Prevalence and bleeding risk associated with the concomitant use of direct oral anticoagulants and antiarrhythmic drugs in patients with atrial fibrillation, based on the French healthcare insurance database.

PURPOSE: Pharmacokinetic interactions exist between apixaban or rivaroxaban, and CYP3A4 and P-glycoprotein inhibitors such as amiodarone, verapamil and diltiazem. We aimed to estimate the prevalence of exposure to this drug-drug association (DDA) and to assess the bleeding risk associated in patients with atrial fibrillation (AF). METHODS: We conducted a cohort study using a representative 1/97th sample of the French healthcare insurance database between 2014 and 2019. Patients with AF receiving apixaban or rivaroxaban were included and followed-up until hospitalization for bleeding, death, discontinuation of apixaban or rivaroxaban, exposure to strong CYP3A4 inhibitor, or until December 31st 2019, whichever came first. Primary outcome was hospitalization for bleeding registered as primary diagnosis. The association between the exposure to the DDA and hospitalization for bleeding was evaluated as a time-dependent variable in Cox model. RESULTS: Between 2014 and 2019, the AF population under apixaban or rivaroxaban represented 10,392 patients. During the study period, the annual average prevalence of DDA exposure in this population was 38.9%. Among the 10,392 patients, 223 (2.1%) were hospitalized for bleeding, of which 75 (33.6%) received the association and 148 (66.4%) received apixaban or rivaroxaban alone. There was no association between DDA exposure and risk of hospitalization for bleeding (aHR = 1.19, [95% CI: 0.90, 1.58]). Age (HR 1.03 [1.02, 1.05]) and male gender (HR 1.72 [1.28, 2.30]) were associated with an increased risk of hospitalization for bleeding. CONCLUSION: Exposure to antiarrhythmic drugs was not associated with an increased risk of hospitalization for bleeding in patients with AF under rivaroxaban or apixaban.

Comparison among three different follow-up models for obstructive sleep apnea syndrome patients: focus on the physiotherapist's role.

In obstructive sleep apnea syndrome (OSAS) subjects different follow-up modalities have been proposed to improve adherence to the continuous positive airway pressure (CPAP) device. This retrospective study compares three different health professional approaches dedicated to caring OSAS patients in three consecutive follow-up periods of 15 months each. The three different follow-up models are: i) physician-oriented follow-up (P-F); ii) physiotherapist-oriented follow-up (PT-F); and iii) tele-titration plus PT-oriented follow-up (TT-PT-F). Health personal visits and actions delivered, patients' adherence, CPAP efficacy, and problems under CPAP use were considered for comparison. Data from 122 OSAS patients with a new prescription of CPAP were analyzed: 39 (32.0%) in the P-F, 38 (31.1%) in the PT-F, and 45 (36.9%) in the TT-PT-F period. We found a reduction over time (from 40.9% in P-F to 8.2% in TT-PT-F, p<0.001) in patients missing the 1-year follow-up visit. The PT-F and TT-PT-F lead to a reduction in physician visits in comparison to P-F (5.2% and 8.9% vs 100%, p<0.001) with no differences in time to the first follow-up visit, CPAP efficacy, and patients' adherence among the three periods. More device-related problems were found in the PT-F (57.8%), compared with the PF (25.6%) period (p<0.001); the most common troubles were mask problems evaluated in 26.2% of cases. In conclusion, different follow-up models offer similar efficacy and short-term adherence for CPAP leading to a significant reduction in physician visits under the PT-F with or without tele-titration, being mask problems as the most commonly treated. Further analysis should be useful to define the best cost-efficacy follow-up intervention.

Relationship between perceived and neuromuscular fatigue in COPD patients with chronic respiratory failure with long-term oxygen therapy: a cross-sectional study.

