Eleanor Schron

Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study.

Background—The AFFIRM Study showed that treatment of patients with atrial fibrillation and a high risk for stroke or death with a rhythm-control strategy offered no survival advantage over a rate-control strategy in an intention-to-treat analysis. This article reports an “on-treatment” analysis of the relationship of survival to cardiac rhythm and treatment as they changed over time. Methods and Results—Modeling techniques were used to determine the relationships among survival, baseline clinical variables, and time-dependent variables. The following baseline variables were significantly associated with an increased risk of death: increasing age, coronary artery disease, congestive heart failure, diabetes, stroke or transient ischemic attack, smoking, left ventricular dysfunction, and mitral regurgitation. Among the time-dependent variables, the presence of sinus rhythm (SR) was associated with a lower risk of death, as was warfarin use. Antiarrhythmic drugs (AADs) were associated with increased mortality only after adjustment for the presence of SR. Consistent with the original intention-to-treat analysis, AADs were no longer associated with mortality when SR was removed from the model. Conclusions—Warfarin use improves survival. SR is either an important determinant of survival or a marker for other factors associated with survival that were not recorded, determined, or included in the survival model. Currently available AADs are not associated with improved survival, which suggests that any beneficial antiarrhythmic effects of AADs are offset by their adverse effects. If an effective method for maintaining SR with fewer adverse effects were available, it might be beneficial.

Update on Cardiovascular Implantable Electronic Device Infections and Their Management A Scientific Statement From the American Heart Association

Despite improvements in cardiovascular implantable electronic device (CIED) design, application of timely infection control practices, and administration of antibiotic prophylaxis at the time of device placement, CIED infections continue to occur and can be life-threatening. This has prompted the study of all aspects of CIED infections. Recognizing the recent advances in our understanding of the epidemiology, risk factors, microbiology, management, and prevention of CIED infections, the American Heart Association commissioned this scientific statement to educate clinicians about CIED infections, provide explicit recommendations for the care of patients with suspected or established CIED infections, and highlight areas of needed research.

Antihypertensive drugs in very old people: a subgroup meta-analysis of randomised controlled trials

BACKGROUND Beneficial clinical effects of treatment with antihypertensive drugs have been shown in middle-aged patients and in those hypertensive patients over 60 years old, but whether treatment is beneficial in patients over 80 years old is not known. METHODS We collected data from all participants aged 80 years and over in randomised controlled trials of antihypertensive drugs through direct contact with study investigators. Our primary outcome was fatal and non-fatal stroke. Secondary outcomes were death from all causes, cardiovascular death, fatal and non-fatal major coronary and cardiovascular events, and heart failure. FINDINGS There were 57 strokes and 34 deaths among 874 actively treated patients, compared with 77 strokes and 28 stroke deaths among 796 controls, representing 1 non-fatal stroke prevented for about 100 patients treated each year. The meta-analysis of data from 1670 participants aged 80 years or older suggested that treatment prevented 34% (95% CI 8-52) of strokes. Rates of major cardiovascular events and heart failure were significantly decreased, by 22% and 39%, respectively. However, there was no treatment benefit for cardiovascular death, and a non-significant 6% (-5 to 18) relative excess of death from all causes. INTERPRETATIONS The inconclusive findings for mortality contrast with the benefit of treatment for non-fatal events. Results of a large-scale specific trial are needed for definite conclusion that antihypertensive treatment is beneficial in very elderly hypertensive patients. Meanwhile, an age threshold beyond which hypertension should not be treated cannot be justified.

Biobehavioral variables and mortality or cardiac arrest in the Cardiac Arrhythmia Pilot Study (CAPS)

The frequency of ventricular premature complexes and the degree of impairment of left ventricular ejection fraction are major predictors of cardiac mortality and sudden death in the year after acute myocardial infarction. Recent studies have implicated psychosocial factors, including depression, the interaction of social isolation and life stress, and type A-B behavior pattern, as predictors of cardiac events, controlling for known parameters of disease severity. However, results tend not to be consistent and are sometimes contradictory. The present investigation was designed to test the predictive association between biobehavioral factors and clinical cardiac events. This evaluation occurred in the context of a prospective clinical trial, the Cardiac Arrhythmia Pilot Study (CAPS). Five-hundred two patients were recruited with greater than or equal to 10 ventricular premature complexes/hour or greater than or equal to 5 episodes of nonsustained ventricular tachycardia, recorded 6 to 60 days after a myocardial infarction. Baseline behavioral studies, conducted in approximately 66% of patients, included psychosocial questionnaires of anxiety, depression, social desirability and support, and type A-B behavior pattern. In addition, blood pressure and pulse rate reactivity to a portable videogame was assessed. The primary outcome was scored on the basis of mortality or cardiac arrest. Results indicated that the type B behavior pattern, higher levels of depression and lower pulse rate reactivity to challenge were significant risk factors for death or cardiac arrest, after adjusting statistically for a set of known clinical predictors of disease severity. The implication of these results for future research relating behavioral factors to cardiac endpoints is discussed.

