Remdesivir for the Treatment of COVID-19: A Narrative Review.

Despite the wide availability of effective vaccines, COVID-19 continues to be an infectious disease of global importance. Remdesivir is a broad-spectrum antiviral and was the first US Food and Drug Administration-approved treatment for COVID-19. In clinical guidelines, remdesivir is currently the only recommended antiviral for use in hospitalized patients with COVID-19, with or without a supplemental oxygen requirement. It is also recommended for nonhospitalized patients with COVID-19 and hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who are at high risk of progression to severe disease. This narrative review explores the evidence for remdesivir across various clinical outcomes and evolution of clinical guidelines through a survey over time of randomized controlled trials, observational studies, and meta-analyses. Remdesivir, compared to standard of care, appears to improve survival and disease progression in a variety of patient populations with COVID-19 across a spectrum of disease severity and SARS-CoV-2 variant periods. Remdesivir also appears to improve time to clinical recovery, increase rate of recovery, and reduce time on supplemental oxygen and readmission rates. More recent large, real-world studies further support the early use of remdesivir in a range of patient populations, including those with immunocompromising conditions.

When people get sick with COVID-19, which is caused by the SARS-CoV-2 virus, treatment with an antiviral may be needed to prevent serious illness. Remdesivir is an antiviral and was the first US Food and Drug Administration-approved treatment for COVID-19. Studies have found that treating COVID-19 with remdesivir can save lives and keep patients from getting sicker. Remdesivir appears to help patients get better faster, need oxygen treatment for less time, and avoid having to go back to the hospital. Newer studies with patients treated in real-world settings, outside of controlled research environments, show that early treatment with remdesivir is likely to help many different groups of patients, including those with health conditions that weaken their body's ability to fight infection. Because of this research, guidelines recommend that remdesivir should be given to some patients with COVID-19 outside of the hospital and to those who need to stay in the hospital for COVID-19. Remdesivir should also be given to those who need to stay in the hospital for other reasons but have COVID-19 and a health condition that puts them at risk of serious illness.

Patient Perceptions of their COVID-19 Inpatient Hospital Experience: a Survey Exploring Inequities in Healthcare Delivery.

BACKGROUND: Compared with White patients, Black and Latinx patients have higher infection, hospitalization, and mortality rates from COVID-19; yet, little is known about their perspective before, during, and after a COVID-19 hospitalization. The objective of this study conducted in White, Black, and Latinx patients was to assess perceptions of their COVID-19-related hospitalization from onset of symptoms through the post-discharge period to identify disparities in their perceived care. METHODS: A cross-sectional observational study using an online survey from May 19 to June 23, 2021, was conducted by The Harris Poll in 200 White, 200 Black, and 201 Latinx patients hospitalized for COVID-19 in the US. Main measures obtained included baseline demographic variables, socioeconomic status, and social determinants of health. Survey questions were specific to key aspects of the patient experience before, during, and after a COVID-19-related hospitalization. RESULTS: Compared with White patients, Latinx and Black patients faced unique challenges in their healthcare journey including higher likelihood of delaying their hospitalization (10% Black vs. 4% White patients, respectively, P = 0.025), lower perceived satisfaction with care (82% Latinx vs 91% White patients, P = 0.002), and lower trust in providers following their hospitalization (85% White vs. 65% Latinx [P = 0.027] and 73% Black [P = 0.050] patients). CONCLUSIONS: Patient perceptions of their COVID-19 hospitalization experience revealed disparities in perceived quality of care among minority groups. These findings offer insights that health inequities still exist, and strategies need to be taken to make health care delivery more equitable.

Electrocardiographic and blood pressure effects of the ephedra-containing TrimSpa thermogenic herbal compound in healthy volunteers.

