Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has changed our lives. The scientific community has been investigating re-purposed treatments to prevent disease progression in coronavirus disease (COVID-19) patients. OBJECTIVE: To determine whether ivermectin treatment can prevent hospitalization in individuals with early COVID-19. DESIGN, SETTING AND PARTICIPANTS: A randomized, double-blind, placebo-controlled study was conducted in non-hospitalized individuals with COVID-19 in Corrientes, Argentina. Patients with SARS-CoV-2 positive nasal swabs were contacted within 48 h by telephone to invite them to participate. The trial randomized 501 patients between August 19th 2020 and February 22nd 2021. INTERVENTION: Patients were randomized to ivermectin (N = 250) or placebo (N = 251) arms in a staggered dose, according to the patient's weight, for 2 days. MAIN OUTCOMES AND MEASURES: The efficacy of ivermectin to prevent hospitalizations was evaluated as primary outcome. We evaluated secondary outcomes in relationship to safety and other efficacy end points. RESULTS: The mean age was 42 years (SD ± 15.5) and the median time since symptom onset to the inclusion was 4 days [interquartile range 3-6]. The primary outcome of hospitalization was met in 14/250 (5.6%) individuals in ivermectin group and 21/251 (8.4%) in placebo group (odds ratio 0.65; 95% confidence interval, 0.32-1.31; p = 0.227). Time to hospitalization was not statistically different between groups. The mean time from study enrollment to invasive mechanical ventilatory support (MVS) was 5.25 days (SD ± 1.71) in ivermectin group and 10 days (SD ± 2) in placebo group, (p = 0.019). There were no statistically significant differences in the other secondary outcomes including polymerase chain reaction test negativity and safety outcomes. LIMITATIONS: Low percentage of hospitalization events, dose of ivermectin and not including only high-risk population. CONCLUSION: Ivermectin had no significant effect on preventing hospitalization of patients with COVID-19. Patients who received ivermectin required invasive MVS earlier in their treatment. No significant differences were observed in any of the other secondary outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04529525 .

Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19): a structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: To assess the efficacy of ivermectin in addition to standard treatment compared to standard treatment alone in reducing hospitalizations in the COVID-19 patient population. TRIAL DESIGN: IVERCOR-COVID19 will be a single-center, prospective, randomized, double-blind, parallel group (1:1 ratio), placebo-controlled study. PARTICIPANTS: Patients who meet the following criteria will be invited to participate: Inclusion criteria: (1) Over 18 years of age who reside in the province of Corrientes at the time of diagnosis. (2) Confirmed diagnosis of COVID-19 by polymerase chain reaction (PCR) test for detection of SARS-CoV2 in the last 48 h. (3) In the case of women of childbearing age, they must be using a contraceptive method of proven efficacy and safety (barrier, hormonal, or permanent contraceptives) for at least 3 months prior to inclusion in the present study and for the entire period of time for the duration of the study and until at least 30 days after the end of this study. A woman will be considered to have no reproductive capacity if she is postmenopausal (at least 2 years without her menstrual cycles) or if she has undergone surgical sterilization (at least 1 month before the time of inviting her to participate in this study). (4) Weight at the time of inclusion greater than 48 kg. (5) That they sign the informed consent for participation in the study. EXCLUSION CRITERIA: (1) pregnant or breastfeeding women; (2) known allergy to ivermectin or some of the components of ivermectin tablets or placebo; (3) current use of home oxygen; (4) require hospitalization due to COVID-19 at the time of diagnosis or history of hospitalization for COVID-19; (5) presence of mal-absorptive syndrome; (6) presence of any other concomitant acute infectious disease; (7) known history of severe liver disease, for example liver cirrhosis; (8) need or use of antiviral drugs at the time of admission for another viral pathology other than COVID-19; (9) need or use of hydroxychloroquine or chloroquine; (10) use of ivermectin up to 7 days prior to randomization; (11) patients on dialysis or who have required it in the last 2 months or who plan to do it in the next 2 months; and (12) current participation or in the last 30 days in a research study that has included the administration of a drug (Table 1). Table 1 Ivermectin/placebo dose according to patient weight Patient weight Ivermectin/placebo dose Total dose (mg) Equal to or greater than 48 kg and less than 80 kg 2 tablets of 6 mg each at the time of inclusion and 2 tablets 24 h after the first intake 24 Equal or greater than 80 kg and less than 110 kg 3 tablets of 6 mg each at the time of inclusion and 3 tablets 24 h after the first intake 36 Equal or greater than 110 kg 4 tablets of 6 mg each at the time of inclusion and 4 tablets 24 h after the first intake 48 The study will be carried out by the Ministry of Public Health of the Province of Corrientes (Argentina) in coordination with the Institute of Cardiology of Corrientes in the Province of Corrientes, Argentina. INTERVENTION AND COMPARATOR: Intervention group: patients who are randomized to ivermectin will receive the dose according to their weight (patients up to 80 kg will receive 2 tablets of 6 mg ivermectin; patients with more than 80 kg and up to 110 kg will receive 3 tablets of 6 mg of ivermectin; patients weighing more than 110 kg will receive 4 tablets of 6 mg ivermectin) the day they enter the study and the same dose 24 h after the first dose. CONTROL GROUP: patients who are randomized to placebo will receive the dose according to their weight (patients up to 80 kg will receive 2 tablets of 6 mg placebo; patients with more than 80 kg and up to 110 kg will receive 3 tablets of 6 mg of placebo; patients weighing more than 110 kg will receive 4 tablets of 6 mg placebo) on the day they enter the study and the same dose 24 h after the first dose (Table 2). Table 2 Inclusion and exclusion criteria Inclusion criteria Exclusion criteria 1. Over 18 years of age who reside in the province of Corrientes at the time of diagnosis 1. Pregnant or breastfeeding women 2.Confirmed diagnosis of COVID-19 by polymerase chain reaction test for detection of SARS-CoV2 in the last 48 h 2. Known allergy to ivermectin or some of the components of ivermectin tablets or placebo 3. In case of being women of childbearing age, they must be using a contraceptive method of proven efficacy and safety (barrier, hormonal, or permanent contraceptives) for at least 3 months prior to inclusion in the present study, during the entire period of time for the duration of the study, and until at least 30 days after the end of this study. A woman will be considered to have no reproductive capacity if she is postmenopausal (at least 2 years without her menstrual cycles) or if she has undergone surgical sterilization (at least 1 month before the time of inviting her to participate in this study) 3. Current use of home oxygen 4. Weight at the time of inclusion equal to or greater than 48 kg 4. That require hospitalization due to COVID-19 at the time of diagnosis or history of hospitalization for COVID-19 5. That they sign the informed consent for participation in the study 5. Presence of mal-absorptive syndrome 6. Presence of any other concomitant acute infectious disease 7. Known history of severe liver disease, for example liver cirrhosis 8. Need or use of antiviral drugs at the time of admission for another viral pathology other than COVID-19 9. Need or use of hydroxychloroquine or chloroquine 10. Use of ivermectin up to 7 days prior to randomization 11. Patients on dialysis or who have required it in the last 2 months or who plan to do it in the next 2 months 12. Current participation or in the last 30 days in a research study that has included the administration of a drug MAIN OUTCOMES: Primary outcome will be the percentage of hospitalizations in patients with COVID-19 in the intervention and control groups. SECONDARY OUTCOMES: time to hospitalization in each of the arms of the study: number of days elapsed from the inclusion in the study until the hospitalization of the patient; percentage of use of invasive mechanical ventilation in each of the study arms: every patient who is connected to invasive mechanical ventilation after signing the informed consent and before the final study visit; time to invasive mechanical ventilation in each of the arms of the study: number of days elapsed from inclusion in the study to connection to invasive mechanical ventilation of the patient; percentage of patients requiring dialysis in each of the study arms: all patients who require renal replacement therapy of any kind, temporary or permanent, and which begins after signing the informed consent and before the final visit; mortality from all causes in each of the two trial groups: death of the patient, from any cause. Negative PCR swab at 3 ± 1 and 12 ± 2 days after entering the study. Ivermectin safety: it will be analyzed according to the incidence of adverse events that patients present in the intervention and control groups. The end of study (EOS) is recorded as the day the patient is discharged or death. Discharge will be granted according to the current recommendations of the Ministry of Public Health of the Province of Corrientes. A follow-up visit (EOF) will be made by phone 30 days after the EOS when vital status will be verified. RANDOMIZATION: Randomization will be done through a web system with randomly permuted blocks. Randomization will be carried out by one of the investigators who will not participate in the inclusion of patients or in the delivery of medication (Table 3). Table 3 EOS end of study, EOF end of follow-up Visit Basal and randomization, day 0 Day 3 ± 1 Day 12 ± 2 V#1 V#2 V#3 EOS EOF Informed consent X - - - - Inclusion/exclusion criteria X - - - - Demographic data and medical history X - - - - Concomitant medication X - - - - Vital signs* X X - - - Anthropometric data^ X - - - - Basal laboratory X - - - - PCR swab - X X - - Assessment of adverse events - X X X - Final objective evaluation - X X X X Randomization X - - - - Adherence to treatment X X - - - *Includes heart rate, temperature, and oxygen saturation by a digital saturometer ^Includes weight and height BLINDING (MASKING): The participants, investigators, care providers, and outcome assessors will be blinded. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): We will include a total of 500 patients (250 patients in each group). TRIAL STATUS: This is version 1.0, 17 August 2020. The recruitment started on 19 August 2020, and we anticipate the trial will finish recruitment on 31 December 2020. TRIAL REGISTRATION: ClinicalTrials.gov NCT04529525 . Registered on 26 August 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Current status of cardiac rehabilitation in Latin America and the Caribbean.

