The effect of moxifloxacin on QTc and implications for the design of thorough QT studies.

A number of issues have remained unanswered in the design of "thorough QT"(TQT) studies. In this randomized, placebo-controlled, two-period crossover study in 20 healthy subjects, replicate electrocardiograms (ECGs) were recorded on a digital 12-lead Holter recorder, extracted in a core ECG laboratory, and interpreted manually by a cardiologist. The observed within-subject variability was slightly greater when time-matched baselines were employed than when predose baselines were employed, whereas the magnitude of the increase in QTc was similar for both. Moxifloxacin 400 mg was associated with an observed 7.5-12.5 ms increase in the mean placebo- and baseline-corrected QTc interval. A PK-QTc model estimated a 3.9 ms increase in the QTc interval for every 1,000 ng/ml increase in moxifloxacin concentration. The QTc increases associated with moxifloxacin support the appropriateness of its use as a positive control in TQT studies. This crossover study failed to justify the use of time-matched baselines rather than the less resource-intensive predose definition of baseline.

Raltegravir thorough QT/QTc study: a single supratherapeutic dose of raltegravir does not prolong the QTcF interval.

Raltegravir is a novel HIV-1 integrase inhibitor with potent in vitro activity (IC(95) = 31 nM in 50% human serum). A double-blind, randomized, placebo-controlled, double-dummy, 3-period, single-dose crossover study was conducted; subjects received single oral doses of 1600 mg raltegravir, 400 mg moxifloxacin, and placebo. The upper limit of the 2-sided 90% confidence interval for the QTcF interval placebo-adjusted mean change from baseline of raltegravir was less than 10 ms at every time point. For the raltegravir and placebo groups, there were no QTcF values >450 ms or change from baseline values >30 ms. A mean C(max) of approximately 20 muM raltegravir was attained, approximately 4-fold higher than the C(max) at the clinical dose. Moxifloxacin demonstrated an increase in QTcF at the 2-, 3-, and 4-hour time points. Administration of a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. A single supratherapeutic dose design may be appropriate for crossover thorough QTc studies.

T-wave alternans negative coronary patients with low ejection and benefit from defibrillator implantation.

In a trial of prophylactic implantation of a defibrillator, a mortality benefit was seen among patients with previous myocardial infarction and a left-ventricular ejection fraction of 0.30 or less. We identified 129 similar patients from two previously published clinical trials in which microvolt T-wave alternans testing was prospectively assessed. At 24 months of follow-up, no sudden cardiac death or cardiac arrest was seen among patients who tested T-wave alternans negative, compared with an event rate of 15.6% among the remaining patients. Testing of T-wave alternans seems to identify patients who are at low risk of ventricular tachyarrhythmic event and who may not benefit from defibrillator therapy.

A comparison of T-wave alternans, signal averaged electrocardiography and programmed ventricular stimulation for arrhythmia risk stratification.

OBJECTIVES: The goal of this study was to compare T-wave alternans (TWA), signal-averaged electrocardiography (SAECG) and programmed ventricular stimulation (EPS) for arrhythmia risk stratification in patients undergoing electrophysiology study. BACKGROUND: Accurate identification of patients at increased risk for sustained ventricular arrhythmias is critical to prevent sudden cardiac death. T-wave alternans is a heart rate dependent measure of repolarization that correlates with arrhythmia vulnerability in animal and human studies. Signal-averaged electrocardiography and EPS are more established tests used for risk stratification. METHODS: This was a prospective, multicenter trial of 313 patients in sinus rhythm who were undergoing electrophysiologic study. T-wave alternans, assessed with bicycle ergometry, and SAECG were measured before EPS. The primary end point was sudden cardiac death, sustained ventricular tachycardia, ventricular fibrillation or appropriate implantable defibrillator (ICD) therapy, and the secondary end point was any of these arrhythmias or all-cause mortality. RESULTS: Kaplan-Meier survival analysis of the primary end point showed that TWA predicted events with a relative risk of 10.9, EPS had a relative risk of 7.1 and SAECG had a relative risk of 4.5. The relative risks for the secondary end point were 13.9, 4.7 and 3.3, respectively (p < 0.05). Multivariate analysis of 11 clinical parameters identified only TWA and EPS as independent predictors of events. In the prespecified subgroup with known or suspected ventricular arrhythmias, TWA predicted primary end points with a relative risk of 6.1 and secondary end points with a relative risk of 8.0. CONCLUSIONS: T-wave alternans is a strong independent predictor of spontaneous ventricular arrhythmias or death. It performed as well as programmed stimulation and better than SAECG in risk stratifying patients for life-threatening arrhythmias.

