1 169 Mortality in Acute Stroke With Atrial Fibrillation Livia Candelise, MD; Giovanna Pinardi, MD; Alberto Morabito, PhD; and the Italian Acute Stroke Study Group We compared 211 consecutive patients who had acute ischemic hemispheric stroke and atrial fibrillation with 837 consecutive patients who had stroke without atrial fibrillation. The atrial fibrillation group included a higher frequency of women, older subjects, and those with a severe neurologic deficit, abnormal computed tomogram, and elevated heart rate. The 1-month casefatality rate in the atrial fibrillation group was 27% while that in the group without atrial fibrillation was 14%. The 6-month case-fatality rates in the two groups were 40% and %, respectively. The risk of death attributable to atrial fibrillation, adjusted for the effect of other prognostic factors, was significant at 1 month (relative risk=1.55) and at 6 months (relative risk=1.74). The causes of death were equally distributed in the two groups during both the acute and subacute phases. We conclude that atrial fibrillation is a negative prognostic factor in patients hospitalized for acute stroke. Nevertheless, cerebral embolism alone does not completely explain the increase in mortality for stroke patients with atrial fibrillation. Other associated pathogenetic mechanisms must also be taken into account [Stroke 1991^22: ) Atrial fibrillation (AF) is a common cardiac condition in the older population 1-4 and L has an even higher prevalence in hospitalized stroke patients. 5 " 8 The presence of AF is associated with higher stroke recurrence and mortality rates While the association between AF and short-term mortality has been proved, an association with long-term mortality remains to be confirmed. 812 ' 13 To determine the contribution of AF to stroke mortality, we undertook a retrospective case-control study of 211 stroke patients with AF and 837 stroke patients without AF, all of whom were enrolled in the Italian Hemodilution Trial. 14 Subjects and Methods We studied 211 consecutive stroke patients with AF (mean±sd age 73.6±9.5 years, 40% men) and 837 stroke patients without AF (mean±sd age 66.5±11.2 years, 64% men), all of whom were hospitalized for a first hemispheric stroke. We excluded those with symptoms lasting >12 hours or severe coma. Patients with cerebral hemorrhage (22 with From the Istituto di Clinica Neurologica (L.C., G.P.) and the Istituto di Biometria (A.M.), Untversita degli Studi di Milano, Milano, Italy. Supported in part by National Research Council of Italy grant Address for reprints: Dr. Livia Candelise, Universita di Milano, Istituto di Clinica Neurologica, Via F. Sforza 35, 122 Milano, Italy. Received February 27, 1990; accepted October 1, AF and 136 without AF) or an uncertain diagnosis were not considered in the present report. We assessed severity of the neurologic deficit using a standardized five-level neurologic scale as follows: 1, coma; 2, stupor; 3, severe motor deficit; 4, slight motor deficit; and 5, other than motor neurologic deficit. 15 Cardiovascular assessment, performed Sl2 hours after the onset of symptoms, included blood pressure measurement and a 12-lead electrocardiogram (ECG). From the ECG, a local cardiologist determined heart rate and made the diagnosis of AF when disorganized atrial activity was detected without dis- CTete P waves, but with irregular ventricular responses. Computed tomography (CT) was performed in all patients as soon as possible (77% 48 hours after symptom onset in the AF group and 75% in the non-af group), and the scans were reviewed by an independent neuroradiologist. Focal hypodense lesions in the hemisphere contralateral to the side of neurologic symptoms were defined as infarcts and included two hemorrhagic infarctions in the AF group and 12 in the non-af group. Outcome was evaluated at 6 months. The date and cause of any death were confirmed by one researcher who personally reviewed the local clinical and autopsy records. Cause of death was defined as 1) cerebral: deterioration of consciousness starting at least 1 hour before death; 2) myocardial infarction: presence of at least two of pain, ECG manifestations, and enzyme elevation; 3) sudden death: death occur-
