Usefulness of Multisite Ventricular Pacing in Nonresponders to Cardiac Resynchronization Therapy

Cardiac resynchronization therapy (CRT) is an established treatment for heart failure patients with myocardial dysfunction and delayed ventricular activation, but approximately 25% to 40% of patients do not respond to CRT. Left ventricular (LV) multisite pacing (MSP) has been proposed as a tool to improve CRT response. The goal of this study is to examine the safety and efficacy of LV MSP in CRT nonresponders. Between January 2018, and September 2019, the Strategic Management to Improve CRT Using Multi-Site Pacing trial prospectively enrolled 584 CRT-defibrillator recipients for established indications at 52 sites across the United States and evaluated their response at 6 months using the clinical composite score (CCS). Of the nonresponders, 102 patients had the LV MSP feature turned on and 78 patients completed the 12-month CCS evaluation. The LV MSP feature-related complication-free rate was 99.0% with a lower 95% confidence interval limit of 94.9%, which was higher than the performance goal of 90%. The proportion of nonresponders with an improved CCS from 6 to 12 months was 51.3% with a lower 95% confidence interval limit of 41.4%, which was higher than the performance goal of 5%. The estimated mean reduction in battery longevity with the LV MSP feature was about 3.6 months (estimated battery longevity of 8.87 ± 2.08 years at 6 months and 8.07 ± 2.23 years at 12 months). In conclusion, in CRT nonresponders, the use of the LV MSP feature is safe and associated with a ∼50% conversion rate with a small projected reduction in CRT-defibrillator battery longevity. LV MSP should be considered in the management of CRT nonresponders. Cardiac resynchronization therapy (CRT) is an established treatment for heart failure patients with myocardial dysfunction and delayed ventricular activation, but approximately 25% to 40% of patients do not respond to CRT. Left ventricular (LV) multisite pacing (MSP) has been proposed as a tool to improve CRT response. The goal of this study is to examine the safety and efficacy of LV MSP in CRT nonresponders. Between January 2018, and September 2019, the Strategic Management to Improve CRT Using Multi-Site Pacing trial prospectively enrolled 584 CRT-defibrillator recipients for established indications at 52 sites across the United States and evaluated their response at 6 months using the clinical composite score (CCS). Of the nonresponders, 102 patients had the LV MSP feature turned on and 78 patients completed the 12-month CCS evaluation. The LV MSP feature-related complication-free rate was 99.0% with a lower 95% confidence interval limit of 94.9%, which was higher than the performance goal of 90%. The proportion of nonresponders with an improved CCS from 6 to 12 months was 51.3% with a lower 95% confidence interval limit of 41.4%, which was higher than the performance goal of 5%. The estimated mean reduction in battery longevity with the LV MSP feature was about 3.6 months (estimated battery longevity of 8.87 ± 2.08 years at 6 months and 8.07 ± 2.23 years at 12 months). In conclusion, in CRT nonresponders, the use of the LV MSP feature is safe and associated with a ∼50% conversion rate with a small projected reduction in CRT-defibrillator battery longevity. LV MSP should be considered in the management of CRT nonresponders. Cardiac resynchronization therapy (CRT) is an established treatment for heart failure (HF) patients with reduced left ventricular ejection fraction (LVEF).1Al-Khatib SM Stevenson WG Ackerman MJ Bryant WJ Callans DJ Curtis AB Deal BJ Dickfeld T Field ME Fonarow GC Gillis AM Granger CB Hammill SC Hlatky MA Joglar JA Kay GN Matlock DD Myerburg RJ Page RL. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines and the Heart Rhythm Society.Circulation. 2017; 138 (2018): e272-e391Google Scholar, 2Tang AS Wells GA Talajic M Arnold MO Sheldon R Connolly S Hohnloser SH Nichol G Birnie DH Sapp JL Yee R Healey JS Rouleau JL Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators. Cardiac-resynchronization therapy for mild-to-moderate heart failure.N Engl J Med. 2010; 363: 2385-2395Crossref PubMed Scopus (1344) Google Scholar, 3Bristow MR Saxon LA Boehmer J Krueger S Kass DA De Marco T Carson P DiCarlo L DeMets D White BG DeVries DW Feldman AM Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.N Engl J Med. 2004; 350: 2140-2150Crossref PubMed Scopus (4748) Google Scholar, 4Cleland JG Daubert JC Erdmann E Freemantle N Gras D Kappenberger L Tavazzi L Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure.N Engl J Med. 2005; 352: 1539-1549Crossref PubMed Scopus (5151) Google Scholar CRT improves the functional status and myocardial function of patients,5Young JB Abraham WT Smith AL Leon AR Lieberman R Wilkoff B Canby RC Schroeder JS Liem LB Hall S Wheelan K Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD) Trial Investigators. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial.JAMA. 2003; 289: 2685-2694Crossref PubMed Scopus (1431) Google Scholar and decreases HF events and all-cause mortality.3Bristow MR Saxon LA Boehmer J Krueger S Kass DA De Marco T Carson P DiCarlo L DeMets D White BG DeVries DW Feldman AM Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.N Engl J Med. 2004; 350: 2140-2150Crossref PubMed Scopus (4748) Google Scholar,4Cleland JG Daubert JC Erdmann E Freemantle N Gras D Kappenberger L Tavazzi L Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure.N Engl J Med. 2005; 352: 1539-1549Crossref PubMed Scopus (5151) Google Scholar Still, a significant proportion of eligible patients do not clinically benefit from CRT.6Tanaka H Hara H Saba S Gorcsan 3rd, J Prediction of response to cardiac resynchronization therapy by speckle tracking echocardiography using different software approaches.J Am Soc Echocardiogr. 2009; 22: 677-684Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 7Tanaka H Nesser HJ Buck T Oyenuga O Jánosi RA Winter S Saba S Gorcsan 3rd, J Dyssynchrony by speckle-tracking echocardiography and response to cardiac resynchronization therapy: results of the Speckle Tracking and Resynchronization (STAR) study.Eur Heart J. 2010; 31: 1690-1700Crossref PubMed Scopus (213) Google Scholar, 8Adelstein EC Saba S. Baseline scintigraphic abnormalities by myocardial perfusion imaging predict echocardiographic response to cardiac resynchronization therapy in nonischemic cardiomyopathy.Clin Cardiol. 2008; 31: 217-224Crossref PubMed Scopus (9) Google Scholar, 9Varma N Auricchio A Connolly AT Boehmer J Bahu M Costanzo MR Leonelli F Yoo D Singh J Nabutovsky Y Gold M. The cost of non-response to cardiac resynchronization therapy: characterizing heart failure events following cardiac resynchronization therapy.Europace. 2021; 23: 1586-1595Crossref PubMed Scopus (4) Google Scholar Patient baseline clinical characteristics1Al-Khatib SM Stevenson WG Ackerman MJ Bryant WJ Callans DJ Curtis AB Deal BJ Dickfeld T Field ME Fonarow GC Gillis AM Granger CB Hammill SC Hlatky MA Joglar JA Kay GN Matlock DD Myerburg RJ Page RL. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines and the Heart Rhythm Society.Circulation. 2017; 138 (2018): e272-e391Google Scholar and the specific region of left ventricular (LV) pacing, away from the scar8Adelstein EC Saba S. Baseline scintigraphic abnormalities by myocardial perfusion imaging predict echocardiographic response to cardiac resynchronization therapy in nonischemic cardiomyopathy.Clin Cardiol. 2008; 31: 217-224Crossref PubMed Scopus (9) Google Scholar,10Liu J Adelstein E Saba S. Targeting left ventricular lead placement to improve cardiac resynchronization therapy outcomes.Curr Cardiol Rep. 2013; 15: 390Crossref PubMed Scopus (5) Google Scholar, 11Adelstein EC Tanaka H Soman P Miske G Haberman SC Saba SF 3rd Gorcsan J Impact of scar burden by single-photon emission computed tomography myocardial perfusion imaging on patient outcomes following cardiac resynchronization therapy.Eur Heart J. 2011; 32: 93-103Crossref PubMed Scopus (136) Google Scholar, 12Adelstein EC Saba S. Scar burden by myocardial perfusion imaging predicts echocardiographic response to cardiac resynchronization therapy in ischemic cardiomyopathy.Am Heart J. 2007; 153: 105-112Crossref PubMed Scopus (209) Google Scholar and close to the site of the latest mechanical10Liu J Adelstein E Saba S. Targeting left ventricular lead placement to improve cardiac resynchronization therapy outcomes.Curr Cardiol Rep. 2013; 15: 390Crossref PubMed Scopus (5) Google Scholar,13Saba S Marek J Schwartzman D Jain S Adelstein E White P Oyenuga OA Onishi T Soman P 3rd Gorcsan J Echocardiography-guided left ventricular lead placement for cardiac resynchronization therapy: results of the Speckle Tracking Assisted Resynchronization Therapy for Electrode Region trial.Circ Heart Fail. 2013; 6: 427-434Crossref PubMed Scopus (259) Google Scholar,14Khan FZ Virdee MS Palmer CR Pugh PJ O'Halloran D Elsik M Read PA Begley D Fynn SP Dutka DP. Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial.J Am Coll Cardiol. 