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Istaroxime – A Novel Lusitropic and Inotropic Agent: Results of a Phase I-II Study
S152
Journal of Cardiac Failure Vol. 11 No. 6 Suppl. 2005
230
232
Istaroxime – A Novel Lusitropic and Inotropic Agent: Results of a Phase I-II Study Jalal Ghali1, William Smith2, Guillermo Torre-Amione3, William Haynos4, Barry Rayburn5, Antonino Amato6, Dan Zhang6, Doug Cowart6, Giovanni Valentini7, Paolo Carminati7, Mihai Gheorghiade8; 1Cardiology, L.S.U - H.S.C., Shreveport, LA; 2New Orleans-C.C.R., New Orleans, LA; 3Baylor Col. of Med., Houston, TX; 4Univ. of Iowa, Iowa City, IA; 5Univ. Alabama, Birmingham, AL; 6Sigma-Tau Research, Inc, Gaithersburg, MD; 7Sigma-Tau S.p.A., Pomezia, Italy; 8Northwestern University, Chicago, IL
The Genetic Risk Assessment Sub-Study of the African-American Heart Failure Trial (A-HeFT): Impact of Genetic Variation of NOS3 Dennis M. McNamara, S. William Tam, Michael L. Sabolinski, Amy Palmer, Page Tobelman, Karen Janosko, Arthur M. Feldman, Manuel Worcel; Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA; NitroMed, Inc., Lexington, MA; Jefferson Medical College, Philadelphia, PA
Animal studies have shown that Istaroxime (PST 2744) is a luso-inotrope that stimulates SERCA IIa, has no chronotropic effect and has beneficial effect on myocardial energetics. Istaroxime was evaluated for the first time in 18 chronic stable heart failure (HF) patients (pts) in a Phase I-II clinical trial. Methods: Three cohorts of 6 pts were exposed to 4 sequentially increasing 1 hour infusions with a random placebo. Dosage was from 0.3 to 300 mcg/kg/hr. Safety and hemodynamics were evaluated by Impedance Cardiography (ICG), digital Holter and EKG. PK was obtained over 1 hour during treatment and for 6 hours following the completion of dosage. Results: Pts characteristics: age 53 ⫾ 7; men 61%; HF duration 6.5 ⫾ 3.2 yrs; EF 27 ⫾ 8%; CAD 75%; Beta-Blocker 93% and ACE/ARB 100%. ICG demonstrated enhanced indices of contractility (Acceleration Index-ACI), Left Cardiac Work Index (LCWI), Cardiac Index (CI) and Pulse Pressure (PP) at doses of 60 mcg/kg/hr and higher. Following termination of infusion, hemodynamic effect rapidly dissipated over 1–2 hours. MEAN CHANGE IN KEY PARAMETERS (LVCF ⫾ SD) Placebo
Low Dose
Medium Dose
High Dose
Plc N ⫽ 4; Low ⫽ 100 µg/kg/hr N ⫽ 6; Medium ⫽ 200 µg/kg/hr N ⫽ 6; High ⫽ 300 µg/kg/hr N ⫽ 3 ACI % LCWI % CI % PP % QTc (ms)
⫺14.5 ⫾ 8.0 ⫺4.9 ⫾ 12.2 ⫺9.5 ⫾ 7.5 ⫺0.2 ⫾ 19.5 ⫺0.5 ⫾ 19.0
29.8 ⫾ 23.5 26.2 ⫾ 26.3 11.1 ⫾ 22.2 39.5 ⫾ 35.7 ⫺43.7 ⫾ 19.4
52.3 ⫾ 41.0 46.3 ⫾ 22.1 31.1 ⫾ 22.8 53.8 ⫾ 18.2 ⫺41.2 ⫾ 36.4
60.7 ⫾ 7.0 53.7 ⫾ 36.8 35.9 ⫾ 16.4 29.9 ⫾ 5.6 ⫺36.0 ⫾ 0.0
Introduction: Genetic background influences heart failure outcomes. Endothelial nitric oxide synthase (NOS3) is the predominant source of vascular nitric oxide (NO). Genetic variation exists at the NOS3 locus with polymorphisms in the promoter region (position –786 T/C), intron 4 (variable numbers of a 27 bp repeat) and exon 7 (Asp298Glu) which have functional significance in vitro and in clinical studies. The allele frequencies of the NOS3 polymorphisms differ markedly between whites and African Americans. The Asp298 variant has been associated with poorer heart failure outcomes in a predominantly white population (GRACE study, Circulation, 2003). The impact of the NOS3 variants on outcomes in African Americans and the therapeutic efficacy of the NO donor isosorbide dinitrate/ hydralazine have not been previously evaluated. Hypothesis: The Genetic Risk Assessment in Heart Failure (GRAHF) sub-study of the African-American Heart Failure Trial (A-HeFT) will evaluate the