Cardiac resynchronization therapy for mild-to-moderate heart failure

For reprint orders, please contact reprints@expert-reviews.com Cardiac resynchronization therapy for mild-to-moderate heart failure Expert Rev. Med. Devices 8(3), 313 317 (2011) Haran Burri Electrophysiology Unit, Cardiology Service, University Hospital of Geneva, 23 Rue Gabrielle-Gentil, 1211 Geneva, Switzerland Tel.: +41 223 727 200 Fax: +41 223 727 229 haran.burri@hcuge.ch Evaluation of: Tang AS, Wells GA, Talajic M Cardiac-resynchronization therapy for mild-to-moderate heart failure. N. Engl. J. Med. 363(25), 2385 2395 (2010). Cardiac resynchronization therapy (CRT) is recognized as a class indication according to American and European practice guidelines since 2005 in selected patients with systolic heart failure and New York Heart Association (NYHA) /V symptoms. There is growing evidence that CRT may also benefit patients who are less symptomatic, as it may delay or even reverse the disease process. n the Resynchronization Defibrillation for Ambulatory Heart Failure Trial (RAFT), Tang randomized 1798 patients with left ventricular ejection fraction of 30%, QRS duration of ms (or paced QRS 200 ms), and NYHA class or heart failure to receive an implantable cardioverter defibrillator (CD) or an CD CRT. After a mean follow-up of 40 months, there was a 25% relative reduction both in the primary outcome of death or heart failure hospitalization (p < 0.001), as well as in the secondary outcome of total mortality (p = 0.003). This landmark trial adds evidence to the efficacy of CRT in selected patients with mild-to-moderate heart failure, at the time of implementation of new guidelines. Keywords: biventricular pacing cardiac resynchronization therapy heart failure Cardiac resynchronization therapy (CRT) consists of pacing both ventricles to improve the coordination of cardiac contraction in selected patients with systolic heart failure. Randomized trials have demonstrated this therapy to improve patient outcome in terms of heart failure symptoms, exercise tolerance, hospitalization and mortality. These trials have led to CRT being indicated in patients with a left ventricular ejection fraction (LVEF) of %, QRS duration of ms and New York Heart Association (NYHA) /V symptoms according to American and European guidelines since 2005. A number of randomized trials have extended inclusion criteria to patients with mild-tomoderate heart failure and have shown favorable results (Table 1). The most recent of these trials is the Resynchronization Defibrillation for Ambulatory Heart Failure Trial (RAFT) [1], which is discussed in this article. Methods & results This is a multicenter, double-blind, randomized, controlled study, designed to determine whether a device combining CRT and an implantable cardioverter defibrillator (CRT CD) and optimal medical therapy would reduce mortality and the rate of hospitalization for heart failure in patients with NYHA class or symptoms, LVEF of 30% and a wide QRS complex ( ms or paced 200 ms), compared with patients with optimal medical therapy receiving an CD only. The protocol was amended in 2006 to include only patients with NYHA symptoms after evidence that CRT reduces mortality in NYHA patients [2]. The primary outcome was death from any cause or heart failure hospitalization. Principal secondary outcomes included mortality and heart failure hospitalization that were analyzed separately in patients with NYHA and heart failure. The study was supported by the Canadian nstitutes of Health Research and Medtronic (MN, USA). A total of 1798 patients were enrolled (mostly in Canada) and randomized 1:1 to receive an CD (single or dual chamber; n = 904) or an CD CRT (n = 894). The mean follow-up was 40 ± 20 months and was available in 99% of patients. The main results are shown in Table 2. The number of patients needed to treat with an www.expert-reviews.com 10.1586/ERD.11.6 2011 Expert Reviews Ltd SSN 1743-4440 313

Burri Table 1. Randomized cardiac resynchronization therapy trials including patients with New York Heart Association symptoms. Study CONTAK CD PATH CHF MRACLE CD REVERSE REVERSE European cohort MADT- CRT RAFT Author (year) Higgins (2003) Auricchio (2003) Abraham (2004) Linde (2008) Daubert (2009) Moss (2009) Tang (2010) n Design NYHA QRS (ms) 490 Crossover then parallel CRT 86 Crossover CRT off vs on 186 Parallel, CRT off vs on 610 Parallel CRT (12 month follow-up) 262 Parallel CRT (24 month follow-up) 1820 Parallel CD vs 1798 Parallel CD vs (33%) V (33%) V (83%) (83%) (86%) (80%) (160 ± 27) (155 ± 20) 130 (166 ± 25) (153 ± 21) (155 ± 22) 130 or paced 200 (157 ± 23.6) LVEF (%) (21 ± 7) (23 ± 7) (24.4 ± 6.6) 40 (26.8 ± 7) 40 (28.1 ± 7.2) 30 (24 ± 5) 30 (22.6 ± 5.4) Rhythm Device Results (for patients in class /) No change in peak VO 2, QOL or 6MWT mprovement in LV dimensions (40%) (60%) No separate ana lysis in NYHA patients No change in peak VO 2, QOL