2012; 59: 1509-1518Crossref PubMed Scopus (505) Google Scholar or electrical activation,15Gold MR Birgersdotter-Green U Singh JP Ellenbogen KA Yu Y Meyer TE Seth M Tchou PJ. The relationship between ventricular electrical delay and left ventricular remodelling with cardiac resynchronization therapy.Eur Heart J. 2011; 32: 2516-2524Crossref PubMed Scopus (250) Google Scholar have been implicated in patient response to CRT. Recently, pacing at multiple sites in the LV has been associated with improved response rates in smaller studies,16Cazeau S Leclercq C Lavergne T Walker S Varma C Linde C Garrigue S Kappenberger L Haywood GA Santini M Bailleul C Daubert JC Multisite Stimulation in Cardiomyopathies (MUSTIC) Study Investigators. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay.N Engl J Med. 2001; 344: 873-880Crossref PubMed Scopus (2508) Google Scholar, 17Sohal M Shetty A Niederer S Lee A Chen Z Jackson T Behar JM Claridge S Bostock J Hyde E Razavi R Prinzen F Rinaldi CA. Mechanistic insights into the benefits of multisite pacing in cardiac resynchronization therapy: the importance of electrical substrate and rate of left ventricular activation.Heart Rhythm. 2015; 12: 2449-2457Abstract Full Text Full Text PDF PubMed Google Scholar, 18Thibault B Dubuc M Khairy P Guerra PG Macle L Rivard L Roy D Talajic M Karst E Ryu K Paiement P Farazi TG. Acute haemodynamic comparison of multisite and biventricular pacing with a quadripolar left ventricular lead.Europace. 2013; 15: 984-991Crossref PubMed Scopus (102) Google Scholar but larger trials have not substantiated these findings or had mixed results.19Niazi I Baker 2nd, J Corbisiero R Love C Martin D Sheppard R Worley SJ Varma N Lee K Tomassoni G Investigators MPP Safety and efficacy of multipoint pacing in cardiac resynchronization therapy: the multipoint pacing trial.JACC Clin Electrophysiol. 2017; 3: 1510-1518Crossref PubMed Scopus (56) Google Scholar The present multicenter, observational trial was therefore designed to examine the safety and efficacy of LV multisite pacing (MSP) in improving symptomatic HF as measured by the clinical composite score (CCS)20Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure.J Card Fail. 2001; 7: 176-182Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar in nonresponders to 6 months of conventional CRT. The Strategic Management to Improve CRT Using Multi-Site Pacing trial was a multicenter, study by and in with the and The was by the of and A Clinical safety and HF a of study and The of the trial was to the of the LV MSP to improve CRT rate and the safety of the feature in an The trial was at The study at approximately at and 12-month to conventional CRT from the point of to the the evaluated with the CCS and as or the study at the LV MSP was in for an 6 with LV MSP MSP by of CCS at the 12-month to evaluate their response to LV The study is in years of or a or with an quadripolar LV lead for established clinical SM Stevenson WG Ackerman MJ Bryant WJ Callans DJ Curtis AB Deal BJ Dickfeld T Field ME Fonarow GC Gillis AM Granger CB Hammill SC Hlatky MA Joglar JA Kay GN Matlock DD Myerburg RJ Page RL. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines and the Heart Rhythm Society.Circulation. 2017; 138 (2018): e272-e391Google Scholar considered for in this was to patients to HF Heart Association to a than or to and patients with left with or ischemic or nonischemic HF or ischemic LV had or had a of than 12 or or to the of the The CCS was by the or study for at the and 12-month and the following all-cause HF patient and (4) HF site at and to the study clinical and as or on CCS considered improved a by at functional or in the patient or and of HF considered from an HF or of at functional or of the patient considered improved with an improved CCS as with an or CCS as HF was as an with a of and HF events by the Clinical for to The safety end point was the LV MSP feature-related complication-free rate between the LV MSP was and in nonresponders with LV MSP on for LV MSP feature-related as by the site as or to the LV MSP A of was to evaluate the safety end point to a of The performance goal for the LV MSP feature-related complication-free rate was 90%. The end point for the study was the proportion of the LV MSP with an improved CCS at 12 The study of was by the end The performance goal of conversion from to a of to 95% the estimated of in by the response to this The LV MSP feature-related complication-free rate between the and 12-month was using LV MSP was turned on or the and The 95% lower confidence limit of the LV MSP feature complication-free rate was using the and with the performance had LV MSP at 6 months but to of without an end point from the safety end point The end point was the 12-month was completed by in the LV MSP was to with LV MSP pacing with