K. I. Lie

Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure

BACKGROUND Drugs that improve symptoms in patients with heart failure must also be assessed for their effects on survival. Ibopamine stimulates DA-1 and DA-2 receptors and causes peripheral and renal vasodilatation; the drug improves symptoms of heart failure. We assessed the effect of ibopamine on survival in patients with advanced heart failure in a multicentre, randomised placebo-controlled study. METHODS Patients with advanced severe heart failure (New York Heart Association classes III and IV) and evidence of severe left-ventricular disease, who were already receiving optimum treatment for heart failure, were randomly allocated oral ibopamine 100 mg three times daily or placebo. The primary endpoint was all-cause mortality. The study was designed to recruit 2200 patients, and the minimum duration of treatment would be 6 months. We did intention-to-treat and on-treatment analyses; a post-hoc subgroup analysis was also done. FINDINGS After we had recruited 1906 patients the trial was stopped early, because of an excess of deaths among patients in the ibopamine group. 232 (25%) of 953 patients in the ibopamine group died, compared with 193 (20%) of 953 patients in the placebo group (relative risk 1.26 [95% CI 1.04-1.53], p = 0.017). The average length of follow-up was 347 days in the ibopamine group and 363 days in the placebo group. In multivariate analysis, only the use of antiarrhythmic drugs at baseline was a significant independent predictor of increased fatality in ibopamine-treated patients. INTERPRETATION Ibopamine seems to increase the risk of death among patients with advanced heart failure who are already receiving optimum therapy, but the reasons for this increase are not clear. Our finding that antiarrhythmic treatment was a significant predictor of increased mortality in ibopamine-treated patients may be important, but exploratory analyses must be interpreted with caution.

To operate or not on elderly patients with aortic stenosis: the decision and its consequences

OBJECTIVE To evaluate the application of guidelines in the decision making process leading to medical or surgical treatment for aortic stenosis in elderly patients. DESIGN Cohort analysis based on a prospective inclusive registry. SETTING 205 consecutive patients (⩾ 70 years) with clinically relevant isolated aortic stenosis and without serious comorbidity, seen for the first time in the Doppler-echocardiographic laboratories of three university hospitals in the Netherlands. RESULTS The initial choice was surgery in 94 patients and medical treatment in 111. Only 59% of the patients who should have had valve replacement according to the practice guidelines were actually offered surgical treatment. These were mainly symptomatic patients under 80 years of age with a high gradient. Operative mortality (30 days) was only 2%. The three year survival was 80% in the surgical group (17 deaths among 94 patients) and 49% in the medical group (43/111). Multivariate analysis showed that only patients with a high baseline risk, mainly determined by impaired left ventricular function, had a significantly better three year survival with surgical treatment than with medical treatment. CONCLUSIONS In daily practice, elderly patients with clinically relevant symptomatic aortic stenosis are often denied surgical treatment. This study indicates that a surgical approach, especially where there is impaired systolic left ventricular function, is associated with better survival.

Time course of hemodynamic changes and improvement of exercise tolerance after cardioversion of chronic atrial fibrillation unassociated with cardiac valve disease

This study prospectively assessed the time course, magnitude and mechanism of the hemodynamic changes after restoration of sinus rhythm in patients with chronic atrial fibrillation (AF) unassociated with valvular disease. Severe cardiac dysfunction may occur after chronic supraventricular tachycardia in patients with and without underlying cardiac disease. Improvement may follow abolishment of the arrhythmia or adequate slowing of the ventricular rate. Eight patients were studied with a mean previous duration of AF of 10 +/- 9 months. Ejection fraction, exercise capacity and the atrial contribution to the left ventricular filling (only during sinus rhythm) were studied before cardioversion, after cardioversion and 1 week, 1 month and 6 months thereafter. A significant improvement in ejection fraction from 36 +/- 13 to 53 +/- 8% (p < 0.05) occurred at 1 month after cardioversion. Concomitantly, peak oxygen consumption had increased at 1 month, from 20.1 +/- 7 to 25.2 +/- 6 ml/min/kg (p < 0.05). Thereafter, no further improvement in hemodynamic parameters occurred. The atrial systole improved already at 1 week (from 3 +/- 5 to 16 +/- 11%, p < 0.05) and remained unchanged thereafter. Thus, restoration of sinus rhythm was associated with a delayed improvement in ejection fraction and maximal exercise capacity, preceded by an early restoration of atrial contractility and an acute slowing of the heart rate. The discrepancy in time course of restoration of atrial and ventricular function parameters suggests that an intrinsic left ventricular cardiomyopathy is present in patients with AF.

