Lack of Prognostic Value of T-Wave Alternans for Implantable Cardioverter-Defibrillator Benefit in Primary Prevention

BACKGROUND: New methods to identify patients who benefit from a primary prophylactic implantable cardioverter-defibrillator (ICD) are needed. T-wave alternans (TWA) has been shown to associate with arrhythmogenesis of the heart and sudden cardiac death. We hypothesized that TWA might be associated with benefit from ICD implantation in primary prevention. METHODS AND RESULTS: In the EU-CERT-ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter-Defibrillators) study, we prospectively enrolled 2327 candidates for primary prophylactic ICD. A 24-hour Holter monitor reading was taken from all recruited patients at enrollment. TWA was assessed from Holter monitoring using the modified moving average method. Study outcomes were all-cause death, appropriate shock, and survival benefit. TWA was assessed both as a contiguous variable and as a dichotomized variable with cutoff points <47 μV and <60 μV. The final cohort included 1734 valid T-wave alternans samples, 1211 patients with ICD, and 523 control patients with conservative treatment, with a mean follow-up time of 2.3 years. TWA ≥60 μV was a predicter for a higher all-cause death in patients with an ICD on the basis of a univariate Cox regression model (hazard ratio, 1.484 [95% CI, 1.024–2.151]; P=0.0374; concordance statistic, 0.51). In multivariable models, TWA was not prognostic of death or appropriate shocks in patients with an ICD. In addition, TWA was not prognostic of death in control patients. In a propensity score–adjusted Cox regression model, TWA was not a predictor of ICD benefit. CONCLUSIONS: T-wave alternans is poorly prognostic in patients with a primary prophylactic ICD. Although it may be prognostic of life-threatening arrhythmias and sudden cardiac death in several patient populations, it does not seem to be useful in assessing benefit from ICD therapy in primary prevention among patients with an ejection fraction of ≤35%

Electrocardiogram and diabetes mellitus as predictors of mortality benefit from ICD therapy in primary prophylactic patients

