials suggest an effect of intervention or medication.
Recently, a meta-analysis using individual patient level data from TAPAS, TASTE and TOTAL trials, concluded that routine thrombus aspiration did not improve clinical outcomes . However, in those patients with highest thrombus burden, thrombus aspiration was associated with reduced cardiovascular death at the expense of higher risk of stroke or transient ischaemic attack (TIA).
There are clear limitations to the current technology available in aspiration thrombectomy, such as iatrogenic thrombus embolization during the crossing of the lesion with a guide wire, difficulty in treating large organized thrombi, potential displacement of thrombi into other vessels and systemic circulation during removal of the aspiration catheter. It is possible that as technology improves, especially if the risk of stroke is mitigated, mechanical thrombectomy may prove a useful strategy in infarct size reduction.
The use of mechanical and aspiration thrombectomy has limited impact on infarct size reduction and is not recommended for routine use.
4.1.4
M guard stents
Polyethylene terephthalate micronet mesh-covered stent (M guard, Inspire-MD, Israel) was designed to prevent distal embolization by facilitating the capture of thrombus behind the mesh covering the stent. M guard has shown superior rates of epicardial coronary flow and complete ST-segment resolution in comparison to bare metal stent .
However, one trial revealed higher target lesion revascularization (TLR) rates associated with M guard stents, raising questions about their long-term safety profile . Nonetheless, there is compelling evidence from clinical trials as well as registries showing improved outcomes in acute MI patients treated with this stent .
Further trials are needed to test the concept of covered stent platforms in STEMI.
4.2
Pharmacological therapies
4.2.1
Thrombolytic therapy
Although thrombolysis is a well validated and widely used therapy, it restores coronary perfusion in only 60–80% of cases .
Large-scale clinical trials have demonstrated infarct size reduction and improvement in regional and global LV function in patients where intra-venous thrombolytic therapy has been successful . It has been reported that intracoronary thrombolysis with primary PCI leads to improved myocardial perfusion and TIMI blood flow as shown in data from a pilot study and a randomized trial demonstrating that intracoronary streptokinase administration immediately after PCI significantly improves infarct size and left ventricular volumes and function .
There is convincing evidence that a timely administration of intravenous thrombolytic therapy can help reduce the infarct size. Further studies are needed to test the effect of intracoronary fibrinolysis.
4.2.2
Anticoagulant therapy antiplatelet therapy
A wide variety of anti-coagulant and antiplatelet agents have been used in the treatment of acute myocardial infarction.
These agents have a potential role in infarct size reduction by having an impact on the no-reflow phenomenon and MVO, associated with embolization of particles during acute MI. There is a combination of fibrin and blood cells in the formation of these thrombi and hence logically we need a combination of antiplatelet and anticoagulants. The thrombi formation is a combination of activation of blood coagulation cascade as well as platelets. These mechanisms are linked to each other in a vicious cycle as, thrombin, is an enzyme generated by blood coagulation that leads to platelet activation.
The thrombo-embolic state during no reflow is composed of platelet aggregates with associated fibrin strands .
Different antiplatelet agents with their potential role in infarct size reduction are listed in Table 4 . A high loading dose (600 mg) of clopidogrel has been shown to be more effective than low dose (300 mg) in reducing the CMR measured infarct size in patients undergoing PPCI for STEMI . In a small study, upstream treatment with clopidogrel compared to those clopidogrel loading after reaching the catheterization laboratory was noted to have reduced MVO although the infarct sizes were not different . The newer generation of antiplatelet agents has shown promising results in clinical studies. The recently published CV-TIME trial randomized 76 STEMI patients to receiving clopidogrel or ticagrelor loading doses prior to Primary PCI. The index of microcirculatory resistance (IMR) measured immediately afterwards, wall motion score index assessed by echocardiography and peak cardiac enzyme (CK) levels were assessed, all of which were in favor of ticagrelor . A post hoc analysis of the Complete Versus Lesion-Only PRImary PCI Trial-CMR (CvLPRIT-CMR) substudy found that newer antiplatelet agents (ticagrelor and prasugrel) were associated with reduced infarct size compared with clopidogrel in patients undergoing primary PCI . Animal studies suggest that the benefit seen with ticagrelor as compared to clopidogrel was dependent on adenosine-receptor activation with downstream upregulation of endothelial nitric oxide synthase and Cyclo-oxygenase-2 activity . Ticagrelor is also thought to have potential protective effects against ischemia–reperfusion injury, which is mediated by adenosine, due to its action on the adenosine transporter type 1 equilibrative nucleoside transporter (ENT1) leading to increased concentration of adenosine, particularly at sites of ischemia and tissue injury . The ability of chronic ticagrelor use in reducing infarct size has been tested in a preclinical setting in comparison to clopidogrel . The clinical benefits seen in the PLATO (The multicenter, randomized, placebo-controlled Platelet inhibition and patient Outcomes) trial could potentially be due to cardio protective properties of ticagrelor. Prasugrel has less data supporting its role in infarct size reduction. There is evidence that prasugrel inhibits platelet–leukocyte interactions and may reduce platelet-mediated inflammatory responses .