Effect of Antihypertensive Drug Treatment on Cardiovascular Outcomes in Women and Men: A Meta-Analysis of Individual Patient Data from Randomized, Controlled Trials

The effectiveness of antihypertensive drug treatment is well established and has been quantified in terms of overall reduction in the relative risk for stroke and other cardiovascular disease events [1, 2]. Risk for cardiovascular events (especially myocardial infarction) differs greatly between men and women, and these differences are not explained by other risk factors [3]. It remains unclear, however, whether the effect of antihypertensive treatment in reducing cardiovascular risk is dependent on sex. In a 1986 review, MacMahon and colleagues [4] stated that event rates, particularly those for fatal events and nonfatal myocardial infarction, were substantially lower in women than in men. The striking benefits of study treatments for the risk of fatal and non-fatal stroke were evident for both men and women. A reduction in total mortality could not be demonstrated for women, but the treatment effect for women was not significantly different from that in men, among whom there was an important and statistically significant reduction in mortality. This comment was based on the results of two trials: the Hypertension Detection and Follow-up Program (HDFP) [5] and the Medical Research Council trial of treatment of mild hypertension (MRC35-64) [6]. In their 1991 analysis of data from these trials plus data from the European Working Party on High Blood Pressure in the Elderly (EWPHE) trial [7] and the Australian therapeutic trial in mild hypertension [8], Anastos and colleagues [9] concluded that the few data that do exist suggest that gender, like race and age, significantly influences the natural course of hypertension and the response to treatment . The data regarding aggressive treatment of white women are equivocal; there is concern that such treatment may actually be harmful. Since these reviews were published, reports of three additional trials of antihypertensive treatment in older hypertensive men and women have appeared in print: the Medical Research Council trial of treatment of hypertension in older adults (MRC 65-74) [10], the Systolic Hypertension in the Elderly Program (SHEP) [11], and the Swedish Trial in Old Patients with Hypertension (STOP) [12]. More recently, other reviewers have stated that antihypertensive medications do not appear to be as effective in women as in men [13] and that when treated, women often achieve less benefit than do men [14]. The INDANA (INdividual Data ANalysis of Antihypertensive intervention trials) project [15] offers the opportunity to provide more evidence on the effects of antihypertensive treatment in women; results are based on individual patient data from all of the randomized, controlled trials mentioned in the preceding paragraphs. The two main objectives of the current study are to quantify the average treatment effect in each sex separately and to determine whether treatment effect differs significantly between women and men. Methods The INDANA project (whose rationale, objectives, and methods are described in detail elsewhere [15]) is a collaboration of representatives from most of the large randomized, controlled trials of antihypertensive drug treatment. Its results are derived from centralized files of the baseline and follow-up data available for all patients enrolled in the trials. The Trials Our report is based on seven trials [5-710-12, 16] (Table 1) in which both men and women were enrolled. The inclusion criteria for the trials in the INDANA project are discussed elsewhere [15]. In summary, the steering group of the project made the following decisions: The data from the Australian trial [8] were not included in the analysis because separate outcomes are not available without censoring bias; the EWPHE trial [7] data were included only for the analysis of mortality end points (separate nonfatal outcomes are not available without censoring bias); and the data from HDFP [5] were considered in a sensitivity analysis (analysis was done with and without these data because of the originality of the trial design, which compared specific antihypertensive care systems with usual care). The data from the Veterans Administration and National Heart, Lung, and Blood Institute feasibility trial [17] are available in the INDANA database but have not yet been submitted to control and extraction procedures. Thus, these data were not used in our analysis. Because this trial has only a small weight in terms of patient-years and observed events, its exclusion is unlikely to change the results presented here. Table 1. Main Characteristics of the Seven Antihypertensive Drug Trials That Enrolled Men and Women* Outcomes According to the INDANA protocol, seven outcomes were analyzed: 1) fatal strokes; 2) fatal and nonfatal strokes, excluding transient ischemic attacks; 3) fatal coronary events [including sudden death, which was defined as unexpected and unexplained death occurring within a maximal interval of 24 hours