Prognostic risk of atrial fibrillation in acute myocardial infarction complicated by left ventricular dysfunction: the OPTIMAAL experience
Mika Lehto1,*,
Steven Snapinn2,
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Kenneth Dickstein3,
Karl Swedberg4,
Markku S. Nieminen1 on behalf of the OPTIMAAL investigators
1Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland
2Merck Research Laboratories, West Point, PA, USA
3University of Bergen, Cardiology Division, Central Hospital in Rogaland, Stavanger, Norway
4Department of Medicine, Sahlgrenska University Hospital, Göteborg, Sweden
Received 8 July 2004; revised 26 October 2004; accepted 28 October 2004; online publish-ahead-of-print 9 December 2004.
* Corresponding author. Tel: +358 9 4711; fax: +358 9 47174574. E-mail address: mika.lehto{at}fimnet.fi
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Abstract
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Aims The present study aimed to determine the frequency and the impact on clinical outcome of atrial fibrillation (AF) in patients with acute myocardial infarction (AMI) and left ventricular dysfunction.
Methods and results In the OPTIMAAL trial, 5477 patients with AMI and signs of left ventricular dysfunction were included. At baseline, 655 patients (12%) had AF, and 345 (7.2%) developed new-onset AF during follow-up (2.7±0.9 years). Older patients, patients with history of angina and worse Killip class had and developed AF more frequently (P<0.001). Patients with AF at baseline were at increased risk relative to those without AF for mortality [adjusted hazard ratio (HR) of 1.32, P=0.001] and for stroke (HR 1.77, P<0.001). New-onset AF was associated with increased subsequent mortality for the first 30 days following randomization (HR 3.83, P<0.001) and the entire trial period (HR 1.82, P<0.001). Risk of stroke was increased for the first 30 days (HR 14.6, P<0.001) and for the whole trial period (HR 2.29, P<0.001).
Conclusion AF is frequently observed in patients with AMI complicated by heart failure. Current AF, and the development of new AF soon after AMI, is associated with increased risk of death and stroke.
Key Words: Atrial fibrillation Acute myocardial infarction Heart failure Cardiovascular mortality and morbidity Prospective randomized endpoint trial
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Introduction
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Atrial fibrillation (AF) is the most common sustained arrhythmia in the general population with about 1% prevalence and 0.10.2% annual incidence.14 The frequency of AF increases markedly with age, and in octogenarians the annual prevalence and incidence of AF are reported to be greater than 6 and 2%, respectively.4,5 AF is also a frequent arrhythmia complicating acute myocardial infarction (AMI) observed in up to 20% of AMI patients.69 AF may have been pre-existing before AMI or developed acutely following AMI due to ischaemia of the sinus node or atrial myocardium, or sub-acutely following the development of congestive heart failure or pericarditis.10
AF seen during AMI is reported to be associated with longer duration of hospitalization, higher in-hospital and long-term mortality and an increased incidence of stroke compared with patients without AF.7,8,11 Data confirming the impact of baseline AF on clinical outcomes, however, are not always reported when multivariate analyses are performed.6,12 The poorer prognosis associated with AF, developing after an AMI, has also been confirmed in multivariate analyses.710,13 However, the increased risk associated with new AF in AMI populations with left ventricular dysfunction has not been established. Also, the impact of development of new AF in any AMI population has not been analysed when AF is included in the model as a time-dependent co-variate. This type of analysis permits better estimation of the temporal relationships between new-onset AF and the complications. In this post hoc analysis of the OPTIMAAL trial, we investigated the prevalence of AF at baseline in patients with AMI and heart failure, and the incidence of new-onset AF. The impact of baseline AF, or new-onset AF, on clinical outcomes is reported.
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Materials and methods
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The OPTIMAAL trial (The Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan) compared losartan with an angiotensin-converting enzyme inhibitor (ACE-I), captopril, on mortality and morbidity in patients with evidence of heart failure or left ventricular dysfunction and/or anterior Q-waves after AMI. The background, rationale, and results for the OPTIMAAL trial have been described previously.14,15 The trial included 5477 patients with AMI who developed clinical signs of heart failure or evidence of left ventricular dysfunction (ejection fraction <40% or left ventricular diastolic dimension >65 mm) within 10 days of hospitalization. The study patients were randomized to captopril 50 mg three times daily or losartan 50 mg daily as background therapy.
