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Canadian Journal of Cardiology

ICDs for Patients With Stable VT, Cardiomyopathy, and Relatively Preserved LVEF: Core Therapy, Precision Medicine, or Indication Creep?

      Unexpected sudden cardiac death (SCD) remains one of the most common causes of mortality.
      • Kuriachan V.P.
      • Sumner G.L.
      • Mitchell L.B.
      Sudden cardiac death.
      The majority of SCDs are caused by ventricular tachycardia (VT) or ventricular fibrillation (VF), with fewer related to asystole, electromechanical dissociation, or sudden hemodynamic catastrophes.
      • Kuriachan V.P.
      • Sumner G.L.
      • Mitchell L.B.
      Sudden cardiac death.
      A normally functioning implantable cardioverter defibrillator (ICD) will terminate the vast majority of VT/VF episodes and will preclude asystole, thereby reducing the probability of SCD in high risk patients by ∼50% and of all-cause mortality by ∼25% in comparison with antiarrhythmic drug (AAD) therapy.
      • Connolly S.J.
      • Hallstrom A.P.
      • Cappato R.
      • et al.
      Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials.
      Nevertheless, the placement and subsequent presence of ICDs have risks including surgical complications, system infections, component failures, inappropriate therapies, and death.
      • Persson R.
      • Earley A.
      • Garlitski A.C.
      • Balk E.M.
      • Uhlig K.
      Adverse events following implantable cardioverter defibrillator implantation: a systematic review.
      Accordingly, ICDs are reserved for patients judged to have higher risks of SCD, a judgement that, at present, is neither sensitive nor specific.
      Because most SCDs result from VT/VF, the strongest predictors of SCD are predictors of future episodes of VT/VF, the strongest of which is a past episode of VT/VF. Thus, early trials of ICDs focused on patients who had survived life-threatening VT/VF (secondary prevention). In these trials, the incidence of SCD in patients randomized to AAD therapy was 6.1% per year vs 2.8% per year in patients randomized to ICDs.
      • Connolly S.J.
      • Hallstrom A.P.
      • Cappato R.
      • et al.
      Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials.
      Subgroup analyses of these trials suggested that the mortality benefit of an ICD was limited to patients with advanced left ventricular systolic dysfunction.
      • Connolly S.J.
      • Hallstrom A.P.
      • Cappato R.
      • et al.
      Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials.
      Accordingly, subsequent ICD trials in patients without previous VT/VF (primary prevention) focused on patients with cardiomyopathies and left ventricular ejection fractions (LVEFs) ≤ 0.35, wherein the incidence of SCD in patients randomized to conventional therapy was 3.4% per year vs 1.2% per year in patients randomized to ICDs.
      • Kołodziejczak M.
      • Andreotti F.
      • Kowalewski M.
      • et al.
      Implantable cardioverter-defibrillators for primary prevention in patients with ischemic or nonischemic cardiomyopathy: a systematic review and meta-analysis.
      Patients with hemodynamically stable VT were excluded from the secondary prevention ICD trials, as they were believed to have low probability of SCD, based on the conviction that, despite being likely to re-experience stable VT, they were not likely to experience life-threatening VT/VF. Observational reports of the probabilities of SCD or rapid, potentially life-threatening VT/VF in patients with hemodynamically stable VT are at odds; some report a low probability,
      • Brugada P.
      • Talajic M.
      • Smeets J.
      • Mulleneers R.
      • Wellens H.J.
      The value of the clinical history to assess prognosis of patients with ventricular tachycardia or ventricular fibrillation after myocardial infarction.
      ,
      • Sarter B.H.
      • Finkle J.K.
      • Gerszten R.E.
      • Buxton A.E.
      What is the risk of sudden cardiac death in patients presenting with hemodynamically stable sustained ventricular tachycardia after myocardial infarction?.
      whereas others report a high probability of these events.
      • Olshansky B.
      • Hahn E.A.
      • Hartz V.L.
      • Prater S.P.
      • Mason J.W.
      ESVEM Investigators: Clinical significance of syncope in the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial.
      • Olson P.J.
      • Woelfel A.
      • Simpson Jr., R.J.
      • Foster J.R.
      Stratification of sudden death risk in patients receiving long-term amiodarone treatment for sustained ventricular tachycardia or ventricular fibrillation.
      • Böcker D.
      • Block M.
      • Isbruch F.
      • et al.
      Benefits of treatment with implantable cardioverter-defibrillators in patients with stable ventricular tachycardia without cardiac arrest.