STUDY OBJECTIVE: To determine the effect of an ephedra-containing thermogenic herbal compound (TrimSpa) on rate-corrected QT (QTc) interval duration and systolic blood pressure. DESIGN: Randomized, double-blind, placebo-controlled, crossover, intent-to-treat study. SETTING: Student laboratory at a college of pharmacy. SUBJECTS: Thirteen healthy volunteers (eight men, five women). INTERVENTION: Participants were given TrimSpa, which contains more than 30 ingredients including ephedra 15 mg and caffeine 60 mg, or matching placebo 3 times/day for 7 days in a crossover fashion with a 7-day washout period between treatments. MEASUREMENTS AND MAIN RESULTS: Each subject's QTc interval and systolic blood pressure were measured on days 1, 4, and 7. These measurements were performed immediately before study drug ingestion (baseline) and 0.5, 1, and 3 hours after ingestion. No differences in these variables were found between the TrimSpa and placebo groups. In one subject taking TrimSpa, the QTc interval increased 96 msec from baseline, more than double the largest increase in the placebo group. CONCLUSION: Standard doses of TrimSpa did not induce changes in subjects' QTc intervals or systolic blood pressures. However, because the QTc interval dramatically changed in one subject taking TrimSpa, a large study is needed to determine if the effect is an artifact or if the subject represents a subset of people for whom the drug may pose a risk.

The impact of catecholamines on defibrillation threshold in patients with implanted cardioverter defibrillators.

OBJECTIVES: To determine the effect of physiologic catecholamine concentrations on the defibrillation threshold (DFT) in patients with implanted cardioverter defibrillators. BACKGROUND: DFT is the minimum energy delivered by an implanted cardioverter defibrillator that successfully converts ventricular fibrillation. DFT testing is performed under conscious sedation. Since activities of daily living enhance sympathetic tone substantially over these nadir levels, it is important to explore the impact of catecholamines on DFT. METHODS: In this double-blind study, we determined DFT by the step-down method. Patients (n = 50) were stratified by beta-blocker use and then randomized to a 7-minute infusion of epinephrine, norepinephrine, or placebo. After study infusion, DFT testing was repeated. Changes in DFT with different study medications were compared. Subgroup analyses of the effects of catecholamines on DFT, based on beta-blocker use, were also performed. RESULTS: Norepinephrine reduced DFT from baseline measurements by 22.6% (P = 0.008). Neither epinephrine nor placebo impacted DFT (P = 0.999, P = 0.317, respectively). In the subgroup analyses, DFT was reduced with norepinephrine regardless of beta-blocker use, while epinephrine reduced DFT among those receiving beta-blockers. No change in DFT was observed in either of the placebo subgroups. CONCLUSIONS: Elevation of plasma norepinephrine concentrations reduces the DFT, while elevations in epinephrine had no effect. Norepinephrine seems to reduce DFT regardless of beta-blocker therapy but epinephrine's effects are beta-blocker dependent.

Impact of fluid balance on incidence of atrial fibrillation after cardiothoracic surgery.

Excessive fluid administration after cardiothoracic surgery has been proposed as a cause of postoperative atrial fibrillation. In this study, we observed that fluid balance and volume administered on postoperative day 2 was greater in patients who developed postoperative AF than in those who did not. We also found that net fluid balance on postoperative day 2 was an independent predictor of postoperative AF among patients not receiving prophylactic therapy.

Economic analysis of intravenous plus oral amiodarone, atrial septal pacing, and both strategies to prevent atrial fibrillation after open heart surgery.

