An international perspective on heart failure and left ventricular systolic dysfunction complicating myocardial infarction: the VALIANT registry

Eric J. Velazqueza,*, Gary S. Francisb, Paul W. Armstrongc, Phillip E. Aylwardd, Rafael Diaze, Christopher M. O'Connora, Harvey D. Whitef, Marc Henisg, Lois M. Rittenhousea, Rakhi Kilarua, Wiek van Gilsth, Georg Ertli, Aldo P. Maggionij, Jiri Spack, W. Douglas Weaverl, Jean-Lucien Rouleaum, John J.V. McMurrayn, Marc A. Pfeffero and Robert M. Califfa

a Division of Cardiology, Department of Medicine, Duke University Medical Center and Duke Clinical Research Institute, P.O. Box 17969, Durham, NC 27715, USA
b The Cleveland Clinic Foundation, Cleveland, OH, USA
c University of Alberta, Edmonton, Alberta, Canada
d Flinders Medical Centre, Bedford Park, South Australia
e Estudios Cardiologicos, Latinoamerica, Santa Fe, Argentina
f Green Lane Hospital, Auckland, New Zealand
g Medical Pharmaceutical Consultants, Randolph, NJ, USA
h Rijksuniversiteit Groningen, Groningen, The Netherlands
i Medizinische Universitätsklinik, Würzburg, Germany
j ANMCO Research Center, Florence, Italy
k Faculty Hospital of St. Anna, Brno, Czech Republic
l Henry Ford Hospital, Detroit, MI, USA
m University of Toronto, Ont., Canada
n University of Glasgow, Glasgow, UK
o Brigham and Women's Hospital, Boston, MA, USA

Received October 2, 2003; revised July 20, 2004; accepted August 5, 2004 * Corresponding author. Tel.: +1 919 668 8041; fax: +1 919 668 7169 (E-mail: velaz002{at}dcri.duke.edu).


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
AIMS: We analysed the contemporary incidence, outcomes, and predictors of heart failure (HF) and/or left ventricular systolic dysfunction (LVSD) before discharge in patients with acute myocardial infarction (MI).

The baseline presence of HF or LVSD, or its development during hospitalisation, increases short- and long-term risk after MI, yet its incidence, predictors, and outcomes have not been well described in a large, international, general MI population.

METHODS AND RESULTS: The VALIANT registry included 5573 consecutive MI patients at 84 hospitals in nine countries from 1999 to 2001. A multivariable logistic survival model was constructed using baseline variables to determine the adjusted mortality risk for those with in-hospital HF and/or LVSD. Baseline variables were also tested for associations with in-hospital HF and/or LVSD.

Of the 5566 patients analysed, 42% had HF and/or LVSD during hospitalisation. Their in-hospital mortality rate was 13.0% compared with 2.3% for those without HF and/or without LVSD. After adjustment for other baseline risk factors, in-hospital HF and/or LVSD carried a hazard ratio for in-hospital mortality of 4.12 (95% confidence interval: 3.08–5.56). Patients with HF and/or LVSD also had disproportionately higher rates of other cardiovascular events.

CONCLUSIONS: HF and/or LVSD is common in the general contemporary MI population and precedes 80.3% of all in-hospital deaths after MI. Survivors of early MI-associated HF and/or LVSD have more complications, longer hospitalisations, and are more likely to die during hospitalisation. Although baseline variables can identify MI patients at highest risk for HF and/or LVSD, such patients are less likely to receive indicated procedures and medical therapies.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Major advances have occurred in the clinical diagnosis and treatment of myocardial infarction (MI) over the past decade. With the availability of new biomarkers, guideline committees have refined the diagnosis and inclusivity of patients with suspected MI.1 The establishment of effective treatments beyond reperfusion strategies,2,3 such as antiplatelet agents,4,5 β-blockade,6 and angiotensin-converting enzyme (ACE) inhibitors,7 has been linked to reduced in-hospital mortality. Concurrently, these improvements have increased the proportion of the MI population who survive with left ventricular systolic dysfunction (LVSD) or heart failure (HF) with its associated morbidity and mortality.8

Although previous reports have described increased morbidity and mortality in patients with HF and/or LVSD after MI,9–12 less is known about the consequences of HF or LVSD occurring during the acute MI hospitalisation, the comparative uptake in MI patients with HF and/or LVSD of therapies and procedures, and whether the prevalence of HF and LVSD complicating MI has been altered by modern MI treatment strategies. The important population with LVSD without symptoms of HF has never been well characterised, nor have international practice patterns been evaluated. Furthermore, although multiple professional society recommendations exist,13–15 their use related to the MI population with HF and/or LVSD is relatively uncharacterised.

