Pharmacological Treatment of Tachyarrhythmias in Acute Myocardial Infarction-a Review

Contact address: Silvia DEACONU, 8 Floreasca Avenue, 1st District, Bucharest, Romania. E-mail: si.deaconu@gmail.com 1 „Carol Davila” University of Medicine and Pharmacy, Bucharest Romania 2 Department of Cardiology, Emergency Clinical Hospital, Bucharest, Romania ABSTRACT Acute myocardial infarction (AMI) causes severe metabolic and electrophysiological changes that induce silent or symptomatic life-threatening arrhythmias. Ventricular arrhythmias and atrial fi brillation are common during the early phase of AMI and are also important prognostic factors. Rapid identifi cation and treatment of these arrhythmias can be life-saving, since in-hospital mortality rises dramatically in patients who develop arrhythmias with a fast ventricular rate following an AMI. Along with myocardial revascularization, adequate pharmacological therapy of hemodynamically relevant arrhythmias is generally useful. Since there are no controlled randomized trials comparing different antiarrhythmic drugs (AADs) in AMI, optimal decision making is based on medical societies guidelines recommendations and clinical judgement.


INTRODUCTION
Both atrial and ventricular arrhythmias may occur in the setting of acute myocardial infarction (AMI). Therapy for AMI and arrhythmia management are now based increasingly on invasive approaches, with early reperfusion therapy as paramount action. In addition to myocardial revascularization, a 'wait and see' strategy for arrhythmias with no or moderate haemodynamic relevance seems reasonable 1 . However, when arrhythmias result in hemodynamic instability, careful use of antiarrhythmic drugs is generally recommended and alternative treatment options such as electrical cardioversion or catheter ablation should be considered. Frequently, sustained ventricular tachyarrhythmias (VAs) may lead to hemodynamic collapse and warrant immediate treatment 2 . While the urgent treatment for VAs with haemodynamic instability remains direct current cardioversion (DCC), recurrent sustained VAs requires drug therapy. Atrial fi brillation (AF) may also require urgent treatment when it presents with a fast ventricular rate which results in hemodynamic deterioration 2 .The management of other arrhythmias is also based mainly on symptoms and their hemodynamic impact.

SUPRAVENTRICULAR ARRHYTHMIAS
AF is the most frequent supraventricular arrhythmia occurring in up to 21% of the patients presenting with ST elevation acute myocardial infarction (STEMI) 1,3 . AF occurring in STEMI patients is associated with a worse short-and long-term prognosis 1 . Signifi cant multivariable predictors of AF include three-vessel coronary artery disease and initial thrombolysis, advanced age, higher peak creatine kinase levels, worse Killip class and increased heart rate 4 . Lower socioeconomic status seems to predict prevalence of AF in some populations in a similar fashion to other cardiovascular diseases 5,6 .
In the acute setting, AF results in reduced cardiovascular performance through a variety of mechanisms. These include loss of atrioventricular synchrony and atrial systole, reduced ejection time due to high ventricular rates, and rhythm irregularity 7,8 . Patients with AMI and AF have a more adverse clinical course of their disease due to older age, increased number of comorbidities, worse Killip class, severe LV dysfunction, more extensive coronary artery disease and poorer perfusion after thrombolysis or primary PCI9. Moreover, the presence of AF adds a burden on the therapeutical decisions considering the need for anticoagulation.

Pathophysiology
The most common etiology of AF in the setting of AMI appears to be atrial stretching due to heart failure with elevation in left atrial pressures 10 . In patients with AMI complicated with severely depressed left ventricle systolic function, AF is precipitated or exacerbated by on-going atrial ischemia or infarction, abnormalities of autonomic regulation, increased sympathetic tone 11 , pericardial infl ammation and by iatrogenic factors such as positive inotropic agents. One must also consider the reverse relationship between AF and AMI: AF with rapid ventricular response could also lead to a Type II MI. In this case, invasive therapy may not be warranted 12 .
Acute pharmacological management of AF Typically, recent onset AF is well-tolerated and no specifi c treatment is required, except anticoagulation. Episodes are often repetitive and may last from minutes to hours 2 . However, when it leads to hemodynamic instability, urgent treatment is needed to ensure rate control or return to sinus rhythm 1 . When the fast ventricular rate results in haemodynamic collapse, direct current cardioversion is generally required.