2 170 Stroke Vol 22, No 2, February 1991 TABLE 1. Clinical Characteristics of Stroke Patients With and Without Atrial Fibrillation With (n=211) Without (n=837) Characteristic Sei Men Women Age(yr) < >75 Neurologic deficit Coma or stupor Severe motor deficit Slight motor deficit Other deficit Computed tomogram Normal Infarct Blood pressure (mm Hg) Systolic < >160 Diastolic < >100 Heart rate (beats/min) < >100 No % No % *tp<0.001 and <0.01, respectively. Total (n = 1,048) 624* ' t t * ring within 1 hour without other known causes; 4) pulmonary edema: sudden dyspnea and orthopnea with basal pulmonary rales; 5) pulmonary embolism: sudden dyspnea with recent documentation of deepvein thrombosis; 6) pneumonia: fever, dyspnea, cough, sputum production, and typical signs on chest examination; 7) other: systemic infection, systemic hemorrhage, renal failure, and cachexia. Specific treatments were similar in the two groups during both the acute and subacute phases, except for anticoagulant treatments, which were prescribed in 9% of the AF patients and 2% of the non-af patients. Significance of the association between mortality and prognostic risk factors was assessed using multiple logistic regression. 16 Two separate analyses were performed to verify the magnitude of this association for acute (1 month after stroke) and subacute (6 months after stroke) mortality. The relative risks and their 95% confidence intervals were derived from the value of j3 for the multiple logistic regression equations. Results Of the 1,048 patients with hemispheric stroke, 211 (%) showed AF and 837 (80%) sinus rhythm on ECG done sl2 hours after the initial neurologic symptoms. Patients with AF were older and had more severe neurologic deficits than those without AF (Table 1). The CT scan showed focal hypodense lesions in 54% of the AF cases and in 45% of the non-af cases. Arterial blood pressure did not differ significantly between groups, while a small but significant number of AF patients had tachycardia when first evaluated. By 6 months, 256 patients had died, 85 with AF and 171 without AF. The association of AF with a higher fatality rate was significant during both the acute and subacute phases. The probability of death was higher in the AF group 1 month after stroke (p<0.0001) and increased further in the subsequent 5 months (/><0.0001) (Figure 1). To avoid the effect of interactions due to the association of AF with other potential negative prognostic factors, we performed multiple logistic regres-
3 Candelise et al Stroke Mortality and AF r % o > I 1 33 O a! Months FIGURE 1. Cumulative probability of death afterfirststroke in 837 patients with sinus rhythm (dashed line) and 211 patients with atrialfibrillation (solid line) on admission sion analysis in which the dependent variable was mortality and the predictor variables were female sex, age of >75 years, severe neurologic deficit (score of S3), and infarct on CT scan as well as presence of AF. The adjusted relative risk of death in the AF group was 1.55 at 1 month (Table 2) and 1.74 at 6 months for patients who survived the first month (Table 3). Both increases in risk with AF were significant. We also analyzed the distribution of cause of death in the two groups, comparing the acute and subacute phases. Of the 85 patients with AF who died during follow-up, the cause of death was cerebral in 43 (50%); cardiac, which includes all myocardial infarctions, sudden deaths, and ventricular fibrillations, in 22 (26%); pulmonary embolism in four (5%); pneumonia in seven (8%); and other in nine (11%). The causes of death in the non-af group presented a very similar distribution: cerebral in 77 (45%), cardiac in 54 (32%), pulmonary embolism in five (3%), pneumonia in 17 (10%), and other in 18 (10%). In both groups, the causes of death during the first month were mostly cerebral, whereas after this period cardiac deaths predominated (Figure 2) without any difference between groups. A more detailed diagnosis of cardiac deaths showed a greater proportion of deaths due to pulmonary edema with cardiac failure in the AF group (83%) than in the non-af group (45%). TABLE 2. Estimated Relative Risk of Death 1 Month After Stroke According to Multiple Logistic Regression Analysis Variable Female sex Age >75 yr Severe neurologic deficit Infarct on computed tomogram Atrial fibrillation NS, not significant. Relative risk % Confidence interval P NS < < NS <0.05 Discussion An ECG done upon admission to the hospital is a quick and simple way of identifying a subgroup of stroke patients with a high risk of death. We found the mortality rate of stroke patients with AF to be 27% at 1 month and 40% at 6 months, twice that of stroke patients with sinus rhythm. Therefore, AF is not only associated with acute mortality, but also significantly influences long-term mortality (Table 4). Since structural cardiac diseases documented by echocardiography are equally distributed among stroke patients with and without AF, 6-17 dysrhythmia per se is implicated in poor prognosis independently of underlying cardiac disease. On the other hand, intensive monitoring of ECG after stroke reveals AF undetected by the admission ECG in only 3% of stroke cases. 