      • Glikson M.
      • Lipchenca I.
      • Viskin S.
      • Ballman K.V.
      • Trusty J.M.
      • Gurevitz O.T.
      Long-term outcome of patients who received implantable cardioverter defibrillators for stable ventricular tachycardia.
      Patients in these studies were dominated by those with LVEFs ≤ 0.35. Two studies reported the probabilities of rapid (presumed hemodynamically unstable) VT/VF in patients with previous hemodynamically stable VT who had received ICDs.
      • Böcker D.
      • Block M.
      • Isbruch F.
      • et al.
      Benefits of treatment with implantable cardioverter-defibrillators in patients with stable ventricular tachycardia without cardiac arrest.
      ,
      • Glikson M.
      • Lipchenca I.
      • Viskin S.
      • Ballman K.V.
      • Trusty J.M.
      • Gurevitz O.T.
      Long-term outcome of patients who received implantable cardioverter defibrillators for stable ventricular tachycardia.
      Böcker et al.
      • Böcker D.
      • Block M.
      • Isbruch F.
      • et al.
      Benefits of treatment with implantable cardioverter-defibrillators in patients with stable ventricular tachycardia without cardiac arrest.
      studied 50 such patients (82% ischemic cardiomyopathy, mean LVEF 0.39 ± 0.16 ), who had received ICDs after failure to identify predicted effective AAD therapy. Their 2-year actuarial probability of any ICD-treated VT/VF was 77%. Their 2-year actuarial probability of unstable VT/VF (VF or VT with a cycle length both < 250 ms and > 50 ms less than the baseline VT) was 29%. Data specific to patients with relatively preserved LVEF was not provided. Glikson et al.
      • Glikson M.
      • Lipchenca I.
      • Viskin S.
      • Ballman K.V.
      • Trusty J.M.
      • Gurevitz O.T.
      Long-term outcome of patients who received implantable cardioverter defibrillators for stable ventricular tachycardia.
      studied 82 such patients (89% ischemic cardiomyopathy, mean LVEF 0.32 ± 0.11) who had received ICDs. Their degree of AAD resistance was not specified, although 28% were receiving AADs at the time of their hemodynamically stable VT. Their 2-year actuarial probability of any ICD-treated VT/VF was 67%. Their 2-year actuarial probability of hemodynamically unstable VT/VF (VF or VT with a cycle length > 100 ms less than the baseline VT or 50 ms less than the baseline VT if the resulting cycle length was < 300 ms) was 12%. Seventeen patients had LVEFs ≥ 0.40. They had 4-year actuarial probabilities of any ICD-treated VT/VF of 80% and of hemodynamically unstable VT/VF of 11%. The 56 patients with LVEFs of < 0.40 had 4-year actuarial probabilities of any ICD-treated VT/VF of 76% and of hemodynamically unstable VT/VF of 29%. The difference in rates of hemodynamically unstable VT/VF did not reach statistical significance (P = 0.29), “probably because of the small number of subjects.”
      • Glikson M.
      • Lipchenca I.
      • Viskin S.
      • Ballman K.V.
      • Trusty J.M.
      • Gurevitz O.T.
      Long-term outcome of patients who received implantable cardioverter defibrillators for stable ventricular tachycardia.
      Guidelines are relatively silent regarding patients with hemodynamically stable VT, ischemic or nonischemic cardiomyopathy, and LVEF ≥ 0.40. European Society of Cardiology (ESC)
      • Priori S.G.
      • Blomström-Lundqvist C.
      • Mazzanti A.
      • et al.
      2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.
      guidelines provide a Class IIa/Level of Evidence C recommendation for ICDs in such patients, without specifically mentioning patients with hemodynamically stable VT; American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS)
      • Al-Khatib S.M.
      • Stevenson W.G.
      • Ackerman M.J.
      • et al.
      2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
      guidelines provide a Class I/Level of Evidence B-NR recommendation for ICDs in such patients, without specifically mentioning patients with relatively preserved LVEF; and Canadian Cardiovascular Society (CCS)
      • Bennett M.
      • Parkash R.
      • Nery P.
      • et al.
      Canadian Cardiovascular Society/Canadian Heart Rhythm Society 2016 implantable cardioverter defibrillator guidelines.
      ,
      • Deyell M.W.
      • AbdelWahab A.
      • Angaran P.
      • et al.
      2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society position statement on the management of ventricular tachycardia and fibrillation in patients with structural heart disease.
      guidelines provide a Strong Recommendation/Moderate-Quality Evidence guideline for ICDs in such patients, without specifically mentioning patients with either hemodynamically stable VT or patients with relatively preserved LVEF.

