Impact of the Implantable Defibrillator on Mortality: The Axiom of Overall Implantable Cardioverter-Defibrillator Survival

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of the Implantable Defibrillator on Mortality: The Axiom of Overall ~mplantable Cardioverter-Defibrillator Survival Richard N. Fogoros, MD

As soonas itwasestablished thattheimplantable cardiove~r-defibrillator(lCD)effectively preventssudden death,it becameaxiomaticthatwhetherIhe ICD W-II prolongoverallsurvivaldependsentiretyon thepopulationof @ients to whichit is applied.Thisaxiomof overallICD survivalimmediately reveaktheonly vital questionthat remainsregardingusageof the ICD; namely,How doesone selectthosepatientsin whom prevention of suddendeathby theICDwillalsoprolong life?Thisaxiomalsorevealsthe essential futilityof rcmdomizedtrialsnowbeingconducted for thepurposeof discerning thetrueefficaey of theICD.Claimstothescientifichighgroundnotwithstanding, if a studydcs the

wrongquestionfromthebeginning,thenthedesignof thatstudy(including whetherthestudyis n?ndomized or nonrandomized),is completelyirrelwant. ideally, funds now being spenton theserandomizedkials shouldbe divertedto thedesignand initiationof more appropriatetrials,trialsthatwill teachus to selectpatients fortheICDmoreeffectively. Attheveryleast,however,we shouldrecognize theproblemsinherentin the ongoingti-als,sothatwhentheirresults arefinallypublished(andare loudlytoukdby whichwerfactionfeels vindicated by them), we will notbe carriedaway into inappropriate clinicalbehavior. (AmJCardiol1996;78(suppl5A):57-61)

he implantable cardioverter defibrillator (ICD) is T universally acknowledged to be the most effective therapy available for preventing sudden death

total mortality is the primary endpoint. Although objections to these trials have been raised, centering on both design and ethical issues, “’15proponents of the trials have remained steadfast in insisting on randomized studies to document the effect of the ICD on total survival.16-18 The present article will attempt to examine the issue of the ICD and overall survival at a more fundamental level. If one begins with what is known (or given) about the ICD, namely, that it prevents sudden death from ventricular tachyarrhythmias, then the relationship between the ICD and overall survival can be stated as an axiom. By examining the implications of this axiom and its corollaries, it becomes apparent that the aforementioned trials are based on an inappropriate hypothesis and are therefore of highly questionable value, whatever the scientific merit of their randomized designs. In addition, the axiom of overall ZCD survival suggests the sorts of randomized trials that might be of help in directing the appropriate use of this expensive technology.

from ventricular tachyarrhythmias. Still, controversy remains as to whether this device prolongs the overall survival of its recipients. The effect of the ICD on total mortality is an important question since, if overall survival is not improved, it matters little whether sudden death has been prevented. It is also a timely question. Regulatory agencies and thirdparty payers, observing the expanding use of these expensive devices, are justifiably interested in evidence of the true efficacy of the ICD. Several authors have argued that the ICD already has convincingly demonstrated its ability to prolong survival, citing several observational series ‘-7 to make their point. Others, claiming the scientific high ground, have entirely dismissed the validity of such nonrandomized data and have insisted that proof of the ability of the ICD to prolong life must come only from randomized trials.8-11The argument for randomized trials has been compelling enough for at least 3 randomized, prospective trials to have been initiated to address the issue of overall survival with the ICD: the Antiarrhythmics Versus Implantable Defibrillator study (AVID),ll the Cardiac Arrest Study in Hamburg (CASH),12 the Canadian Implantable Defibrillator Study (CIDS ) .13In all 3 trials, patients with ventricular tachyarrhythmias are being randomized to therapy with the ICD or with antiar-, rhythmic drugs (predominantly, amiodarone), and From the Departmentof Medicine, Medical College of Pennsylvania and Hahnemann Universi~, Allegheny General Hospital, Pittsburgh, Pennsylvania. Address far reprints: Richard N. Fogoras, MD, Departmentof Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania.

@ 1996 by ExcerptaMedica,Inc. All rights resewed.