PURPOSE: To evaluate perceived fatigue (PF) and neuromuscular fatigue (NMF) in patients with COPD and chronic respiratory failure (CRF) on long-term oxygen therapy (CRF-COPD group), and the relationships between PF, NMF, patient's characteristics, comparing severe patients with COPD to patients without CRF (COPD group). METHODS: This cross-sectional study compared 19 CRF-COPD patients with 10 COPD patients attending a rehabilitation program. PF was determined by Fatigue Severity Scale (FSS), while dyspnea by the Barthel Dyspnea Index (BDI). We assessed quadriceps NMF via electrical nerve stimulation during and following a Maximal Voluntary Contraction (MVC) detecting changes after a Constant Workload Cycling Test (CWCT) at 80% of the peak power output at exhaustion. RESULTS: CRF-COPD patients showed higher PF (+ 1.79 of FSS score, p = 0.0052) and dyspnea (+ 21.03 of BDI score, p = 0.0023) than COPD patients. After the fatiguing task and normalization for the total work, there was a similar decrease in the MVC (CRF-COPD -1.5 ± 2.4 vs COPD -1.1 ± 1.2% baseline kJ-1, p = 0.5819), in the potentiated resting twitch force (CRF-COPD -2.8 ± 4.7 vs COPD -2.0 ± 3.3% baseline kJ-1, p = 0.7481) and in the maximal voluntary activation (CRF-COPD -0.1 ± 3.9 vs COPD -0.9 ± 1.2 -2.0 ± 3.3% baseline kJ-1, p = 0.4354). FSS and BDI were closely related (R = 0.5735, p = 0.0011), while no correlation between PF and NMF was found. CONCLUSION: Patients with CRF-COPD develop higher levels of perceived fatigue and dyspnea than patients with COPD; while neuromuscular fatigue is similar, suggesting a mismatch between symptoms and neuromuscular dysfunction.

Respiratory rehabilitation for patients with COVID-19 infection and chronic respiratory failure: a real-life retrospective study by a Lombard network.

The Lombardy region has been one of the areas most affected by the COVID-19 pandemic since the first months of 2020, providing real-life experiences in the acute phase. It is unclear how the respiratory rehabilitation network responded to this emergency. The aims of this retrospective study were: i) to analyze clinical, functional, and disability data at admission; ii) describe assessment tools and rehabilitative programs; iii) evaluate improvement after rehabilitation. The study was conducted on data collected from ten pulmonary rehabilitation centers in Lombardy, between the period of March 1st 2020 to March 1st 2021, in patients with respiratory failure recovering from COVID-19 both at admission and discharge. The study included demographics, comorbidities, nutritional status, risk of falls, disability status (Barthel index; Short Physical Performance Battery (SPPB); 6 minutes walking test (6MWT), symptoms (dyspnoea with Barthel Dyspnoea and MRC Dyspnoea Scale), length of stay, discharge destination, need for mechanical ventilation, respiratory function, assessment/outcomes indices, and prescribed rehabilitative programs. 413 patients were analyzed. Length of stay in acute and rehabilitative units was less than 30 days. Fifty % of patients used non-invasive ventilation during their stay. Functional status was mildly compromised for forced volumes and oxygenation, while severely compromised for diffusion capacity. Independency was low while physical performance status very low.  At discharge, 318 (77%) patients were sent home, 83 (20.1%) were transferred to an acute unit and 12 (2.9%) passed away. Barthel Index and 6MWT were the most used, while MRC score was the least used outcome parameter. The 5 main rehabilitative activities were walking (90.8 %), transfer from bed to armchair (77.5%), limb mobilization in bed (76%), balance (71.2%), and cycle-ergometer or treadmill (43.1%). A huge difference was found in admission, discharge, and delta change among different rehabilitative centers. When available, all outcomes showed a significant improvement. With the limitation of a retrospective study with a clear amount of missing data, COVID-19 subjects admitted to rehabilitative centers presented a reduced physical performance, symptoms of dyspnoea, and severe disability. The 6MWT and Barthel index were the most used measurement.

Hospital-Provider Company Network for Home Non-Invasive Ventilation: A Feasibility Pilot Study.

This study assessed the feasibility of implementing a hybrid hospital-provider company (PC) clinical pathway for patients with chronic respiratory failure (CRF) through the adaptation and follow-up of non-invasive ventilation (NIV). Over a 3-month period, a PC physiotherapist case manager oversaw the adaptation process, making adjustments as necessary, using remote monitoring and home visits. Outcome measures, including the number of patients enrolled, serious adverse events, hospitalizations, survival rates, professional time allocation, NIV adherence, nocturnal apnea-hypopnea, and oxygen saturation, Δ arterial carbon dioxide pressure (PaCO2), dyspnea, Short Physical Performance Battery (SPPB), exercise tolerance, quality of life, physical activity, and patient satisfaction, were collected. The recruitment rate was 74% (nineteen patients). Commonly reported adverse events included leakage, discomfort and sleep disturbance. Predominant interventions were four home visits (3; 4) and two NIV adjustments (1; 5). The overall program time commitment averaged 43.97 h per patient (being hospital 40 ± 11% and PC 60 ± 11%). Improvements in PaCO2, dyspnea, SPPB and exercise tolerance were observed by the third month. Adherence to NIV was high, with good or very good satisfaction with its use. This study demonstrates that a hybrid hospital-PC service for NIV adaptation and follow-up is not only feasible but also shows validity, reliability, and acceptability.

Upper-limb interval versus constant-load exercise in patients with COPD: a physiological crossover study.

