The prognostic value of pre-discharge exercise testing after myocardial infarction treated with either primary PCI or fibrinolysis: a DANAMI-2 sub-study

Nana Valeur*, Peter Clemmensen, Kari Saunamäki and Peer Grande for the DANAMI-2 investigators

Department of Cardiology B, The Heart Center, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark

Received 10 July 2004; revised 29 September 2004; accepted 14 October 2004; online publish-ahead-of-print 6 December 2004.

* Corresponding author. Tel: +45 35 45 29 06; fax: +45 35 45 25 13. E-mail address: nvaleur{at}dadlnet.dk

See page 105 for the editorial comment on this article (doi:10.1093/eurheartj/ehi075)


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Discussion
 Conclusions
 Acknowledgements
 References
 
Aims To evaluate the prognostic importance of pre-discharge maximal symptom-limited exercise testing (ET) following acute myocardial infarction (AMI) in the era of aggressive reperfusion.

Methods and results In the DANAMI-2 (the second DANish trial in AMI) study, patients with ST-elevation AMI (STEMI) were randomized to primary angioplasty (PCI) or fibrinolysis. Of 1462 patients discharged alive, 1164 (79.6%) performed an ET. Primary endpoint was a composite of death and re-infarction.

Patients randomized to fibrinolysis developed ST-depression to a greater extent than patients randomized to primary PCI (21.7 vs. 15.3%, P=0.007). Multivariable predictors of death and re-infarction included age, gender, diabetes, previous stroke, anterior AMI, randomization to fibrinolysis, and exercise capacity [risk ratio (RR) 0.82 (0.72–0.93); P<0.001]. ST-depression was predictive of the clinical outcome [RR 1.57 (1.00–2.48); P<0.05] in multivariable analysis, but stratified according to treatment groups there was a significant association between ST-depression and outcome in the fibrinolysis group [RR 1.95 (1.11–3.44); P<0.05], but not in the primary PCI group [RR 1.06 (0.47–2.36); P=ns]. However, the P-value for interaction was 0.15.

Conclusion Exercise testing after contemporary reperfusion therapies for STEMI confers important prognostic information. Exercise capacity is a strong prognostic predictor of death and re-infarction irrespective of treatment strategy, whereas the prognostic significance of ST-depression seems to be strongest in the fibrinolysis-treated patients.

Key Words: ST-elevation acute myocardial infarction • Primary PCI • Exercise test • Prognosis • Reperfusion


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Discussion
 Conclusions
 Acknowledgements
 References
 
Maximal symptom-limited exercise test (ET) is routinely used for detection of residual ischaemia, prognostic stratification, and assessment of exercise capacity in patients with acute myocardial infarction (AMI).13 Revascularization of patients with exercise-induced ischaemia after fibrinolysis treatment of AMI was associated with improved prognosis in the randomized DANAMI-1 study,4 and pre-discharge exercise testing after AMI is a class 1 recommendation according to the ACC/AHA 2002 Guidelines for Exercise testing.5

Currently, the treatment of patients with acute ST-elevation AMI (STEMI) consists of either primary percutaneous coronary intervention (PCI) or fibrinolysis with an increasing ratio of primary PCI.6

Studies of ET have almost entirely been performed prior to the introduction of primary PCI. In the current era with more aggressive reperfusion strategies including facilitated or primary PCI, the prognostic value of ET is less well established. It is therefore necessary to re-evaluate the role of ET.

The aim of this DANAMI-2 sub-study was to evaluate the prognostic significance of ET performed at discharge in patients with AMI treated with either primary PCI or fibrinolysis followed by modern adjunctive pharmacological treatment. Our primary hypothesis was that ST-depression during exercise testing was of less prognostic importance in patients treated with primary PCI than in patients treated with fibrinolysis.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Discussion
 Conclusions
 Acknowledgements
 References
 
Prospectively collected data from the large DANish multi-centre trial in Acute Myocardial Infarction-2 (DANAMI-2) were used in the present study. Details of the design and results of the main study have been published previously.7,8 From December 1997 to October 2001, patients with ST-elevation of more than 4 mm in the ECG were randomized to fibrinolysis or primary PCI. Patients were randomized within 12 h of symptom onset. Exclusion criteria were contraindication towards fibrinolysis or angiography/PCI, AMI and/or fibrinolysis within the last 30 days, left bundle branch block, cardiogenic shock (systolic BP<65 mmHg), repeated life-threatening arrhythmias, need of mechanical ventilation, need for acute surgical intervention, severe valvular or pericardial disease, severe non-cardiac disease with an expected survival of less than 12 months, pregnancy, lack of informed consent or non-compliance, previous participation in DANAMI-2, or present participation in other trials.