Definitions
AF was recorded on the cardiovascular medical history case report form (CRF) as a pre-existing medical condition at the time of randomization, or as an adverse experience based on ECGs taken at baseline or at follow-up visits (4 weeks and 1, 2, and 3 years after the randomization and at final visit). AF at baseline was defined as either AF recorded on the medical history CRF or seen on ECG at randomization.
New-onset AF was defined as AF detected on an ECG after the randomization in a patient without baseline AF. Patients with AF or atrial flutter, or both, were pooled together and considered as having AF.
Statistical analyses
All randomized OPTIMAAL patients were included in this analysis, and an independent Endpoint Classification Committee adjudicated all reported endpoints. Continuous variables are presented as means [standard deviation (SD)] and discrete variables as numbers of patients (percentages). Differences between the groups at baseline were analysed with the Student's t-test for continuous variables and Pearson's
2 test for categorical variables.
The risk of developing AF associated with various baseline variables was evaluated using age-adjusted Cox regression models. The risk of total mortality, cardiovascular death, stroke, and all-cause hospitalization associated with AF was analysed in two models. First, patients with or without AF at baseline were compared in a Cox regression model. This model was run with and without adjustment for age, heart rate, prior MI, smoking, diabetes, history of hypercholesterolaemia, history of chronic heart failure, Killip Class, thrombolytic use, and statin use. Secondly, in patients without AF at baseline, new AF was included as a time-dependent co-variate in order to estimate the impact of new-onset AF after AMI. The hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated with and without adjustment for the co-variates listed above. Event rates over time are presented as KaplanMeier curves; these curves allow visual inspection of the Cox model's assumption of proportional hazards.
The impact of new-onset AF on endpoint risk was illustrated using modified KaplanMeier curves.16 In this modification, the cohorts are continually updated as follows: for the time prior to developing AF, the patient contributes to the no-AF cohort, but for the time after developing AF, the patient contributes to the AF cohort. This modification makes the method correspond to the Cox regression model with AF as a time-dependent co-variate. All reported P-values are two-sided. Due to the large number of statistical tests, P-values should be interpreted with caution. While no specific level of statistical significance is defined, a P-value of 0.001 should be considered to indicate strong evidence in support of a true effect.
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Results
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Study population
Of the 5477 randomized OPTIMAAL patients, 655 had AF at baseline; 331 were randomized to losartan and 324 were randomized to captopril. Of the 4822 patients without AF at baseline, 96 (2.0%) developed new-onset AF during the first 3 months after randomization, and a total of 345 patients (7.2%) developed new AF during the entire follow-up period, median 3.0 years (interquartile range 2.73.3 years). The total number of patients with AF was therefore 1000.
Patient characteristics
Table 1 provides the baseline characteristics and therapy prior to randomization of patients according to the presence of AF at baseline. Patients with AF were significantly older and had a significantly greater history of hypertension, ischaemic heart disease, congestive heart failure, and cerebrovascular disease compared with those who did not have AF at baseline. Patients without AF at baseline were more frequently current smokers or had a history of hyperlipidaemia.
Patients with AF had significantly higher blood pressure and heart rate at baseline, while patients without AF had higher prevalence of anterior as well as new transmural infarctions and exhibited less severe Killip class. These groups also differed regarding therapy prior to randomization (Table 1). Patients with AF at baseline were less likely to be treated with thrombolytics, aspirin, and statins, but were more frequently treated with calcium channel blockers, digitalis, diuretics, and warfarin.
Prognostic effect of baseline AF
Presence of AF at baseline was associated with significantly higher total mortality, cardiovascular death, stroke, and hospitalization (Table 2, Figures 1 and 2). These patients also had significantly longer index hospitalization: 14.1 (10.6) days for those with AF and 12.3 (9.8) days in patients without AF (P<0.001). The impact of baseline AF on 30 day mortality and rate of stroke did not reach statistical significance (P-values 0.27 and 0.13, respectively).