Incorporating exposure-response modeling into the assessment of QTc interval: A potential alternative to the thorough QT study.

ICH E14 mandates that a thorough QTc study (TQT) is conducted as part of the clinical drug development program to provide an accurate and precise estimate of a drug's effect on the QTc. In the April issue of CPT, Darpo et al. report the results of a study which validated an alternative approach to evaluating the effect of a drug on QTc using exposure-response modeling in phase I which has the potential to make the TQT study obsolete.

Indications, methodology, and classification of results of tilt-table testing.

Tilt-table testing has become an important part of the evaluation of patients with unexplained syncope, although not every patient with vasovagal syncope requires it. Studies have attested to the effectiveness of the technique for providing direct diagnostic evidence of a patient's susceptibility to vasovagal syncope. This article reviews the need for tilt-table testing and the recommended methods for performing a test. In addition, a detailed classification of the hemodynamic patterns of collapse displayed over the course of a tilt-table study is provided. These distinctive collapse patterns document the evolution of a syncopal event and are particularly important to identify because they can influence the selection of therapy.

Putting it together: a new treatment algorithm for vasovagal syncope and related disorders.

The consensus process that culminated in this symposium established an algorithm to guide the diagnosis and treatment of patients with vasovagal syncope and related disorders. In some patients, the hemodynamic response to standing may identify an abnormality-postural orthostatic tachycardia syndrome or orthostatic hypotension-that can often be treated without further testing. When the response to standing is normal, tilt-table testing may be useful in making the diagnosis of vasovagal syncope and guiding treatment. In some patients, however, the diagnosis is clear from the history, and tilt-table testing may not be necessary. Not all patients with vasovagal syncope need to be treated, and many can be treated effectively with education, reassurance, and a simple increase in dietary salt. In evaluating the results of tilt-table testing, an important consideration is the distinction between vasovagal syncope and the dysautonomic response to tilt characterized by a gradual and progressive decrease in blood pressure that leads to syncope. Current practice patterns suggest that beta blockers, fludrocortisone, and midodrine, are commonly used to treat patients with vasovagal syncope, and patients with the dysautonomic response are generally treated with fludrocortisone and midodrine. Permanent pacing with specialized pacing algorithms should be considered for patients with frequent vasovagal syncope that is refractory to medical therapy. The guidelines proposed here are an amalgam of clinical experience, expert opinion, and research evidence; however, they do not suggest a standard of care for all patients.

Long-term carvedilol therapy increases parasympathetic nervous system activity in chronic congestive heart failure.

To determine the effect of beta blockade on parasympathetic nervous system activity, we assessed RR variability during 24-hour Holter monitoring in 10 patients with congestive heart failure before and after 3 to 4 months of treatment with the beta blocker carvedilol. High-frequency power increased from 26 to 64 ms2, root-mean-square of successive differences in RR interval increased from 14.3 to 23.7 ms2, and percentage of absolute differences >50 ms between successive normal RR intervals increased from 0.8% to 4.7%, all p <0.01, indicating a substantial increase in parasympathetic modulation of RR intervals.

Vagal modulation of RR intervals during head-up tilt and the infusion of isoproterenol.

