Heart failure on admission and the risk of stroke following acute myocardial infarction: the VALIANT registry
Karolina E. Szummer1,
Scott D. Solomon2,
Eric J. Velazquez3,
Rakhi Kilaru3,
John McMurray4,
Jean-Lucien Rouleau5,
Kenneth W. Mahaffey3,
Aldo P. Maggioni6,
Robert M. Califf3,
Marc A. Pfeffer2,
Harvey D. White7,* on behalf of the VALIANT registry
1Department of Cardiology, Karolinska University Hospital Huddinge, Stockholm, Sweden
2Brigham and Women's Hospital, Boston, MA, USA
3Division of Cardiology, Department of Medicine, Duke University Medical Center and Duke Clinical Research Institute, Durham, NC, USA
4University of Glasgow, Glasgow, UK
5University of Toronto, Ontario, Canada
6Italian Association of Hospital Cardiologists Research Center, Florence, Italy
7Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92 024, Auckland 1003, New Zealand
Received 22 October 2004; revised 11 February 2005; accepted 28 April 2005; online publish-ahead-of-print 21 June 2005.
* Corresponding author. Tel: +64 9 307 4949 ext. 23669; fax: +64 9 307 4949 ext. 23670. E-mail address: harveyw{at}adhb.govt.nz
This paper was guest edited by Prof. Freek W.A. Verheugt, University Medical Center Nijmegen, The Netherlands
 |
Abstract
|
---|
Aims We sought to assess the relative contribution of heart failure (HF) on admission for an acute myocardial infarction (MI) to the subsequent in-hospital stroke risk.
Methods and results The VALsartan In Acute myocardial iNfarcTion (VALIANT) registry enrolled 5573 consecutive MI patients at 84 international sites from 1999 to 2001. We calculated odds ratios (ORs) for stroke and adjusted for baseline characteristics, Killip Class, and risk factors for stroke, such as diabetes and prior HF.
In-hospital stroke occurred in 81 (1.5%) patients. HF was present on admission in 38% of patients who developed a stroke and in 24% who did not (P=0.001). Older age (OR 1.03 increase/year, 95% confidence interval (CI) 1.011.04), Killip Class III (OR 1.66, CI 0.863.19) or IV (OR 4.85, CI 1.6913.93), history of hypertension (OR 1.73, CI 1.062.82), and history of stroke (OR 1.89, CI 1.063.37) were more common in patients who had in-hospital stroke. In-hospital mortality in patients with and without stroke was 27.2 and 6.5%, respectively (P<0.001).
Conclusion Patients with stroke after MI have a dismal prognosis. The presence of HF on admission for an acute MI increases in-hospital stroke risk. HF treatments may modify the risk of stroke.
Key Words: Stroke Risk factors Myocardial infarction
 |
Introduction
|
---|
Stroke is an uncommon but devastating complication in patients with acute myocardial infarction (MI). Within the first month following an MI, between 1 and 2% of patients have a stroke,1,2 and half of these post-MI strokes occur within the first week.3 Stroke following an MI is associated with an early mortality approaching 50%.4,5 The incidence of stroke varies with individual factors as well as the type and size of the MI. Generally, patients with larger and anterior MIs and patients with higher heart rate on admission have been shown to have a higher stroke risk following MI,3,5,6 probably due to larger wall motion abnormalities pre-disposing to left ventricular thrombi formation and embolic strokes. Reduced left ventricular function is associated with long-term stroke risk following MI.7
Higher Killip Class assessed on admission for an MI is a predictor of post-MI mortality.8 In contrast, the association of heart failure (HF) on presentation for an MI and the subsequent stroke risk in a broad MI population has not been systematically examined. A worse haemodynamic state with more HF symptoms has been reported more frequently in patients who experience a stroke following MI, both in patients enrolled in thrombolytic trials as well as in general MI populations.3,9 Killip Class was shown to increase the risk of stroke (one-third of strokes were haemorrhagic) in one thrombolytic trial,5 although it has not been shown to be an independent predictor of stroke following MI.3 Reperfusion therapy increases the risk of haemorrhagic stroke, but at the same time decreases embolic stroke. Overall stroke rates are not altered by thrombolytic therapy. Even though stroke rates are lower in patients with non-ST-elevation acute coronary syndromes, stroke occurs nearly twice as often in those patients who also have in-hospital congestive HF.6
In this study, we assessed the relative contribution of HF status on admission to the subsequent in-hospital stroke risk following an MI in a general MI-population that comprised patients with both ST- and non-ST-elevation MI treated with contemporary therapies.