Objective: Upper-limb exercise is recommended for patients with COPD, albeit there are limited data concerning the optimal modality to implement. We compared interval (INT-EX) to continuous (CONT-EX) upper-limb exercise in terms of exercise tolerance, ventilatory and metabolic responses when both conditions were sustained at an equivalent work rate. Methods: 26 stable COPD patients undertook three upper-limb exercise sessions to initially establish peak work rate (PWR) via an incremental exercise test and subsequently two equivalent work rate tests to the limit tolerance in balanced order: 1) INT-EX consisting of 30-s work at 100% PWR interspersed with 30-s work at 40% of PWR; and 2) CONT-EX at 70% PWR. Results: 20 patients (76.9%) had longer tolerance during INT-EX, while six out of 26 (23.1%) exhibited longer tolerance during CONT-EX. The average endurance time was 434.1±184.7 and 315.7±128.7 s for INT-EX and CONT-EX, respectively. During INT-EX at isotime (i.e. when work completed was the same between INT-EX and CONT-EX), the majority of patients manifested lower oxygen uptake, minute ventilation, pulmonary hyperinflation, heart rate, symptoms and higher CO2 blood concentration. Patients with longer INT-EX had a lower comorbidity score (Cumulative Illness Rating Scale: 1.58±0.30 versus 1.88±0.29, p=0.0395) and better-preserved lung function (forced vital capacity 84.7±15.31% versus 67.67±20.56%, p=0.0367; forced expiratory volume in 1 s 57.15±14.59 versus 44.67±12.99% predicted, p=0.0725) compared to patients with longer CONT-EX. Conclusion: INT-EX is more sustainable than CONT-EX for the majority of COPD patients with moderate obstruction, leading to lower dynamic hyperinflation and symptoms at isotime. Further studies need to define the benefits of its application during pulmonary rehabilitation.

Airflow grades, outcome measures and response to pulmonary rehabilitation in individuals after an exacerbation of severe chronic obstructive pulmonary disease.

BACKGROUND: Individuals with COPD may be staged according to symptoms and exacerbation history (GOLD groups: A-D) and on airflow obstruction (GOLD grades: 1-4). Guidelines recommend pulmonary rehabilitation (PR) for these individuals, including those recovering from an exacerbation (ECOPD) OBJECTIVE: To evaluate whether in individuals with clinically severe COPD, recovering from an ECOPD, the effect size of an in-hospital PR program would be affected by airflow severity grades and assessed outcome measures. METHODS: Retrospective, multicentre study. Participants were compared according to different GOLD airflow grades. In addition to the MRC dyspnoea scale, six-minute walking distance test and COPD assessment test (CAT), Barthel dyspnoea index (Bid), and Short Physical Performance Battery (SPPB) were assessed, evaluating the proportion of individuals reaching the minimum clinically important difference (MCID) (responders). RESULTS: Data of 479 individuals, completing the program were evaluated. Most of the participants were allocated in GOLD grades 4, (57.6%) and 3 (22.1%). All outcome measures significantly improved after PR (p < 0.05), without any significant difference in the proportion of responders in any measure. CONCLUSIONS: in individuals with severe COPD, recovering from ECOPD the success rate of PR does not depend on airflow severity, or outcome measure assessed. In addition to the most used outcome measures, also Bid and SPPB are sensitive to PR.

In-Patient Trajectories and Effects of Training in Survivors of COVID-19-Associated Acute Respiratory Failure.

BACKGROUND: Pulmonary rehabilitation (PR) is useful in survivors of COVID-19-associated acute respiratory failure (ARF). The aim of this retrospective study on in-patient PR was to report rehabilitative trajectories and effects of cycle training. METHODS: According to the Short Physical Performance Battery (SPPB) score at admission (T0), participants were allocated to stage 1 (SPPB < 6), stage 2 (SPPB ≥ 6 and < 10), or stage 3 (SPPB ≥ 10) and performed increasing level of activities from passive exercises to free walking, balance exercises, strength exercises, and tailored cycle-ergometer endurance training. The primary outcome was SPPB. 6-min walk distance (6MWD), Medical Research Council score, Barthel dyspnea index, and rate of subjects able to cycling were also assessed. RESULTS: Data of 123 participants were analyzed. At T0, 44 (35.8%), 50 (40.6%), and 29 (23.6%) participants were allocated to stages 1-3, respectively. At discharge, participants showed significant improvements in SPPB, independent of the initial stage, 81 (65.8%) improving more than its minimal clinically important difference. At T1, the proportion of participants in stages 1 and 2 decreased, whereas significantly increased in stage 3 (P = .003), (being 9.8%, 33.3%, and 56.9% for stages 1-3, respectively; P <.001). Sixty-nine of 123 participants (56.1%) underwent cycle exercise training. In participants able to perform it, 6MWD improved by 115 (65-240) m and 60 (40-118) m in participants with and without exercise-induced desaturation, respectively, with significant difference between groups (P = .044). CONCLUSIONS: In-patient PR could be tailored and progressively increased to survivors of COVID-19-associated ARF; cycle training was feasible in half of the participants. Benefits were independent of initial stage of physical performance and allowed participants to move from lower to higher levels of activities.

