Publications by authors named "Jennifer Cautela"

45 Publications

Intensified immunosuppressive therapy in patients with immune checkpoint inhibitor-induced myocarditis.

J Immunother Cancer 2020 12;8(2)

University Mediterranean Centre of Cardio-Oncology (MEDI-CO centre), Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Nord Hospital, Centre for CardioVascular and Nutrition research (C2VN), INSERM 1263, INRAE 1260, Aix-Marseille University, Assistance Publique - Hôpitaux de Marseille, Marseille, Provence-Alpes-Côte d'Azur, France

Background: Myocarditis is a rare but life-threatening adverse event of cancer treatments with immune checkpoint inhibitors (ICIs). Recent guidelines recommend the use of high doses of corticosteroids as a first-line treatment, followed by intensified immunosuppressive therapy (IIST) in the case of unfavorable evolution. However, this strategy is empirical, and no studies have specifically addressed this issue. Therefore, we aimed to investigate and compare the clinical course, management and outcome of ICI-induced myocarditis patients requiring or not requiring IIST.

Methods: This case-control study included all patients consecutively admitted to The Mediterranean University Center of Cardio-Oncology (Aix-Marseille University, France) for the diagnosis of ICI-induced myocarditis according to Bonaca's criteria and treated with or without IIST. In addition, we searched PubMed and included patients from previously published case reports treated with IIST in the analysis. The clinical, biological, imaging, treatment, all-cause death and cardiovascular death data of patients who required IIST were compared with those of patients who did not.

Results: A total of 60 patients (69±12 years) were included (36 were treated with IIST and 24 were not). Patients requiring IIST were more likely to have received a combination of ICIs (39% vs 8%, p=0.01), and developed the first symptoms/signs of myocarditis earlier after the onset of ICI therapy (median, 18 days vs 60 days, p=0.002). They had a significantly higher prevalence of sustained ventricular arrhythmia, complete atrioventricular block, cardiogenic shock and troponin elevation. Moreover, they were more likely to have other immune-related adverse events simultaneously (p<0.0001), especially myositis (p=0.0002) and myasthenia gravis (p=0.009). Patients who required IIST were more likely to die from any cause (50% vs 21%, p=0.02). Among them, patients who received infliximab were more likely to die from cardiovascular causes (OR, 12.0; 95% CI 2.1 to 67.1; p=0.005).

Conclusion: The need for IIST was more common in patients who developed myocarditis very early after the start of ICI therapy, as well as when hemodynamic/electrical instability or neuromuscular adverse events occurred. Treatment with infliximab might be associated with an increased risk of cardiovascular death.
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http://dx.doi.org/10.1136/jitc-2020-001887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725077PMC
December 2020

Cardiovascular Toxicity Related to Cancer Treatment: A Pragmatic Approach to the American and European Cardio-Oncology Guidelines.

J Am Heart Assoc 2020 09 5;9(18):e018403. Epub 2020 Sep 5.

Unit of Heart Failure and Valvular Heart Diseases Department of Cardiology Nord Hospital Center for CardioVascular and Nutrition Research (C2VN) University Mediterranean Center of Cardio-Oncology (MEDI-CO Center) Assistance Publique - Hôpitaux de MarseilleAix-Marseille University Marseille France.

The considerable progress made in the field of cancer treatment has led to a dramatic improvement in the prognosis of patients with cancer. However, toxicities resulting from these treatments represent a cost that can be harmful to short- and long-term outcomes. Adverse events affecting the cardiovascular system are one of the greatest challenges in the overall management of patients with cancer, as they can compromise the success of the optimal treatment against the tumor. Such adverse events are associated not only with older chemotherapy drugs such as anthracyclines but also with many targeted therapies and immunotherapies. Recognizing this concern, several American and European governing societies in oncology and cardiology have published guidelines on the cardiovascular monitoring of patients receiving potentially cardiotoxic cancer therapies, as well as on the management of cardiovascular toxicities. However, the low level of evidence supporting these guidelines has led to numerous discrepancies, leaving clinicians without a consensus strategy to apply. A cardio-oncology expert panel from the French Working Group of Cardio-Oncology has undertaken an ambitious effort to analyze and harmonize the most recent American and European guidelines to propose roadmaps and decision algorithms that would be easy for clinicians to use in their daily practice. In this statement, the experts addressed the cardiovascular monitoring strategies for the cancer drugs associated with the highest risk of cardiovascular toxicities, as well as the management of such toxicities.
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http://dx.doi.org/10.1161/JAHA.120.018403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727003PMC
September 2020

All rise! Orthostatic hypotension in heart failure: reply.

Eur J Heart Fail 2020 09 7;22(9):1742. Epub 2020 Jul 7.

Department of Cardiology, Heart Failure and Valvular Heart Diseases Unit, Mediterranean University Cardio-Oncology Center (MEDI-CO Center), Hôpital Nord, Aix-Marseille I University, Marseille, France.

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http://dx.doi.org/10.1002/ejhf.1927DOI Listing
September 2020

Management of low blood pressure in ambulatory heart failure with reduced ejection fraction patients.

Eur J Heart Fail 2020 08 30;22(8):1357-1365. Epub 2020 Apr 30.

Faculté de Médecine, Université de Lorraine, Centre d'Investigations Cliniques Plurithématique 1433, Institut Lorrain du Cœur et des Vaisseaux, Vandoeuvre les Nancy France Groupe choc, INSERM U1116, Vandoeuvre les Nancy, France.

