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Pharmacotherapy to reduce arrhythmic mortality
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Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/ihj
Review Article
Pharmacotherapy to reduce arrhythmic mortality Amit Vora*, Samhita Kulkarni Glenmark Cardiac Centre, Smt. S.R. Mehta Cardiac Institute, India
article info
abstract
Article history:
Fatal ventricular arrhythmias and heart failure are the common modes of death in patients
Received 30 November 2013
with cardiovascular diseases. Intracardiac defibrillator (ICD) implantation reduces
Accepted 19 December 2013
arrhythmic mortality to a significant extent in the high risk patient. However, there con-
Available online 21 January 2014
tinues to be a need for effective drug therapy to reduce the arrhythmic and overall mortality in patients with or without an ICD. Although anti-arrhythmic drugs (AAD) appear
Keywords:
inferior to ICD, the role of beta-blockers and to an extent amiodarone along with non AAD
Sudden cardiac death
like angiotensin converting enzyme inhibitors (ACE-I), mineralocorticoid blockers (MRB)
Beta-blockers
and HMG-CoA reductase inhibitors (statins) need to be emphasized. There have been many
Intracardiac defibrillator
drug trials and meta-analysis to this effect and we review the role of drugs especially in
Myocardial infarction
their ability to reduce arrhythmic mortality and sudden cardiac death (SCD). The focus is
Heart failure
on post myocardial infarction (MI) and heart failure patients with a brief overview of role of drugs in channelopathies. Copyright ª 2013, Cardiological Society of India. All rights reserved.
1.
Introduction
Last five decades have shown remarkable improvement in the cardiovascular mortality with advances in drug and nondrug therapy in heart diseases. In drug therapy, from aspirin to thrombolytics, beta-blockers to angiotensin receptor antagonists to statins, all have contributed in improving survival in patients with coronary artery disease, hypertension and left ventricular dysfunction. Although from a practical stand-point reduction in all-cause mortality is what is desired, from a scientific perspective the reasons driving mortality reduction is important. The current review is specifically aimed to determine the influence of drugs on reduction of arrhythmic mortality in various subsets of cardiac diseases.
2.
Post myocardial infarction
Post MI, there is a mortality of 5e15% in the first year.1,2 With advances in pharmacotherapy and interventional treatment there has been a steady decline in mortality. Beta-blockers e the BHAT3 trial was one of the early study that established the role of beta-blockers in reducing total and arrhythmic mortality, in patients after MI. Despite subsequent more evidences to suggest the benefit of beta-blocker post MI, it continued to be under-utilized. The Cooperative Cardiovascular Project revealed that only 34% patients post MI received beta-blockers and there was a 40% reduction in mortality when they were prescribed at discharge.4 A metaanalysis by Freemantle5 showed an overall 23% mortality reduction with long-term trials using beta-blockers post MI
* Corresponding author. Glenmark Cardiac Centre, Flat No. 10, Nandadeep, 209-d, Dr. Ambedkar Road, Matunga (East), Mumbai 400019, India. Tel.: þ91 22 24185808, þ91 9821084160 (mobile); fax: þ91 22 24162538. E-mail address: [email protected] (A. Vora). 0019-4832/$ e see front matter Copyright ª 2013, Cardiological Society of India. All rights reserved. http://dx.doi.org/10.1016/j.ihj.2013.12.049
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even in the era of fibrinolytic therapy. The CAPRICORN6 trial of carvedilol in post MI patients with LVEF < 0.40, established mortality benefit in patients with LV dysfunction. A long-term analysis of CAPRICORN patients showed a reduction of 63% in sustained ventricular tachyarrhythmias.7 Importantly, benefit with beta-blockers persisted even in patients taking ACE-I. Class I AAD e the CAST I and II study compared Class I antiarrhythmic drugs (encainide, flecainide or morcizine) with placebo in the post MI patients with premature ventricular complexes (PVC).8,9 There was a higher arrhythmic and nonarrhythmic mortality in the AAD arm despite suppression of PVCs. Mexiletine and disopyramide also met similar fate. In fact, a meta-analysis of 61 RCTs in over 23,000 patients, with Class I AAD showed an increased overall mortality.10 Class III AAD e Julian et al studied d,l-sotalol, post MI (5e15 days), and showed a lower mortality at 1 year follow-up, however this was not statistically significant.11 The SWORD study on d-sotalol in immediate post MI (6e42 days) and remote MI (>42 days) with LVEF < 0.40, was terminated prematurely as there was a higher arrhythmic and all-cause mortality with sotalol.12 D-sotalol has virtually no beta-blocking property and was chosen in SWORD trial to prevent heart failure in LV dysfunction patients. Absence of beta-blocking effect in fact became counter-productive and increased mortality. Interest in d,l-sotalol has been revived in the ICD era as it lowers the defibrillation threshold and importantly reduces the frequency of ICD shocks and lowers mortality.13 The BASIS trial, was a small study (312 patients) on amiodarone in post MI patients with frequent multifocal or repetitive PVC. There was a significant reduction in total mortality and arrhythmic events with amiodarone.14 The Polish study, though demonstrated a borderline reduction in cardiac mortality and ventricular arrhythmias, it did not improve overall survival at one year follow-up with amiodarone in the post MI patients.15 The CAMIAT randomized post MI patients with greater than 10 PVC/h, comparing amiodarone versus placebo. Amiodarone showed a significant reduction in arrhythmic deaths (4.5% versus 6.9%, p ¼ 0.016); however there was no significant reduction in total mortality.16 The EMIAT study, in post MI patient with LVEF < 0.40, showed a 35% relative risk reduction in arrhythmic deaths with no reduction in total mortality.17 Thus, amiodarone does reduce arrhythmic but not overall mortality in the post MI primary prevention trials. A meta-analysis on amiodarone including 15 trials and 8522 patients, showed a significant 29% reduction of SCD and 18% reduction of cardiovascular mortality.18 A subgroup analysis of the post MI patients in this meta-analysis showed a relative risk reduction of 34% in arrhythmic deaths and 12% reduction in all-cause deaths. However, amiodarone trials have demonstrated more non-cardiac deaths and noncardiac side effects in the intermediate term follow-up. Thus, in the post MI patients beta-blockers reduce arrhythmic and all-cause mortality and should be used in everyone without an absolute contra-indication. Amiodarone reduces arrhythmic but not overall mortality and is known to have non-cardiac side effects and hence is not recommended as a primary prophylaxis drug but may be considered when necessary, especially when ICD implantation is not feasible. Sotalol may be considered in patients with recurrent ICD shocks.