Effectiveness of pulmonary rehabilitation in individuals with Chronic Obstructive Pulmonary Disease according to inhaled therapy: The Maugeri study.

BACKGROUND AND AIM: Real-life studies report discordant prescribing of inhaled triple therapy (TT) among individuals with COPD. Guidelines recommend pulmonary rehabilitation (PR) for persistent breathlessness and/or exercise limitation. This real-life study aimed to assess the effects of in-patient PR in individuals under TT as compared to other inhaled therapies (no TT). METHODS: Multicentric, retrospective analysis of data from individuals admitted to in-hospital PR. Baseline characteristics were recorded and lung function was assessed. Outcome measures were: 6-min walking test (6MWT: primary outcome), Medical Research Council (MRC) scale for dyspnoea, and COPD assessment test (CAT). RESULTS: Data of pre and post program 6MWT of 1139 individuals were available. Pulmonary rehabilitation resulted in significant improvement in 6MWT in both groups, however, the effect size (by 54.3 ± 69.7 vs 42.5 ± 64.2 m, p = 0.004) and proportion of individuals reaching the minimal clinically important difference (MCID) of 6MWT (64.2%, vs 54.3%, p = 0.001) were higher in TT group. Both groups significantly improved also the other outcome measures. The significant independent predictors of reaching the MCID of 6MWT were hospital provenience, TT use, and high eosinophils count. CONCLUSION: Pulmonary rehabilitation results in significant benefits in individuals with COPD irrespective of the use of TT. However, individuals under TT report larger benefits in exercise tolerance than those under no TT.

Management of drug-drug interactions with nirmatrelvir/ritonavir in patients treated for Covid-19: Guidelines from the French Society of Pharmacology and Therapeutics (SFPT).

OBJECTIVES: Nirmatrelvir in association with ritonavir (PAXLOVID™, Pfizer) is an antiviral agent targeting the 3-chymotrypsin-like cysteine protease enzyme (3C-like protease or Mpro) which is a key enzyme of the viral cycle of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This combination with a well-known pharmacokinetic enhancer leads to a high risk for drug-drug interactions in a polymedicated elected population for treatment. The aim of this work was to provide recommendations on behalf of the national French society of pharmacology (French Society of Pharmacology and Therapeutics; SFPT), by suggesting optimal and pragmatic therapeutic strategies if nirmatrelvir/ritonavir is to be given together with drugs commonly used, in order to ensure secured physicians' prescription. METHODS: Six clinical pharmacologists search the scientific literature to provide a first draft of recommendations. Thereafter, twelve other clinical pharmacologists verified the recommendations and proposed modifications. The final draft was then validated by all 18 participants. RESULTS: Five distinct recommendations were issued: i) contra-indications, ii) "PAXLOVID™ not recommended with the comedication", iii) "PAXLOVID™ possible whether the comedication is discontinued", iv) "PAXLOVID™ possible only after an expert advice" and v) "PAXLOVID™ possible without modification of the associated treatment". The final document comprises recommendations for 171 drugs/therapeutic classes aiming to secure prescription. In complex situations, clinicians are advised to contact their pharmacology department to obtain specific recommendations on the management of drug-drug interactions with nirmatrelvir/ritonavir. CONCLUSION: These recommendations intend to be a help for clinicians willing to prescribe nirmatrelvir/ritonavir and to prevent drug-drug interactions leading to adverse drug reactions or loss of efficacy. They constitute a guideline for primary care situations. Of course, some complex situations may require expert advices and here, again, clinical pharmacologists are at the forefront in providing therapeutic advice.

Potential drug-drug interactions associated with drugs currently proposed for COVID-19 treatment in patients receiving other treatments.

Patients with COVID-19 are sometimes already being treated for one or more other chronic conditions, especially if they are elderly. Introducing a treatment against COVID-19, either on an outpatient basis or during hospitalization for more severe cases, raises the question of potential drug-drug interactions. Here, we analyzed the potential or proven risk of the co-administration of drugs used for the most common chronic diseases and those currently offered as treatment or undergoing therapeutic trials for COVID-19. Practical recommendations are offered, where possible.