Improving survival after out-of-hospital cardiac arrest requires new tools

Transcription

1 European Heart Journal (2016) 37, doi: /eurheartj/ehv485 CURRENT OPINION Improving survival after out-of-hospital cardiac arrest requires new tools Hein J. Wellens 1 *, Fred W. Lindemans 2, Richard P. Houben 3, Anton P. Gorgels 4, Paul G. Volders 5, Rachel M.A. ter Bekke 5, and Harry J. Crijns 5 1 Cardiovascular Research Center, Henric van Veldekeplein 21, Maastricht 6211 TG, The Netherlands; 2 Device Research Consulting, Sittard, The Netherlands; 3 Applied Biomedical Systems BV, Maastricht, The Netherlands; 4 Department of Cardiology, Maastricht University Medical Center+, Maastricht, The Netherlands; and 5 Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center+, Maastricht, The Netherlands Received 20 May 2015; revised 13 August 2015; accepted 25 August 2015; online publish-ahead-of-print 14 September 2015 Introduction In the western world, 20% of all deaths among people between 20 and 80 years old are sudden and unexpected and this has not changed much during recent decades, whereas mortality from cardiac disease has diminished substantially. 1 Sudden death is most often caused by the onset of ventricular fibrillation (VF) or ventricular tachycardia, interfering with the heart s function to pump blood into the circulation and thus causing a cardiac (and circulatory) arrest. We know that immediate termination of the life-threatening arrhythmia by means of defibrillation, thereby restoring spontaneous circulation, provides many cardiac arrest victims several saved lifeyears of satisfactory quality. 2 Over the years numerous articles have addressed two crucial questions: Can we identify a person with increased risk of cardiac arrest before the event? and, How to optimize the resuscitation attempt and the management of the victim after return of a stable cardiac rhythm? Regarding the first question, we know that our current methods of risk stratification identify only a small fraction of the victims before the event. 3 6 Also, no new methods have been published that provide cardiac arrest predictors with sufficient sensitivity and specificity to both identify a substantial portion of all arrest victims in advance and to be specific enough to make preventive action (defibrillator implantation) practical and cost-effective. This somewhat disappointing conclusion forces us to concentrate on the second question. Recent publications Several recent articles discussed our current insights into incidence of cardiac arrest, profile of the victim, rhythm at arrest, and results of the resuscitation attempt They show that outcomes of witnessed cardiac arrests have improved in recent years due to greater emphasis on resuscitation training, increased density of automatic external defibrillators (AEDs) in communities, better organization of emergency medical systems (EMS), and improved post-resuscitation care. Typically, reported percentages of cardiac arrest victims leaving the hospital alive, however, are still not better than 10%. In two editorials, 11,12 possible initiatives to further improve out-of-hospital cardiac arrest (OHCA) outcome were discussed. Obviously, all steps in the chain of survival should be optimized. In our opinion, however, methods to shorten the critical time interval between arrest and the start of resuscitation did not yet get the attention they deserve. In witnessed arrests, crucial time is lost before the bystander realizes that a cardiac arrest has occurred and that immediate action is required, thus wasting precious minutes in the chain of survival. Additionally, questioning and decision making by the dispatch centre further delay EMS arrival at the scene. Obviously, those time intervals will be much longer in the 40% of cardiac arrest cases that are not witnessed. 4 Eliminating delays The importance of eliminating delays is illustrated by an outcome study of arrests occurring in casinos with staff trained in using AEDs 13 : The survival rate was 74 percent for those who received their first defibrillation no later than three minutes after a witnessed collapse and 49 percent for those who received their first defibrillation after more than three minutes.. 13 In the same study, 105 of the 148 victims (71%) had VF as the initial rhythm recorded, 90 of them were witnessed arrests, showing 59% survival to discharge from hospital. None of those without VF as initial recorded rhythm survived. A 1-year survival rate of 55%, with good neurological outcome, was reported for cardiac arrest victims found in VF at Chicago airports equipped with well-distributed AEDs. 14 The Swedish survey on OHCA 15 shows that the median interval between collapse and call for an ambulance was 4 min and that the chance of 30-day survival is significantly influenced by this interval (6.9% for The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. * Corresponding author. Tel: , hwellens@xs4all.nl Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 1500 H.J. Wellens et al. 4 min, 2.8% for.4 min). In our interpretation of these, and other, results, reducing the time interval from arrest to defibrillation is the only presently viable option for increasing cardiac arrest survival from around 10% towards the 40 70% range and for decreasing the incidence of cerebral damage with its long-term medical costs. Implanting a cardiac arrest monitor More than a decade ago it was suggested to develop an implantable device that continuously monitors cardiac activity and that is designed to shorten the time interval between cardiac arrest and the necessary subsequent steps to increase the chance of survival. 