John H. Horgan

Contemporary reperfusion therapy for cardiogenic shock : the GUSTO-I trial experience

OBJECTIVES This study sought to examine the incidence, temporal profile and clinical implications of shock in a large trial of thrombolytic therapy for acute myocardial infarction. BACKGROUND Despite advances in the treatment of acute ischemic syndromes, cardiogenic shock remains associated with significant morbidity and mortality. METHODS Patients who presented within 6 h of symptom onset were randomized to four treatment strategies: 1) streptokinase plus subcutaneous heparin; 2) streptokinase plus intravenous heparin; 3) accelerated recombinant tissue-type plasminogen activator (rt-PA) plus intravenous heparin; or 4) streptokinase and rt-PA plus intravenous heparin. The primary end point was 30-day all-cause mortality. RESULTS Shock occurred in 2,972 patients (7.2%): 315 (11%) had shock on arrival, and 2,657 (89%) developed shock after hospital admission. Reinfarction occurred in 11% of patients who developed shock compared with 3% of patients without shock. The mortality rate was significantly higher in patients who presented with (57%) or developed (55%) shock than in those without shock (3%) (p < 0.001). Shock developed significantly less frequently in patients receiving rt-PA. There were fewer deaths in patients who presented with shock and were treated with streptokinase plus intravenous heparin or who developed shock and were treated with streptokinase plus subcutaneous heparin. Patients who developed shock had a significantly lower 30-day mortality rate if angioplasty was performed. CONCLUSIONS Because cardiogenic shock occurred most often after admission and with recurrent ischemia and reinfarction, recognizing signs of incipient shock may improve outcome. Fewer patients treated with rt-PA developed shock, yet those developing shock had the same high mortality rate as those presenting with shock, regardless of treatment. Only angioplasty was associated with a significantly lower mortality rate.

Digoxin in the elderly: Pharmacokinetic consequences of old age

A study of single‐dose digoxin kinetics was performed in 6 young and 7 elderly patients. The rate of absorption, determined by the time to peak concentration after an oral dose, was more rapid in the younger group. The extent of absorption, as measured by comparison of the area under the plasma concentration/time curve after oral and intravenous administration, was similar in both groups. Mean plasma half‐life was longer and individual values were more variable in the elderly patients. The absolute apparent volume of distribution was reduced in the older patients and correlated inversely with age. When corrected for weight, however, the difference in the apparent volume of distribution did not approach significance. Both absolute and weight‐corrected values for plasma clearance of digoxin were reduced in the elderly subjects.

Early detection of acute myocardial infarction: additional diagnostic information from serum concentrations of myoglobin in patients without ST elevation.

The value of the 12 lead electrocardiogram, serum total creatine kinase, creatine kinase MB isoenzyme, and myoglobin for the early detection of infarction was evaluated within one hour of admission to the coronary care unit in 82 consecutive patients with suspected myocardial infarction. The 51 patients in whom infarction was diagnosed during the first 24 hours after admission had a higher prevalence of ST elevation (64% v 11%), higher median serum myoglobin (136 micrograms/l v 34 micrograms/l), higher serum creatine kinase (77 IU/l v 34 IU/l), and higher MB isoenzyme (7 IU/l v 4 IU/l) than those in whom it was not. Stepwise logistic regression analysis in 70 patients in whom the electrocardiogram and serum myoglobin were suitable for analysis showed that serum myoglobin was the variable most closely associated with infarction, and contributed additional diagnostic information when ST elevation was entered into the model first. Serum myoglobin remained associated with myocardial infarction when patients who had had symptoms for less than six hours were analysed. An algorithm based on a rapid agglutination test for myoglobin and ST elevation on the electrocardiogram gave an accurate diagnosis in 82% of patients. This approach gave early and rapid recognition of acute myocardial infarction and warrants further examination.