      A More Focused Reassessment

      In this issue of the Canadian Journal of Cardiology, Gula et al.
      • Gula L.J.
      • Frydman A.
      • Khan H.R.
      • et al.
      Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.
      provide additional data relative to recurrence of VT/VF from 64 patients with cardiomyopathy and LVEF 0.36 to 0.49 who had received ICDs after hemodynamically stable VT. The primary outcome variable was the first occurrence of ICD-treated VT/VF following a 7-day blanking period after ICD placement. Their major findings were that such patients have high probability of ICD-treated VT/VF (2-year actuarial probability of 55%); such patients have high probability of shock-treated VT/VF (2-year actuarial probability of 20%); the mean rate of recurrent VT/VF (199 ± 37 beats per minute [bpm]) in the 37 patients with VT/VF recurrence was statistically significantly faster (P = 0.048) than their baseline VT (183 ± 27 bpm); and no clinical variables were identified that independently predicted recurrent VT/VF.

      Comparison to Existing Literature

      Frequent recurrence of VT in the patients of Gula et al.
      • Gula L.J.
      • Frydman A.
      • Khan H.R.
      • et al.
      Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.
      is expected, as the arrhythmogenic substrate for hemodynamically stable VT in most patients with cardiomyopathy includes a continuously present re-entrant circuit that will sustain VT when initiated by a trigger. The 2-year actuarial incidence of any ICD-treated VT/VF reported by Gula et al.
      • Gula L.J.
      • Frydman A.
      • Khan H.R.
      • et al.
      Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.
      (55%) appears to be less than previously reported by Böcker et al.
      • Böcker D.
      • Block M.
      • Isbruch F.
      • et al.
      Benefits of treatment with implantable cardioverter-defibrillators in patients with stable ventricular tachycardia without cardiac arrest.
      (77%) and by Glikson et al.
      • Glikson M.
      • Lipchenca I.
      • Viskin S.
      • Ballman K.V.
      • Trusty J.M.
      • Gurevitz O.T.
      Long-term outcome of patients who received implantable cardioverter defibrillators for stable ventricular tachycardia.
      (67%). This may reflect either interim improvement in patient prognosis and ICD technology or that Gula et al.
      • Gula L.J.
      • Frydman A.
      • Khan H.R.
      • et al.
      Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.
      restricted their study to patients with relatively preserved LVEF. The only previous comparable study of patients with both stable VT and relatively preserved LVEF, comprising 17 patients, reported a 4-year actuarial incidence of any ICD-treated VT/VF of 80% (if linearity is assumed, 40% after 2 years).
      • Glikson M.
      • Lipchenca I.
      • Viskin S.
      • Ballman K.V.
      • Trusty J.M.
      • Gurevitz O.T.
      Long-term outcome of patients who received implantable cardioverter defibrillators for stable ventricular tachycardia.
      Note that the study of Gula et al.
      • Gula L.J.
      • Frydman A.
      • Khan H.R.
      • et al.
      Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.
      shares bias of previous studies of having included many patients with demonstrated resistance to AAD. Whether or not these recurrence rates are representative of drug-naïve patients with hemodynamically stable VT and relatively preserved LVEF cannot be determined from available data. Nevertheless, the study of Gula et al.
      • Gula L.J.
      • Frydman A.
      • Khan H.R.
      • et al.
      Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.
      nearly triples the number of published patients with hemodynamically stable VT, cardiomyopathy, and relatively preserved LVEF addressing the natural history of VT/VF recurrence.
      The presence of a continuously present re-entrant circuit capable of supporting stable VT predicts that recurrent VTs should have the same rate as the baseline VT in the absence of therapy changes. Indeed, in patients with LVEF ≥ 0.40 and VT/VF, more than 90% of recurrent VT/VF have a cycle length within 30 msec of the baseline VT/VF.
      • Mondésert B.
      • Khairy P.
      • Schram G.
      • et al.
      Impact of revascularization in patients with sustained ventricular arrhythmias, prior myocardial infarction, and preserved left ventricular ejection fraction.
      Nevertheless, there remains a worrisome possibility of a recurrent VT/VF with a faster rate that could be life threatening. As discussed earlier, based on 17 patients, the 4-year actuarial probability of hemodynamically unstable ICD-treated VT/VF was 11% in patients with stable VT, cardiomyopathy, and LVEF ≥ 0.40.
      • Glikson M.
      • Lipchenca I.
      • Viskin S.
      • Ballman K.V.
      • Trusty J.M.
      • Gurevitz O.T.
      Long-term outcome of patients who received implantable cardioverter defibrillators for stable ventricular tachycardia.
      Three patients (4.7%) in the study of Gula et al.
      • Gula L.J.
      • Frydman A.
      • Khan H.R.
      • et al.
      Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.
      had unstable VT/VF as defined by Böcker et al.
      • Böcker D.
      • Block M.
      • Isbruch F.
      • et al.
      Benefits of treatment with implantable cardioverter-defibrillators in patients with stable ventricular tachycardia without cardiac arrest.
      over a median follow-up of 827 days, translating into a 5-year probability of potentially life-threatening VT/VF of approximately 8.5% (likely an underestimate, as Gula et al.
      • Gula L.J.
      • Frydman A.
      • Khan H.R.
      • et al.
      Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.
      only considered first recurrences of VT/VF). This rate is greater than the ≥ 6% estimated 5-year rate of SCD used by ESC
      • Priori S.G.
      • Blomström-Lundqvist C.
      • Mazzanti A.
      • et al.
      2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.
      guidelines to recommend a Class IIa/Level of Evidence B recommendation for an ICD when considering precision medicine in individualized patients. Nevertheless, we must recognize the dangers of equating presumed life-threatening ICD-treated VT/VF with SCD.
      Gula et al.
      • Gula L.J.
      • Frydman A.
      • Khan H.R.
      • et al.
      Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.
      also provide novel evidence of a statistically significant increase in the rate of VT/VF over time in patients with stable VT, cardiomyopathy, and relatively preserved LVEF. Nevertheless, the extent to which changes in ADD therapy contributed to this observation cannot be determined from available data.

