Causes of Cardiovascular Hospitalization and Death in Patients With Transthyretin Amyloid Cardiomyopathy (from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial [ATTR-ACT])

Abstract

In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and cardiovascular (CV)-related hospitalizations compared with placebo in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This analysis aimed to assess the causes of CV-related death and hospitalization in ATTR-ACT to provide further insight into the progression of ATTR-CM and efficacy of tafamidis. ATTR-ACT was an international, double-blind, placebo-controlled, and randomized study. Patients with hereditary or wild-type ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. The independent Endpoint Adjudication Committee determined whether certain investigator-reported events met the definition of disease-related efficacy endpoints using predefined criteria. Cause-specific reasons for CV-related deaths (heart failure [HF], arrhythmia, myocardial infarction, sudden death, stroke, and other CV causes) and hospitalizations (HF, arrhythmia, myocardial infarction, transient ischemic attack/stroke, and other CV causes) were assessed. Total CV-related deaths was 53 (20.1%) with tafamidis and 50 (28.2%) with placebo, with HF (15.5% tafamidis, 22.6% placebo), followed by sudden death (2.7% tafamidis, 5.1% placebo), the most common causes. The number of patients with a CV-related hospitalization was 138 (52.3%) with tafamidis and 107 (60.5%) with placebo; with HF the most common cause (43.2% tafamidis, 50.3% placebo). All predefined causes of CV-related death or hospitalization were less frequent with tafamidis than placebo. In conclusion, these data provide further insight into CV disease progression in patients with ATTR-CM, with HF the most common adjudicated cause of CV-related hospitalization or death in ATTR-ACT.Clinical trial registration ClinicalTrials.gov: NCT01994889. In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and cardiovascular (CV)-related hospitalizations compared with placebo in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This analysis aimed to assess the causes of CV-related death and hospitalization in ATTR-ACT to provide further insight into the progression of ATTR-CM and efficacy of tafamidis. ATTR-ACT was an international, double-blind, placebo-controlled, and randomized study. Patients with hereditary or wild-type ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. The independent Endpoint Adjudication Committee determined whether certain investigator-reported events met the definition of disease-related efficacy endpoints using predefined criteria. Cause-specific reasons for CV-related deaths (heart failure [HF], arrhythmia, myocardial infarction, sudden death, stroke, and other CV causes) and hospitalizations (HF, arrhythmia, myocardial infarction, transient ischemic attack/stroke, and other CV causes) were assessed. Total CV-related deaths was 53 (20.1%) with tafamidis and 50 (28.2%) with placebo, with HF (15.5% tafamidis, 22.6% placebo), followed by sudden death (2.7% tafamidis, 5.1% placebo), the most common causes. The number of patients with a CV-related hospitalization was 138 (52.3%) with tafamidis and 107 (60.5%) with placebo; with HF the most common cause (43.2% tafamidis, 50.3% placebo). All predefined causes of CV-related death or hospitalization were less frequent with tafamidis than placebo. In conclusion, these data provide further insight into CV disease progression in patients with ATTR-CM, with HF the most common adjudicated cause of CV-related hospitalization or death in ATTR-ACT. Clinical trial registration ClinicalTrials.gov: NCT01994889. Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive cardiac disease leading to death within a few years, typically due to cardiac causes including heart failure (HF) and sudden death.1Gillmore JD Damy T Fontana M Hutchinson M Lachmann HJ Martinez-Naharro A Quarta CC Rezk T Whelan CJ Gonzalez-Lopez E Lane T Gilbertson JA Rowczenio D Petrie A Hawkins PN A new staging system for cardiac transthyretin amyloidosis.Eur Heart J. 2018; 39: 2799-2806Crossref PubMed Scopus (334) Google Scholar, 2Rapezzi C Merlini G Quarta CC Riva L Longhi S Leone O Salvi F Ciliberti P Pastorelli F Biagini E Coccolo F Cooke RM Bacchi-Reggiani L Sangiorgi D Ferlini A Cavo M Zamagni E Fonte ML Palladini G Salinaro F Musca F Obici L Branzi A Perlini S Systemic cardiac amyloidoses: Disease profiles and clinical courses of the 3 main types.Circulation. 