Low blood pressure is common in patients with heart failure and reduced ejection fraction (HFrEF). While spontaneous hypotension predicts risk in HFrEF, there is only limited evidence regarding the relationship between hypotension observed during heart failure (HF) drug titration and outcome. Nevertheless, hypotension (especially orthostatic hypotension) is an important factor limiting the titration of HFrEF treatments in routine practice. In patients with signs of shock and/or severe congestion, hospitalization is advised. However, in the very frequent cases of non-severe and asymptomatic hypotension observed while taking drugs with a class I indication in HFrEF, European and US guidelines recommend maintaining the same drug dosage. In instances of symptomatic or severe persistent hypotension (systolic blood pressure < 90 mmHg), it is recommended to first decrease blood pressure reducing drugs not indicated in HFrEF as well as the loop diuretic dose in the absence of associated signs of congestion. Unless the management of hypotension appears urgent, a HF specialist should then be sought rather than stopping or decreasing drugs with a class I indication in HFrEF. If symptoms or severe hypotension persist, no recommendations exist. Our HF group reviewed available evidence and proposes certain steps to follow in such situations in order to improve the pharmacological management of these patients.
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http://dx.doi.org/10.1002/ejhf.1835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540603PMC
August 2020

Identification of anticancer drugs associated with atrial fibrillation - analysis of the WHO pharmacovigilance database.

Eur Heart J Cardiovasc Pharmacother 2020 Apr 30. Epub 2020 Apr 30.

Normandie Univ, UNICAEN, CHU de Caen Normandie, PICARO Cardio-oncology Program, Department of Pharmacology, EA 4650, Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, F-14000 CAEN, France.

Aims: The explosion of novel anticancer therapies has meant emergence of cardiotoxicity signals including atrial fibrillation (AF). Reliable data concerning the liability of anticancer drugs in inducing AF are scarce. Using the World Health Organization individual case safety report database, VigiBase®, we aimed to determine the association between anticancer drugs and AF.

Methods And Results: A disproportionality analysis evaluating the multivariable adjusted reporting odd-ratios (aROR) for AF with their 99.97% confidence intervals (CI) was performed for 176 FDA- or EMA-labeled anticancer drugs in VigiBase®, followed by a descriptive analysis of AF cases for the anticancer drugs identified in VigiBase®. ClinicalTrial registration number: NCT03530215.A total of 11,757 AF cases associated with at least one anticancer drug were identified in VigiBase® of which 95.8% were deemed serious. Nineteen anticancer drugs were significantly associated with AF of which 14 (74%) are used in hematologic malignancies and 9 (45%) represented new AF associations not previously confirmed in literature including immunomodulating agents (lenalidomide, pomalidomide), several kinase inhibitors (nilotinib, ponatinib, midostaurin), antimetabolites (azacytidine, clofarabine), docetaxel (taxane) and obinutuzumab, an anti-CD20 monoclonal antibody.

Conclusion: Although cancer malignancy itself may generate AF, we identified 19 anticancer drugs significantly associated with a significant increase in AF over-reporting. This pharmacovigilance study provides evidence that anticancer drugs themselves could represent independent risk factors for AF development. Dedicated prospective clinical trials are now required to confirm these 19 associations. This list of suspected anticancer drugs should be known by physicians when confronted to AF in cancer patients, particularly in case of hematologic malignancies.
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http://dx.doi.org/10.1093/ehjcvp/pvaa037DOI Listing
April 2020

Immune Checkpoint Inhibitor Rechallenge After Immune-Related Adverse Events in Patients With Cancer.

JAMA Oncol 2020 06;6(6):865-871

Normandie University, University of Caen Normandy, Centre Hospitalier Universitaire (CHU) de Caen Normandie, PICARO Cardio-oncology Program, Department of Pharmacology, EA 4650, Signalisation, Électrophysiologie et Imagerie des Lésions d'Ischémie-Reperfusion Myocardique, Caen, France.

Importance: Limited information is available on the safety of a rechallenge with an immune checkpoint inhibitor (ICI) after an immune-related adverse event (irAE).

Objective: To identify the recurrence rate of the same irAE that prompted discontinuation of ICI therapy after an ICI rechallenge in patients with cancer and to identify the clinical features associated with such recurrences.

Design, Setting, And Participants: This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database VigiBase, which contains case reports from more than 130 countries. Case reports were extracted from database inception (1967) to September 1, 2019. All consecutive ICI cases with at least 1 associated irAE were included.

Main Outcomes And Measures: The primary outcome was the rate of recurrence of the initial irAE after an ICI rechallenge. Secondary outcomes included the factors associated with the recurrence after a rechallenge among informative rechallenges, the recurrence rate according to the ICI regimen (anti-programmed cell death 1 or anti-programmed cell death ligand 1 monotherapy, anti-cytotoxic T-lymphocyte antigen-4 monotherapy, or combination therapy), and the rate of occurrence of a different irAE after a rechallenge.

Results: A total of 24 079 irAE cases associated with at least 1 ICI were identified. Among the irAEs, 452 of 6123 irAEs associated with ICI rechallenges (7.4%) were informative rechallenges. One hundred thirty recurrences (28.8%; 95% CI, 24.8-33.1) of the initial irAE were observed. In a rechallenge, colitis (reporting odds ratio [OR], 1.77; 95% CI, 1.14-2.75; P = .01), hepatitis (reporting OR, 3.38; 95% CI, 1.31-8.74; P = .01), and pneumonitis (reporting OR, 2.26; 95% CI, 1.18-4.32; P = .01) were associated with a higher recurrence rate, whereas adrenal events were associated with a lower recurrence rate (reporting OR, 0.33; 95% CI, 0.13-0.86; P = .03) compared with other irAEs.

Conclusions And Relevance: This cohort study found a 28.8% recurrence rate of the same irAE associated with the discontinuation of ICI therapy after a rechallenge with the same ICI. Resuming ICI therapy could be considered for select patients, with appropriate monitoring and use of standard treatment algorithms to identify and treat toxic effects.
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http://dx.doi.org/10.1001/jamaoncol.2020.0726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163782PMC
June 2020

[Valvular heart disease].

Rev Prat 2019 Nov;69(9):e291-e305

Unité Nord insuffisance cardiaque et valvulopathies, Aix-Marseille Université, Assistance publique-Hôpitaux de Marseille, hôpital Nord, 13015 Marseille, France.