18 For these two reasons, the cardiologic evaluation of hospitalized stroke patients with AF does not necessarily have to include echocardiography and/or 24-hour ECG. In fact, a simple ECG, as we have used, can provide important data for prognostic and therapeutic purposes. Independent of age and severity of the neurologic deficit at entry, AF significantly contributes to stroke mortality. In recent years, new prognostic indicators have been identified in acute stroke, 19 but age and severity of the neurologic deficit remain the most TABLE 3. Estimated Relative Risk of Death 6 Months After Stroke for Patients Who Survived First Month According to Multiple Logistic Regression Analysis Variable Female sex Age >75 yr Severe neurologic deficit Infarct on computed tomogram Atrial fibrillation NS, not significant. Relative risk % Confidence interval P NS < < <0.01 <0.05
4 172 Stroke Vol 22, No 2, February V. 30'/. - 60V. - 30V. " AF 60V. - AF 30V. - Deaths «1 month 60*/.- 30V. - no AF ^,!- < no AF Deaths >1month FIGURE 2. Bar graphs of causes of death during (top) acute and (bottom) subacute phases after stroke according to atrial fibrillation (AF). important ones. It has never been demonstrated that other factors such as hypercoagulability, hyperglycemia, or ECG abnormality 23 have a prognostic value independent of both age and severity of the neurologic deficit. Without clear evidence of their role in stroke progression, such factors could simply be markers of secondary stroke reactions We show clearly for the first time that AF is an independent prognostic factor in acute stroke. Many authors agree that embolism is the pathogenetic mechanism of stroke in patients with AF and, in accordance with this view, preventive clinical trials of anticoagulant therapy have been proposed On the other hand, several recent reviews underline that it is difficult and at times impossible to differentiate embolic from thrombotic stroke by clinical and radiologic signs. 28 " 30 Our results suggest that cardiac embolism alone does not completely explain the poor prognosis in stroke patients with AF. In our AF and non-af groups the temporal distribution of deaths was very similar, while with an embolic pathogenesis we would expect the frequency of deaths (especially cerebral deaths) in AF cases to be greater following the first cerebrovascular episode. Furthermore, even if we attribute all cerebral deaths in the AF group to embolic stroke recurrence, they would account for only 60% of the acute deaths. Hemodynamic alterations of the systemic and cerebral circulations could also partly explain the higher mortality rate. Lavy et al 31 showed a reduction in regional cerebral blood flow (CBF) in stroke patients with chronic AF compared with age-matched controls. A significant increase in CBF after electrical cardioversion was found by Petersen and Godtfredsen 32 in patients with AF. Britton and Gustafsson 30 reported a lower blood pressure during the acute phase in stroke patients with AF. Patients with AF and congestive heart failure had a poor prognosis in the study of Pritz and Kinott, 33 and finally, in our patients with AF the most frequent cause of cardiac death was pulmonary edema with cardiac failure. This body of evidence suggests that the poor clinical prognosis in stroke patients with AF is due at least partially to their reduced cardiovascular reserves. The contribution of hemodynamic factors to stroke outcome in AF patients should be analyzed in future studies to improve further the treatment strategy for acute stroke. Appendix 1. Italian Acute Stroke Study Group Investigators are listed in alphabetical order of location. Ancona. L. Provinciali, M. Del Pesce, P. Di Bella, and F. Logullo (Istituto delle Malattie del Sistema Nervoso, Universita degli Studi). TABLE 4. Acute and Long-Term Case-Fatality Rate in Stroke Patients With AF Case-fatality rate Patients Acute Long-term Authors) Marquardsen 9 Wolf et al 2 Lowe ct al 10 Oxfordshire" Britton and Roden 8 Present study Year Total ,048 With AF No. % With Without RR With Without RR Acute, 30 days; long-term, 6 months; AF, atrial fibrillation; RR, relative risk.