STUDY OBJECTIVES: To compare the cost-effectiveness of intravenous plus oral amiodarone, atrial septal pacing, and both strategies combined to prevent atrial fibrillation after open heart surgery. Secondary objectives were to compare the cost-effectiveness of amiodarone versus no amiodarone and of pacing versus no pacing, and to compare hospitalization costs of the various strategies. DESIGN: Piggyback cost analysis of a randomized, 2 x 2 factorial trial. SETTING: Urban academic hospital. PATIENTS: One hundred and sixty patients with coronary artery and/or valvular disease. INTERVENTION: Patients were randomized to receive amiodarone or matching placebo and then further randomized to receive atrial septal pacing or no pacing. MEASUREMENTS AND MAIN RESULTS: The economic analysis was conducted from a hospital perspective. Charges were converted to costs using cost:charge ratios. For the cost-effectiveness analysis, a joint distribution of costs and effectiveness was performed using the nonparametric bootstrap method. Amiodarone plus pacing significantly decreased the frequency of atrial fibrillation after open heart surgery, compared with amiodarone alone, pacing alone, and placebo. Total costs (mean+/-SD) were $27,026+/-30,226 for the placebo group, $22,725+/-17,661 for the amiodarone group, $33,868+/-60,309 for the pacing group, and $18,697+/-8174 for the amiodarone plus pacing group (p=0.27). In the joint distribution cost-effectiveness analysis, when compared with placebo, the probability of lower cost but higher effect (superiority) was 67% for amiodarone, 15% for pacing, and 97% for amiodarone plus pacing. In the multivariate analysis, preoperative beta-blockers and amiodarone were negatively associated with hospital costs (p<0.05). CONCLUSIONS: Data suggest that both amiodarone alone and the combination of amiodarone plus pacing are cost-effective compared with placebo. Additional comparative studies of these strategies are warranted to confirm these findings.

An evaluation of postoperative P-wave variables after cardiothoracic surgery.

Postoperative atrial fibrillation is common after cardiac surgery. Prediction of which patients will develop postoperative atrial fibrillation would be clinically useful. Increased P-wave duration, suggesting atrial conduction delay and measured from preoperative electrocardiograms, predicts postoperative atrial fibrillation. However, postoperative P-wave duration has not been evaluated after cardiac surgery. In this study, we evaluated postoperative P-wave variables (maximum P-wave duration and P-wave dispersion) over 5 days in cardiac surgery patients receiving amiodarone, pacing or no atrial fibrillation prophylaxis. P-wave variables gradually shortened as time passed from surgery. Amiodarone did not shorten P-wave measurements throughout therapy, while pacing shortened P-waves in the immediate postoperative period; however, shortening was not sustained. P-waves did not differ between those who did and did not develop atrial fibrillation with amiodarone or pacing. Our findings suggest that atrial conduction delay resulting from cardiothoracic surgery tends to resolve over time and may not play a critical role in the etiology of postoperative atrial fibrillation.

Novel uses for current and future direct thrombin inhibitors: focus on ximelagatran and bivalirudin.

Ximelagatran and bivalirudin are direct thrombin inhibitors that have been studied for the prevention and treatment of thrombosis and have potential advantages over the traditional indirect thrombin inhibitors (i.e., warfarin, unfractionated heparin and low molecular-weight heparin). They are both reversible inhibitors of thrombin and block both circulating and fibrin-bound thrombin. Ximelagatran and bivalirudin possess favourable pharmacokinetic and pharmacodynamic profiles including wider therapeutic indices, faster onsets of action and less interpatient variability compared to indirect thrombin inhibitors. Ximelagatran has shown favourable clinical trial results in venous thromboembolism prophylaxis and atrial fibrillation. Similarly, bivalirudin has shown positive results in patients with acute coronary syndromes, however, further investigation is needed. Ximelagatran and bivalirudin have shown promising results in the management of thrombosis and the results of future studies confirming their use for the aforementioned indications are anticipated.

Indicators of atrial fibrillation risk in cardiac surgery patients on prophylactic amiodarone.