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November 2019

Acute Coronary Syndrome With Immune Checkpoint Inhibitors: A Proof-of-Concept Case and Pharmacovigilance Analysis of a Life-Threatening Adverse Event.

Can J Cardiol 2020 04 11;36(4):476-481. Epub 2019 Dec 11.

University Mediterranean Centre of Cardio-Oncology, Assistance Publique-Hôpitaux de Marseille, Aix-Marseille University, and Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Hôpital Nord, Marseille, France; Groupe Méditerranéen de Cardio-Oncologie, Marseille, France; Centre for Cardiovascular and Nutrition Research, Aix-Marseille University, INSERM 1263, INRA 1260, Marseille, France. Electronic address:

Isolated cases of acute coronary syndrome (ACS) associated with immune checkpoint inhibitors (ICIs) have been described without the establishment of a formal cause-and-effect relationship between treatment and adverse event. We reported a case of ACS after the first administration of an ICI and with a fatal recurrence in another coronary area immediately after readministration. According to guidelines, causality was considered to be certain. Subsequently, we queried the French pharmacovigilance database and found 4 cases of ACS with coronary artery thrombosis. Causality was probable in those patients. These data suggest that ACS may be another life-threatening cardiac adverse event occurring with ICI exposure.
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http://dx.doi.org/10.1016/j.cjca.2019.11.035DOI Listing
April 2020

Late cardiac adverse events in patients with cancer treated with immune checkpoint inhibitors.

J Immunother Cancer 2020 01;8(1)

CHU de Caen, PICARO Cardio-oncology Program, Department of Pharmacology, CHU de Caen, Caen, France.

Background: Immune checkpoint inhibitor (ICI)-associated early cardiac adverse events (CAEs), mostly acute and fulminant myocarditis, have been well characterized and mainly occur during the first 90 days after ICI therapy initiation. ICI-associated late CAEs (occurring after the first 90 days of treatment) have not yet been described.

Methods: First, we compared characteristics of a cohort involving early (defined as a CAE time to onset (TTO) of <90 days after ICI therapy initiation) and late (defined as a CAE TTO of ≥90 days after ICI therapy initiation) ICI-associated CAE consecutive cases who were referred to three French cardio-oncology units. Second, ICI-associated CAE cases were searched in VigiBase, the WHO global individual case safety report database, and early and late ICI-associated CAEs were compared.

Results: In the cohort study, compared with early CAE cases (n=19, median TTO of 14 days), late ICI-associated CAE cases (n=19, median TTO of 304 days) exhibited significantly more left ventricular systolic dysfunction (LVSD) and heart failure (HF) and less frequent supraventricular arrhythmias. In VigiBase, compared with early cases (n=437, 73.3%, median TTO 21 days), the late ICI-associated CAE reports (n=159, 26.7%, median TTO 178 days) had significantly more frequent HF (21.1% vs 31.4%, respectively, p=0.01). Early and late ICI-associated CAE cases had similarly high mortality rates (40.0% vs 44.4% in the cohort and 30.0% vs 27.0% in VigiBase, respectively).

Conclusions: Late CAEs could occur with ICI therapy and were mainly revealed to be HF with LVSD.

Trial Registration Numbers: NCT03678337, NCT03882580, and NCT03492528.
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http://dx.doi.org/10.1136/jitc-2019-000261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057417PMC
January 2020

[Myocarditis: Uncommon but severe toxicity of immune checkpoint inhibitors].

Bull Cancer 2019 Nov 15;106(11):1050-1056. Epub 2019 Oct 15.

Hôpital de la Croix-Rousse et Hôpital Lyon Sud, hospices civils de Lyon, Cardiology Department, 69004, Lyon, France; Université de Lyon, université Claude-Bernard Lyon 1, hospices civils de Lyon, CREATIS ; CNRS UMR5220, INSA-Lyon, IMMUCARE, Inserm U1044, 69004, Lyon, France.

Traditional cancer therapies, such as treatment with anthracyclines and chest radiation, are known to induce cardiovascular complications. Currently, the increase of cancer therapies will involve new mechanisms such as cancer immunotherapies, also called immune checkpoint inhibitors (PD-1, PD-L1 and CTLA-4 inhibitors). These treatments have shown long-term remissions in subgroup of cancers, including melanomas, non-small-cell lung cancer, urothelial carcinoma, renal cell carcinoma, squamous cell carcinoma of the head and neck and colorectal cancer. Although these treatments will change the natural course of these cancers, they may sometimes induce cardiovascular complications, which has been reported as about 1 % in the literature. Currently, the physicians must keep in mind one uncommon but severe cardiac complication: auto-immune myocarditis. The clinical presentation may include various symptoms like chest pain, heart failure or rhythm disorders. In this situation, a baseline cardiologic check-up before starting cancer immunotherapy may be very helpful. Cardiac biomarkers (troponin and brain natriuretic peptide) and 12-lead resting electrocardiogram must be promptly performed when myocarditis is suspected. A cardiologist's opinion must be requested in emergency to discuss both a transthoracic echocardiography and the appropriate treatment (stopping immunotherapy, adding immunosuppressive treatment such as corticoids) and the monitoring in an intensive care unit. Cardiac MRI and endomyocardial biopsies may help to approach the final diagnosis. In this situation, other cancer therapies may be discussed.
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http://dx.doi.org/10.1016/j.bulcan.2019.09.003DOI Listing
November 2019

Pulmonary hypertension in patients with myeloproliferative neoplasms: A large cohort of 183 patients.

Eur J Intern Med 2019 Oct 14;68:71-75. Epub 2019 Aug 14.

Hematology and Cellular Therapy Department, La Conception, University Hospital of Marseille, France; Aix-Marseille University, INSERM, UMR1090 TAGC, Marseille F_13288, France.