CCS and from the study an HF in the end point and as nonresponders. with the LV MSP feature on for than 6 months in the The 95% lower confidence limit of the response rate was using for a proportion and with the performance goal of 5%. with CCS from the 12-month considered to have the of study on the end multiple The baseline and clinical of patients enrolled in in The of CRT The mean of at was and White The proportion of patients with ischemic of was and a significant for prevention of sudden cardiac The mean of patients was 25% and their of on in between patients and MSP of study ± ± ventricular ejection fraction ± ± ± ± cardiac conduction Heart Association Heart Association Heart Association Heart Association I in a new The of patient in the trial is in Of the 584 enrolled the study or had response CRT at 6 and nonresponders. in baseline between and nonresponders, to have an electrical delay of at between the and left at the of the Of the nonresponders and enrolled in the 102 had the LV MSP feature at 6 months and for 6 months for of the safety end Of 78 patients in the end point on the MSP patients not in the in Of the 102 with LV by the site as to the LV MSP the the LV MSP feature-related complication-free rate at was which A for and events a feature-related complication-free rate of with a 95% lower confidence limit of which CCS at 12 months of of LV MSP patients from to the end point of of LV MSP as and of of the trial of patients and nonresponders to conventional CRT by CCS at 6 patients at 12 months on LV MSP was by rates different pacing not the LV MSP pacing of but had CCS patients from sites to have 12-month completed the 12-month of the (4) patients 12-month using of the these the 12-month conversion rates and than a of CCS outcomes on patients or at 6 the conversion to rate is between the and In patients had their LV MSP feature turned on at or close to the HF events with events of to HF in was a of HF conventional CRT therapy with LV conventional patients at HF patients an HF with LV HF events in the CRT and in the MSP patients an HF on on conventional and on LV A for was a significant in to the HF by to of response to the LV MSP feature in nonresponders to conventional CRT. of the LV MSP was the of CCS response The response rate in patients pacing was with in pacing rates in at 6 months and in MSP 12 months the was was not for LV CRT response rates higher in patients the was the cost of LV MSP to battery battery longevity from and 12-month in LV MSP patients with The estimated battery longevity was ± years at 6 months and ± years at 12 a of years or the between the the of the LV MSP feature on battery longevity was estimated at 3.6 for the of the The trial the use of LV MSP in patients do not respond to 6 months of conventional CRT is safe with a rate of feature-related and with than response rate by CCS approximately 6 months of Of the of response to LV MSP in CRT nonresponders was the use of the on the quadripolar LV lead LV MSP the of LV MSP on battery longevity was the use of this the LV MSP feature is an tool for CRT The present have clinical to conventional CRT is in and has G E M De R N L De E R M E M A C G G T M B of on Investigators. Cardiac therapy in patients with left ventricular dysfunction and heart failure: on outcomes and of J Heart Fail. PubMed Scopus Google Scholar and R Buck D R N is the cost of non-response to cardiac resynchronization and in the Card Electrophysiol. PubMed Scopus Google Scholar as nonresponders to advanced HF as ventricular or cardiac or have for HF to G E M De R N L De E R M E M A C G G T M B of on Investigators. Cardiac therapy in patients with left ventricular dysfunction and heart failure: on outcomes and of J Heart Fail. PubMed Scopus Google R Buck D R N is the cost of non-response to cardiac resynchronization and in the Card Electrophysiol. PubMed Scopus Google Scholar to conventional CRT has been associated with specific patient as the of or on MR C Linde C Abraham WT B S M Daubert of and on cardiac resynchronization therapy outcomes in heart failure: results from the resynchronization in left ventricular dysfunction 2012; PubMed Scopus Google Scholar and with as pacing at a site to the region of latest LV or electrical J Adelstein E Saba S. Targeting left ventricular lead placement to improve cardiac resynchronization therapy outcomes.Curr Cardiol Rep. 2013; 15: 390Crossref PubMed Scopus (5) Google Scholar,13Saba S Marek J Schwartzman D Jain S Adelstein E White P Oyenuga OA Onishi T Soman P 3rd Gorcsan J Echocardiography-guided left ventricular lead placement for cardiac resynchronization therapy: results of the Speckle Tracking Assisted Resynchronization Therapy for Electrode Region trial.Circ Heart Fail. 2013; 6: 427-434Crossref PubMed Scopus (259) Google Scholar,14Khan FZ Virdee MS Palmer CR Pugh PJ O'Halloran D Elsik M Read PA Begley D Fynn SP Dutka DP. Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial.J Am Coll Cardiol. 2012; 59: 1509-1518Crossref PubMed Scopus (505) Google Scholar these not of the clinical of patients CRT. to with CRT LV lead MA R K L between left ventricular lead using a and with resynchronization Card Electrophysiol. 2008; 23: PubMed Scopus Google or and D U E of and delay on clinical and echocardiographic outcomes of patients with cardiac resynchronization therapy: a J. 2013; Scopus Google LV MSP is and an response rate in nonresponders, with of safety and cost to battery longevity. the of benefit from LV MSP clinical trials have established the of pacing the LV at a site to the of the latest by speckle tracking S Marek J Schwartzman D Jain S Adelstein E White P Oyenuga OA Onishi T Soman P 3rd Gorcsan J Echocardiography-guided left ventricular lead placement for cardiac resynchronization therapy: results of the Speckle Tracking Assisted Resynchronization Therapy for Electrode Region trial.Circ Heart Fail. 2013; 6: 427-434Crossref PubMed Scopus (259) Google Scholar,14Khan FZ Virdee MS Palmer CR Pugh PJ O'Halloran D Elsik M Read PA Begley D Fynn SP Dutka DP. Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial.J Am Coll Cardiol. 2012; 59: 1509-1518Crossref PubMed Scopus (505) Google Scholar or the site of the latest electrical MR Birgersdotter-Green U Singh JP Ellenbogen KA Yu Y Meyer TE Seth M Tchou PJ. The relationship between ventricular electrical delay and left ventricular remodelling with cardiac resynchronization therapy.Eur Heart J. 2011; 32: 2516-2524Crossref PubMed Scopus (250) Google Scholar pacing from LV sites with be a higher of the pacing is to the site of LV pacing, to a response. In pacing from sites of the LV myocardial to a response. be the I Baker 2nd, J Corbisiero R Love C Martin D Sheppard R Worley SJ Varma N Lee K Tomassoni G Investigators MPP Safety and efficacy of multipoint pacing in cardiac resynchronization therapy: the multipoint pacing trial.JACC Clin Electrophysiol. 2017; 3: 1510-1518Crossref PubMed Scopus (56) Google Scholar had response with LV pacing the pacing and present to this the of these proposed of benefit from LV The present trial has is a trial at 52 sites across the United patients not to the LV MSP turned on or with the patients to conventional CRT the is the of response between 6 and 12 months is about and is therefore to be by response the smaller response of in the The present study a significant in HF events following LV MSP activation, but the the present study a and have decreases in HF rates 6 N Auricchio A Connolly AT Boehmer J Bahu M Costanzo MR Leonelli F Yoo D Singh J Nabutovsky Y Gold M. The cost of non-response to cardiac resynchronization therapy: characterizing heart failure events following cardiac resynchronization therapy.Europace. 2021; 23: 1586-1595Crossref PubMed Scopus (4) Google Scholar of this effect is to to HF clinical or have following MSP N Boehmer J K Yoo D Leonelli F Costanzo M A L Gold MR Singh J J Auricchio and outcomes of patients to cardiac resynchronization Am Coll Cardiol. PubMed Scopus Google Scholar the present trial the CCS as the without echocardiographic in LV this study have between LV and MSP as by Varma N Baker 2nd, J Tomassoni G Love Martin D Sheppard R I G Lee K Corbisiero R Left ventricular cardiac resynchronization therapy and of multipoint Electrophysiol. Scopus Google Scholar Still, the M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure.J Card Fail. 2001; 7: 176-182Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar on by and is an established HF end point has been in HF J R R M J P JA A J S A A R E A T A J J JM E F for for improving outcomes in patients with heart and a multicenter, clinical Heart J. PubMed Scopus Google Scholar, AB Worley SJ P M in clinical outcomes with biventricular ventricular the HF Am Coll Cardiol. PubMed Scopus Google Scholar, J F M MA B Rouleau JL DJ F MR AS B J J E T M B M SJ J AR J Investigators and in heart failure with ejection Engl J Med. PubMed Scopus Google Scholar not examine to with LV Study and S. Study and and Patient M. S. S. M. Trial S. Study Study and Ellenbogen Saba has from and and from and and from and and from from and from from and from Jain from and Ellenbogen from and from and for from and and of The have of to and at trial sites across the United States for to this trial and with