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PubMed2006

Pharmacologic approaches to rhythm versus rate control in atrial fibrillation--where are we now?

Until recently, contemporary drug treatment of atrial fibrillation (AF) focused primarily on restoration and maintenance of sinus rhythm, predicated on the belief that if AF is abolished then problems associated with AF would be abolished too. Recently completed clinical trials using drug therapy and comparing maintenance of sinus rhythm with control of ventricular rate have challenged this assumption, showing that simple control of ventricular rate with anticoagulation is an acceptable primary therapy, notably in older patients with persistent AF, minimally symptomatic or asymptomatic, and at increased risk for thromboembolic events. However, rate control and anticoagulation is not a panacea; existing trial results should not be interpreted to mean all patients should be treated with the rate control approach. Despite the limited efficacy and poor safety of current antiarrhythmic drugs, strategies for maintenance of sinus rhythm remain justified in many patients, such as those with first-episode AF, highly symptomatic patients, younger patients, and those with a history of congestive heart failure (CHF). Commonly used current and some investigational agents designated for "rhythm control" have enough pharmacologic overlap with rate control agents to be considered to have a dual mode of action, simultaneously addressing both rhythm and rate control. Furthermore, there is much interest in non-pharmacologic therapies, such as radiofrequency ablation, for rhythm control. The lack of appropriately designed and controlled trials at this time makes it difficult to determine the place of radiofrequency ablation and its impact on the rhythm versus rate question.

Animals↗
PubMedDate not supplied

[Atrial fibrillation: rhythm vs. rate control].

The atrial fibrillation treatment has been controversial since almost a century. Several studies have been done and there is not a clear therapeutic strategy despite the new technological advances. The disyuntive persist between sinus rhythm control vs. ventricular rate control. The main studies like AFFIRM, RACE, PIAF, PAF2 and STAF have not shown a definitive strategy treatment. Recently, several subgroups have been stablished and variables like life quality and functional state have been included. New therapeutic strategies have resulted. Heart rate control is recommendable for asymptomatic 65 years old patients and older, whereas rhythm control is better for patients with severe symptoms.

Atrial Fibrillation↗
PubMed1981

Age-related changes of cardiac control function in man. With special reference to heart rate control at rest and during exercise.

Heart rate control function at rest and during exercise in regard to age were studied in 39 healthy male volunteers (age 15 to 75). The heart rate control function during exercise was evaluated by using system analysis of heart rate response to two-step exercises (66 and 84 steps/min). No age-related changes were found in the resting heart rate at supine position or in oxygen consumption at upright rest and during the exercises. However, the mean value and the magnitude of variation of the heart rate at upright rest and the difference of heart rate at upright and supine rest showed significant negative correlations with age. As age advanced, the transfer function of the system during exercise exhibited characteristic changes depending on the frequency ranges. These findings suggest that activity of both sympathetic and parasympathetic nervous systems were depressed at rest, and that contributions of sympathetic and vagal nervous systems during exercise are more enhanced and more depressed, respectively, in older subjects than in younger subjects.

Adolescent↗
PubMed1979

Instructed heart rate control in a high heart rate population.

Forty college students were selected from a large number of introductory psychology students on the basis of high heart rate during an initial screening session. Subjects were then contacted and participated in two additional sessions during which heart rate, respiration rate, and skin conductance measures were obtained. Each session consisted of a baseline period followed by five trial periods during which subjects attempted to control their heart rate or performed a visual tracking task. Subjects were randomly assigned to one of four groups. One group served as a control and monitored a visual feedback display driven by their own heart rate but received no instructions to decrease their heart rate. In contrast, the three heart rate control groups were instructed to decrease heart rate during the trial periods by utilizing a relaxation procedure, proportional biofeedback, or proportional biofeedback plus criterion information. No group differences were present during the baseline periods. During feedback trials, however, all the training groups differed from the control in heart rate but did not differ from each other. It is suggested that feedback displays may not facilitate heart rate reduction beyond the level achieved by instructing subjects to use a general relaxation procedure.

Attention↗
PubMed2004

Ventricular rate control as an endpoint for treatment of atrial fibrillation.