Background: Chronic myeloproliferative neoplasms (MPN) are recognized as a cause of pulmonary hypertension (pH). We ought to describe the prevalence and characteristics of PH in a cohort of MPN who were screened using transthoracic echocardiography (TTE).

Methods: One hundred eighty-three newly diagnosed consecutive MPN patients were prospectively evaluated using TTE to detect PH.

Results: Two patients were diagnosed with chronic eosinophilic leukemia, two patients had post-essential thrombocythemia (ET) myelofibrosis (MF), two patients had post-polycythemia vera (PV) MF, 11 patients had primary myelofibrosis (PMF), 28 patients had chronic myeloid leukemia (CML), 51 patients had PV, and 87 patients had ET. TTE was used to determine PH, and PH was suspected in 16 of 183 patients as follows: four with PV, seven with ET, two with PMF, and three with CML. Two patients with ET were excluded because of global cardiac failure. Three patients underwent right heart catheterization to confirm PH. The 14 (7.7%) patients with PH had no cardiac or lung disease that directly involved MPN in PH development.

Conclusion: In this large cohort of 183 MPN patients, TTE was used to diagnose PH, and 14 patients (7.7%) developed PH. This prevalence was lower than expected based on previously reported data, but it remains higher than in the general population.
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http://dx.doi.org/10.1016/j.ejim.2019.08.004DOI Listing
October 2019

Mechanical characterisation of human ascending aorta dissection.

J Biomech 2019 Sep 31;94:138-146. Epub 2019 Jul 31.

Aix Marseille Univ, APHM, IFSTTAR, LBA, North Hospital, Department of Vascular Surgery, Marseille, France.

Mechanical characteristics of both the healthy ascending aorta and acute type A aortic dissection were investigated using in vitro biaxial tensile tests, in vivo measurements via transoesophageal echocardiography and histological characterisations. This combination of analysis at tissular, structural and microstructural levels highlighted the following: (i) a linear mechanical response for the dissected intimomedial flap and, conversely, nonlinear behaviour for both healthy and dissected ascending aorta; all showed anisotropy; (ii) a stiffer mechanical response in the longitudinal than in the circumferential direction for the healthy ascending aorta, consistent with the histological quantification of collagen and elastin fibre density; (iii) a link between dissection and ascending aorta stiffening, as revealed by biaxial tensile tests. This result was corroborated by in vivo measurements with stiffness index, β, and Peterson modulus, E, higher for patients with dissection than for control patients. It was consistent with histological analysis on dissected samples showing elastin fibre dislocations, reduced elastin density and increased collagen density. To our knowledge, this is the first study to report biaxial tensile tests on the dissected intimomedial flap and in vivo stiffness measurements of acute type A dissection in humans.
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http://dx.doi.org/10.1016/j.jbiomech.2019.07.028DOI Listing
September 2019

High incidence of atrial fibrillation in patients treated with ibrutinib.

Open Heart 2019;6(1):e001049. Epub 2019 May 8.

Department of Cardiology, Unit of Heart Failure and Valvular Heart Diseases, Mediterranean University Cardio-Oncology Center (MEDI-CO Center), Hôpital Nord, Aix-Marseille I University, Marseille, France.

Objective: Atrial fibrillation (AF) is one of the most common side effects of ibrutinib, a drug that has dramatically improved the prognosis of chronic B-cell malignancies such as chronic lymphocytic leukaemia (CLL). The true incidence of ibrutinib-related AF (IRAF) is not well known and its therapeutic management poses unique challenges especially due to the inherent risk of bleeding. We aimed to determine the incidence and predictors of IRAF, and to analyse its management and outcome.

Methods: A standardised monitoring was applied at two cardio-oncology clinics in consecutive patients referred before and during ibrutinib therapy. The primary endpoint was the incidence of IRAF. The excess of AF incidence with ibrutinib was studied by comparing the incidence of IRAF with the expected incidence of AF in general population and in patients with CLL not exposed to ibrutinib.

Results: 53 patients were included. The incidence of IRAF was 38% at 2 years and the risk was 15-fold higher than the AF risk in both the general population and patients with CLL not exposed to ibrutinib (p<0.0001). The majority of cases occurred in asymptomatic patients within the first 6 months. Left atrial volume index ≥40 mL/m at treatment initiation identified patients at high risk of developing IRAF. No major bleeding events occurred in patients on ibrutinib, although the majority of patients with IRAF were treated with anticoagulants.

Conclusions: This cardio-oncology study showed that the risk of IRAF was much higher than previously reported. The majority of cases occurred in asymptomatic patients justifying close monitoring.
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http://dx.doi.org/10.1136/openhrt-2019-001049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519413PMC
May 2019

Dynamic iron status after acute heart failure.

Arch Cardiovasc Dis 2019 Jun - Jul;112(6-7):410-419. Epub 2019 Apr 18.

Heart Failure and Valvular Heart Disease Unit, Mediterranean University Cardio-Oncology (MEDI-CO) Centre, Department of Cardiology, Aix-Marseille University, hôpital Nord, AP-HM, chemin des Bourrely, 13015 Marseille, France; Inserm 1263, INRA, centre de recherche cardiovasculaire et nutrition (C2VN), Aix-Marseille University, 13385 Marseille, France. Electronic address:

Background: Iron deficiency (ID) is common in heart failure (HF), and is associated with unfavourable clinical outcomes. Although it is recommended to screen for ID in HF, there is no clear consensus on the optimal timing of its assessment.

Aim: To analyse changes in iron status during a short-term follow-up in patients admitted for acute HF.

Methods: Iron status (serum ferritin concentration and transferrin saturation) was determined in 110 consecutive patients (median age: 81 years) admitted to a referral centre for acute HF, at three timepoints (admission, discharge and 1 month after discharge). ID was defined according to the guidelines.

