Safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor in adults with cystic fibrosis: randomised, double-blind, controlled, phase 2 trials

Background Elexacaftor–tezacaftor–ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing. Methods We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftor–tezacaftor–deutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftor–tezacaftor–deutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftor–deutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)–tezacaftor–deutivacaftor or tezacaftor–ivacaftor active control for 4 weeks, following a 4-week tezacaftor–ivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete. Findings In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV1 of 3·1 percentage points (95% CI –0·8 to 7·0) and 2·7 percentage points (–1·0 to 6·5) from baseline at week 12, respectively, versus –0·8 percentage points (–6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)–tezacaftor–deutivacaftor (n=9), vanzacaftor (10 mg)–tezacaftor–deutivacaftor (n=19), vanzacaftor (20 mg)–tezacaftor–deutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV1 of 4·6 percentage points (−1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (−4·1 to 8·0), respectively, in sweat chloride concentration of −42·8 mmol/L (–51·7 to –34·0), −45·8 mmol/L (95% CI –51·9 to –39·7), −49·5 mmol/L (–55·9 to –43·1), and 2·3 mmol/L (−7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (−10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)–tezacaftor–deutivacaftor (n=18) and tezacaftor–ivacaftor (n=10) had mean changes relative to baseline (taking tezacaftor–ivacaftor) at day 29 in ppFEV1 of 15·9 percentage points (11·3 to 20·6) and −0·1 percentage points (−6·4 to 6·1), respectively, in sweat chloride concentration of −45·5 mmol/L (−49·7 to −41·3) and −2·6 mmol/L (−8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and −5·0 points (−16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftor–tezacaftor–deutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity. Interpretation Once-daily dosing with vanzacaftor–tezacaftor–deutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftor–tezacaftor–deutivacaftor in phase 3 clinical trials compared with elexacaftor–tezacaftor–ivacaftor. Funding Vertex Pharmaceuticals

Very late neoatherosclerotic plaque rupture in drug-eluting stent restenosis

International audienceA 71-year-old man presented in emergency department for non-ST-elevation myocardial infarction. At admission, 12-lead ECG was in sinus rhythm without sign of myocardial ischemia, and troponin slightly increased. The only notable feature of the patient's medical history was single-vessel coronary artery disease revealed 10 years previously, treated by stenting of the second segment of the right coronary artery with a 3.0 x 25 mm bare metal stent. Three months later, intrastent restenosis was managed by implantation of a 3.0 x 28 mm paclitaxel-eluting stent. Two years before the present admission, following a non contributive stress test for atypical chest pain, coronary angiogram had found a 60% diffuse intrastent restenosis. The present coronary angiogram performed via a right transradial approach demonstrated a focal intrastent restenosis (85%) with irregular contours. Optical coherence tomography (OCT) showed an atherosclerotic intrastent neolesion with intimal tear. OCT demonstrated more precisely a minimal luminal area of 1.02 mm (77.9% area stenosis), two wide cavities (length 1.1 and 1.4 mm) separated by a plaque rupture of 6.8 mm. Myocardial ischemia was evenly demonstrated on this artery with a fractional flow reserve under 0.50 after 150 mg intracoronary adenosine bolus. The culprit lesion was treated by a 3.0 x 38 mm everolimus-eluting stent, with good angiographic results, confirmed on OCT

Geriatric oncologists should be aware of cardio-oncology: Impact of age and gender on 5-FU-mediated TakoTsubo cardiomyopathy

International audienc

Association Between Protein Intake and Mortality in Hypertensive Patients Without Chronic Kidney Disease in the OLD-HTA Cohort