Risks of developing new AF
Advanced age, male gender, history of angina, higher Killip classes, higher diastolic blood pressure, and higher pulse rate during the randomization were significantly associated with the development of AF during the trial (Table 3). Linearity of the continuous variables (systolic and diastolic blood pressure and pulse rate) was examined by including additional quadratic terms; none of these terms was statistically significant. The rate of developing new AF during the study is illustrated in Figure 3. No difference in the frequency of new-onset AF between the losartan and captopril groups was observed (7.3 and 7.0%, respectively).
Prognostic impact of new AF
New-onset AF was associated with HRs for 30 day risk of mortality and for 30 day risk of stroke of 3.83 (95% CI 1.977.43, P<0.001) and 14.6 (95% CI 5.8736.3, P<0.001), respectively (Table 4). During the whole trial, new-onset AF was associated with HRs of 1.82 (95% CI 1.392.39, P<0.001) for total mortality and 2.29 (95% CI 1.433.68, P<0.001) for stroke. Figures 4 and 5 show the KaplanMeier curves of mortality and stroke, respectively, comparing the groups who developed or did not develop AF during the study. Figure 6 shows the adjusted HRs and their 95% CIs for the new-onset AF.

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Figure 4 KaplanMeier curves for total mortality stratified by the time-dependent presence of AF. Patients with AF at baseline excluded.
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Figure 5 KaplanMeier curves for stroke stratified by the time-dependent presence of AF. Patients with AF at baseline excluded.
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Discussion
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In the present post hoc analysis, 1000 patients with AF at baseline or developing AF during follow-up out of a total of 5477 patients (18%) included in the OPTIMAAL trial, were analysed and compared with patients without AF. The main findings of this report are: AF is a common arrhythmia observed in patients with complicated AMI. Older patients and patients with more serious heart disease have and develop AF more often, and the existence, and particularly, the development of AF are associated with a poor prognosis and an increased incidence of stroke.
Prevalence of AF
In epidemiological studies, AF has been found to affect 1016% of AMI patients during the hospitalization with an increasing prevalence over time.6,10 Rathore et al.8 reported the proportion of patients with AF during the hospitalization to be as high as 22%, but this study was performed in an elderly population
65 years. Paroxysmal AF has been recorded in 10% of AMI patients during the pre-thrombolytic era and in 9% during the thrombolytic era in AMI patients.17
The OPTIMAAL trial was, however, a prospective randomized study with distinctive inclusion criteria and, out of the 5477 patients in this study, 12% had AF at baseline. In the TRACE trial, which also included patients with AMI and left ventricular dysfunction, the percentage of AF patients was 21% during hospitalization.7 In other prospective studies, the percentage of AF patients during the index hospitalization has been somewhat lower; i.e. 10% in the GUSTO-I study and 9% in the GISSI-3 study, reflecting the milder disease.9,12
Impact of AF at baseline
Patients with AF at randomization had significantly higher total mortality, cardiovascular death, stroke, and all-cause hospitalization when adjusted for all the major baseline characteristics as well as for the severity of heart failure at randomization. The study populations and definitions of baseline AF vary between AMI studies, and baseline AF is not always associated with poorer prognosis after multivariate analysis.6,12 Our results confirm previous analyses in AMI patients with documented AF at baseline; patients with AF have increased mortality measured during both in-hospital stay and long-term follow-up.7,8,11 Whether baseline AF during AMI itself causes a poor prognosis, or is a marker of death or stroke, is not known.
Development of new-onset AF
The incidence of new AF after AMI and during the study period was high, as 345 patients (7.2% during a mean follow-up of 2.7 years) developed new-onset AF. In the TRACE study placebo group, where ACE-I trandolapril was not administered, the incidence of new AF during 24 year follow-up was 5.3%.18 In the DIAMOND-AMI study, patients were similar to those in our study and 2.0% of patients in the placebo group (without dofetilide, of whom 57% received ACE-I) developed AF during the first 12 months.19
Also in the present study, age was the strongest predictor of new AF after AMI.8,9,12,13 The other risk factors associated with the development of new-onset AF (e.g. higher Killip class and angina) most probably reflect more advanced cardiovascular disease in those patients, and the risk factors for new AF reported here are well in accordance with those previously reported.8,9,12,13 Patients who develop AF after AMI have also been reported to have more extensive coronary artery disease assessed with respect to both the number of involved vessels and coronary artery flow.10,12
New-onset AF also seems to have been associated with coronary-artery bypass grafting (CABG). Among patients without AF at baseline, 704 underwent CABG at some time during the trial, of whom 132 developed new-onset AF (18.8%), compared with 213 patients with new-onset AF in the 4118 patients without CABG (5.2%). Because CABG was a pre-specified endpoint, it was not analysed in the model as a risk for the development of new AF.