Abstract Cardiovascular diseases are the leading cause of death worldwide. Approximately as many as half of all cardiac deaths occur suddenly. For almost two decades, implantable cardioverter-defibrillator (ICD) has been used for primary prevention to reduce the risk of sudden cardiac death. Primary prophylactic ICD implantation is used in patients with ischemic and non-ischemic cardiomyopathy and impaired left ventricular ejection fraction (&#8804; 35%). Current guidelines are mainly based on studies published at the beginning of the millennium. Both pharmaceutical and invasive treatment as well as device programming have evolved since then, and the benefit-risk ratio of ICD implantation has become less favorable. The need for better identification of patients who truly benefit from ICD implantation is obvious. The aim of this thesis was to assess the role of diabetes mellitus and different electrocardiographic variables in predicting the mortality benefit from primary prophylactic ICD implantation. The study population included retrospective and prospective cohorts of the EU-CERT-ICD (EUropean Comparative Effectiveness Research to assess the use of primary prophylacTic Implantable Cardioverter-Defibrillators) multicenter study (ClinicalTrials.gov Identifier: NCT02064192). In study I, we evaluated the role of diabetes mellitus in a retrospective cohort of 3,535 primary prophylactic ICD patients. We found that diabetes associated with lower risk for appropriate ICD shock, and patients with diabetes had significantly higher all-cause mortality. The results suggest limited benefit from primary prophylactic ICD among patients with diabetes. In study II, we constructed a low-risk ECG combination including normal QRS-complex duration, normal corrected QT interval, and sinus rhythm. In a retrospective cohort of 1,687 primary prophylactic ICD patients, low-risk ECG predicted survival without appropriate shock. Based on the results, patients with low-risk EGC prior to the ICD implantation may not have significant benefit from the device. In study III, single traditional and novel ECG variables were coded and investigated in a prospective cohort of 1,477 patients with primary prophylactic ICD and 700 control patients with conventional treatment. Pathological Q waves were a significant predictor of ICD benefit on mortality. In addition, corrected QT interval associated with ICD shocks in ICD patients and with death in control patients, QRS complex duration predicted death in control patients, atrial fibrillation was prognostic for all-cause mortality in ICD patients, and lateral QRS complex fragmentation predicted all-cause mortality in patients with ICD. The results showed a major beneficial effect of primary prophylactic ICD implantation among patients with pathological Q waves. Overall, the findings provide increasing understanding of different benefits from primary prophylactic ICD in patient subgroups. Some patients may have substantially limited mortality benefit from the device, and the indications for ICD implantation require re-assessment.Tiivistelmä Sydän- ja verisuonisairaudet ovat maailmanlaajuisesti yleisin kuolinsyy. Arvion mukaan jopa noin puolet sydänperäisistä kuolemista on äkillisiä. Jo noin kahden vuosikymmenen ajan rytmihäiriötahdistimia on käytetty sydänperäisten äkkikuolemien riskin vähentämiseksi primaaripreventiona. Rytmihäiriötahdistinta primaaripreventiona käytetään sekä iskeemisessä että ei-iskeemisessä kardiomyopatiassa kun vasemman kammion ejektiofraktio on alentunut (&#8804; 35 %). Nykyiset hoitosuositukset perustuvat pääasiassa tutkimuksiin, jotka on julkaistu vuosituhannen alussa. Tämän jälkeen sekä lääkkeelliset että invasiiviset hoitomenetelmät ovat kehittyneet ja myös rytmihäiriötahdistinten ohjelmointi on edistynyt, ja laitehoidon hyöty-haittasuhde näyttää heikentyneen. On ilmeinen tarve tunnistaa paremmin potilaat, jotka todella hyötyvät rytmihäiriötahdistimen asennuksesta. Tämän väitöskirjatutkimuksen tavoitteena oli arvioida diabeteksen sekä erilaisten sydänsähkökäyrän muuttujien kykyä ennustaa rytmihäiriötahdistinhoidon kuolleisuushyötyä primaaripreventiossa. Tutkimuksen potilasaineisto koostui EU-CERT-ICD (EUropean Comparative Effectiveness Research to assess the use of primary prophylacTic Implantable Cardioverter-Defibrillators) -monikeskustutkimuksen (ClinicalTrials.gov, tunniste: NCT02064192) retrospektiivisesta ja prospektiivisesta kohortista. Ensimmäisessä osatutkimuksessa arvioimme diabeteksen ennusteellista merkitystä retrospektiivisen kohortin 3535 potilaalle, joille oli asennettu rytmihäiriötahdistin primaaripreventiona. Havaitsimme, että diabetes liittyy matalampaan rytmihäiriötahdistimen tarkoituksenmukaisen iskun riskiin ja diabetesta sairastavien potilaiden kokonaiskuolleisuus on merkitsevästi suurempi. Tulosten perusteella voidaan rytmihäiriötahdistinhoidosta saatavan hyödyn arvioida olevan diabetesta sairastavilla potilailla rajallinen. Toisessa osastutkimuksessa muodostimme matalan riskin yhdistelmän sydänsähkökäyrän muuttujista, joihin kuuluivat normaali QRS-kompleksin leveys, normaali korjatun QT-intervallin kesto sekä sinusrytmi. Retrospektiivisessa 1687:n rytmihäiriötahdistinhoitoa primaaripreventiona saavan potilaan kohortissa matalan riskin sydänsähkökäyrän muuttujien yhdistelmä ennusti elossa pysymistä ilman tarkoituksenmukaisia rytmihäiriötahdistimen iskuja. Tämän tutkimuksen tulosten perusteella voidaan arvioida, että potilaat, joiden sydänsähkökäyrässä on matalan riskin muuttujien yhdistelmä, eivät välttämättä saa rytmihäiriötahdistimesta merkittävää hyötyä. Kolmannessa osatutkimuksessa analysoimme ja tutkimme perinteisiä sekä uudentyyppisiä sydänsähkökäyrän muuttujia prospektiivisessa potilaskohortissa, joka koostui 1477 primaaripreventiona rytmihäiriötahdistinhoitoa saavasta potilaasta sekä 700 kontrollipotilaan ryhmästä. Patologiset Q-aallot ennustivat rytmihäiriötahdistinhoidosta merkittävää hyötyä. Lisäksi korjattu QT-intervalli assosioitui tarkoituksenmukaisiin rytmihäiriötahdistimen iskuihin tahdistinpotilailla ja kuolemaan kontrolliryhmän potilailla, QRS-kompleksin kesto ennusti kuolemaa kontrollipotilaiden ryhmässä, ja eteisvärinä sekä lateraalinen QRS-kompleksin fragmentaatio olivat ennusteellisia tahdistinpotilaiden kokonaiskuolleisuudelle. Tutkimustulokset osoittivat rytmihäiriötahdistinhoidon erityisen kuolleisuushyödyn potilailla, joiden sydänsähkökäyrässä havaittiin patologinen Q-aalto. Tämän väitöstutkimuksen osatutkimuksista saatiin lisää tietoa ja ymmärrystä rytmihäiriötahdistinhoidosta eri tavoin hyötyvistä potilasryhmistä primaaripreventiossa. Osalla potilaista laitehoidosta saatava hyöty on hyvin rajallinen, ja rytmihäiriötahdistinasennusten indikaatioita olisi syytä tarkastella uudelleen