ACE inhibitors e are a part of the standard treatment regimen in post MI patients. The TRACE and AIRE trials evaluated ACE-I in the post MI population with LV dysfunction.19,20 There was a 24% and 30% reduction in arrhythmic mortality in the TRACE and AIRE studies respectively. Both these trials showed a significant reduction in total mortality. A meta-analysis of ACE inhibitors in the post MI period, from 15 trials showed a decrease in SCD, with a 20% relative risk reduction for SCD (an odds ratio of 0.80, 95% CI 0.70e0.92).21 Direct anti-arrhythmic effect of ACE inhibitors is speculated but not well understood. It is likely the indirect effects of preventing LV remodeling, improvement in LV function and thus preventing fatal ventricular arrhythmias. In the high risk population for cardiovascular mortality (vascular disease or diabetes with a cardiac risk factor of hypertension, raised serum lipids etc.), the HOPE study showed a 37% reduction in cardiac arrests and 26% reduction in cardiovascular mortality.22 ACE-I should therefore be prescribed to all patients post MI and those with high risk for coronary risk factors to prevent arrhythmic and overall mortality. Statinsereduce burden of CAD, MI and cardiovascular mortality in subjects with known ischemic heart disease/ coronary risk factors. There was a suggestion of nonsignificant reduction in fatal arrhythmic outcomes with statins. Retrospective analysis of AVID sub-group showed a 40% reduction in arrhythmic death or appropriate ICD shock and similar results were seen in MADIT-II with 28% reduction in arrhythmic outcomes.23,24 Further, a meta-analysis of 10 RCTs of 22,275 patients on statin therapy, showed a reduction in SCD from 3.8% to 3%, a 19% risk reduction.25 Retrospective analysis in the SCD-HeFT trial revealed the mortality reduction with statins was similar in the ischemic and non-ischemic cardiomyopathy patients. The retrospective sub-analysis with statin use was overall favorable in arrhythmic death reduction. However prospective trials like CORONA26 and GISSI-HF with rosuvastatin failed to show any benefit. This discrepancy is likely because of the type and dose of statin studied and severity of heart disease. Beri et al reviewed 42 clinical trials in the MEDLINE database addressing the issue of arrhythmic death reduction with statins.27 They concluded that the reduction in VT/VF and sudden death was restricted to patients with coronary artery disease or ischemic cardiomyopathy. No benefit of arrhythmic death was seen in the non-ischemic cardiomyopathy group. They surmised that an anti-ischemic rather than a primary anti-arrhythmic effect is the likely cause of SCD reduction with statins. Statins are strongly recommended for primary and secondary prevention of CAD. It is not certain whether statins improve arrhythmic mortality, however they seem to be useful in patients with ICD to reduce shocks for VT/VF. Mineralocorticoid receptor blockade e helps to achieve the final neurohumoral blockade of the renin-angiotensinaldosterone pathway by blocking the synthesis of aldosterone. Aldosterone blockade decreases sympathetic activation, prevents parasympathetic inhibition and avoids myocardial fibrosis. EPHESUS28 trial (6642 patients), study of eplerenone in the post MI patients with LVEF < 0.40
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showed a significant 21% reduction in SCD at 16 months follow-up.28 Eplerenone should be considered in patients with recent MI and LV dysfunction, however, monitoring renal function and preventing hyperkalemia should be appropriately addressed. Ranolazine e the TIMI 36 MERLIN29 study on ranolazine in the acute coronary syndrome patients did not show benefit in cardiovascular death, MI or recurrent ischemia. However there was 37% reduction in VTs lasting 8 or more complexes. Although there is a potentially perceived benefit with ranolazine in arrhythmia reduction, it is not conclusively proven to affect the hard end-point of arrhythmic and overall mortality.
3.
Non-ischemic dilated cardiomyopathy
There is scanty data in this subset as most studies in heart failure population have included LV dysfunction of combined, ischemic and non-ischemic etiology. Beta-blockers and ACE-I have shown to improve outcomes in all patients with LV dysfunction and are reviewed later in the heart failure section. Only the GESICA study, which had significant proportion of non-ischemic cardiomyopathy showed a 27%, non-significant reduction in arrhythmic deaths with amiodarone as compared to placebo (12.3% and 14.2% respectively).30 Although the CHF-STAT study overall did not show any difference in outcomes with amiodarone, a sub-set analysis of the non-ischemic group showed a trend towards reduction in overall mortality.31 The DEFINITE and MADIT-CRT trials sub-analysis of the non-ischemic cardiomyopathy sub-group, reveal a significant (>70%) relative risk reduction in the risk of VT/VF or death in patients with non-ischemic cardiomyopathy, on statin drug therapy. Beta-blockers and ACE-I or ARBs should be prescribed to all patients with non-ischemic dilated cardiomyopathy. Amiodarone is of value in secondary prevention of arrhythmic events. Amiodarone and statins may be considered in patients with recurrent ICD shocks to reduce the frequency of shocks.
4.
Heart failure
Over the years the incidence and prevalence of the heart failure population is on the rise. Drug therapy has certainly contributed to improved survival and outcomes in this high risk group. The risk of arrhythmic death is high in the heart failure patients, averaging 5e15% per year, based on the New York Heart Association (NYHA) class, etiology of heart failure and the ejection fraction.32 The proportion of patients dying suddenly is highest in the less severe heart failure group i.e. NYHA II or III. Beta-blockerseimproving the symptoms status and survival in heart failure was the turning point in management of these patients. The concept of up-regulation of beta-blockers and subsequently neurohumoral blockade was confirmed in clinical trials. The US Carvedilol trial was the first to show a 65% reduction in mortality with carvedilol in heart failure patients with LVEF < 0.35.33 Arrhythmic death reduced from 3.8% to 1.7%. These impressive results led to the premature
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termination of the trial favoring the use of carvedilol. The CIBIS-II trial with bisoprolol showed a marked reduction in arrhythmic mortality from 6.3% to 3.6%, a robust 44% relative risk reduction. This trial too was prematurely terminated because of a significant 34% reduction of all-cause mortality.34 The MERIT-HF trial with sustained release metoprolol showed a significant, 41% relative risk reduction of arrhythmic mortality.35 The COPERNICUS trial with carvedilol in severe heart failure patients showed a significant reduction in SCD (6.1% with placebo and 3.9% with carvedilol) and a 35% reduction in all-cause mortality.36 A recent metaanalysis on beta-blockers of 30 RCTs including 24,779 patients, for prevention of SCD in heart failure population was studied by Al-Gobari et al. There was a significant 31% reduction of SCD risk; the 1 year absolute risk of SCD was 5.5% with beta-blockers and 8.1% with placebo in heart failure patients.37 Of all anti-arrhythmic drugs, only beta-blockers have convincingly shown reduction in arrhythmic and all-cause mortality. Important caveats from trial data are the benefit of beta-blockers is dose dependant, in addition to the ACE-I and ARBs and should be continued during hospitalization for heart failure. In the era of ICD, beta-blockers are known to decrease the frequency of ICD shocks, increase the time to first shock in secondary prevention of SCD and lower mortality. Furthermore higher dose of beta-blockers also improve the success of anti-tachycardia pacing. ACE-I or ARBs e ACE inhibitors in heart failure patients have shown not only reduction in all-cause and cardiovascular mortality but also a trend in reduction of arrhythmic deaths. The V-HEFT II trial compared enalapril to hydralazine and isosorbide dinitrate in patients with chronic congestive heart failure. There was a 28% reduction in mortality at 2 years, primarily due to a reduction in SCD.38 The SOLVD-Prevention trial with enalapril, showed a modest, non-significant mortality reduction but no impact on SCD. A meta-analysis of 7105 patients with heart failure on ACE-I, showed a nonsignificant reduction of SCD from 5.6% to 4.7%.39,40 Angiotensin receptor blockers have been compared or added to ACE-I, in the, ELITE I and II, Val-HeFT and CHARM trials.41e44 Only the smaller ELITE I study demonstrated a 36% reduction in SCD, which was not reproduced in the larger ELITE II or any other ARB trial. Overall the ARBs did not show improvement in outcomes as compared to ACE inhibitors in heart failure patients. ACE-I and ARBs exert a multifactorial benefit in patients with dilated cardiomyopathy. With a decrease in catecholamines and calcium overload, ACE-I suppress endogenous endothelin secretion, reduce sudden vasoconstriction, lessen ventricular dysfunction and thus reduce arrhythmias. ACE inhibitors increase ATP and coronary blood flow and potentially decrease the risk of VF. There appears to be a genetic basis for the benefits of ACE inhibitors. Patients with an ACE DD genotype and angiotensin II type 1C allele have a higher risk for ventricular arrhythmias. ACE-I are pivotal in improving outcomes in patients with LV dysfunction. The survival benefit is predominantly due to the improvement in heart failure status and there is a non-significant trend towards reduction in arrhythmic mortality. ARBs are not superior to ACE-I and are used when patients are intolerant to the latter.