BACKGROUND: The prevalence of coronary artery disease (CAD) in Latin America is increasing and contributes importantly to the global burden of cardiovascular diseases. Advanced resources for the diagnosis and treatment of CAD are available in most of the region. However, preventive approaches such as cardiovascular rehabilitation programs (CVRP) may not be widely implemented. METHODS: We carried out a telephone-based survey to hospitals sampled in a random and population-weighted fashion from a list of 202 centers with cardiac catheterization laboratories in Mexico, Central and South America, and the Caribbean. We collected information of availability of cardiac procedures and imaging techniques and also extensive data about the presence, characteristics, and quality measures of CVRP. RESULTS: A total of 98 centers were contacted, and a complete survey was provided by 59 centers (60%) from 13 countries. Cardiovascular rehabilitation programs were available in only 56% of centers. There were no differences between centers with and without CVRP regarding type of hospital, availability of cardiac surgery, and annual volume of patients with myocardial infarction. Among centers with CVRP, 70% offered all phases of CVRP. The lack of CVRP was attributed to lack of qualified personnel in 41% of centers, financial constraints in 33%, and lack of physical space in 13%. All centers without CVRP performed cardiac surgery and percutaneous interventions. CONCLUSIONS: Despite the presence of state-of-the-art technology for the diagnosis and treatment of CAD, availability of CVRP, a less expensive yet effective tool for the treatment of CAD, appears to be limited in Latin America and the Caribbean.

Efecto del carvedilol sobre la fracción de eyección y capacidad de ejercicio en pacientes con insuficiencia cardíaca / Effect of carvedilol on left ventricular ejection fraction and exercise performance in patients with chronic heart failure

Se evaluó el uso del carvedilol en pacientes con insuficiencia cardíaca mediante un ensayo clínico a doble ciego, valorándose la fracción de eyección y la capacidad de ejercicio. Se incluyó a 33 pacientes, a 14 se les administró placebo y a 19 carvedilol. La fracción de eyección basal fue 26,2 por ciento y 22 por ciento (p< 0,11), el tiempo de ejercicio fue 9,5 minutos y 9 minutos (p< 0,73), para los grupos tratados con carvedilol y con placebo respectivamente. La fracción de eyección, al final del estudio, fue 34,5 por ciento y 24,5 por ciento para los pacientes tratados con carvedilol y placebo en cada caso (p< 0,03). El tiempo de ejrcicio aumentó significativamente, 13,8 minutos y 10,6 minutos (p< 0,02)

