Do octogenarians benefit from primary prevention implantable cardiac defibrillators?

Dr Joanna Grogono (Clinical Research Fellow, Health and Life Sciences, Oxford Brookes University / Honorary ST6 Cardiology, John Radcliffe Hospital)
jogrogono@hotmail.com


Introduction

The benefit of implantable cardioverter-defibrillator (ICD) therapy in the primary prevention of sudden cardiac death in patients with a left ventricular ejection fraction (LVEF) <35% has been proven in randomised controlled trials1-3.  In primary prevention ICD trials the mean age of patients enrolled was <65yrs (MADIT-I4, MADIT-II2  and DEFINITE3had a combined mean age of 61years, and MUSTT5and SCD-HeFT6had a combined median age of 62years.)  The elderly are poorly represented in these trials with most studies only having a small minority or a total absence of octogenarians7.  The elderly included in these trials were also a highly selected group as shown in MADIT-II where few differences in sub-group characteristics were observed between <75 and >75years age groups2.  Guidelines have been developed from these randomised controlled trials with a lack of reference to age.  Registry data shows that increasing numbers of octogenarians are having ICDs implanted for primary prevention8-11.  However, a survey in the USA of over 1400 physicians noted that one quarter of physicians frequently withheld ICD referral because of age12

The benefit of ICDs is controversial in elderly patients.   Some studies suggested that it is effective treatment for life threatening arrhythmias irrespective of age13,14 however this has to be balanced with studies showing that mortality is higher in the elderly with an increase in non-arrhythmic death15,16 which may negate the benefit of ICD therapy.


The guidelines

In June 2014 NICE guidelines expanded the indication for defibrillator therapy without any reference to specific age limits (Table 1).

 

NYHA

QRS Duration

I

II

III

IV

<120 milliseconds

ICD if there is a high risk of sudden cardiac death

ICD and CRT not

clinically indicated

120–149 milliseconds

without LBBB

ICD

ICD

ICD

CRT-P

120–149 milliseconds with

LBBB

ICD

CRT-D

CRT-P or CRT-D

CRT-P

≥150 milliseconds with or

without LBBB

CRT-D

CRT-D

CRT-P or CRT-D

CRT-P

LBBB, left bundle branch block; NYHA, New York Heart Association

Table 1.  NICE guidelines. Treatment options with implantable cardioverter-defibrillator (ICD) or cardiac resynchronisation therapy (CRT) for people with heart failure who have left ventricular dysfunction with an LVEF of 35% or less (according to NYHA class, QRS duration and presence of LBBB).  CRT-P (pacemaker), or a CRT-D (defibrillator).

The 2013 Appropriate Use Criteria for Implantable Cardioverter-Defibrillators and Cardiac Resynchronization Therapy guidelines state that primary ICD implantation in patients >90years old is rarely appropriate if they are in NYHA Class I but may be appropriate if they are in NYHA class II-III or if they are 80-89years old.  They state that it is rarely appropriate in patients with life expectancy less than 1 year from cardiac or non-cardiac conditions but may be appropriate if they have a non-cardiac disease with life expectancy 1 to 2 years17.


The current situation

Real world data from 2 registries8,9 of primary and secondary prevention ICD implantation rates in the USA show that ~12% of patients are ≥80years.  The rates were lower in  Canadian10 and UK based registries18 at 8% and 5%, respectively. The majority of defibrillators were implanted for primary prevention in those ≥80years, with registry data showing that this accounts for approximately 77% of defibrillators19

As the population ages the number of elderly patients meeting the criteria for primary ICD implantation is increasing. Ruskin et al found that octogenarians fulfilled 28% of the population eligible for implantation19 (those with a diagnosis of ventricular tachycardia (VT), ventricular fibrillation (VF), ventricular flutter, or cardiac arrest, with previous myocardial infarction or congestive cardiac failure.) 

Elderly patients have a higher prevalence of coexisting conditions/comorbidities such as AF, hypertension, coronary artery disease, chronic lung disease, liver disease and cancer compared to their younger counterparts20,21.


Arrhythmias in the elderly

Do the elderly die of sudden cardiac death/ventricular arrhythmias and will an ICD potentially be of benefit?

It is difficult to obtain data solely for octogenarians as many trials use a different age range for ‘elderly’.  Both Fauchier et al21 (≥75yrs) and Yung et al10 (≥80yrs) found that  rates of appropriate therapy were similar in the older age groups compared to rates found in younger patients in primary prevention ICD implantation. Fauchier et al also showed the rates of inappropriate therapy were reduced in the elderly.