 |
Methods
|
---|
Study population: the VALIANT registry
The VALIANT (VALsartan In Acute myocardial iNfarcTion) registry was an ancillary study to the VALIANT trial.10 The VALIANT trial was designed to assess the efficacy of the angiotensin receptor blocker valsartan, the angiotensin-converting enzyme inhibitor captopril, and their combination in patients with an acute MI complicated by either clinical HF (Killip Class
II), left ventricular systolic dysfunction, or both.10 The VALIANT registry was much more encompassing in that it was created to estimate the proportion of the general MI population to whom the VALIANT trial results would apply. In total, 5573 consecutive MI patients from 84 participating hospitals in nine countries (Argentina, Australia, Canada, Czech Republic, Germany, Italy, the Netherlands, New Zealand, and the United States) were included in the VALIANT registry between November 1999 and June 2001.
The MI diagnosis for inclusion into the VALIANT registry was based on the individual hospital's MI criteria, although the use of VALIANT trial MI inclusion criteria (elevated biochemical markers of myocardial necrosis combined with symptoms and/or electrocardiogram changes consistent with MI) was recommended.10 Both ST- and non-ST elevation could be consistent with MI diagnosis. Baseline characteristics, medication prior to admission, electrocardiogram on admission, therapy given on the initial day of MI diagnosis, clinical events, in-hospital procedures, discharge medication, and disposition were prospectively recorded. There were no follow-up appointments after discharge.
HF status was assessed on admission and graded according to Killip Class. Worsening HF was defined as the unplanned use of intravenous inotropes, vasodilators, and/or diuretics.
Dyslipidaemia refers to any abnormality of cholesterol, triglycerides, or other blood lipids. Chronic renal insufficiency was defined as a serum creatinine >2.0 mg/dL (>177 µmol/L) before the qualifying MI. Peripheral arterial disease (PAD) was defined as having claudication or prior arterial surgery.
Stroke classification
Stroke was defined as an acute focal neurological deficit consistent with the diagnosis and lasting more than 24 h or resulting in death. Stroke was identified by the treating physician and reported prospectively as one of the clinical in-hospital events on the case report form. The exact timing of the stroke was not recorded. Imaging was not required for the diagnosis of stroke and was performed as deemed appropriate by the treating physician. No classification into haemorrhagic or ischaemic stroke types was made.
Statistical analysis
Continuous baseline characteristics and clinical outcomes were reported as medians with interquartile ranges. The Wilcoxon ranksum test was used to assess the differences in the distributions between the stroke groups (stroke vs. non-stroke). Categorical variables were analysed using the likelihood ratio
2 test. Simple unadjusted mortality rates were generated to explore the distribution of deaths across stroke groups. Patients with missing values were included in the relevant denominator to calculate per cent by stroke group.
Model building using selection algorithms was not possible because of the low stroke event rate; hence statistically significant and clinically relevant variables were used in multivariable logistic regression to predict in-hospital survival along with stroke. A second multivariable logistic regression using the same variables was used to predict both stroke and in-hospital death. Adjustments were made for the following variables: age, history of stroke, PAD, chronic obstructive pulmonary disease (COPD), hypertension, diabetes, prior HF, and Killip Class at presentation. Relationship between age (a continuous variable) and in-hospital survival was examined using spline functions with inflection points. The independent splines were incorporated into the model.
For all analyses, a two-tailed P<0.05 was considered statistically significant. All analyses were performed using SAS statistical software (SAS Institute, Cary, NC, USA).
 |
Results
|
---|
A total of 81 (1.5%) patients suffered in-hospital strokes out of the 5573 patients with MI enrolled in the VALIANT registry. Table 1 shows baseline characteristics and medications on hospital admission for patients with and without stroke. The patients who had a stroke during the acute MI were significantly older, and the incidence increased up to 84 years of age (Figure 1). Prior stroke, known PAD, and hypertension were more common in patients who experienced a stroke. Initial blood pressures and heart rates were similar on admission (Table 2). When analysed as a cut-off value, a borderline significant number of patients with stroke had a heart rate
100 b.p.m. compared with patients without stroke (27.2 vs. 19.3%, P=0.06). History of atrial fibrillation was not documented on admission, but this arrhythmia was reported almost twice as often, after admission, in patients who experienced a stroke than in those who did not (Table 3).
