Abstract 16450: The Impact of Left Ventricular versus Simultaneous Biventricular Pacing on Structural and Biochemical Reverse Remodeling in Patients With Heart Failure: Insights From the EvAluation of Resynchronization Therapy for Heart Failure (EARTH) Trial
Sabah SkafBernard ThibaultEileen O’MearaPaul KhairyAnnik FortierH. PrylutskaCéline PitreMichel WhiteAnique Ducharme
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Introduction: Cardiac Resynchronization Therapy (CRT) with simultaneous biventricular pacing (BiVP) is recommended for patients with heart failure and wide QRS, however up to a third of patients do not respond. GREATER-EARTH has demonstrated similar benefits with BiVP or LV pacing (LVP). Herein, we evaluate the effects of these two CRT modes on cardiac remodeling, evaluated by echocardiography and circulating biomarkers. Methods: 121 patients (LVEF≤35% and QRS≥120ms) referred for defibrillator implantation were randomized to BiVP or LVP for consecutive 6-month periods with cross-over. The primary endpoint was the change in LV end-systolic volume (LVESV) between patients with BiVP vs LVP from baseline to 6 months. Secondary endpoints included changes in LVEF, mitral regurgitation, RV and diastolic function. Changes in levels of markers of cardiac remodeling were also compared. Results: Both CRT pacing modes led to remodeling benefits after 6-months of therapy: LVESV decreased from 162±57mL at baseline to 130±63mL with BiVP vs 130±60 mL with LVP (p=0.68 between CRTs), with a positive response (≥15% LVESV reduction) being observed in 49% of patients with BiVP and 33% of LVP, p=0.09. Similarly, RV remodeling (dimension and RV-MPI) was equally improved with both pacing strategies (p=0.69 and p=0.38 respectively, between CRTs). Interestingly, estimated systolic PAP (from 43±14 to 37±10 and 41±14, p=0.008), selected indices of LV diastolic function such as indexed LA volume (p=0.045) and diastolic dysfunction grade (p=0.019), as well as changes in MR grade (p=0.004) were significantly improved only with BiVP. In parallel, there was a non-statistically significant decrease in NT-proBNP, from 2559±3296 to 1554±2092 and 1630±1950 ng/L, with BiVP and LVP respectively (p=0.093) as well as a trend in decreasing PIIINP levels, from 8.3±3.0 to 7.5±2.7 and 7.6±2.3 with BiVP and LVP respectively, p=0.097. Conclusions: In this prospective, multicenter, randomized, double-blind study, both BiVP and LVP resulted in improvements in LV remodelling assessed by echocardiography, while more patients responded to BiVP. BiVP may be superior to LVP to improve multiple aspects of myocardial remodeling and should remain the preferred mode of CRT in patients with advanced HF.Keywords:
Ventricular remodeling
Clinical endpoint
Surrogate endpoint
Drs. Manyara, Ciani, and Taylor make the important point that randomized controlled trials (RCTs) using a primary surrogate endpoint should be more transparent in their reporting details of biomarkers in trials. They suggest a clear statement concerning use of a surrogate primary endpoint and providing information on validity and limitations of the surrogate. They announce a new project to develop SPIRIT and CONSORT extensions specific to surrogate endpoints SPIRIT-SURROGATE and CONSORT-SURROGATE. There are no fully qualified and validated surrogate biomarkers for Alzheimer's disease (AD) RCTs and none that could serve as a primary RCT endpoint. As described by the US Food and Drug Administration (FDA) a surrogate endpoint is a clinical trial endpoint used as a substitute for a direct measure of how a patient feels, functions, or survives.1 A surrogate endpoint does not measure the clinical benefit of primary interest in and of itself, but rather is expected to predict clinical benefit. Epidemiologic, therapeutic, pathophysiologic, or other scientific data provide the evidentiary basis for establishing a biomarker as a surrogate. A surrogate must change in response to multiple therapies across multiple RCTs and must explain the change