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Mineralocorticoid blockersethe RALES study with spironolactone in class IIIeIV CHF patients and LVEF < 35%, showed a significant 36% reduction in heart failure and 29% reduction in SCD.45 Similar to eplerenone use, care should be taken to avoid hyperkalemia with the use of spironolactone. Amiodarone vis a vis ICDeAmiodarone has been evaluated in comparison to ICD in patients presenting with ventricular arrhythmias or resuscitated SCD and in patients at high risk of VT/VF/SCD, as primary prophylaxis. The AVID trial, compared anti-arrhythmic (predominantly amiodarone) drugs to ICD in patients presenting with VT/VF or resuscitated SCD.46 The overall survival was significantly more with ICD at 3 years. The benefit of ICD was not significant in a sub-group of patients with EF > 35%. The CIDS study also showed a nonsignificant trend towards reduced arrhythmic death and allcause mortality with ICD (p ¼ 0.09) as compared to amiodarone.47 In the CASH study, ICD showed a 23%, non-significant reduction of all-cause mortality versus amiodarone/metoprolol.48 Both these trials suggest that amiodarone or metoprolol and may be a combination of both these antiarrhythmics might be a viable alternative for patients in whom ICD cannot be implanted. However a meta-analysis of these secondary prevention trials clearly identifies a 28% relative reduction in death primarily because of a 50% reduction in arrhythmic mortality with ICD.49 Amongst the primary prevention trials, in the non-ischemic dilated cardiomyopathy patients e the CAT and AMIOVIRT (smaller studies) did not show benefit with ICD as compared to amiodarone.50,51 However SCD-HeFT, a larger trial in heart failure patients with near equal representation of ischemic and non-ischemic cardiomyopathy patients showed amiodarone was no better than placebo and established the superiority of ICD in heart failure patients.52 The OPTIC study suggests the usefulness of amiodarone and beta-blockers in patients with ICD implantation to reduce the ICD shocks.53 Amiodarone, though a class III antiarrhythmic drug in the Vaughan-Williams classification, exerts properties of all other class as well and therefore less prone to proarrhythmias. However the non-cardiovascular side effects of amiodarone e 2e5 fold increase in lung and thyroid toxicity are the major limitations in its long-term use. A prospective registry database of patients not implanted with ICD because of cost constraints might help to further establish the extent with which anti-arrhythmic drugs like betablockers and amiodarone alone or in combination, help to reduce overall and arrhythmic deaths. ICD is the most effective therapy, as both primary and secondary prevention of arrhythmic deaths in the heart failure population. Its evidence is much stronger in the ischemic cardiomyopathy patients but also benefits patients with non-ischemic cardiomyopathy. Amiodarone may be considered for secondary prevention of VT/VF/ SCD in those whom ICD cannot be implanted. Amiodarone along with beta-blockers are known to reduce the incidence of ICD shocks.
5.
Fish oils
The interest in n-3 poly-unsaturated fatty acids (omega-3 fats, fish oils) to prevent cardiovascular disease dates back to 1976. The GISSI-Prevenzione trial showed a significant all-cause and
cardiovascular deaths primarily driven by reduction in SCD.54 Hence an interest generated in fish oils to reduce arrhythmic deaths. The JELIS study in over 18,645 patients showed a 19% relative reduction in major coronary events but sudden cardiac death and coronary deaths did not differ between the eicosapentaenoic plus statins group versus statins only on a long-term follow up.55 A systematic review and meta-analysis of 20 studies including 68,680 patients clarifies that omega-3 supplements do not lower all-cause mortality, cardiac or sudden death, in patients randomized to fish oil or placebo over more than one year follow-up in primary or secondary prevention of cardiovascular diseases or in addition to ICD implantation.56 The varying event rates, baseline risk estimates, co-interventions and drug dosing along with compliance issues were the important reasons for conflicting outcomes in the earlier RCTs and therefore a meta-analysis seems more reliable to predict real life outcomes. Omega-3 fatty acids are not to be routinely prescribed to improve cardiovascular outcomes and needs to be tailored to individual patient profile.
6.
Channelopathies
Various ion channel gene defects result in VT/VF and SCD in the young. ICD is the definitive therapy for prevention of arrhythmic deaths in these patients. However drug therapy in isolation or in combination of device therapy is required in many patients. Cost, young age, recurrent shocks for VT/VF precipitating arrhythmic storm are some of the reasons wherein drug therapy continues to play an important role despite the availability and implantation of ICD in these patients. Long QT syndromeecongenital long QT (LQT) syndrome results from gene defect in the ion channels responsible for repolarization. Most often decreased outward Kþ current IKS or IKR or gain of function of the Naþþ current results in propensity to polymorphic VT and SCD. Almost 12 different genetic mutations have been identified. Beta-blockers have a significant positive impact in reducing the incidence of syncope and sudden cardiac death.57 A high dose of beta-blocker i.e. 2e4 mg/kg/day of propranolol has been successful to an extent in reducing mortality. In patients persisting to have syncope despite betablockers, pacemaker implantation, left cardiac sympathetic denervation and ICD implantation help further improve outcomes. Based on the genotype, experimental and small studies have suggested the role of Kþ channel openers like nicorandil, Naþþ channel blocker like flecainide or QT shortening drug like mexiletine to have a role in certain subset of LQT syndrome patients. However there has been no trial data evaluating these drugs, because the number of such patients is too small to be tested in clinical trials. Brugada syndrome e is a genetic, hereditary disorder, manifesting as characteristic ST elevation in the right precordial leads predisposing to VT/VF and SCD. Most often mutation in SCN5A gene resulting in loss of function of INa causes heterogeneity of repolarization, predominantly in the right ventricular outflow region and resulting in reentrant arrhythmias. There is clear evidence for ICD implantation in
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Table 1 e Drugs that impact arrhythmic, cardiovascular and all-cause mortality. Clinical condition
Arrhythmic mortality reduction
Cardiovascular mortality reduction
All-cause mortality reduction
Post MI, CHF Post MI Post MI, CHF CHF, post MI CAD CAD, CHF
þþ þ þ þ þ e
þþþ Neutral þþþ þþ þþ e
þþþ Neutral þþþ þþ þþ e
Beta-blockers Amiodarone ACE-I/ARB MRB Statins Fish oil
þ: Statistically non-significant reduction. þþ/þþþ: Statistically significant reduction. e: No benefit. ACE-I: Angiotensin converter enzyme inhibitor. ARB: Angiotensin receptor blocker. MRB: Mineralocorticoid blocker.