The frequency of ST-elevation or ST-depression on the admission electrocardiogram was similar in both groups (Table 2). The frequency of initial therapy with either a thrombolytic agent (21% in patients with stroke vs. 20% in those without, P=0.947) or primary percutaneous coronary intervention (PCI) (10 vs. 13%, P=0.347) was also similar in both groups. Reperfusion therapy did not significantly alter the incidence of stroke compared with not receiving thrombolytics or undergoing PCI (Table 4). There was no difference in the use of unfractionated heparin (67 vs. 64%, P=0.587) or low molecular weight heparin (15 vs. 23%, P=0.098) in the two groups within the first day of admission, although patients with stroke were less likely to receive aspirin on admission (67 vs. 78%, P=0.013). Pre-admission and discharge medications are shown in Tables 1 and 5.
HF signs were present in 31 (38%) patients with stroke and 1292 (24%) patients without stroke (Table 2, Figure 2A). Patients presenting with Killip Class II had a stroke risk similar to that of patients with no HF signs on admission (OR 1.0, 95% CI 0.651.83) (Figure 2B). Patients with Killip Class III had a 1.5 times increased OR for stroke compared with Killip Class I (OR 1.66, 95% CI 0.863.19), whereas Killip Class IV patients had more than four times higher OR (OR 4.85, 95% CI 1.6913.93). In-hospital worsening of HF and hypotension requiring therapy occurred more frequently in patients who experienced a stroke (Table 3). Approximately 54% of patients with stroke and 44% without stroke had echocardiography during the hospital stay. There was a trend for the left ventricular ejection fraction to be lower in patients with stroke (Table 3).


View larger version (19K):
[in this window]
[in a new window]
|
Figure 2 (A) ORs and CIs for stroke with increasing Killip Class, compared with Killip Class I, (B) Distribution of Killip Class IIV in the stroke and no-stroke group.
|
|
After adjusting for all significant baseline characteristics and a limited number of previously described factors associated with an increased stroke risk (Killip Class on admission, diabetes, and prior HF),4,5,7 we found that age (OR 1.03 increase/year, 95% CI 1.011.04), history of stroke (OR 1.89, 95% CI 1.063.37), prior hypertension (OR 1.73, 95% CI 1.062.82), and Killip Class IV (OR 4.85, 95% CI 1.6913.93) were independently associated with having a stroke.
Patients who experienced a stroke remained in-hospital longer and were less likely to be discharged home (Table 3). In-hospital mortality was more than four times higher (27.2 vs. 6.5%) in patients who had a stroke. Stroke deaths accounted for 5.8% of all in-hospital post-MI deaths. All the factors associated with an increased risk of stroke were also associated with an increased likelihood of death (data not shown).
 |
Discussion
|
---|
In this contemporary, international population consisting of 5573 patients presenting with either ST- or non-ST-elevation MI, the incidence of in-hospital stroke was 1.5%. We assessed the relative contribution of HF status on admission to the in-hospital risk of stroke. Evidence of HF was present on admission in 38% of patients who developed a stroke vs. 24% of patients who did not. Patients presenting with Killip Class III and above had a substantially increased risk of subsequent stroke, whereas patients in Killip Class II had a risk similar to that of patients without any HF signs.
With contemporary therapy for acute MI, the overall incidence of stroke is reported to be between 1 and 2%.2,3,5 The use of thrombolytic therapy has been associated with an increase in the proportion of non-haemorrhagic to haemorrhagic strokes, with the contemporary stroke rate between 0.9 and 1.5% in selected trial patients11,12,13 and between 0.7 and 1.6% in registries.2,14 With primary PCI, the incidence of stroke is around 1%.15 Although the incidence of stroke has been reported to be lower in patients undergoing PCI compared with those undergoing thrombolytic therapy,15 stroke rates were similar with these non-randomized therapies in this registry.