in clinical outcome as well as correlate with it.2 Designation as a surrogate requires substantial statistical evidence based on trial meta-analyses.3 Robert Califf, US Commissioner of Food and Drugs, makes the point that “the single most common and serious error in the evaluation of biomarkers is the assumption that a correlation between the measured level of a biomarker and a clinical outcome means that the biomarker constitutes a valid surrogate.”2 The primary outcome of the RCTs of the aducanumab trials was the Clinical Dementia Rating–Sum of Boxes (CDR-SB; NCT02484547; NCT02477800) and the primary endpoint was the drug–placebo difference on this outcome at week 76. Accelerated approval of aducanumab was based on amyloid plaque lowering as shown by amyloid positron emission tomography (PET) considered reasonably likely to predict clinical benefit.4 Reasonably likely surrogate endpoints are supported by a strong mechanistic and/or epidemiologic rationale, but the amount of clinical data available is not sufficient to support them as a validated surrogate endpoint (defined above). Reasonably likely surrogate endpoints are used to support the FDA's Accelerated Approval program, which is intended to provide patients with serious diseases more rapid access to promising therapies.5 Accelerated approval is followed by post-marketing studies to determine whether the reasonably likely surrogate endpoint, in fact, predicts the clinical benefit. The aducanumab trials would not have been included in reporting requirements for trials using surrogate primary endpoints; their primary endpoints were drug–placebo differences on clinical measures; amyloid lowering was not a primary or a secondary endpoint and was not included in the sequential testing rank order implemented (NCT02484547; NCT024778006). I concur with Drs. Manyara, Ciani, and Taylor that biomarkers should be described in greater detail in the SPIRIT and CONSORT criteria. Using the FDA biomarker lexicon, these measures would be described as risk/susceptibility, diagnosis, monitoring, pharmacodynamic/response, predictive, prognostic, or safety biomarkers.7, 8 Candidate surrogate biomarkers or biomarkers that might be considered reasonably likely to predict clinical benefit are pharmacodynamic biomarkers. Biomarkers that have been qualified for a specific context of use in the RCT should be described in the SPIRIT and CONSORT reporting framework.9 The SPIRIT-SURROGATE and CONSORT-SURROGATE initiative is important and might be more broadly conceived as a SPIRIT-BIOMARKER and CONSORT-BIOMARKER initiatives. Another important adjustment to the SPIRIT and CONSORT criteria is to require the reporting of ethnicity and race among trial participants. These data are sometimes not collected and often omitted from clinical trial reports.10 They are critically important to assess our success in increasing the diversity of clinical trial populations. JC is supported by NIGMS grant P20GM109025; NINDS grant U01NS093334; NIA grant R01AG053798; NIA grant P20AG068053; NIA grant P30AG072959; NIA grant R35AG71476; Alzheimer’s Disease Drug Discovery Foundation (ADDF); Ted and Maria Quirk Endowment; and the Joy Chambers-Grundy Endowment. J.C. has provided consultation to Acadia, Alkahest, AlphaCognition, AriBio, Biogen, Cassava, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, Karuna, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, Prothena, ReMYND, Resverlogix, Roche, Signant Health, Suven, and United Neuroscience pharmaceutical, assessment, and investment companies. Author disclosures are available in the supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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Indications for cardiac-resynchronization therapy (CRT) in patients with heart failure include a prolonged QRS interval (≥120 msec), in addition to other functional criteria. Some patients with narrow QRS complexes have echocardiographic evidence of left ventricular mechanical dyssynchrony and may also benefit from CRT.