survivors of SCD and spontaneous or induced ST elevation and or VT/VF in such patients. Quinidine suppresses Ito current and can reduce the incidence of arrhythmias.58 However, benefit with quinidine is proposed based on theoretical and experimental considerations and lacks trial data scrutiny. Catecholaminergic polymorphic VT/VFeresults in exercise induced syncope and SCD. The mutation is in the ryanodine receptor (RyR2), is autosomal dominant. The resting ECG is normal and therefore making it difficult to diagnose. Characteristic ECG changes may be seen during exercise like bidirectional VT or simply high grade ventricular ectopy and polymorphic VT. As in LQT syndrome patients, beta-blockers are recommended in symptomatic patients and asymptomatic gene carriers. There is no clinical trial data available. Left cardiac sympathetic denervation is suggested in patients not responsive to beta-blockers and ICD appears to be the most effective life-saving measure.59 Short QT syndromeeis a relatively recent addition to the list of channelopathies with a smaller number of patients with established diagnosis. The genetic defect responsible is the Kþ channel with gain in function resulting in resting ECG showing a short QT (240e320 ms) and resulting in atrial fibrillation and VT/VF. ICD implantation may be the primary therapy, however quinidine may be useful as adjunctive therapy based on some clinical and experimental data.60
high risk patients may or may not have an ICD but every patient with cardiovascular diseases should be on optimal drug therapy to improve survival outcomes. The non AADs like ACE-I have shown reduction in arrhythmic and overall mortality by favorable alteration of remodeling and improvement in LV function. The ARBs have no advantage over the ACE-I but can be substituted in patients not tolerant to ACE-I. Aldosterone antagonists have shown a reduction in arrhythmic and overall mortality in heart failure and post MI patients. Statins show a favorable reduction in arrhythmic mortality in patients with CAD. Ranolazine, fish oils are more speculative in reduction of cardiovascular mortality and not corroborated by large RCTs or meta-analysis. The role of AAD in various channelopathies as primary and secondary prophylaxis in prevention of SCD has not been evaluated in RCTs and this is not likely to happen knowing the limited population pool in this subset. Hence ICD remains the therapy of choice in survivors of SCD and in the high risk group. However the young age of patients continue to remain a challenge for ICD implantation and therefore drug therapy remains a practical, first step solution for some of these patients.
Conflicts of interest All authors have none to declare.
7.
Conclusion
Appropriate drug therapy reduces arrhythmic and often allcause mortality in post MI and heart failure patients (Table 1). Amongst the AADs only beta-blockers convincingly improve survival and prevent SCD in post MI and CHF patients. Amiodarone in the post MI group reduces arrhythmic mortality but not overall mortality. It is neutral for mortality and therefore a safe AAD to consider when required. ICD remains the most effective strategy in reducing arrhythmic deaths. ICD is expensive and in some patients amiodarone is a reasonable alternative (not as a replacement for ICD) for secondary prophylaxis and also in conjunction with an ICD to reduce the frequency of shocks. However it is not desirable to use amiodarone as primary prophylaxis with no proven benefit and serious long-term side effects. In the era of ICD it would be prudent to remember that all
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ramipril on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Eng J Med. 2000;342:145e153. Mitchell LB, Powell JL, Gillis AM, Kehl V, Hallstrom AP, AVID investigators. Are lipid-lowering drugs also antiarrhythmic drugs? An analysis of the Anti-arrhythmics versus Implantable Defibrillators (AVID) trial. J Am Coll Cardiol. 2003;42:81e87. Vyas AK, Guo H, Moss AJ, et al. Reduction in ventricular tachyarrhythmias with statins in the Multicentre Automatic Defibrillator Implantation Trial (MADIT II). J Am Coll Cardiol. 2006;47:769e773. Levantesi G, Scarano M, Marifisi R, et al. Meta-analysis of effect of statin treatment on risk of sudden death. Am J Cardiol. 2007;100:1644e1650. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patietns with systolic heart failure. N Engl J Med. 2007;357:2248e2261. Beri Abhimanyu, Contractor Tahmeed, Khasnis Atul, Thakur Ranjan. Statins and the reduction of sudden cardiac death: antiarrhythmic or anti-ischaemic effect? Am J Cardiovasc Drugs. 2010;10:155e164. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. NEJM. 2003;348:1309e1321. Scirica BM, Morrow DH, Hod H, et al. Effect of Ranolazine, an anti-anginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non-ST segment elevation ACS: results of the metabolic efficacy with ranolazine for ischaemia in non-ST elevation ACS thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36). Circulation. 2007;116:1647e1652. Doval H, Nul D, Grancelli H, et al. GESICA. A randomised trial of low dose amiodarone in severe congestive heart failure. Lancet. 1994;344:493e498. Singh SN, Fisher SG, Deedwania PC, et al. Congestive heart failure: survival trial of antiarrhythmic therapy (CHF STAT). The CHF STAT Investigators. Control Clin Trials. 1992 Oct;13:339e350. Mozaffarian D, Anker SD, Anand I, et al. Prediction of mode of death in heart failure: the Seattle Heart Failure Model. Circulation. 2007;116:392e398. Packer M, Bristow MR, Cohn JN, et al. Effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996;334:1349e1355. A randomised trial of beta blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS-II). Lancet. 1999;353:9e13. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet. 1999;353:2001e2007. Packer M, Coats AJ, Fowler MB, et al. Carvedilol Prospective Randomised Cumulative Survival Study (COPERNICUS) Study Group. Effect of carvedilol on the morbidity of patients with severe chronic heart failure. Circulation. 2002;106:2194e2199. Al-Gobari Muaamar, El Khatib Chadia, Pillon Francois, Gueyffier Francois. Beta blockers for the prevention of sudden cardiac death in heart failure patients: a meta analysis of randomized controlled trials. BMC Cardiovasc Disord. 2013;13:52. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in treatment of chronic congestive heart failure. NEJM. 1991;325:303e310. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions the SOLVD investigators. N Engl J Med. 1992;327:685e691.