Electrocardiogram as a predictor of survival without appropriate shocks in primary prophylactic ICD patients: A retrospective multi -center study

BACKGROUND: Abnormal 12-lead electrocardiogram (ECG) can predict cardiovascular events, including sudden cardiac death. We tested the hypothesis that ECG provides useful information on guiding implantable cardioverter defibrillator (ICD) therapy into individuals with impaired left ventricular ejection fraction (LVEF). METHODS: Retrospective data of primary prevention ICD implantations from 14 European centers were gathered. The registry included 5111 subjects of whom 1687 patients had an interpretable pre-implantation ECG available (80.0% male, 63.3 ± 11.4 years). Primary outcome was survival without appropriate ICD shocks or heart transplantation. A low-risk ECG was defined as a combination of ECG variables that were associated with the primary outcome. RESULTS: A total of 1224 (72.6%) patients survived the follow-up (2.9 ± 1.7 years) without an ICD shock, 224 (13.3%) received an appropriate shock and 260 (15.4%) died. Low-risk ECG defined as QRS duration <120 ms, QTc interval <450 ms for men and <470 ms for women, and sinus rhythm, were met by 515 patients (30.5%). Multivariable Cox regression showed that the hazard (HR) for death, heart transplantation or appropriate shock were reduced by 42.5% in the low-risk group (HR 0.575; 95% CI 0.45-0.74; p < 0.001), compared to the high-risk group. The HR for the first appropriate shock was 42.1% lower (HR 0.58; 95% CI 0.41-0.82; p = 0.002) and the HR for death was 48.0% lower (HR 0.52; 95% CI 0.386-0.72; p < 0.001) in the low-risk group. CONCLUSION: Sinus rhythm, QRS <120 ms and normal QTc in standard 12-lead ECG provides information about survival without appropriate ICD shocks and might improve patient selection for primary prevention ICD therapy.status: publishe

Electrocardiogram as a predictor of survival without appropriate shocks in primary prophylactic ICD patients: A retrospective multi-center study.