hypothesis that the variation in NOS3 will influence the relative risk of clinical events (death or hospitalization due to heart failure) in a black population with heart failure and will investigate whether the genetic profile predicts the impact of nitric oxide-enhancing therapy. Methods: Patients (365) with NYHA class III and IV heart failure from A-HeFT were enrolled in the GRAHF genetic sub-study, and genotyped for the NOS3 exon 7, promoter and intron 4 polymorphisms. Results: For the Asp298Glu polymorphism, the Asp298 variant was present in 75 subjects (21%), while 280 (79%) were Glu298Glu homozygotes. In contrast in a population of 427 white subjects from GRACE, the Asp298 variant was present in 59%, while only 41% were Glu298Glu. The genotype frequencies in GRAHF of the promoter variant (T-786C: % TT/TC/ CC ⫽ 72/ 26/ 2) and intron 4 polymorphism (a allele, 4 repeat, present 51%, absent 49%) also differ markedly from the white cohort in GRACE. As previously reported, the three NOS3 polymorphisms are in significant linkage disequilibrium. Conclusion: The NOS3 allele frequencies from GRAHF differ markedly from a comparative white cohort with heart failure. The impact of these variant on the clinical outcomes in AHeFT and the pharmacogenetic interactions with the clinical response to isosorbide dinitrate and hydralazine will be presented.
Istaroxime was well tolerated at doses of up to 200 mcg/kg/hr. Side effects were related to GI symptoms and injection site pain. Istaroxime shortened QTc in this same dosage range. Ventricular ectopy was not altered by Istaroxime. This initial study suggests that Istaroxime is potentially useful in the treatment of HF and may offer a unique new treatment for systolic and/or diastolic dysfunction.
231
233
Left Ventricular Mass Is Lower with Candesartan Compared to Placebo in Patients with Heart Failure and Preserved Systolic Function. Results from the CHARM Echocardiographic Substudy - CHARMES Robert S. McKelvie1, Eva Lonn1, Magnus Edner2, Larry Baruch3, Chim C. Lang4, John J. Morton5, Jan Ostergren6, Hans E. Persson2; 1Hamilton Health Sciences, McMaster University, Hamilton, ON, Canada; 2Section of Cardiology, Danderyd University Hospital, Stockholm, Sweden; 3Mt. Sinai School of Medicine, Bronx, NY; 4Ninewells Hospital and Medical School, Dundee, United Kingdom; 5Western Infirmary, University of Glasgow, Glasgow, United Kingdom; 6Dept of Medicine, Karolinska University Hospital, Stockholm, Sweden
A New Symptom Assessment in Acute Heart Failure Trials: The Change in the Area under the Curve (AUC) of Patient Dyspnea over 24 Hours in the VERITAS Trial John R. Teerlink1, John J.V. McMurray2, Guillermo Torre-Amione3, Gad Cotter4, Christopher M. O’Connor4, Aline Frey5, Isaac Kobrin5, On Behalf of the VERITAS Steering Committee and Investigators1; 1Cardiology, SFVAMC/UCSF, San Francisco, CA; 2University of Glasgow, Glasgow, United Kingdom; 3Baylor, Houston, TX; 4Duke University/DCRI, Durham, NC; 5Actelion Pharmaceuticals, LTD, Allschwil, Switzerland
Background: The effects of therapy have not been well studied in heart failure patients with preserved systolic function (HF-PSF). CHARM-Preserved provided an opportunity to examine the effects of candesartan on left ventricular (LV) function and mass in HF-PSF. Purpose: The objectives of this study were to evaluate the effects of the angiotensin receptor blocker candesartan compared to placebo on 1) LV diastolic function, 2) LV mass 3) LV systolic function and 4) LV size (LVD, LVS) in HF-PSF patients. Methods: 312 patients enrolled in the CHARM-Preserved Study underwent a cross-sectional Doppler echocardiographic examination