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Hypertension is frequent in patients with atrial fibrillation (AF) and is an independent risk factor for stroke. The Randomized Evaluation of Long Term Anticoagulant TherapY (RE-LY) trial found dabigatran 110 mg (D110) and 150 mg twice daily (D150) noninferior or superior to warfarin for stroke reduction in patients with AF, with either a reduction (D110) or similar rates (D150) of major bleeding. Baseline characteristics and outcomes were compared in patients with and without hypertension. The quality of blood pressure control was also assessed. In RE-LY, 14,283 patients (78.9%) had hypertension. The mean blood pressure at baseline was 132.6 ± 17.6/77.7 ± 10.6 and 124.8 ± 16.7/74.6 ± 10.0 mm Hg for patients with and without hypertension, respectively. More patients with hypertension were diabetic (25.6% vs 14.8%, p0.001), women (38.6% vs 28.3%, p0.001), and had greater CHADS2 (2.3 vs 1.4, p0.001) and CHA2DS2-VASc scores (3.8 vs 2.8, p0.001). Mean blood pressure in all treatment arms in hypertensive patients was similar (130 ± 18/76 ± 11 mm Hg) during the trial. The efficacy and safety of D110 and D150 compared to warfarin were similar (p = nonsignificant) in hypertensive (stroke/systemic embolism rate of 1.47%, 1.20%, and 1.81% and major bleed rate of 2.89%, 3.70%, and 3.69% in the D110, D150, and W, respectively) and normotensive patients (stroke/systemic embolism rate of 1.79%, 0.78%, and 1.36% and major bleed rate of 2.84%, 2.37%, and 3.03% per year in the D110, D150, and W, respectively). Hypertensive patients had more major bleeds (3.39% vs 2.76%; p = 0.007). Intracranial bleeds were similar (0.47% vs 0.31%; p = 0.12). In conclusion, patients with hypertension in RE-LY were more likely female, diabetic, with a greater CHADS2 and CHA2DS2-VASc scores. Blood pressure control in RE-LY was excellent. The benefits of dabigatran over warfarin, including a substantial reduction of intracranial hemorrhage, were similar in both hypertensive and non-hypertensive patients.

The mortality rate of most patients with atrial fibrillation (AF) exceeds the stroke rate, but predictors of mortality have not been well defined. The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE A) recruited patients with AF who were unsuitable to receive vitamin K-antagonists and were randomized to aspirin alone versus aspirin plus clopidogrel. We investigated independent predictors of all-cause mortality by multivariable Cox regression analysis and explored interactions with assigned antiplatelet therapy. Of the 7,554 patients enrolled with a mean age of 71 years, 1,687 (22%) patients died during the median follow-up of 3.7 years (annualized mortality rate 6.4%/year). Assignment to dual antiplatelet therapy had no effect on mortality (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.90 to 1.1) or on vascular and nonvascular death. Independent predictors of all-cause mortality were advancing age, lower body mass index (HR 1.4

Azimilide hydrochloride (azimilide), an investigational antiarrhythmic drug, has shown variable efficacy in preventing atrial fibrillation (AF). This study was designed to assess its efficacy in maintaining sinus rhythm in patients with paroxysmal AF and heart disease. Patients with symptomatic paroxysmal AF were screened for 1 month by transtelephonic monitoring. After recording 1 episode of AF in the screening period, they were randomized to receive azimilide 125 mg or placebo once daily. Patients were stratified by the presence or absence of congestive heart failure or coronary heart disease (CHF/CHD). A maximum of 220 patients without CHF/CHD were randomized, with the remainder having CHF/CHD. Patients with CHF/CHD were monitored for 3 days during loading. The primary efficacy analysis was the time to the first symptomatic recurrence of AF in the CHF/CHD group. Secondary analyses were the time to the first recurrence in the entire population and the time to the first recurrence in those with significant structural heart disease. The median time to recurrence of AF in the CHF/CHD group was 10 days in the 2 treatment arms. Nonsignificant trends were seen toward efficacy of azimilide in the CHF/CHD group (hazard ratio 1.28, 95% confidence interval 0.97 to 1.70, p=0.087), structural heart disease group (hazard ratio 1.22, 95% confidence interval 0.96 to 1.56, p=0.11), and overall group (hazard ratio 1.22, 95% confidence interval 1.00 to 1.49, p=0.053). No patient died. In conclusion, azimilide showed a nonsignificant trend toward efficacy in maintaining sinus rhythm in patients with AF.