2009; 120: 1203-1212Crossref PubMed Scopus (575) Google Scholar, 3Castaño A Drachman BM Judge D Maurer MS Natural history and therapy of TTR-cardiac amyloidosis: Emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs.Heart Fail Rev. 2015; 20: 163-178Crossref PubMed Scopus (166) Google Scholar, 4Ruberg FL Maurer MS Judge DP Zeldenrust S Skinner M Kim AY Falk RH Cheung KN Patel AR Pano A Packman J Grogan DR. Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: The Transthyretin Amyloidosis Cardiac Study (TRACS).Am Heart J. 2012; 164 (.e221): 222-228Crossref PubMed Scopus (189) Google Scholar ATTR-CM remains both underdiagnosed and misdiagnosed.5Ruberg FL Grogan M Hanna M Kelly JW Maurer MS Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review.J Am Coll Cardiol. 2019; 73: 2872-2891Crossref PubMed Scopus (501) Google Scholar,6Witteles RM Bokhari S Damy T Elliott PM Falk RH Fine NM Gospodinova M Obici L Rapezzi C Garcia-Pavia P Screening for transthyretin amyloid cardiomyopathy in everyday practice.JACC Heart Fail. 2019; 7: 709-716Crossref PubMed Scopus (185) Google Scholar Greater awareness of ATTR-CM, and what to expect during the course of the disease, could aid earlier diagnosis and improve treatment, which is crucial to facilitate effective patient care.6Witteles RM Bokhari S Damy T Elliott PM Falk RH Fine NM Gospodinova M Obici L Rapezzi C Garcia-Pavia P Screening for transthyretin amyloid cardiomyopathy in everyday practice.JACC Heart Fail. 2019; 7: 709-716Crossref PubMed Scopus (185) Google Scholar In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and cardiovascular (CV)-related hospitalizations compared with placebo in patients with ATTR-CM.7Maurer MS Schwartz JH Gundapaneni B Elliott PM Merlini G Waddington-Cruz M Kristen AV Grogan M Witteles R Damy T Drachman BM Shah SJ Hanna M Judge DP Barsdorf AI Huber P Patterson TA Riley S Schumacher J Stewart M Sultan MB Rapezzi C Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.N Engl J Med. 2018; 379: 1007-1016Crossref PubMed Scopus (1325) Google Scholar All-cause mortality was significantly lower with tafamidis (29.5%) than with placebo (42.9%), as was the rate of CV-related hospitalization (0.48 per year with tafamidis compared with 0.70 per year with placebo).7Maurer MS Schwartz JH Gundapaneni B Elliott PM Merlini G Waddington-Cruz M Kristen AV Grogan M Witteles R Damy T Drachman BM Shah SJ Hanna M Judge DP Barsdorf AI Huber P Patterson TA Riley S Schumacher J Stewart M Sultan MB Rapezzi C Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.N Engl J Med. 2018; 379: 1007-1016Crossref PubMed Scopus (1325) Google Scholar There was also a reduction in all-cause mortality with tafamidis in patients with less and more severe disease and both hereditary and wild-type ATTR-CM.8Rapezzi C Elliott P Damy T Nativi-Nicolau J Berk JL Velazquez EJ Boman K Gundapaneni B Patterson TA Schwartz JH Sultan MB Maurer MS Efficacy of tafamidis in patients with hereditary and wild-type transthyretin amyloid cardiomyopathy: Further analyses from ATTR-ACT.JACC Heart Fail. 2021; 9: 115-123Crossref PubMed Scopus (60) Google Scholar Further information on the causes of hospitalization and death may help guide physicians on what to expect when treating patients with ATTR-CM. We therefore evaluated the causes of CV-related deaths and hospitalizations in ATTR-ACT. ATTR-ACT was a phase 3, multicenter, international, 3-arm, parallel-design, placebo-controlled, double-blind, randomized study for which the design has been previously published (NCT01994889).7Maurer MS Schwartz JH Gundapaneni B Elliott PM Merlini G Waddington-Cruz M Kristen AV Grogan M Witteles R Damy T Drachman BM Shah SJ Hanna M Judge DP