One-Year Survival Among Patients With Acute Myocardial Infarction Complicated by Cardiogenic Shock, and its Relation to Early Revascularization Results From the GUSTO-I Trial

BACKGROUND Although 30-day survival is increased in patients with acute myocardial infarction complicated by cardiogenic shock who undergo coronary revascularization, the longer-term outcome in such patients and the duration of benefit from revascularization are unknown. METHODS AND RESULTS We analyzed 30-day survivors of acute myocardial infarction in the Global Utilization of Streptokinase and Tissue-Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial and identified 36 333 who had not had cardiogenic shock (systolic blood pressure <90 mm Hg for >/=1 hour, group 1) and 1321 patients who had shock (group 2). Group 2 patients were older and sicker. At 1 year, 97.4% of group 1 patients were alive versus 88.0% of group 2 (P=0.0001). Among group 2 patients, 578 (44%) had undergone revascularization within 30 days (group 2A) and 728 (56%) had not (group 2B). Revascularization was not required by protocol but was selected by the attending physicians. At 1 year, 91.7% of group 2A patients were alive versus 85.3% of group 2B (P=0.0003). With the use of multivariable logistic regression analysis to adjust for differences in baseline characteristics of shock patients alive at 30 days, revascularization within 30 days was independently associated with reduced 1-year mortality (odds ratio 0.6, [95% confidence interval 0.4, 0.9], P=0.007). CONCLUSIONS Most patients (88%) with acute myocardial infarction complicated by cardiogenic shock who are alive at 30 days survived at least 1 year. Shock patients who underwent revascularization within 30 days had improved survival at 1 year compared with shock patients who did not receive revascularization, even after adjustment for differences in baseline characteristics between the 2 groups.

Psychosocial outcome assessments for use in cardiac rehabilitation service evaluation: a 10-year systematic review.

A variety of measures are currently used to assess psychosocial outcome (quality of life) in cardiac rehabilitation programmes. However, there is no consensus on the most appropriate instruments to use. Instruments that are not sufficiently responsive to change in cardiac populations are unsuitable as audit tools as they underrepresent the benefits of programme attendance. To identify the most responsive instruments in cardiac rehabilitation populations a systematic overview of studies for the 10-year period 1986-1995 was conducted. The following databases were searched: Medline, Psychlit, Cinahl and Sociofile and 32 relevant studies were identified. The effect size statistic (a comparison of the magnitude of change to the variability in baseline scores) was used to determine those instruments most responsive to change. The following instruments were identified as being responsive in more than one study: Beck Depression Inventory, Global Mood Scale, Health Complaints Checklist, Heart Patients Psychological Questionnaire and Speilberger State Anxiety Inventory. There is little consensus on psychosocial evaluation instrument use in the cardiac rehabilitation literature. A number of measures show significant potential for routine outcome assessment. Formal assessment of these instruments is recommended to inform final recommendations about instrument selection for audit and evaluation purposes in cardiac rehabilitation.

Four-week multidisciplinary cardiac rehabilitation produces similar improvements in exercise capacity and quality of life to a 10-week program.

BACKGROUND Cardiac rehabilitation (CR) is widely accepted as beneficial for patients with myocardial infarction (MI) and coronary artery bypass graft (CABG). A need exists to evaluate how different formats of delivery can best meet CR service demands. METHODS AND RESULTS Cardiac patients (n = 60) were randomly assigned to either a standard 10-week (30 sessions) or a 4-week (20 sessions) multifactorial rehabilitation program. Patients underwent exercise testing using the Bruce protocol before, immediately after, and then 6 months after CR. Patients also completed the SF-36 quality of life questionnaire and the Hospital Anxiety and Depression scale at each time point. Compared with pre-CR, exercise time and metabolic equivalents attained were significantly increased, and heart rate significantly decreased both immediately (P<.05) and 6 months after CR (P<.05) in both groups, with no between-group differences. Significant improvements (P<.05) in energy, pain, and general health were reported after CR, and in energy and emotional and social well-being at 6 months after CR. No differences were seen between the groups. CONCLUSIONS Cardiac rehabilitation after MI and CABG significantly improved exercise capacity and general health and well-being. No significant differences were detected between groups undergoing a 10-week or 4-week course. These preliminary data suggest that shortened courses of CR may be beneficial to cardiac patients and such courses may also facilitate more widespread use of CR.