We evaluated the efficacy and safety of azimilide, a new class III antiarrhythmic agent that blocks both the slow and fast components of the cardiac-delayed rectifier potassium currents in 4 randomized, double-blind, placebo-controlled trials with similar protocols. The purpose of this study was to assess the relation between dose and effect. A total of 1,380 patients with a documented history of symptomatic atrial fibrillation (AF), atrial flutter, or both, were enrolled. After a 3-day loading period during which the assigned dose was given twice a day, subjects received placebo or azimilide (35, 50, 75, 100, or 125 mg once a day) for the duration of the study period. The primary end point of the studies was the time to symptomatic arrhythmia recurrence with a transtelephonic electrocardiogram typical of AF, atrial flutter, or paroxysmal supraventricular tachycardia. For each study, Kaplan-Meier estimates of the median time to recurrence were computed for placebo and for each azimilide dose. Cox proportional-hazards modeling was used to estimate hazard ratios for each active dose. Each of the 2 highest azimilide doses (100 and 125 mg/day) significantly prolonged the time to recurrence of arrhythmia. For the 100 mg/day dose, the hazard ratio was 1.34, 95% confidence interval 1.05 to 1.72; p = 0.02. For the 125 mg/day dose, the hazard ratio was 1.32, 95% confidence interval 1.07 to 1.62; p = 0.01. Patients with a history of either ischemic heart disease or congestive heart failure had a significantly greater treatment effect from azimilide than those without it. Torsades de Pointes occurred in 0.9% of patients receiving either of the 2 effective doses. Thus, doses of azimilide

The circadian variation of paroxysmal atrial fibrillation (AF) was studied in 67 patients who received a dual-chamber pacemaker 3 months before a planned atrioventricular node ablation. A distinct circadian variation of AF was observed with 2 time peaks in initiation (1 in the early morning and 1 in the early evening hours), which was modulated by atrial pacing, the duration of AF, and the use of beta-adrenergic blocking agents.

It is unknown whether left ventricular hypertrophy (LVH) diagnosis by electrocardiography improves risk stratification in patients with atrial fibrillation (AF). We investigated the prognostic impact of LVH diagnosis by electrocardiography in a large sample of anticoagulated patients with AF included in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Study. We defined electrographic LVH (ECG-LVH) by strain pattern or Cornell voltage (R wave in aVL plus S wave in V3)2.0 mV (women) or2.4 mV (men). LVH prevalence was 22.7%. During a median follow-up of 2.0 years, 303 patients developed a stroke, 778 died (497 from cardiovascular causes), and 140 developed a myocardial infarction. LVH was associated with a greater risk of stroke (1.99% vs 1.32% per year, hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.18 to 1.93, p0.001), cardiovascular death (4.52% vs 1.80% per year, HR 2.56, 95% CI 2.14 to 3.06, p0.0001), all-cause death (6.03% vs 3.11% per year, HR 1.95, 95% CI 1.68 to 2.26, p0.0001), and myocardial infarction (1.11% vs 0.55% per year, HR 2.07, 95% CI 1.47 to 2.92, p0.0001). In multivariate analysis, the prognostic value of LVH was additive to CHA2DS2-VASc score and other covariates. The category-free net reclassification index and integrated discrimination improvement increased significantly after adding LVH to multivariate models. In conclusion, our study demonstrates for the first time that ECG-LVH, a simple and easily accessible prognostic indicator, improves risk stratification in anticoagulated patients with AF.