To further examine the incidence of HF and/or LVSD complicating contemporary MI, we developed a nested registry as part of the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial. Using this cohort, we tested the hypothesis that HF and/or LVSD was common, was associated with a significantly increased adjusted mortality, and could be predicted by clinical variables available at presentation.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Study design
Our registry was conducted as an ancillary study to the main VALIANT trial, the design and results for which have been reported.16,17 Briefly, VALIANT investigators tested whether the angiotensin receptor blocker (ARB) valsartan, alone or combined with the ACE-inhibitor captopril, reduces mortality compared with captopril alone in patients with MI complicated by HF and/or LVSD. The VALIANT registry was constructed to estimate the proportion of the general MI population for whom the VALIANT trial results apply. During a specified portion of the VALIANT trial randomisation period, 84 sites representing nine countries of the 932 potential VALIANT trial sites across 24 countries, agreed to enter all patients clinically diagnosed with MI into a consecutive screening registry. All of the registry sites were led by cardiologist investigators, 83 (99%) had experience with mortality-endpoint trials, and 46 (55%) of the investigators were affiliated with academic centres. A screening form was devised to collect medical history, previous medication use before MI presentation, initial electrocardiographic (ECG) results, medication use within the initial day of MI diagnosis, clinical events occurring and procedures performed before discharge, as well as the discharge disposition.

Study population
At interested investigative sites during specified screening periods, all patients admitted with a clinical diagnosis of MI as determined by the physician were entered into the VALIANT registry. Sites chose between limited participation over a 2-week period and a more comprehensive registry enrolment over 6 months. Although not required for registry enrolment, sites were instructed to use the VALIANT trial MI inclusion criteria as a guide,18 which required biomarker evidence of myocardial necrosis regardless of ST-segment deviation and either a symptom complex or ECG consistent with MI.

For each patient entered into the registry, investigators were asked questions pertaining to VALIANT trial eligibility, including whether trial HF and/or LVSD criteria16 were met (see Appendix A). These criteria were applied by the enrolling investigators and based on a compendium of the HF or LVSD inclusion criteria used in placebo-controlled comparative trials of ACE-inhibitors.19–21 Patients with Killip class ≥II were eligible for VALIANT whether LVSD was present or not; conversely, patients without clinical HF were eligible if imaging evidence indicated LVSD. Registry patients were segregated into two cohorts – HF/LVSD and no-HF/no-LVSD – for the purpose of our analyses, based on whether the patient met the trial HF and/or LVSD enrolment criteria as indicated on the case report form.

Statistical analysis
Continuous baseline characteristics and clinical outcomes were reported as means with standard deviations, and the Wilcoxon rank-sum test was used to assess differences in the distributions between the HF/LVSD and no-HF/no-LVSD groups. Categorical variables were analysed by using the likelihood ratio {chi}2 test. Simple unadjusted mortality rates were generated to explore the distribution of deaths across HF/LVSD groups. Patients with missing values were included in the relevant denominator to calculate percentages by HF/LVSD.

Multivariable logistic regression was used to predict in-hospital survival after adjusting for baseline demographic and clinical variables, medical history, and the initial ECG. The model was selected using the following baseline and presentation variables: age, sex, weight, race, history of angina, prior MI, prior percutaneous coronary intervention (PCI), prior bypass surgery, prior HF, stroke, peripheral vascular disease, dyslipidaemia, chronic obstructive pulmonary disease, renal insufficiency, hypertension, diabetes, current smoking, first recorded blood pressures, heart rate, Killip class, ST-segment category (elevation, depression, non-specific changes, Q waves in infarct zone, left bundle-branch block), and MI location (anterior versus inferior).

Relationships between continuous baseline variables and in-hospital survival were examined by using spline functions with inflection points; the independent splines were then incorporated into the model. All baseline factors collected, including demographics, previous medical history, and presenting haemodynamic and ECG variables, were considered as potential candidates for predicting in-hospital survival (see Appendix B). Different algorithmic selection procedures (forward, backward, and stepwise) were used to select variables that were most predictive. Those variables commonly selected by all the selection procedures were used in the final model. Similarly, multivariable logistic regression was used to predict HF/LVSD before discharge or death after adjusting for baseline characteristics.22–25

For all analyses, a two-tailed P value <0.05 was considered statistically significant. All analyses were performed by using SAS statistical software (SAS Institute, Cary, NC, USA).