Parenteral anticoagulation
Parenteral anticoagulation is recommended in addition to antiplatelet therapy in all AMI patients under-going PCI 1 . AF may be only a transient arrhythmia accompanying an acute MI, in an anticoagulant-naive patient. Consequently, in the periprocedural setting, parenteral anticoagulation is indicated. Routine of unfractionated heparin (UFH)is recommended 1 . As an alternative to UFH, routine use of enoxaparin i.v. should be considered 1 .

Amiodarone
If an acute rhythm control strategy is pursued, amiodarone is the only pharmacological option 1 . Intravenous amiodarone could facilitate electrical cardioversion and/or decrease the risk for early recurrence of AF after electrical cardioversion 1 . Amiodarone may also be considered for rate control, if this strategy is chosen 1,11 , with an initial dose of 5 mg/kg in 1 h followed by 50 mg/h 12 .

Beta-blockers
Intravenous beta-blockers, including esmolol, propranolol and metoprolol are indicated for rate control and to reduce myocardial oxygen demands, if no clinical signs of acute heart failure (AHF) or hypotension are present 13,14 . In these cases, the negative inotropic effect of -blockers may result in further compromise of pump function. In the setting of AMI without AHF, short-acting beta blockers are preferred to allow rapid adjustment of the dose, based on the patient's blood pressure and heart rate response. Close to the time of discharge, longer-acting beta blockers may be preferred.

Digoxin
In selected patients, intravenous digitalis should be considered for rate control when concomitant AHF and hypotension are present 15 . Usual dosage is 0.25 mg each 2 h up to 1.5 mg 12 . Digoxin is ineffective in converting recent onset AF to sinus rhythm16. However, data from the ARISTOTLE AF trial showed that digoxin was independently associated with higher mortality rate in patients with AF regardless of HF 17 . In these patients, the risk of death increased with higher serum digoxin concentrations 17 . Among patients whose digoxin levels were greater than 1.2 ng/ml, the death rate increased by 56% 17 .

Nondihydropyridine calcium antagonists
Administration of nondihydropyridine calcium antagonists might be considered to slow a rapid ventricular response in patients with AMI and AF only in the absence of signifi cant HF or hemodynamic instability 11 .
Vernakalant, fl ecainide and propafenone should not be used for rhythm control in patients with AMI 11 . Alexandru DEACONU et al.

Pharmacological Treatment of Tachyarrhythmias in Acute Myocardial Infarction
Post-procedural management of AF Patients with AF and moderate-to-severe thromboembolic risk (CHA 2 DS 2 -VASc score ≥2) should be adequately treated with oral anticoagulants (either vitamin K antagonists or novel oral anticoagulants) to reduce the risk of stroke or systemic embolism 2 . Consequently, patients with AMI and AF require combined antithrombotic therapy which results in a signifi cant bleeding risk. Concomitant risks of cerebro-vascular and coronary ischemic events and bleeding need to be balanced when deciding the duration and the type of antithrombotic therapy 11 . Generally, dual antithrombotic therapy with a novel oral anticoagulant (NOAC) and a P2Y12 inhibitor (preferably clopidogrel) is recommended for the fi rst 12 months after percutaneous coronary intervention (PCI) for an acute coronary syndrome (ACS), since it results in less major bleeding than triple therapy18. NOACs and the recommended doses are show in Table 1.
However, in AF patients with AMI, at least a short course of triple therapy (e.g. ≤1 week) is desirable 11 and should be continued up to one month when the bleeding risks are low and ischemic concerns prevail 1 23 -vs. triple therapy with a VKA in AF patients with a recent ACS or undergoing PCI. All trials have shown a signifi cant reduction of major or clinically signifi cant bleeding, comparable rates of ischemic stroke, AMI and stent thrombosis with dual (NOAC + P2Y12) vs. triple (VKA + P2Y12 + aspirin) therapy. Since patients with AMI who develop AF are usually frail, with severe cardiovascular diseases and multiple comorbidities, they frequently have a high risk for both thrombotic and bleeding events. Consequently, the duration of the triple antithrombotic therapy should always take into consideration the balance between these risks. Assessment of ischemic and bleeding risks should be done using validated risk predictors (e.g. CHA 2 DS 2 -VASc, ABC, and HAS-BLED) with a focus on modifi able risk factors 24 .
For paroxysmal AF, long-term antiarrhythmic therapy is not indicated when moderate to severe left ventricular systolic dysfunction or HF are absent 25 associated with increased in-hospital and long-term mortality rates. This notion is based on data collected before thrombolysis and additional modem methods of treatment became widely available, and no information is available on the signifi cance of PAF in the general population with AMI in the thrombolytic era. The aim of the present study was to defi ne the incidence, associated clinical parameters, and short-and longterm prognostic signifi cance of PAF in patients with AMI in the thrombolytic era. Methods and Results -A prospective, nationwide survey was conducted of 2866 consecutive patients admitted with AMI in all 25 coronary care units in Israel during January/February 1992, 1994, and 1996 (thrombolytic era [TE].
In patients with AMI complicated with LV dysfunction, angiotensin-converting enzyme inhibitors appears to reduce the incidence of AF 26,13 .
Statin therapy, possibly owing to an antiinfl ammatory effect, has been associated with a reduction in paroxysmal AF in patients with ischemic heart disease. In a retrospective study of over 3300 patients presenting with AMI and in sinus rhythm, early statin therapy (prescription within 48 hours of hospitalization) was associated with a reduced risk of AF 27 .
In patients at risk of gastrointestinal bleeding, concomitant use of proton-pump inhibitors is reasonable 28 .