16 Such a device should provide prompt and accurate recognition of circulatory arrest, trigger an auditory alarm to activate bystanders and immediately transmit the location of the victim to the EMS dispatch services and the nearest site of an AED in the community, see Figure 1. Of course, as indicated in the article, there were major technical challenges to develop such a device like continuous, artefact free monitoring of cardiac activity, selection of the best sensor (ECG?), location of the device (external, subcutaneous?), wireless transmission of the signals, reliable circulatory arrest detection, exact localization of the victim, low power consumption, miniaturization, and a clock to register the time interval between arrest and the start of resuscitation and defibrillation. Since this initial proposition, sparse attention has been given to the subject. Arzbaecher and coworkers developed a prototype Figure 1 Illustration of a subcutaneously implanted cardiac arrest monitor (blue dumbbell) that, on detecting cardiac arrest, activates a smartphone to generate an audible alarm and to automatically call emergency medical systems, transmitting GPS location and identification of the victim, possibly combined with an ECG tracing. Emergency medical systems staff then decide to dispatch an ambulance for providing advanced life-support, including defibrillation, and notifies by telephone short message service the nearest members of a network of trained volunteers to proceed to the site of the arrest with an automatic external defibrillator. device and published on their subcutaneous electrogram monitor capable of meeting some of the requirements mentioned above. 17,18 Rickard et al. 19 proposed a watch-based device to detect absence of the pulse and several patents exist describing aspects of automatic detection of and alarming after OHCA. To the best of our knowledge, however, these efforts have not resulted in a clinically useful cardiac arrest alarming device thus far. Available technology Since our publication in 2003, 16 technological progress seems to have brought a reliable, clinically applicable arrest device within reach. Widespread use of implantable loop recorders has demonstrated that long-term subcutaneous ECG recording and monitoring is practical. These devices store ECGs of arrhythmia episodes for later verification by the physician, which makes inappropriate detection of fast tachycardia, reported at an incidence of 1.9 events per patient-year, 20 acceptable for this application. For an implantable cardiac arrest monitor that automatically alarms EMS; however, 1.9 false alarms per patient-year are clearly unacceptable as only arrests per patient-year would be expected in a proof of concept study as described in the next section. It thus remains to be demonstrated that VF detection can be improved to a sufficiently low rate of false alarms, while maintaining close to 100% sensitivity, for being used as the basis for automatically alerting the EMS. Communication between implanted and external devices is common nowadays and the use of a standard protocol like Bluetooth would allow a smartphone with a dedicated app to react to an alarm message from the implanted device. In case of VF detection, the phone must call the EMS number, provide (GPS) location and patient identification, while at the same time alerting bystanders to take action. This approach, which can be described as the development of an implantable cardiac arrest alarm device, has the potential to substantially reduce the time interval between cardiac arrest and appropriate action and to turn unwitnessed arrests ( 40% of all arrests 4 ) into witnessed arrests as illustrated in Figure 2. Of course, all this can only be translated into improved survival if emergency services embrace and equip for such an approach, preferably also involving and activating a community-based network of professionals and volunteers equipped with AEDs. Placing AEDs at the homes of high-risk patients and training spouses or companions in their use has been another approach to shorten the time interval between arrest and defibrillation. The randomized Home Use of Automated External Defibrillators for Sudden Cardiac Arrest or HAT study 21 demonstrated that this did not result in improved arrest survival in patients with a prior anterior infarction without implantable cardioverter defibrillator (ICD) indication. With a median age of 62, a median ejection fraction of 45%, a median QRS duration of 91 ms, a time interval since MI of over 1 year in 60 and 95% in NYHA I or II, these 7001 patients experienced about half the expected annual sudden cardiac arrest rate of 2% over the median follow-up period of 37 months. Of 222 deaths in the AED at home group (3495 people), 82 were adjudicated as tachyarrhythmic and sudden. Of these, 57 (70%) occurred at home, of which 27 were witnessed, and the AED was applied to 32 victims, producing 8 survivors. As potential explanations for this negative result, the authors suggest lack of power due to the low cardiac arrest

