ECHO-CRT: Resynchronization No Help, May Be Harmful in Narrow-QRS Heart Failure

September 03, 2013

AMSTERDAM — No, cardiac resynchronization therapy (CRT) will not improve outcomes in patients with narrow QRS intervals (ie, <130 ms) who nonetheless have evidence of ventricular dyssynchrony by echocardiographic criteria. In fact, it may actually increase the risk of cardiovascular death.

That's the take-away from the Echocardiography Guided Cardiac Resynchronization Therapy (EchoCRT) study [1], published today in the New England Journal of Medicine in sync with its release here at the European Society of Cardiology (ESC) 2013 Congress. The findings all but shut down hopes that the usefulness of CRT might be extended to HF patients without significant QRS prolongation who have echo evidence of ventricular dyssynchrony.

"Our results reinforce the notion that, at least until new methods of assessment are developed, QRS width (with or without mechanical dyssynchrony) remains the primary determinant of response to CRT," write the authors, led by Dr Frank Ruschitzka (University Hospital Zurich, Switzerland).

An accompanying editorial from Dr Clyde W Yancy (Northwestern University, Chicago, IL) and Dr John JV McMurray (University of Glasgow, UK) agrees, adding that the study also suggests that "CRT use in patients with a QRS duration of less than 120 ms is unwarranted and should not be considered" [2]. It also argues against the use of echo criteria for trying to identify patients with <130-ms QRS intervals who might respond to CRT.

Dr Kurt Huber (Wilhelminen Hospital, Vienna, Austria), who officiated at a press conference on EchoCRT, pointed out for heartwire that the trial's patients clearly needed an ICD, "but it hadn't been clear whether the CRT function was really necessary. And now the study shows that it's not necessary and it could also be harmful." He cautioned, however, that there were too few patients in the trial to make any firm conclusions about harm from CRT. "What clear is that we shouldn't use CRT in patients with narrow QRS intervals."

Although guidelines sanction CRT in HF patients with a QRS of at least 120 ms (and an LVEF <35%), they increasingly recognize that its effectiveness goes up with greater QRS prolongation, especially in the presence of left-bundle-branch block.

As described at its formal presentation at the ESC sessions by senior author Dr Johannes Holzmeister (University Hospital, Zurich, Switzerland), EchoCRT was conducted at 115 centers in the US, Canada, Israel, Australia, and Europe. It had enrolled 809 patients when it was halted for futility; they had been followed for an average of 19.4 months.

The trial had entered adult patients with NYHA class 3-4 heart failure stable on medical therapy, with an LVEF <35%, an indication for an implantable cardioverter defibrillator (ICD), a QRS duration <130 ms, a left ventricular end-diastolic diameter >55 mm, and echocardiographic evidence of LV dyssynchrony. In the final randomized population, the mean QRS interval was 105 ms, according to Holzmeister.

Dyssynchrony was defined as an opposing-wall delay in the peak systolic velocity of at least 80 ms by tissue-Doppler imaging (TDI) or a delay in the anteroseptal-to-posterior wall >130 ms by speckle-tracking radial strain imaging.

All patients were implanted with an ICD-CRT device (CRT-D) and transvenous atrial, right ventricular, and LV leads and then randomized to CRT-on (n=404) and CRT-off (n=405) groups; the defibrillator was engaged in all patients. Treatment assignment was blinded to everyone except the implanting physicians.

Hazard Ratio (95% CI) for Outcomes, CRT-On Group vs CRT-Off Group

End point HR (95% CI) p
Primary: All-cause mortality or HF hospitalization 1.20 (0.92–1.57) 0.15
HF hospitalization 1.16 (0.87–1.55) 0.25
All-cause mortality 1.81 (1.11–2.93) 0.02
Death from CV event 2.26 (1.27–4.01) 0.004
Death from heart failure 1.74 (0.80–3.81) 0.15

When the trial halted, the primary end point had occurred in 218 patients with no significant difference between the two groups; however, there was a significant mortality increase in the CRT-on group (p=0.02). The group showed an even greater imbalance in cardiovascular death (p=0.004).

There was no significant difference in changes in NYHA class from baseline to six months, nor were there differences in quality of life by the Minnesota Living with Heart Failure Questionnaire.

About 19% of CRT-on and 15.6% of CRT-off patients received ICD shocks, and significantly more CRT-on patients had inappropriate shocks, 5.0% vs 1.7% (p=0.01).

"The excess risk of CRT among patients included in the EchoCRT study who had heart failure and a narrow QRS complex is of particular concern," write the authors, "because it serves as a reminder that the implantation of LV leads and the ongoing care of patients treated with CRT . . . are not without challenges." They point out that adverse events after device implantation were significantly more common in the CRT-on group, primarily due to lead-related issues.

As the assigned discussant for Holzmeister's presentation, Dr Stefan D Anker (Charité Universitätsmedizin, Berlin, Germany) proposed that the suggestion of a hazard from the leads in the CRT-on group could represent information bias, that it "could simply be due to the fact you have looked more carefully in one group than in the other."

Anker said EchoCRT's findings are in line with those of a recent meta-analysis [3] that posited that CRT may be of little benefit, with respect to hard clinical end points, in patients with QRS intervals <130 ms, and there are questions about such a benefit even in the 130-ms to 139-ms range, he said. "In this particular group, we need more evidence from clinical trials. And whether this uncertainty extends to patients beyond 140 ms and even up to 149 ms is uncertain." What is certain, according to Anker, "is that there is a strong mortality reduction in patients with a QRS above 150 ms."

EchoCRT was supported by Biotronik and GE Healthcare. Ruschitzka discloses receiving fees as an executive committee member for the trial and for serving on speaker's bureaus for Servier and St Jude Medical and an advisory board for Cardiorentis. Disclosures for the coauthors are listed on www.nejm.org . Yancy had no disclosures. McMurray discloses grants from Guidant Europe and Cardiokinetix. Huber has previously disclosed being a member of a speaker's bureau for AstraZeneca, Daiichi Sankyo, and Eli Lilly. Anker has recently disclosed consulting for Amgen, Bosch Healthcare, GlaxoSmithKline, Helsinn, LoneStar Heart, Novartis, Professional Dietetics, PsiOxus, Relypsa, SHL Telemedicine, and Thermo Fisher; receiving grant support from Vifor Pharm and lecture fees from Novartis; holding patents with Brahms and Charité Berlin, and receiving royalties from Imperial College.

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