BACKGROUND: Atrial fibrillation is a common complication of cardiothoracic surgery (coronary artery bypass graft surgery or cardiac valve repair or replacement). Although predictors of postoperative atrial fibrillation have been explored in patients not receiving prophylactic antiarrhythmic therapy, independent predictors of postoperative atrial fibrillation in patients receiving prophylactic amiodarone have not been elucidated. METHODS: This was a substudy of a clinical trial evaluating the efficacy of an amiodarone regimen or an atrial-septal pacing strategy on the occurrence of postoperative atrial fibrillation. The association between the occurrence of postoperative atrial fibrillation and preoperative, intraoperative, and postoperative data from the total study population and the amiodarone and placebo subpopulations were explored using multiple logistic regression analysis. RESULTS: The following clinical factors were independent predictors of postoperative atrial fibrillation in the total population: age (p < 0.001), history of atrial fibrillation (p = 0.021), diabetes mellitus (p = 0.008), and high-dose postoperative nonsteroidal antiinflammatory drug use (p = 0.038). Age (p = 0.016), history of mitral regurgitation (p = 0.029), heart failure (p = 0.010), and postoperative nonsteroidal antiinflammatory drug use (p = 0.038) were independent predictors when amiodarone was used, and age was the only predictor of postoperative atrial fibrillation (p = 0.024) among patients treated with placebo. CONCLUSIONS: This subanalysis demonstrates some novel predictors of postoperative atrial fibrillation, including diabetes mellitus and postoperative nonsteroidal antiinflammatory drug use. We have also demonstrated that predictors of atrial fibrillation differ when prophylactic amiodarone is used.

Glycosylated hemoglobin, cardiovascular, and renal outcomes in a pharmacist-managed clinic.

BACKGROUND: Pharmacists' responsibilities in caring for patients with diabetes mellitus are expanding. However, few data are available to support pharmacists optimizing therapy and improving outcomes in these patients. OBJECTIVE: To determine the effect of a clinical pharmacist-directed diabetes management clinic on glycemic control and cardiovascular and renal parameters in patients with type 2 diabetes. METHODS: A nonrandomized, prospective study was conducted in 70 Veterans Affairs patients. Patients met with the pharmacist every 6-8 weeks for approximately 30 minutes for education, medication counseling, monitoring, and management. The primary endpoint was the impact of 9-12 months of participation in the clinic on glycosylated hemoglobin (HbA1C). Secondarily, we evaluated body weight, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglycerides, systolic and diastolic blood pressure, and level of microalbuminuria. All comparisons were made using a paired t-test at a significance level of p < or = 0.05. RESULTS: HbA1C significantly decreased from 10.3% +/- 2.2% at baseline to 6.9% +/- 1.1% (mean +/- SD) during the 9- to 12-month evaluation period (p < 0.001). The secondary endpoints including systolic (p < 0.001) and diastolic (p < 0.001) blood pressure, total cholesterol (p < 0.001), LDL-C (p < 0.001), triglycerides (p = 0.006), and level of microalbuminuria (p < 0.001) also were reduced at 9-12 months. CONCLUSIONS: This study demonstrated that a clinical pharmacist can effectively care for patients with diabetes referred by their primary care provider because of poor glycemic control.

Bivalirudin in percutaneous coronary intervention.

The chemistry and pharmacology, pharmacokinetics, pharmacodynamics, adverse effects, drug interactions, dosing and administration, and pharmacoeconomics of bivalirudin are reviewed; clinical trials of bivalirudin's application in percutaneous coronary intervention (PCI) are also discussed. Bivalirudin is a direct thrombin inhibitor approved for use in PCI. It reversibly binds to thrombin's catalytic site and substrate recognition site and blocks both circulating and fibrin-bound thrombin. Peak concentrations occur in less than 5 minutes after bolus-dose administration, and its half-life is approximately 25 minutes. It is primarily eliminated renally, and dosage reduction may be required in patients with severe renal dysfunction. Two clinical trials have demonstrated that bivalirudin is at least as effective as unfractionated heparin (UFH) in preventing ischemic complications in PCI. Other trials have shown that bivalirudin has beneficial ischemic and hemorrhagic outcomes in a more modern PCI setting (i.e., intracoronary stent placement, clopidogrel, and glycoprotein IIb/IIIa-receptor inhibitors). Bivalirudin combined with provisional glycoprotein IIb/IIIa inhibitors was noninferior to UFH with planned glycoprotein IIb/IIIa inhibitors and superior to UFH alone with respect to ischemic and hemorrhagic endopoints in PCI. Major bleeding with bivalirudin has occurred in approximately 3% of patients in clinical trials, and it is not known to have any interactions with the cytochrome P-450 isoenzyme system. The acquisition cost of bivalirudin in one study was less than the combination of UFH and glycoprotein IIb/IIIa inhibitors. Bivalirudin combined with provisional glycoprotein IIb/IIIa inhibitors appears to be an acceptable alternative to the standard of care and is superior to UFH alone in PCI.

