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Heart Failure Patients with Reduced Ejection Fraction Have Higher Prevalence of Cognitive Impairment Despite Normal MMSE
S68 Journal of Cardiac Failure Vol. 23 No. 8S August 2017 Conclusion: Women are underrepresented in the overall population undergoing complex supported PCI suggesting that women may encounter a barrier to access to highly specialized medical care. Despite being older and sicker women have similar favorable outcomes as men, suggesting a mitigating effect of the Impella hemodynamic support during PCI.
180 Heart Failure Patients with Reduced Ejection Fraction Have Higher Prevalence of Cognitive Impairment Despite Normal MMSE Deepak J. Pattanshetty, Dana Cook, Dinesh Sharma, Mark E. Dunlap; Metrohealth Campus of Case Western Reserve University, Cleveland, Ohio Background: Cognitive impairment (CI) is one of the major contributing factors for increased morbidity and mortality in Heart failure with reduced ejection fraction (HFrEF) patients, unfortunately this is frequently unrecognized and un-addressed. Often, these patients go untested prospectively for cognitive impairment. CNSVitals Signs (CNSVS) is a computerized test with high test-retest reliability able to detect subtle to severe degrees of CI in multiple domains, though it has not been studied in HF previously. Objective: We sought to determine the prevalence of CI in HFrEF. Specifically, we tested the hypothesis that stable chronic HFrEF outpatients without clinically apparent CI have significant moderate to severe CI, compared to controls. Methods: 2680 subjects were screened. Subjects with moderate to severe CI were excluded using the Mini-Mental Status Exam (MMSE score < 20), as were subjects on medications known to cause CI and subjects with known CI. 38 HFrEF patients and 26 age matched nonHF controls were included. Cognitive function was tested using CNSVS, and t-tests were used to examine between-group differences. Results: Table 1 shows baseline demographics, and Fig. 1 shows prevalence of CI (%) in different domains. Despite similar MMSE scores in each group, compared to age-matched controls, HFrEF subjects demonstrated significantly higher prevalence of moderate-severe CI across all domains and overall neurocognitive index. Conclusion: Stable chronic HFrEF patients not previously recognized to have CI, despite normal MMSE showed higher prevalence of Moderate-severe CI. Cognitive damage involving different domains, interferes with the ability for patient to self-care and to cope with treatment regimens, hence increased morbidity, mortality and financial impact. This study suggests that routine formal testing for CI is beneficial in HFrEF, though further studies are needed to determine the reversible factors of CI and hence improve outcomes in these patients.
181 Safety, Pharmacokinetics and Pharmacodynamics of TD-0714, a Novel Non-Renally Cleared Neprilysin Inhibitor, in Healthy Humanvolunteers: Potential for Once-Daily Dosing and Predictable Exposure in Patients Regardless of Baseline Renal Function Jitendra Kanodia, Michael Baldwin, Arthur Lo, Denise Wang, Kefei Zhou, Jonathan Lee, Kenneth Colley, Whedy Wang, David Bourdet; Theravance Biopharma, South San Francisco, California Introduction: TD-0714 is an orally active, potent, and selective inhibitor of human neprilysin (NEP) in development for the treatment of a range of cardiorenal diseases including chronic heart failure (CHF) and chronic kidney disease (CKD). A significant population of these patients exhibit moderate to severe renal impairment. NEP inhibitors exhibiting non-renal excretion and a once-daily dosing regimen may provide optimal therapy for such patients. A multiple dose, double–blind, placebo–controlled, dose– escalation study in healthy subjects was conducted to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of TD–0714. Methods: Forty healthy adult subjects (n = 10/group) were randomized to one of four cohorts and received a daily oral dose of TD–0714 (10 to 200 mg) or placebo in a 4:1 ratio for 14 days. In addition, ten elderly healthy subjects were randomized to receive either 100 mg TD-0714 or placebo in a 4:1 ratio. Safety and tolerability were evaluated by monitoring treatment-emergent adverse events (TEAE), ECG, vital signs and laboratory parameters. PK and corresponding PD response (cGMP and ANP), were assessed. Results: TD-0714 was generally well tolerated up to the highest dose level tested (200 mg). No SAEs were reported. No clinically significant effects on vital signs or ECG parameters