which included assessment of pulmonary venous flow profiles and/or determination of NT-proBNP ⬎ ⫽ 14 months after randomisation to candesartan 4-(target dose) 32 mg once daily or placebo. Based on age-adjusted normal values for Doppler and NT-proBNP, patients were classified into 1 of 4 diastolic function groups: normal, relaxation abnormality (mild dysfunction), pseudonormal (moderate dysfunction) and restrictive (severe dysfunction). Results: The 312 patients (34% females) analyzed in the echo substudy, CHARMES, were well balanced, as regards baseline characteristics. Mean age was 66 ⫾ 11 years, EF 50 ⫾ 10%. See Table 1 for results. Conclusions: LV size, diastolic and systolic function were similar in the two groups. However, LV mass was 10% lower in the candesartan group. Our results suggest that candesartan reduces LV mass in patients with HF-PSF. Table 1 Candesartan n ⫽ 166 Normal/abnormal diastolic function, % Ejection fraction, % LV mass, g LVMI, g/m2 LVD, mm LVS, mm
Placebo n ⫽ 146 Diff of means
95% CI
P
34%/66%
32%/68%
-
-
0.805
48 ⫾ 11 225 ⫾ 75 111 ⫾ 35 63 ⫾ 19 49 ⫾ 26
49 ⫾ 10 250 ⫾ 109 124 ⫾ 49 64 ⫾ 19 50 ⫾ 27
⫺1.5 ⫺25 ⫺13 ⫺0.9 ⫺0.8
⫺3.9; 0.9 ⫺49; ⫺1.8 ⫺24; ⫺1.5 ⫺5.4; 3.4 ⫺6.8, 5.2
0.226 0.041 0.023 0.657 0.802
Results are presented as proportions (%) or mean ⫾ SD as indicated. 95% CI ⫽ 95% confidence interval for differences between means. LVMI ⫽ LV mass index (per m2 body surface area).
Background: Demonstrating clinical benefit with new therapies for acute heart failure (AHF) has been challenging. Regulatory agencies have recommended that dyspnea be used as an endpoint, but there is limited experience or validation of the instruments with which to assess it. VERITAS used a novel approach to assess the effect of a new therapy on dyspnea. Methods/Results: VERITAS randomized 1435 patients between two identical trials (VERITAS 1&2) within 24 hours of admission with AHF who were dyspneic at rest to placebo or tezosentan, an IV endothelin receptor antagonist, in addition to standard therapy. A co-primary endpoint of the program was the change in dyspnea during 24 hours. Dyspnea was assessed by the patient (baseline and at 3, 6 and 24 h after initiation of study drug) using a visual analog scale (VAS), scored from 0 to 100, and the AUC of the change in dyspnea from baseline over 24 hours is calculated for each patient. The median dyspnea VAS score at baseline was 65 and the 24-hour AUC was ⫺448 ⫾ 649 (mean ⫾ SD) in the placebo (n ⫽ 699) and ⫺465 ⫾ 634 in the tezosentan (n ⫽ 716) groups (mean treatment effect ⫺17, p ⫽ 0.49). Placebo patients experienced over 50% of their improvement after 3 hrs and over 90% after 6 hrs of therapy. There were no significant differences in the performance of the instrument between the two trials (VERITAS 1&2), however, patients with EF ⬍40% (placebo-corrected mean ⫺133 mm*hr; 95% confidence interval ⫺221 to ⫺45; *p ⬍ 0.05), history of MI (⫺113; ⫺209 to ⫺17*), receiving cardiac glycosides at baseline (⫺195; ⫺313 to ⫺77*), or a serum sodium ⬍135 (⫺165; ⫺335 to ⫹5; p ⬍ 0.10), all had improvements in dyspnea on tezosentan compared to placebo. Conclusions: VERITAS is the largest trial of a new AHF therapy to-date, yet a novel symptom endpoint could not detect an improvement in dyspnea with tezosentan. Whether this absence of a difference is due to the insensitivity of the instrument or the lack of efficacy of tezosentan is unclear. As in other AHF trials, the placebo group had rapid improvement in dyspnea, suggesting that there may not be a need for therapies to address this symptom or that this symptom needs to be assessed earlier in the patient’s course.