Efecto del carvedilol sobre la fracción de eyección y capacidad de ejercicio en pacientes con insuficiencia cardíaca / Effect of carvedilol on left ventricular ejection fraction and exercise performance in patients with chronic heart failure

Se evaluó el uso del carvedilol en pacientes con insuficiencia cardíaca mediante un ensayo clínico a doble ciego, valorándose la fracción de eyección y la capacidad de ejercicio. Se incluyó a 33 pacientes, a 14 se les administró placebo y a 19 carvedilol. La fracción de eyección basal fue 26,2 por ciento y 22 por ciento (p< 0,11), el tiempo de ejercicio fue 9,5 minutos y 9 minutos (p< 0,73), para los grupos tratados con carvedilol y con placebo respectivamente. La fracción de eyección, al final del estudio, fue 34,5 por ciento y 24,5 por ciento para los pacientes tratados con carvedilol y placebo en cada caso (p< 0,03). El tiempo de ejrcicio aumentó significativamente, 13,8 minutos y 10,6 minutos (p< 0,02) (AU)

Efecto del carvedilol sobre la función ventricular y capacidad de ejercicio en insuficiencia cardíaca / Effect of carvedilol on ventricular function and exercise capacity in heart failure

Para evaluar el efecto del carvedilol, bloqueante b1 y a1, en pacientes con insuficiencia cardíaca se llevó a cabo un ensayo clínico a doble ciego con asignación al azar, valorándose la fracción de eyección ventricular izquierda y capacidad de ejercicio medida por ergometría. Se incluyeron 33 pacientes, 14 recibieron placebo y 19 carvedilol en dosis creciente hasta 25 mg/día, agregado a la terapia convencional. No hubo diferencias en las características basales de ambos grupos. La fracción de eyección basal fue 26,22 por ciento (ñ 8) y 22 por ciento (ñ 5,7) (p = 0,11) y el tiempo de ejercicio 9,52 min (ñ 3,6) y 9 min (ñ 4) (p = 0,73), para los grupos carvedilol y placebo respectivamente. La fracción de eyección, al final del estudio, fue 34,5 por ciento (ñ 12) y 24,5 por ciento (ñ 7,8) (p = 0,03) y el tiempo de ejercicio (en minutos) 13,8 (ñ 2,3) y 10,6 (ñ 3,4) (p = 0,02) para los grupos tratados y control. El carvedilol administrado crónicamente a pacientes con insuficiencia cardíaca aumenta significativamente la fracción de eyección ventricular izquierda y la capacidad de ejercicio

Efecto del carvedilol sobre la función ventricular y capacidad de ejercicio en insuficiencia cardíaca / Effect of carvedilol on ventricular function and exercise capacity in heart failure

Para evaluar el efecto del carvedilol, bloqueante b1 y a1, en pacientes con insuficiencia cardíaca se llevó a cabo un ensayo clínico a doble ciego con asignación al azar, valorándose la fracción de eyección ventricular izquierda y capacidad de ejercicio medida por ergometría. Se incluyeron 33 pacientes, 14 recibieron placebo y 19 carvedilol en dosis creciente hasta 25 mg/día, agregado a la terapia convencional. No hubo diferencias en las características basales de ambos grupos. La fracción de eyección basal fue 26,22 por ciento (ñ 8) y 22 por ciento (ñ 5,7) (p = 0,11) y el tiempo de ejercicio 9,52 min (ñ 3,6) y 9 min (ñ 4) (p = 0,73), para los grupos carvedilol y placebo respectivamente. La fracción de eyección, al final del estudio, fue 34,5 por ciento (ñ 12) y 24,5 por ciento (ñ 7,8) (p = 0,03) y el tiempo de ejercicio (en minutos) 13,8 (ñ 2,3) y 10,6 (ñ 3,4) (p = 0,02) para los grupos tratados y control. El carvedilol administrado crónicamente a pacientes con insuficiencia cardíaca aumenta significativamente la fracción de eyección ventricular izquierda y la capacidad de ejercicio (AU)