Patients assigned to fibrinolysis were treated at the primary hospital, and patients randomized to primary PCI were transferred to the nearest angioplasty centre within 3 h. Patients performed an ET and had an echocardiography performed at discharge if possible. Endpoints were registered during a 5 year follow-up. After 3 years of follow-up, only mortality data were/are registered. There were no drop-outs during the follow-up.

Patients assigned to fibrinolysis received aspirin orally, a beta-blocker intravenously, tissue plasminogen activator, and unfractionated heparin, followed by additional intravenous heparin for 48 h. Patients assigned to primary PCI received aspirin, a beta-blocker, and unfractionated heparin intravenously. During PCI, additional heparin was given and glycoprotein IIb/IIIa receptor blockers were administered if indicated. The culprit lesion was treated with a stent and other lesions left untreated. Ticlopidine or clopidogrel was given daily for 1 month after stenting.

Exercise test protocol
A maximal symptom-limited pre-discharge ET was planned in all patients and performed in 79.6% of the patients discharged alive. Inability to perform exercise was due to advanced age, heart failure, significant non-cardiac diseases, hip and knee arthrosis, or refusal.

The ET was performed using a bicycle protocol as in the first DANAMI trial.4,8 Initial supine resting BP and a 12-lead ECG were recorded. Workload at test onset was 25 W and increased by 25 W every 2 min. During the ET, chest pain, arrhythmias, or other symptoms were recorded. The patients were encouraged to continue exercise until limiting symptoms or signs were experienced. The reasons for discontinuing exercise were: general fatigue or shortness of breath (94%), angina pectoris (2%), arrhythmias (1%), and miscellaneous reasons (3%).

All ETs were evaluated in a core laboratory by one person (N.V.) according to a protocol, which specified blinding of the interpreter to knowledge of the clinical status, treatment, and outcome of the patients. The following variables were registered: presence of pathological Q-waves, ST-elevation in relation to the presence and location of Q-waves (anterior/inferior), ST-depression location (anterior/inferior), exercise capacity at start of ST-segment deviation, maximal exercise capacity, maximal heart rate, arrhythmias, ventricular ectopies, development of bundle branch block, reason for discontinuation of exercise. Angina and blood pressure were registered by the investigator during the test.

Exercise capacity was measured in Watts (W) and converted to a maximal oxygen consumption calculated as metabolic equivalents (METS)9:

ST-segment changes were classified as ischaemic if ST-depression (horizontal or descending) was larger than 1.0 mm, 0.08 s after the J-point in three consecutive beats in any lead during exercise, or ST-elevation (measured in J-point) was more than 2.0 mm in three consecutive beats in any leads without Q-waves. Q-waves were defined as Q-wave amplitude >1/3 of total QRS amplitude and/or duration of more than 0.04 s. In cases of ST-segment abnormalities at rest, deviation was measured as changes from rest.

The ST-response was recorded as inconclusive, if maximal heart rate was less than 70% of expected (220 minus age) and there were no ST-segment changes.

Increase of the pressure-rate-product (dPRP) was calculated as the difference from rest to maximal exercise.

Endpoints
We used death as the endpoint to compare patients performing an ET with those not able to exercise. For the purpose of the present sub-analyses in patients who performed an ET, we used the combination of death and re-infarction as the primary endpoint. Death alone was used as secondary endpoint. All endpoints were evaluated by an independent endpoint committee.

Statistics
Comparison of exercising and non-exercising patients was made using the entire DANAMI-2 (intention-to-treat) population. Due to the bias introduced by the incapacity of patients with an early endpoint to perform an ET this analysis was repeated for patients discharged alive without endpoints within 14 days after entrance in the study (the 95th percentile confidence interval of time to ET).

For descriptive purposes, a comparison of baseline characteristics in patients with and without an ET was performed. Dichotomous variables were compared using the {chi}2 test, while continuous variables were compared using a rank-sum test. Baseline dichotomous variables were presented as the incidence in per cent, while continuous variables were presented as medians with 5th, 95th percentiles. Mortality data and combined endpoints were compared using the log-rank test in univariate analyses. Multivariable analyses were performed using Cox proportional hazard analyses. Mortality data and combined endpoints are presented using the Kaplan–Meier method. The assumptions for linearity and proportional hazard were checked graphically and were met for all variables studied. Univariate analysis was performed for all baseline variables and for the variables from the exercise test. Significant variables were included in the multivariable backward selection model excluding all variables with a P-value above 0.05. All exercise variables were forced into the final model together with other significant variables. ST-elevation was excluded from this model as it was only found in one patient. Also, maximal heart rate and blood pressure were not included due to the correlation with dPRP.