Spinal cord stimulation in chronic intractable angina pectoris: A randomized, controlled efficacy study

BACKGROUND Spinal cord stimulation is known to be a successful treatment for chronic intractable angina pectoris. Its effect may be anti-ischemic. It is uncertain if the clinical effect is partly caused by a placebo effect of surgery for implantation of a stimulator. In this study, clinical efficacy is investigated, together with a possible placebo effect. METHODS AND RESULTS Efficacy of spinal cord stimulation as a treatment for chronic intractable angina pectoris was studied for 6 weeks in 13 treated patients and 12 control patients with chronic angina. Assessments were exercise capacity and ischemia, daily frequency of anginal attacks and nitrate tablet consumption, and quality of life (perceived quality of life and pain). Compared with control, exercise duration (P =.03) and time to angina (P =.01) increased; anginal attacks and sublingual nitrate consumption (P =.01) and ischemic episodes on 48-hour electrocardiogram (P =.04) decreased. ST-segment depression on the exercise electrocardiogram decreased at comparable workload (P =.01). Anginal attacks and consumption of sublingual nitrates decreased (P =.01), perceived quality of life increased (P =.03), and pain decreased (P =.01). CONCLUSIONS Spinal cord stimulation is effective in chronic intractable angina pectoris, and its effect is exerted through anti-ischemic action. Efficacy is unlikely to be explained as a placebo effect from surgery.

Prognostic value of heart rate variability during long-term follow-up in patients with mild to moderate heart failure

OBJECTIVES We sought to assess the prognostic value of heart rate variability measures, including Poincaré plots, in patients with mild to moderate chronic heart failure. BACKGROUND Mortality is high in patients with heart failure, and many of them die suddenly. However, identification of high risk patients, particularly those with an increased risk for sudden death, has remained difficult. METHODS We studied 95 patients with heart failure (mean [+/- SD] age 60 +/- 8 years, left ventricular ejection fraction 0.29 +/- 0.09, New York Heart Association functional class II [81%] and III [19%]) during up to 4 years of follow-up. Heart rate variability measures and Poincaré plots were obtained from 24-h Holter recordings. RESULTS During follow-up, 17 (18%) of the 95 patients died. In 15 patients, death was cardiac related (11 patients experienced sudden death). None of the conventional time and frequency domain measures of heart rate variability were related to survival. In contrast, abnormal Poincaré plots identified a significantly higher risk for all-cause cardiac death (Cox proportional hazards ratio 5.7, 95% confidence interval [CI] 1.6 to 20.6, univariate analysis) and for sudden cardiac death (hazards ratio 6.8, 95% CI 1.5 to 31.4) compared with those with normal Poincaré plots. Patients with abnormal Poincaré plots were shown to have a lower left ventricular ejection fraction (0.26 +/- 0.10 vs. 0.31 +/- 0.08, p < 0.05) and higher plasma norepinephrine concentrations (506 +/- 207 pg/ml vs. 411 +/- 175 pg/ml, p < 0.05). In multivariate analysis, abnormal Poincaré plots still had independent prognostic value, both for all-cause cardiac mortality and for sudden cardiac death (hazards ratio 5.3, 95% CI 1.2 to 17.1, hazards ratio 4.5, 95% CI 1.0 to 27.5, respectively. CONCLUSIONS Heart rate variability analysis, as assessed by Poincaré plots, has independent prognostic value in patients with mild to moderate chronic heart failure and identifies an increased risk for all-cause and sudden cardiac death in these patients.

Double-blind placebo-controlled study of ibopamine and digoxin in patients with mild to moderate heart failure: results of the Dutch Ibopamine Multicenter Trial (DIMT).