3 Detection of out-of-hospital cardiac arrest 1501 Figure 2 Comparing expected delays between arrest and defibrillation when using the current approach and when using an implanted arrest alarm device. The latter will eliminate delays caused by a witness not immediately recognizing the arrest, then not knowing what to do, and then explaining the situation to an emergency medical systems operator following a protocol of questions and answers to assess the situation. Apart from turning unwitnessed into witnessed arrest, the device may be expected to provide all information required by the emergency medical system operator to initiate life-saving action 5 min earlier than under the current approach. rate observed and insufficient training of spouses and companions, who deployed the AED substantially less often than intended. They concluded that it is conceivable that some form of a home automatic alert system might be of value. Indications, proof of concept, and clinical evaluation An important question is in which patients initial testing of such a device should be conducted. In order to keep size of initial studies limited, a high risk of OHCA is mandatory but those meeting present indications for an ICD 22 are obviously excluded. Thus, the best population for proof of concept and clinical evaluation of safety and effectiveness would consist of high-risk cardiac patients not qualifying for an ICD. An attractive group might consist of post-mi patients with ejection fraction between 35% and 50%, diabetes, scar characteristics on MRI, heart failure, and ECG findings such as QRS widening, and presence of (supra) ventricular arrhythmias. An annual cardiac arrest rate of 2.5% would be expected in such a population, with a similar non-arrhythmic mortality. As a reference, a recent study of 2790 ICD patients with a mean follow-up of 22 months revealed an appropriate shock rate of 5% per year. 23 Also, one might consider a familial population with inherited VF in which a genetic diagnosis, distinguishing carriers from non-carriers of this trait, is not yet available. In such a case, all family members could be candidates for the device. It is beyond the scope of this paper to develop precise patient selection criteria for such a study but this is clearly needed. Obviously, proof of concept testing should focus on demonstrating the clinical and technical feasibility of the cardiac arrest alarm device, including communication to and subsequent response by the EMS service, with special attention for the incidence of false alarms. Under the assumption that an arrest alarm can improve OHCA survival to 40%, a single arm feasibility study would require 18 OHCAs to demonstrate that the device increases survival.10%, which would require 18/2.5% ¼ 720 patient-years of follow-up. A co-operative and well-organized EMS service, preferably supported by a high-density community first responder system in the region of the study is of course a pre-requisite. Clinical and technical feasibility could also be studied during the first phase of a randomized controlled trial designed to demonstrate clinical and cost-effectiveness with interim analysis after a pre-defined number of arrests in order to confirm acceptable false alarm and rescue rates. Under the same annual incidence assumptions of 2.5% cardiac arrests, 2.5% non-arrhythmic mortality, 10% and 40% arrest survival in the control and active arms, respectively, demonstrating significantly improved total survival (P, 0.05; 80% power) by an implantable alarm device would need close to 3750 patients randomized during 5 years with 5 years follow-up. On the other hand, demonstrating for P, 0.05 and 90% power that OHCA survival improved from 10 to 40% in a randomized trial would require 100 OHCAs, thus 1000 patients followed during 4 years. Of course, all patients surviving an OHCA should be considered for defibrillator implantation. For these annual arrest and mortality rates, combined with expected arrest survival rates of 10% in the control arm and 40% in the active (arrest alarm device) arm of a randomized trial, a simple generic model (Table 1) suggests that an incremental E per patient can be spent in the active arm for achieving a cost per lifeyear saved of E (a rather arbitrary but curiously resilient threshold for cost-effectiveness 24 ) for a device with a 10-year longevity. This number should be interpreted as a rough, model-based estimate for how much money can be spent on the combined costs of implanting and subsequently following a patient with such a device, including the potential costs of setting-up and maintaining the EMS component, while respecting a threshold of E per life-year saved. An additional financial benefit, not considered here, could come from reducing the number of sudden cardiac death survivors with cerebral damage requiring costly long-term medical care. Depending on the results of initial clinical studies, indications may be widened by studies based on other patient selection criteria, as has typically happened in device therapy. Only patients with a cardiac history, representing 50% of all OHCA victims, 4 would be included, at least until non-invasive, wearable arrest detection devices will achieve sufficient sensitivity and specificity at substantially lower cost. Clearly, such studies would require important investments in time, effort, and money, like past studies that demonstrated clinical and economic effectiveness of ICDs and cardiac resynchronization devices. We are convinced that such investments are justified considering the societal impact of sudden cardiac death. Reported incidences of sudden cardiac death in populations vary widely, probably largely due to the different and often incomplete data sources used in the analyses. Numbers provided in a recent paper 25 seem to