were observed. One subject at the lowest dose level (10 mg) exhibited an asymptomatic increase in liver enzymes (ALT, AST). This subject was subsequently rechallenged at the same dose level (10 mg QD for 14days) and no elevations in liver enzymes were observed upon rechallenge. No clinically relevant changes in laboratory parameters were observed in any other subjects during the study. PK (Cmax and AUC) of TD-0714 was dose–proportional from 10 mg to 200 mg, no accumulation was observed from day 1 to day 14 and renal excretion remained low at <1% of the administered dose. In addition, PK of TD-0714 was similar in elderly vs adult subjects. Dose-dependent increases in plasma and urine cGMP levels were observed. The increases in cGMP were sustained for 24 hr after a single dose and remained significantly above the baseline for the entire 24 hr interval on day 14 indicating that sustained cGMP elevations are achieved at steady state. Maximal PD effects were observed at doses of ≥50 mg based on plasma cGMP on day 14. Conclusions: Multiple doses of TD-0714 from 10 to 200 mg were generally well tolerated. PK was dose-proportional with negligible renal elimination. PD effects consistent with NEP target engagement were sustained for and remained significantly over baseline during the entire dosing interval at steady state. The TD-0714 PK and PD profiles continue to support the potential for once-daily administration and predictable exposure in patients with cardiorenal diseases across all levels of renal function.
182
Fig. 1. Comparisons of moderate to severe cognitive impairment.
Table 1. Comparison of characteristics
Third Heart Sound Measured by Implanted Accelerometer in Heart Failure Patients is Coincident with the Deceleration Phase of Early Diastolic Filling Elizabeth Klodas1, Pramodsingh Thakur2, Qi An2, Alan Bank3; 1Preventive Cardiology Consultants, Edina, Minnesota; 2Boston Scientific, Arden Hills, Minnesota; 3United Heart and Vascular Clinic, St Paul, Minnesota Introduction: The third heart sound (S3), an early and specific sign of heart failure and elevated filling pressure, is caused by rapid deceleration of the blood against a stiff ventricle during early diastolic filling. Prior studies have shown phonocardiogram based S3 to be coincident with the deceleration phase of E-wave. More recently, ambulatory monitoring of heart sounds (HS) has been enabled using accelerometers (XL) embedded in implantable medical devices. Whether S3 measured using this novel modality is coincident with the deceleration phase of early diastolic filling had not been previously established. Methods: The PRE-SENSE study enrolled patients with COGNIS CRT-D modified to enable collection of HS data using device based XL. HS waveforms were collected within 20 minutes of an echocardiogram. Waveforms were excluded if device heart rate (HR) differed from the echo reported HR by more than 5 beats per minute (bpm). An independent core laboratory measured parameters from the echo images, including E-wave timing within the cardiac cycle. An algorithm processed the individual HS waveforms to extract S3 amplitude by automatically deducing a window for S3 measurement based on a proprietary method. Timing of the S3 measurement window employed by the automatic S3 amplitude extraction algorithm was validated by comparing with E-wave timings within the cardiac cycle on the echocardiogram. Results: Of the 70 enrolled patients, 59 patients had HS data collected within 20 minutes of the echo at HR within 5 bpm. The start of S3 measurement window within the cardiac cycle occurred 624 ± 5 msec after R-event and was comparable to Q-E interval of 625 ± 9 msec (P = .89 paired t-test), indicating that the start of S3 window was not different from the peak of E-wave, assuming a minimal Q-R interval due to paced beats. Additionally, the end of the measurement window occurred 749 ± 5 msec after R-event, which was significantly after peak of E-wave (P < .0001 paired t-test), but prior to the end of E-wave obtained as the sum of Q-E interval and E-wave deceleration time (QE + EDT interval: 890 ± 16 msec; P < .0001 paired t-test). Thus S3 measurement window occurred substantially during the deceleration phase of E-wave. Conclusion: This analysis confirms that device-measured S3 occurs during early diastolic filling, which is consistent with its known physiologic genesis. Further studies are warranted to investigate if such serial S3 measurements in ambulatory patients may enable chronic monitoring of diastolic filling patterns in heart failure patients.