The objective of this study was to characterize the autonomic effects of 2 interventions, head-up tilt and isoproterenol infusion, which alter autonomic balance by different mechanisms but produce the same RR intervals. We compared the effect of head-up tilt with the effect of isoproterenol on autonomic balance as measured by power spectral analysis of RR variability. Fifteen normal subjects had baseline measurements and then underwent head-up tilt. After return to baseline supine values, isoproterenol was infused at a rate of 1 microgram/min (low-dose isoproterenol), which was then increased to 2.1 +/- 0.5 microgram/min (high-dose isoproterenol). All subjects underwent a second tilt during high-dose isoproterenol, and 9 subjects completed this second tilt study. During the experiment, normal RR intervals were recorded and 5-minute segments were used to calculate power spectra. High-frequency (HF) power (0.15 to 0.40 Hz) was used as a measure of vagal activity. The effects of head-up tilt were compared with the effects of low-dose isoproterenol. Despite nearly identical mean RR intervals (784 ms with tilt vs 792 ms with low-dose isoproterenol, p = NS), there was significantly (p < 0.05) less HF power during head-up tilt in the drug-free state (172 ms2) than during low-dose isoproterenol in the supine position (307 ms2). A second head-up tilt was performed during the infusion of high-dose isoproterenol. During high-dose isoproterenol, tilt caused a decrease in RR intervals (from 573 to 491 ms; p < 0.01) and a decrease in HF power (from 68 to 28 ms2; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise and autonomic function.

The complex interplay between the dichotomous subdivisions of the autonomic nervous system establishes and maintains a delicately tuned homeostasis in spite of an ever-changing environment. Aerobic exercise training can increase activity of the parasympathetic nervous system and decrease sympathetic activity. Conversely, it is well-documented that cardiac disease is often characterized by attenuated parasympathetic activity and heightened sympathetic tone. A correlation between autonomic disequilibrium and disease has led to the hypothesis that exercise training, as a therapy that restores the autonomic nervous system towards normal function, may be associated with, and possibly responsible for, outcome improvements in various populations. This is merely one of the many benefits that is conferred by chronic exercise training and reviewed in this issue.

Exercise and autonomic function in health and cardiovascular disease.

Autonomic nervous system activity contributes to the regulation of cardiac output during rest, exercise, and cardiovascular disease. Measurement of HRV has been particularly useful in assessing parasympathetic activity, while its utility for assessing sympathetic function and overall sympathovagal balance remains controversial. Studies have revealed that parasympathetic tone dominates the resting state, while exercise is associated with prompt withdrawal of vagal tone and subsequent sympathetic activation. Conversely, recovery is characterized by parasympathetic activation followed by sympathetic withdrawal, although clarification of the normal trajectory and autonomic basis of heart rate decay following exercise is needed. Abnormalities in autonomic physiology--especially increased sympathetic activity, attenuated vagal tone, and delayed heart rate recovery--have been associated with increased mortality. Exercise training is associated with a relative enhancement of vagal tone, improved heart rate recovery after exercise, and reduced morbidity in patients with cardiovascular disease. However, whether exercise training leads to reduced mortality in this population because of its ability to specifically modulate autonomic function is unknown at the present time. Although the results of a recent randomized study in patients with CHF and a meta-analysis in the setting of a recent myocardial infarction determined that exercise training leads to improved outcomes in these populations, neither study measured autonomic function. Improved autonomic function due to exercise training is a promising rationale for explaining improvements in outcome, although more research is needed to confirm this hypothesis.

Physical fitness as a determinant of vagal modulation.

The association between increasing age and decreasing vagal modulation is well known. However, the importance of fitness as a determinant of the decline in vagal modulation with age is not established. To test the hypothesis that decreasing vagal modulation is largely a function of declining fitness rather than increasing age, we studied a sample of healthy volunteers with a wide range of fitness levels, but a narrow age range. We assessed fitness by measuring the maximal oxygen uptake (VO2max) achieved during incremental bicycle exercise. Vagal modulation was assessed by calculating high frequency power (0.15-0.40 Hz) of the RR variability power spectrum from 24-h ECG recordings. We studied 37 healthy volunteers who were 22-44 yr old. In our sample, VO2max ranged from 25 to 70 mL.min-1.kg-1 (mean of 45 +/- 13). Age was not significantly related to high frequency power, but VO2max was highly correlated with high frequency power (r = 0.74, P = 0.0001), indicating that physical fitness is strongly associated with vagal modulation. Thus, the decline in vagal modulation often attributed to increasing age may, instead, be the result of a decline in fitness.