after symptom onset]; 4) fatal and nonfatal major coronary events (using criteria for major coronary heart disease obtained from patient histories in HDFP) [1]; 5) cardiovascular-related mortality, including death from pulmonary thromboembolism; 6) major cardiovascular events [combining the second, fourth, and fifth outcomes and excluding such minor cardiovascular events as angina pectoris, intermittent claudication, or nonfatal congestive heart failure]; and 7) total mortality. Statistical Analysis Summarized data (number of patients and number of events) were extracted from the INDANA database by sex and by trial according to the intention-to-treat principle. For the group assigned to receive active treatment, the odds ratio compared with controls was estimated by sex for each outcome according to the Peto method [18]. The odds ratio in women was compared with the odds ratio in men by determining whether the ratio was different from 1. This interaction between sex and treatment effect was checked after adjustment for the main baseline risk factors (age, baseline smoking habits, systolic blood pressure, serum cholesterol level, presence of diabetes, and history of stroke or myocardial infarction) in a multivariate logistic model [19] fitted by outcome. For HDFP [5], we censored data at the date of the end of the trial intervention. Two deaths in the trial by Coope and Warrender [16] that were caused by pulmonary embolism were included with cardiovascular-related mortality in our analysis; one early cancer-related death in this trial was included in the analyses of total mortality because of the intention-to-treat principle. To illustrate the difference in the treatment effect between men and women, we applied two graphical approaches to the second and fourth outcomes (all strokes and all coronary events). First, each trial was represented by sex in a treatment-effect graph [20] in which the x-axis is the risk observed in the control group (Rc) and the y-axis is the risk observed in the treated group (Rt) (Figure 1). The odds ratio line, with a slope equal to the odds ratio and a null intercept, indicates the treatment effect by sex. The principal diagonal of the plane Rt x Rc represents the absence of treatment effect (Rt = Rc; odds ratio, 1). The vertical distance between the odds ratio line and the principal diagonal indicates the absolute risk reduction for a given untreated risk. Second, the absolute risk reduction attributable to treatment and its CI were computed by tertiles of individually predicted risk for each sex and were plotted against the average predicted risk in each tertile (Figure 2). The predicted risk was derived from individual scoring built on the results of a multivariate logistic model, including the major risk factors mentioned above. Tertiles were computed to contain similar numbers of events. Figure 1. Effect of antihypertensive treatment on absolute risk for fatal and nonfatal stroke (left) and fatal and nonfatal coronary events (right). Figure 2. Absolute risk reduction of fatal and nonfatal stroke (left) and fatal and nonfatal coronary events (right) by untreated risk level and sex. Meta-analysis computations were done using Easy-MA software [21]; data management and logistic regression were done using SAS software [22]. Results The key features of the seven trials are presented in Table 1. Five of the trials addressed hypertension in older persons, and two studied mild to moderate hypertension in younger persons. The drugs used in the trials were primarily thiazide diuretics, -blockers, or both. The data for these seven trials contained in the INDANA database represent 97.5% of all existing data from all applicable trials in terms of patient-years of follow-up during the active phase of the trials. The combined trial data on risk factors by sex (Table 2) show that, on average, women were older; had a higher baseline cholesterol level, a higher systolic blood pressure, and a lower smoking rate; and less frequently had a history of myocardial infarction. Because these baseline characteristics were similar for the active treatment and control groups, these groups are combined in Table 2. Table 2. Main Cardiovascular Risk Factors by Sex* For each of the seven outcomes, Table 3 and Table 5 shows the number of events in the active treatment and control groups that occurred in men and women, both within each trial and in all trials combined. Table 3. Events by Trial and Sex* Table 5. Table 3. Continued The exclusion of the HDFP data from the analysis changes neither the direction nor the magnitude of the odds ratio for either sex and does not affect the differences between men and women. These data are therefore included in the results presented. In Table 4, the combined odds ratios for all trials are shown separately for men and women; these odds ratios were estimated using a fixed-effects method. In women, odds ratios favoring treatment were statistically significant for strokes (both fatal and either fatal or nonfatal) and major car

Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group.

CONTEXT Heart failure is often preceded by isolated systolic hypertension, but the effectiveness of antihypertensive treatment in preventing heart failure is not known. OBJECTIVE To assess the effect of diuretic-based antihypertensive stepped-care treatment on the occurrence of heart failure in older persons with isolated systolic hypertension. DESIGN Analysis of data from a multicenter, randomized, double-blind, placebo-controlled clinical trial. PARTICIPANTS A total of 4736 persons aged 60 years and older with systolic blood pressure between 160 and 219 mm Hg and diastolic blood pressure below 90 mm Hg who participated in the Systolic Hypertension in the Elderly Program (SHEP). INTERVENTION Stepped-care antihypertensive drug therapy, in which the step 1 drug is chlorthalidone (12.5-25 mg) or matching placebo, and the step 2 drug is atenolol (25-50 mg) or matching placebo. MAIN OUTCOME MEASURES Fatal and nonfatal heart failure. RESULTS During an average of 4.5 years of follow-up, fatal or nonfatal heart failure occurred in 55 of 2365 patients randomized to active therapy and 105 of the 2371 patients randomized to placebo (relative risk [RR], 0.51; 95% confidence interval [CI], 0.37-0.71; P<.001; number needed to treat to prevent 1 event [NNT], 48). Among patients with a history of or electrocardiographic evidence of prior myocardial infarction (MI), the RR was 0.19 (95% CI, 0.06-0.53; P=.002; NNT, 15). Older patients, men, and those with higher systolic blood pressure or a history of or electrocardiographic evidence of MI at baseline had higher risk of developing heart failure. CONCLUSION In older persons with isolated systolic hypertension, stepped-care treatment based on low-dose chlorthalidone exerted a strong protective effect in preventing heart failure. Among patients with prior MI, an 80% risk reduction was observed.

Relative effectiveness of the implantable cardioverter-defibrillator and antiarrhythmic drugs in patients with varying degrees of left ventricular dysfunction who have survived malignant ventricular arrhythmias

OBJECTIVES We sought to assess the effect of baseline ejection fraction on survival difference between patients with life-threatening ventricular arrhythmias who were treated with an antiarrhythmic drug (AAD) or implantable cardioverter-defibrillator (ICD). BACKGROUND The Antiarrhythmics Versus Implantable Defibrillators (AVID) study demonstrated improved survival in patients with ventricular fibrillation or ventricular tachycardia with a left ventricular ejection fraction (LVEF) < or =0.40 or hemodynamic compromise. METHODS Survival differences between AAD-treated and ICD-treated patients entered into the AVID study (patients presenting with sustained ventricular arrhythmia associated with an LVEF < or =0.40 or hemodynamic compromise) were compared at different levels of ejection fraction. RESULTS In patients with an LVEF > or =0.35, there was no difference in survival between AAD-treated and ICD-treated patients. A test for interaction was not significant, but had low power to detect an interaction. For patients with an LVEF 0.20 to 0.34, there was a significantly improved survival with ICD as compared with AAD therapy. In the smaller subgroup with an LVEF <0.20, the same magnitude of survival difference was seen as that in the 0.20 to 0.34 LVEF subgroup, but the difference did not reach statistical significance. CONCLUSIONS These data suggest that patients with relatively well-preserved LVEF (> or =0.35) may not have better survival when treated with the ICD as compared with AADs. At a lower LVEF, the ICD appears to offer improved survival as compared with AADs. Prospective studies with larger patient numbers are needed to assess the effect of relatively well-preserved ejection fraction (> or =0.35) on the relative treatment effect of AADs and the ICDs.