BACKGROUND Abnormal 12-lead electrocardiogram (ECG) can predict cardiovascular events, including sudden cardiac death. We tested the hypothesis that ECG provides useful information on guiding implantable cardioverter defibrillator (ICD) therapy into individuals with impaired left ventricular ejection fraction (LVEF). METHODS Retrospective data of primary prevention ICD implantations from 14 European centers were gathered. The registry included 5111 subjects of whom 1687 patients had an interpretable pre-implantation ECG available (80.0% male, 63.3 ± 11.4 years). Primary outcome was survival without appropriate ICD shocks or heart transplantation. A low-risk ECG was defined as a combination of ECG variables that were associated with the primary outcome. RESULTS A total of 1224 (72.6%) patients survived the follow-up (2.9 ± 1.7 years) without an ICD shock, 224 (13.3%) received an appropriate shock and 260 (15.4%) died. Low-risk ECG defined as QRS duration <120 ms, QTc interval <450 ms for men and <470 ms for women, and sinus rhythm, were met by 515 patients (30.5%). Multivariable Cox regression showed that the hazard (HR) for death, heart transplantation or appropriate shock were reduced by 42.5% in the low-risk group (HR 0.575; 95% CI 0.45-0.74; p < 0.001), compared to the high-risk group. The HR for the first appropriate shock was 42.1% lower (HR 0.58; 95% CI 0.41-0.82; p = 0.002) and the HR for death was 48.0% lower (HR 0.52; 95% CI 0.386-0.72; p < 0.001) in the low-risk group. CONCLUSION Sinus rhythm, QRS <120 ms and normal QTc in standard 12-lead ECG provides information about survival without appropriate ICD shocks and might improve patient selection for primary prevention ICD therapy

Q waves are the strongest electrocardiographic variable associated with primary prophylactic implantable cardioverter-defibrillator benefit: a prospective multicentre study.

AIM The association of standard 12-lead electrocardiogram (ECG) markers with benefits of the primary prophylactic implantable cardioverter-defibrillator (ICD) has not been determined in the contemporary era. We analysed traditional and novel ECG variables in a large prospective, controlled primary prophylactic ICD population to assess the predictive value of ECG in terms of ICD benefit. METHODS AND RESULTS Electrocardiograms from 1477 ICD patients and 700 control patients (EU-CERT-ICD; non-randomized, controlled, prospective multicentre study; ClinicalTrials.gov Identifier: NCT02064192), who met ICD implantation criteria but did not receive the device, were analysed. The primary outcome was all-cause mortality. In ICD patients, the co-primary outcome of first appropriate shock was used. Mean follow-up time was 2.4 ± 1.1 years to death and 2.3 ± 1.2 years to the first appropriate shock. Pathological Q waves were associated with decreased mortality in ICD patients [hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.35-0.84; P < 0.01] and patients with pathological Q waves had significantly more benefit from ICD (HR 0.44, 95% CI 0.21-0.93; P = 0.03). QTc interval increase taken as a continuous variable was associated with both mortality and appropriate shock incidence, but commonly used cut-off values, were not statistically significantly associated with either of the outcomes. CONCLUSION Pathological Q waves were a strong ECG predictor of ICD benefit in primary prophylactic ICD patients. Excess mortality among Q wave patients seems to be due to arrhythmic death which can be prevented by ICD

Q waves are the strongest electrocardiographic variable associated with primary prophylactic implantable cardioverter-defibrillator benefit:a prospective multicentre study