Mortality in the elderly

When discussing mortality it is important to consider that an appropriate shock does not equal a life saved.  For example, in SCD-HeFT 21% of patients had shocks appropriate for fast VT/VF yet the absolute mortality reduction at 5 years was only 7.2%6.  Also in the DEFINITE trial patients in the ICD group had double the shocks than there were fatal events in the control group, yet there was no survival benefit22

As to be expected age is an independent risk factor for mortality irrespective of baseline co-morbidity data23.  Fauchier et al21 reported that the annual mortality rate increased with age for primary prevention ICD recipients in France, with older age associated with a greater risk of death.    As patients with cardiomyopathy age they have an increased rate of both sudden and non-sudden death, although proportionally are more likely to die from a non-sudden death than a sudden arrhythmic death.  One study analysed over 6000 patients with structural heart disease and showed that only 26% of deaths are sudden above the age of 80yrs24.  Another study showed that there was an increased mortality with age, mostly due to heart failure deaths25.  However, a study by Epstein et al8  found that overall mortality was increased in patients >75years compared to those <75years and this was mainly due to non-cardiac death, yet found a similar rate of sudden and non-sudden cardiac death rate in the different age groups.  Fauchier et al21 had similar findings to Epstein et al in that the proportion of cardiac deaths including ICD-unresponsive sudden death was similar across different age ranges. Masoudi et al20 found that mortality and hospitalisations for heart failure was significantly higher in patients >65years compared to <65years, but not for all cause hospitalisations.  Most studies are consistent in the finding that there is a greater risk of non-arrhythmic death.  This increased relative contribution to non-arrhythmic mortality may negate the survival benefits of ICD therapy19,24,26.  

A systematic literature review and meta-analysis of primary prevention ICDs assessed 579 patients above 75years from 4 RCTs (MADIT-II, SCD-HeFT, DEFINITE, MUSTT) found that primary ICD therapy remains efficacious in reducing all-cause mortality (HR 0.73, 95% CI 0.51-0.97; p = 0.03).  They recommend that ICD should not be withheld on the basis of age alone27

However, the median survival of elderly patients with an ICD has been shown to be <5years in most studies18,23,28,29 and yet the benefit of ICD in primary prevention of sudden cardiac death was only seen over 2-5years in MADIT-II.  One study reported that just under 50% of patients ≥75years died within 5 years of primary prevention ICD implantation versus 15% of those <65years.  If they have an appropriate shock 22% died within 1 year if >75years, versus 5% if less than 65years28. Another study found the death rate in primary prevention octogenarians is 10.2 deaths per 100 person-years10. Goonewardene et al18 in a retrospective study of 42 patients with ICD implantation ≥80years old found that 65% died within 3 years of the procedure. In patients who had devices implanted for primary prevention the risk of mortality was higher compared to secondary prevention and most episodes of VT were in those with ICDs for secondary prevention.  There were no ventricular fibrillation triggered ICD therapies.  They found that the median additional years of life after ICD implantation in patients who died before data retrieval was 2.5.

Chan et al30 in a prospective cohort study of 494 patients, with 269patients above 75years showed comparable absolute and relative mortality risk reductions with ICD use amongst older patients despite higher annual mortality rates.   

The evidence suggests that ICD therapy should be considered in the elderly for the prevention of sudden cardiac death as suggested by focused studies/subgroup analysis/observation and registry data21,27,30,31.  Barra et al31 have reviewed the data for implantable cardioverter-defibrillators in the elderly and looked at the rationale and specific age-related considerations.  They conclude that although octogenarians have a higher annual all-cause mortality rates, ICD therapy may remain effective in highly selected patients at high risk of arrhythmic death and with minimum comorbidities despite advanced age. 


Disadvantages of an ICD

The disadvantages include complications which are increased at the time of generator change, lead displacement, cost, anxiety/psychological distress including inappropriate shocks.  Many studies have reported on the complications of ICD implantation in the elderly.  Most recently Fauchier et al21 showed a higher risk of early device-related complications requiring surgical intervention with older age.  Masoudi et al20 also found that older patients had higher risk of haematoma requiring evacuation or transfusion compared with younger patients but other complications were not statistically significant20.  These studies conflict with some other studies which show complication rates are not significantly different to the younger age groups10,25,28,32-35.


Generator change

I have not reviewed the data for generator replacement in elderly in this editorial, however one recent study has looked at this and concluded that ‘in patients who need an elective generator replacement above the age of 80yrs who have had no previous ICD therapies there is hardly any clinical benefit’18


Summary

Elderly patients have a similar chance of receiving appropriate ICD therapies and therefore can gain as much benefit as those in the younger age groups.  On the other hand, mortality (total, cardiac and non-cardiac) is strongly associated with increasing age, even after controlling for potential confounders and comorbidities.  There is a significantly larger proportion increase in non-sudden death, which is unlikely to be prevented by ICD therapy. 