Intravenous plus oral amiodarone, atrial septal pacing, or both strategies to prevent post-cardiothoracic surgery atrial fibrillation: the Atrial Fibrillation Suppression Trial II (AFIST II).

BACKGROUND: The effect of a hybrid intravenous and oral prophylactic amiodarone regimen on postcardiothoracic surgery (CTS) atrial fibrillation (AF) is unknown. The impact of active atrial septal pacing on post-CTS AF has not been well characterized. In addition, the effect of using both amiodarone and atrial septal pacing together to prevent atrial fibrillation is unknown. METHODS AND RESULTS: Patients (n=160) were randomized to amiodarone or placebo and then to pacing or no pacing using a 2x2 factorial design. All therapies began within 6 hours post-CTS. Amiodarone was given by intravenous infusion for the first 24 hours (1050 mg total) followed by oral therapy for 4 postoperative days (4800 mg total). Atrial septal pacing was given for 96 hours. Amiodarone reduced the risk of AF by 43% and the risk of symptomatic AF by 68% (P=0.037 and P=0.019) versus placebo. Atrial septal pacing did not reduce AF or symptomatic AF incidence versus no pacing. The risk of post-CTS AF in the patients receiving amiodarone+pacing was lower than the placebo+no pacing and the placebo+pacing groups (57.9% and 60.5% reductions, P=0.047 and P=0.040, respectively). CONCLUSIONS: Amiodarone given as both an intravenous and oral regimen is effective at reducing post-CTS AF but atrial septal pacing is ineffective. Combining amiodarone and pacing is better than placebo with or without pacing but not amiodarone alone.

Effects of intravenous magnesium sulfate on the QT interval in patients receiving ibutilide.

STUDY OBJECTIVE: To determine the effect of intravenous magnesium sulfate on the QT and QTc intervals in patients receiving ibutilide for immediate chemical cardioversion of atrial flutter or fibrillation. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Hospital cardiology unit. PATIENTS: Twenty patients (mean age 72 +/- 14 yrs) with atrial fibrillation (12 patients) or atrial flutter (8 patients) who were scheduled to receive ibutilide. INTERVENTION: After determining that the patients' baseline QTc intervals were less than 440 msec and baseline serum magnesium levels were within normal limits (mean 2.1 +/- 0.29 mg/dl), the patients were randomly assigned to receive either a 10-minute infusion of magnesium sulfate 2 g in 50 ml of 0.9% sodium chloride or placebo immediately before ibutilide therapy. An additional 2 g of intravenous magnesium sulfate or placebo was given over 1 hour, 10 minutes after the first dose of ibutilide. MEASUREMENTS AND MAIN RESULTS: QT interval duration was measured manually in all 12 leads by using a 0.5-mm-scale precision ruler and magnifying lens. The QT interval increased 29% from baseline at 30 minutes after ibutilide therapy in the placebo group (p=0.007), but no significant change from baseline occurred in the magnesium sulfate group. The 30-minute QTc interval in the placebo group was 18% higher than the baseline value (p=0.01) but did not change significantly in the magnesium sulfate group. QTc changes from baseline were greater in the placebo group than in the magnesium sulfate group at 30 minutes (75 vs 19 msec, respectively, p=0.04). Magnesium sulfate reduced the risk of an ibutilide-induced QTc interval increase of greater than 30 msec or greater than 60 msec and reduced the risk of a QTc interval value of more than 500 msec by 65%, 60%, and 68%, respectively (p=0.07, p=0.175, and p=0.160). CONCLUSIONS: Prophylactic administration of intravenous magnesium sulfate prevents increases in the QT and QTc interval 30 minutes after the last infusion of ibutilide.

