Holzmeister, Johannes

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ESC CLINICAL TRIAL UPDATECOMMENTARYTime to RethinQ PROSPECT?Johannes Holzmeister*Cardiology, University Hospital Zurich, CH-8091 Zurich, SwitzerlandOnline publish-ahead-of-print 30 August 2009This commentary refers to ‘Characteristics of heartfailure patients associated with good and poor responseto cardiac resynchronization therapy: a PROSPECT(Predictors of Response to CRT) subanalysis’†, by R.J.van Bommel et al., on page 2470Cardiac resynchronization therapy (CRT) is the most successfultherapy in treating chronic heart failure patients since the introduc-tion of b-blockers, angiotensin-converting enzyme (ACE) inhibi-tors, and spironolactone into the therapeutic regimen. Recentstudies (REVERSE, MADIT-CRT) will probably expand the indi-cation for CRT to mild and asymptomatic heart failure patients[New York Heart Association (NYHA) functional class I and II],an enormous task for physicians and healthcare providers. CRTwith current indications appears to improve the clinical status in70% of patients. This compares well with the effects of treat-ments of chronic and life-threatening diseases in other medicalfields.However, indications for CRT are currently based to a largedegree on QRS width in an attempt to detect mechanical dyssyn-chrony under the assumption that correction of dyssynchrony isthe main mechanism of action. The idea behind the original Predic-tors of Response to CRT (PROSPECT) study was to identify in anon-randomized observational design the predictive value of pre-defined echocardiographic parameters of mechanical dyssynchronywith regard to clinical and left ventricular mechanical outcomeafter CRT.1 Twelve previously published parameters of dyssyn-chrony, both conventional and tissue Doppler-based methods,had finally been used in 426 CRT patients at 53 centres. Consider-ing the intended purpose of the PROSPECT study, the overallresults were not encouraging, with no single echocardiographicdyssynchrony parameter being highly predictive of the CRTresponse at follow-up. There seemed to be no ‘holy grail’ of echo-cardiographic dyssynchrony parameter which by itself could beused for decision making regarding CRT.Is this the end of the ‘mechanical dyssynchrony’ hypothesis? Isechocardiography useless in predicting CRT respsonse despitenumerous single-centre studies showing high sensitivity and speci-ficity? Immediately after publication of the PROSPECT results,numerous concerns regarding the design of the study and theway in which it was conducted were raised, especially regardingpatient selection as well as echocardiographic assessment. Con-cerning patient selection, 20.2% had a left ventricular ejection frac-tion (LVEF) .35%, and 37.8% had a left ventricular end-diastolicdiameter (LVEDD) ,65 mm, which ultimately raised the questionof how reverse remodelling could be achieved in a non-dilatedheart.2 This, together with a substantial interobserver variabilityand large percentage of non-assessable echocardiographicstudies, indicated a lack of standardized data acquisition and analy-sis. In addition, tissue Doppler imaging (TDI) data were obtainedusing echo machines from thee different ultrasound providerswithout standardization of frame rates, and three different soft-ware programs were used for offline data analysis. Furthermore,there was no information on left ventricular lead placement andpercentage biventricular pacing. Taken together, important techni-cal limitations as well as suboptimal patient selection may impor-tantly confound and limit the interpretation of the initialPROSPECT study results.Van Bommel et al. have performed a subgroup analysis of 286 ofthe total of 498 patients which had initially been enrolled intoPROSPECT;3 426 of those had been originally analysed in themain PROSPECT study after 31 early exits and the exclusion of41 patients with narrow QRS (,130 ms). Eventually, this substudyanalysed 57% of the total PROSPECT population, further excluding15 patients who died, 18 patients who had been lost for the6-month follow-up visit, and 44 patients with incomplete datafrom the 6-month follow-up visit, thus ending up with 286 patientswith a complete data set and paired left ventricular end-systolicvolume (LVESV) measurements. Overall, this represents quite asubstantial reduction compared with the 498 originally enrolledpatients.In order to dissect the response to CRT, the authors groupedpatients according to both a combined clinical and a pure echocar-diographic response. Echocardiographically, subgroups wereformed consisting of so-called ‘super-responders’ with a reductionof .30% in LVESV; ‘responders’ with a 15–29% reduction inLVSEV; ‘non-responders’ without evidence of reverse remodellingand reduction of LVESV between 0 and 14%; and ‘negative respon-ders’ with echocardiographic signs of disease progression despiteCRT with an increase in LVESV after 6 months. Clinically, theyThe 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: þ41 44 2552438, Fax: þ41 44 2554401, Email: Johannes.Holzmeister@usz.ch† doi:10.1093/eurheartj/ehp368Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.European Heart Journal (2009) 30, 2436–2437doi:10.1093/eurheartj/ehp367grouped their patients according to a combined clinical compositescore (CCS) measured 6 months after implantation. A positiveclinical response was defined as the patient surviving and notbeing hospitalized for heart failure, demonstrating improvementin NYHA class at the last observation carried forward, or havingmoderate or marked improvement in patient global assessmentscore at the last observation carried forward. Finally, using bothclinical and echocardiographic data, they formed three subgroupsaccording to clinical and/or echocardiographic response: (1)þ/þ responders (improved CCS and a reduction in LVESV.15%); (2) þ/2 responders (improved CCS or a reduction inLVESV .15%); and (3) 2/2 responders (no improvement inCCS and no reduction in LVESV .15%).When looking at the pure mechanistic outcome, i.e. echocardio-graphic parameters of left ventricular structure and function, of the286 studied patients, 56.3% had significant evidence of reverseremodelling. It is well known that some patients have an extraordi-narily good response to CRT (the so-called ‘super-responders’)with a .30% reduction of LVESV. Compared with patients whodeteriorated, the ‘negative responders’, it is not surprising that sig-nificantly more patients had a non-ischaemic aetiology (resulting inless scar burden and more viable myocardium for reverse remo-delling) in the ‘super-responder’ subgroup. These patients alsoless commonly had a history of ventricular tachycardia, whichmight be explained by the underlying disease aetiology and thedisease state, with significantly fewer patients in NYHA class IVin this subgroup. Interestingly, at baseline ‘super-responders’were significantly more dyssynchronous than the ‘negative respon-ders’, as evidenced by a larger interventricular mechanical delay(IVMD; 55+35 ms vs. 25+ 39 ms, P ¼ 0.0002) and septal tolateral delay on tissue Doppler (68+44 ms vs. 44+ms; P ¼0.0022). This observation is in line with a recent report in theCARE-HF trial, showing that patients with wide QRS and andIVMD .49 ms treated with CRT showed superior survival.4Indeed, pathophysiologically, IVMD reflects left to right heart inter-action and is useful only in patients with a broad QRS complex;conversely, IVMD is virtually absent in patients with a narrowQRS complex.5 Importantly, both echocardiographic parameterscan be measured relatively easily, and IVMD is one of the mostrobust parameters with respect to interobserver variability.Hence, the findings of van Bommel and colleagues3 support forthe first time in a multicentre environment with .53 centresthe concept that we are in fact treating mechanical dyssynchronywith CRT.When looking at the CCS after 6 months, a greater percentageof patients showed signs of clinical benefit than evidence of reverseremodelling. In fact, 209 out of 286 patients (73%) had a positiveCCS, while only 114 patients showed a clinical response withoutsignificant change in LVSEV (40%). This is remarkable but notvery surprising. CRT can stabilize patients with advanced heartfailure, i.e. ‘non-progressors’; however, these patients do notnecessarily have signs of reverse remodelling, possibly due to analready too advanced disease and/or scar burden. Yet, clinicalimprovement is of great interest for the patient and shouldtherefore importantly be counted as therapeutic success. This iswhy withholding CRT from a patient with a QRS .130 ms justbecause of a lack of echocardiographic signs of dyssynchronydoes not seem to be justified, merely based on a slightly inferiorprediction of reverse remodelling.Taken together, the current substudy of PROSPECT by vanBommel et al.3 adds important evidence to the current literature.However, even after this careful examination of the available datawithin the PROSPECT cohort and a positive correlation betweenbaseline echocardiographic dyssynchrony and reverse remodelling,the presented evidence does not appear to be strong enough tochange current clinical practice and exclude patients fulfillingcurrent guidelines for CRT simply based on lack of dyssynchronyon echocardiography. Other limitations, which were equallyinherent to the original PROSPECT trial, are also problematicfor the current substudy. Importantly, the short-term follow upof only 6 months is far too little to assess the entire effect ofCRT on remodelling and, eventually, morbidity and mortality.Indeed, had CARE-HF been stopped after 6 months, no significanteffect on morbidity and mortality would have been observed; fur-thermore, ongoing reverse remodelling was evident even after 18months of follow-up in the CRT substudy.6 As the authors state,the goal is to measure the impact of mechanical dyssynchronyon clinical outcome after CRT. In the end, this question can onlybe answered by an adequately powered randomized clinical trial.Such a trial is already underway investigating the impact onmorbidity and mortality of baseline dyssynchrony in patients withsymptomatic heart failure, LVEF ,35% and a QRS ,130 ms(Echocardiography Guided Cardiac Resynchronization Therapy,EchoCRT, NCT00683696).Conflict of interest: none declared.References1. Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J,Abraham WT, Ghio S, Leclercq C, Bax JJ, Yu CM, Gorcsan J 3rd, St JohnSutton M, De Sutter J, Murillo J. Results of the Predictors of Response to CRT(PROSPECT) trial. Circulation 2008;117:2608–2616.2. Bax JJ, Gorcsan J 3rd, Echocardiography and noninvasive imaging in cardiac resyn-chronization therapy: results of the PROSPECT (Predictors of Response toCardiac Resynchronization Therapy) study in perspective. J Am Coll Cardiol 2009;53:1933–1943.3. Van Bommel RJ, Bax JJ, AbrahamWT, Chung ES, Pires LA, Tavazzi L, Zimetbaum PJ,Gerritse B, Kristiansen N, Ghio S. Characteristics of heart failure patients associ-ated with good and poor response to cardiac resynchronization therapy: aPROSPECT (Predictors of Response to CRT) subanalysis. Eur Heart J 2009;30:2470–2477. First published on 30 August 2009. doi:10.1093/eurheartj/ehp368.4. Richardson M, Freemantle N, Calvert MJ, Cleland JG, Tavazzi L; CARE-HF StudySteering Committee and Investigators. Predictors and treatment response withcardiac resynchronization therapy in patients with heart failure characterized bydyssynchrony: a pre-defined analysis from the CARE-HF trial. Eur Heart J 2007;28:1827–1834.5. Beshai JF, Grimm RA, Nagueh SF, Baker JH 2nd, Beau SL, Greenberg SM, Pires LA,Tchou PJ; RethinQ Study Investigators. Cardiac-resynchronization therapy in heartfailure with narrow QRS complexes. N Engl J Med 2007;357: 2461–2471.6. Ghio S, Freemantle N, Scelsi L, Serio A, Magrini G, Pasotti M, Shankar A,Cleland JG, Tavazzi L. Long-term left ventricular reverse remodelling withcardiac resynchronization therapy: results from the CARE-HF trial. Eur J HeartFail 2009:11:480–488.Commentary 2437

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