180 Heart Failure Patients with Reduced Ejection Fraction Have Higher Prevalence of Cognitive Impairment Despite Normal MMSE Deepak J. Pattanshetty, Dana Cook, Dinesh Sharma, Mark E. Dunlap; Metrohealth Campus of Case Western Reserve University, Cleveland, Ohio Background: Cognitive impairment (CI) is one of the major contributing factors for increased morbidity and mortality in Heart failure with reduced ejection fraction (HFrEF) patients, unfortunately this is frequently unrecognized and un-addressed. Often, these patients go untested prospectively for cognitive impairment. CNSVitals Signs (CNSVS) is a computerized test with high test-retest reliability able to detect subtle to severe degrees of CI in multiple domains, though it has not been studied in HF previously. Objective: We sought to determine the prevalence of CI in HFrEF. Specifically, we tested the hypothesis that stable chronic HFrEF outpatients without clinically apparent CI have significant moderate to severe CI, compared to controls. Methods: 2680 subjects were screened. Subjects with moderate to severe CI were excluded using the Mini-Mental Status Exam (MMSE score < 20), as were subjects on medications known to cause CI and subjects with known CI. 38 HFrEF patients and 26 age matched nonHF controls were included. Cognitive function was tested using CNSVS, and t-tests were used to examine between-group differences. Results: Table 1 shows baseline demographics, and Fig. 1 shows prevalence of CI (%) in different domains. Despite similar MMSE scores in each group, compared to age-matched controls, HFrEF subjects demonstrated significantly higher prevalence of moderate-severe CI across all domains and overall neurocognitive index. Conclusion: Stable chronic HFrEF patients not previously recognized to have CI, despite normal MMSE showed higher prevalence of Moderate-severe CI. Cognitive damage involving different domains, interferes with the ability for patient to self-care and to cope with treatment regimens, hence increased morbidity, mortality and financial impact. This study suggests that routine formal testing for CI is beneficial in HFrEF, though further studies are needed to determine the reversible factors of CI and hence improve outcomes in these patients.
181 Safety, Pharmacokinetics and Pharmacodynamics of TD-0714, a Novel Non-Renally Cleared Neprilysin Inhibitor, in Healthy Humanvolunteers: Potential for Once-Daily Dosing and Predictable Exposure in Patients Regardless of Baseline Renal Function Jitendra Kanodia, Michael Baldwin, Arthur Lo, Denise Wang, Kefei Zhou, Jonathan Lee, Kenneth Colley, Whedy Wang, David Bourdet; Theravance Biopharma, South San Francisco, California Introduction: TD-0714 is an orally active, potent, and selective inhibitor of human neprilysin (NEP) in development for the treatment of a range of cardiorenal diseases including chronic heart failure (CHF) and chronic kidney disease (CKD). A significant population of these patients exhibit moderate to severe renal impairment. NEP inhibitors exhibiting non-renal excretion and a once-daily dosing regimen may provide optimal therapy for such patients. A multiple dose, double–blind, placebo–controlled, dose– escalation study in healthy subjects was conducted to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of TD–0714. Methods: Forty healthy adult subjects (n = 10/group) were randomized to one of four cohorts and received a daily oral dose of TD–0714 (10 to 200 mg) or placebo in a 4:1 ratio for 14 days. In addition, ten elderly healthy subjects were randomized to receive either 100 mg TD-0714 or placebo in a 4:1 ratio. Safety and tolerability were evaluated by monitoring treatment-emergent adverse events (TEAE), ECG, vital signs and laboratory parameters. PK and corresponding PD response (cGMP and ANP), were assessed. Results: TD-0714 was generally well tolerated up to the highest dose level tested (200 mg). No SAEs were reported. No clinically significant effects on vital signs or ECG parameters were observed. One subject at the lowest dose level (10 mg) exhibited an asymptomatic increase in liver enzymes (ALT, AST). This subject was subsequently rechallenged at the same dose level (10 mg QD for 14days) and no elevations in liver enzymes were observed upon rechallenge. No