Evaluating QTc in patients with advanced Parkinson's disease: overcoming artifact.

Electrocardiograms (ECGs) in patients with Parkinson's disease are affected by artifacts related to muscle tremor. Malik et al. report methods used in QTc study in patients with Parkinson's disease that markedly reduce the noise and variance of QTc in a sample of ECGs that are undeniably difficult to interpret. This study adds significant experience and novel methods that have the potential to further enhance the evaluation of the effect of a drug on QTc.

A critical appraisal of quantitative spectro-temporal analysis of the signal-averaged ECG: predicting arrhythmic events after myocardial infarction.

The objective of this study was to determine if spectro-temporal analysis of the signal-averaged ECG (SAECG) predicts spontaneous sustained ventricular tachyarrhythmias and sudden death in patients prospectively followed after myocardial infarction (MI). A SAECG was recorded in 177 patients 9 +/- 5 days after MI. Spectro-temporal analysis of the SAECG involved incrementing a Hanning window every 3 ms beginning 20 mg before the end of the QRS complex and extending into the ST segment. Quantitative analysis was performed using a cross-correlation function to create a normality factor. A normality factor < 0.3 was deemed abnormal. The SAECG was abnormal in 41% of patients using time-domain analysis and 44% of patients using spectro-temporal analysis. There was no correlation between an abnormal SAECG in the time domain and the frequency domain. Patients with inferior wall MI were more likely to have an abnormal spectro-temporal map (odds ratio 2.26, P < 0.05). Time-domain analysis of the SAECG (relative risk (RR) 2.6) was a statistically significant univariate predictor of arrhythmic events. Spectro-temporal analysis of the SAECG was only weakly (RR 1.8) and not significantly (P = 0.15) associated with the spontaneous occurrence of these arrhythmias. When both time-domain analysis and spectro-temporal analysis of the SAECG were abnormal, the relative risk for an arrhythmic event was increased by 3.3-fold. Quantitative spectro-temporal analysis of high frequency signals within the SAECG cannot by itself predict the occurrence of spontaneous ventricular arrhythmias in patients after MI.

Upright posture and postprandial hypotension in elderly persons.

BACKGROUND: Syncope and falls are common in elderly persons and often result from the interaction of multiple clinical abnormalities. Both orthostatic hypotension and postprandial hypotension increase in prevalence with age. OBJECTIVE: To determine whether meal ingestion enhances orthostatic hypotension in elderly persons. DESIGN: Controlled paired comparison. SETTING: Clinical research center. PATIENTS: 50 functionally independent elderly persons recruited from local senior centers (n = 47) and from patients hospitalized with an unexplained fall or syncope (n = 3) (mean age, 78 years [range, 61 to 96 years]). Twenty-five participants (50%) were taking antihypertensive medication. MEASUREMENTS: Sequential head-up tilt-table testing at 60 degrees was performed before and 30 minutes after ingestion of a standardized warm liquid meal that was high in carbohydrates. Heart rate and blood pressure were continuously monitored. RESULTS: Meal ingestion (P < 0.01) and time spent upright (P < 0.001) were significantly associated with systolic blood pressure, but no significant interaction was found between meal ingestion and time spent upright (P > 0.2). These findings suggest that the association between meal ingestion and head-up tilt-table testing were additive and not synergistic. However, the proportion of participants with symptomatic hypotension increased during head-up tilt-table testing after meal ingestion (12% during preprandial testing and 22% during postprandial testing). Symptomatic hypotension tended to occur more often and sooner after meal ingestion than before meal ingestion (P = 0.03). CONCLUSIONS: Meal ingestion and head-up tilt-table testing are associated with increasing occurrences of symptomatic hypotension. After meal ingestion and head-up tilt-table testing, 22% of functionally independent elderly persons had symptomatic hypotension.