Journal of Cardiac Failure Vol. 11 No. 6 Suppl. 2005
230
232
Istaroxime – A Novel Lusitropic and Inotropic Agent: Results of a Phase I-II Study Jalal Ghali1, William Smith2, Guillermo Torre-Amione3, William Haynos4, Barry Rayburn5, Antonino Amato6, Dan Zhang6, Doug Cowart6, Giovanni Valentini7, Paolo Carminati7, Mihai Gheorghiade8; 1Cardiology, L.S.U - H.S.C., Shreveport, LA; 2New Orleans-C.C.R., New Orleans, LA; 3Baylor Col. of Med., Houston, TX; 4Univ. of Iowa, Iowa City, IA; 5Univ. Alabama, Birmingham, AL; 6Sigma-Tau Research, Inc, Gaithersburg, MD; 7Sigma-Tau S.p.A., Pomezia, Italy; 8Northwestern University, Chicago, IL
The Genetic Risk Assessment Sub-Study of the African-American Heart Failure Trial (A-HeFT): Impact of Genetic Variation of NOS3 Dennis M. McNamara, S. William Tam, Michael L. Sabolinski, Amy Palmer, Page Tobelman, Karen Janosko, Arthur M. Feldman, Manuel Worcel; Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA; NitroMed, Inc., Lexington, MA; Jefferson Medical College, Philadelphia, PA
Animal studies have shown that Istaroxime (PST 2744) is a luso-inotrope that stimulates SERCA IIa, has no chronotropic effect and has beneficial effect on myocardial energetics. Istaroxime was evaluated for the first time in 18 chronic stable heart failure (HF) patients (pts) in a Phase I-II clinical trial. Methods: Three cohorts of 6 pts were exposed to 4 sequentially increasing 1 hour infusions with a random placebo. Dosage was from 0.3 to 300 mcg/kg/hr. Safety and hemodynamics were evaluated by Impedance Cardiography (ICG), digital Holter and EKG. PK was obtained over 1 hour during treatment and for 6 hours following the completion of dosage. Results: Pts characteristics: age 53 ⫾ 7; men 61%; HF duration 6.5 ⫾ 3.2 yrs; EF 27 ⫾ 8%; CAD 75%; Beta-Blocker 93% and ACE/ARB 100%. ICG demonstrated enhanced indices of contractility (Acceleration Index-ACI), Left Cardiac Work Index (LCWI), Cardiac Index (CI) and Pulse Pressure (PP) at doses of 60 mcg/kg/hr and higher. Following termination of infusion, hemodynamic effect rapidly dissipated over 1–2 hours. MEAN CHANGE IN KEY PARAMETERS (LVCF ⫾ SD) Placebo
Low Dose
Medium Dose
High Dose
Plc N ⫽ 4; Low ⫽ 100 µg/kg/hr N ⫽ 6; Medium ⫽ 200 µg/kg/hr N ⫽ 6; High ⫽ 300 µg/kg/hr N ⫽ 3 ACI % LCWI % CI % PP % QTc (ms)
⫺14.5 ⫾ 8.0 ⫺4.9 ⫾ 12.2 ⫺9.5 ⫾ 7.5 ⫺0.2 ⫾ 19.5 ⫺0.5 ⫾ 19.0
29.8 ⫾ 23.5 26.2 ⫾ 26.3 11.1 ⫾ 22.2 39.5 ⫾ 35.7 ⫺43.7 ⫾ 19.4
52.3 ⫾ 41.0 46.3 ⫾ 22.1 31.1 ⫾ 22.8 53.8 ⫾ 18.2 ⫺41.2 ⫾ 36.4
60.7 ⫾ 7.0 53.7 ⫾ 36.8 35.9 ⫾ 16.4 29.9 ⫾ 5.6 ⫺36.0 ⫾ 0.0
Introduction: Genetic background influences heart failure outcomes. Endothelial nitric oxide synthase (NOS3) is the predominant source of vascular nitric oxide (NO). Genetic variation exists at the NOS3 locus with polymorphisms in the promoter region (position –786 T/C), intron 4 (variable numbers of a 27 bp repeat) and exon 7 (Asp298Glu) which have functional significance in vitro and in clinical studies. The allele frequencies of the NOS3 polymorphisms differ markedly between whites and African Americans. The Asp298 variant has been associated with poorer heart failure outcomes in a predominantly white population (GRACE study, Circulation, 2003). The impact of the NOS3 variants on outcomes in African Americans and the therapeutic efficacy of the NO donor isosorbide dinitrate/ hydralazine have not been previously evaluated. Hypothesis: The Genetic Risk Assessment in Heart Failure (GRAHF) sub-study of the African-American Heart Failure Trial (A-HeFT) will evaluate the hypothesis that the variation in NOS3 will influence the relative risk of clinical events (death