Interest in the use of rate control as an endpoint for managing atrial fibrillation likely will increase given the results of recent randomized clinical trials. As an endpoint, rate control has favorable attributes of ease of measurement and clear numerical definitions. Pharmacologic rate control is achieved in approximately 80% of patients in large clinical trials. Ablation and pacing may achieve rate control in all patients. Rate control has been shown to improve quality of life over pretreatment status. However, several issues regarding the use of rate control as an endpoint are unsettled. Technical issues concerning when and how to measure heart rate remain. The current definitions of rate control are lacking in scientific foundation and demonstration of clinical relevance. Heart rate control during exercise may be difficult to achieve in many patients despite control at rest. Finally, the relationship of rate control to some important clinical outcomes has not been established.

Atrial Fibrillation↗
PubMed2003

Rate control in atrial fibrillation: choice of treatment and assessment of efficacy.

The clinical relevance and high social costs of atrial fibrillation have boosted interest in rate control as a cost-effective alternative to long-term maintenance of sinus rhythm (i.e. rhythm control). Prospective studies show that rate control (coupled with thromboembolic prophylaxis) is a valuable treatment option for all forms of atrial fibrillation. The rationale for rate control is that high ventricular rates, frequently found in atrial fibrillation, lead to haemodynamic impairment, consisting of a variable combination of loss of atrial kick, irregularity in ventricular response and inappropriately rapid ventricular rate, depending on the type of underlying heart disease. Long-term persistence of tachycardia at a high ventricular rate can lead to various degrees of ventricular dysfunction and even to tachycardiomyopathy-related heart failure. Identification of this reversible and often concealed form of left ventricular dysfunction can permit effective management by rate (or rhythm) control. Although acute rate control (to reduce ventricular rate within hours) is still often based on digoxin administration, for patients without left ventricular dysfunction, calcium channel antagonists or beta-adrenoceptor antagonists (beta-blockers) are generally more appropriate and effective. In chronic atrial fibrillation, long-term rate control (to reduce morbidity/mortality and improve quality of life) must be adapted to patients' individual characteristics to grant control during daily activities, including exercise. According to current guidelines, the clinical target of rate control should be a ventricular rate below 80-90 bpm at rest. However, in many patients, assessment of the appropriateness of different drugs should include exercise testing and 24h-Holter monitoring, for which specific guidelines are needed. In practice, rate control is considered a valid alternative to rhythm control. Recent prospective trials (e.g. the Pharmacological Intervention in Atrial Fibrillation [PIAF] and the Atrial Fibrillation Follow-up Investigation of Rhythm Management [AFFIRM] trials) have shown that in selected patients, rate control provides similar benefits, more economically, in terms of quality of life and long-term mortality. The choice of a rate control medication (digoxin, beta-blockers, calcium channel antagonists or possibly amiodarone) or a non-pharmacological approach (mainly atrioventricular node ablation coupled with pacing) must currently be based on clinical assessment, which includes assessing the presence of underlying heart disease and haemodynamic impairment. Definite guidelines are required for each different subset of patients. Rate control is particularly tricky in patients with heart failure, for whom non-pharmacological options can also be considered. The preferred pharmacological options are beta-blockers for stabilised heart failure and digoxin for unstabilised forms.

Animals↗
PubMed2003

Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study.

OBJECTIVES: This study was designed to compare two treatment strategies in patients with atrial fibrillation(AF): rhythm-control (restoration and maintenance of sinus rhythm) and rate-control (pharmacologic or invasive rate-control and anticoagulation). BACKGROUND: Atrial fibrillation is the most common arrhythmia. It is unclear whether a strategy of rhythm- or rate-control is better in terms of mortality, morbidity, and quality of life. METHODS: The Strategies of Treatment of Atrial Fibrillation (STAF) multicenter pilot trial randomized 200 patients (100 per group) with persistent AF to rhythm- or rate-control. The combined primary end point was a combination of death, cardiopulmonary resuscitation, cerebrovascular event, and systemic embolism. RESULTS: After 19.6 +/- 8.9 months (range 0 to 36 months) there was no difference in the primary end point between rhythm-control (9/100; 5.54%/year) and rate-control (10/100; 6.09%/year; p = 0.99). The percentage of patients in sinus rhythm in the rhythm-control group after up to four cardioversions during the follow-up period (rate-control group) was 23% (0%) at 36 months. Eighteen primary end points occurred in atrial fibrillation; only one occurred in sinus rhythm (p = 0.049). CONCLUSIONS: The STAF pilot study showed no differences between the two treatment strategies in all end points except hospitalizations. These data suggest that there was no benefit in attempting rhythm-control in these patients with a high risk of arrhythmia recurrence. It remains unclear whether the results in the rhythm-control group would have been better if sinus rhythm had been maintained in a higher proportion of patients, as all but one end point occurred during AF.