WHAT IS KNOWN ABOUT THE ICD: THE IMPACT OF THE ICD ON SUDDEN DEATH

That the ICD prevents sudden death, and does so more effectively than any other therapy, is clear and inarguable. Aside from countless eyewitness accounts of cardiac arrests being aborted by ICDS,published reports have, from the very beginning, clearly documented the remarkable effectiveness of this devic~4/..2$erminating lethal ventricular arrhythmias. ‘ ‘ Table I shows results from the first decade of the clinical use of the ICD. In the 1980s (before tieredtherapy devices were available), patients treated 0002-9149/96/$15.00 Pll S0002-9149(96)00503-6

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Corollary1:Any statement describing the efficacy of the ICD in prolonging overall survival must include a description of the population being treated. Follow-up (%) From this corollary, the statement, “The ICD does (or does not) prolong overall survival’ has no mean1 Year 2 Years 5 Years No. Patients ing. This statement incorrectly attributes to the ICD Borbola et al’9 25 0 itself a property that exists only in regard to a specific 91 <2 Kelleyet alzo population of patients. A correct version of such a 0 Monolis et alz’ 77 0 4 Veltri et alzz 163 statement would be “Zn Population X, the ICD does Fogaras et a14 70 1 A (or does not) prolong overall survival.” 270 4 Winkle et alz 1 Corollary2: If a clinical trial is performed in which Thomas et a123 3,610 2 6 the ICD results in no overall improvement in survival, then either the risk of sudden death in the population being studied was relatively low or the risk with ICDS almost universally had histories of susof death from other causes was relatively high, or tained, drug-resistant ventricular tachyarrhythmias that had caused a cardiac arrest, syncope, or some both. From this corollary, a study showing no overall other manifestation of severe hemodynamic compro- benefit with the ICD would imply nothing about the mise. UIJ to 40% of such r)atients experience recur- ICD itself, only about the population in which it was rent life~~eatening arrh~thmias du~ng the first 2 used. years of follow-upZ’25and, if treated without an ICD, have almost an 80% chance of dying suddenly with THE EFFECT OF THE ICD ON their next recurrence.4’26As shown, in patients who IDEALIZED ~PUIATIONS received the ICD the incidence of sudden death was As an illustration of the axiom of overall ICD reduced to <270 at 1 year and s690 at 5 years. Thus, survival, it is possible to deduce how the ICD by the late 1980s, accumulated data from around the would impact qualitatively on certain idealized world provided ample proof that the ICD was highly populations of patients. Figures 1–3 depict the risk effective at doing exactly what it was designed to do of dying, over time t,in 3 such idealized populaand that no other therapy provided the same level of tions. Specifically, these figures illustrate the magprotection against sudden death. nitude of—and the relationship between—the risk of sudden death and the risk of death from all other causes. From these figures, one can easily visualize THE AXIOM OF OVERALL ICD the potential impact of the ICD on overall survival SURVIVAL That fact that the ICD prevents sudden death over time t. In Population 1 (Figure 1), analogous to the popleads immediately to a truth that is so self-evident ulation at large, the risk (over time t)of both sudden and indisputable as to constitute an axiom: In a given population of patients followed for a death and death from all other causes is low. Imgiven period of time, the ICD will measurably pro- planting ICDS in such a population of patients will long overall survival as long as the risk of sudden not measurably improve overall survival. Patients in Population 2 (Figure 2) carry a high death from l~e-threatening ventricular tachyarrhythmias is sufficiently greater than the risk of dy- risk of sudden death but a relatively low risk of death from other causes. Such a risk profile might ing from all other causes combined. Stated more simply: the ability of the ICD to be seen, for instance, in patients whose electrical measurably prolong overall survival depends— disease predominates (at least in terms of risk) completely and solely—on the population of pa- over their structural heart disease. In such a poptients to which it is applied. This axiom of overall ulation it is evident that the ICD would signifiICD survival, in turn, immediately suggests 2 cor- cantly improve overall survival. It should be noted, ollaries that are relevant to the ongoing random- however, that even in these patients the ability of the ICD to measurably improve survival is highly ized trials (Table II). TABLE I Incidenceof Sudden Death in High-Risk Patients with Irnrdantable Cordioverter-Defibrillators