Relation of Increased Arterial Blood Pressure to Mortality and Stroke in the Context of Contemporary Thrombolytic Therapy for Acute Myocardial Infarction: A Randomized Trial

Thrombolytic therapy improves survival after acute myocardial infarction [1-3]. This appears to apply to all patients with ST-segment elevation, regardless of blood pressure at time of treatment or history of hypertension [4]. However, thrombolysis can cause serious complications, such as bleeding, which includes intracranial hemorrhage and stroke [4-7]. A history of hypertension and high systolic or diastolic blood pressure at presentation have been shown to increase the risk for bleeding complications and intracranial hemorrhage in patients treated with thrombolytic agents [4, 8-11]. It has also been suggested that the risks of thrombolysis outweigh the benefits of it in some patients with elevated blood pressure [11]. The risk for intracranial hemorrhage is greater with alteplase therapy, especially in patients with high blood pressure [11-14]. Streptokinase has therefore been suggested as the agent of choice in patients with elevated blood pressure [15]. Unfortunately, many of the data on the relation between blood pressure and outcomes after thrombolysis have come from studies with small numbers of patients [8, 16, 17]. Our objective was to assess the influence of previous hypertension and blood pressure at study entry on the outcomes of death, any stroke, intracranial hemorrhage, and death plus disabling stroke using data from the GUSTO-I (Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries) trial of 41 021 patients. We reviewed data from hypertensive patients who were at low risk for death from cardiac causes to assess relative risks for stroke and other outcomes. We also reviewed the influence of blood pressure at the time of study entry on outcomes with different thrombolytic agents. Methods Patients In the GUSTO-I trial, 41 021 patients with acute myocardial infarction and ST-segment elevation who presented within 6 hours of symptom onset were randomly assigned to one of four thrombolytic treatment regimens [18]. Patients were excluded if they had previously had stroke (or known cerebrovascular pathology, such as a neoplasm, an aneurysm, or intracranial surgery), had active bleeding or had recently had bleeding, had recently had trauma or major surgery, had noncompressible vascular punctures, or had previously received streptokinase or anistreplase. Hypertension (in the past or at the time of presentation) was not an exclusion criterion. However, if a patients initial systolic blood pressure was 200 mm Hg or more (or the diastolic blood pressure was 100 mm Hg) at the time of randomization, the following statement was read to the investigator: We have been advised to let you know that with a blood pressure this high there is an increased risk of intracranial bleeding. It would be advisable to bring the blood pressure down before starting thrombolytic therapy. The final decision about whether to enroll the patient was left to the investigator. To estimate whether patients enrolled in GUSTO-I who had very elevated blood pressure were a highly selected group, data from the GUSTO-I myocardial infarction registry, a randomly selected group of 92 hospitals (primarily in North America) that collected information on all patients who had had acute myocardial infarction, were analyzed. Eligible patients were randomly assigned to receive one of four regimens: 1) streptokinase, 1.5 million U, and subcutaneous heparin, 12 500 U twice daily, beginning 4 hours after initiation of thrombolysis; 2) streptokinase, 1.5 million U, and intravenous heparin, a 5000-U bolus and 1000 U/h-infusion with dose adjustment to maintain an activated partial thromboplastin time of 60 to 85 seconds; 3) accelerated-dose alteplase, given as a 15-mg bolus, 0.75 mg/kg of body weight (to a maximum of 50 mg) over 30 minutes, and 0.5 mg/kg [to a maximum of 35 mg] over the next hour, and intravenous heparin, a 5000-U bolus and 1000 U/h-infusion with dose adjustment to maintain an activated partial thromboplastin time of 60 to 85 seconds; or 4) standard-dose alteplase, 1.0 mg/kg over 60 minutes (to a maximum of 90 mg) with 10% as a bolus, and streptokinase, 1.0 million U, with intravenous heparin, a 5000-U bolus and 1000 U/h-infusion with dose adjustment to maintain an activated partial thromboplastin time of 60 to 85 seconds. Subcutaneous heparin treatment was administered for 7 days or until hospital discharge; intravenous heparin was given for at least 48 hours. Chewable aspirin was given as soon as possible and then daily for at least 1 year. Intravenous -block-ade, unless contraindicated, was given as soon as possible and was followed with daily oral therapy. All other medications were administered at the discretion of the attending physician. End Points The primary end point was death from any cause within 30 days after randomization. Secondary end points included in-hospital stroke and primary intracranial hemorrhage. The composite of