R-R variability detects increases in vagal modulation with phenylephrine infusion.

High-frequency power, measured from power spectral analysis of R-R variability, reflects vagal modulation of the sinus node. Unexpectedly, a recent study reported a decrease in high-frequency power during the infusion of phenylephrine despite a prolongation of R-R intervals, indicating an increase in vagal activity. To better define the limitations of high-frequency power to quantify vagal modulation, we measured high-frequency power during the infusion of phenylephrine (0.4, 0.8, and 1.2 micrograms.kg-1.min-1) into 10 normal subjects. We found increasing doses of phenylephrine produced progressive increases in systolic blood pressure from 118 +/- 4 to 129 +/- 5 mmHg (P < 0.005), R-R intervals from 881 +/- 44 to 1,274 +/- 69 ms (P < 0.0001), and the logarithm of high-frequency power from 5.83 +/- 0.22 to 7.73 +/- 0.24 ln(ms2) (P < 0.0001). The conclusion was high-frequency power increases with increasing doses of phenylephrine. These data strongly support the ability of high-frequency power to detect an increase in vagal modulation during baroreceptor activation from an increase in systolic blood pressure with the infusion of phenylephrine.

Comparison of spontaneous vs. metronome-guided breathing on assessment of vagal modulation using RR variability.

R-R interval variability (RR variability) is increasingly being used as an index of autonomic activity. High-frequency (HF) power reflects vagal modulation of the sinus node. Since vagal modulation occurs at the respiratory frequency, some investigators have suggested that HF power cannot be interpreted unless the breathing rate is controlled. We hypothesized that HF power during spontaneous breathing would not differ significantly from HF power during metronome-guided breathing. We measured HF power during spontaneous breathing in 20 healthy subjects and 19 patients with heart disease. Each subject's spontaneous breathing rate was determined, and the calculation of HF power was repeated with a metronome set to his or her average spontaneous breathing rate. There was no significant difference between the logarithm of HF power measured during spontaneous and metronome-guided breathing [4.88 +/- 0.29 vs. 5.29 +/- 0.30 ln(ms(2)), P = 0.32] in the group as a whole and when patients and healthy subjects were examined separately. We did observe a small (9.9%) decrease in HF power with increasing metronome-guided breathing rates (from 9 to 20 breaths/min). These data indicate that HF power during spontaneous and metronome-guided breathing differs at most by very small amounts. This variability is several logarithmic units less than the wide discrepancies observed between healthy subjects and cardiac patients with a heterogeneous group of cardiovascular disorders. In addition, HF power is relatively constant across the range of typical breathing rates. These data indicate that there is no need to control breathing rate to interpret HF power when RR variability (and specifically HF power) is used to identify high-risk cardiac patients.

Passive head-up tilt and actively standing up produce similar overall changes in autonomic balance.

The primary objective of this study was to compare, in normal subjects, the average change in autonomic balance during a 5-minute period by using two methods of changing posture: actively standing up and passive head-up tilt. We hypothesized that the average effect of these two methods of changing posture on autonomic balance would not significantly differ. After collecting supine baseline measurements, subjects were first tilted head up to 60 degrees for 15 minutes, then returned to the supine position for 5 minutes, before they stood up for 5 minutes. Comparing the average (over a 5-minute period) autonomic response to head-up tilt with that of standing, there were no significant differences in the decrease in average R-R intervals (-18% vs -18%, p = not significant), the drop in high-frequency power (-73% vs -69%, p = not significant), or the increase in the low-frequency/high-frequency ratio (+252% vs +298%, p = not significant). The changes in autonomic balance that occur during the first 5 minutes of passive 60-degree head-up tilt are nearly identical to the change in autonomic balance that occurs during the first 5 minutes of quiet standing.