Abstract Aim: The association of standard 12-lead electrocardiogram (ECG) markers with benefits of the primary prophylactic implantable cardioverter-defibrillator (ICD) has not been determined in the contemporary era. We analysed traditional and novel ECG variables in a large prospective, controlled primary prophylactic ICD population to assess the predictive value of ECG in terms of ICD benefit. Methods and results: Electrocardiograms from 1477 ICD patients and 700 control patients (EU-CERT-ICD; non-randomized, controlled, prospective multicentre study; ClinicalTrials.gov Identifier: NCT02064192), who met ICD implantation criteria but did not receive the device, were analysed. The primary outcome was all-cause mortality. In ICD patients, the co-primary outcome of first appropriate shock was used. Mean follow-up time was 2.4 ± 1.1 years to death and 2.3 ± 1.2 years to the first appropriate shock. Pathological Q waves were associated with decreased mortality in ICD patients [hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.35–0.84; P &lt; 0.01] and patients with pathological Q waves had significantly more benefit from ICD (HR 0.44, 95% CI 0.21–0.93; P = 0.03). QTc interval increase taken as a continuous variable was associated with both mortality and appropriate shock incidence, but commonly used cut-off values, were not statistically significantly associated with either of the outcomes. Conclusion: Pathological Q waves were a strong ECG predictor of ICD benefit in primary prophylactic ICD patients. Excess mortality among Q wave patients seems to be due to arrhythmic death which can be prevented by ICD.the EU-CERT-ICD Study Investigators: Elena Arbelo, MD, Axel Bauer MD, Frieder Braunschweig MD PhD, Josep Brugada MD, PhD, David Conen MD, Iwona Cygankiewicz MD, Michael Dommasch MD, Christian Eick, MD, Panagiota Flevari MD, Tim Friede PhD, Jan Galuszka MD, Jim Hansen MD, Robert Hatala MD, Markus Harden PhD, Katerina Hnatkova PhD, Heikki V. Huikuri MD, Juhani M. Junttila, MD PhD, Stefan Kääb MD, Gabriela Kaliska MD, Jaroslaw D. Kasprzak MD, Andreas Katsimardos MD, Milan Kozak MD, Tomasz Kuczejko MD, Andrzej Lubinski MD, Jozef Martinek PhD, Béla Merkely MD, PhD, Tomáš Novotný MD, Marek Malik PhD MD, Peter Perge MD, Burkert Pieske MD, Pyotr Platonov MD PhD, Pawel Ptaczyński, MD, Dariusz Qavoq MD, L. Rotkvić, MD, Zoltan Sallo MD, Simon Schlögl MD, Georg Schmidt MD, Moritz Sinner, MD, Rajeeva Sritharan MSc, Stefan Stefanow MD, Christian Sticherling MD PhD, Jesper Hastrup Svendsen MD DMSc, Martin Svetlosak MD, Janko Szavits-Nossan MD, Milos Taborsky MD, Anton Tuinenburg, MD, Bert Vandenberk MD, Marc A. Vos PhD, Rik Willems MD PhD, Stefan N Willich MD PhD, Christian Wolpert MD, Markus Zabel MD, Ante Anic, MD, Zoran Bakotic MD, Steffen Behrens MD, Dieter Bimmel MD, Sandro Brusich MD, Rüdiger Dissmann MD, Gerian Grönefeld, MD, Przemyzlav Guzik MD, Svetoslav Iovev MD, Zrinka Jurisic MD, Thomas Klingenheben, MD, Nikola Pavlović MD, Joachim Seegers MD, Robert H.G. Schwinger MD, Tchavdar Shalganov MD, Vassil Traykov MD, Vasil Velchev M

Appropriate shocks and mortality in patients with versus without diabetes with prophylactic implantable cardioverter defibrillators

OBJECTIVE: Diabetes increases the risk of all-cause mortality and sudden cardiac death (SCD). The exact mechanisms leading to sudden death in diabetes are not well known. We compared the incidence of appropriate shocks and mortality in patients with versus without diabetes with a prophylactic implantable cardioverter defibrillator (ICD) included in the retrospective EU-CERT-ICD registry. RESEARCH DESIGN AND METHODS AND RESULTS: A total of 3,535 patients from 12 European EU-CERT-ICD centers with a mean age of 63.7 ± 11.2 years (82% males) at the time of ICD implantation were included in the analysis. A total of 995 patients (28%) had a history of diabetes. All patients had an ICD implanted for primary SCD prevention. End points were appropriate shock and all-cause mortality. Mean follow-up time was 3.2 ± 2.3 years. Diabetes was associated with a lower risk of appropriate shocks (adjusted hazard ratio [HR] 0.77 [95% CI 0.62-0.96], P = 0.02). However, patients with diabetes had significantly higher mortality (adjusted HR 1.30 [95% CI 1.11-1.53], P = 0.001). CONCLUSIONS: All-cause mortality is higher in patients with diabetes than in patients without diabetes with primary prophylactic ICDs. Subsequently, patients with diabetes have a lower incidence of appropriate ICD shocks, indicating that the excess mortality might not be caused primarily by ventricular tachyarrhythmias. These findings suggest a limitation of the potential of prophylactic ICD therapy to improve survival in patients with diabetes with impaired left ventricular function

