Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial.

BACKGROUND: Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings. METHODS: endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations. DISCUSSION: The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.

QTc prolongation and treatment of multidrug-resistant tuberculosis.

Electrocardiographic (ECG) monitoring is recommended for some of the new and re-purposed drugs used in the treatment of multidrug-resistant tuberculosis (MDR-TB), as these drugs have been shown to prolong the QTc interval. ECG monitoring is relatively new in the management of TB patients, and has several implications for programs and providers. This review discusses what is known about QTc prolongation and the medications currently being studied or used to treat MDR-TB, and discusses strategies for managing QTc prolongation in the context of treating such a serious infectious disease. It also reviews some major implications of ECG monitoring in the field, including interpretation of ECGs and QTc intervals, management of patients with prolonged QTc intervals, and contextualizing the risk of QTc prolongation for patients being treated for MDR-TB.

The association of lactate and vasopressor need for mortality prediction in survivors of cardiac arrest.

BACKGROUND: Currently there are few tools available for clinicians to predict outcomes in cardiac arrest survivors. Our objective was to determine if the combination of simple clinical parameters (initial blood lactate and vasopressor use) can predict outcome in post-cardiac arrest patients. METHODS: The design was a retrospective medical record review. The study was carried on in two urban, tertiary-care, university teaching hospitals. As for patients, inclusion criteria were: 1) age ≥18 years; 2) non-traumatic out-of-hospital cardiac arrest with return of spontaneous circulation; 3) lactic acid measured within one hour of return of circulation. No interventions was performed. RESULTS: Patients were divided into groups based on two variables: 1) vasopressor status (receipt of vasopressors vs. no vasopressors); and 2) initial blood lactate (categories defined as lactate <5 mmol/L, lactate 5 to 10 mmol/L, lactate ≥10 mmol/L); 128 out-of-hospital cardiac arrest patients met study inclusion criteria. Overall mortality was 71% (95%CI 63-79%). Patients who received vasopressors had significantly higher mortality rates compared to patients who did not receive vasopressors (80% vs. 52%; P=0.002). A stepwise increase in mortality is associated with increasing lactate levels (39% lactate <5 mmol/L, 67% lactate 5 mmol/L to10 mmol/L, and 92% lactate ≥10 mmol/L; P<0.001). The AUC for our model was 0.82. CONCLUSION: The combination of two clinical parameters, vasopressor need and lactic acid levels, is an accurate severity of illness classification system and can predict mortality in patients following out-of-hospital cardiac arrest. Prospective validation of these variables in post-cardiac arrest is needed.

The yield of head CT in syncope: a pilot study.

UNLABELLED: Although head CT is often routinely performed in emergency department (ED) patients with syncope, few studies have assessed its value. OBJECTIVES: To determine the yield of routine head CT in ED patients with syncope and analyse the factors associated with a positive CT. METHODS: Prospective, observational, cohort study of consecutive patients presenting with syncope to an urban tertiary-care ED (48,000 annual visits). INCLUSION CRITERIA: age >or=18 and loss of consciousness (LOC). Exclusion criteria included persistent altered mental status, drug-related or post-trauma LOC, seizure or hypoglycaemia. Primary outcome was abnormal head CT including subarachnoid, subdural or parenchymal haemorrhage, infarction, signs of acute stroke and newly diagnosed brain mass. RESULTS: Of 293 eligible patients, 113 (39%) underwent head CT and comprise the study cohort. Ninety-five patients (84%) were admitted to the hospital. Five patients, 5% (95% CI=0.8%-8%), had an abnormal head CT: 2 subarachnoid haemorrhage, 2 cerebral haemorrhage and 1 stroke. Post hoc examination of patients with an abnormal head CT revealed focal neurologic findings in 2 and a new headache in 1. The remaining 2 patients had no new neurologic findings but physical findings of trauma (head lacerations with periorbital ecchymoses suggestive of orbital fractures). All patients with positive findings on CT were >65 years of age. Of the 108 remaining patients who had head CT, 45 (32%-51%) had signs or symptoms of neurologic disease including headache, trauma above the clavicles or took coumadin. Limiting head CT to this population would potentially reduce scans by 56% (47%-65%). If age >60 were an additional criteria, scans would be reduced by 24% (16%-32%). Of the patients who did not have head CT, none were found to have new neurologic disease during hospitalisation or 30-day follow-up. CONCLUSIONS: Our data suggest that the derivation of a prospectively derived decision rule has the potential to decrease the routine use of head CT in patients presenting to the ED with syncope.