Results: The prevalence rates of ID at admission, discharge and 1 month were, respectively, 75% (95% confidence interval [CI] 67-83%), 61% (95% CI: 52-70%), and 70% (95% CI: 61-79%) (P=0.008). Changes in prevalence were significant between admission and discharge (P=0.0018). Despite a similar ID prevalence at admission and 1 month (P=0.34), iron status changed in 25% of patients. Between admission and discharge, variation in C-reactive protein correlated significantly with that of ferritin (ρ=0.30; P=0.001). Advanced age, anaemia, low ferritin concentration and low creatinine clearance were associated with the persistence of ID from admission to 1 month.

Conclusions: Iron status is dynamic in patients admitted for acute HF. Although ID was as frequent at admission as at 1 month after discharge, iron status varied in 25% of patients.
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http://dx.doi.org/10.1016/j.acvd.2019.02.002DOI Listing
December 2019

Physiological stress markers during breath-hold diving and SCUBA diving.

Physiol Rep 2019 03;7(6):e14033

C2VN, INSERM, INRA, Aix-Marseille Université (AMU), Marseille, France.

This study investigated the sources of physiological stress in diving by comparing SCUBA dives (stressors: hydrostatic pressure, cold, and hyperoxia), apneic dives (hydrostatic pressure, cold, physical activity, hypoxia), and dry static apnea (hypoxia only). We hypothesized that despite the hypoxia induces by a long static apnea, it would be less stressful than SCUBA dive or apneic dives since the latter combined high pressure, physical activity, and cold exposure. Blood samples were collected from 12SCUBA and 12 apnea divers before and after dives. On a different occasion, samples were collected from the apneic group before and after a maximal static dry apnea. We measured changes in levels of the stress hormones cortisol and copeptin in each situation. To identify localized effects of the stress, we measured levels of the cardiac injury markers troponin (cTnI) and brain natriuretic peptide (BNP), the muscular stress markers myoglobin and lactate), and the hypoxemia marker ischemia-modified albumin (IMA). Copeptin, cortisol, and IMA levels increased for the apneic dive and the static dry apnea, whereas they decreased for the SCUBA dive. Troponin, BNP, and myoglobin levels increased for the apneic dive, but were unchanged for the SCUBA dive and the static dry apnea. We conclude that hypoxia induced by apnea is the dominant trigger for the release of stress hormones and cardiac injury markers, whereas cold or and hyperbaric exposures play a minor role. These results indicate that subjects should be screened carefully for pre-existing cardiac diseases before undertaking significant apneic maneuvers.
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http://dx.doi.org/10.14814/phy2.14033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434169PMC
March 2019

[How to organise cardiovascular management of cancer patients?]

Rev Prat 2018 Mar;68(3):332-335

Aix-Marseille université, Assistance publique-Hôpitaux de Marseille, unité Nord insuffisance cardiaque et valvulopathies, centre méditerranéen hospitalo-universitaire de cardiologie oncologique - Medi-CO Center, hôpital Nord, Marseille, France.

How to organise cardiovascular management of cancer patients? Advances in cancer therapy have reduced cancer mortality. However, these results are sometimes achieved at the cost of cardiovascular adverse events that may limit the overall benefit of treatment. Cardio-oncology is a recent discipline that aims to prevent, screen and manage cardiovascular diseases associated with or secondary to cancer treatment without compromising its effectiveness. These goals must therefore be integrated into the patient care program at the time of cancer diagnosis. Therefore, a cardiovascular toxicity risk assessment should be conducted prior treatment to identify patients candidate for closer monitoring. In parallel with their oncologic follow-up, these high-risk patients should receive cardiovascular follow-up that should not be restricted to a solely measurement of the left ventricular ejection fraction. Indeed, toxicities can be multiple, so the assessment must be comprehensive and should include at least clinical examination, ECG, cardiac imaging, and sometimes biomarkers. In the case of cardiovascular events, this organisation will enable an earlier and coordinated management with oncologists, which will result in an improvement of the patients' overall prognosis.
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March 2018

OCT Analysis of Very Early Strut Coverage of the Synergy Stent in Non-ST Segment Elevation Acute Coronary Syndrome Patients.

J Invasive Cardiol 2019 01 11;31(1):10-14. Epub 2018 Nov 11.

Service de Cardiologie, Hôpital Nord Chemin des Bourrely, 13015, Marseille, France.

Objectives: Early endothelialization of drug-eluting stent (DES) is a major challenge to reduce the risk of stent thrombosis and the duration of dual-antiplatelet therapy (DAPT) in high bleeding-risk patients. The aim of the present study is to evaluate very early strut coverage with optical coherence tomography (OCT) of the Synergy stent (Boston Scientific) at 1 month in non-ST segment elevation acute coronary syndrome (NSTE-ACS) patients.

Methods: This substudy of the EARLY trial prospectively included NSTE-ACS patients treated with the Synergy DES. OCT analysis of the Synergy stent was performed during a staged PCI of additional lesions at 1 month. The primary endpoint was the percentage of covered struts assessed with OCT at 1 month.

Results: Twenty-four patients were included, with a mean stent length of 35.9 ± 10.1 mm per patient. The rate of covered struts was 78.5% out of 3839 struts analyzed. Nineteen patients (79.2%) had at least 70% of their struts covered. The average neointimal thickness was 0.0508 ± 0.016 mm.

Conclusions: In NSTE-ACS patients undergoing culprit percutaneous coronary intervention with the Synergy stent, the rate of covered struts at 1 month was 78.5%. This rapid coverage is in line with the results of clinical trials demonstrating the safety of short-duration DAPT in selected patients who are at high bleeding risk and treated with new-generation DES options.
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January 2019

Device-Related Thrombus After Left Atrial Appendage Occlusion With the Amulet Device.

Heart Lung Circ 2019 Nov 27;28(11):1683-1688. Epub 2018 Sep 27.