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40. Garg R, Yusuf S. Overview of randomised trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA. 1995;273:1450e1456. 41. Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997;349:747e752. 42. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial e the Losartan Heart Failure Survival Study, ELITE II. Lancet. 2000;355:1582e1587. 43. Cohn J, Tognoni G, Valsartan Heart Failure Investigators. A randomised trial of angiotensin receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667e1675. 44. McMurray JJ, Ostergren J, Swedberg K, et al. Effect of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin converting enzyme inhibitor: the CHARM-Added trial. Lancet. 2003;362:767e771. 45. Pitt B, Zannad F, Remme WJ, et al, The Randomised Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. NEJM. 1999;341:709e717. 46. The Antiarrhythmic Versus Implantable Defibrillator (AVID) investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near fatal ventricular arrhythmias. N Engl J Med. 1997;337:1576e1583. 47. Connoly SJ, Gent M, Roberts RS, et al. Canadian Implantable Defibrillator Study (CIDS) e a randomised trial of implantable cardioverter defibrillator against amiodarone. Circulation. 2000;101:1297e1302. 48. Kuck Karl-Heinz, Cappato Riccardo, Siebels Ju¨rgen, et al. Randomised comparison of anti-arrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH). Circulation. 2000;102:748e754. 49. Connoly SJ, Hallstrom AP, Cappato R, et al. Meta analysis of ICD secondary prevention trials e AVID, CASH & CIDS. Eur Heart J. 2000;21:2071e2078. 50. Bansch D, Antz M, Boczor S, et al. Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy:
51.
52.
53.
54.
55.
56.
57.
58.
59. 60.
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the Cardiomyopathy Trial (CAT). Circulation. 2002;105:1453e1458. Strickberger SA, Hummel JD, Bartlett TG, et al. Amiodarone versus implantable cardioverter defibrillator: randomised trial in patients with nonischaemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardiaeAMIOVIRT. J Am Coll Cardiol. 2003;41:1707e1712. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352:225e237. Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta blockers, amiodarone plus beta blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators. The OPTIC study: a randomised trial. JAMA. 2006;295:165e171. Marchioli Roberto, Barzi Federica, Bomba Elena, et al. GISSI e Prevenzione Group. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-P trial. Lancet. 1999;354:447e455. Yokoyama M, Origasa H, Matsuzaki M, et al. Japan EPA Lipid Intervention Study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients: a randomised open label, blinded endpoint analysis. Lancet. 2007;369:1090e1098. Rizos EC, Ntzani Evangelia, Bika Eftichia, Kostapanos Michael, Elisaf Moses. Association between omega e 3 fatty acid supplementation and risk of major cardiovascular disease events: a systemic review and meta analysis. JAMA. 2012;308:1024e1033. Schwartz PJ, Locati E. The idiopathic Long QT syndrome: pathogenetic mechanisms and therapy. Eur Heart J. 1985;6:103e114. Kaufman EF. Mechanisms and clinical management of inherited channelopathies: long QT syndrome, Brugada syndrome, Catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome. Heart Rhythm. 2009;6:S51eS55. Wilde AA, Bhuiyan ZA, Crotti L, et al. Left cardiac sympathetic denervation for CPVT. N Engl J Med. 2008;358:2024e2029. Gaita F, Guistetto C, Bianchi F, et al. Short QT syndrome: pharmacological treatment. J Am Coll Cardiol. 2004;43:1494e1499.
Available online at www.sciencedirect.com
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Review Article
Pharmacotherapy to reduce arrhythmic mortality Amit Vora*, Samhita Kulkarni Glenmark Cardiac Centre, Smt. S.R. Mehta Cardiac Institute, India
article info
abstract
Article history:
Fatal ventricular arrhythmias and heart failure are the common modes of death in patients
Received 30 November 2013
with cardiovascular diseases. Intracardiac defibrillator (ICD) implantation reduces
Accepted 19 December 2013
arrhythmic mortality to a significant extent in the high risk patient. However, there con-
Available online 21 January 2014
tinues to be a need for effective drug therapy to reduce the arrhythmic and overall mortality in patients with or without an ICD. Although anti-arrhythmic drugs (AAD) appear
Keywords:
inferior to ICD, the role of beta-blockers and to an extent amiodarone along with non AAD
Sudden cardiac death
like angiotensin converting enzyme inhibitors (ACE-I), mineralocorticoid blockers (MRB)
Beta-blockers
and HMG-CoA reductase inhibitors (statins) need to be emphasized. There have been many
Intracardiac defibrillator
drug trials and meta-analysis to this effect and we review the role of drugs especially in
Myocardial infarction
their ability to reduce arrhythmic mortality and sudden cardiac death (SCD). The focus is
Heart failure
on post myocardial infarction (MI) and heart failure patients with a brief overview of role of drugs in channelopathies. Copyright ª 2013, Cardiological Society of India. All rights reserved.
1.
Introduction
Last five decades have shown remarkable improvement in the cardiovascular mortality with advances in drug and nondrug therapy in heart diseases. In drug therapy, from aspirin to thrombolytics, beta-blockers to angiotensin receptor antagonists to statins, all have contributed in improving survival in patients with coronary artery disease, hypertension and left ventricular dysfunction. Although from a practical stand-point reduction in all-cause mortality is what is desired, from a scientific perspective the reasons driving mortality reduction is important. The current review is specifically aimed to determine the influence of drugs on reduction of arrhythmic mortality in various subsets of cardiac diseases.
2.