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Table 1 Simple exponential hazards total survival model for patients at risk for out-of-hospital cardiac arrest as well as for other causes of death for two different saving rates for out-of-hospital cardiac arrest Size of model population per arm 1000 Annual OHCA incidence in study population 2.5% The annual % of the study population experiencing OHCA Annual non-ohca mortality in study population 2.5% The annual % of the study population dying from other causes than OHCA Saved from cardiac arrest with current approach 10% The % of OHCA victims saved with current approach (control group) Saved from cardiac arrest with implanted alarm 40% The % of OHCA victims saved when implanted with an arrest alarm device Selected value of 1 life-year saved in (E 1000s) 50 Value used for calculating break-even costs After N years Surviving patients with current approach Surviving patients with implanted arrest alarm Lives saved by arrest alarm during year Cumulative lives saved at year end Cumulative life-years saved at year end Break-even cost for 5-year device longevity E 4089 Break-even cost for 7-year device longevity E 7572 Break-even cost for 10-year device longevity E The model represents a randomized trial comparing survival of patients implanted with a cardiac arrest alarm device (active arm) vs. survival of patients without such device (control arm or current approach ). Break-even costs represent the total amount of incremental spending for a patient with an implanted arrest alarm device that achieves the indicated value per life-year saved (E ). represent the middle of the range, estimating that 690 sudden cardiac arrests per million inhabitants occur annually in the USA, causing 2 million years of potential life lost for men and 1.3 million YPLL for women. Conclusions We agree with Stecker et al. 25 that SCD prevention must be a major public health priority. It is highly unlikely that risk assessment techniques will soon be available with sufficient positive predictive accuracy for identifying such a significant portion of future SCD victims as ICD candidates, while maintaining acceptable costeffectiveness, that this will provide a substantial reduction in SCD mortality in the population. Thus, substantially improving resuscitation outcomes after a cardiac arrest seems the only way available for reducing SCD mortality. Of course, efforts to improve our present approach must continue, including deployment of networks of trained volunteers with AEDs, but the only hope we presently see for substantial progress rests in systematically shortening the time interval between arrest and defibrillation. Technology has contributed in major ways to the success of cardiologists to reduce cardiovascular mortality. We are convinced that the time has come to apply technology for attacking the most important obstacle for improving cardiac arrest survival. This means: to eliminate avoidable delays between arrest and defibrillation by developing an implantable device that automatically alerts bystanders and EMS upon detecting a cardiac arrest. This approach has many similarities with the ecall system that automatically communicates a vehicle s exact location to emergency services in case of a severe accident and it may benefit from its infrastructure. In April 2015, The European Parliament voted for its introduction in all new cars by Like an implantable cardiac arrest alarm system, ecall only transmits location data in case of an emergency, thus mitigating privacy concerns. Before receiving such a device, patients must of course be informed about privacy aspects and they must understand that wearing the device indicates that they want to be resuscitated in case of a cardiac arrest. Designing a detection algorithm with sufficiently high positive predictive accuracy appears to be the main technical challenge, defining indications will be the main medical challenge for introducing an implantable arrest alarm device. It will only succeed if deployed in areas with an EMS organization willing to support such approach and the introduction of ecall may be of help in this respect. Because total costs to the healthcare system of a subcutaneously implantable cardiac arrest alarm device can be substantially lower than those of an ICD, indications for an alarm device can achieve an acceptable cost per life-year saved while including high-risk patients not meeting current ICD indications. Acknowledgements The authors thank Bart Gerritse PhD for his highly valuable advice on study design and statistics. Conflict of interest: none declared. References 1. Berdowski J, Berg R, Tijssen JGP, Koster RW. Global incidences of out-of-hospital cardiac arrest and survival rates: systematic review of 67 prospective studies. Resuscitation 2010;81: Smith K, Andrews E, Lijovic M, Nehme Z, Bernard S. Quality of life and functional outcomes 12 months after out-of-hospital cardiac arrest. Circulation 2015;131: Myerburg RJ, Castellanos A. Cardiac arrest and sudden cardiac death. In: Braunwald E (ed.), Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: WB Saunders Company; 1992, p De Vreede-Swagemakers JJ, Gorgels AP, Dubois-Arbouw WJ, Daemen M, van Ree J, Houben L, Wellens H. Out-of-hospital cardiac arrest in the 1990 s: a