OBJECTIVES This study was conducted to determine the efficacy and safety of long-term treatment with the orally active dopamine agonist ibopamine in patients with mild to moderate chronic congestive heart failure and to compare the results with those of treatment with digoxin and placebo. BACKGROUND Ibopamine and digoxin are drugs that exert hemodynamic and neurohumoral effects. Because there is accumulating evidence that progression of disease in chronic heart failure is related not only to hemodynamic but also to neurohumoral factors, both drugs might be expected to have a favorable long-term effect. METHODS We studied 161 patients with mild to moderate chronic heart failure (80% in New York Heart Association functional class II and 20% in class III), who were treated with ibopamine (n = 53), digoxin (n = 55) or placebo (n = 53) for 6 months. Background therapy consisted of furosemide (0 to 80 mg); all other drugs for heart failure were excluded. Clinical assessments were made at baseline and after 1, 3 and 6 months. RESULTS Of the 161 patients, 128 (80%) completed the study. Compared with placebo, digoxin but not ibopamine significantly increased exercise time after 6 months (p = 0.008 by intention to treat analysis). Ibopamine was only effective in patients with relatively preserved left ventricular function, as it significantly increased exercise time in this subgroup (for patients with a left ventricular ejection fraction > 0.30; p = 0.018 vs. placebo). No patient receiving digoxin withdrew from the study because of progression of heart failure, compared with six patients receiving ibopamine and two receiving placebo. At 6 months, plasma norepinephrine was decreased with digoxin and ibopamine therapy (-106 and -13 pg/ml, respectively) but increased with placebo administration (+62 pg/ml) (both p < 0.05 vs. placebo). Plasma aldosterone was unaffected, but renin was decreased by both agents after 6 months (p < 0.05 vs. placebo). Total mortality and ambulatory arrhythmias were not significantly affected by the two drugs. CONCLUSIONS Ibopamine and digoxin both inhibit neurohumoral activation in patients with mild to moderate chronic heart failure. However, the clinical effects of these drugs are different and appear to be related to the degree of left ventricular dysfunction.

High- versus low-dose ACE inhibition in chronic heart failure: a double-blind, placebo-controlled study of imidapril

OBJECTIVES To determine dose-related clinical and neurohumoral effects of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic heart failure (CHF), we conducted a double-blind, placebo-controlled, randomized study of three doses (2.5 mg, 5 mg and 10 mg) of the long-acting ACE inhibitor imidapril. BACKGROUND The ACE inhibitors have become a cornerstone in the treatment of CHF, but whether high doses are more effective than low doses has not been fully elucidated, nor have the mechanisms involved in such a dose-related effect. METHODS In a parallel group comparison, the effects of three doses of imidapril were examined. We studied 244 patients with mild to moderate CHF (New York Heart Association class II-III: +/-80%/20%), who were stable on digoxin and diuretics. Patients were treated for 12 weeks, and the main end points were exercise capacity and plasma neurohormones. RESULTS At baseline, the four treatment groups were well-matched for demographic variables. Of the 244 patients, 25 dropped out: 3 patients died, and 9 developed progressive CHF (3/182 patients on imidapril vs. 6/62 patients on placebo, p < 0.05). Exercise time increased 45 s in the 10-mg group (p = 0.02 vs. placebo), but it did not significantly change in the 5-mg (+16 s), and 2.5-mg (+11 s) imidapril group, compared to placebo (+3 s). Physical working capacity also increased in a dose-related manner. Plasma brain and atrial natriuretic peptide decreased (p < 0.05 for linear trend), while (nor)epinephrine, aldosterone and endothelin were not significantly affected. Renin increased in a dose-related manner, but plasma ACE activity was suppressed similarly (+/-60%) on all three doses. CONCLUSIONS Already within 3 months after treatment initiation, high-dose ACE inhibition (with imidapril) is superior to low-dose. This is reflected by a more pronounced effect on exercise capacity and some of the neurohormones, but it does not appear to be related to the extent of suppression of plasma ACE.

Effects of spinal cord stimulation on myocardial ischaemia during daily life in patients with severe coronary artery disease. A prospective ambulatory electrocardiographic study.