There is conflicting evidence for the potential role of various anticoagulant therapies in infarct size reduction . Newer antiplatelet agents, in particular ticagrelor seem to reduce infarct size as compared to clopidogrel.
| Agents | Preclinical evidence | Clinical evidence | Number of subjects | Findings |
|---|---|---|---|---|
| Anticoagulants | ||||
| UFH | – | HORIZON AMI HORIZON AMI CMRI sub-study | 51 | No difference in infarct size, MVO, LVEF, or LV volume in comparison to bivalirudin Infarct size reduction when used in addition to bivalirudin |
| Enoxaparin | Dog model | – | 71 | Significant reduction in infarct size |
| Fondaparinux | – | OASIS 5 | 20,078 | Non-inferior to enoxaparin in prevention of cardiac death, and MI |
| Bivalirudin | – | HORIZON AMI CMRI sub-study | 51 | No benefit in infarct size reduction as compared to Heparin |
| Anti-platelet agents | ||||
| Aspirin /NCX4016 (NO-aspirin) | Pig model | – | 19 | NCX4016 (nitro-derivative of aspirin), reduces the extent of myocardial injury following ischaemia and reperfusion Aspirin has no beneficial role in infarct size reduction |
| Thromboxane synthetase inhibitors. Benzylimidazole and OKY-046 | Dog model | – | 72 | Reduced infarct size |
| Clopidogrel | – | Observational study | 198 | High dose (600 mg) reduced myocardial infarct size and improved myocardial salvage compared with a 300-mg loading dose |
| Ticagrelor | Rat model | – | 32 | Ticagrelor protects against reperfusion injury |
| Cangrelor | Monkey model | – | 31 | Significantly decreased infarct size by an amount equivalent to that seen with ischemic post conditioning . |
| Prasugrel | – | INFUSE AMI | 452 | Showed better, TIMI 3 flow, lower corrected TIMI frame counts, and lower infarct size |
| Abciximab | – | Prospective randomized trial | 200 | Improved recovery of microvascular perfusion and myocardium at risk . |
| RELAX MI | 210 | Improved ventricular function recovery . | ||
| Tirofiban | – | On-TIME2 | 984 | Improved ST-segment resolution and clinical outcomes. |
| Vaso-active agents | ||||
| Alpha blockers | ||||
| Urapidil/Phentolamine | – | Multicentre, prospective, non-randomized trial | 40 | Attenuates vasoconstriction and post ischemic LV dysfunction |
| Beta blockers | ||||
| Metoprolol | – | METOCARD-CNIC | 270 | Reduced infarct size and improved left ventricular ejection. |
| – | COMMIT | 45,852 | Reduces the risks of reinfarction and ventricular fibrillation . | |
| Calcium channel blockers | ||||
| Diltiazem (Intracoronary) | Dog model | – | 25 | Increases the salvage of myocardium |
| Nitrates/Nitrites/NO donors | ||||
| Sodium nitrite | – | NIAMI Trial | 229 | No benefit in infarct size reduction |
| Tilarginine | – | TRIUMPH | 398 | No benefit in infarct size reduction |
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