In this study, we found a correlation between higher Killip Class and the occurrence of stroke in a general population with MI. The mechanism for this relationship remains unknown. Killip Class was a predictor of subsequent in-hospital stroke in one thrombolytic trial (in which one-third of strokes were haemorrhagic),5 but it was not an independent predictor of ischaemic stroke in the GUSTO-1 trial.3 This discrepancy might be at least partly explained by selection bias for healthier patients but not for patients in Killip Class III or IV, to be enrolled in a trial rather than in a registry. No patients were excluded from the registry on the basis of worse haemodynamic status, which probably would have occurred in a randomized trial, and therefore a trial population would be less appropriate to assess risk factors for stroke in a general MI population. Despite differences in patient selection and MI characteristics in previous studies, the reported independent predictors of post-MI stroke have been similar, including higher age, prior stroke, higher heart rate, and diabetes.3,6
The presence of atrial fibrillation is a powerful risk factor for stroke.16,17 In this study, in-hospital atrial fibrillation was more frequent in patients who experienced a stroke. However, the proportion of patients with either new-onset or chronic atrial fibrillation was not documented. New-onset atrial fibrillation is an independent predictor of 30-day mortality,16 which might partially be explained by a higher stroke rate.17 Atrial fibrillation is a direct cause of as well as a marker for stroke risk and other possible stroke causes, such as embolism from atheromatous aortic arches or platelet emboli from ulcerated carotid plaques. Additionally, the occurrence of new-onset atrial fibrillation following an MI has been independently predicted by other stroke-related states, such as worsening HF, presence of hypotension, and ventricular fibrillation.17
Larger and anterior infarcts have been associated with an increased risk of stroke,6 probably due to a combination of impaired left ventricular function, worse haemodynamic status with low flow mechanisms, and greater regional wall motion abnormalities that contribute to the formation of left ventricular thrombus and systemic embolism. A depressed left ventricular ejection fraction increases the long-term risk of stroke following an MI.7 This relationship could not be fully assessed in the current study, as left ventricular ejection fractions were not systematically evaluated. However, there was a trend on univariate analysis for patients with stroke to have lower ejection fractions.
Stroke was more frequent in the elderly, and the incidence increased proportionally with age. The lower stroke rate in the very elderly may reflect the higher mortality in this age group.3,6,18 Approximately one-third of the strokes were fatal, which is lower than the previously reported rates between 40 and 50% in patients with a stroke following MI.7,11
Although many risk factors for the occurrence of post-MI stroke have been identified, many mechanisms remain unexplored. Markers of thrombosis and inflammation, such as fibrinogen or C-reactive protein, have been shown to predict the risk of stroke in the long term, though their contribution in the acute phase following an MI is unknown.19,20
Limitations
There are a number of limitations to our study related to the nature of a registry. As no cerebral imaging results were available, we were unable to account for the different types of stroke (haemorrhagic or ischaemic) and their relationship to different therapies in this population. Treatment strategies differed non-significantly in patients with stroke, but treatments were not randomly assigned and could be biased by the clinical course; hence, their influence on the risk of stroke cannot be evaluated.
Left ventricular function was examined in only 44% of patients, and without standardization which limited further multivariate analysis. The occurrence of ventricular thrombus was not reported and we did not record the exact timing of the occurrence of a stroke. Also, no adjustment was made for the variation in the length of post-MI hospital stay across different centres.
 |
Conclusion
|
---|
Stroke complicating an MI is uncommon, but the public health impact is enormous because of the high prevalence of coronary artery disease and the impact on survival, quality of life, and cost. Higher age, prior cerebrovascular disease, and history of hypertension increase the likelihood of a subsequent stroke and point to the importance of treating patients with these features to prevent both MI and stroke. Once a stroke has occurred, the prognosis is poor, with high morbidity and mortality. The duration of hospitalization is 1.5 times longer for these patients, and the associated costs are substantial. Despite the recognition of several different factors that identify patients at heightened risk for stroke following an MI, the mechanisms are multifactorial, and therapies to decrease the incidence are elusive. Major efforts must be directed towards the primary risk factors causing acute MI and towards those factors associated with the occurrence of stroke after MI.
In this study, HF on admission complicated
24% of the MIs and significantly increased the risk of stroke. Strategies that reduce the incidence of HF in this early time period, when the stroke risk is highest, may decrease the number of early strokes and the associated dismal prognosis. It is not known whether therapies that may improve the outcome of patients who develop HF after MI may also decrease the risk of stroke.
 |
Acknowledgements
|
---|
The authors gratefully acknowledge the patients who participated in the VALIANT registry and the investigators and coordinators for their tireless dedication to this project. Without them, these analyses and this article would not have been possible. The authors also thank John M. Daniel and Jennifer Sharpe for their editorial support and help in preparing this manuscript.