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patient population and HF/LVSD incidence
Between November 1999 and June 2001, 5573 patients with MI were enrolled into the VALIANT registry at 84 hospitals in nine countries (Table 1 and Fig. 1). Of these, seven patients lacked data for HF/LVSD, leaving 5566 patients for analysis: 2347 patients (42%) identified by the enrolling investigators as having had HF/LVSD at baseline or during hospitalisation and 3219 were considered not to have HF/LVSD. Of those with HF/LVSD, 992 (42%) were in Killip class I but had a measured ejection fraction ⩽40%, 382 (16%) had Killip class ≥II HF and an ejection fraction <40%, 377 (17%) had Killip class ≥II HF and an ejection fraction ≥40%, and 524 (22%) had Killip class ≥II HF and no recorded in-hospital ejection fraction. There were 72 patients who lacked Killip class data but were in the HF/LVSD subset. In the subset of patients who were in Killip class I, the mean ejection fraction was 37% (interquartile range 30–45%). Of the patients with symptomatic HF (55%) as defined by Killip class ≥II (35% class II, 17% class III, and 2.6% class IV), an ejection fraction was reported for 59% of these patients, which averaged 40% (interquartile range 30–50%).


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Table 1. VALIANT registry enrollment
 


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Fig. 1 Patient flow diagram. EF, ejection fraction.

 
In general, patients in the HF/LVSD group were at higher risk at baseline (Table 2) – they were older, more often female, and had higher rates of prior MI, bypass surgery, stroke, peripheral arterial disease, hypertension, and diabetes. They also were more likely to present with left bundle-branch block or anterior MI, and they were less likely to be current smokers or have ST-segment elevation at presentation. Despite a greater history of hypertension, the HF/LVSD group presented with lower blood pressure and faster heart rates.


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Table 2. Baseline characteristics
 
Early in-hospital MI management (Table 3)
Of the patients with ST-segment elevation MI, 1060 (39%) received intravenous fibrinolytic therapy within 24 h of MI diagnosis. Percutaneous intervention was performed <24 h after MI symptom onset in 534 patients (9.6%). The HF/LVSD group was less likely to undergo early PCI (7.4% vs. 11%; P<0.001). Among MI patients without ST-segment elevation, 20% received a platelet glycoprotein (GP) IIb/IIIa inhibitor during this period. Overall, 82% of patients received either unfractionated heparin or low molecular weight heparin. However, patients with HF/LVSD were significantly less likely to receive these therapies as well as antiplatelet agents, β-blockers, and nitrates. Patients with HF/LVSD were more likely, however, to receive early ACE-inhibitors, lidocaine, and amiodarone (see Table 3).


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Table 3. Medications used within 24 h after MI diagnosis
 
In-hospital procedures (Table 4)
Patients with HF/LVSD were more likely to undergo echocardiography, pulmonary artery catheterisation, intra-aortic balloon counterpulsation, pacemaker insertion, and implantable defibrillator implantation. In contrast, these patients were less likely to undergo coronary angiography, PCI, or stress testing before discharge. Patients with HF/LVSD who did undergo angiography were less likely than those in the no-HF/no-LVSD group to then undergo revascularisation (78% vs. 85%; P<0.001). GP IIb/IIIa inhibitors were used as adjunctive therapies in 28.3% of the procedures, and stents in 36.4%. Among HF/LVSD patients who underwent PCI, GP IIb/IIIa inhibitors and stents were used less often (20% and 27%, respectively; see Table 4).


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Table 4. In-hospital procedures
 
In-hospital clinical events (Fig. 2)
The HF/LVSD group had significantly higher rates of mortality, atrial fibrillation, ventricular tachycardia or fibrillation, stroke or transient ischemic attack, and hypotension requiring intervention or cardiogenic shock (all P<0.001). The incidence of ECG- or biomarker-determined reinfarction was higher among those with, versus without, HF/LVSD (2.5% vs. 1.4%; P=0.002; Fig. 2).



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Fig. 2 In-hospital clinical events among patients with and without HF/LVSD. P<0.001 for all events except reinfarction. fib., fibrillation; V. tach/fib., ventricular tachycardia or fibrillation.

 
Those with HF/LVSD who died prior to discharge (n=305) were more likely to suffer pre-fatal morbid clinical events. In patients with HF/LVSD who died (n=305), 27% experienced worsening HF, 19% experienced ventricular fibrillation or ventricular tachycardia, and 6.2% had a recurrent MI. In those without HF/LVSD (n=75) who died, these proportions were 1.3%, 11%, and 1.3%, respectively.