Adult↗
PubMed2005

Gender-related differences in rhythm control treatment in persistent atrial fibrillation: data of the Rate Control Versus Electrical Cardioversion (RACE) study.

OBJECTIVES: This study sought to compare whether gender affects the outcome of rate versus rhythm control treatment in patients with persistent atrial fibrillation (AF). BACKGROUND: Large trials have shown that rate control is an acceptable alternative to rhythm control. However, the effects of treatment may differ between male and female patients. METHODS: In the Rate Control versus Electrical Cardioversion (RACE) study, 522 patients (192 female) were included and randomized to rate or rhythm control. The occurrence of cardiovascular end points and quality of life (QoL) were compared between female and male patients. RESULTS: At baseline, female patients differed from male patients with regard to age, underlying heart disease, diabetes mellitus, and left ventricular function. Female patients had more AF-related complaints, and QoL was significantly lower. After a mean follow-up of 2.3 +/- 0.6 years, cardiovascular morbidity and mortality was equally distributed between female (21%) and male patients (19%). However, in contrast to male patients, female patients randomized to rhythm control developed more end points (adjusted hazard ratio was 3.1 [95% confidence interval 1.5 to 6.3], p = 0.002), mainly heart failure, thromboembolic complications, and adverse effects of antiarrhythmic drugs, compared with rate control randomized female patients. During follow-up, QoL in female patients remained worse compared with that for male patients. Randomized strategy did not influence QoL in female patients. CONCLUSIONS: In female patients with persistent AF, a rhythm control approach leads to more cardiovascular morbidity and mortality. Because treatment strategy did not influence QoL in female patients, a rate control approach may be considered in these patients.

Aged↗
PubMed1979

The effect of side chain structure of ester substrates in determining the rate-controlling step in alpha-chymotrypsin-catalyzed hydrolysis.

Presteady state and steady state analyses of the alpha-chymotrypsin [EC 3.4.21.1]-catalyzed hydrolysis of three specific ester substrates and three ring-substituted derivatives were carried out to elucidate the effect of hydrophobic interactions due to the different side chains of the substrates on the individual steps of the reaction. Hydrolysis of all the substrates except for N alpha-acetyl-Nin-formyltryptophan methyl ester (Ac-Trp(CHO)-OMe) was controlled by the deacylation rate. In spite of their comparable Ks values, the substrates with small kcat, such as N alpha-acetyltryptophan methyl ester and N alpha-acetyl-2-(2-nitro-4-carboxyphenylsufenyl)-tryptophan methyl ester, characteristically gave Km values one order of magnitude smaller than the others. For the reaction of Ac-Trp(CHO)-OMe, it was ascertained that the deacylation step was not rate-controlling. It is suggested that the acylation step controls the rate in this case.

Animals↗
PubMed2005

Clinical factors associated with abandonment of a rate-control or a rhythm-control strategy for the management of atrial fibrillation in the AFFIRM study.

OBJECTIVE: The objective of the current study was to determine the clinical factors that were associated with abandonment of a rate-control or a rhythm-control strategy in patients with atrial fibrillation (AF). BACKGROUND: Although the AFFIRM Study demonstrated that outcomes are similar with a primary strategy of rate-control or rhythm-control for AF, there may be clinical or demographic factors associated with abandonment of the initial treatment strategy. Knowledge of these risk factors would be useful so that patients may be given appropriate initial therapy and, as appropriate, switched to alternative treatments earlier. METHODS: Patients in the AFFIRM Study were subdivided into those who were maintained on their initial treatment strategy versus those who abandoned initial treatment strategy for alternative therapies. We determined the clinical and demographic factors associated with change in initial treatment strategy. RESULTS: At 5 years the original treatment strategy was maintained in 85% of the patients in the rate-control arm versus 62% of those in the rhythm-control arm (P <.0001). Length of the qualifying episode of AF was associated with abandonment of both rhythm-control and rate-control strategies. Antiarrhythmic drug failure before randomization and a history of thyroid disease also were associated with abandonment of rhythm-control. Patients were more likely to maintain rate-control if they already had an implanted pacemaker or if they were older than 75 years, while an ejection fraction <30% was associated with abandonment of the rate-control strategy. CONCLUSIONS: In patients with AF, rhythm-control strategies are abandoned significantly more often than rate-control strategies. Patients with long durations of AF on presentation or previous antiarrhythmic drug failure might be considered for rate-control as initial treatment.