VENTRICULAR ARRHYTHMIAS
Ventricular tachyarrhythmias (VAs) commonly appear early in ischemia and markedly increase the risk of mortality in patients with an AMI 29 . The incidence of VAs has declined with the use of reperfusion strategies but they still occur in 6-8% of the AMI patients 30 . prompt and complete revascularization is the mainstay of treatment 37,1 . Correction of electrolyte imbalances (especially hypokalemia and hypomagnesemia) is recommended in patients with VT and/or VF1. Hypokalemia during an AMI is a risk factor for VF. In the GISSI-2 trial, the probability of VF among patients with a serum potassium <3.6 mEq/L was almost twice as high as among patients with a higher serum potassium 38 . Statin therapy has been showed to lower the incidence of premature ventricular complexes (PVCs) and non-sustained VT in patients with ACS 39 . Drugs that inhibit the renin-angiotensin-aldosterone system, namely angiotensin converting enzyme (ACE) inhibitors also reduce the incidence of VAs in AMI 40 . For the temporary management of malignant VT/VF refractory to usual treatment, deep sedation (preferably with benzodiazepines) is a viable therapeutic option which provides a reduction of the sympathetic drive associated with post-MI Vas 41,42 . For patients with AMI without VAs, prophylactic antiarrhythmic drug treatment, with the exception of beta-blockers is not indicated and may be harmful 2 .

Antiarrhythmic drugs
The use of antiarrhythmic drugs (AAD) for VAs in AMI has been questioned and is largely based on observational data. Controlled randomized trials on the use of AAD for VAs in AMI are lacking 2 . Prophylactic treatment with AADs is not indicated (with the possible exception of beta-blockers 43 ) and may be harmful1. Useful antiarrhythmics, their classifi cation, mechanisms of action, indications, dosing and possible side-effects are shown in Table 2.

Beta-blockers
Beta-blockers are fi rst-line therapy in the management of VA in patients with AMI 36 . Intravenous beta-blocker treatment is indicated for patients with VAs, in the absence of contraindications 1 . VAs in the early or acute stages of an MI are in part related to enhanced automaticity, resulting from elevated catecholamines and beta receptor stimulation. At cellular level, the favorable electrophysiological effects of beta-blockers include decreased automaticity, which reduces the predisposition for triggered VA, and reduced conduction velocity, which impacts on the stability of re-entrant circuits 29 . Beta-blocker use in the fi rst 24 hours after AMI was associated with reduced in-hospital mortality in patients with sustained VT/VF 44 . In the CAPRI-CORN trial, Carvedilol was shown to have signifi cant anti-arrhythmic effects after AMI, suppressing both atrial and ventricular arrhythmias in these patients 45 .

Pathophysiology
The mechanisms of arrhythmogenesis depend on the stage of evolution of an AMI. Acute ischemia results in harmful consequences on the myocardial metabolism causing anaerobic glycolysis leading to acidosis and accelerated potassium effl ux from the myocytes 31 . This generates electrolyte imbalance and electrical instability, which facilitate VAs development in the early phase of AMI 31 . Myocardial reperfusion may also result in abrupt changes in ionic and electrical balance promoting life-threatening Vas 32,12 . Acute phase arrhythmias arise in the fi rst 30 to 60 minutes and are attributed to reentry and abnormal automaticity 33 . Chronic phase VAs appear after more than 48 hours following an AMI and are usually re-entrant and scar mediated, owing to a large MI resulting in a severely depressed LV function and LV remodeling. Monomorphic ventricular tachycardia (VT) is generally scar-related and is the typical presentation in patients with older fi brotic infarct areas in the myocardium 12 .