This study documents mortality from acute myocardial infarction (AMI), in hospital and at 1 year, for each of 3 selected 1-year periods in a stable community over a 13-year period beginning in 1979 and continuing into the thrombolytic era, to detect any changes occurring in conjunction with the introduction of new therapies. Every patient with AMI occurring in a geographically defined stable community (Hamilton, Ontario, Canada) in 3 1-year periods (1979 to 1980 [n = 816], 1986 to 1987 [n = 816], and 1991 to 1992 [n = 831]) was identified and clinically characterized by standardized criteria. Subsequent in-hospital and 1-year survival were ascertained prospectively. The 3 cohorts were similar in prognostic factors. Mean age was progressively greater over the study period from 63 years in 1979 to 1980, to 67 years in 1991 to 1992 (p = 0.02). There was no change in in-hospital mortality rates from 1979 to 1980 (17%) and 1986 to 1987 (16%). However, from 1986 to 1987 and 1991 to 1992, in-hospital mortality decreased from 16% to 9% (p < 0.001) and 1-year mortality decreased from 26% to 19% (p < 0.001). For patients who survived the hospital phase of AMI, 1-year mortality did not change and was between 11% and 12% in each of the 3 study periods. From 1986 to 1987 and 1991 to 1992, there was an increase in the use of thrombolytic therapy from 5% to 44% of patients. The acute use of aspirin increased from 30% to 88% and the acute use of beta blockers increased from 19% to 48% of patients. The observed increase in use of these agents could account for half of the actual mortality reduction observed. This prospective population-based survey demonstrates improved in-hospital survival after AMI associated with increased use of established effective therapies between 1987 and 1992. The 1-year mortality of hospital survivors of AMI was unchanged throughout the period of study, remaining at 11% to 12%.

This report presents the outcome of a cohort of 94 patients with atrial fibrillation from the Canadian Registry of Atrial Fibrillation, in which we paid particular attention to the probability of stroke and death. We also evaluated warfarin use over time and compared left atrial dimensions in patients with atrial flutter with those with atrial fibrilliation.

The Canadian Amiodarone Myocardial Infarction Trial (CAMIAT) is a multicenter, triple-blind, randomized, placebo-controlled trial. Eligible patients are those found on 24-hour ambulatory electrocardiographic monitoring within 6-45 days of acute myocardial infarction to have ventricular premature depolarizations (VPDs) that are frequent (> or = 10/hr) or repetitive (> or = 1 three-beat run of ventricular tachycardia). Consenting patients are randomized to amiodarone or placebo with an oral loading dose of 10 mg/kg/day for 2 weeks; maintenance dose is 300-400 mg/day for 3.5 months, 200-300 mg/day for 4 months, and 200 mg/day for 5 or 7 days/week for 16 months. Patients are followed by alternate telephone and clinical visit at 2-month intervals for 24 months. The principal outcome is a composite of presumed arrhythmic death or resuscitated ventricular fibrillation. Outcomes are determined by an external validation committee. The anticipated rate of arrhythmic death is 7.5% over 2 years; the sample size is 1,200 patients. CAMIAT began in June 1990 and is anticipated to conclude enrollment by June 1994 and follow-up by June 1995. Recruitment rate is about 92% of projected.

The Canadian Implantable Defibrillator Study (CIDS) is an on-going randomized multicenter clinical trial that compares implantable cardioverter-defibrillator (ICD) therapy against amiodarone in patients with prior cardiac arrest or hemodynamically unstable ventricular tachycardia. Eligible patients are equally randomized to receive or not receive an ICD as initial management. Those not receiving an ICD receive amiodarone. All patients are seen in follow-up every 6 months. The primary outcome event cluster is arrhythmic death or any other death occurring within 30 days of therapy initiation. Secondary outcomes are all-cause mortality and nonfatal occurrences of ventricular tachycardia or fibrillation. The goal of the study is to recruit 400 patients over 4 years. All patients will be followed to the end of the year. This will result in an 80% chance of detecting a reduction in arrhythmic death of 58% by ICD if such a difference in truth exists. Recruitment began in October 1990 and 184 patients have been enrolled to date.