Aix-Marseille University, Assistance Publique - Hôpitaux de Marseille (APHM), Department of Cardiology, Nord Hospital, Chemin des Bourrelly, 13915 Marseille, Cedex, France; MARS Cardio, Mediterranean Association for Research and Studies in Cardiology, Nord Hospital, Chemin des Bourrelly, 13915 Marseille, Cedex, France.

Background: Left atrial appendage occlusion (LAAO) is increasingly used for stroke prevention in patients with atrial fibrillation who are considered unsuitable for a lifelong oral anticoagulant regimen. Recently, a single-centre study reported device-related thrombus formation in 16.7% of patients treated with the second-generation Amulet device (St. Jude Medical, St. Paul, MN, USA), presenting a potential major safety concern. As "real-world" data on device-related thrombus formation following LAAO with the Amulet occluder are scarce, we aimed to evaluate this outcome in a retrospective registry.

Methods: Clinical and tranosesophageal echocardiography data after LAAO with the Amulet in consecutive patients from three centres were collated.

Results: Among 38 patients (mean age 75.8 years), mean (standard deviation) CHADS-VASc and HAS-BLED scores were 4.4 (1.2) and 3.4 (0.9), respectively. All patients underwent successful device placement without procedure-related adverse events. The antithrombotic regimen at discharge consisted of dual antiplatelet therapy (DAPT) in 27 patients (71.1%), single antiplatelet therapy in 10 patients (26.3%), and no antithrombotic therapy in one patient (2.6%). Device-related thrombus was observed in one patient (2.6%) despite DAPT regimen. The outcome of this patient was uncomplicated after adjustment of oral anticoagulant therapy. No patients presented with a thromboembolic event following LAAO during a mean (standard deviation) follow-up of 15 (5) months.

Conclusions: In this retrospective study, device-related thrombus formation with the second-generation Amulet device was rare and occurred at a rate similar to that of the previous device. Importantly, no patient experienced a device-related thromboembolic event during follow-up. Larger real-life studies are required to confirm the safety profile of this increasingly used device.
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http://dx.doi.org/10.1016/j.hlc.2018.08.022DOI Listing
November 2019

Doppler echocardiography for assessment of systemic vascular resistances in cardiogenic shock patients.

Eur Heart J Acute Cardiovasc Care 2020 Mar 20;9(2):102-107. Epub 2018 Aug 20.

Intensive Care Unit, Aix-Marseille University, France.

Objective: Impaired vascular tone plays an important role in cardiogenic shock. Doppler echocardiography provides a non-invasive estimation of systemic vascular resistance. The aim of the present study was to compare Doppler echocardiography with the transpulmonary thermodilution method for the assessment of systemic vascular resistance in patients with cardiogenic shock.

Methods: This prospective monocentric comparison study was conducted in a single cardiology intensive care unit (Hopital Nord, Marseille, France). We assessed the systemic vascular resistance index by both echocardiography and transpulmonary thermodilution in 28 patients admitted for cardiogenic shock, on admission and after the introduction of an inotrope or vasopressor treatment.

Results: A total of 35 paired echocardiographic and transpulmonary thermodilution estimations of the systemic vascular resistance index were compared. Echocardiography values ranged from 1309 to 3526 dynes.s.m/cm and transpulmonary thermodilution values ranged from 1320 to 3901 dynes.s.m/cm. A statistically significant correlation was found between echocardiography and transpulmonary thermodilution (=0.86, 95% confidence interval (CI) 0.74, 0.93; <0.0001). The intraclass correlation coefficient was 0.84 (95% CI 0.72, 0.92). The mean bias was -111.95 dynes.s.m/cm (95% CI -230.06, 6.16). Limits of agreement were -785.86, 561.96.

Conclusions: Doppler echocardiography constitutes an accurate non-invasive alternative to transpulmonary thermodilution to provide an estimation of systemic vascular resistance in patients with cardiogenic shock.
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http://dx.doi.org/10.1177/2048872618795514DOI Listing
March 2020

Response by Thuny et al to Letter Regarding Article, "Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor-Related Cardiotoxicity".

Circulation 2018 05;137(22):2423-2424

Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Mediterranean University Cardio-Oncology Center, Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Hôpital Nord, Marseille, France (F.T., M.E., J.C.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.033783DOI Listing
May 2018

Uric acid levels are associated with endothelial dysfunction and severity of coronary atherosclerosis during a first episode of acute coronary syndrome.

Purinergic Signal 2018 06 6;14(2):191-199. Epub 2018 Apr 6.

Department of Cardiology, Hopital Nord, Marseille, France.

The role of serum uric acid in coronary artery disease has been extensively investigated. It was suggested that serum uric acid level (SUA) is an independent predictor of endothelial dysfunction and related to coronary artery lesions. However, the relationship between SUA and severity of coronary atherosclerosis evaluated via endothelial dysfunction using peripheral arterial tone (PAT) and the reactive hyperhemia index (RHI) has not been investigated during a first episode of acute coronary syndrome (ACS). The aim of our study was to address this point. We prospectively enrolled 80 patients with a first episode of ACS in a single-center observational study. All patients underwent coronary angiography, evaluation of endothelial function via the RHI, and SUA measurement. The severity of the coronary artery lesion was assessed angiographically, and patients were classified in three groups based on the extent of disease and Gensini and SYNTAX scores. Endothelial function was considered abnormal if RHI < 1.67. We identified a linear correlation between SUA and RHI (R = 0.66 P < 0.001). In multivariable analyses, SUA remained associated with RHI, even after adjustment for traditional cardiovascular risk factors and renal function. SUA was associated with severity of coronary artery disease. SUA is associated with severity of coronary atherosclerosis in patients with asymptomatic hyperuricemia. This inexpensive, readily measured biological parameter may be useful to monitor ACS patients.
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http://dx.doi.org/10.1007/s11302-018-9604-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940631PMC
June 2018

Takotsubo-Like Syndrome in Cancer Patients Treated With Immune Checkpoint Inhibitors.

JACC Cardiovasc Imaging 2018 08 14;11(8):1187-1190. Epub 2018 Mar 14.