Analyses of exercise variables were based on comparisons between patients randomized to primary PCI or fibrinolysis who performed an ET at discharge. Baseline characteristics, mortality data, and combined endpoints were compared as described above. Comparisons of time-to-events in patients following exercise testing are performed with time of ET as starting date. Possible interaction was checked using multivariable analyses with an interaction variable. It was primarily examined for interactions between prognostic factors from the ET and treatment allocation, age, gender, and co-morbidity (i.e. diabetes, hypertension etc). A P-value (two-sided) <0.05 was considered significant for the primary hypothesis of a difference in the prognostic importance of ST-depression. Due to multiple testing, a P-value (two-sided) of <0.01 was considered significant for explorative analyses. Explorative analyses aimed at identifying factors from the ET that added independent prognostic information in relation to clinical outcome. All analyses were performed in the entire population performing an ET at discharge as well as sub-groups according to randomization.

The statistical software package SAS version 8.0 (SAS Institute, Cary, NC, USA) was used to perform all analyses.

Ethical considerations
This project is a sub-study of the DANAMI-2 trial, which was accepted by the Ethics Committee of Science and was carried out in accordance with the Declaration of Helsinki.

Results
In total, 1572 patients were randomized to either primary PCI or fibrinolysis and 1462 of them were discharged alive (57 died in the fibrinolysis group and 43 in the PCI group). A total of 1164 (79.6%) of the patients discharged alive were capable of performing the ET. Median time from randomization to exercise test was 6 days (4–14 days). Follow-up period was 1–5 years, median 2.9 years for the entire cohort and 3.1 years for exercise tested patients.

Prognosis and ability to perform an ET
Baseline characteristics of patients performing an ET and of those incapable of exercising are presented in Table 1. The two groups differed considerably. Those able to perform an ET were younger, more often male, less often had a history of diabetes, ischaemic heart disease (IHD), or heart failure (HF), fewer in-hospital complications, and had a higher ejection fraction at discharge.


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Table 1 Baseline demographics for patients in DANAMI-2 according to ability to perform an excercise test
 
Death and re-infarction was significantly less frequent in patients who performed an ET compared with those who did not. Death occurred in 6.1% of exercise tested patients vs 40.9% in the non-exercising group after 3 years of follow-up, P<0.0001 (Figure 1), and corresponding figures for re-infarction were 7.7 vs. 12.3% (P=0.0048).



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Figure 1 Death, according to participation in an ET, following myocardial infarction. ET, exercise test performed.

 
Comparing data for patients without a major event during the first 14 days, mortality was still significantly lower in patients who performed an ET than in those not capable (5.9 vs. 21.5% after 3 years of follow-up, P<0.0001).

Exercise test response in primary PCI and fibrinolysis-treated patients
Baseline demographics and results from the ET are shown in Table 2. The two groups are well matched; however, a history of HF and HF at discharge was more common among those randomized to fibrinolysis.


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Table 2 Baseline demographics among exercise tested patients in DANAMI-2
 
As shown in Table 3, patients treated with primary PCI had significantly less ST-depression, less angina, and achieved a slightly higher maximal systolic blood pressure during the test.


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Table 3 ET variables according to treatment allocation in the DANAMI-2 trial
 
Prognostic significance of ET—primary endpoint
Total population
For the combined endpoint of death and re-infarction, exercise capacity, dPRP, inconclusive ST-response, and heart rate recovery were of prognostic significance in a univariate model, and exercise capacity and ST-depression were prognostically significant in a multivariable analysis in the total population (Table 4). In Figure 2 the exercise capacity is divided into tertiles and shows a strong relationship with risk of death and re-infarction.


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Table 4 Prognostic importance of ET variables for combined endpoint (death and re-infarction) in the DANAMI-2 trial
 


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Figure 2 Combined endpoint of death and re-infarction according to exercise capacity expressed in metabolic equivalents (METS). Re-MI, recurrent myocardial infarction.

 
Treatment sub-groups
Exercise capacity and ST-depression showed prognostic importance in multivariable analysis in the fibrinolysis, but not in the PCI-treated group (Table 4). Interactions between treatment group and exercise capacity and ST-depression were not significant (P=0.13 and P=0.15, respectively).