Different patterns of interatrial conduction in clockwise and counterclockwise atrial flutter.

BACKGROUND: The terms counterclockwise (CC) and clockwise (C) atrial flutter (Afl) are used to describe right atrial activation around the tricuspid valve in the left anterior oblique view. The manner in which the left atrium is activated, as reflected by coronary sinus (CS) recordings, has not been systematically evaluated. METHODS AND RESULTS: Nine patients with both CC and C Afl underwent electrophysiological study with CS recordings during both rhythms with the use of a decapolar catheter with the tip placed in the distal CS. Patterns of CS activation during each type of Afl as well as during during sinus rhythm were categorized into 1 of 3 patterns: sequential proximal-to-distal, sequential distal-to-proximal, and fused, indicating activation from different directions. In 7 of 9 patients, the pattern of CS activation in CC Afl and C Afl differed, with a proximal-to-distal pattern in CC Afl and a fused pattern in C Afl. In 2 patients, pacing the high right atrial septum near the presumed site of Bachmann's bundle in sinus rhythm showed a similar fused pattern of CS activation. CONCLUSIONS: These results demonstrate different patterns of CS activation in CC Afl and C Afl in the majority of patients and are consistent with a model in which the left atrium is activated predominantly over Bachmann's bundle during C Afl and over the CS os in CC Afl. These findings may have implications for maintenance of Afl, interpretation of flutter wave morphology on surface ECG, and left atrial mechanical function in Afl.

Inpatient or outpatient initiation of antiarrhythmic medications: why the controversy?

The decision of whether to initiate antiarrhythmic medications in or out of the hospital for patients with atrial fibrillation remains an issue of significant controversy. The current review analyzes the available data pertaining to the safety of antiarrhythmic agent initiation in patients with atrial fibrillation and provides a practice guideline.

Incidence and predictors of myocardial infarction among patients with atrial fibrillation.

OBJECTIVES: We sought to evaluate the utility of excluding myocardial infarction (MI) in patients presenting to the emergency department (ED) with atrial fibrillation (AF) and to identify predictors of MI in this group. BACKGROUND: Patients with AF are frequently admitted to the hospital, in part, to exclude an associated MI. There are no prospective data on unselected patients to support this common practice. METHODS: We conducted a prospective cohort study of all patients who presented to a single-center ED with the primary diagnosis of AF. RESULTS: Of a total of 255 patients, 190 (75%) were admitted to the hospital, and 109 of them underwent a standard "rule-out MI" protocol. Of these 109 patients, six (5.5%) were identified as having an acute MI at the time of admission. Chest pain was present in 39% of patients, with a sensitivity and specificity for the occurrence of MI of 100% and 65%, respectively. ST segment elevation or depression was present in 43% of patients, with a sensitivity and specificity of 100% and 51%. The presence of either major ST segment depression (>2 mm) or elevation on the admission electrocardiogram (ECG) was present in 6%, with a sensitivity of 100% and a specificity of 99%. The resulting positive and negative predictive values were 86% (95% confidence interval [CI] 42% to 99%) and 100% (95% CI 96% to 100%), respectively. Use of this criterion would have reduced the number of rule-out MIs in our study group by 94%, with no loss of sensitivity. CONCLUSIONS: Chest pain and ST segment depression are extremely common findings in patients presenting to the ED with AF and have limited power to predict MI. In contrast, ECG evidence of ST segment elevation or depression >2 mm appears to be a reliable discriminator of which patients are at risk for MI. Patients without significant ST segment changes are at very low risk for MI and may not require performance of the rule-out MI protocol or hospital admission if clinically stable.