Department of Cardiology, Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Paris, France; INSERM U 856, Thrombose, Athérothrombose et Pharmacologie Appliquée, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jcmg.2017.11.036DOI Listing
August 2018

Impact of the time-to-treatment concept on the outcome of acute heart failure: A pilot study.

Arch Cardiovasc Dis 2018 Apr 28;111(4):270-275. Epub 2018 Feb 28.

Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, Hôpital Nord, Mediterranean Cardio-Oncology University Centre (MEDI-CO Centre), Aix-Marseille University, AP-HM, 13015 Marseille, France; Centre for CardioVascular and Nutrition research (C2VN), Inserm 1263, Inra 1260, Aix-Marseille University, 13385 Marseille, France. Electronic address:

Background: An optimal maximum time of 60minutes has been recommended in recent guidelines for the first evaluation and treatment of patients with acute heart failure (AHF); however, this has not been tested prospectively.

Aim: To analyze the impact of a time-to-treatment (TTT) strategy of <60minutes on the in-hospital outcome of patients with AHF.

Methods: During a single 1-month period, we consecutively enrolled all patients hospitalized with AHF in a prospective cohort. In this pilot study, TTT was defined as the time between the first medical contact to the onset of the first medical intervention. The primary outcome was a composite including in-hospital death or worsening AHF.

Results: Of the 74 patients included, 23 (31%) had a TTT of <60minutes. Although these patients were more likely to have a more severe episode of AHF, the primary outcome occurred only in patients with a TTT of ≥60minutes. The primary outcome was significantly associated with a TTT of ≥60minutes (P=0.036), low systolic blood pressure (P<0.01), rales more than halfway up the lung fields (P=0.02), infectious precipitating factor (P=0.04) and high serum concentrations of B-type natriuretic peptide (P<0.01) and urea (P=0.03). No significant differences were observed in the rate of treatment-induced acute renal insufficiency or in the long-term rates of death or rehospitalization for heart failure according to TTT.

Conclusions: This study suggests that the recently recommended TTT strategy of <60minutes in the setting of AHF might be associated with a better prognosis during hospitalization. Further large prospective works are needed to confirm these preliminary results, and to define more precisely which types of AHF could benefit from this strategy.
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http://dx.doi.org/10.1016/j.acvd.2017.11.005DOI Listing
April 2018

Response to the letter: The high burden of coronary artery disease in heart failure with preserved ejection fraction.

Arch Cardiovasc Dis 2018 03 5;111(3):227. Epub 2018 Jan 5.

Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, hôpital Nord, Aix-Marseille University, AP-HM, 13015 Marseille, France; Centre de recherche cardiovasculaire et nutrition (C2VN), UMR MD2, Inserm 1263, Inra, Aix-Marseille université, 13005 Marseille, France.

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http://dx.doi.org/10.1016/j.acvd.2017.12.003DOI Listing
March 2018

Prevalence and characteristics of coronary artery disease in heart failure with preserved and mid-range ejection fractions: A systematic angiography approach.

Arch Cardiovasc Dis 2018 Feb 12;111(2):109-118. Epub 2017 Oct 12.

Unit of Heart Failure and Valvular Heart Diseases, Department of Cardiology, hôpital Nord, Aix-Marseille University, AP-HM, chemin des Bourrely, 13015 Marseille, France; Mediterranean Association for Research and Studies in Cardiology (MARS Cardio), 13015 Marseille, France. Electronic address:

Background: Guidelines recommend careful screening and treatment of coronary artery disease (CAD) in heart failure with preserved or mid-range ejection fraction (HFpEF/HFmEF).

Aim: We aimed to determine the prevalence and characteristics of CAD using a prospective systematic coronary angiography approach.

Methods: A systematic coronary angiography protocol was applied in consecutive patients admitted for HFpEF/HFmEF during a 6-month period in a single centre. History of CAD and results of angiography, including revascularization, were reported.

Results: Of the 164 patients with HFpEF/HFmEF who were included, an angiography assessment was applied in 108 (66%) (median age: 79 years [interquartile range: 70-85 years]; 54% were women). In our analysis, 64% (95% confidence interval [CI] 55-73%) of patients had a significant coronary stenosis corresponding to a global CAD prevalence of 80% (95% CI 73-88%). The prevalence of CAD was similar for HFpEF and HFmEF. The left main coronary artery presented a significant stenosis in 6.5% of cases and 39% of patients had a two- or three-vessel disease. The rate of significant coronary stenosis was non-significantly higher in patients with a history of CAD. Patients with HFpEF/HFmEF with and without CAD did not differ in clinically meaningful ways, in terms of symptoms or laboratory and echocardiography results. This strategy led to complete revascularization in 36% of patients with significant stenosis and in 23% of all patients with HFpEF/HFmEF.

Conclusions: Our study differs from others in that we used a systematic angiography approach. The results suggest a much higher prevalence of CAD in HFpEF/HFmEF than previously reported and should encourage clinicians to aggressively identify this co-morbidity.
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http://dx.doi.org/10.1016/j.acvd.2017.05.006DOI Listing
February 2018

Ventricular Arrhythmia Occurrence and Compliance in Patients Treated With the Wearable Cardioverter Defibrillator Following Percutaneous Coronary Intervention.

Heart Lung Circ 2018 Aug 25;27(8):984-988. Epub 2017 Sep 25.

Aix-Marseille University, Assistance Publique - Hôpitaux de Marseille (AP-HM), Department of Cardiology, Nord Hospital, France; Mediterranean Academic Association for Research and Studies in Cardiology (MARS Cardio), France. Electronic address:

Background: The wearable cardioverter defibrillator (WCD) is a life-saving therapy in patients with high risk of arrhythmic death. We aimed to evaluate ventricular arrhythmia (VA) occurrence rate and compliance with the WCD during the first 90 days following myocardial revascularisation with percutaneous coronary intervention (PCI) in patients with left ventricular ejection fraction (LVEF) <30%.