International audienceProtein intake may have some benefits on reducing blood pressure and cardiovascular events, but their effects are still debated. The objective of this study was to test the prognostic value of protein intake assessed by 24-hour urinary urea in a cohort of hypertensive patients with preserved renal function. A total of 1128 hypertensive patients were followed according to tertile of protein intake adjusted for ideal body weight: \textless0.70, 0.70 to 0.93, and \textgreater0.93 g/kg. Baseline characteristics (mean+/-standard deviation) were age 45.1+/-13.2 years, systolic/diastolic blood pressure 185+/-32/107+/-20 mm Hg, and estimated glomerular filtration rate 82+/-32 mL/min. After 10 years of follow-up, 289 deaths occurred, 202 of which were of cardiovascular cause. After adjustment for major cardiovascular risk factors, patients in the second and third tertiles of protein intake had a decreased risk of all-cause death (hazard ratio [95% confidence interval], 0.71 [0.56-0.91]) and cardiovascular death (0.72 [0.54-0.96]), but not of stroke death (0.72 [0.41-1.28]) in comparison to patients in the low protein intake tertile. Normal-high protein intake was associated with a better outcome in a subset of the population: younger patients, low salt intake, without aortic atherosclerosis, or previous cardiovascular events (Pinteraction\textless0.10 for all). Hypertensive patients having a protein intake \textgreater0.7 g/kg ideal body weight, particularly those at low risk, had lower all-cause and cardiovascular mortality rates. Physicians may encourage hyper tensive patients to have normal or high protein diet in addition to low salt consumption, moderate alcohol consumption, and regular physical activity

Significance of different ECG indices for left ventricle enlargement and systolic dysfunction assessment: A cardiac MRI study

[DOI:\hrefhttps://dx.doi.org/10.1016/j.ijcard.2016.04.15710.1016/j.ijcard.2016.04.157] [PubMed:\hrefhttps://www.ncbi.nlm.nih.gov/pubmed/2714924027149240]International audienc

Screening for hypertension-mediated organ damage and aetiology: still of value after 65 years of age?

International audienceBACKGROUND: Secondary forms and hypertension-mediated organ damage (HMOD) may differ between younger and older hypertensive patients. The aim of the present study was to explore the specificity of HMOD and secondary forms in patients ≥ 65 years in comparison to younger ones in a contemporary cohort. METHODS: We analysed 938 patients recruited between 2004 and 2014 (Cardiology department, Croix-Rousse Hospital, Lyon) who had at baseline HMOD and secondary forms screening among them 190 were ≥ 65 years. RESULTS: The mean (2.1 ± 0.8 vs. 1.2 ± 0.9, P \textless 0.001) and frequency of HMOD (96.3% vs. 72.9%, P \textless 0.001) was higher in patients ≥ 65 years than younger ones. Carotid femoral pulse wave velocity \textgreater 10 m/s was the most frequent HMOD in patients ≥ 65 years (90.1%), while echocardiographic left ventricular hypertrophy was the most common in the younger patients (45.0%). Among ECG left ventricular indexes, only R wave in aVL lead was significantly more frequently observed in patients ≥ 65 years (32.6%) than in younger ones (19.0%, P \textless 0.001). The frequency of secondary hypertension was not significantly different between younger and older patients (respectively; 30.5% vs. 27.8%, P = 0.487). The most frequent aetiology was primary aldosteronism regardless of age, followed by renovascular hypertension (6.3% vs. 3.3%, P = 0.038). Among older patients, 3.2% were treated with adrenalectomy and 6.3% with percutaneous transluminal renal angioplasty. CONCLUSION: Extensive screening of HMOD in older patients may be questionable as nearly all patients had one; aetiology must however be explored as a third of older patients had a secondary form

Screening for hypertension-mediated organ damage and aetiology: still of value after 65 years of age?

