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European Journal of Heart Failure 2007 9(8):814-819; doi:10.1016/j.ejheart.2007.04.005
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© 2007 European Society of Cardiology

Differential prognostic importance of QRS duration in heart failure and acute myocardial infarction associated with left ventricular dysfunction

Emil Loldrup Fosbøla,*, Marie Seibækc, Bente Brendorpa, Daniél Vega Møllera, Mads Ersbølla, Christian Torp-Pedersenb, Lars Købera and for the Danish Investigations and Arrhythmia ON Dofetilide (DIAMOND) study group

a The Heart Centre, University Hospital of Copenhagen, Rigshospitalet Blegdamsvej 9, DK 2100 Copenhagen, Denmark
b Department of Cardiology Y, Bispebjerg Hospital Denmark
c Department of Cardiology, Glostrup University Hospital Glostrup, Denmark

* Corresponding author. Tel.: +45 26845552. E-mail address: ELF{at}heart.dk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background/Aims: Studies of the prognostic importance of QRS duration in patients with heart failure (HF) have shown conflicting results and few studies have estimated the importance after myocardial infarction (MI).

Methods: The Danish Investigations and Arrhythmia ON Dofetilide (DIAMOND) study randomised 3028 patients to dofetilide (class III antiarrhythmic) or placebo. The study consisted of two almost identical trials conducted simultaneously. One trial included 1518 patients with chronic HF and the other trial 1510 patients with a recent MI. All patients had left ventricular dysfunction. Dofetilide did not influence mortality in either trial. QRS duration was systematically measured at randomisation and was available in 2972 patients.

Results: Over a 10 year observation period 1037 (70%) patients in the MI study and 1324 (87%) in the HF study died. In the MI study, risk of death increased 6% for each 10 ms increase in QRS duration (HR=1.06/10 ms increase in QRS (CI=1.04–1.09), p<0.0001) whereas QRS duration had no influence in the HF study after multivariable adjustment. The difference between HF and MI was significant (p<0.0004 for interaction).

Conclusion: QRS duration predicts death in patients with left ventricular dysfunction who have suffered MI. In patients with HF QRS duration is not predictive of mortality.

Key Words: QRS duration • Prognosis • Heart failure • Acute myocardial infarction • Left ventricular dysfunction

Received October 17, 2006; Revised February 7, 2007; Accepted April 26, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
A wide QRS complex in patients with heart failure (HF) is an important finding that may require cardiac resynchronisation therapy [1]. Some studies of QRS duration in HF have shown increased mortality with increasing QRS duration [2-5], but other studies have not confirmed this finding [6,7]. There are fewer studies on QRS duration in myocardial infarction (MI) [8-11]. These studies indicate increasing mortality with increasing QRS duration. A comprehensive study of the importance of QRS duration could help direct future studies of relevant interventions such as resynchronisation therapy.

The Danish Investigations and Arrhythmia ON Dofetilide (DIAMOND) studies were two simultaneously performed trials in patients with left ventricular dysfunction associated with either HF or MI. QRS duration was measured in both studies and the DIAMOND studies therefore provide a unique opportunity to study the prognosis associated with QRS prolongation and to compare the importance of QRS prolongation in patients with left ventricular dysfunction associated with HF or an acute MI.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Patients
The two DIAMOND studies enrolled 3028 patients. Study design and characteristics have been published [12,13]. The DIAMOND studies were two separate randomised, parallel-group, multicentre, double blind, and placebo controlled trials of the efficacy of the class III antiarrhythmic agent dofetilide on mortality in patients with acute MI or HF.

The trials were conducted in departments of cardiology or internal medicine at 37 hospitals in Denmark from 1993 to 1996. In both trials patients recruited were hospitalised and had left ventricular dysfunction (wall motion index ≤1.2 with a reverse scoring system, corresponding to a left ventricular ejection fraction ≤35%). The DIAMOND-MI trial also required an enzyme verified myocardial infarction within 7 days and the DIAMOND-HF trial required symptomatic heart failure (and no recent infarction). Key exclusion criteria were untreated bradycardia or heart block, severe renal dysfunction, QTc>460 ms, or severe concomitant disease likely to influence mortality over the coming years. As dofetilide did not influence mortality in either of the trials, we pooled the treatment groups for these analyses.

At inclusion, medical history, physical examination and left ventricular function were recorded. QRS length was measured by the investigator from an electrocardiogram obtained at the time of randomisation. QRS duration was divided into four groups (QRS duration≤80 ms, 80 ms<QRS≤100 ms, 100 ms<QRS≤120 ms, QRS>120 ms) in order to be able to analyse how an increase in QRS complex duration affects mortality and baseline data in the study population.