or hospitalization due to heart failure) in a black population with heart failure and will investigate whether the genetic profile predicts the impact of nitric oxide-enhancing therapy. Methods: Patients (365) with NYHA class III and IV heart failure from A-HeFT were enrolled in the GRAHF genetic sub-study, and genotyped for the NOS3 exon 7, promoter and intron 4 polymorphisms. Results: For the Asp298Glu polymorphism, the Asp298 variant was present in 75 subjects (21%), while 280 (79%) were Glu298Glu homozygotes. In contrast in a population of 427 white subjects from GRACE, the Asp298 variant was present in 59%, while only 41% were Glu298Glu. The genotype frequencies in GRAHF of the promoter variant (T-786C: % TT/TC/ CC ⫽ 72/ 26/ 2) and intron 4 polymorphism (a allele, 4 repeat, present 51%, absent 49%) also differ markedly from the white cohort in GRACE. As previously reported, the three NOS3 polymorphisms are in significant linkage disequilibrium. Conclusion: The NOS3 allele frequencies from GRAHF differ markedly from a comparative white cohort with heart failure. The impact of these variant on the clinical outcomes in AHeFT and the pharmacogenetic interactions with the clinical response to isosorbide dinitrate and hydralazine will be presented.
Istaroxime was well tolerated at doses of up to 200 mcg/kg/hr. Side effects were related to GI symptoms and injection site pain. Istaroxime shortened QTc in this same dosage range. Ventricular ectopy was not altered by Istaroxime. This initial study suggests that Istaroxime is potentially useful in the treatment of HF and may offer a unique new treatment for systolic and/or diastolic dysfunction.
231
233
Left Ventricular Mass Is Lower with Candesartan Compared to Placebo in Patients with Heart Failure and Preserved Systolic Function. Results from the CHARM Echocardiographic Substudy - CHARMES Robert S. McKelvie1, Eva Lonn1, Magnus Edner2, Larry Baruch3, Chim C. Lang4, John J. Morton5, Jan Ostergren6, Hans E. Persson2; 1Hamilton Health Sciences, McMaster University, Hamilton, ON, Canada; 2Section of Cardiology, Danderyd University Hospital, Stockholm, Sweden; 3Mt. Sinai School of Medicine, Bronx, NY; 4Ninewells Hospital and Medical School, Dundee, United Kingdom; 5Western Infirmary, University of Glasgow, Glasgow, United Kingdom; 6Dept of Medicine, Karolinska University Hospital, Stockholm, Sweden
A New Symptom Assessment in Acute Heart Failure Trials: The Change in the Area under the Curve (AUC) of Patient Dyspnea over 24 Hours in the VERITAS Trial John R. Teerlink1, John J.V. McMurray2, Guillermo Torre-Amione3, Gad Cotter4, Christopher M. O’Connor4, Aline Frey5, Isaac Kobrin5, On Behalf of the VERITAS Steering Committee and Investigators1; 1Cardiology, SFVAMC/UCSF, San Francisco, CA; 2University of Glasgow, Glasgow, United Kingdom; 3Baylor, Houston, TX; 4Duke University/DCRI, Durham, NC; 5Actelion Pharmaceuticals, LTD, Allschwil, Switzerland
Background: The effects of therapy have not been well studied in heart failure patients with preserved systolic function (HF-PSF). CHARM-Preserved provided an opportunity to examine the effects of candesartan on left ventricular (LV) function and mass in HF-PSF. Purpose: The objectives of this study were to evaluate the effects of the angiotensin receptor blocker candesartan compared to placebo on 1) LV diastolic function, 2) LV mass 3) LV systolic function and 4) LV size (LVD, LVS) in HF-PSF patients. Methods: 312 patients enrolled in the CHARM-Preserved Study underwent a cross-sectional Doppler echocardiographic examination which included assessment of pulmonary