Discharge disposition
The hospital stay among survivors was significantly longer for the HF/LVSD group (median 8 vs. 6 days). After excluding patients who died during hospitalisation, 76% of the HF/LVSD patients were discharged to home versus 85% of the no-HF/no-LVSD group, and 7.3% and 6.4% of patients, respectively, were transferred to another acute-care facility.

Patients in the HF/LVSD group were prescribed ACE-inhibitors, ARBs, loop diuretics, spironolactone, digoxin, amiodarone, nitrates, and warfarin significantly more often at discharge than the no-HF/no-LVSD group, whereas those without HF/LVSD group were prescribed β-blockers, aspirin, clopidogrel, and statin drugs significantly more often (Table 5).


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Table 5. Discharge medications
 
Predictors of mortality
Overall in-hospital mortality in the registry was 6.91%, but the rate for the HF/LVSD group was more than 5 times higher than for the no-HF/no-LVSD group (13% [n=305] vs. 2.3% [n=75]; P<0.001). HF and/or LVSD preceded 80% of all in-hospital deaths after MI in our registry population. To compare in-hospital mortality after adjustment for baseline risk, we developed a multivariable logistic model (C-index value: 0.81; global likelihood ratio chi-square: 451.6). Male sex, older age, lower systolic blood pressure, weight above or below the interquartile range, prior HF, hyperlipidaemia, and renal insufficiency were independently associated with in-hospital mortality (all P<0.05). After adjusting for these independent baseline predictors of risk, patients with HF/LVSD continued to have a higher risk of in-patient mortality (hazard ratio: 4.12; 95% confidence interval: 3.08–5.56).

Baseline predictors of HF/LVSD (Table 6)
Using all baseline and presentation factors, we constructed a multivariable logistic model to predict which MI patients were most likely to present with or develop in-hospital HF and/or LVSD (C-index value: 0.756; global likelihood ratio chi square: 1136.46). The following baseline factors were associated with the greatest risk: higher heart rate, higher systolic blood pressure, prior HF, older age, and left bundle-branch block or anterior MI on ECG (all P<0.001).


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Table 6. Baseline predictors of HF/LVSD
 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
This study extends previous findings and shows that despite advances in both reperfusion therapy and prevention and treatment of HF, post-infarction HF/LVSD remains the major intermediate disease state between acute MI and death or morbid outcomes. Furthermore, despite extensive trials that have been translated into clinical practice guidelines, treatment appears to be suboptimal for this population. Given that 80% of the patients who die and 59% of patients with other major complications have HF and/or LVSD either at admission or during hospitalisation, attention to and aggressive treatment of this disorder may substantially improve outcomes for the general MI population.

Recognition of the importance of HF in MI started with the key work of Peel, Killip, and Kimball, and others.26–28 Studies in the fibrinolytic era29,30 have pointed out the continuing critical importance of HF and LVSD to in-hospital and long-term survival. The fact that this population was singled out for key studies of the use of ACE-inhibitors after MI19–21 shows the importance that the clinical research world places on this issue.

O'Connor and colleagues have reported that in patients treated with fibrinolytic therapy, 21% of those who developed HF had died by 1-year follow-up compared with only 5% of patients without HF.31 More recently, in non-ST-elevation acute coronary syndromes, we reported a tripling of mortality in patients with symptomatic HF compared with those without HF.32 The National Registry of Myocardial Infarction (NRMI) found an in-hospital death rate for patients with HF at admission of 21.4% compared with a rate of 7.2% for patients without HF, but no information was available about later development of HF.12 Steg and colleagues reported that ~15% of MI patients and 9% of unstable angina patients in the Global Registry of Acute Coronary Events (GRACE) registry had HF at admission. Patients with HF at admission had fewer percutaneous procedures, were given β-blockers less often, and had >300% higher mortality and longer hospital stays than did patients without HF at admission.33 The independent importance of HF/LVSD to survival and major complications is unsurprising. All studies have found the same basic relationships – patients with HF/LVSD are more likely to have risk factors for death before the onset of HF, but these factors do not fully account for the effects of the disorder.

Occult LVSD with no signs or symptoms of HF is a common but poorly studied issue. Although our study is confounded by the fact that left ventricular systolic function was not measured systematically, patients with LVSD and no symptoms of HF remained at high risk, whereas those who had both HF and LVSD were shown to have the highest risk (Fig. 3). This finding provides support for the clinical practice guidelines13,34 recommending the routine quantification of left ventricular function for risk stratification.



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Fig. 3 In-hospital mortality among the groups detailed in Fig. 1. EF, ejection fraction.

