Author + information
- Published online August 2, 2017.
- aMercy Hospital-North Iowa, Mason City, Iowa
- bDepartment of Cardiology, University of Iowa, Iowa City, Iowa
- ↵∗Address for correspondence:
Dr. Brian Olshansky, Department of Cardiology, University of Iowa, 200 Hawkins Drive, Room 4462A JCP, Iowa City, Iowa 52242.
The prognostic significance of the PR interval is controversial in healthy subjects (1). Long considered benign, even in recent reports (2), in the Framingham population, prolonged PR intervals were associated with a 2-fold adjusted risk of atrial fibrillation, 3-fold adjusted risk of pacemaker implantation, and a 1.4-fold adjusted risk of all-cause mortality (3). Pooled data from prospective cohort studies support the relationship of PR prolongation and atrial fibrillation (4). In the Copenhagen ECG study, data from 288,181 individuals followed over 5.7 years showed that a PR interval in the ≥95th percentile was associated with increased risk of atrial fibrillation in a multivariable model but increased risk was also present in the bottom 5th percentile, at least, for women (5). Thus, the relationship was nonlinear.
PR prolongation in patients with stable coronary artery disease in the Heart and Soul Study was associated with greater risk of heart failure hospitalization, mortality, cardiovascular mortality, and the combined endpoint of heart failure hospitalization or cardiovascular mortality (6). In the MOST (MOde Selection Trial in sinus node dysfunction) trial, although patients with PR intervals >200 ms were older, more likely men, and more likely having heart failure or hypertension, in a multivariable model, first-degree atrioventricular (AV) block was associated with greater risk of death, stroke, and heart failure hospitalization (7). Mechanisms responsible for association of outcomes related to PR prolongation may be due to specific components of the PR interval (8), genetics (9), physiology, or electrophysiology.
The importance of the PR interval in patients undergoing cardiac resynchronization therapy (CRT) is inconclusive. An analysis of the CARE-HF (CArdiac REsynchronization-Heart Failure) study indicated that a PR interval >200 ms predicted death or unplanned heart failure hospitalization strongly despite shortening with CRT-P (cardiac resynchronization pacemaker) (6). Prognostic implication of PR prolongation is supported further by data showing less reverse remodeling in patients with PR intervals ≥200 ms, particularly for those with a non–left bundle branch block (LBBB) (10). As a continuous variable, PR interval had no prognostic significance regarding a clinical composite score in the PROSPECT-ECG (Predictors of Response to CRT PROSPECT-ECG study) study (11).
The COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial (12), a trial of 1,520 patients, randomized to CRT or optimal medical therapy, evaluated the primary endpoint of heart failure hospitalization and total mortality. In a subanalysis, evaluating the same endpoint, the association of the PR interval (all >150 ms but 52% >200 ms) to outcomes was considered. Those with PR intervals <200 ms, randomized to optimal medical therapy, fared better than did those with PR intervals ≥200 ms (hazard ratio [HR]: 1.41; p = 0.044) but patients randomized to CRT improved with similar outcomes regardless of the baseline PR interval (HR: 1.14; p = 0.19). Although CRT was superior to optimal medical management, the strength of the association appeared greater for those patients with longer (HR: 0.54; p < 0.01) rather than shorter (HR: 0.71; p = 0.02) PR intervals. However, the interaction between PR interval and treatment was not significant (p = 0.17). Similar to the Copenhagen ECG study (5), the relationship between the PR interval and outcomes was nonlinear. Thus, not surprisingly, as a continuous variable, and similar to data mentioned previously, PR interval did not predict outcomes (12). However, although PR prolongation appeared to be a risk marker and may be a modifiable physiological parameter, the study was not powered to provide definitive data in this regard.
One particular, and important, group for which the PR interval may be modifiable is the population with non-LBBB, a group notoriously unresponsive to CRT. Data from the MADIT-CRT (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy) trial (13) showed that those with PR prolongation ≥230 ms and non-LBBB had an 81% decrease in risk of all-cause mortality and 73% reduction in risk of heart failure hospitalization and death with CRT versus an implantable cardioverter-defibrillator (ICD) alone (13). For those with shorter PR intervals, CRT was associated with an increased risk of heart failure and death versus ICD alone (HR: 1.45; p = 0.078; interaction p < 0.001) and a >2-fold mortality (HR: 2.14; p = 0.022; interaction p < 0.001).