Holter monitoring: are two days better than one?

The optimal duration of Holter monitoring (HM) to minimize costs and maximize yield is unknown. In a retrospective review of 164 patients referred to a tertiary care center for evaluation with 2 days of HM, we found that 48 hours was not cost effective when compared with the traditional 24-hour period.

The evolving role of ambulatory arrhythmia monitoring in general clinical practice.

PURPOSE: To evaluate the efficacy of various ambulatory electrocardiographic monitors for the diagnosis of arrhythmia-related disorders and to provide recommendations for their use in clinical practice. DATA SOURCES: Studies published since 1988 were identified through search of the MEDLINE database. STUDY SELECTION: Studies that met methodologic criteria for minimal bias and had clinical relevance were selected. DATA EXTRACTION: Descriptive and analytic data from each study. DATA SYNTHESIS: Ambulatory electrocardiographic monitors, specifically transtelephonic continuous-loop event recorders, are highly effective for establishing a diagnosis in patients with palpitations but are less effective for establishing a diagnosis in patients with syncope. Clinicians may use these devices to monitor for nonsustained ventricular tachycardia in patients at potentially high risk for sudden arrhythmic death; however, few data are available to support this practice. Ambulatory monitors are useful for assessment of the safety and efficacy of antiarrhythmic medications and the recurrence of symptomatic supraventricular arrhythmias. New ambulatory arrhythmia monitoring devices are being developed that may facilitate outpatient management of chronic cardiac disease. CONCLUSIONS: Ambulatory electrocardiographic monitors, particularly transtelephonic continuous-loop event recorders, aid in the diagnosis of symptomatic arrhythmias. These devices are also useful for monitoring the effectiveness and safety of antiarrhythmic medications. Guidelines are lacking for use of these devices to assess prognosis in patients at potential risk for sudden arrhythmic death.

Evaluation of outpatient initiation of antiarrhythmic drug therapy in patients reverting to sinus rhythm after an episode of atrial fibrillation.

The safety of a method of outpatient antiarrhythmic drug loading utilizing a continuous loop event recorder was evaluated. The findings suggest that the standard 2-day hospital admission for drug loading is not necessary in all patients and a method of outpatient loading may be equally safe.

Hybrid pharmacologic and ablative therapy: a novel and effective approach for the management of atrial fibrillation.

INTRODUCTION: Maintenance of sinus rhythm in patients with recurrent atrial fibrillation is often difficult to achieve with pharmacologic therapy. Complex catheter ablative procedures are being developed, but efficacy and safety issues remain to be clarified. We hypothesized that combined pharmacologic and simple ablative therapies in a targeted subset of patients will improve success in the treatment of atrial fibrillation. METHODS AND RESULTS: We identified 13 patients (mean age 61.5 +/- 16.2 years) with atrial fibrillation who converted to electrocardiographic atrial flutter during antiarrhythmic drug treatment. Surface ECG suggested "typical" atrial flutter in 11 patients and "atypical" atrial flutter in 2. Intracardiac mapping and entrainment studies revealed 9 patients had counterclockwise isthmus-dependent atrial flutter, and the remaining 4 had complex activation patterns, suggesting the presence of multiple wavefronts. All 9 patients with typical atrial flutter underwent successful ablation. None of the 4 patients with complex activation patterns had successful ablation. Patients were followed for recurrences of atrial arrhythmias via clinic visits, record review, and interviews. In patients who underwent successful ablation and continued on antiarrhythmic drugs, 88.9% remain in sinus rhythm after a mean follow-up of 14.3 +/- 6.9 months (range 1 to 28). CONCLUSION: In patients who experience conversion of atrial fibrillation to atrial flutter during antiarrhythmic drug treatment, ablation and continuation of pharmacologic therapy is a safe and effective means of achieving and maintaining sinus rhythm.

Diagnostic yield and optimal duration of continuous-loop event monitoring for the diagnosis of palpitations. A cost-effectiveness analysis.