T he implantable cardioverter defibrillator (ICD) is an important and unique new method of potentially preventing sudden death due to ventricular arrhythmia, and it is increasingly being used to treat survivors of cardiac arrest (not associated with acute myocardial infarction). Recently, the North American Society for Pacing and Electrophysiologyl stated that the ICD is indicated for patients with sustained ventricular tachycardia and fibrillation, except those who become noninducible at electrophysiologic drug testing. However, the effectiveness of the ICD for reduction of both sudden death and overall mortality has not been conclusively demonstrated. Some commentators2m4 stated that based on nonrandomized studies in survivors of sudden death, the effectiveness of the ICD is “obvious” and essentially proven, rendering a randomized trial unethical. It is reasonable to accept that a randomized trial is neither necessary, nor even perhaps ethical, when the benefits of a new treatment are of very great magnitude, or when the outcome is uniformly poor with conventional therapy, and the benefits are moderate. However, in other circumstances, nonrandomized comparisons can potentially be very misleading, and great caution is needed when adopting a new treatment in the absence of data from randomized trials. The question that needs to be answered is not whether the ICD can effectively terminate malignant arrhythmias that would otherwise be fatal, because this has been amply documented by ambulatory electrocardiographic monitoring.5-8 The relevant clinical question is whether the ICD reduces overall mortality among survivors of cardiac arrest (not associated with myocardial infarction) compared with the best medical therapy. The answer to the latter question is complex, because it must account for multiple issues including perioperative mortality, concurrent competing risks of death from pump failure and acute ischemia, the potential risks and benefits of medical therapy, and the possibility that the ICD may only change the mode of death (in some patients) from arrhythmic to nonarrhythmic. The only way to reliably answer this question currently is by means of a randomized trial. Patients who are resuscitated from cardiac arrest have substantial degrees of left ventricular dysfunction and often have myocardial ischemia. In such patients

To compare 1-, 6- and 24-hour ambulatory electrocardiograms for prediction of mortality after acute myocardial infarction (AMI), all patients with AMI hospitalized in Hamilton, Ontario during 1 year were identified. There were 683 patients discharged alive after AMI. One-, 6- and 24-hour ambulatory electrocardiographic results were available in 565 patients, and follow-up mortality data at 1 year was available in 560. Mean age of the patients was 64 years; 160 (29%) had previous AMI and 105 (19%) had had congestive heart failure. One hundred and fifty-two patients (27%) were receiving β blockers, and 31 (6%) were receiving antiarrhythmic drugs. Regression modeling of survival times up to 1 year showed that all 3 durations of recording were univariate predictors of mortality. Using >10 ventricular premature complexes/hour as the criterion of a positive test, neither the 6- nor 24-hour data contained statistically significant residual explanatory power after the 1-hour data were accounted for by the model. The longer durations of recording increased sensitivity at a cost of decreased specificity. The positive and negative predictive values of the 3 durations of recording were virtually identical. The presence of ventricular tachycardia was not a significant predictor of mortality in this population. There appears to be no benefit to ambulatory electrocardiographic recordings >1 hour when they are to be used for prediction of 1-year mortality after AMI.

Atrial fibrillation and hypertension are 2 prevalent, and often coexistent, conditions in the North American population. Their incidence increases with advancing age, and they are responsible for considerable morbidity and mortality. Although the relation between the 2 conditions has long been known, the treatment of hypertension is not currently a focus in the clinical management of atrial fibrillation. Hypertension is associated with left ventricular hypertrophy, impaired ventricular filling, left atrial enlargement, and slowing of atrial conduction velocity. These changes in cardiac structure and physiology favor the development of atrial fibrillation, and they increase the risk of thromboembolic complications. Conventional therapy of atrial fibrillation has focused on interventions to control heart rate and rhythm and the prevention of stroke through the use of anticoagulant medications. In patients with atrial fibrillation, aggressive treatment of hypertension may reverse the structural changes in the heart, reduce thromboembolic complications, and retard or prevent the occurrence of atrial fibrillation. Specific pharmacotherapy could potentially play a major role in the primary and secondary prevention of atrial fibrillation and its complications.