Age Factors↗
PubMed2001

Acute ventricular rate control in atrial fibrillation: IV combination of diltiazem and digoxin vs. IV diltiazem alone.

OBJECTIVE: To analyze the efficacy of an IV combination of diltiazem and digoxin vs IV diltiazem alone for acute ventricular rate control in patients with atrial fibrillation. DESIGN: Prospective, randomized, open-label study. PATIENTS AND METHODS: Fifty-two patients with atrial fibrillation and uncontrolled ventricular rates were randomized to receive either an IV combination of diltiazem and digoxin or IV diltiazem alone and were observed for 12 h. The successful rate control was defined as a ventricular rate < 100 beats per minute (bpm) persisting for 1 h or conversion to sinus rhythm. The loss of rate control was defined as an increase in the ventricular rate to > 100 bpm persistently for > 30 min or rebound to atrial fibrillation. RESULTS: In both treatment arms (n = 26 each), all patients achieved successful and comparable ventricular rate control at 12 h. The mean (+/- SD) time taken to achieve successful rate control was shorter in the combination arm (15 +/- 16 vs. 22 +/- 22 min). Six patients in the combination arm and 11 in the diltiazem-alone arm experienced episodes of loss of rate control. This loss in the combination arm was less than that in the diltiazem-alone arm (14 vs 39 episodes; p = 0.05). The loss of rate control per patient in the combination arm was also less than that in the diltiazem-alone arm (2.0 +/- 1.0 vs. 3.5 +/- 1.9 episodes per patient; p = 0.04). CONCLUSIONS: This study demonstrates that in patients with atrial fibrillation who have a rapid ventricular response, the IV combination of diltiazem and digoxin results in a more efficacious ventricular rate control with fewer fluctuations than that achieved by therapy with IV diltiazem alone.

Adolescent↗
PubMed2006

Does intensity of rate-control influence outcome in atrial fibrillation? An analysis of pooled data from the RACE and AFFIRM studies.

AIMS: The AFFIRM and RACE studies showed that rate control is an acceptable treatment strategy for atrial fibrillation (AF). We examined whether strict rate control offers benefit over more lenient rate control. METHODS AND RESULTS: We compared the outcome of patients enrolled in the rate-control arms of AFFIRM and RACE, using data from patients who met a composite of overlapping inclusion and exclusion criteria. We evaluated 1091 patients, 874 from AFFIRM and 217 from RACE. In AFFIRM, the rate-control strategy aimed for a resting heart rate < or =80 bpm and heart rate during daily activity of < or =110 bpm. In RACE, a more lenient approach was taken: resting heart rate <100 bpm. Primary endpoint was a composite of mortality, cardiovascular hospitalization, and myocardial infarction. Mean heart rate across all follow-up visits for patients in AF was lower in AFFIRM (76.1 vs. 83.4 bpm). Event-free survival for the occurrence of the primary endpoint did not differ (64% in AFFIRM vs. 66% in RACE). Patients with mean heart rates during AF within the AFFIRM (< or =80) or RACE (<100) criteria had a better outcome than patients with heart rates > or =100 (hazard ratios 0.69 and 0.58, respectively, for < or =80 and <100 compared with > or =100 bpm). CONCLUSION: Stringency of the approach to rate control, based on the comparison of the AFFIRM and RACE studies, was not associated with an important difference in clinical events.

Aged↗
PubMed2003

Rhythm versus rate control trials in atrial fibrillation.

The recent completion of five trials comparing the strategy of rhythm control versus the strategy of rate control in the management of recurrent atrial fibrillation has advanced considerably our understanding of the treatment of this common clinical problem. The background to this research question is outlined, followed by an overview of the five trials and their results. Data on important clinical events from four of the trials are pooled and presented. The aggregate results of the trials do not demonstrate any clear advantage of the rhythm control approach. The findings elevate rate control to the position of an acceptable primary therapy in the types of patients studied and underline the concept that the primary goal of antiarrhythmic therapy for atrial fibrillation at this time is control of symptoms. Under these circumstances, a "safety first" approach is prudent and monitoring for adverse drug effects is mandatory. The results underscore the importance of continuous anticoagulation in patients with stroke risk factors. Finally, the results from these trials help to set the agenda for future research on rhythm management in atrial fibrillation.

Aged↗
PubMed1998

Controlled-rate versus uncontrolled-rate cryopreservation of peripheral blood progenitor cells: a prospective multicenter study. Group for Cryobiology and Biology of Bone Marrow Transplantation (CBTMO), Spain.