BACKGROUND: Continuous-loop event recorders are widely used for the evaluation of palpitations, but the optimal duration of monitoring is unknown. OBJECTIVE: To determine the yield, timing, and incremental cost-effectiveness of each week of event monitoring for palpitations. DESIGN: Prospective cohort study. PATIENTS: 105 consecutive outpatients referred for the placement of a continuous-loop event recorder for the evaluation of palpitations. MEASUREMENTS: Diagnostic yield, incremental cost, and cost-effectiveness for each week of monitoring. RESULTS: The diagnostic yield of continuous-loop event recorders was 1.04 diagnoses per patient in week 1, 0.15 diagnoses per patient in week 2, and 0.01 diagnoses per patient in week 3 and beyond. Over time, the cost-effectiveness ratio increased from $98 per new diagnosis in week 1 to $576 per new diagnosis in week 2 and $5832 per new diagnosis in week 3. CONCLUSIONS: In patients referred for evaluation of palpitations, the diagnostic yield of continuous-loop event recording decreases rapidly after 2 weeks of monitoring. A 2-week monitoring period is reasonably cost-effective for most patients and should be the standard period for continuous-loop event recording for the evaluation of palpitations.

Usefulness of ST-segment elevation in lead III exceeding that of lead II for identifying the location of the totally occluded coronary artery in inferior wall myocardial infarction.

The presence of ST-segment elevation in lead III exceeding that of lead II, particularly if combined with ST elevation in lead V1, proved to be a powerful marker for occlusion of the proximal or midportion of the right coronary artery. These findings helped to determine the extent of myocardium at risk in inferior wall myocardial infarction and may further guide the decision to administer thrombolytics.

Pathophysiologic substrate for sustained ventricular tachycardia in coronary artery disease.

Sustained ventricular tachycardia (VT) in the presence of coronary artery disease (CAD) is almost always associated with prior infarction. Its mechanism is reentrant excitation and it can be initiated > 95% of the time. Disrupted and delayed endocardial activation and prolonged, fragmented electrograms recorded during sinus rhythm distinguish patients with VT from those with normal ventricles and those of prior infarction without VT. The extent of abnormalities of activation and number of abnormal, fragmented and late electrograms are greatest in patients with sustained VT. These abnormalities are associated with scar tissue separating the viable myocytes. Fragmented electrograms are due to discontinuous activation due to nonuniform anisotropy caused by the scar tissue. Patients with CAD demonstrate depressed excitability and prolonged relative refractory periods (ie, an upward shift in the strength-interval curve) at sites of infarction but effective refractory periods measured at 10 mA comparable to normals and dispersion of refractory periods. However the associated abnormalities of conduction and activation produce an abnormal dispersion of recovery. Intraoperative mapping of patients with CAD has shown that most of the abnormalities of endocardial activation and conduction are in the subendocardial layers and subendocardial resection of these areas cures VT and abolishes delayed, fragmented electrograms and split potentials and normalizes the electrograms recorded from the subjacent tissue. This supports the hypothesis that abnormalities of conduction are the critical pathophysiologic substrate of VT in CAD.

Utility of patient-activated cardiac event recorders in general clinical practice.

A retrospective study of 729 consecutive patient-activated continuous loop recorders shows that these devices provide useful diagnostic information about the presence or absence of transient arrhythmias in carefully selected patients with certain specific complaints.

Pathophysiologic substrate for ventricular tachycardia in coronary artery disease and non-ischemic heart disease.

Sustained uniform monomorphic ventricular tachycardia is usually due to abnormalities of conduction, including coronary artery disease and right ventricular dysplasia. These conduction abnormalities are due to non-uniform anisotropy which is characterized by fragmented electrograms. Less is known about the pathophysiologic substrate of sustained ventricular tachycardia in the absence of coronary artery disease or cardiomyopathy.

Plasma lipids and lipoproteins and the incidence of cardiovascular disease in the very elderly. The Bronx Aging Study.