Figure 3A and B shows the ST-response in relation to death and re-infarction. Patients without ST-depression on a conclusive heart rate level had the lowest event rate in both groups. In the PCI group, patients with ST-depression had as low an event rate as those without ST-depression. In the fibrinolysis group, ST-depression was associated with a significantly higher event rate than no ST-depression (P=0.01). An inconclusive ST-response was associated with the worst prognosis in univariate analysis, but was insignificant in multivariable analysis (P=0.06; Table 4).




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Figure 3 Combined endpoint of death and re-infarction according to ST-response, (A) for fibrinolytic-treated patients and (B) for PCI treated patients. Re-MI, recurrent myocardial infarction; STD, ST-depression; STR, ST-response.

 
Other sub-groups
The prognostic values of exercise capacity and ST-depression were the same in sub-groups of gender, infarct location, and Q-wave versus non-Q-wave infarction (data not shown). In PCI-treated patients, information concerning the completeness of revascularization is available. Compared with patients with complete revascularization, patients with incomplete revascularization more often had ST-depression (20 vs. 13%; P=0.02) and lower exercise capacity (6.5 vs. 7.0 METS; P=0.04), but the prognostic information was the same in the two groups [risk ratio for ST-depression was 0.72 (fully revascularized) and 1.16 (not fully revascularized; P-value for interaction=0.23) and risk ratio for exercise capacity was 0.75 and 0.58, respectively (P-value for interaction=0.06)].

Prognostic significance of exercise testing—individual endpoints
After 3 years of follow-up, death occurred in 71 (6.1%) and re-infarction in 69 (5.9%) of the exercised patients. Each of these endpoints was less frequent in the PCI than in the fibrinolysis group: death 5.7 vs. 6.4% (P=0.622), re-infarction 5.2 vs. 6.6% (P=0.318), respectively.

For death alone, the exercise capacity, ST-depression, and dPRP were of prognostic importance in univariate analyses of the entire exercise tested cohort. Exercise capacity was the only significant ET variable in multivariable analyses, relative risk (CI) for all patients was 0.73 (0.61–0.87) P=0.0007, for patients treated with fibrinolysis 0.76 (0.59–0.98) P=0.037, and with PCI 0.68 (0.52–0.90) P=0.006. Other prognostically important variables were age and reduced left ventricular ejection fraction (LVEF) at discharge in the fibrinolysis group, and age alone in the PCI-treated group. There was an interaction between the LVEF and the treatment group, P=0.035.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Discussion
 Conclusions
 Acknowledgements
 References
 
Several previous studies have dealt with the prognostic assessment of post-AMI patients by means of exercise testing both before and after fibrinolysis was introduced as a standard treatment.2,3,1014 No previous studies have addressed the prognostic value of exercise testing after primary PCI for AMI. Our main findings were that exercise capacity was a strong prognostic predictor of death and that there was a significant difference in the prevalence of ST-depression depending on the mode of acute reperfusion therapy for STEMI. ST-depression was predictive of death and re-infarction in the fibrinolysis group but not in the PCI group. However, testing for interaction of this difference was not significant.

Prognostic importance of exercise capacity
Previous post-AMI studies have shown that exercise capacity and increase in heart rate and blood pressure during exercise are powerful predictors of subsequent mortality.2,3,1014 We found that exercise capacity was a strong predictor of subsequent outcome, whether this was death alone or the combined endpoint of death and recurrent AMI. For prediction of mortality, exercise capacity was the only variable from the ET that added independent information. Every 1-METS increase implied a 20% decrease in mortality and re-infarction, and 27% decrease in death alone. There was more than a three-fold difference in death and re-infarction between patients with exercise capacity >8 METS and those with <6 METS (Figure 2).

Inability to perform a pre-discharge ET was a strong marker of poor prognosis. The risk of death within the follow-up period increased from 11% in patients performing an ET to 27% in patients not performing an ET. This is in accordance with earlier studies,3,14,15 and in the latest meta-analysis from 1996 including 20 000 patients, the 6-month mortality was five times higher in patients unable to perform an ET compared with those capable of performing the test.3 As in other trials, these patients were older, more often female, and had more severe concomitant heart disease.14,16 Treatment of these patients cannot be guided by the exercise response, thus patients have to be treated according to rehabilitation guidelines and referred to further investigation based on clinical symptoms.