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TABLE II The Axiom of Overall Implantable Cardioverter-Defibrillator Survival and Its Corollaries Given: The implantable cardioverterdefibrillator (lCD) prevents sudden death from ventricular tachyarrhythmias. Therefore, in a given population followed for a given period of time, the ICD will measurably prolong overall survival whenever the risk of sudden death from ventricular tachyarrhythmias is sufficiently greater than the risk of dying from all other causes combined. Thus: Axiom:The ability of the ICD to measurably prolong overall survival over a given period of time depends, completelyand solely, on the population of patients to which it is applied. Corollary 1: Any statementdescribing the efficacy of the ICD in prolonging overall survival is meaningless unless it includes a description of the population of patients being treated. Corollary 2: If a clinical trial is performed in which the ICD has affected no measurable prolongation in overall survival, then one of the following is true: (a) the risk of sudden death in the study population was relatively low over the time of the trial; (b) the risk of death from other causes was relatively high over the time of the trial; or (c) both.

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Population1

Population3

0 FIGURE 1.InPopdatian1,therisksof bd suddendeathand nonsudden deathovertimef arwrelatively small,asrepresented by theareaof therectangle. Theimpfcmtable deWriilator would notmeasum improve ovemllsurvival inthispopulation. lhe risk bin% isIi ureismostIi representative of therisk Prafi?% thepopu?afion atlarge. % riskof suddendeathis rearesentucf bv he shadedcircle, andtheriskofdeathfromall by tkeopencircle. otker causes i; represented

FIGURE 3. InPapufation 3, theriskof wcfden deathagainis high.However, inthesepatients theriskof nonsudden deathis evenhigherthan,andI “~~a*p’’briskdsuwen&* s overlqp represents patients athigh“ TheareainwhichtheCIK riskforbothsuddenandnonsudden decrth. Although implantaMecardiav#er-Mb”llatorscouldbeexpeckdtoprevent numerous eaisodes of suddendeathinthisaoaulaiion, ovemllsur-

~-l~~*~rn-sum~irnd~ny*n~~*

end-stage cardiac lobe wou hkefyfitsucha nskprdle.

Population2

Population4

0 FIGURE 2. in Population 2, theriskof sudden deathovertimefis relatively large[shaded circle) andissubstantially largerthanthe riskof nonsudden death(mencircle]. TheimrJantable delMwilfatorwouldsignificantly impbvetill survival inthispopulapatienkwhoseelectrical cardiac disease tion,whichrepresents predominotsrs overstructuml cardiac disease.

dependent on time t.If the follow-up time is too short, the relative risk of sudden death for this population will resemble that of Population 1, and no benefit from the ICD will be demonstrable. Population 3 (Figure 3), like Population 2, also carries a substantial risk of sudden death. However, here the risk of all-cause death during time t is even higher than— and largely overlaps—the risk of sudden death (meaning that there are many patients who are at high risk for both events, and in whom death is still likely even if sudden death is prevented). Although ICDSmay prevent numerous episodes of sudden death in Population 3, overall survival would not be measurably improved. Many patients with severe

FIGURE 4. Although Populations 1-3 represent idealized populationsof tients, Population 4 represe o&tksnkcornmodymferredt%&&*y%~~for %%&nkdorsuspectecventricukrrtachyarrhythmias.These R:”::srcYA%Y,:2*g::s&:!:i:r&in cardiac andother ri&brmnsu*nd~~~~”&(~7~*%,~~’ viewedasbeinga composite of Populations 1-3. Theeffect of theim antabfe cardioverter-defibriffator (lCD)on prolonging ovemlsurvival ? inthispopulation woulddependonthemixture of patienk“s&ted” toreceive theICD.

end-stage cardiac disease would likely fit such a risk profile. These examples clearly demonstrate how the ability of the ICD to prolong overall survival is intrinsically dependent on the population to which it is being applied. In Population 1 or Population 3, the ICD will not prolong overall survival. In Population 2, the ICD will prolong overall survival, as long as one is willing to wait for time t. A SYMPOSIUM:

ICD THERAPY

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EFFECT OF KDs POPULATIONS

ON

CLINICAL

entire population. The issue is how one can identify those patients in whom the ICD will prolong life and those in whom it offers little benefit. In attempting to make the use of the ICD both medically correct and fiscally sound, this is where limited research funds should be directed. From the foregoing analysis, spending money, energy, and time on the ongoing randomized trials can be seen as unwise. Yet, these trials carry an implication that is even more disturbing than being wasteful of precious resources; namely that, despite the basic flaw in their design, they are widely advertised as gathering definitiveevidence of the ICD’s efficacy (or lack thereof). This inappropriate expectation invites—and almost demands—the inappropriate use of the results, whichever way those results turn out. Proponents of these trials, for instance, have all but announced that a negative result will essentially prove that the apparent efficacy of the ICD is but an illusion. The government and other payers will predictably latch onto this notion, and usage of the ICD will be inappropriately stifled. On the other hand, if the results are positive for the ICD (since it is unlikely that a positive result will be treated any more temperately than a negative result), usage of the ICD will be inappropriately encouraged (though in this case, presumably, by parties other than the government and insurers). Thus, not only is it difficult to see how these trials will lead to any useful information, it is also difficult to see how they will lead to anything but harm to patients.

Patients commonly referred to electrophysiologists for documented or suspected ventricular tachyarrhythmias do not fit into any of these idealized populations. “Real” patients comprise a heterogeneous group. They have varying degrees of ventricular tachyarrhythmias (and therefore a spectrum of risks for sudden death) and varying degrees of underlying cardiac and other organic disease (and, thus, a spectrum of risks for nonarrhythmic death). In fact, the typical population of patients presenting with ventricular arrhythmias can be viewed as being a composite of Populations 1–3 (shown as Population 4 in Figure 4). This composite group carries both a substantial risk of sudden death and a substantial risk of death from other causes, and these 2 risks partially overlap (so that some patients are at high risk for both events and some are not). Will the ICD improve overall survival in such a population? The answer is: it depends. It depends on the absolute and relative magnitudes of risk for sudden and nonsudden death, as well as the degree of overlap of those risks. In other words, the overall survival that one measures depends on the precise mixture of patients in the sample being measured. Thus, a major problem becomes apparent in designing a clinical trial to measure the effect of the ICD on a population resembling Population 4: the results will be directly determined by how one selects patients for enrollment into the trial. If relatively few patients from the Population 2 subset are enrolled (either by design, by chance, or by covert preelection) or, alternatively, if the time of follow- 1. Tchou PJ, Kadri N, Anderson J, Caceres JA, Jazayeri M, Akfrtar M. Autoup is not sufficient for the risk of sudden death in matic implarrtable curdioverter defibriflators arrd survival of patients with left that subset to manifest itself, then the ICD will fail ventricular dysfunction and maligrraut ventricular arrhythmias. Arm Intern Med to affect a measurable prolongation in overall sur- 2.1988;109:529-534. Wirrkle R, Mead H, Ruder MA, Gaudiarri VA, SnrhfrNA, Buch WS, Scbmidt vival. On the other hand, if patients from the Popu- P, ShipmarrT. Long-term outcome with the automatic implantable cardioverterAm J Coil Cardiol 1989;13:1353–1361. lation 2 subset are enrolled in sufficient proportion, defibrillator. 3. Foguros RN, Elson JJ, Bomet CA, Fiedler SB, Burkholder JA. Efficacy of the and are followed for a sufficient time, then an im- automatic irnphrrrtablecardioverterdefibriflator irr prulongiag survival in patients proved overall survival will be measurable. Depend- with severe urrderlyiagcardiac disease. JAm Co/l CarrJiol 1993;16:381–386. Fogoros RN, Elson JJ, Bonnet CA, Fiedler SB, Chenarides JG. Long-term ing on the vagaries both of study design and of pa- 4.outcome of survivors of cardiac arrest whose therapy is guided by electrophystient selection, the results of such a trial could easily iologic testing. JAm CM Cardiol 1992;19:780–788. come out either way—and either way, those results 5. Newmarr D, Sauve MJ, Herre J, Larrgberg JJ, Lee MA, Titus C, Franklin J, Scheinman MM. Survival titer implantation of the curdioverter defibrillator. would not tell us about the efficacy of the ICD. In- Am J Cardiol 1992;69:899–903. stead, theresults would tell us only about our usage 6. Becker D, Block M, Isbruch F, Wietfrolt D, Hammel D, Borggrefe M, BreiG. Do patients with arr implarrtable defibrillator live longer? J Am Coil of the ICD—whether we managed to enroll enough tbardt Cardiol 1993;21:1638-1644. patients from the Population 2 subset to affect over- 7. Powell A, Fuchs T, Firrkelstein DM, Garan H, Canrrom DS, McGoverrr BA, all results. Even if patients were somehow enrolled Kelly E, Vkdrakes GJ, Torchiarra DF, Ruskirr JN. Influence of impkmtable cudioverter-defibrillators on the long-term prognosis of survivors of out-of-hosin perfect proportion to their actual prevalence in pital curdiac arrest. Circulation 1993;88:1083–1092. Population 4 (leaving aside the issue of how the tar- 8. F.rrrma S. AICD Benefit. PACE 1989;12:399-400. get population is defined in the first place), the re- 9. Kim S. Implaatable defibrillator therapy: does it really prolong life? How carr we prove it? Am J COUCardiol 1993;71:1213-1218. sults still would reflect merely an average prolon- 10.Cormolly S, Yusuf S. Ewduation oftbe irnplantable cardioverterdefibrillator gation of survival in a heterogeneous group. This sort in survivors of curdiac urrest: the need for raadornized triafs. Am J Cardiol of data might be interesting to some, but it is difficult 1992;69:959-962. 11. Green HL. Arrtiarrhythmic drugs versus implarrtable defibrillator: the need to see how it would be of practical use to anybody. for a randomized controlled study. Am Heart J 1993;127:1171-1178. Thus does the axiom of overall ZCDsurvival lead 12. Siebels J, Cappato R, Ruppel R, Schneider MAE, Kuck KH, and the CASH Preliminary results of the Cardiac Arrest Study Hamburg to the crux of the matter. When one is presented with Investigators. (CASH). Am J Cardiol 1993;72(suPP1):109F- 113F. a heterogeneous population of patients—a popula- 13. Connolly SJ, Gent M, Roberts RS, Dorian P, Green MS, Klein GJ, Mitchell Shelton RS, Roy D, and the CIDS Co-Investigators. Carradian Implantable tion consisting of definable (and potentially identi- LB, Defibrillator Study (CIDS): study design arrd organization. Am J Cardirrl fiable) subgroups that respond very differently to 1993;72(suPP1) :103F–1O8F. therapy—the issue is not the average response of the 14. Fogoros RN. An AVID dissent. (Editorial.) PACE 1994;17:1707-1710. 60