Barsdorf AI Huber P Patterson TA Riley S Schumacher J Stewart M Sultan MB Rapezzi C Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.N Engl J Med. 2018; 379: 1007-1016Crossref PubMed Scopus (1325) Google Scholar,9Maurer MS Elliott P Merlini G Shah SJ Cruz MW Flynn A Gundapaneni B Hahn C Riley S Schwartz J Sultan MB Rapezzi C Design and rationale of the phase 3 ATTR-ACT clinical trial (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial).Circ Heart Fail. 2017; 10e003815Crossref PubMed Scopus (56) Google Scholar Briefly, those eligible to enroll were patients aged ≥18 and ≤90 years with a diagnosis of ATTR-CM defined by the presence of either variant TTR (ATTRv), or wild-type amyloid (ATTRwt) and a medical history of HF with at least 1 prior hospitalization due to HF, or clinical signs and symptoms associated with HF (volume overload or elevated intracardiac pressures) that required treatment with a diuretic. Eligible patients also had end-diastolic intraventricular septal wall thickness >12 mm demonstrated by echocardiography, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration ≥ 600 pg/ml and confirmed the presence of amyloid deposits in biopsy tissue from cardiac and noncardiac sites. Patients were randomized (2:1:2) to tafamidis 80 mg, tafamidis 20 mg, or matching placebo once daily for 30 months, with analyses performed on the pooled tafamidis treatment group (combined tafamidis 80 mg and 20 mg groups) compared with placebo. The primary efficacy endpoint of ATTR-ACT was a hierarchical combination of all-cause mortality and frequency of CV-related hospitalizations comparing tafamidis with placebo. CV-related mortality (in which heart transplant or durable cardiac mechanical assist device (CMAD) implantation [for circulatory support] counted as death) and the rate of CV-related hospitalizations were also assessed by Cox proportional hazards model and Poisson regression analysis, respectively.9Maurer MS Elliott P Merlini G Shah SJ Cruz MW Flynn A Gundapaneni B Hahn C Riley S Schwartz J Sultan MB Rapezzi C Design and rationale of the phase 3 ATTR-ACT clinical trial (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial).Circ Heart Fail. 2017; 10e003815Crossref PubMed Scopus (56) Google Scholar The study was approved by the independent review boards or ethics committees at each participating site and was conducted in accordance with the provisions of the Declaration of Helsinki and the International Council for Harmonization Good Clinical Practice guidelines. All patients provided written informed consent. The independent Endpoint Adjudication Committee conducted a blinded review of all potential study endpoints to determine whether investigator-reported events met the definition of disease-related efficacy endpoints using predefined criteria. All cases of death during the study were reported to the Endpoint Adjudication Committee, which reviewed the case to determine the cause of death. Death due to any cause was included in the primary efficacy evaluation (together with a heart transplant and implantation of a durable CMAD, which were counted as death for the efficacy analyses). All deaths were reviewed to determine if they were CV-related or not, with CV-related causes recorded as HF, arrhythmia, myocardial infarction (MI), sudden death, stroke, and other CV causes (see Supplementary Table 1). At each visit, it was reported by the investigator if the patient had been hospitalized (including the reason for hospitalization), with all hospitalizations reported to the Endpoint Adjudication Committee. Hospitalization for endpoint adjudication was defined as a nonelective admission to an acute care setting for medical therapy that resulted in at least a 24-hour stay (or a date change if the time of admission/discharge was not available). Hospitalization reports were also reviewed by the Endpoint Adjudication Committee to determine if they were CV-related or not, with CV-related causes recorded as HF, arrhythmia, MI, transient ischemic attack/stroke, and other CV causes (see Supplementary Table 2). The hazard ratio for time to mortality was