5 Detection of out-of-hospital cardiac arrest 1503 population based study in the Maastricht area on incidence, characteristics and survival. J Am Coll Cardiol 1997;30: Goldberger JJ, Basu A, Boineau R, Buxton AE, Cain ME, Canty JM Jr, Chen PS, Chugh SS, Constantini O, Exner DV, Kadish AH, Lee B, Lloyd-Jones D, Moss AJ, Myerburg RJ, Olgin JE, Passman R, Stevenson WG, Tomaselli GF, Zareba W, Zipes DP, Zoloth L. Risk stratification for sudden cardiac death: a plan for the future. Circulation 2014;129: Wellens HJ, Schwartz PJ, Lindemans FW, Buxton AE, Goldberger JJ, Hohnloser SH, Huikuri HV, Kaab S, La Rovere MT, Malik M, Myerburg RJ, Simoons ML, Svedberg K, Tijssen J, Voors AA, Wilde AA. Risk stratification for sudden cardiac death: current status and challenges for the future. Eur Heart J 2014;35: Hansen CM, Lippert FK, Wissenberg M, Weeke P, Zinckernagel L, Ruwald MH, Karlsson L, Gislason GH, Nielsen SL, Kober L, Torp-Pedersen C, Folke F. Temporal trends in coverage of historical cardiac arrests using a volunteer-based network of automated external defibrillators accessible to laypersons and emergency dispatch centers. Circulation 2014;130: Blom MT, Beesems SG, Homma PCM, Zijlstra JA, Hulleman M, van Hoeijen DA, Bardai A, Tijssen JGP, Tan HL, Koster RW. Improved survival after out-of-hospital cardiac arrest and use of automated external defibrillators. Circulation 2014;130: Chan PC, McNally B, Tang F, Kellerman A, for the CARES surveillance group. Recent trends in survival from out-of-hospital cardiac arrest in the United States. Circulation 2014;130: Wong MKI, Morrison LJ, Qiu F, Austin PC, Cheskes S, Dorian P, Scales DC, Tu JV, Verbeek PR, Wijeysundera C, Ko DT. Trends in short- and long-term survival among out-of-hospital cardiac arrest patients alive at hospital arrival. Circulation 2014;130: Myerburg RJ. Initiatives for improving out-of-hospital cardiac arrest outcomes. Circulation 2014;130: Nicol G, Elrod JA, Becker LB. Treatment for out-of-hospital cardiac arrest: is the glass half empty or half full? Circulation 2014;130: Valenzuela TD, Roe DJ, Nichol G, Clark LL, Spaite DW, Hardman RG. Outcomes of rapid defibrillation by security officers after cardiac arrest in casinos. N Engl J Med 2000;343: Caffrey SL, Willoughby PJ, Pepe PE, Becker LB. Public use of automated external defibrillators. N Engl J Med 2002;347: Herlitz J, Engdahl J, Svensson L, Young M, Ängquist K-A, Holmberg S. A short delay from out of hospital cardiac arrest to call for ambulance increases survival. Eur Heart J 2003;24: Wellens HJ, Gorgels AP, de Munter H. Cardiac arrest outside of a hospital. How can we improve results of resuscitation? Circulation 2003;107: Arzbaecher R, Jenkins J, Burke M, Song Z, Garrett M. Database testing of a subcutaneous monitor with wireless alarm. J Electrocardiol 2006;39(suppl.):S50 S Arzbaecher R, Hampton DR, Burke MC, Garrett MC. Subcutaneous electrocardiogram monitors and their field of view. J Electrocardiol 2010;43: Rickard J, Ahmed S, Baruch M, Klocman B, Martin DO, Menon V. Utility of a novel watch-based pulse detection system to detect pulselessness in human subjects. Heart Rhythm 2011;8: Volosin K, Stadler RW, Wyszynski R, Kirchhof P. Tachycardia detection performance of implantable loop recorders: results from a large real-life patient cohort and patients with induced ventricular arrhythmias. Europace 2013;15: Bardy GH, Lee KL, Mark DB, Poole JE, Toff WD, Tonkin AM, Smith W, Dorian P, Packer DL, White RD, Longstreth WT Jr, Anderson J, Johnson G, Bischoff E, Yallop JJ, McNulty S, Davidson Ray L, Clapp-Channing NE, Rosenberg Y, Schron EB, for the HAT Investigators. Home use of automated external defibrillators for sudden cardiac arrest. N Engl J Med 2008;358: Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos GI, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL, Smith SC Jr, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B; ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death executive summary: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death), Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Eur Heart J 2006;27: Auricchio A, Schloss EJ, Kurita T, Meijer A, Gerritse B, Zweibel S, Al Smadi FM, Leng CT, Sterns LD. Low inappropriate shock rates in patients with single and dual/triple chamber ICDs using a novel suite of detection algorithms: PainFree SST Trial Primary Results. Heart Rhythm 2015;12: Neumann PJ, Cohen JT, Weinstein MC. Updating cost-effectiveness the curious resilence of the $50,000-per-QALY threshold. N Engl J Med 2014;371: Stecker EC, Reinier K, Marijon E, Narayanan K, Teodorescu C, Uy-Evanado A, Gunson K, Jui J, Chugh SS. Public health burden of sudden cardiac death in the United States. Circ Arrhythm Electrophysiol 2014;7: