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255study. On average, CAFR achieved 80.8±14.3% eCRT pacing and 83.2±11.9% Vp during AF. There are

256very limited data for delivery of CRT during AF in CRT patients without such an algorithm. Based on

257the limited acute data from this study, the eCRTAF algorithm may produce large increases in %Vp

258and %eCRT when compared to patients without a rate regularization algorithm.

259Although there are data on the optimal %Vp for CRT during AF, there are no similar dataTfor %eCRT

260during AF. Because each beat classified as effective CRT is a V pace beat byCRIPdefinition, loss of %eCRT

261will be at least as clinically important as the loss of %Vp. However, establishing a %eCRT threshold

262for optimal CRT will require additional clinical data.

263It has been demonstrated in several retrospective analyses that small decreases in %Vp (1-3%) are

264associated with a significant increase in mortality.1MANUS-3 Koplan et al. showed that a decrease of as little

265as 1-4 % in V pacing was associated with a significant negative impact on survival free from HF

266hospitalization and all-cause mortality.2 In addition, a history of AF was a significant independent

267predictor of mortality in CRT patients. Hayes et al. also showed in a retrospective study of over

26836,000 CRT patients that a reduction from 1-5% in Vpacing was associated with increased mortality.

269Their analysis alsoACCEPTEDshowed AF had an additive negative effect on mortality.1 The magnitude of the

270increase in %Vp in the current study (7%) suggests that this algorithm could have a significant clinical

271benefit in CRT patients with high AF burden.

272The multi-variate analysis suggests that the biggest impact of the algorithm may be in patients with

273paroxysmal AF although the small number of subjects (N=5) makes it difficult to extrapolate these

274results. This is, however, a plausible correlation as a retrospective analysis of over 12,000 CRT

275subjects with AF demonstrated that those with paroxysmal AF saw the greatest drop in %Vp during

276AF compared to persistent or permanent AF.8 Since low %Vp during AF was also a strong predictor of

277response in the multivariate analysis, its correlation with paroxysmal AF provides an explanation for

278why this group may see the largest effect.

279Our data show that with the eCRTAF algorithm, 5 subjects improved from <90% to >90% eCRT and

280an additional 5 subjects improved from <95% to >95% eCRT. Moreover, in the cohort receiving <80

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281%Vp during Control, the algorithm improved %eCRT by a mean of 16%. The ability to deliver more

282eCRT during AF may lead to better resynchronization and consequently reduce heart failure

283symptoms. AV junctional ablation (AVJA) is associated with improved outcomes in observational

284trials of patients with permanent AF who did not experience clinical improvement and/or an

285adequate biventricular pacing percentage with rate limiting drugs,9-13 but there are no randomizedT

286controlled trials of AVJA for this indication. The eCRTAF algorithm has theCRIPpotential to increase

287biventricular capture during AF without AVJA . This could improve outcomes in patients not

288previously known to have AF and avoid the need for AVJA in others by achieving high rates of

289biventricular capture. It may also help to identify others for whom AVJA is the only appropriate way

290to achieve sufficient biventricular capture. MANUS

291When considering the applicability of this algorithm to the general CRT patient population, it is

292important to keep in mind that, while most CRT patients do not have AF at initial implant, many will

293develop AF over the course of their disease. A recent retrospective analysis by Hayes et al. suggests

294that as many as 30% of CRT patients will experience clinically significant AF (≥1 day of AT/AF for > 6

295hours) within 2ACCEPTEDyears of implant.14

296Because the eCRTAF algorithm involves additional processing, the impact on device longevity may be

297a concern. According to the manufacturer, a patient with permanent AF (worse-case scenario) will

298experience a 2-3% decrease in device longevity. A 2.5 BPM increase in pacing rate will have an

299additional 1-2% impact on device longevity.

300Limitations

301The majority of the subjects included in this study had permanent or persistent AF. Given the small

302number of paroxysmal AF subjects in the study, additional clinical data is needed to confirm the

303preliminary findings about the algorithm behavior in this group. In addition, the comparison of the

304new algorithm to a control of no rate regularization algorithm at all was only done with a small acute

305dataset. The difference in a chronic ambulatory setting remains to be determined.

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321References

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