To add to the complexity, in an inverse probability-weighted analysis of 26,451 CRT eligible patients from the National Cardiovascular Data Registry (NCDR), a PR interval ≥230 ms was associated with older patients and with more comorbidities but, after adjustment, a PR interval ≥230 ms was associated with increased risk of heart failure hospitalization or death among CRT defibrillator recipients but not among ICD recipients (14). Without an optimal therapy control group, it is hard to draw substantial conclusions. Thus, implications regarding PR prolongation remain incomplete in the CRT population.
The REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) study was a double-blind, randomized, controlled trial of CRT “on” versus “off” for 2 years (and then “on” for 5 years for all) in 610 patients with mild heart failure. The study was negative based on the primary endpoint of a clinical composite score response but heart failure hospitalization and mortality favored CRT. In this issue of JACC: Clinical Electrophysiology, Senfield et al. (15) revisited the REVERSE study and performed a retrospective analysis evaluated the PR interval (considered as <180 ms or >180 ms, by 20-ms increments and as a continuous variable) as it related to first heart failure hospitalization and mortality in patients undergoing CRT during the 2-year randomized period and as part of a 5-year follow-up.
In the REVERSE study, CRT had similar effectiveness for those with shorter (HR: 0.34) versus those with longer (HR: 0.57) PR intervals; the interaction between PR and CRT was not significant (p = 0.33). Similar results were found with incremental changes in PR interval and PR interval as a continuous variable (not surprisingly). Specifically, for the non-LBBB patients with PR intervals >230 ms, the findings from MADIT-CRT trial were not replicated. However, only 46 patients had PR intervals ≥240 ms and only 174 had PR intervals ≥200 ms (of whom some were randomized to CRT “off”); even fewer had a non-LBBB at these PR intervals. Although the Kaplan-Meier curves diverged when considering PR intervals at a cutpoint of 180 ms, the results remained insignificant (HR: 1.13). In an adequately powered trial, considering other PR interval values, this may become significant.
Many in the “prolonged PR interval” group were still in the normal range. This is problematic especially because relationships between PR interval and outcomes are nonlinear. Programming characteristics of the devices and minimal PR interval at study entry were not discussed but both factors may play a role in outcomes because to capture the ventricles with short PR–AV intervals, of necessity, the programming characteristics may be such that the short AV intervals have caused a “pacemaker syndrome,” in which the AV paced relationships caused nearly simultaneous atrial and ventricular contraction. The nonlinear relationship of PR to outcomes may in part be due to this.
In the REVERSE study, it is unclear when and after what drugs the PR interval was measured. The bottom line is that these results are no more definitive than those already available and they cannot refute results from prior reports. The data are inadequate to make claims about the relationship of the PR interval to CRT.
Data from the REVERSE study, COMPANION trial, MADIT-CRT trial, National Cardiovascular Data Registry, and the Januszkiewicz et al. (10) study reflect a compelling point: the analyses are retrospective and not designed to address the issue of the PR interval. Moreover, the studies do not have the same comparator. In the National Cardiovascular Data Registry database and MADIT-CRT trial, it was an ICD. In the COMPANION trial, it was optimal medical therapy without a device. In the REVERSE study, CRT was off for part of the follow-up in some patients.
Those with longer PR intervals tend to be sicker and at greater risk. Multivariable models from underpowered retrospective studies may not tease out relationships no matter how carefully data are juggled. Based on what we know, it is not possible to determine definitively if a prolonged PR interval has prognostic importance or whether CRT is more effective in those with the most prolonged PR intervals.
Questions remain regarding PR prolongation in CRT candidates: 1) Does PR prolongation independently predict adverse outcomes? 2) Is one determination of the PR interval enough? 3) Does CRT have preferential benefit in those with longer PR intervals and, if so, at what interval? and 4) Why is the PR relationship to outcome in CRT patients nonlinear?
Data mining, “big data,” and meta-analyses do not always lead to the truth particularly regarding the implications of PR prolongation in CRT patients. Combining databases may provide a more powerful tool, but, performed improperly, may just combine errors. The only way to address the unresolved issues is to perform a well-powered, well-designed, prospective, randomized, controlled clinical trial evaluating PR interval and select measurable outcomes (mortality, heart failure hospitalization, atrial fibrillation) in relation to CRT focusing on specific high-risk subgroups, especially those who have shown less than optimal responses to CRT.
↵∗ Editorials published in JACC: Clinical Electrophysiology reflect the views of the authors and do not necessarily represent the views of JACC: Clinical Electrophysiology or the American College of Cardiology.
Dr. Olshansky has served as a consultant and speaker for Lundbeck, On-X, Cryolife, and Daiichi Sankyo; a project coordinator for Boehringer Ingelheim; and is on the data safety and monitoring board for Amarin.
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