death and nonfatal, disabling stroke was intended to provide a single measure of outcome for comparisons of thrombolytic strategies that can reduce the risk for death from cardiac causes while increasing the risk for hemorrhagic stroke. In the GUSTO-I protocol, stroke was defined as an acute, new neurologic deficit that resulted in death or lasted more than 24 hours. All cases of suspected stroke were reviewed by an independent committee, the members of which were blinded to treatment assignments. Computed tomography, magnetic resonance imaging, or autopsy was done in 93% of cases to enable classification of strokes. A complete description of the identification, categorization, and incidence of stroke in the GUSTO-I trial has been published [19]. Bleeding complications were classified as severe or life-threatening if they were intracerebral or if they caused substantial hemodynamic compromise that required intervention. Moderate bleeding was defined as bleeding that required transfusion. Measurement of Blood Pressure Two blood pressure measurements were recorded on each case report form: one taken at the time of presentation at the hospital and another taken just before randomization. Statistical Analysis For descriptive purposes, measurements of systolic and diastolic blood pressures at study entry were divided into categories. Measurements of systolic blood pressure at entry were divided into four strata: 100 to 124 mm Hg, 125 to 149 mm Hg, 150 to 174 mm Hg, and 175 mm Hg or more. Measurements of diastolic blood pressure at entry were divided into four strata: 70 to 79 mm Hg, 80 to 89 mm Hg, 90 to 99 mm Hg, and 100 mm Hg or more. Baseline characteristics are given as percentages for discrete variables and as medians (25th, 75th percentiles) for continuous characteristics. Continuous systolic and diastolic blood pressure variables were used for reporting P values. Although analysis of the relation between blood pressure at entry and outcome was prospectively planned, our results should be interpreted in light of the retrospective nature of some of the specific analyses and the multiple comparisons done. Any results of borderline statistical significance should be considered exploratory and for the generation of hypotheses only. The statistical importance of blood pressure at study entry with respect to clinical outcomes was computed by using logistic regression modeling techniques. Spline transformations [20, 21] were used for systolic and diastolic blood pressures in evaluating the assumption of a linear relation between these continuous variables and the logit of each outcome. In the few cases in which the relation was nonlinear, spline functions of the blood pressure measurements were used in the modeling process. Both systolic blood pressure at study entry and a history of hypertension have been shown to be important predictors of death within 30 days in a multivariable model [22]. Diastolic blood pressure was added to this model to determine whether it would provide additional important prognostic information. Similarly, these three factors were added to a predictive model for intracranial hemorrhage that has been described elsewhere [19]. Because no model has been developed for the outcome of death plus nonfatal, disabling stroke, all variables found to be significant in either the mortality model or the stroke model were combined. The relative importance of the three factors was then evaluated within this new model. We also assessed the differential effect of blood pressure on outcomes with respect to location of infarction and thrombolytic treatment assignment. For each blood pressure measurement and outcome, a univariable logistic model was first developed. The additive effect of infarction location or treatment assignment was evaluated with the addition of each factor separately to the univariable model. The differential effect of infarction location or treatment assignment was determined by testing the inclusion of the interaction factor for the blood pressure of interest, after adjustment for the two main effects. Results History of Hypertension A history of hypertension was present in 15 544 patients (38.1%). The baseline characteristics of this group and those of the other 25 309 patients (62.1%) are shown in Table 1. Patients with previous hypertension were a higher-risk group: They were more likely to be older, female, diabetic, and in a worse Killip class and, as a group, they had more previous infarctions. Table 1. Baseline Characteristics of Study Patients Patients with a history of hypertension had significantly higher rates of total stroke and combined death and disabling stroke (Table 2), as well as higher rates of death [22] and intracranial hemorrhage [19], as described elsewhere. Patients with a history of hypertension also fared worse with regard to other clinical events, with the exception of the use of angioplasty. Table 2. History of Hypertension and Clinical Outcomes* Systolic Blood Pressure at Study Entry The baseline characteristics of patients with