The Bronx Aging Study is a 10-year prospective investigation of very elderly volunteers (mean age at study entry, 79 years; range, 75-85 years) designed to assess risk factors for dementia and coronary and cerebrovascular (stroke) diseases. Entry criteria included the absence of terminal illness and dementia. All subjects (n = 350) included in this report had at least two lipid and lipoprotein determinations. Overall, more than one third of subjects showed at least a 10% change in lipid and lipoprotein levels between the initial and final measurements. Moreover, mean levels for women were consistently different than those for men, and because of this finding subjects were classified into potential-risk categories based on the changes observed by using their sex-specific lipid and lipoprotein distributions. The incidences of cardiovascular disease, dementia, and death were compared between risk groups. Proportional-hazards analysis showed that in men a consistently low high density lipoprotein cholesterol level (less than or equal to 30 mg/dl) was independently associated with the development of myocardial infarction (p = 0.006), cardiovascular disease (p = 0.002), or death (p = 0.002). For women, however, a consistently elevated low density lipoprotein cholesterol level (greater than or equal to 171 mg/dl) was associated with myocardial infarction (p = 0.032). Thus, low high density lipoprotein cholesterol remains a powerful predictor of coronary heart disease risk for men even into old age, while elevated low density lipoprotein cholesterol continues to play a role in the development of myocardial infarction in women. The findings suggest that an unfavorable lipoprotein profile increases the risk of cardiovascular morbidity and mortality even at advanced ages for both men and women.

Serum lipids and lipoproteins in advanced age. Intraindividual changes.

The Bronx Aging Study is a longitudinal investigation of nondemented, nonterminally ill, community-residing, old old volunteer subjects, designed to assess risk factors for the development of dementia and coronary and cerebrovascular diseases. During the first five annual evaluations, total cholesterol, high-density (HDL) and low-density lipoprotein (LDL), and triglyceride levels were measured. Mean cholesterol values (+/- standard error of the mean) for subjects at baseline were significantly higher for women than for men. Respectively, the values for total cholesterol were 6.1 +/- .1 mm/L (234 +/- 3 mg/dL) and 5.3 +/- .1 mm/L (207 +/- 3 mg/dL); for LDL cholesterol, 4.1 +/- .1 mm/L (158 +/- 2 mg/dL) and 3.7 +/- .1 mm/L (141 +/- 3 mg/dl); and for HDL cholesterol, 1.2 +/- .1 mm/L (47 +/- 1 mg/dL) and 1.0 +/- .1 mm/L (38 +/- 1 mg/dL). Mean triglyceride levels were 1.5 +/- .1 mm/L (135 +/- 5 mg/dL) for women and 1.6 +/- .1 mm/L (138 +/- 5 mg/dL) for men. Further, mean values remained stable over time. However, there was considerable intraindividual change observed in a substantial proportion of subjects between initial and final determinations. Changes of at least 10% from baseline were observed in 41%, 63%, 52%, and 78% of the cohort for cholesterol, HDL, LDL, and triglycerides, respectively. Thus, single measurements appear inadequate for establishing a diagnosis of hyperlipidemia in the elderly.

Nicotinic acid for the treatment of hyperlipoproteinemia.

Nicotinic acid is a water-soluble B-complex vitamin that has been shown, in high doses, to lower total plasma cholesterol (C), LDL-C, and VLDL-triglycerides (Tg), while raising HDL-C in patients with type II, III, IV, and V hyperlipoproteinemia. Its exact mechanism of action is not known, but it appears to lower the production of VLDL in the liver while activating lipoprotein lipase. The drug may also influence the metabolism of HDL-C. The drug is a second or third choice for isolated hypercholesterolemia because of a high incidence of side effects. However, it has a therapeutic advantage as a monotherapy when reduction of both LDL-C and triglycerides are needed in patients with severe combined hyperlipidemia. The drug can be used in combination with other cholesterol-lowering agents to maximize lipid-lowering activity. Nicotinic acid has been associated with a reduced risk of cardiovascular morbidity in clinical trials.