The effect of head-upright tilt table testing for vasovagal syncope on P-wave duration.

Fluid shifts in vasovagal syncope may be reflected in electrocardiographic P-wave duration. We examined the effect of head-upright tilt-table testing (HUT) on P-wave duration among patients with positive or negative HUT. P-wave duration was measured at baseline and several post-HUT time points. In patients with a positive HUT, the test was immediately discontinued. P-wave duration measurements obtained at the completion of the test or when symptoms occurred were compared to baseline measurements. The P-wave duration among patients with a positive HUT was significantly reduced at the onset of symptoms as compared to baseline (-14.0 ms, P = .0054) and 2-minute tilt measurements (-11.3 ms, P = .0246). P-wave duration measurements were not reduced in patients experiencing a negative HUT at any follow-up time. We showed a significant reduction in P-wave duration among patients experiencing positive HUT that suggests a dynamic relationship between atrial volume and P-wave duration.

Effect of diuresis on P-wave duration and dispersion.

STUDY OBJECTIVE: To evaluate the effects of changing volume status on P-wave duration and dispersion in patients with decompensated heart failure. DESIGN: Prospective analysis. SETTING: Hospital cardiology unit. PATIENTS: Twenty-one patients with symptoms of decompensated heart failure who were treated with diuretics on admission. INTERVENTION: Twelve-lead electrocardiograms were obtained at baseline and after diuresis. Average, minimum, and maximum P-wave duration and P-wave dispersion (minimum minus maximum duration) were determined. MEASUREMENTS AND MAIN RESULTS: P-wave duration was measured manually in all 12 leads by using a 0.5-mm-scale precision ruler and magnifying lens. After 40+/-23 hours of diuresis, 3+/-1 L of fluid was removed. A significant correlation was found between average P-wave duration and amount of fluid removed (r = -0.59, p=0.015). Also, average and maximum P-wave duration were significantly decreased with diuresis (p=0.001 and 0.022, respectively). No other P-wave variables were significantly affected. CONCLUSIONS: Diuresis may attenuate electrophysiologic changes caused by fluid overload.

Electrocardiographic and hemodynamic effects of Panax ginseng.

OBJECTIVE: To determine whether Panax ginseng ingestion can acutely or chronically alter electrocardiographic parameters: PR, QRS, QT, QTc, and RR intervals, and QT and QTc interval dispersion. Effects of P. ginseng on blood pressure and heart rate also were evaluated. METHODS: This is a prospective, randomized, double-blind, placebo-controlled study of healthy adults at the University of Connecticut. Thirty subjects were randomly allocated to receive 28 days of therapy with either P. ginseng extract 200 mg or placebo. Baseline 12-lead electrocardiograms (ECGs) were obtained. Subsequent ECGs were performed following study drug ingestion at 50 minutes, 2 hours, and 5 hours on days 1 and 28. Blood pressure readings were taken with each ECG. RESULTS: P. ginseng ingestion increased the QTc interval by 0.015 seconds on day 1 at 2 hours compared with the placebo group (p = 0.03). It also reduced diastolic blood pressure from 75 +/- 5 mm Hg at baseline to 70 +/- 6 mm Hg at the same time point (p = 0.02). The observed effects are not believed to be clinically significant. No other statistically significant changes were found in electrocardiographic or hemodynamic variables on days 1 or 28. CONCLUSIONS: P. ginseng, at doses of 200 mg of the extract daily, increases the QTc interval and decreases diastolic blood pressure 2 hours after ingestion in healthy adults on the first day of therapy.