Prognostic importance of ST-depression
In conventional diagnostic exercise testing, a conclusive negative ST-response is defined as no ST-depression at a heart rate of 85% or more of the age-predicted maximum.17 Severe coronary heart disease and previous myocardial infarction are associated with impaired chronotropic response during exercise.17,18 Therefore, in pre-discharge post-AMI exercise testing, 70% of the age-predicted maximum has been used as the limit for conclusive heart rate level when evaluating the ST-response.2 Low maximal heart rate without ST-depression has been associated with significantly increased subsequent mortality both in post-AMI series and in patients with chronic coronary heart disease.2,18,19

In the present study, more than half of the patients had maximal heart rate above the 70% limit despite routine treatment with a beta-blocker. Conclusive negative ST-response was registered in 58%, ST-depression in 18.5%, and inconclusive ST-response in 23.5% of the patients. In univariate analysis (Figure 3), an inconclusive ST-response was associated with the same prognosis as ST-depression, but not in the multivariable analysis. Patients with an inconclusive ST-response were more often treated with beta-blockers or calcium channel blockers, and the use of beta-blockers or heart rate lowering calcium antagonists is a frequent cause of chronotropic incompetence.19,20

Exercise-induced ST-depression has previously been shown to have limited ability to predict mortality in post-AMI patients.2,3,10,1214,21 In the present study, ST-depression was more frequent in patients treated with fibrinolysis than in the PCI group and, in multivariable analysis, ST-depression remained an independent risk predictor in the fibrinolysed patients but not in the PCI group (Table 4). This was expected as primary PCI leads to more complete revascularization of the infarct-related artery than fibrinolysis. Since the interaction for a difference of prognostic importance of ST-depression in the two treatment groups was not significant (P=0.15), this result can only be hypothesis generating. However, the number of endpoints in our study was relatively low, which may explain why the interaction test did not reach statistical significance.

Thus, ST-depression seems to add prognostic information in the fibrinolysis group only. Patients in the PCI group with and without ST-depression had virtually identical event rates. ST-depression after AMI, when the infarct-related artery is treated with stent angioplasty, may to a lesser degree be related to obstructive coronary artery disease than to myocardial and microvascular changes. Following stent angioplasty in patients with stable angina, ST-depression is related to microvascular and myocardial changes.2123 This result implies that patients following primary PCI are less likely to benefit from an ET for detection of residual ischaemia. Referral for repeat invasive investigation should be made on clinical grounds in the early period after STEMI.

Responses in exercise capacity and ST-depression are different in sub-groups, but the prognostic importance obtained from these was the same, indicating that our findings are stable. This implies that the same information can be achieved in all patients, which is important for setting up treatment strategies. However, due to a limited number of events, minor differences between sub-groups cannot be ruled out.

Prognostic importance of other ET variables
In previous post-AMI exercise studies, the increase of heart rate and blood pressure during exercise are powerful predictors of the subsequent mortality.2,3,1014 In a study of fibrinolysis vs. placebo,24 maximal heart rate and dPRP were significantly higher in the fibrinolysis group than in the placebo group, while maximal systolic blood pressure was not. This finding indicated improved chronotropic response in patients receiving reperfusion therapy. No such differences were found between fibrinolysis- and PCI-treated patients in the present study, and neither maximal heart rate nor dPRP showed any prognostic importance in multivariable analyses.

Limitations
Although we studied a large cohort of patients with STEMI, the exercise-tested patients were a low-risk subset. Therefore our analyses had to include softer endpoints than death alone. Patients randomized in clinical trials are not a random sample of patients with STEMI due to inclusion and exclusion criteria. Thus, the results may only be applicable to the same low-risk population as participated in the trial.


    Conclusions
 Top
 Abstract
 Introduction
 Materials and methods
 Discussion
 Conclusions
 Acknowledgements
 References
 
Exercise testing is still an important clinical investigation after AMI, irrespective of reperfusion therapy being applied in the acute phase. In patients capable of performing an ET, exercise capacity remains the most significant prognostic indicator for death and death/recurrent AMI in the era of more aggressive reperfusion therapy. It is possible that ST-depression cannot be used as a prognostic factor in pre-discharge ET after STEMI treated with primary PCI; this may have implications for the future role of exercise testing.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Discussion
 Conclusions
 Acknowledgements
 References
 
The present study was supported by grants from the Danish Heart Foundation. The authors are grateful to the DANAMI-2 investigators and study nurses and to Henning Rud Andersen and Torsten Toftegaard, from the steering committee of the DANAMI-2 trial, for support.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Discussion
 Conclusions
 Acknowledgements
 References
 

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