During the past 15 years, the efficacy of antiarrhythmic drugs has been investigated for reducing premature death in patients at high risk of arrhythmia. Whereas the benefits of beta-blocker therapy are well established, a reduction in mortality with other antiarrhythmic drugs remains unproved and in some cases, there is evidence of increased mortality with class I and some class III agents. A limitation of individual clinical trials is inadequate sample size to detect significant differences between interventions. Meta-analysis, by combining results from multiple clinical trials, provides a technique to overcome sample size limitations and assess the benefits and limitations of an intervention. Thirteen randomized clinical trials evaluated the role of prophylactic amiodarone in patients at risk of death from cardiac arrhythmias. Whereas 3 of these studies reported a reduction in mortality, several others revealed no benefits of amiodarone. Because neither trial was designed to detect reductions in total mortality, it remained unclear whether the beneficial effect of amiodarone on arrhythmic death and resuscitated ventricular fibrillation translated into a beneficial effect on total mortality. To address this, a meta-analysis was performed from the 13 trials of amiodarone in patients after an acute myocardial infarction or with congestive heart failure. The results showed a significant reduction in mortality and in arrhythmic death with amiodarone.

The Canadian Registry of Atrial Fibrillation (CARAF) is a nondirected, follow-up study of 1,086 patients who are enrolled at 6 centers across Canada at the time of initial electrocardiographically documented diagnosis of atrial fibrillation (AF). Enrollment commenced in 1991 with an intended 10-year follow-up. Comprehensive baseline data, including clinical history, laboratory, and echocardiographic variables were collected. The patients were treated by their own referring physicians and CARAF did not direct their care. Detailed follow-up was performed at 3 months, 1 year, then yearly, with echocardiograms repeated every 2 years. Several studies, which evaluated patient populations, predictors of events, and cardiac structure and functioning, have been performed and are ongoing. Thyroid function was evaluated at baseline, and, of 707 patients evaluated, only 6 patients were found to be hyperthyroid. Symptoms during AF were evaluated and a profile of the types of symptoms and the predictors of symptoms was compiled. Antiarrhythmic drug use is being followed. Sotalol and propafenone were the most commonly used medications, with the use of antiarrhythmic drugs increasing with recurrence of AF. The use of anticoagulants was assessed. The overall use of warfarin was relatively low, but its use increased dramatically with the presence of various risk factors including congestive heart failure, hypertension, and previous stroke. The one risk factor that did not result in increased use of warfarin was hypertension. Therefore, CARAF was able to identify that hypertension appears to be under-recognized and undertreated in its risk for thromboembolic events. CARAF is just now reaching maturity, with the majority of patients having > or=4 years of follow-up. Therefore, extensive investigations are currently under way that will evaluate the baseline characteristics and utilize these as predictors of recurrence of AF, progression to chronicity, and the occurrence of major events such as stroke and death. A very large cohort of patients with serial echocardiograms over 4 years will permit an understanding of the progression of structural and valvular disease. Therefore, CARAF offers a unique opportunity for comprehensive, nondirected follow-up of patients from their initial diagnosis of AF.

Sixteen patients with ventricular tachycardia (VT) or nonfatal cardiac arrest were treated with propafenone (P), 900 mg/day. Electrophysiologic studies were performed before and during therapy with P. All patients had inducible sustained VT at the baseline study. During P therapy, VT was not inducible in 1 patient, was unsustained in 1 and was harder to induce in 2 patients. P increased the cycle length of VT from 307 +/- 67 to 382 +/- 107 ms. Five patients began outpatient therapy with P, including 2 in whom VT was slowed to less than 125 beats/min. Two are arrhythmia-free during follow-up of 2 and 8 months. P significantly increased intraatrial conduction time (from 44 +/- 12 to 72 +/- 22 ms), AH interval (from 115 +/- 36 to 152 +/- 45 ms), HV interval (from 55 +/- 18 to 92 +/- 42 ms), QRS duration (from 140 +/- 36 to 180 +/- 48 ms) and QT interval (from 402 +/- 30 to 459 +/- 60 ms). P increased atrial (from 247 +/- 36 to 288 +/- 38 ms) and ventricular (from 249 +/- 20 to 277 +/- 32 ms) effective refractory periods, Sinus cycle length did not change, but the corrected sinus node recovery time increased (from 162 +/- 85 to 821 +/- 1,607 ms). P aggravated arrhythmias in 4 patients. The plasma P concentration, measured either at the time of electrophysiologic studies of when therapy was discontinued, was 753 +/- 428 ng/ml. P suppressed ventricular ectopic beats in 33% and increased them in 1 patient. P has antiarrhythmic activity against VT similar to that of other antiarrhythmic drugs and has potential for serious adverse effects in some patients.