Post myocardial infarction
Post MI, there is a mortality of 5e15% in the first year.1,2 With advances in pharmacotherapy and interventional treatment there has been a steady decline in mortality. Beta-blockers e the BHAT3 trial was one of the early study that established the role of beta-blockers in reducing total and arrhythmic mortality, in patients after MI. Despite subsequent more evidences to suggest the benefit of beta-blocker post MI, it continued to be under-utilized. The Cooperative Cardiovascular Project revealed that only 34% patients post MI received beta-blockers and there was a 40% reduction in mortality when they were prescribed at discharge.4 A metaanalysis by Freemantle5 showed an overall 23% mortality reduction with long-term trials using beta-blockers post MI
* Corresponding author. Glenmark Cardiac Centre, Flat No. 10, Nandadeep, 209-d, Dr. Ambedkar Road, Matunga (East), Mumbai 400019, India. Tel.: þ91 22 24185808, þ91 9821084160 (mobile); fax: þ91 22 24162538. E-mail address: [email protected] (A. Vora). 0019-4832/$ e see front matter Copyright ª 2013, Cardiological Society of India. All rights reserved. http://dx.doi.org/10.1016/j.ihj.2013.12.049
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even in the era of fibrinolytic therapy. The CAPRICORN6 trial of carvedilol in post MI patients with LVEF < 0.40, established mortality benefit in patients with LV dysfunction. A long-term analysis of CAPRICORN patients showed a reduction of 63% in sustained ventricular tachyarrhythmias.7 Importantly, benefit with beta-blockers persisted even in patients taking ACE-I. Class I AAD e the CAST I and II study compared Class I antiarrhythmic drugs (encainide, flecainide or morcizine) with placebo in the post MI patients with premature ventricular complexes (PVC).8,9 There was a higher arrhythmic and nonarrhythmic mortality in the AAD arm despite suppression of PVCs. Mexiletine and disopyramide also met similar fate. In fact, a meta-analysis of 61 RCTs in over 23,000 patients, with Class I AAD showed an increased overall mortality.10 Class III AAD e Julian et al studied d,l-sotalol, post MI (5e15 days), and showed a lower mortality at 1 year follow-up, however this was not statistically significant.11 The SWORD study on d-sotalol in immediate post MI (6e42 days) and remote MI (>42 days) with LVEF < 0.40, was terminated prematurely as there was a higher arrhythmic and all-cause mortality with sotalol.12 D-sotalol has virtually no beta-blocking property and was chosen in SWORD trial to prevent heart failure in LV dysfunction patients. Absence of beta-blocking effect in fact became counter-productive and increased mortality. Interest in d,l-sotalol has been revived in the ICD era as it lowers the defibrillation threshold and importantly reduces the frequency of ICD shocks and lowers mortality.13 The BASIS trial, was a small study (312 patients) on amiodarone in post MI patients with frequent multifocal or repetitive PVC. There was a significant reduction in total mortality and arrhythmic events with amiodarone.14 The Polish study, though demonstrated a borderline reduction in cardiac mortality and ventricular arrhythmias, it did not improve overall survival at one year follow-up with amiodarone in the post MI patients.15 The CAMIAT randomized post MI patients with greater than 10 PVC/h, comparing amiodarone versus placebo. Amiodarone showed a significant reduction in arrhythmic deaths (4.5% versus 6.9%, p ¼ 0.016); however there was no significant reduction in total mortality.16 The EMIAT study, in post MI patient with LVEF < 0.40, showed a 35% relative risk reduction in arrhythmic deaths with no reduction in total mortality.17 Thus, amiodarone does reduce arrhythmic but not overall mortality in the post MI primary prevention trials. A meta-analysis on amiodarone including 15 trials and 8522 patients, showed a significant 29% reduction of SCD and 18% reduction of cardiovascular mortality.18 A subgroup analysis of the post MI patients in this meta-analysis showed a relative risk reduction of 34% in arrhythmic deaths and 12% reduction in all-cause deaths. However, amiodarone trials have demonstrated more non-cardiac deaths and noncardiac side effects in the intermediate term follow-up. Thus, in the post MI patients beta-blockers reduce arrhythmic and all-cause mortality and should be used in everyone without an absolute contra-indication. Amiodarone reduces arrhythmic but not overall mortality and is known to have non-cardiac side effects and hence is not recommended as a primary prophylaxis drug but may be considered when necessary, especially when ICD implantation is not feasible. Sotalol may be considered in patients with recurrent ICD shocks.
ACE inhibitors e are a part of the standard treatment regimen in post MI patients. The TRACE and AIRE trials evaluated ACE-I in the post MI population with LV dysfunction.19,20 There was a 24% and 30% reduction in arrhythmic mortality in the TRACE and AIRE studies respectively. Both these trials showed a significant reduction in total mortality. A meta-analysis of ACE inhibitors in the post MI period, from 15 trials showed a decrease in SCD, with a 20% relative risk reduction for SCD (an odds ratio of 0.80, 95% CI 0.70e0.92).21 Direct anti-arrhythmic effect of ACE inhibitors is speculated but not well understood. It is likely the indirect effects of preventing LV remodeling, improvement in LV function and thus preventing fatal ventricular arrhythmias. In the high risk population for cardiovascular mortality (vascular disease or diabetes with a cardiac risk factor of hypertension, raised serum lipids etc.), the HOPE study showed a 37% reduction in cardiac arrests and 26% reduction in cardiovascular mortality.22 ACE-I should therefore be prescribed to all patients post MI and those with high risk for coronary risk factors to prevent arrhythmic and overall mortality. Statinsereduce burden of CAD, MI and cardiovascular mortality in subjects with known ischemic heart disease/ coronary risk factors. There was a suggestion of nonsignificant reduction in fatal arrhythmic outcomes with statins. Retrospective analysis of AVID sub-group showed a 40% reduction in arrhythmic death or appropriate ICD shock and similar results were seen in MADIT-II with 28% reduction in arrhythmic outcomes.23,24 Further, a meta-analysis of 10 RCTs of 22,275 patients on statin therapy, showed a reduction in SCD from 3.8% to 3%, a 19% risk reduction.25 Retrospective analysis in the SCD-HeFT trial revealed the mortality reduction with statins was similar in the ischemic and non-ischemic cardiomyopathy patients. The retrospective sub-analysis with statin use was overall favorable in arrhythmic death reduction. However prospective trials like CORONA26 and GISSI-HF with rosuvastatin failed to show any benefit. This discrepancy is likely because of the type and dose of statin studied and severity of heart disease. Beri et al reviewed 42 clinical trials in the MEDLINE database addressing the issue of arrhythmic death reduction with statins.27 They concluded that the reduction in VT/VF and sudden death was restricted to patients with coronary artery disease or ischemic cardiomyopathy. No benefit of arrhythmic death was seen in the non-ischemic cardiomyopathy group. They surmised that an anti-ischemic rather than a primary anti-arrhythmic effect is the likely cause of SCD reduction with statins. Statins are strongly recommended for primary and secondary prevention of CAD. It is not certain whether statins improve arrhythmic mortality, however they seem to be useful in patients with ICD to reduce shocks for VT/VF. Mineralocorticoid receptor blockade e helps to achieve the final neurohumoral blockade of the renin-angiotensinaldosterone pathway by blocking the synthesis of aldosterone. Aldosterone blockade decreases sympathetic activation, prevents parasympathetic inhibition and avoids myocardial fibrosis. EPHESUS28 trial (6642 patients), study of eplerenone in the post MI patients with LVEF < 0.40
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showed a significant 21% reduction in SCD at 16 months follow-up.28 Eplerenone should be considered in patients with recent MI and LV dysfunction, however, monitoring renal function and preventing hyperkalemia should be appropriately addressed. Ranolazine e the TIMI 36 MERLIN29 study on ranolazine in the acute coronary syndrome patients did not show benefit in cardiovascular death, MI or recurrent ischemia. However there was 37% reduction in VTs lasting 8 or more complexes. Although there is a potentially perceived benefit with ranolazine in arrhythmia reduction, it is not conclusively proven to affect the hard end-point of arrhythmic and overall mortality.
3.
Non-ischemic dilated cardiomyopathy
There is scanty data in this subset as most studies in heart failure population have included LV dysfunction of combined, ischemic and non-ischemic etiology. Beta-blockers and ACE-I have shown to improve outcomes in all patients with LV dysfunction and are reviewed later in the heart failure section. Only the GESICA study, which had significant proportion of non-ischemic cardiomyopathy showed a 27%, non-significant reduction in arrhythmic deaths with amiodarone as compared to placebo (12.3% and 14.2% respectively).30 Although the CHF-STAT study overall did not show any difference in outcomes with amiodarone, a sub-set analysis of the non-ischemic group showed a trend towards reduction in overall mortality.31 The DEFINITE and MADIT-CRT trials sub-analysis of the non-ischemic cardiomyopathy sub-group, reveal a significant (>70%) relative risk reduction in the risk of VT/VF or death in patients with non-ischemic cardiomyopathy, on statin drug therapy. Beta-blockers and ACE-I or ARBs should be prescribed to all patients with non-ischemic dilated cardiomyopathy. Amiodarone is of value in secondary prevention of arrhythmic events. Amiodarone and statins may be considered in patients with recurrent ICD shocks to reduce the frequency of shocks.