      Future Research and Practice Implications

      The study of Gula et al.
      • Gula L.J.
      • Frydman A.
      • Khan H.R.
      • et al.
      Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.
      provides weak support for placement of ICDs in patients with stable VT, cardiomyopathy, and relatively preserved LVEF, particularly in patients with demonstrated resistance to AAD. Nevertheless, further research is clearly required, including prospective observational studies focused on patients early in their course before demonstrated AAD resistance that consider all recurrences of VT/VF following guidelines for high-quality observational trials.
      • von Elm E.
      • Altman D.G.
      • Egger M.
      • et al.
      STROBE Initiative
      The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
      Nevertheless, whether or not such patients truly benefit from ICD placement can only be determined by an appropriately designed randomized clinical trial, if, indeed, such a trial is feasible. Meanwhile, other approaches to reducing the risk of SCD in patients with cardiomyopathy and relatively preserved LVEF are focusing on identifying markers of increased SCD risk other than previous hemodynamically stable VT/VF and randomizing the population, so chosen, in a clinical trial of ICD therapy. One such ongoing study, the Risk Estimation Following Infarction Noninvasive Evaluation-ICD (REFINE-ICD) trial (NCT00673842) is randomizing patients with myocardial infarction (MI) and LVEF 0.36 to 0.49 to usual care vs usual care plus ICDs. Study patients are selected based on both abnormal Holter-based T-wave alternans and abnormal Holter-based heart-rate turbulence, predicting ∼9-fold higher risk of mortality. Enrollment in Refine-ICD is anticipated to be complete in the next 12 months, and it will provide much needed evidence on the optimal care for these patients.

      Funding Sources

      No funding has been provided for this article.

      Disclosures

      Dr Mitchell has a consulting or advisory relationship with Medtronic Inc. Dr Exner has a consulting or advisory relationship with Abbott that includes funding grants and a relationship with GE Healthcare that includes consulting or advisory and funding grants; he reports a consulting or advisory relationship with Medtronic Inc that includes funding grants and a relationship with Helpwear that includes equity or stocks. He has patents issued to GE Medical and Helpwear.