International audienceBACKGROUND: Secondary forms and hypertension-mediated organ damage (HMOD) may differ between younger and older hypertensive patients. The aim of the present study was to explore the specificity of HMOD and secondary forms in patients ≥ 65 years in comparison to younger ones in a contemporary cohort. METHODS: We analysed 938 patients recruited between 2004 and 2014 (Cardiology department, Croix-Rousse Hospital, Lyon) who had at baseline HMOD and secondary forms screening among them 190 were ≥ 65 years. RESULTS: The mean (2.1 ± 0.8 vs. 1.2 ± 0.9, P \textless 0.001) and frequency of HMOD (96.3% vs. 72.9%, P \textless 0.001) was higher in patients ≥ 65 years than younger ones. Carotid femoral pulse wave velocity \textgreater 10 m/s was the most frequent HMOD in patients ≥ 65 years (90.1%), while echocardiographic left ventricular hypertrophy was the most common in the younger patients (45.0%). Among ECG left ventricular indexes, only R wave in aVL lead was significantly more frequently observed in patients ≥ 65 years (32.6%) than in younger ones (19.0%, P \textless 0.001). The frequency of secondary hypertension was not significantly different between younger and older patients (respectively; 30.5% vs. 27.8%, P = 0.487). The most frequent aetiology was primary aldosteronism regardless of age, followed by renovascular hypertension (6.3% vs. 3.3%, P = 0.038). Among older patients, 3.2% were treated with adrenalectomy and 6.3% with percutaneous transluminal renal angioplasty. CONCLUSION: Extensive screening of HMOD in older patients may be questionable as nearly all patients had one; aetiology must however be explored as a third of older patients had a secondary form

Screening for hypertension-mediated organ damage and aetiology: still of value after 65 years of age?

International audienceBACKGROUND: Secondary forms and hypertension-mediated organ damage (HMOD) may differ between younger and older hypertensive patients. The aim of the present study was to explore the specificity of HMOD and secondary forms in patients ≥ 65 years in comparison to younger ones in a contemporary cohort. METHODS: We analysed 938 patients recruited between 2004 and 2014 (Cardiology department, Croix-Rousse Hospital, Lyon) who had at baseline HMOD and secondary forms screening among them 190 were ≥ 65 years. RESULTS: The mean (2.1 ± 0.8 vs. 1.2 ± 0.9, P \textless 0.001) and frequency of HMOD (96.3% vs. 72.9%, P \textless 0.001) was higher in patients ≥ 65 years than younger ones. Carotid femoral pulse wave velocity \textgreater 10 m/s was the most frequent HMOD in patients ≥ 65 years (90.1%), while echocardiographic left ventricular hypertrophy was the most common in the younger patients (45.0%). Among ECG left ventricular indexes, only R wave in aVL lead was significantly more frequently observed in patients ≥ 65 years (32.6%) than in younger ones (19.0%, P \textless 0.001). The frequency of secondary hypertension was not significantly different between younger and older patients (respectively; 30.5% vs. 27.8%, P = 0.487). The most frequent aetiology was primary aldosteronism regardless of age, followed by renovascular hypertension (6.3% vs. 3.3%, P = 0.038). Among older patients, 3.2% were treated with adrenalectomy and 6.3% with percutaneous transluminal renal angioplasty. CONCLUSION: Extensive screening of HMOD in older patients may be questionable as nearly all patients had one; aetiology must however be explored as a third of older patients had a secondary form

Arrhythmogenic effect of flecainide toxicity

Flecainide is a class 1C antiarrhythmic drug especially used for the management ofsupraventricular arrhythmia. In overdose cases, flecainide can induce life treating ventriculararrhythmias and cardiogenic shock. We report the case of a 72-year-old woman admitted toour intensive care unit for a regular monomorphic wide complex tachycardia (QRS duration240 ms, right bundle branch block and superior axis morphology) without apparent P waves.Clinical examination showed slight left congestive heart failure signs without cardiogenicshock. An intravenous bolus of 10 mg adenosine 5’-triphosphate (ATP) was ineffective to stopthe tachycardia. The diagnosis of ventricular tachycardia induced by flecainide overdose wasconsidered. 500 mL of intravenous 84‰ sodium bicarbonate was administrated. The patient’sQRS narrowed immediately and 12-lead ECG showed sinus rhythm. Blood samples confirmed theflecainide overdose and the clinical status progressively improved