The mortality status of all randomised patients was obtained from the Danish Person Register which records all deaths in the country within 2 weeks of occurrence. The duration of follow up was at least 10 years.

2.2. Statistics
Statistical comparison of discrete variables was performed with chi-square test and continuous variables were compared with trend tests. We defined p<0.05 as significant and in multivariable tests p<0.01 was used because of the sheer volume of tests that we performed on the data. Kaplan-Meier curves were constructed to analyse QRS duration and its effect on prognosis, and differences in survival were compared using the log rank test. To evaluate the effect on mortality of different levels of QRS duration, relative risks and 95% confidence intervals were calculated as hazard ratios derived from the Cox proportional hazard regression models. Multivariable models were fitted using the available clinical covariates in the model (Table 1). The final models presented include only the variables that added independent significant information. The assumptions underlying the proportional hazard model (proportional hazard, lack of interaction and linearity of continuous variables) were tested and found valid unless otherwise indicated. All analyses were performed with SAS® version 9.1.


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  		Table 1 Baseline data according to QRS duration in four groups split into subgroups of patients with heart failure or myocardial infarction

 

   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
A total of 1518 patients with left ventricular dysfunction were included in the DIAMOND-HF trial and 1510 in the DIAMOND-MI trial making a total study population of 3028 patients. We excluded 56 individuals due to unavailable QRS duration leaving 2972 patients for analyses in the present study (nCHF=1495 and nAMI=1477). Demographic characteristics according to QRS duration are shown in Table 1. The cohort was elderly: median age 71 years (CI: 50-84) and the majority were men. In addition, a prolonged QRS correlated with a more severe left ventricular dysfunction in both HF and MI patients (PHF<0.0001 and PMI<0.0001, trend test, Table 1). However, the correlation was weak with a Pearson correlation coefficient of –0.17 (p<0.001) for MI patients and –0.17 (p<0.0001) for HF patients, respectively.

3.1. Univariable analysis of mortality
During the 10 years of follow-up 2361 (79%) patients died, 1037 (69%) in the MI group and 1324 (87%) in the HF-group. Mortality curves (Fig. 1) show 10 year mortality by QRS duration split into the 4 predefined groups and in the two study populations. Overall risk increased by 11% in the MI trial for every 10 ms increase in QRS duration (p<0.0001). Overall risk of mortality increased by 5% for every 10 ms increase in QRS duration (p<0.0001). The discrepancy in importance of QRS duration between the MI and the HF study was highly statistically significant (p<0.0004 for interaction). Separating the MI population into 2 groups, 1-year, 5-year and 10-year mortality was 19%, 44%, and 63% for patients with a QRS duration <120 ms, and 32%, 67% and 86% for patients with a QRS duration ≥120 ms, respectively. For HF patients the same analyses showed a 1-year, 5-year and 10-year mortality of 27%, 63% and 83% for patients with QRS<120 ms and 29%, 72% and 91% for patients with QRS≥120 ms, respectively. In univariable analyses the hazard ratio associated with QRS duration ≥120 ms was 1.87 (1.64-2.14); p<0.0001 and 1.30 (1.16-1.45); p<0.0001) in the MI and HF trial, respectively (Table 2).


Figure 01
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  		Fig. 1 Long-term mortality according to QRS duration (in ms) split into the four predefined groups in patients with left ventricular dysfunction and myocardial infarction (MI) (A) or patients with left ventricular dysfunction and heart failure (HF) (B). The curves are not adjusted (univariable analyses).

 


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  		Table 2 Mortality analysis due to increase in QRS duration in patients with left ventricular dysfunction and either heart failure or myocardial infarction

 
3.2. Multivariable analysis of mortality
Results of a multivariable cox proportional hazard model are shown in Table 2. Significant covariates included in the final model were sex, age, and history of diabetes, renal function, heart rate, clinical heart failure and Wall Motion Index. After adjustment for covariables there was a 6% increase in mortality per 10 ms increase in QRS duration in the MI study (p<0.0001). However, after multivariable adjustment overall risk of death did not depend on QRS duration in the HF study (hazard ratio 1.02 (0.99-1.04) p=0.2) and the interaction was highly significant (p<0.0004 for interaction). In multivariable analyses the hazard ratio associated with QRS duration ≥120 ms was 1.38 (1.19-1.61; p<0.0001) compared to patients with QRS<120 ms and 1.09 (0.95-1.24; p=0.2) in the MI and the HF trial, respectively (Table 2).