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15. Fogoros RN. RepIy to the Editor. PACE 1995:18:748-749. 16. Epstein A. AVID necessity. (Editorial.) PACE 1994;16:1773–1775. 17. Hallstrom A. Letter to the Editor. PACE 1995;18:747. 18. Connolly S. An AVID dissent: commentary. PACE 1994;17:1712–1713. 19. Borbola J, Denes P, Ezri MS, Hauser RG, Serry C, Goldin MD. The automatic impkmtable cardioverter-defibrillator: clinical experience, complications, and follow-up in 25 patients. Arch Intern Med 1988;148:70–76. 20. Kelley PA, Cannom DS, Guran H, Mirabal GS, Hawthorne JW, Hrrrvitz RJ, Vluhakes GJ, Jacobs ML, Ilvento JP, Buckley MJ, Ruskin JN. The automatic implantable cardioverter-defibrillator: efficacy, complications and survival in patients with malignant ventricular arrhythmias. J Am Coil Cardiol 1988;11:1278–1286, 21. Manolis AS, Tarr-DeGuzmurrW, Lee MA, Rastegar H, Haffajee CI, Huang SKS, Estes NAM. Clinical experience in seventy-seven patients with the automatic impluntable curdioverter-defibrillator. Arn Heart J 1989;118:445-450. 22. Veltri EP, Mower MM, Mirowski M, Juarrteguy J, Watkins L, Levine JH, GrrurrrieriT, Reid PR, Griffith LSC. Follow-up of patients with verrtriculatachynrrhythmias treated with the automatic implantable cardioverter defibrillator: programmed electrical stimulation results do not predict clinical outcome. J Electrophysiol 1989;3:467–476. 23. Thomas AC, Moser SA, Smutka ML, Wilson PA. Implantabledetibrillation: eight years clinical experience. PACE 1988;11:2053–2058. 24. Wilber JD, Gararr H, Finkelstein D, Kelly E, Newell J, McGovern B, Ruskirr JN. Out-of-hospital curdiac arrest: use of electrophysiologic testirrg in the prediction of long-term outcome. N Engl JMed 1988;318:19–24. 25. Fumkawa T, Rozanski JJ, Nogarni A, Moroe K, Gosselin AJ, Lister JW. Time-dependent risk of und predictors of curdiac arrest recurrence in survivors of out-of-hospital cardiac urrest with chronic cororruryartery disease. CircuJatirm 1989;80:599–608. 26. Fogoros RN, Fiedler SJ, Elson JJ. The automatic implantable cardioverterdefibrillator in dreg-refractory ventricular tachyamhythmias. Ann Intern Med 1987;107:635–641.