5 Candelise et al Stroke Mortality and AF 173 Aosta. A. Mamoli, G. D'Akssandro, M. Camerlingo, E. Bottacchi, and P. Gambaro (Servizio di Neurologia, Presidio Ospedaliero). Arezzo. M. Ghezzi, A. Bianchi, G.M. Malentacchi (Unita Operativa Neurologia), and C. Refi (Servizio TC-Radiologia, Presidio Ospedaliero). Bart F. Federico, G. De Luca, V. Lucivero, A. Fiore, P. Lamberti, and E. Ferrari (I Clinica Neurologica, Universita degli Studi). Brescia. L. A. Vignolo, V. Di Monda, D. Vangi, G. Dalla Volta, C. Lazzari, and M. Magoni (Clinica Neurologica, Universita degli Studi). Busto Arsizio-VA. P. Perrone, D. Porazzi, G. Bonzi, and P. Secchi (Divisione Neurologica, Ospedale Regionale). Chiari-BS. L. Faggi, E. Donati, and L. Callea (Divisione Neurologica, Presidio Ospedaliero). Chieti. D. Gambi, L. Marchionno, L. Aquilone, R. Cutarella, and S. D'Annunzio (Qinica Neurologica, Universita degli Studi). Cremona. L. De Lorenzi, G. Chiodello, G. Galli, and M. Guarneri (Divisione Neurologica, Istituti Ospedalieri). Firenze. D. Inzitari, P. Marini, A. Ginanneschi, P. Nencini, D. Sita (Istituto di Clinica Neurologica I, Universita degli Studi), and P. Cioni (Medicina d'urgenza, Ospedale di Careggi). Genova. L. Garello, P. Piola, G.A. Ottonello, and M. Fonzari (Divisione Neurologica, Ospedale Civile S. Martino). Mantova. F. Mironi and P. Previdi (Divisione Neurologica, Presidio Ospedaliero). Milano. F. Enninio, S. Cappa, R. Sterzi, N. Galbiati (Divisione Neurologica, Ospedale Generale Regionale, Niguarda-Ca Granda), G. Scarlato, L. Candelise, R. Colombo, M. Rango, G. Pinardi (Istituto di Clinica Neurologica, Universita degli Studi), A. Randazzo, and F. Porro (Medicina d'urgenza, Ospedale Maggiore). Parma. O. Ponari, M. Squeri, and A. Mombelloni (Divisione Medicina Generale IV, Ospedali Riuniti). Pavia. G. L. Brambilla, G. Sangiovanni, V. Silvani (Qinica Neurochirurgica), P. Fratino, D. Rogledi, and M.G. Ranieri (Clinica Medica II, Universita degli Studi). Perugia. G. Nenci, E. Boschetti, A. Scortecci, M. Taramelli (Istituto de Semeiotica Medica), and C. Chiurulla (Neuroradiologia, Universita degli Studi); L. Agostini, S. Ricci, P. Brustenghi, M.G. Scarcella (Qinica Neurologica), and E. Signorini (Neuroradiologia, Universita degli Studi); U. Senin, G. Aisa, G. Valigi (II Clinica Medica Generale e Terapia Medica), A. Del Favero (I Qinica Medica Generale e Terapia Medica), and V. Gallai (Qinica Neurologica, Universita degli Studi); and F. Santucci, P. Caselli, and G.L. Piccinin (Divisione Medicina, Sede "R. Sirvestrini," Ospedale Regionale). Pisa. A. Muratorio, C. Giraldi, A. Martini, L. Valpentesta, M.C. Masi, and D. Bizzarri (Qinica Neurologica, Universita degli Studi). Poggibonsi, Siena. M. D'Ettorre, M.B. Biotti, V. Caterini (Divisione Medica, Presidio Ospedaliero), G.M. Fabrizi (Qinica Neurologica), and C. Venturi (Neuroradiologia, Universita degli Studi). Ravenna. G.G. Rebucci, G. Bissi, and F. Benazzi (Divisione Neurologica, Ospedale S. Maria delle Croci). Roma. C. Fieschi, C. Argentino, M. Rasura, F. Giubilei, M. Silvestrini, M.L. Sacchetti, D. Toni, and S. Bastianello (III Cattedra di Clinica Neurologica, Universita degli Studi). Saronno-VA. D. Zerbi and A. Gomitoni (Divisione Neuurologica, Ospedale Regionale). Seriate-BG. C.A. De Fanti, A. Brambilla, and L.C. Erli (Divisione Neurologica, Ospedale Regionale Bolognini). Sondrio. M. Lozza, S. Tomaiuolo, I. Votta, and D. Baldini (Divisione Neurologica, Ospedale Regionale). Taranto. L. Sallusto, N. Gigante, A. Calogero, F. Pignatelli, S. Interno, B. Rotunno, F. Lincesso (Divisione Neurologica), and C. Scapati (Divisione Neuroradiologica, Ospedale Civile). Varallo Sesia-VC. E. Nardozza and M. Dellasette (Divisione Neurologica, Ospedale SS Trinita). Verona. M. Montanari, P. Bovi, G. Gambina, L. Deotto (Divisione Neurologica), and A. Beltramello (Neuroradiologia, Ospedale Civile Maggiore). Vicenza. F. 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