      References

        • Kuriachan V.P.
        • Sumner G.L.
        • Mitchell L.B.
        Sudden cardiac death.
        Curr Probl Cardiol. 2015; 40: 133-200
        • Connolly S.J.
        • Hallstrom A.P.
        • Cappato R.
        • et al.
        Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials.
        Eur Heart J. 2000; 21: 2071-2078
        • Persson R.
        • Earley A.
        • Garlitski A.C.
        • Balk E.M.
        • Uhlig K.
        Adverse events following implantable cardioverter defibrillator implantation: a systematic review.
        J Interv Card Electrophysiol. 2014; 40: 191-205
        • Kołodziejczak M.
        • Andreotti F.
        • Kowalewski M.
        • et al.
        Implantable cardioverter-defibrillators for primary prevention in patients with ischemic or nonischemic cardiomyopathy: a systematic review and meta-analysis.
        Ann Intern Med. 2017; 167: 103-111
        • Brugada P.
        • Talajic M.
        • Smeets J.
        • Mulleneers R.
        • Wellens H.J.
        The value of the clinical history to assess prognosis of patients with ventricular tachycardia or ventricular fibrillation after myocardial infarction.
        Eur Heart J. 1989; 10: 747-752
        • Sarter B.H.
        • Finkle J.K.
        • Gerszten R.E.
        • Buxton A.E.
        What is the risk of sudden cardiac death in patients presenting with hemodynamically stable sustained ventricular tachycardia after myocardial infarction?.
        J Am Coll Cardiol. 1996; 28: 122-129
        • Olshansky B.
        • Hahn E.A.
        • Hartz V.L.
        • Prater S.P.
        • Mason J.W.
        ESVEM Investigators: Clinical significance of syncope in the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial.
        Am Heart J. 1999; 137: 878-886
        • Olson P.J.
        • Woelfel A.
        • Simpson Jr., R.J.
        • Foster J.R.
        Stratification of sudden death risk in patients receiving long-term amiodarone treatment for sustained ventricular tachycardia or ventricular fibrillation.
        Am J Cardiol. 1993; 71: 823-826
        • Böcker D.
        • Block M.
        • Isbruch F.
        • et al.
        Benefits of treatment with implantable cardioverter-defibrillators in patients with stable ventricular tachycardia without cardiac arrest.
        Br Heart J. 1995; 73: 158-163
        • Glikson M.
        • Lipchenca I.
        • Viskin S.
        • Ballman K.V.
        • Trusty J.M.
        • Gurevitz O.T.
        Long-term outcome of patients who received implantable cardioverter defibrillators for stable ventricular tachycardia.
        J Cardiovasc Electrophysiol. 2004; 15: 658-664
        • Priori S.G.
        • Blomström-Lundqvist C.
        • Mazzanti A.
        • et al.
        2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.
        Eur Heart J. 2015; 36: 2793-2867
        • Al-Khatib S.M.
        • Stevenson W.G.
        • Ackerman M.J.
        • et al.
        2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.
        J Am Coll Cardiol. 2018; 72: e91-e220
        • Bennett M.
        • Parkash R.
        • Nery P.
        • et al.
        Canadian Cardiovascular Society/Canadian Heart Rhythm Society 2016 implantable cardioverter defibrillator guidelines.
        Can J Cardiol. 2017; 33: 174-188
        • Deyell M.W.
        • AbdelWahab A.
        • Angaran P.
        • et al.
        2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society position statement on the management of ventricular tachycardia and fibrillation in patients with structural heart disease.
        Can J Cardiol. 2020; 36: 822-836
        • Gula L.J.
        • Frydman A.
        • Khan H.R.
        • et al.
        Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.
        Can J Cardiol. 2022; 38: 1271-1276
        • Mondésert B.
        • Khairy P.
        • Schram G.
        • et al.
        Impact of revascularization in patients with sustained ventricular arrhythmias, prior myocardial infarction, and preserved left ventricular ejection fraction.
        Heart Rhythm. 2016; 13: 1221-1227
        • von Elm E.
        • Altman D.G.
        • Egger M.
        • et al.
        • STROBE Initiative
        The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
        Int J Surg. 2014; 12: 1495-1499

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