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Abstract Investigators use a surrogate endpoint when the endpoint of interest is too difficult and/or expensive to measure routinely and when they can define some other, more readily measurable, endpoint, that is sufficiently well correlated with the first to justify its use as a substitute. A surrogate endpoint is usually proposed on the basis of a biologic rationale. In cancer studies with survival time as the primary endpoint, surrogate endpoints frequently employed are tumour response, time to progression, or time to reappearance of disease, since these events occur earlier and are unaffected by use of secondary therapies. In early drug development studies, tumour response is often the true primary endpoint. We discuss the investigation of the validity of carcinoembryonic antigen (a tumour marker present in the blood) as a surrogate for tumour response. In considering the validity of surrogate endpoints, one must distinguish between study endpoints that provide a basis for reliable comparisons of therapeutic effect, and clinical endpoints that are useful for patient management but have insufficient sensitivity and/or specificity to provide reproducible assessments of the effects of particular therapies.
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Surrogate endpoints predict the occurrence and timing of a clinical endpoint of interest (CEI). Substitution of a surrogate endpoint for a CEI can dramatically reduce the time and cost necessary to complete a Phase III clinical trial. However, assurance that use of a surrogate endpoint will result in a correct conclusion regarding treatment effect on a CEI requires prior rigorous validation of the surrogate. Surrogate endpoints can also be of substantial use in Phase I and II studies to assess whether the intended therapeutic pathway is operative, thus providing assurance regarding the reasonableness of proceeding to a Phase III trial. This paper discusses the uses and validation of surrogate endpoints.
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There are strong ethical and practical reasons for hastening decision-making about the efficacy of new treatments for human immunodeficiency virus (HIV) infection. One strategy is to use early markers of disease progression, such as CD4+ lymphocyte levels, as surrogates for ultimate clinical endpoints, such as the development of acquired immune deficiency syndrome (AIDS) or death, in the evaluation of new therapies. We used a simple model of transitions among three health states (well; alive but with an adverse marker; and having experienced a definitive clinical endpoint) to examine the extent to which treatment comparisons based on the surrogate endpoint predict ultimate clinical benefits. With parameters chosen to model the treatment of HIV infection, computer simulations of clinical trials demonstrated substantial time savings by use of the surrogate endpoint. However, reliance on the surrogate led to serious overestimates of ultimate clinical benefit if treatment entailed delayed toxicity or had only transient beneficial effects. Likewise, reliance on the surrogate led to serious underestimates of ultimate clinical benefit when the treatment had no effect on the transition from well to the marker state but did reduce the rates of transition from the marker state to the ultimate clinical endpoint and directly from the well state to the ultimate clinical endpoint.
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Background: Surrogate endpoint trials can test strategies more efficiently, but are accompanied by uncertainty about the relationship between changes in surrogate markers and clinical outcomes. We sought to determine recent trends in the publication of cardiovascular trials with surrogate outcomes. Methods: We identified cardiovascular trials with primary surrogate endpoints published in NEJM, Lancet, and JAMA from January 1990 to December 2011. Trends in publication of surrogate endpoint trials, and the success of the trials in meeting their primary endpoint were evaluated. We also tracked the above three journals for publication of clinical outcome trials on the interventions tested in surrogate trials. Results: We screened 3016 articles and identified 848 primary hypothesis cardiovascular trials, which included 220 surrogate endpoint trials. There was an increase over time in the number of surrogate endpoint trials (P=0.01). From the total of 220 surrogate trials, 157 (71.4 %) were positive for their primary endpoint. Sixty (27.5%) surrogate trials were followed by at least one clinical outcome trial. Among these 60 surrogate trials, in 24 cases the outcomes trial results validated the positive surrogates; whereas in 21 subsequent outcome trials were negative following positive results on a surrogate. However, we identified only 3 examples in which the surrogate trial was negative but a subsequent outcomes trial was conducted and showed benefit (Figure). Conclusions: Cardiovascular surrogate outcomes trials are common, frequently show superiority of the tested intervention and are infrequently followed by a prominent outcomes trial. However, when there was a high profile clinical outcomes study, half of the positive surrogate trials were not validated. Cardiovascular surrogate outcome trials may be more appropriate for excluding benefit from the patient perspective than for identifying it.
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