derived from a Cox proportional hazards model with genotype (ATTRv and ATTRwt) and New York Heart Association (NYHA) baseline classification (NYHA classes I and II combined, and NYHA class III) in the model. Frequency of all-cause hospitalization was compared using a Poisson regression model with treatment, genotype (ATTRv and ATTRwt), NYHA baseline classification (NYHA classes I and II combined, and NYHA class III), treatment-by-genotype interaction, and treatment-by-NYHA baseline classification interaction terms as factors adjusted for treatment duration.7Maurer MS Schwartz JH Gundapaneni B Elliott PM Merlini G Waddington-Cruz M Kristen AV Grogan M Witteles R Damy T Drachman BM Shah SJ Hanna M Judge DP Barsdorf AI Huber P Patterson TA Riley S Schumacher J Stewart M Sultan MB Rapezzi C Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.N Engl J Med. 2018; 379: 1007-1016Crossref PubMed Scopus (1325) Google Scholar Comorbidities, numbers of deaths, and hospitalizations are shown using descriptive statistics. Causes of hospitalization are shown with multiple occurrences of the same hospitalization admittance reason in a single patient counted once. For efficacy analyses and frequency of hospitalization, all hospitalizations in each patient are counted. As previously reported,7Maurer MS Schwartz JH Gundapaneni B Elliott PM Merlini G Waddington-Cruz M Kristen AV Grogan M Witteles R Damy T Drachman BM Shah SJ Hanna M Judge DP Barsdorf AI Huber P Patterson TA Riley S Schumacher J Stewart M Sultan MB Rapezzi C Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.N Engl J Med. 2018; 379: 1007-1016Crossref PubMed Scopus (1325) Google Scholar demographic and clinical characteristics were similar in the tafamidis and placebo groups, with the majority of patients being male, with a mean age of 74 years, and over 75% ATTRwt. Most patients (approximately 60%) were NYHA class II with median NT-proBNP concentrations being approximately 3,000 pg/ml, and mean left ventricular ejection fraction approximately 48%.7Maurer MS Schwartz JH Gundapaneni B Elliott PM Merlini G Waddington-Cruz M Kristen AV Grogan M Witteles R Damy T Drachman BM Shah SJ Hanna M Judge DP Barsdorf AI Huber P Patterson TA Riley S Schumacher J Stewart M Sultan MB Rapezzi C Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.N Engl J Med. 2018; 379: 1007-1016Crossref PubMed Scopus (1325) Google Scholar Patients had a number of CV-related comorbidities, with the most common being hypertension (54.9% of tafamidis patients; 47.5% of placebo patients), atrial fibrillation (53.0% tafamidis; 50.3% placebo), congestive cardiac failure (25.0% tafamidis; 27.7% placebo), and coronary artery disease (19.3% tafamidis; 22.6% placebo). There was a significant 30.9% reduction in the risk of CV-related death with tafamidis compared with placebo (Figure 1). The majority of deaths in the study were CV-related (103 of 144 total deaths, 71.5%). Total deaths were less frequent with tafamidis compared with placebo, as were both CV-related and non-CV-related deaths (Table 1). All predefined causes of death were less frequent with tafamidis than with placebo (Table 1). There was a nonsignificant 30.2% reduction in the risk of HF death with tafamidis (Figure 1). Within each treatment group, the proportions of each cause of CV-related death were similar, with HF the most common cause of CV-related death, followed by sudden death.Table 1Patient deaths and adjudicated causes of deathDeathsTafamidis(N = 264)Placebo(N = 177)Total deaths72 (27.3%)72 (40.7%) CV-related deaths53 (20.1%)50 (28.2%) Cause of CV-related death Heart failure41 (15.5%)40 (22.6%) Sudden death7 (2.7%)9 (5.1%) Stroke01 (0.6%)*Reported as “hypoxic ischemic encephalopathy with cardiac arrest due to disease progression.” Other CV5 (1.9%)†Including 1 case each reported as “withdrawal of total artificial heart support due to right frontal lobe hemorrhagic cerebrovascular accident,” “multiple organ dysfunction syndrome caused by disease under study,” “brain hemorrhage,” “cardiomyopathy caused by disease under study,” and “disease progression (disease under study).”0Non-CV-related deaths14 (5.3%)13 (7.3%)Indeterminate deaths5 (1.9%)9 (5.1%)CV = cardiovascular.Not counted in this table are heart transplant (7 with tafamidis, 4 with placebo) and implantation of a durable cardiac mechanical assist device (2 with tafamidis, 0 with placebo), which were counted as death in the mortality analysis. Reported as “hypoxic ischemic encephalopathy with cardiac arrest due to disease progression.”