4.
Heart failure
Over the years the incidence and prevalence of the heart failure population is on the rise. Drug therapy has certainly contributed to improved survival and outcomes in this high risk group. The risk of arrhythmic death is high in the heart failure patients, averaging 5e15% per year, based on the New York Heart Association (NYHA) class, etiology of heart failure and the ejection fraction.32 The proportion of patients dying suddenly is highest in the less severe heart failure group i.e. NYHA II or III. Beta-blockerseimproving the symptoms status and survival in heart failure was the turning point in management of these patients. The concept of up-regulation of beta-blockers and subsequently neurohumoral blockade was confirmed in clinical trials. The US Carvedilol trial was the first to show a 65% reduction in mortality with carvedilol in heart failure patients with LVEF < 0.35.33 Arrhythmic death reduced from 3.8% to 1.7%. These impressive results led to the premature
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termination of the trial favoring the use of carvedilol. The CIBIS-II trial with bisoprolol showed a marked reduction in arrhythmic mortality from 6.3% to 3.6%, a robust 44% relative risk reduction. This trial too was prematurely terminated because of a significant 34% reduction of all-cause mortality.34 The MERIT-HF trial with sustained release metoprolol showed a significant, 41% relative risk reduction of arrhythmic mortality.35 The COPERNICUS trial with carvedilol in severe heart failure patients showed a significant reduction in SCD (6.1% with placebo and 3.9% with carvedilol) and a 35% reduction in all-cause mortality.36 A recent metaanalysis on beta-blockers of 30 RCTs including 24,779 patients, for prevention of SCD in heart failure population was studied by Al-Gobari et al. There was a significant 31% reduction of SCD risk; the 1 year absolute risk of SCD was 5.5% with beta-blockers and 8.1% with placebo in heart failure patients.37 Of all anti-arrhythmic drugs, only beta-blockers have convincingly shown reduction in arrhythmic and all-cause mortality. Important caveats from trial data are the benefit of beta-blockers is dose dependant, in addition to the ACE-I and ARBs and should be continued during hospitalization for heart failure. In the era of ICD, beta-blockers are known to decrease the frequency of ICD shocks, increase the time to first shock in secondary prevention of SCD and lower mortality. Furthermore higher dose of beta-blockers also improve the success of anti-tachycardia pacing. ACE-I or ARBs e ACE inhibitors in heart failure patients have shown not only reduction in all-cause and cardiovascular mortality but also a trend in reduction of arrhythmic deaths. The V-HEFT II trial compared enalapril to hydralazine and isosorbide dinitrate in patients with chronic congestive heart failure. There was a 28% reduction in mortality at 2 years, primarily due to a reduction in SCD.38 The SOLVD-Prevention trial with enalapril, showed a modest, non-significant mortality reduction but no impact on SCD. A meta-analysis of 7105 patients with heart failure on ACE-I, showed a nonsignificant reduction of SCD from 5.6% to 4.7%.39,40 Angiotensin receptor blockers have been compared or added to ACE-I, in the, ELITE I and II, Val-HeFT and CHARM trials.41e44 Only the smaller ELITE I study demonstrated a 36% reduction in SCD, which was not reproduced in the larger ELITE II or any other ARB trial. Overall the ARBs did not show improvement in outcomes as compared to ACE inhibitors in heart failure patients. ACE-I and ARBs exert a multifactorial benefit in patients with dilated cardiomyopathy. With a decrease in catecholamines and calcium overload, ACE-I suppress endogenous endothelin secretion, reduce sudden vasoconstriction, lessen ventricular dysfunction and thus reduce arrhythmias. ACE inhibitors increase ATP and coronary blood flow and potentially decrease the risk of VF. There appears to be a genetic basis for the benefits of ACE inhibitors. Patients with an ACE DD genotype and angiotensin II type 1C allele have a higher risk for ventricular arrhythmias. ACE-I are pivotal in improving outcomes in patients with LV dysfunction. The survival benefit is predominantly due to the improvement in heart failure status and there is a non-significant trend towards reduction in arrhythmic mortality. ARBs are not superior to ACE-I and are used when patients are intolerant to the latter.
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Mineralocorticoid blockersethe RALES study with spironolactone in class IIIeIV CHF patients and LVEF < 35%, showed a significant 36% reduction in heart failure and 29% reduction in SCD.45 Similar to eplerenone use, care should be taken to avoid hyperkalemia with the use of spironolactone. Amiodarone vis a vis ICDeAmiodarone has been evaluated in comparison to ICD in patients presenting with ventricular arrhythmias or resuscitated SCD and in patients at high risk of VT/VF/SCD, as primary prophylaxis. The AVID trial, compared anti-arrhythmic (predominantly amiodarone) drugs to ICD in patients presenting with VT/VF or resuscitated SCD.46 The overall survival was significantly more with ICD at 3 years. The benefit of ICD was not significant in a sub-group of patients with EF > 35%. The CIDS study also showed a nonsignificant trend towards reduced arrhythmic death and allcause mortality with ICD (p ¼ 0.09) as compared to amiodarone.47 In the CASH study, ICD showed a 23%, non-significant reduction of all-cause mortality versus amiodarone/metoprolol.48 Both these trials suggest that amiodarone or metoprolol and may be a combination of both these antiarrhythmics might be a viable alternative for patients in whom ICD cannot be implanted. However a meta-analysis of these secondary prevention trials clearly identifies a 28% relative reduction in death primarily because of a 50% reduction in arrhythmic mortality with ICD.49 Amongst the primary prevention trials, in the non-ischemic dilated cardiomyopathy patients e the CAT and AMIOVIRT (smaller studies) did not show benefit with ICD as compared to amiodarone.50,51 However SCD-HeFT, a larger trial in heart failure patients with near equal representation of ischemic and non-ischemic cardiomyopathy patients showed amiodarone was no better than placebo and established the superiority of ICD in heart failure patients.52 The OPTIC study suggests the usefulness of amiodarone and beta-blockers in patients with ICD implantation to reduce the ICD shocks.53 Amiodarone, though a class III antiarrhythmic drug in the Vaughan-Williams classification, exerts properties of all other class as well and therefore less prone to proarrhythmias. However the non-cardiovascular side effects of amiodarone e 2e5 fold increase in lung and thyroid toxicity are the major limitations in its long-term use. A prospective registry database of patients not implanted with ICD because of cost constraints might help to further establish the extent with which anti-arrhythmic drugs like betablockers and amiodarone alone or in combination, help to reduce overall and arrhythmic deaths. ICD is the most effective therapy, as both primary and secondary prevention of arrhythmic deaths in the heart failure population. Its evidence is much stronger in the ischemic cardiomyopathy patients but also benefits patients with non-ischemic cardiomyopathy. Amiodarone may be considered for secondary prevention of VT/VF/ SCD in those whom ICD cannot be implanted. Amiodarone along with beta-blockers are known to reduce the incidence of ICD shocks.