 
The frequent failure to use beneficial therapies in this population has been reported in several other recent studies.30,35 In a recent NRMI study,12 patients with HF at admission were less likely to receive aspirin, heparin, β-blockers, fibrinolytics, or primary PCI. Although they were more likely to receive ACE-inhibitors, only 25% of them were so treated. Our study highlights and extends this issue, given that our more contemporary cohort was no more likely to receive indicated treatment even though our investigators were predominantly cardiologists and many were at academic centres. In fact, even though our registry patients were enrolled at research sites, where standards of care might be expected to be above the norm, nearly 20% of HF/LVSD patients were not prescribed aspirin, >30% were not prescribed β-blockers, and >40% of patients did not receive ACE-inhibitors at discharge. Furthermore, as we have reported for both ST-segment elevation MI36 and non-ST-elevation acute coronary syndromes,32 patients with HF/LVSD were less likely to undergo angiography or revascularisation although guidelines almost universally recommend these procedures for this high-risk population.

The limitations of this study include the lack of detailed data collection for issues such as the timing of HF and detailed indications and contraindications for therapy. For this reason, we cannot provide specific information about when HF or LVSD occurred in the course of the acute event or how many of these patients met specific criteria (indications or lack of contraindications) for proven effective therapies. The clinical events, although a priori defined, where investigator reported and additional, independent event adjudication was not performed. Furthermore, this registry enrolled MI patients at sites led by cardiologists, many of whom were affiliated with a university, and whose practices and outcomes may not be representative of all hospitals.

This study shows the critical importance of identifying HF/LVSD. Previous reports,29,37 as well as these results, support the feasibility of using baseline variables to define the population most likely to develop HF and/or LVSD. Early identification of at-risk patients should allow an aggressive approach to revascularisation, blockade of the renin–angiotensin–aldosterone system,19–21,38 use of β-blockers,39 and monitoring for dysrhythmias and clinical deterioration before morbid or fatal outcomes occur, thereby improving overall survival after MI. The poor outcomes of patients with LVSD but no symptoms points to the importance of measuring left ventricular function, even in patients who appear to be doing well, to provide more appropriate use of limited resources. The excess rate of pre-fatal worsening HF, recurrent MI, and life-threatening ventricular arrhythmias in the HF/LVSD group when compared to the no-HF/no-LVSD group strongly suggests that the cascade of events associated with a higher mortality for this population may be interruptable. Given that almost all of the morbidity and mortality is confined to the HF/LVSD cohort, this approach should translate into improved outcomes across the spectrum of patients with MI.

The concept of disease management is becoming crucial in clinical care as the field migrates from static models to the idea of continuous risk assessment. This study, combined with previous ones, shows that when a clinician finds evidence of either HF or LVSD in a patient with myocardial necrosis, surveillance and treatment should become more aggressive, particularly regarding the therapies that have been proven beneficial for this population.

Appendix A: Enrolment Criteria for HF/LVSD
In addition to being ≥18 years old and having MI symptom onset within 12 h and 10 days before randomisation, patients were required to have ≥1 of the following:

1. Pulmonary venous congestion on X-ray with interstitial or alveolar oedema or clinical evidence of HF (pulmonary oedema, bilateral post-tussive rales in at least the lower third of the lung fields and/or an S3 gallop with persistent tachycardia).
2. Left ventricular ejection fraction (35%) or wall-motion index 1.2 as defined by the TRACE investigators on echocardiography.
3. Left ventricular ejection fraction of 40% on radionuclide angiography or 35% on contrast angiography.

Appendix B

List of variables independently associated with in-hospital mortality (P<0.05)

Sex: male vs. female
Previous history of HF
Previous history of dyslipidaemia
Previous history of chronic renal insufficiency
First recorded SBP
Age
Weight


List of variables not associated (P>0.05) or not selected in the final model

Days to admission after MI symptom onset
First recorded pulse
First recorded DBP
Country: US vs. non-US
ST≥2 leads
ST depression
Non-specific ST or T wave abnormalities
Q wave
LBBB
Anterior location of infarct
Inferior location of infarct
Race: white vs. non-white
Previous history of angina
Previous MI
Previous PTCA
Previous history of CABG
Previous history of stroke
Previous history of peripheral vascular disease
Previous history of COPD
Previous history of hypertension
Previous history of diabetes
Current smoking status

 


    Acknowledgments
 
The VALIANT trial was funded by a grant from Novartis Pharmaceutical Corporation, East Hanover, New Jersey. Dr. Velazquez has received research support under the Joseph C. Greenfield, Jr. Scholars Program.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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