† Including 1 case each reported as “withdrawal of total artificial heart support due to right frontal lobe hemorrhagic cerebrovascular accident,” “multiple organ dysfunction syndrome caused by disease under study,” “brain hemorrhage,” “cardiomyopathy caused by disease under study,” and “disease progression (disease under study).” Open table in a new tab CV = cardiovascular. Not counted in this table are heart transplant (7 with tafamidis, 4 with placebo) and implantation of a durable cardiac mechanical assist device (2 with tafamidis, 0 with placebo), which were counted as death in the mortality analysis. The total number of patients with at least 1 hospitalization during the study was 326; 190 (72.0%) in the tafamidis group and 136 (76.8%) in the placebo group. There was a significant 32.4% reduction in the rate of CV-related hospitalizations, and a significant 20.7% reduction in the rate of all-cause hospitalization, with tafamidis compared with placebo (Figure 2). The total proportion of patients hospitalized, and the proportion with CV-related hospitalizations, was greater with placebo than with tafamidis (Table 2). All predefined causes of CV-related hospitalization were less frequent with tafamidis than placebo (Table 2). There was a significant 35.1% reduction in the rate of HF hospitalization, and nonsignificant reductions in the rate of hospitalization and other CV-related hospitalizations with tafamidis compared with placebo (Figure 2). Within each treatment group, the proportions of each cause of CV-related hospitalization were similar, with HF the most common cause of CV-related hospitalization, followed by other CV causes and hospitalized and adjudicated cause of = 264)Placebo(N = 177)Total patients with (76.8%) Patients with CV-related (60.5%) Patients with non-CV-related Patients with of CV-related hospitalization Heart Other = = transient ischemic cause of hospitalization, all new hospitalizations are with multiple occurrences of the same hospitalization reason in a single patient counted once. Open table in a new tab CV = = transient ischemic For cause of hospitalization, all new hospitalizations are with multiple occurrences of the same hospitalization reason in a single patient counted once. In tafamidis was shown to significantly mortality and CV-related hospitalizations in patients with ATTR-CM.7Maurer MS Schwartz JH Gundapaneni B Elliott PM Merlini G Waddington-Cruz M Kristen AV Grogan M Witteles R Damy T Drachman BM Shah SJ Hanna M Judge DP Barsdorf AI Huber P Patterson TA Riley S Schumacher J Stewart M Sultan MB Rapezzi C Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.N Engl J Med. 2018; 379: 1007-1016Crossref PubMed Scopus (1325) Google Scholar In to this this analysis evaluated the causes of death and The majority of deaths were CV-related and the most common cause of CV-related death and hospitalization was provide insight into the of this disease in terms of morbidity and mortality that ATTR-CM is a disease of ATTR-CM is a disease and treatment may not CV-related death was more than non-CV-related death in both and lower in the tafamidis group. sudden death has been as an cause of death in patients with all of FL Maurer MS Judge DP Zeldenrust S Skinner M Kim AY Falk RH Cheung KN Patel AR Pano A Packman J Grogan DR. Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: The Transthyretin Amyloidosis Cardiac Study (TRACS).Am Heart J. 2012; 164 (.e221): 222-228Crossref PubMed Scopus (189) Google C Quarta CC Riva L Longhi S I M Ciliberti P Biagini E Salvi F Branzi A and the A clinical Cardiol. 