Home use of automated external defibrillators for sudden cardiac arrest

BACKGROUND The most common location of out-of-hospital sudden cardiac arrest is the home, a situation in which emergency medical services are challenged to provide timely care. Consequently, home use of an automated external defibrillator (AED) might offer an opportunity to improve survival for patients at risk. METHODS We randomly assigned 7001 patients with previous anterior-wall myocardial infarction who were not candidates for an implantable cardioverter-defibrillator to receive one of two responses to sudden cardiac arrest occurring at home: either the control response (calling emergency medical services and performing cardiopulmonary resuscitation [CPR]) or the use of an AED, followed by calling emergency medical services and performing CPR. The primary outcome was death from any cause. RESULTS The median age of the patients was 62 years; 17% were women. The median follow-up was 37.3 months. Overall, 450 patients died: 228 of 3506 patients (6.5%) in the control group and 222 of 3495 patients (6.4%) in the AED group (hazard ratio, 0.97; 95% confidence interval, 0.81 to 1.17; P=0.77). Mortality did not differ significantly in major prespecified subgroups. Only 160 deaths (35.6%) were considered to be from sudden cardiac arrest from tachyarrhythmia. Of these deaths, 117 occurred at home; 58 at-home events were witnessed. AEDs were used in 32 patients. Of these patients, 14 received an appropriate shock, and 4 survived to hospital discharge. There were no documented inappropriate shocks. CONCLUSIONS For survivors of anterior-wall myocardial infarction who were not candidates for implantation of a cardioverter-defibrillator, access to a home AED did not significantly improve overall survival, as compared with reliance on conventional resuscitation methods. (ClinicalTrials.gov number, NCT00047411 [ClinicalTrials.gov].).

Effect of Antihypertensive Treatment in Patients Having Already Suffered From Stroke: Gathering the Evidence

BACKGROUND AND PURPOSE Drug treatment of high blood pressure has been shown to reduce the associated cardiovascular risk. Stroke represents the type of event more strongly linked with high blood pressure, responsible for a high rate of death or invalidity, and with the highest proportion of events that can be avoided by treatment. Hypertensive patients with a history of cerebrovascular accident are at particularly high risk of recurrence. Specific trials of blood pressure lowering drugs in stroke survivors showed inconclusive results in the past. METHODS We performed a meta-analysis using all available randomized controlled clinical trials assessing the effect of blood pressure lowering drugs on clinical outcomes (recurrence of stroke, coronary events, cause-specific, and overall mortality) in patients with prior stroke or transient ischemic attack. RESULTS We identified 9 trials, including a total of 6752 patients: 2 trials included 551 hypertensive stroke survivors; 6 trials of hypertensive patients included a small proportion of stroke survivors (536 patients); 1 trial included stroke survivors, whether hypertensive or not (5665 patients). The recurrence of stroke, fatal and nonfatal, was significantly reduced in active groups compared with control groups consistently across the different sources of data (relative risk of 0.72, 95% confidence interval: 0.61 to 0.85). There was no evidence that this intervention induced serious adverse effect. CONCLUSIONS Blood pressure lowering drug interventions reduced the risk of stroke recurrence in stroke survivors. Available data did not allow to verify whether such benefit depends on initial blood pressure level. More data are needed before considering antihypertensive therapy in normotensive patients at high cerebrovascular risk.

Cardiovascular Outcomes With Atrial-Based Pacing Compared With Ventricular Pacing Meta-Analysis of Randomized Trials, Using Individual Patient Data

Background— Several randomized trials have compared atrial-based (dual-chamber or atrial) pacing with ventricular pacing in patients with bradycardia. No trial has shown a mortality reduction, and only 1 small trial suggested a reduction in stroke. The goal of this review was to determine whether atrial-based pacing prevents major cardiovascular events. Methods and Results— A systematic review was performed of publications since 1980. For inclusion, trials had to compare an atrial-based with a ventricular-based pacing mode; use a randomized, controlled, parallel design; and have data on mortality, stroke, heart failure, or atrial fibrillation. Individual patient data were obtained from 5 of the 8 identified studies, representing 95% of patients in the 8 trials, and a total of 35 000 patient-years of follow-up. There was no significant heterogeneity among the results of the individual trials. There was no significant reduction in mortality (hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.87 to 1.03; P=0.19) or heart failure (HR, 0.89; 95% CI, 0.77 to 1.03; P=0.15) with atrial-based pacing. There was a significant reduction in atrial fibrillation (HR, 0.80; 95% CI, 0.72 to 0.89; P=0.00003) and a reduction in stroke that was of borderline significance (HR, 0.81; 95% CI, 0.67 to 0.99; P=0.035). There was no convincing evidence that any patient subgroup received special benefit from atrial-based pacing. Conclusions— Compared with ventricular pacing, the use of atrial-based pacing does not improve survival or reduce heart failure or cardiovascular death. However, atrial-based pacing reduces the incidence of atrial fibrillation and may modestly reduce stroke.