venous flow profiles and/or determination of NT-proBNP ⬎ ⫽ 14 months after randomisation to candesartan 4-(target dose) 32 mg once daily or placebo. Based on age-adjusted normal values for Doppler and NT-proBNP, patients were classified into 1 of 4 diastolic function groups: normal, relaxation abnormality (mild dysfunction), pseudonormal (moderate dysfunction) and restrictive (severe dysfunction). Results: The 312 patients (34% females) analyzed in the echo substudy, CHARMES, were well balanced, as regards baseline characteristics. Mean age was 66 ⫾ 11 years, EF 50 ⫾ 10%. See Table 1 for results. Conclusions: LV size, diastolic and systolic function were similar in the two groups. However, LV mass was 10% lower in the candesartan group. Our results suggest that candesartan reduces LV mass in patients with HF-PSF. Table 1 Candesartan n ⫽ 166 Normal/abnormal diastolic function, % Ejection fraction, % LV mass, g LVMI, g/m2 LVD, mm LVS, mm
Placebo n ⫽ 146 Diff of means
95% CI
P
34%/66%
32%/68%
-
-
0.805
48 ⫾ 11 225 ⫾ 75 111 ⫾ 35 63 ⫾ 19 49 ⫾ 26
49 ⫾ 10 250 ⫾ 109 124 ⫾ 49 64 ⫾ 19 50 ⫾ 27
⫺1.5 ⫺25 ⫺13 ⫺0.9 ⫺0.8
⫺3.9; 0.9 ⫺49; ⫺1.8 ⫺24; ⫺1.5 ⫺5.4; 3.4 ⫺6.8, 5.2
0.226 0.041 0.023 0.657 0.802
Results are presented as proportions (%) or mean ⫾ SD as indicated. 95% CI ⫽ 95% confidence interval for differences between means. LVMI ⫽ LV mass index (per m2 body surface area).
Background: Demonstrating clinical benefit with new therapies for acute heart failure (AHF) has been challenging. Regulatory agencies have recommended that dyspnea be used as an endpoint, but there is limited experience or validation of the instruments with which to assess it. VERITAS used a novel approach to assess the effect of a new therapy on dyspnea. Methods/Results: VERITAS randomized 1435 patients between two identical trials (VERITAS 1&2) within 24 hours of admission with AHF who were dyspneic at rest to placebo or tezosentan, an IV endothelin receptor antagonist, in addition to standard therapy. A co-primary endpoint of the program was the change in dyspnea during 24 hours. Dyspnea was assessed by the patient (baseline and at 3, 6 and 24 h after initiation of study drug) using a visual analog scale (VAS), scored from 0 to 100, and the AUC of the change in dyspnea from baseline over 24 hours is calculated for each patient. The median dyspnea VAS score at baseline was 65 and the 24-hour AUC was ⫺448 ⫾ 649 (mean ⫾ SD) in the placebo (n ⫽ 699) and ⫺465 ⫾ 634 in the tezosentan (n ⫽ 716) groups (mean treatment effect ⫺17, p ⫽ 0.49). Placebo patients experienced over 50% of their improvement after 3 hrs and over 90% after 6 hrs of therapy. There were no significant differences in the performance of the instrument between the two trials (VERITAS 1&2), however, patients with EF ⬍40% (placebo-corrected mean ⫺133 mm*hr; 95% confidence interval ⫺221 to ⫺45; *p ⬍ 0.05), history of MI (⫺113; ⫺209 to ⫺17*), receiving cardiac glycosides at baseline (⫺195; ⫺313 to ⫺77*), or a serum sodium ⬍135 (⫺165; ⫺335 to ⫹5; p ⬍ 0.10), all had improvements in dyspnea on tezosentan compared to placebo. Conclusions: VERITAS is the largest trial of a new AHF therapy to-date, yet a novel symptom endpoint could not detect an improvement in dyspnea with tezosentan. Whether this absence of a difference is due to the insensitivity of the instrument or the lack of efficacy of tezosentan is unclear. As in other AHF trials, the placebo group had rapid improvement in dyspnea, suggesting that there may not be a need for therapies to address this symptom or that this symptom needs to be assessed earlier in the patient’s course.