7: PubMed Scopus Google M A Natural history and therapy of cardiac Fail Rev. 2015; 20: PubMed Scopus Google Scholar in ATTR-ACT were few of CV-related sudden death, of all patients compared with 5.1% of patients over 30 months. In in patients with HF with reduced ejection fraction in which cause of death was a lower of sudden cardiac death has been L Petrie S HJ J L R M B K L J F risk of sudden death in heart Engl J Med. 2017; PubMed Scopus Google Scholar This reduction has been to the of L Petrie S HJ J L R M B K L J F risk of sudden death in heart Engl J Med. 2017; PubMed Scopus Google Scholar patients with ATTR-CM typically ejection T B E M A S D O G JL M F and clinical of hereditary transthyretin amyloid cardiomyopathy in patients with left ventricular wall Heart J. PubMed Scopus Google MS Hanna M Grogan M A Witteles R Drachman B Judge DP Shah SJ S D S Kristen AV Damy T T R Cruz M Rapezzi C and of transthyretin cardiac amyloidosis: Am Coll Cardiol. PubMed Scopus Google Scholar with the mean ejection fraction in ATTR-ACT being approximately 48%.7Maurer MS Schwartz JH Gundapaneni B Elliott PM Merlini G Waddington-Cruz M Kristen AV Grogan M Witteles R Damy T Drachman BM Shah SJ Hanna M Judge DP Barsdorf AI Huber P Patterson TA Riley S Schumacher J Stewart M Sultan MB Rapezzi C Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.N Engl J Med. 2018; 379: 1007-1016Crossref PubMed Scopus (1325) Google Scholar In the trial in patients with HF with ejection fraction ejection fraction of the cause of death, as a of all patients in the was more adjudicated as sudden death of all patients than HF B R B R JL I B E JL T Shah SJ S for heart failure with ejection Engl J Med. PubMed Scopus Google Scholar In were deaths adjudicated as sudden death of the 144 total and adjudicated as HF of the 144 total In were total deaths, adjudicated as sudden death and adjudicated as HF on this it that in patients with ATTR-CM, in to other patients with HF with ejection the cause of death is The frequency of CV-related hospitalizations per year with tafamidis compared with placebo with the risk ratio for the treatment were previously reported as of the predefined from MS Schwartz JH Gundapaneni B Elliott PM Merlini G Waddington-Cruz M Kristen AV Grogan M Witteles R Damy T Drachman BM Shah SJ Hanna M Judge DP Barsdorf AI Huber P Patterson TA Riley S Schumacher J Stewart M Sultan MB Rapezzi C Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy.N Engl J Med. 2018; 379: 1007-1016Crossref PubMed Scopus (1325) Google Scholar The number of CV-related hospitalizations per patient the of in the of the In other hospitalizations were not In the comparing with placebo in a number of patients with HF with reduced ejection fraction (n = and with a similar time HF hospitalizations in of M I M L JL M E K of on hospitalization for heart failure in patients with heart the Heart J. 2012; PubMed Scopus Google Scholar a fraction of the hospitalizations reported in ATTR-ACT. The majority of CV hospitalizations in both were due to HF, followed by with a in the placebo this was similar to other HF clinical ATTR-CM is a disease and is associated with a and number of in this adjudication of in the main reason for hospitalization, is all events were adjudicated by an endpoint adjudication with predefined to CV causes. the number of hospitalizations during may as was the mortality is mortality a on the total number of hospitalizations, which may more frequent in the group with a lower death In of this total and CV-related hospitalizations were less frequent with tafamidis compared with placebo. In conclusion, patients randomized in all adjudicated causes of CV-related death and hospitalization were less common with tafamidis than with placebo, with most deaths HF was the most common cause of CV-related death and and to provide the data that support the of this study. to certain and may also provide to the for more J. analysis reports from and is a of the of has support from and from and and in clinical endpoint boards for and J. reports support from and and Sultan are of and with reports from to the and from and support was provided by of and by with

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