General management
Management of VAs is dependent on whether the arrhythmia is sustained or non-sustained, and if it results in hemodynamic compromise or occurs in an otherwise stable patient. The timing of the VA relative to the AMI plays another important role in the therapeutical decision. AMI related VAs can occur in multiple instances: pre-reperfusion VAs, reperfusion-induced VAs, early post-reperfusion VAs (within 48 h), late post-reperfusion VAs (>48 h after reperfusion), postdischarge arrhythmias 12 . Ventricular fi brillation (VF) is the most frequent mechanism of prehospital sudden cardiac death (SCD) 12 and warrants immediate DCC. The development of VF in patients with an AMI, if occurring within the fi rst 48 h, is associated with an increase in early mortality, but little or no increase in long term mortality after hospital discharge 34,12 . Recurrent VF and/or polymorphic VT may be an indicator of incomplete reperfusion or recurrence of acute ischemia (e.g. acute stent thrombosis) 35 . Urgent coronary angiography should consequently be considered 36 . Generally, sustained VAs (monomorphic or polymorphic) which result in hemodynamic instability call for rapid treatment by DCC. Non-sustained, recurrent or well-tolerated VAs require correction of the underlying ischemic substrate, possible added triggers and should not be treated with anti-arrhythmic drugs before reperfusion.
If ongoing myocardial ischemia is suspected to be responsible for the VA, coronary angiography and Alexandru DEACONU et al.

Pharmacological Treatment of Tachyarrhythmias in Acute Myocardial Infarction
a wide spectrum of action that includes blockade of depolarizing sodium currents and potassium channels that generate repolarizing currents. This results in prolongation of the refractoriness of the His-Purkinje system and ventricular contractile fi bers thus preventing micro reentry 47 . Consequently, amiodarone may inhibit or terminate VAs by decreasing automaticity and re-entry 36 . Amiodarone (150-300 mg i.v. bolus) should be considered to acutely suppress recurrent VT or VF 36 . However, over the long term, amiodaro-Furthermore, in patients with severe recurrent VAs such as VT/VF storm, an intravenous beta-blocker can be useful 46 . The mortality reduction observed with beta-blockade in the fi rst 24 hours after AMI suggested that patients with sustained VAs benefi ted from acute beta-blockade without an increase in worsening heart failure 44 .

Amiodarone
Intravenous amiodarone is recommended for treatment of recurrent polymorphic VT 1 . Amiodarone has  ne treatment may result in increased mortality at 6 months 30 . This outcome is most likely explained by confounding factors (e.g. patients with worse prognosis received amiodarone) 30 . It may also occur due to residual adverse effects from amiodarone, possibly by further reducing myocardial contractility in already severely depressed left ventricles 47,48 . Intravenous amiodarone may cause phlebitis (it is advisable to use a large peripheral vein, avoid administration >24 h and use preferably volumetric pump) and arterial hypotension 12 .

Lidocaine
Lidocaine may be used to treat recurrent VT with haemodynamic deterioration despite repetitive electrical cardioversion, if beta-blockers, amiodarone and overdrive stimulation are not effective or applicable 1,2 . An observational study by Piccini et al suggested that lidocaine might be preferred over amiodarone for the treatment of sustained VT/VF complicating acute MI 30 . In the fi rst hours after VAs complicating acute MI, both amiodarone and lidocaine are associated with better survival 30 . On longer term, amiodarone use was associated with a higher risk of death at 30 days and 6 months, while lidocaine use did not result in benefi t or harm 30 .

CONCLUSION
Both supraventricular and ventricular arrythmias which occur in the setting of an AMI are associated with a worse short-and long-term prognosis, increasing the risk of mortality in these patients. Adequate use of antiarrhythmic drugs in the management of hemodynamically relevant arrhythmias is generally useful. At the same time, it is also challenging since, with the exception of beta-blockers, data derived from randomized clinical trials on antiarrhythmic drugs in the management of patients with AMI and life-threatening arrhythmias are scarce, outdated and inconclusive. In this setting, clinical judgement is mandatory.