or 6MWT Significant LV remodeling (LV volume and LVEF) and improvement in clinical composite score (83%) (17%) (66%) (34%) No difference in clinical composite score LV dimensions and LVEF Significant delay to first HF hospitalization mproved clinical composite score LV dimensions and LVEF Significant delay to first HF hospitalization HF-free survival LV volume and LVEF No difference in mortality and AF Significant reduction in total mortality and HF hospitalization, as a combined end point or individually Primary end point. Values in brackets indicate mean ± standard deviation of patients in the CRT group 6MWT: 6-min walk test; AF: Atrial fibrillation and flutter; CRT: Cardiac resynchronization therapy; : Cardiac resynchronization therapy with a defibrillator device; : Cardiac resynchronization therapy with a pacing device; HF: Heart failure; CD: mplantable cardioverter defibrillator; LV: Left ventricular; LVEF: Left ventricular ejection fraction; MADT: Multicenter Automatic Defibrillator mplantation Trial; NYHA: New York Heart Association; PATH CHF : Pacing Therapies for Congestive Heart Failure ; QOL: Quality of life; RAFT: Resynchronization Defibrillation for Ambulatory Heart Failure Trial; REVERSE: Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction; VO 2 : Maximal oxygen consumption. Ref. [11] [12] [13] [5] [14] [4] [1] CD CRT for 5 years to prevent one death was 14, and to prevent one heart failure hospitalization was 11. Subgroup analyses demonstrated that the effect of CD CRT was similar in patients with NYHA and heart failure, as well as in those with ischemic or nonischemic cardiomyopathy. However, there was significant interaction of treatment effect with QRS duration (less effect in patients with intrinsic QRS <150 ms or paced QRS 200 ms compared with those with intrinsic QRS 150 ms; p = 0.003) as well as QRS morphology (less effect in patients with right bundle branch block or nonspecific intraventricular conduction disorder compared with those with left bundle branch block [LBBB]; p = 0.046). There were more device-related complications at 30 days in patients in the CRT CD group compared with the CD group (13.2 vs 6.8%; p < 0.001). The most frequent complication was lead dislodgment requiring intervention, which occurred in 6.9% of patients in the CRT CD group, compared with 2.2% in the CD group. This complication rate was surprisingly high and occurred more frequently than in the Cardiac Resynchronization-Heart Failure (CARE-HF) study [3], which used the same implantation tools (2.7% of any lead dislodgment in the CRT arm). The higher rate 314 Expert Rev. Med. Devices 8(3), (2011)

Cardiac resynchronization therapy for mild-to-moderate heart failure Key Paper Evaluation of complications led to more device-related hospitalizations in the CD CRT group compared with the CD group (20.0 vs 12.2%, respectively; hazard ratio: 1.68; 95% C: 1.32 2.13; p < 0.001). Expert commentary This landmark trial confirms the improvement in outcome with CRT CD in patients with NYHA symptoms and shows, for the first time, a significant reduction in total mortality with this therapy compared with an CD alone. This contrasts with the Multicenter Automatic Defibrillator mplantation Trial with Cardiac Resynchronization Therapy (MADT)-CRT trial [4], which did not show any survival benefit of CRT CD compared with CD in NYHA / heart failure patients. Reasons for these differences may be a longer follow-up and more advanced disease in patients included in RAFT. Another important finding was the subgroup ana lysis of response to treatment according to QRS duration and morphology. The finding that benefit of CRT is limited to the subgroup of patients with a baseline QRS duration of 150 ms is in agreement with data from the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial [5] and MADT-CRT [4]. The European Society of Cardiology has issued a focused update on device therapy in heart failure in 2010 [6] that now extends CRT indication to patients with NYHA symptoms (with LVEF % and sinus rhythm), as long as the QRS duration is 150 ms (class level of evidence A to reduce patient morbidity or prevent disease progression). However, QRS morphology also seems to be an important factor, and RAFT confirms the findings of MADT-CRT that biventricular pacing has less effect in patients with non-lbbb. ndeed, data from MADT-CRT (available at [101] and now published [7]) demonstrated that patients with LBBB benefited from CRT and those with non-lbbb did not, regardless of QRS duration. This led to an FDA panel meeting in March 2010 voting unanimously in favor of extending CRT indication to patients with LBBB (rather than placing a restriction on a QRS duration of <150 ms) and it is likely that the upcoming American guidelines will diverge from the 2010 European guidelines in this matter. Challenges of implementing these guidelines will be: To accurately grade NYHA symptoms To precisely measure QRS duration To classify QRS morphology Data from the CARE-HF trial demonstrated that one in five patients evaluated by the enrolling physicians to be in NYHA /V heart failure in fact reported NYHA / symptoms according to a standardized questionnaire. Measurement of QRS duration on a 25 mm/s 12-lead electrocardiogram has been demonstrated to have a median intra- and inter-observer variability of approximately 30 ms [8], which means that there is likely to be significant inconsistency with categorizing patients using the 150-ms cutoff. Finally, the criteria for diagnosing intraventricular conduction disturbances have been standardized recently [9]; they are relatively complicated and not adapted for routine clinical use. Unlike previous CRT trials in patients with NYHA symptoms, RAFT also included patients with atrial fibrillation/flutter (12.7% of patients) or with previous ventricular pacing upgraded to CRT (7.5% of patients). The patient population was therefore more heterogeneous but reflected a more real-life situation than those of previous trials. However, results were negative in these subgroups. Five-year view Selected patients with NYHA symptoms qualify for CRT in the 2010 European guidelines and are also likely to be included in the upcoming 2011 American guidelines. This means that Table 2. Main results of the Resynchronization Defibrillation for Ambulatory Heart Failure Trial in the entire cohort and in patients with New York Heart Association symptoms at baseline. Outcome CD, n (%) CD-CRT, n (%) Hazard ratio (95% C) All patients Patients (n) 904 894 Primary outcome Death or hospitalization for heart failure Secondary outcomes p-value 364 (40.3) 297 (33.2) 0.75 (0.64 0.87) <0.001 Death from any cause 236 (26.1) 186 (20.8) 0.75 (0.62 0.91) 0.003 Death from cardiovascular cause Hospitalization for heart failure Patients in NYHA class Patients (n) 730 708 Primary outcome Death or hospitalization for heart failure Secondary outcomes 162 (17.9) 130 (14.5) 0.76 (0.60 0.96) 0.02 236 (26.1) 174 (19.5) 0.68 (0.56 0.83) <0.001 253 (34.7) 193 (27.3) 0.73 (0.61 0.88) 0.001 Death from any cause 154 (21.1) 110 (15.5) 0.71 (0.56 0.91) 0.006 Death from cardiovascular cause Hospitalization for heart failure 100 (13.7) 74 (10.5) 0.73 (0.54 0.99) 0.04 159 (21.8) 115 (16.2) 0.70 (0.55 0.89) 0.003 CRT: Cardiac resynchronization therapy; CD: mplantable cardioverter defibrillator; NYHA: New York Heart Association. Reproduced with permission from [1]. www.expert-reviews.com 315

Burri the number of CRT implantations will significantly increase, although the total number of devices will not be much affected, as these patients have an CD indication anyway. t is likely that many centers have already been implanting CRT CDs (rather than CDs) in NYHA patients before the new guidelines were published; as many as 22% of patients were in NYHA / functional class in the European CRT survey [10]. Nevertheless, it is likely that there will be an increased need for physicians to be proficient with CRT implantation, especially as these procedures occupy more operating room time than for standard devices (and are more affected by operator experience and skill). Although CRT CD improves patients outcome, this is at the expense of a greater rate of device-related complications compared with CD implantation. Evolution in lead design will hopefully improve lead stability and avoid redo procedures for lead displacement, high thresholds or phrenic nerve capture (e.g., with the advent of multipolar leads and electrical repositioning). Also, improvement in battery technology and more widespread use of features such as automatic left ventricular capture algorithms will hopefully prolong device lifespan of CRT CDs, which currently require more frequent box changes than standard CDs. This factor will also affect the overall cost of CRT-CD therapy, which is more expensive than standard CD therapy. ncremental cost effectiveness needs be to evaluated, taking into account the savings resulting from reduced heart failure hospitalization. Financial & competing interests disclosure Haran Burri is funded in part by the Research Foundation of La Tour Hospital, Meyrin, Switzerland, and has received speaker honoraria and fellowship support from Biotronik, Boston Scientific, Medtronic, St Jude Medical and Sorin. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Key issues Cardiac resynchronization therapy (CRT) with biventricular pacing has been demonstrated to improve clinical outcome and is indicated in patients with systolic heart failure who have a left ventricular ejection fraction of %, QRS duration of ms and New York Heart Association (NYHA) /V symptoms. A number of trials have also demonstrated the efficacy of CRT in patients with NYHA symptoms. The Resynchronization Defibrillation for Ambulatory Heart Failure Trial (RAFT) is a large randomized study that confirms the findings of these trials, and shows a significant reduction in the combined end point of mortality and heart failure hospitalization with CRT and an implantable cardioverter defibrillator (CRT-CD) compared with CD alone. The trial shows for the first time a significant reduction in mortality attributed to CRT in patients with NYHA symptoms. Subgroup analyses of the trial indicate that QRS duration and morphology significantly affect the response to therapy. There were more device-related adverse effects in the CRT-CD group compared with the CD group, the most frequent of which was lead dislodgment (that was unusually high in this study). Current European guidelines also include patients with NYHA symptoms for CRT, as long as QRS duration is 150 ms. American guidelines are currently being revised and are expected in 2011. References Papers of special note have been highlighted as: of interest of considerable interest 1 Tang AS, Wells GA, Talajic M Cardiac-resynchronization therapy for mild-to-moderate heart failure. N. Engl. J. Med. 363(25), 2385 2395 (2010). 2 Cleland JG, Daubert JC, Erdmann E The effect of cardiac resynchronization on morbidity and mortality in heart failure. N. Engl. J. Med. 352(15), 1539 1549 (2005). 3 Gras D, Bocker D, Lunati M mplantation of cardiac resynchronization therapy systems in the CARE-HF trial: procedural success rate and safety. Europace 9(7), 516 522 (2007). 4 Moss AJ, Hall WJ, Cannom DS Cardiac-resynchronization therapy for the prevention of heart-failure events. N. Engl. J. Med. 361(14), 1329 1338 (2009). The Multicenter Automatic Defibrillator mplantation Trial with Cardiac Resynchronization Therapy (MADT-CRT) was another large-scale landmark study randomizing CRT and an implantable cardioverter defibrillator (CRT CD) to CD in patients with New York Heart Association (NYHA) / symptoms, and found a significant reduction in heart-failure events in the CRT CD group. 5 Linde C, Abraham WT, Gold MR, St. John Sutton M, Ghio S, Daubert C. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J. Am. Coll. Cardiol. 52(23), 1834 1843 (2008). Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) was the first large-scale study of CRT in patients with NYHA symptoms. Although the primary end point of progression of heart failure was negative, the study showed significant reverse remodeling and reduced hospitalization with CRT. 6 Dickstein K, Vardas PE, Auricchio A 2010 focused update of ESC guidelines on device therapy in heart failure: an update of the 2008 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC guidelines for cardiac and resynchronization therapy. Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association. Europace 12(11), 1526 1536 (2010). 316 Expert Rev. Med. Devices 8(3), (2011)

Cardiac resynchronization therapy for mild-to-moderate heart failure Key Paper Evaluation The revised European guidelines include for the first time NYHA heart failure patients as an indication for CRT. 7 Zareba W, Klein H, Cygankiewicz Effectiveness of cardiac resynchronization therapy by QRS morphology in the Multicenter Automatic Defibrillator mplantation Trial-Cardiac Resynchronization Therapy (MADT-CRT). Circulation 123, 1061 1072 (2011). 8 Tomlinson DR, Bashir Y, Betts TR, Rajappan K. Accuracy of manual QRS duration assessment: its importance in patient selection for cardiac resynchronization and implantable cardioverter defibrillator therapy. Europace 11(5), 638 642 (2009). 9 Surawicz B, Childers R, Deal BJ, Gettes LS. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part : intraventricular conduction disturbances: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society: endorsed by the nternational Society for Computerized Electrocardiology. Circulation 119(10), e235 e240 (2009). 10 Dickstein K, Bogale N, Priori S The European cardiac resynchronization therapy survey. Eur. Heart J. 30(20), 2450 2460 (2009). 11 Higgins SL, Hummel JD, Niazi K Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J. Am. Coll. Cardiol. 42(8), 1454 1459 (2003). 12 Auricchio A, Stellbrink C, Butter C Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular conduction delay. J. Am. Coll. Cardiol. 42(12), 2109 2116 (2003). 13 Abraham WT, Young JB, Leon AR Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter defibrillator, and mildly symptomatic chronic heart failure. Circulation 110(18), 2864 2868 (2004). 14 Daubert C, Gold MR, Abraham WT Prevention of disease progression by cardiac resynchronization therapy in patients with asymptomatic or mildly symptomatic left ventricular dysfunction: insights from the European cohort of the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial. J. Am. Coll. Cardiol. 54(20), 1837 1846 (2009). The European cohort of REVERSE had a prolonged 2-year follow-up that showed a significant improvement of the primary end point of progression of heart failure. Website 101 US FDA www.fda.gov www.expert-reviews.com 317