Methods: From September 2015 to November 2016, clinical characteristics, WCD recordings and compliance data of the aforementioned subset of patients were prospectively collected.

Results: Twenty-four patients (men=20, 80%) were included in this analysis. Mean age was 56±10 years and mean LVEF at enrolment was 26.6±4.3%. During a mean wearing period of 3.0±1.3 months, two episodes of VA occurred in two patients (8.3%): one successfully treated with WCD shock and one with spontaneous termination. The mean and median daily use of the WCD was 21.5hours and 23.5hours a day, respectively. Eighteen patients (75%) wore the WCD more than 22hours a day.

Conclusions: The rate of VA, during the WCD period use after myocardial revascularisation with PCI, was high in our study. Otherwise it underlined that patient compliance is critical during the WCD period use. Remote monitoring and patient education are keys to achieve good compliance.
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http://dx.doi.org/10.1016/j.hlc.2017.08.022DOI Listing
August 2018

Towards Addressing the Body Electrolyte Environment via Sweat Analysis:Pilocarpine Iontophoresis Supports Assessment of Plasma Potassium Concentration.

Sci Rep 2017 09 18;7(1):11801. Epub 2017 Sep 18.

UMR MD2, Aix Marseille University, Marseille, France.

Electrolyte concentration in sweat depends on environmental context and physical condition but also on the pathophysiological status. Sweat analyzers may be therefore the future way for biological survey although how sweat electrolyte composition can reflect plasma composition remains unclear. We recruited 10 healthy subjects and 6 patients to have a broad range of plasma electrolyte concentrations (chloride, potassium and sodium) and pH. These variables were compared to those found in sweat produced following cycling exercise or pilocarpine iontophoresis, a condition compatible with operating a wearable device. We found no correlation between plasma and sweat parameters when exercise-induced sweat was analyzed, and we could identify a correlation only between plasma and sweat potassium concentration (R = 0.78, p < 0.01) when sweat was induced using pilocarpine iontophoresis. We tested measurement repeatability in sweat at 24hr-interval for 3 days in 4 subjects and found a great intra-individual variability regarding all parameters in exercise-induced sweat whereas similar electrolyte levels were measured in pilocarpine-induced sweat. Thus, electrolyte concentration in sweat sampled following physical activity does not reflect concentration in plasma while pilocarpine iontophoresis appears to be promising to reproducibly address sweat electrolytes, and to make an indirect evaluation of plasma potassium concentration in chronic kidney disease and arrhythmia.
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http://dx.doi.org/10.1038/s41598-017-12211-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603548PMC
September 2017

Wearable cardioverter defibrillator: Bridge or alternative to implantation?

World J Cardiol 2017 Jun;9(6):531-538

Jeremie Barraud, Jennifer Cautela, Morgane Orabona, Johan Pinto, Olivier Missenard, Marc Laine, Franck Thuny, Franck Paganelli, Laurent Bonello, Michael Peyrol, Department of Cardiology, Aix-Marseille University, Assistance Publique - Hôpitaux de Marseille, Nord Hospital, 13015 Marseille, France.

The implantable cardioverter-defibrillator (ICD) is effective to prevent sudden cardiac death (SCD) in selected patients with heart disease known to be at high risk for ventricular arrhythmia. Nevertheless, this invasive and definitive therapy is not indicated in patients with potentially transient or reversible causes of sudden death, or in patients with temporary contra-indication for ICD placement. The wearable cardioverter defibrillator (WCD) is increasingly used for SCD prevention both in patients awaiting ICD implantation or with an estimated high risk of ventricular arrhythmia though to be transient. We conducted a review of current clinical uses and benefits of the WCD, and described its technical aspects, limitations and perspectives.
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http://dx.doi.org/10.4330/wjc.v9.i6.531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491470PMC
June 2017

Controlled sedation with midazolam and analgesia with nalbuphine to alleviate pain in patients undergoing subcutaneous implantable cardioverter defibrillator implantation.

J Interv Card Electrophysiol 2017 Aug 23;49(2):191-196. Epub 2017 May 23.

Aix-Marseille University, Marseille, France.

Purpose: Subcutaneous implantable cardioverter defibrillator (S-ICD) is an alternative to transvenous ICD to prevent sudden cardiac death. Subcutaneous ICD implantation frequently requires general anesthesia because of procedure nociceptive steps during creation of a large device pocket and lead tunneling. This study aims to determine if a strategy of operator-guided controlled sedation with midazolam and analgesia with nalbuphine is effective in alleviating pain during S-ICD implantation.

Methods: This prospective study included consecutive patients undergoing S-ICD implantation under controlled sedation with midazolam and combined analgesia with nalbuphine. The Critical-Care Pain Observation Tool (CPOT), a behavioral pain scale, was used for pain assessment during S-ICD placement and the Numeric Rate Scale (NRS) was used for evaluation of pain recollection after patient recovery. CPOT score of 3 or above and NRS score of 4 or above are considered to be associated with significant pain.

Results: Sixteen patients were included in this study: Ten men (62.5%) and six women with a mean age of 54 ± 11 years. Indication for S-ICD implantation was primary prevention in 11 patients (68.8%). Mean dose of administrated midazolam and nalbuphine was 0.11 ± 0.03 and 0.27 ± 0.05 mg/kg, respectively. Mean CPOT during the whole procedure was 1.4 ± 1.6. No patient presented procedural pain recollection as all 16 patients had NRS score less than 4. No serious adverse event related to sedation occurred during S-ICD implantation.

Conclusions: This study suggests that operator-guided controlled sedation with midazolam and analgesia with nalbuphine is effective to alleviate procedural pain in patients undergoing S-ICD implantation and may constitute an alternative to general anesthesia.
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http://dx.doi.org/10.1007/s10840-017-0255-5DOI Listing
August 2017