BACKGROUND AND OBJECTIVE: Cryopreservation of hemopoietic progenitors for transplantation has been traditionally performed by the use of a controlled-rate freezer. Several groups have reported successful cryopreservation of progenitor cells at -80 degrees C without a controlled-rate freezer. In an attempt to elucidate whether both methods are equally efficient, we compared controlled-rate versus uncontrolled cryopreservation of peripheral blood progenitor cells (PBPC) in a prospective, multicenter study. DESIGN AND METHODS: Apheresis products from patients undergoing PBPC mobilization were split into two aliquots, and cryopreserved simultaneously by both methods, in autologous plasma plus 10% dimethylsulfoxide. Controlled-rate samples were placed into a programmable freezer with a cooling rate of 1-2 degrees C/min. Uncontrolled-rate samples were directly introduced into a -80 degrees C mechanical freezer. After thawing, cell counts, assays for viability, clonogenic cultures and CD34+ cell enumeration were performed. RESULTS: A total of 105 cases were included. No significant differences were found in viability (mean 88.8 +/- 13% in the controlled-rate group vs. 89.7 +/- 12% in the uncontrolled-rate group), nucleated cell loss (23.5 +/- 23% vs. 23 +/- 22%), mononuclear cell loss (19 +/- 23% vs. 19.1 +/- 22%), and loss of CD34+ cells (34.3 +/- 33% vs. 28.6 +/- 34%). On the other hand, recovery of granulomonocytic colony-forming units (CFU-GM), was significantly better with the controlled-rate technique, than with the non-controlled-rate method (104.3 +/- 95 vs. 86.5 +/- 80, respectively; p = 0.048). INTERPRETATION AND CONCLUSIONS: Our results indicate that both techniques are suitable for cryopreservation of PBPC, although a better recovery of committed progenitors is achieved by the controlled-rate method. Therefore, the use of controlled-rate freezer should probably be recommended.

Blood Preservation↗
PubMed1999

A comparison of esmolol & diltiazem for heart rate control during coronary revascularisation on beating heart.

This prospective study was done to compare the control of heart rate and haemodynamics during coronary artery revascularisation without cardiopulmonary bypass using either esmolol or diltiazem. Sixty adult patients with one or two vessel coronary artery disease, were randomly divided into 2 equal groups. Group A received a 500 micrograms/kg loading dose of esmolol followed by a 100 micrograms/kg/h infusion, for control of heart rate during surgical anastomosis of the coronary vessel. While Group B received 0.15 mg/kg diltiazem as a loading dose followed by a 5 mg/h infusion for heart rate control, during the anastomosis. It was seen that heart rate control was better in Group A, 51.4 (+/- 1.3) beats/min, than in Group B, 69.6 (+/- 3.9) beats/min but the decrease in heart rate was significant in both the groups at peak effect compared to respective predrug values. Group A patients had unchanged systemic resistance and pulmonary artery wedge pressure but mean pulmonary artery pressure and pulmonary vascular resistance were significantly raised. Group B patients had decreased systemic resistance, mean pulmonary artery pressure and pulmonary artery wedge pressure, and reduced right ventricular stroke work index. We concluded that although esmolol provided dramatically slower heart rates, during surgery, the resulting elevations in mean pulmonary artery pressure and pulmonary vascular resistance would require caution if used in patients with underlying right ventricular dysfunction from ischaemia or infarction. Diltiazem by virtue of its effects on systemic vascular resistance, cardiac output, and lowering of mean arterial pressure may be a better choice in hypertensive patients.

Adrenergic beta-Antagonists↗
PubMed2005

Pharmacological and nonpharmacological methods for rate control.

In many patients with atrial fibrillation, the most appropriate strategy is 'rate control', designed to slow down the rapid ventricular rates often seen with atrial fibrillation. Based on the hypothesis that symptoms, especially palpitations and exercise intolerance, are due to rapid ventricular rates with activity, optimum rate control usually requires reducing ventricular rates at rest and during activity. Beta-blockers and nondihydropyridine calcium channel blockers are likely more effective than digoxin alone, and the adequacy of rate control is best assessed with heart rate measurement during activity or with ambulatory electrocardiographic monitoring. Taking a patient's symptoms into account, reasonable target ventricular rates are less than 80 beats/min at rest and less than 100 beats/min, on average, over 24 h.

Atrial Fibrillation↗