Appropriate shocks and mortality in patients with versus without diabetes with prophylactic implantable cardioverter defibrillators

Abstract Objective: Diabetes increases the risk of all-cause mortality and sudden cardiac death (SCD). The exact mechanisms leading to sudden death in diabetes are not well known. We compared the incidence of appropriate shocks and mortality in patients with versus without diabetes with a prophylactic implantable cardioverter defibrillator (ICD) included in the retrospective EU-CERT-ICD registry. Research design and methods and results: A total of 3,535 patients from 12 European EU-CERT-ICD centers with a mean age of 63.7 ± 11.2 years (82% males) at the time of ICD implantation were included in the analysis. A total of 995 patients (28%) had a history of diabetes. All patients had an ICD implanted for primary SCD prevention. End points were appropriate shock and all-cause mortality. Mean follow-up time was 3.2 ± 2.3 years. Diabetes was associated with a lower risk of appropriate shocks (adjusted hazard ratio [HR] 0.77 [95% CI 0.62–0.96], P = 0.02). However, patients with diabetes had significantly higher mortality (adjusted HR 1.30 [95% CI 1.11–1.53], P = 0.001). Conclusions: All-cause mortality is higher in patients with diabetes than in patients without diabetes with primary prophylactic ICDs. Subsequently, patients with diabetes have a lower incidence of appropriate ICD shocks, indicating that the excess mortality might not be caused primarily by ventricular tachyarrhythmias. These findings suggest a limitation of the potential of prophylactic ICD therapy to improve survival in patients with diabetes with impaired left ventricular function

Clinical effectiveness of primary prevention implantable cardioverter-defibrillators: results of the EU-CERT-ICD controlled multicentre cohort study

Aims: The EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter-Defibrillators (EU-CERT-ICD), a prospective investigator-initiated, controlled cohort study, was conducted in 44 centres and 15 European countries. It aimed to assess current clinical effectiveness of primary prevention ICD therapy. Methods and results: We recruited 2327 patients with ischaemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM) and guideline indications for prophylactic ICD implantation. Primary endpoint was all-cause mortality. Clinical characteristics, medications, resting, and 12-lead Holter electrocardiograms (ECGs) were documented at enrolment baseline. Baseline and follow-up (FU) data from 2247 patients were analysable, 1516 patients before first ICD implantation (ICD group) and 731 patients without ICD serving as controls. Multivariable models and propensity scoring for adjustment were used to compare the two groups for mortality. During mean FU of 2.4 ± 1.1 years, 342 deaths occurred (6.3%/years annualized mortality, 5.6%/years in the ICD group vs. 9.2%/years in controls), favouring ICD treatment [unadjusted hazard ratio (HR) 0.682, 95% confidence interval (CI) 0.537–0.865, P = 0.0016]. Multivariable mortality predictors included age, left ventricular ejection fraction (LVEF), New York Heart Association class <III, and chronic obstructive pulmonary disease. Adjusted mortality associated with ICD vs. control was 27% lower (HR 0.731, 95% CI 0.569–0.938, P = 0.0140). Subgroup analyses indicated no ICD benefit in diabetics (adjusted HR = 0.945, P = 0.7797, P for interaction = 0.0887) or those aged ≥75 years (adjusted HR 1.063, P = 0.8206, P for interaction = 0.0902). Conclusion: In contemporary ICM/DCM patients (LVEF ≤35%, narrow QRS), primary prophylactic ICD treatment was associated with a 27% lower mortality after adjustment. There appear to be patients with less survival advantage, such as older patients or diabetics.peerReviewe