3.3. Other analyses
Adding dofetilide treatment to models did not change the results (data not shown). The importance of QRS was studied in subgroups of age, sex, history of ischaemic heart disease, diabetes, smoking status as well as previous MI and no important differences were found (analyses of interaction with p values above 0.05).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
The main new finding in this study was that QRS duration has different prognostic importance in patients with left ventricular dysfunction associated with HF or MI. We found that QRS duration has important prognostic influence in patients with MI but no influence in patients with HF after multivariable adjustment.

This study is unique in relation to the MI population as, to our knowledge, no previous study has focused on QRS duration in patients with left ventricular dysfunction and MI. The study is also unique in comparing the importance of QRS duration in patients with heart failure to those with MI. Previous studies of MI which did not take left ventricular function into account identified the importance of QRS duration [8-10]. A number of studies have also focused on patients with left ventricular dysfunction and heart failure [4,7,14,15], but the results are conflicting.

We cannot explain conclusively why QRS duration has a different association with prognosis in the two populations. Prolonged QRS duration was associated with reduced left ventricular systolic function in both populations, and in the MI population it was also associated with older age, male sex, diabetes and previous MI (data not shown). Thus, QRS prolongation was clustered to other risk factors, but still had independent prognostic value when all the associated variables were included in the Cox proportional hazard models. When QRS values were dichotomised (cut off value of 120 ms resembling bundle branch block) prolonged QRS duration only had prognostic importance in the MI population and not in the HF population. This result contradicts the result of Stenestrand et al. who reported that LBBB was without prognostic importance in a large register of MI patients [16]. However, our population only included patients with moderate to severe left ventricular systolic dysfunction, which may partly explain this difference. Secondly, we did not look specifically at LBBB but only at QRS duration of 120 ms or more.

The current cohort was elderly (median age was 71 years in the HF population and 70 years in the MI population) which is similar to the age of patients with HF and reduced left ventricular ejection fraction in two recent publications [17,18]. In both MI and HF patients we found a significant correlation between left ventricular function and QRS duration—this finding is in agreement with previous studies of heart failure [15] and confirms speculation about the connection between QRS prolongation and increased desynchronised contraction of the left ventricle. Cardiac resynchronisation therapy (CRT) with biventricular pacing has recently been introduced for treatment of heart failure and results show a significant decrease in overall mortality [1]. It must be emphasised that the lack of association between QRS duration and mortality in our study should not be interpreted as an argument against CRT in HF patients with prolonged QRS duration and left ventricular dysfunction. The beneficial effects are obvious from randomised, clinical trials [1,19]. However, despite the reported benefit of CRT in HF patients with prolonged QRS duration there is still controversy about whether all patients benefit from CRT, since patients with electrical dyssynchrony do not always have mechanical dyssynchrony [20-23]. The relation between QRS prolongation and prognosis in the MI population in our study should provide the stimulus for a CRT trial in MI patients, including measurement of mechanical dyssynchrony.

Another interesting finding in our MI population is that QRS duration above 80 ms and not exceeding 120 ms was associated with a poor prognosis. It is not known how many of these patients have left ventricular dyssynchrony and it would be interesting to investigate this with an echocardiographic study. Secondly, whether CRT is of benefit to patients with dyssynchrony and QRS duration between 80 and 120 ms needs to be tested in a future trial.

Both HF and MI patients benefit from treatment with an ICD [24,25]. The present study suggests that CRT-ICD therapy could possibly be of benefit in patients with an acute MI and a prolonged QRS. Such intervention studies are of relevance and could help in selecting high risk patients early for cardiac resynchronisation therapy. Our study does not include information on mode of death, thus we are unable to provide data on sudden death. Whether these patients could benefit from CRT-ICD needs to be tested in a trial.

4.1. Strengths and weaknesses of the study
This study is large and provides a unique opportunity to compare MI patients and HF patients as data were accumulated simultaneously in the same centres at the same time. Follow-up was 10 years, and only 2% of patients did not have a valid QRS duration registered. A weakness of the study is that the DIAMOND studies were randomised studies testing the influence of dofetilide on mortality [12,13], but since both studies were neutral we pooled the treatment groups for the current study. Adding dofetilide treatment to the models did not change the importance of QRS duration and there was no interaction between QRS duration and dofetilide.

Characterisation of QRS prolongation into left and right bundle branch block was not possible in a sufficient number of patients to make relevant analyses. The endpoint was overall mortality and we cannot distinguish between causes of death.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
In patients with left ventricular dysfunction, QRS duration is an independent predictor of death in patients with a recent MI, whereas QRS duration did not have long-term prognostic importance in patients with HF after multivariable adjustment. The implication is that in addition to HF patients with prolonged QRS duration there seems to be a population of MI patients with prolonged QRS duration that may benefit from biventricular pacing. However, this needs to be tested in a future randomised trial.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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