5.
Fish oils
The interest in n-3 poly-unsaturated fatty acids (omega-3 fats, fish oils) to prevent cardiovascular disease dates back to 1976. The GISSI-Prevenzione trial showed a significant all-cause and
cardiovascular deaths primarily driven by reduction in SCD.54 Hence an interest generated in fish oils to reduce arrhythmic deaths. The JELIS study in over 18,645 patients showed a 19% relative reduction in major coronary events but sudden cardiac death and coronary deaths did not differ between the eicosapentaenoic plus statins group versus statins only on a long-term follow up.55 A systematic review and meta-analysis of 20 studies including 68,680 patients clarifies that omega-3 supplements do not lower all-cause mortality, cardiac or sudden death, in patients randomized to fish oil or placebo over more than one year follow-up in primary or secondary prevention of cardiovascular diseases or in addition to ICD implantation.56 The varying event rates, baseline risk estimates, co-interventions and drug dosing along with compliance issues were the important reasons for conflicting outcomes in the earlier RCTs and therefore a meta-analysis seems more reliable to predict real life outcomes. Omega-3 fatty acids are not to be routinely prescribed to improve cardiovascular outcomes and needs to be tailored to individual patient profile.
6.
Channelopathies
Various ion channel gene defects result in VT/VF and SCD in the young. ICD is the definitive therapy for prevention of arrhythmic deaths in these patients. However drug therapy in isolation or in combination of device therapy is required in many patients. Cost, young age, recurrent shocks for VT/VF precipitating arrhythmic storm are some of the reasons wherein drug therapy continues to play an important role despite the availability and implantation of ICD in these patients. Long QT syndromeecongenital long QT (LQT) syndrome results from gene defect in the ion channels responsible for repolarization. Most often decreased outward Kþ current IKS or IKR or gain of function of the Naþþ current results in propensity to polymorphic VT and SCD. Almost 12 different genetic mutations have been identified. Beta-blockers have a significant positive impact in reducing the incidence of syncope and sudden cardiac death.57 A high dose of beta-blocker i.e. 2e4 mg/kg/day of propranolol has been successful to an extent in reducing mortality. In patients persisting to have syncope despite betablockers, pacemaker implantation, left cardiac sympathetic denervation and ICD implantation help further improve outcomes. Based on the genotype, experimental and small studies have suggested the role of Kþ channel openers like nicorandil, Naþþ channel blocker like flecainide or QT shortening drug like mexiletine to have a role in certain subset of LQT syndrome patients. However there has been no trial data evaluating these drugs, because the number of such patients is too small to be tested in clinical trials. Brugada syndrome e is a genetic, hereditary disorder, manifesting as characteristic ST elevation in the right precordial leads predisposing to VT/VF and SCD. Most often mutation in SCN5A gene resulting in loss of function of INa causes heterogeneity of repolarization, predominantly in the right ventricular outflow region and resulting in reentrant arrhythmias. There is clear evidence for ICD implantation in
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Table 1 e Drugs that impact arrhythmic, cardiovascular and all-cause mortality. Clinical condition
Arrhythmic mortality reduction
Cardiovascular mortality reduction
All-cause mortality reduction
Post MI, CHF Post MI Post MI, CHF CHF, post MI CAD CAD, CHF
þþ þ þ þ þ e
þþþ Neutral þþþ þþ þþ e
þþþ Neutral þþþ þþ þþ e
Beta-blockers Amiodarone ACE-I/ARB MRB Statins Fish oil
þ: Statistically non-significant reduction. þþ/þþþ: Statistically significant reduction. e: No benefit. ACE-I: Angiotensin converter enzyme inhibitor. ARB: Angiotensin receptor blocker. MRB: Mineralocorticoid blocker.
survivors of SCD and spontaneous or induced ST elevation and or VT/VF in such patients. Quinidine suppresses Ito current and can reduce the incidence of arrhythmias.58 However, benefit with quinidine is proposed based on theoretical and experimental considerations and lacks trial data scrutiny. Catecholaminergic polymorphic VT/VFeresults in exercise induced syncope and SCD. The mutation is in the ryanodine receptor (RyR2), is autosomal dominant. The resting ECG is normal and therefore making it difficult to diagnose. Characteristic ECG changes may be seen during exercise like bidirectional VT or simply high grade ventricular ectopy and polymorphic VT. As in LQT syndrome patients, beta-blockers are recommended in symptomatic patients and asymptomatic gene carriers. There is no clinical trial data available. Left cardiac sympathetic denervation is suggested in patients not responsive to beta-blockers and ICD appears to be the most effective life-saving measure.59 Short QT syndromeeis a relatively recent addition to the list of channelopathies with a smaller number of patients with established diagnosis. The genetic defect responsible is the Kþ channel with gain in function resulting in resting ECG showing a short QT (240e320 ms) and resulting in atrial fibrillation and VT/VF. ICD implantation may be the primary therapy, however quinidine may be useful as adjunctive therapy based on some clinical and experimental data.60
high risk patients may or may not have an ICD but every patient with cardiovascular diseases should be on optimal drug therapy to improve survival outcomes. The non AADs like ACE-I have shown reduction in arrhythmic and overall mortality by favorable alteration of remodeling and improvement in LV function. The ARBs have no advantage over the ACE-I but can be substituted in patients not tolerant to ACE-I. Aldosterone antagonists have shown a reduction in arrhythmic and overall mortality in heart failure and post MI patients. Statins show a favorable reduction in arrhythmic mortality in patients with CAD. Ranolazine, fish oils are more speculative in reduction of cardiovascular mortality and not corroborated by large RCTs or meta-analysis. The role of AAD in various channelopathies as primary and secondary prophylaxis in prevention of SCD has not been evaluated in RCTs and this is not likely to happen knowing the limited population pool in this subset. Hence ICD remains the therapy of choice in survivors of SCD and in the high risk group. However the young age of patients continue to remain a challenge for ICD implantation and therefore drug therapy remains a practical, first step solution for some of these patients.
Conflicts of interest All authors have none to declare.
7.
Conclusion
Appropriate drug therapy reduces arrhythmic and often allcause mortality in post MI and heart failure patients (Table 1). Amongst the AADs only beta-blockers convincingly improve survival and prevent SCD in post MI and CHF patients. Amiodarone in the post MI group reduces arrhythmic mortality but not overall mortality. It is neutral for mortality and therefore a safe AAD to consider when required. ICD remains the most effective strategy in reducing arrhythmic deaths. ICD is expensive and in some patients amiodarone is a reasonable alternative (not as a replacement for ICD) for secondary prophylaxis and also in conjunction with an ICD to reduce the frequency of shocks. However it is not desirable to use amiodarone as primary prophylaxis with no proven benefit and serious long-term side effects. In the era of ICD it would be prudent to remember that all
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