Risk associated with new-onset AF
This is the first report demonstrating increased risk of death and stroke associated with new AF in patients with AMI and signs of left ventricular dysfunction. This finding has previously been well established in analyses with adjustment for baseline characteristics, but not focusing on AMI patients with heart failure.810,13 Also, when AF was included in the analyses as a time-dependent co-variate, the temporal relationship of new-onset AF and the clinical outcome is more clearly demonstrated.
The adjusted odds ratio for death among AMI patients who develop AF has been estimated to be from 1.3 to 3.0, including both in-hospital and long-term mortality.810 The corresponding value from the present analyses for the long-term mortality (1.82) is well in accordance with those previous studies. However, 3.83, which was the HR for 30-day mortality when AF was utilized as a time-dependent co-variate is strikingly higher. Parallel with this was the finding that the HR for 30-day risk of stroke was as high as 14.6, indicating the strong prognostic impact of new-onset AF in AMI patients with left ventricular dysfunction.
In a traditional analysis performed from the Framingham database, the onset of AF was also strongly temporally related to imminent stroke, or alternatively, AF was noted for the first time during hospitalization for stroke.20 The proportion of patients that did not suffer from either AMI or heart failure was not documented in that study.
Prevention of new AF
There are no randomized prospective studies investigating the reduction of the rate of new AF as a pre-specified primary endpoint with any pharmacological agent. There are, however, preliminary data suggesting that the development of AF is suppressed with ACE-Is in heart failure patients and with class III anti-arrhythmic drugs in heart failure and post-AMI patients.
In the TRACE study, the risk of new AF was reduced by 45% with trandolapril, and in a sub-analysis of the SOLVD study the risk of new AF was reduced by as much as78% with enalapril.17,21 With the class III anti-arrhythmic drugs, amiodarone and dofetilide, the incidence of AF has been reduced from 51 to 70% in patients with heart failure,22,23 and in post-AMI patients with heart failure dofetilide reduced the incidence of new AF by 64%, but this difference was non-significant.18 Despite the limitations of secondary analyses, these results are important, because the reduction of frequency of new AF with these drugs was associated with neutral or even decreased mortality.
Limitations of the study
The current study has several limitations. All the AF patients were pooled together as a single category without classification of paroxysmal, persistent, or permanent AF. The same limitation also concerns pooling AF and atrial flutter together. However, regardless of the type of AF in the present study, atrial flutter is only rarely observed alone, and the impact on mortality and stroke should be estimated to be the same in AF and atrial flutter.4 It was also found in the present study, that about one-third of patients with atrial flutter were recorded to have AF. These analyses are also prone to selection bias; only AMI patients with signs of heart failure or left ventricle dysfunction were eligible for the randomization. Additionally, the applicability of the findings is limited to the population surviving the acute phase, in that randomization to the trial occurred at a median of 3 days following the AMI. Also, the impact of post-randomization CABG on the development of new-onset AF was not examined in this analysis. Because all the patients were treated with either captopril or losartan, this may have affected the incidence of new-onset AF
Clinical implications
AF, and especially the new-onset AF soon after AMI, was strongly temporally related to the occurrence of stroke and death in patients following complicated AMI. This finding emphasizes that this condition should be recorded and taken into account as a marker of poor prognosis. Randomized prospective studies are warranted to address whether improvement in survival in these patients can be achieved by medical intervention designed to maintain sinus rhythm.
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Footnotes
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Dr Snapinn is currently at Amgen, Thousand Oaks, CA, USA. 
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