This report presents the first study of cardiac arrhythmias and conduction disturbance in a large group (400 patients) with sleep apnea syndrome studied between 1974 and 1979 with 24-hour Holter electrocardiography and a simultaneously recorded polygraph during late afternoon or nocturnal sleep. Of the 400, 193 patients (48%) had cardiac arrhythmias during the recorded night. The mean number of apneic events, age, weight and lowest oxygen saturation during sleep were not significantly different in those with arrhythmias. The most significant abnormalities were unsustained ventricular tachycardia in 8 patients, sinus arrest that lasted for 2.5 to 13 seconds in 43 patients, and second-degree atrioventricular conduction block in 31. Seventy-five had frequent (greater than 2 beats/min) premature ventricular contractions during sleep. Fifty patients with significant arrhythmias had a tracheostomy and were monitored again after surgery. No arrhythmia was present in these patients except for premature ventricular contractions.

Invasive electrophysiologic studies were performed before and during treatment with imipramine in 18 patients with inducible ventricular tachycardia (VT). All received imipramine, 50 mg twice daily for 3 days, and then 100 mg twice daily for 3 days. Imipramine increased the infranodal conduction times (HV) (from 58 +/- 7.8 to 65 +/- 10 ms) and QRS duration (from 133 +/- 21 to 153 +/- 39 ms) and significantly decreased sinus cycle length (from 875 +/- 145 to 711 +/- 116 ms) and maximal corrected sinus nodal recovery time (from 457 +/- 656 to 380 +/- 603 ms). The Wenckebach cycle length tended to decrease and the QT interval to increase, but these changes were not statistically significant. Atrial and ventricular refractory periods, atrioventricular nodal conduction times and induced VT cycle length did not change significantly. Imipramine prevented induction of VT in 2 patients, and VT was more difficult to induce in 1 patient. These 3 patients received chronic imipramine therapy. The 2 patients in whom no VT could be induced while taking imipramine have had no recurrence of arrhythmia at 6 and 12 months of follow-up. The third patient died suddenly 4 months after discharge from the hospital. One patient had worsening of arrhythmias while taking imipramine and 61% had minor adverse effects. The mean combined plasma imipramine and desmethylimipramine concentration at the time of the repeat electrophysiologic study was 227 +/- 114 ng/ml. Imipramine is effective against VT in some patients; however, like other type I antiarrhythmic drugs, the rate of efficacy is low.

To evaluate the efficacy of propafenone for suppression of recurrent paroxysmal symptomatic atrial fibrillation (AF), patients with frequent episodes of AF entered an open-label, dose-ranging study to determine the maximal tolerated dose of propafenone and were subsequently randomized to alternate between propafenone and placebo every month for 4 months. Patients recorded each episode of AF in a diary and recorded a simultaneous electrocardiographic rhythm strip by means of a transtelephonic recorder and transmitter to validate the presence of AF. Eighteen patients were eligible for study. During dose ranging, 4 patients withdrew due to inadequate drug efficacy or poor compliance, 2 withdrew due to intolerable side effects and 1 died. The mean dose of propafenone at the end of dose ranging was 644 +/- 189 mg/day. During the crossover study, the percentage of days with an attack of AF was significantly reduced by propafenone compared with placebo (27 +/- 34 vs 51 +/- 34%, p less than 0.01). The rate of early crossover or withdrawal from the crossover study was 13.6% with propafenone and 45% with placebo (p = 0.056). Five patients went on to receive long-term propafenone and 4 continued treatment with suppression of AF for 12 to 21 months. During the crossover study there were 29 reported minor side effects with propafenone and 11 with placebo.