Responsiveness of health-related quality of life outcome measures in cardiac rehabilitation: comparison of cardiac rehabilitation outcome measures.

Assessment instruments that are not responsive to change are unsuitable as outcome tools in cardiac rehabilitation because they underestimate the psychosocial benefits of program attendance. Nine questionnaires were assessed for responsiveness with the standardized response mean (SRM). Questionnaires were allocated into 3 batteries, and each battery was completed by cardiac rehabilitation and comparison participants at 2 time points (411 and 375 participants in total, respectively). There was a high degree of variability in the responsiveness of instrument subscales. The positive affect subscale of the Global Mood Scale (J. Denollet, 1993a) was the most responsive (SRM = 0.62). Further information on the comparative responsiveness of psychosocial scales is important to optimize instrument selection for outcome studies.

Relationship of Initial Level of Distress to Changes in Health-related Quality of Life During Cardiac Rehabilitation or Usual Care

Objectives: To assess the relationship between changes in health-related quality of life (HRQOL) and initial levels of distress in cardiac patients who received multidisciplinary cardiac rehabilitation (CR) or usual care. High rates of psychological distress have been reported in cardiac patients. Methods: Cardiac patients completed a questionnaire battery at the start and finish of a CR program (n = 131) or at equivalent times after hospital discharge in comparison hospitals where CR was not available (n = 185). The questionnaire battery comprised the Hospital Anxiety and Depression Scale, the Health Complaints Scale, and the Quality of Life Index Cardiac Version III (QLI CV-III). Results: Significant correlations between initial levels and subsequent changes in distress and HRQOL measures were found for both the CR and comparison groups. The CR program was associated with significant changes in both somatic and cognitive complaints for only those in distress. Changes in functional and psychological morbidity were greater in the CR group than in the comparison group. Conclusions: Changes in HRQOL were significantly related to the initial levels of distress found in cardiac patients, regardless of CR attendance. The CR program had beneficial effects on levels of functional ability and on psychological morbidity reduction. Implications of the research for CR outcomes assessment are considered. CR = cardiac rehabilitation; HRQOL = health-related quality of life; HADS = Hospital Anxiety and Depression Scale; HCS = health complaints; QLI CV-III = Quality of Life Index Cardiac Version III.

Cardiac rehabilitation service provision in Ireland: the Irish Association of Cardiac Rehabilitation survey

BackgroundThe first national survey of cardiac rehabilitation services was conducted.AimsTo establish levels of service provision, service formats, and geographic distribution of cardiac rehabilitation services in 1998.MethodsPublic hospitals in the Republic (n=41) and Northern Ireland (n=12) which provide services to cardiac patients were surveyed.ResultsResponse rate was 81%. Twelve centres (29%) in the Republic and nine (75%) in Northern Ireland provided cardiac rehabilitation. There was wide geographic variability in service provision. Most centres were unable to identify-the proportion of eligible patient participation. Most programmes were established for less than five years. All programmes had multidisciplinary teams, multicomponent courses and co-ordihators. Additionally, 44% of hospitats without programmes had plans regarding programme establishment.ConclusionsThe findings highlight the underdeveloped but rapidly expanding nature of cardiac rehabilitation services in Ireland. They provide a baseline from which to address rehabilitation needs and to judge the success of the National Cardiovascular Health Strategy in addressing these needs.