 |
References
|
---|
- The Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 1994;343:311322.[CrossRef][ISI][Medline]
- Becker RC, Burns M, Gore JM, Spencer FA, Ball SP, French W, Lambrew C, Bowlby L, Hilbe J, Rogers WJ for the NRMI-2 participants. Early assessment and in-hospital management of patients with acute myocardial infarction at increased risk for adverse outcomes: a nationwide perspective of current clinical practice. Am Heart J 1998;135:786796.[ISI][Medline]
- Mahaffey KW, Granger CB, Sloan MA, Thompson TD, Gore JM, Weaver WD, White HD, Simoons ML, Barbash GI, Topol EJ, Califf RM. Risk factors for in-hospital nonhemorrhagic stroke in patients with acute myocardial infarction treated with thrombolysis: results from GUSTO-I. Circulation 1998;97:757764.[Abstract/Free Full Text]
- Gore JM, Granger CB, Simoons ML, Sloan MA, Weaver WD, White HD, Barbash GI, Van de Werf F, Aylward PE, Topol EJ, Califf RM. Stroke after thrombolysis. Mortality and functional outcomes in the GUSTO-I trial. Circulation 1995;92:28112818.[Abstract/Free Full Text]
- Maggioni AP, Franzosi MG, Santoro E, White H, Van de Werf F, Tognoni G. The risk of stroke in patients with acute myocardial infarction after thrombolytic and antithrombotic treatment. N Engl J Med 1992;327:16.[Abstract]
- Mahaffey KW, Harrington RA, Simoons ML, Granger CB, Graffagnino C, Alberts MJ, Laskowitz DT, Miller JM, Sloan MA, Berdan LG, MacAulay CM, Lincoff AM, Deckers J, Topol EJ, Califf RM. Stroke in patients with acute coronary syndromes. Circulation 1999;99:23712377.[Abstract/Free Full Text]
- Loh E, Sutton MS, Wun CC, Rouleau JL, Flaker GC, Gottlieb SS, Lamas GA, Moye LA, Goldhaber SZ, Pfeffer MA. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med 1997;336:251257.[Abstract/Free Full Text]
- Khot UN, Jia G, Moliterno DJ, Lincoff AM, Khot MB, Harrington RA, Topol EJ. Prognostic importance of physical examination for heart failure in non-ST-elevation acute coronary syndromes: the enduring value of Killip classification. JAMA 2003;290:21742181.[Abstract/Free Full Text]
- Wu AH, Parsons L, Every NR, Bates ER. Hospital outcomes in patients presenting with congestive heart failure complicating acute myocardial infarction (NRMI-2). J Am Coll Cardiol 2002;40:13891394.[Abstract/Free Full Text]
- Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:18931906.[Abstract/Free Full Text]
- The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001;358:605613.[CrossRef][ISI][Medline]
- The HERO-2 Trial Investigators. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial. Lancet 2001;358:18551863.[CrossRef][ISI][Medline]
- The GUSTO V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet 2001;357:19051914.[CrossRef][ISI][Medline]
- Montalescot G, Barragan P, Wittenberg O, Ecollan P, Elhadad S, Villain P, Boulenc JM, Morice MC, Maillard L, Pansieri M, Choussat R, Pinton P, ADMIRAL Investigators. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 2001;344:18951903.[Abstract/Free Full Text]
- Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361:1320.[CrossRef][ISI][Medline]
- Wong CK, White HD, Wilcox RG, Criger DA, Califf RM, Topol EJ, Ohman EM. New atrial fibrillation after acute myocardial infarction independently predicts death: the GUSTO-III experience. Am Heart J 2000;140:878885.[CrossRef][ISI][Medline]
- Al-Khatib SM, Pieper KS, Lee KL, Mahaffey KW, Hochman JS, Pepine CJ, Kopecky SL, Akkerhuis M, Stepinska J, Simoons ML, Topol EJ, Califf RM, Harrington RA. Atrial fibrillation and mortality among patients with acute coronary syndromes without ST-segment elevation: results from the PURSUIT trial. Am J Cardiol 2001;88:7679.[ISI]
- White HD, Barbash GI, Califf RM, Simes RJ, Granger CB, Weaver WD, Kleiman NS, Aylward PE, Gore JM, Vahanian A, Lee KL, Ross AM, Topol EJ. Age and outcome with contemporary thrombolytic therapy. Results from the GUSTO-I trial. Circulation 1996;94:18261833.[Abstract/Free Full Text]
- Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836843.[Abstract/Free Full Text]
- Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984;311:501505.[Abstract]