Age is a predictor of mortality but it does not identify which patients will benefit from an ICD.  Additional information must be reviewed to guide who will benefit.  I believe that we should use risk scores developed for the prediction of mortality in potential ICD recipients to guide implantation.  An example is Goldenberg et al36 risk stratification for primary implantation of a cardioverter-defibrillator in in patients with ischaemic left ventricular dysfunction.  This has been validation in long-term follow up37 and in the elderly38.  No benefit was seen in patient with zero risk factors (HR 0.96) or in very high risk individuals (HR1.0) whereas in patients with at least one risk factor (age>70years, NYHA >II, Urea >9.3mmol/L, QRS >0.12, AF) ICD therapy was associated with a 49% reduction in risk of death (most had 1-2 risk factors).  Among patients with at least 3 risk factors mortality was only slightly lower in the ICD group than in the conventional therapy group (29% vs 32%).  The 2 year-mortality rate was almost 50% in very high-risk patients irrespective of having an ICD.  There are other scoring systems that also are likely to be useful in guiding the clinician as to whether their patient is likely to benefit from an ICD. 

In summary, I believe that octogenarians who meet the guidelines for primary prevention ICD warrant consideration on an individual basis taking into account comorbidities, quality of life and patient choice.  It is essential to discuss the options with the patient and to emphasize that ICDs may prolong life but usually do not improve quality of life.  Risk scoring should help in the decision making process of this complex issue.


References

1. Goldenberg I, Gillespie J, Moss AJ, et al. Long-term benefit of primary prevention with an implantable cardioverter-defibrillator: an extended 8-year follow-up study of the Multicenter Automatic Defibrillator Implantation Trial II. Circulation. Sep 2010;122(13):1265-1271.

2. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. Mar 2002;346(12):877-883.

3. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. May 2004;350(21):2151-2158.

4. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med. Dec 1996;335(26):1933-1940.

5. Buxton AE, Fisher JD, Josephson ME, et al. Prevention of sudden death in patients with coronary artery disease: the Multicenter Unsustained Tachycardia Trial (MUSTT). Prog Cardiovasc Dis. 1993 Nov-Dec 1993;36(3):215-226.

6. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. Jan 2005;352(3):225-237.

7. Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med. Dec 2004;351(24):2481-2488.

8. Epstein AE, Kay GN, Plumb VJ, et al. Implantable cardioverter-defibrillator prescription in the elderly. Heart Rhythm. Aug 2009;6(8):1136-1143.

9. Hammill SC, Kremers MS, Kadish AH, et al. Review of the ICD Registry's third year, expansion to include lead data and pediatric ICD procedures, and role for measuring performance. Heart Rhythm. Sep 2009;6(9):1397-1401.

10. Yung D, Birnie D, Dorian P, et al. Survival after implantable cardioverter-defibrillator implantation in the elderly. Circulation. Jun 2013;127(24):2383-2392.

11. Masoudi FA, Go AS, Magid DJ, et al. Longitudinal study of implantable cardioverter-defibrillators: methods and clinical characteristics of patients receiving implantable cardioverter-defibrillators for primary prevention in contemporary practice. Circ Cardiovasc Qual Outcomes. Nov 2012;5(6):e78-85.

12. Dewland TA, Hsu JC, Castellanos JM, Smith LM, Marcus GM. Consideration of patient age and life expectancy in implantable cardioverter-defibrillator referral. Am Heart J. Jul 2013;166(1):164-170.

13. Tresch DD, Troup PJ, Thakur RK, et al. Comparison of efficacy of automatic implantable cardioverter defibrillator in patients older and younger than 65 years of age. Am J Med. Jun 1991;90(6):717-724.

14. Trappe HJ, Pfitzner P, Achtelik M, Fieguth HG. Age dependent efficacy of implantable cardioverter-defibrillator treatment: observations in 450 patients over an 11 year period. Heart. Oct 1997;78(4):364-370.

15. Panotopoulos PT, Axtell K, Anderson AJ, et al. Efficacy of the implantable cardioverter-defibrillator in the elderly. J Am Coll Cardiol. Mar 1997;29(3):556-560.

16. Healey JS, Hallstrom AP, Kuck KH, et al. Role of the implantable defibrillator among elderly patients with a history of life-threatening ventricular arrhythmias. Eur Heart J. Jul 2007;28(14):1746-1749.

17. Russo AM, Stainback RF, Bailey SR, et al. ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR 2013 appropriate use criteria for implantable cardioverter-defibrillators and cardiac resynchronization therapy: a report of the American College of Cardiology Foundation appropriate use criteria task force, Heart Rhythm Society, American Heart Association, American Society of Echocardiography, Heart Failure Society of America, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol. Mar 2013;61(12):1318-1368.

18. Goonewardene M, Barra S, Heck P, et al. Cardioverter-defibrillator implantation and generator replacement in the octogenarian. Europace. Mar 2015;17(3):409-416.