BACKGROUND--Spinal cord stimulation (SCS) may be a useful additional therapy for pain in patients with therapeutically refractory angina pectoris. But doubts remain about whether it also relieves ischaemia. METHODS--Indices of ischaemia were studied with and without SCS in 10 patients with otherwise intractable angina and evidence of myocardial ischaemia on 48 h ambulatory electrocardiographic (ECG) recording. Primary end points assessed by 48 h ECG recordings were total ischaemic burden, number of ischaemic episodes, and duration of ischaemic episodes. In addition, symptoms were assessed by a diary of glyceryl trinitrate intake and angina attacks. RESULTS--During SCS the total ischaemic burden of the entire group was significantly reduced from a median of 27.9 (1.9-278.2) before SCS to 0 (0-70.2) mm x min with SCS (p < 0.03). In six out of the 10 patients there was no myocardial ischaemia during 48 h ambulatory ECG monitoring with SCS. The number of ischaemic episodes was reduced from a median of 3 (1-15) before SCS to 0 (0-9) with SCS (p < 0.04). The duration of ischaemic episodes decreased from a median of 20.6 (1.7-155.4) min before SCS to 0 (0-48.3) min with SCS (p < 0.03). This was accompanied by a significant improvement in symptoms with a reduction in daily glyceryl trinitrate intake from a median of 3.0 (0-10) before SCS to 0.3 (0-10) tablets per 48 h (p < 0.02) and a decrease in the frequency of anginal attacks from a median of 5.5 (2-14) before SCS to 1.0 (0-10) per 48 h with SCS (p < 0.03). CONCLUSIONS--SCS not only reduced symptoms but also myocardial ischaemia. Therefore, SCS appears to be both a safe and an effective therapy for patients with refractory angina.

Effects of Lisinopril in Patients With Heart Failure and Chronic Atrial Fibrillation

Although atrial fibrillation is common in patients with heart failure, patients with atrial fibrillation are often excluded from congestive heart failure trials or are not analyzed separately. Consequently, while the effect of angiotensin-converting enzyme inhibitors in patients with sinus rhythm is well established, the effect on patients with atrial fibrillation is unknown. The authors hypothesized that these agents might be particularly effective in this patient category, given their antiadrenergic properties and the importance of adequate rate control. Therefore, the effects of lisinopril 10 mg once daily were evaluated in 30 patients with congestive heart failure and chronic atrial fibrillation (mean age, 68 +/- 6 years) in a double-blind, randomized, placebo-controlled trial. All patients were in New York Heart Association class II or III and were stable on conventional therapy (digoxin, diuretics, nitrates). After 6 weeks, mean peak oxygen consumption increased from 14.7 +/- 3.4 to 15.9 +/- 2.9 mL/min/kg in the lisinopril group (P = .034). Plasma norepinephrine levels during exercise and at peak exercise tended to be lower when the patients were taking lisinopril (10.8 +/- 4.2 to 8.9 +/- 4.4 nmol/L and 16.3 +/- 9.2 to 14.3 +/- 7.7 nmol/L, P < .1). Heart rate during exercise and ambulatory monitoring was not significantly affected. Left ventricular fractional shortening tended to increase after lisinopril (23 +/- 7 to 27 +/- 9%, P = .073). Left atrial volume was unchanged, as were plasma atrial natriuretic peptide levels. After subsequent electrical cardioversion, treatment was continued for 6 more weeks, allowing assessment of the effect of lisinopril on maintenance of sinus rhythm; maintenance of sinus rhythm was 71% in the lisinopril group and 36% in the placebo group (P = NS). This study shows that treatment with an angiotensin- converting enzyme inhibitor improves peak oxygen consumption in patients with congestive heart failure and chronic atrial fibrillation. Attenuation of adrenergic drive during exercise may play a role in mediating this effect.

Supraventricular tachycardia mimicking ventricular tachycardia during flecainide treatment

Abstract As a class IC antiarrhythmic drug, flecainide can produce marked widening of the QRS complex. This effect is use dependent, 1 indicating that widening of the QRS complex becomes more prominent during faster heart rates. Widening of the QRS complex during tachycardia in patients treated with flecainide can be extreme due to this use dependency. It may create difficulty in determining the origin of the tachycardia, especially if bundle branch block (BBB) supervenes. This report describes flecainide-induced wide complex tachycardias of supraventricular origin, mimicking ventricular tachycardia (VT).