clinically relevant changes in laboratory parameters were observed in any other subjects during the study. PK (Cmax and AUC) of TD-0714 was dose–proportional from 10 mg to 200 mg, no accumulation was observed from day 1 to day 14 and renal excretion remained low at <1% of the administered dose. In addition, PK of TD-0714 was similar in elderly vs adult subjects. Dose-dependent increases in plasma and urine cGMP levels were observed. The increases in cGMP were sustained for 24 hr after a single dose and remained significantly above the baseline for the entire 24 hr interval on day 14 indicating that sustained cGMP elevations are achieved at steady state. Maximal PD effects were observed at doses of ≥50 mg based on plasma cGMP on day 14. Conclusions: Multiple doses of TD-0714 from 10 to 200 mg were generally well tolerated. PK was dose-proportional with negligible renal elimination. PD effects consistent with NEP target engagement were sustained for and remained significantly over baseline during the entire dosing interval at steady state. The TD-0714 PK and PD profiles continue to support the potential for once-daily administration and predictable exposure in patients with cardiorenal diseases across all levels of renal function.
182
Fig. 1. Comparisons of moderate to severe cognitive impairment.
Table 1. Comparison of characteristics
Third Heart Sound Measured by Implanted Accelerometer in Heart Failure Patients is Coincident with the Deceleration Phase of Early Diastolic Filling Elizabeth Klodas1, Pramodsingh Thakur2, Qi An2, Alan Bank3; 1Preventive Cardiology Consultants, Edina, Minnesota; 2Boston Scientific, Arden Hills, Minnesota; 3United Heart and Vascular Clinic, St Paul, Minnesota Introduction: The third heart sound (S3), an early and specific sign of heart failure and elevated filling pressure, is caused by rapid deceleration of the blood against a stiff ventricle during early diastolic filling. Prior studies have shown phonocardiogram based S3 to be coincident with the deceleration phase of E-wave. More recently, ambulatory monitoring of heart sounds (HS) has been enabled using accelerometers (XL) embedded in implantable medical devices. Whether S3 measured using this novel modality is coincident with the deceleration phase of early diastolic filling had not been previously established. Methods: The PRE-SENSE study enrolled patients with COGNIS CRT-D modified to enable collection of HS data using device based XL. HS waveforms were collected within 20 minutes of an echocardiogram. Waveforms were excluded if device heart rate (HR) differed from the echo reported HR by more than 5 beats per minute (bpm). An independent core laboratory measured parameters from the echo images, including E-wave timing within the cardiac cycle. An algorithm processed the individual HS waveforms to extract S3 amplitude by automatically deducing a window for S3 measurement based on a proprietary method. Timing of the S3 measurement window employed by the automatic S3 amplitude extraction algorithm was validated by comparing with E-wave timings within the cardiac cycle on the echocardiogram. Results: Of the 70 enrolled patients, 59 patients had HS data collected within 20 minutes of the echo at HR within 5 bpm. The start of S3 measurement window within the cardiac cycle occurred 624 ± 5 msec after R-event and was comparable to Q-E interval of 625 ± 9 msec (P = .89 paired t-test), indicating that the start of S3 window was not different from the peak of E-wave, assuming a minimal Q-R interval due to paced beats. Additionally, the end of the measurement window occurred 749 ± 5 msec after R-event, which was significantly after peak of E-wave (P < .0001 paired t-test), but prior to the end of E-wave obtained as the sum of Q-E interval and E-wave deceleration time (QE + EDT interval: 890 ± 16 msec; P < .0001 paired t-test). Thus S3 measurement window occurred substantially during the deceleration phase of E-wave. Conclusion: This analysis confirms that device-measured S3 occurs during early diastolic filling, which is consistent with its known physiologic genesis. Further studies are warranted to investigate if such serial S3 measurements in ambulatory patients may enable chronic monitoring of diastolic filling patterns in heart failure patients.