19. Ruskin JN, Camm AJ, Zipes DP, Hallstrom AP, McGrory-Usset ME. Implantable cardioverter defibrillator utilization based on discharge diagnoses from Medicare and managed care patients. J Cardiovasc Electrophysiol. Jan 2002;13(1):38-43.

20. Masoudi FA, Go AS, Magid DJ, et al. Age and sex differences in long-term outcomes following implantable cardioverter-defibrillator placement in contemporary clinical practice: findings from the cardiovascular research network. J Am Heart Assoc. 2015;4(6).

21. Fauchier L, Marijon E, Defaye P, et al. Effect of age on survival and causes of death after primary prevention implantable cardioverter-defibrillator implantation. Am J Cardiol. May 2015;115(10):1415-1422.

22. Ellenbogen KA, Levine JH, Berger RD, et al. Are implantable cardioverter defibrillator shocks a surrogate for sudden cardiac death in patients with nonischemic cardiomyopathy? Circulation. Feb 2006;113(6):776-782.

23. Pellegrini CN, Lee K, Olgin JE, et al. Impact of advanced age on survival in patients with implantable cardioverter defibrillators. Europace. Nov 2008;10(11):1296-1301.

24. Krahn AD, Connolly SJ, Roberts RS, Gent M, Investigators A. Diminishing proportional risk of sudden death with advancing age: implications for prevention of sudden death. Am Heart J. May 2004;147(5):837-840.

25. Grimm W, Stula A, Sharkova J, Alter P, Maisch B. Outcomes of elderly recipients of implantable cardioverter defibrillators. Pacing Clin Electrophysiol. Jan 2007;30 Suppl 1:S134-138.

26. Lee DS, Tu JV, Austin PC, et al. Effect of cardiac and noncardiac conditions on survival after defibrillator implantation. J Am Coll Cardiol. Jun 2007;49(25):2408-2415.

27. Kong MH, Al-Khatib SM, Sanders GD, Hasselblad V, Peterson ED. Use of implantable cardioverter-defibrillators for primary prevention in older patients: a systematic literature review and meta-analysis. Cardiol J. 2011;18(5):503-514.

28. van Rees JB, Borleffs CJ, Thijssen J, et al. Prophylactic implantable cardioverter-defibrillator treatment in the elderly: therapy, adverse events, and survival gain. Europace. Jan 2012;14(1):66-73.

29. Koplan BA, Soejima K, Baughman K, Epstein LM, Stevenson WG. Refractory ventricular tachycardia secondary to cardiac sarcoid: electrophysiologic characteristics, mapping, and ablation. Heart Rhythm. Aug 2006;3(8):924-929.

30. Chan PS, Nallamothu BK, Spertus JA, et al. Impact of age and medical comorbidity on the effectiveness of implantable cardioverter-defibrillators for primary prevention. Circ Cardiovasc Qual Outcomes. Jan 2009;2(1):16-24.

31. Barra S, Providência R, Paiva L, Heck P, Agarwal S. Implantable cardioverter-defibrillators in the elderly: rationale and specific age-related considerations. Europace. Feb 2015;17(2):174-186.

32. Duray G, Richter S, Manegold J, Israel CW, Grönefeld G, Hohnloser SH. Efficacy and safety of ICD therapy in a population of elderly patients treated with optimal background medication. J Interv Card Electrophysiol. Dec 2005;14(3):169-173.

33. Reynolds MR, Cohen DJ, Kugelmass AD, et al. The frequency and incremental cost of major complications among medicare beneficiaries receiving implantable cardioverter-defibrillators. J Am Coll Cardiol. Jun 2006;47(12):2493-2497.

34. Al-Khatib SM, Greiner MA, Peterson ED, Hernandez AF, Schulman KA, Curtis LH. Patient and implanting physician factors associated with mortality and complications after implantable cardioverter-defibrillator implantation, 2002-2005. Circ Arrhythm Electrophysiol. Oct 2008;1(4):240-249.

35. Noseworthy PA, Lashevsky I, Dorian P, Greene M, Cvitkovic S, Newman D. Feasibility of implantable cardioverter defibrillator use in elderly patients: a case series of octogenarians. Pacing Clin Electrophysiol. Mar 2004;27(3):373-378.

36. Goldenberg I, Vyas AK, Hall WJ, et al. Risk stratification for primary implantation of a cardioverter-defibrillator in patients with ischemic left ventricular dysfunction. J Am Coll Cardiol. Jan 2008;51(3):288-296.

37. Barsheshet A, Moss AJ, Huang DT, McNitt S, Zareba W, Goldenberg I. Applicability of a risk score for prediction of the long-term (8-year) benefit of the implantable cardioverter-defibrillator. J Am Coll Cardiol. Jun 2012;59(23):2075-2079.

38. Anné W, Theuns DA, Schaer B, et al. ICDs at higher age and clinical risk factors. Neth Heart J. Jun 2014;22(6):279-285.


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