DISCUSSION

Dr. Levy (Marseilles, France): You say the time should be long enough to show in a specific population that the device does decrease mortality. However, if we wait sufficiently long, the patient may die from other causes, and therefore, it may not show that it has contributed to increased survival. Thus time may work both ways. Dr. Fogoros(Pittsburgh,PA, USA): Yes, that is just another way of saying that if you wait long enough, death from nonarrhythmiccausesdominates.So designing these studiesis very tricky,and resultsdependheavily on such vagaries.The mere fact that a trial is randomized doesn’tmean it is necessarilya good trial. Dr. Raviele(Mestre (Venezia), Italy): What type of studies do you suggest to better identify patients belonging to population II (patients with high risk of sudden death, and low risk of death from other causes) ? Dr. Fogoros: This is a difficult question. I have an ethical problem randomizing patients in Population 2 because whether the ICD shows prolongationof survival or not in that group is solely dependent on the time of follow-up—as Sam Levy just said. So if we randomize Population 2 patients, using a 2-year endpoint, you are likely not to show much benefit from the ICD, but if you have a 10–20 year endpoint (for instance, in young survivors of sudden death) I think you will see a pronounced benefit. One study that might be consideredwould be to take the patientswho

were talked about earlier today,1 with a low ejection fraction and in whom overall there does not appear to be a major benefitfrom the ICD, and randomize them. Dr. Raviele: What l@d of patients do you implant in your clinical practice now? Dr. Forogos: We wind up putting ICDS in about 60% of our sudden death survivors, based largely on clinical factors. I use functional capacity, not ejection fraction. If we are considering an ICD because the arrhythmia justifies it, we ask ourselves, What is this person’s chance of being alive in 1–2 years, if they don’t die suddenly? I believe we are pretty good at guessing, based just on the overall clinical situation, and I am afraid that randomized trials will not help us much beyond that. Dr. Farr6 (Madrid, Spain): Several presenters today have referred to the Sweeney publication] but have not mentioned some details also not discussed by the authors. That study consisted of patients referred for heart transplant, of whom only 50% finally got transpkmted. The global mortality at 1 year was the same in those who received “anICD and in those who did not. But after 1 year, the ICD group had a much better survival. It appears that in the first year, patients in NYHA class III–IV who could not get a heart transplant died. Whatever you do, if these patients do not get a new heart, they die—if not suddenly—of heart failure, and therefore in these patients an ICD is totally worthless. But for those who, despite having a very low ejection fraction ( ~20% ), ha~e a functional status that is not that bad, then the ICD increases survival, as seen in the figures of Sweeney et al: mortality was doublefor those who did not get an ZCD.l So I think the ICD plays an important role—as you said so very well—when you exclude those who are going to die of heart failure in the short term. Dr. P. Brugada (Aalst, Belgium): Dr. Fogoros, one of the many clinical parameters from your early study, and on which we also published, is syncopal VT, associated with a 25% incidence of sudden death without an ICD. In most patients with structural heart disease, don’t you think that we already have sufficient parameters -syncopal VT or VF, multiple infarctions? Do you think we need a randomized trial to identify such patients? Dr. Fogoros: I agree. We can take sudden death survivors and patients with syncopal VT and make good rational clinical decisions today without randomized trials. 1. Sweeney MO, Ruskin JN, Gamrr H, McGovern BA, Guy MI, Torchiarra DF, Vlahukes GJ, Newell JB, Sernigmrr MJ, Dec JW. Influence of the implarrtable cardioverter-defibrillator on sudden death and total mortality in patients evaluated for cardiac transplantation. Circuladon 1995;92:3273–3281.

A SYMPOSIUM:

ICD THERAPY

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