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Impact of Patisiran, an RNAi Therapeutic, on Orthostatic Intolerance in Patients with Hereditary Transthyretin-Mediated Amyloidosis
S78 Journal of Cardiac Failure Vol. 25 No. 8S August 2019 both tafamidis 80 mg (P=0.003) and 20 mg (P=0.005). All-cause mortality was significantly reduced with tafamidis 80 mg (Cox-proportional hazard model [95% CI], 0.690 [0.487, 0.979], P=0.0378), and there was a trend towards reduction with tafamidis 20 mg (0.715 [0.450-1.137], P=0.1564), compared with placebo. The increase in NT-proBNP was reduced with tafamidis 80 mg, compared with both 20 mg (P=0.0468) and placebo (P<0.0001). There was no meaningful difference in safety between the doses. Conclusions: Tafamidis 80 mg and tafamidis 20 mg effectively reduced the combination of mortality and cardiovascular-related hospitalizations. Given the lack of dose-related safety concerns, and the NT-proBNP and survival data, tafamidis 80 mg is the preferred dose.
206 Optimal Medical Therapy in Heart Failure: Reasons for Lack of Medication Titration in the GUIDE IT Trial Mona Fiuzat1, Wendimagegn Alemayehu2, Justin Ezekowitz2, Cindy Westerhout2, David Whellan3, Hillary Mulder1, Tariq Ahmad4, Kirkwood Adams5, Ileana Pina6, Kevin Anstrom1, Lawton Cooper7, Brooke Alhanti1, Marco Sbolli8, Daniel Mark1, Eric Leifer7, Michael Felker1, Christopher O’Connor8, James Januzzi9; 1Duke University, Durham, NC; 2Canadian VIGOUR Centre, Alberta, ON, Canada; 3Jefferson University, Philadelphia, PA; 4Yale University, New Haven, CT; 5UNC, Chapel Hill, NC; 6 Detroit Medical Center, Detroit, MI; 7NIH, Bethesda, MD; 8Inova Heart and Vascular Institute, Falls Church, VA; 9Massachusetts General Hospital, Boston, MA Background: The use of guideline directed medical therapy (GDMT) improves clinical outcomes in patients with heart failure (HF). Despite this, many patients are under-treated. This led to the hypothesis that serial measurements of natriuretic peptides may be useful to guide titration of medical therapy, and achieve better outcomes (the GUIDE-IT trial). We evaluated the reported reason for not following the protocol and increasing GDMT medications. Methods: GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDEIT) explored a ‘guided’ therapy with a goal to suppress NT-proBNP 1000 pg/mL on clinical outcomes of HF with reduced Ejection Fraction (HFrEF), utilizing a protocol of suggested medication titrations. For each clinical encounter, medication titrations were captured, along with a reason if a modification was not made. 894 patients were randomized to either the biomarker guided or GDMT group. Reasons were provided by the site in categorical and free-text reasons, and mapped to appropriate groupings. There were no differences between groups in rates and % of target doses achieved, but only about half achieved target doses of B-Blockers and ACE-I/ ARB, and only half were on an MRA by end of study. Results: This analysis included 6223 visits over a maximum of 24 months. In total, medication adjustments were made in 51% of the study visits representing 831(94%) of patients. The majority (74%) of adjustments occurred within the first 6 months, primarily within the first 6 weeks of enrollment (52%). Reasons for not titrating medications are shown in Figure 1. The primary reason for not adjusting medication was clinician decision, with the second top reason listed as already at maximally tolerated therapy. Conclusions: Despite a protocol-driven approach to titrating HF medications, many patients did not receive GDMT medication adjustments in GUIDE IT, particularly in the long term. There may be a gap in opportunities to titrate medications for maximal benefit in HF.
207 Impact of Patisiran, an RNAi Therapeutic, on Orthostatic Intolerance in Patients with Hereditary Transthyretin-Mediated Amyloidosis Daniel P. Judge1, Alejandra Gonzalez-Duarte2, Angela Dispenzieri3, Hollis Lin4, Madeline Merkel4, Yue Wang4, Michael Polydefkis5; 1Medical University of South Carolina, Charleston, SC; 2Instituto Nacional de Ciencias Medicas y Nutricion,
Salvador Zubiran, Mexico City, Mexico; 3Mayo Clinic, Rochester, MN; 4Alnylam Pharmaceuticals, Cambridge, MA; 5Johns Hopkins University, Baltimore, MD Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease which can impact numerous organs, including peripheral and autonomic nerves and heart. Orthostatic intolerance (OI), caused by amyloid deposition in the autonomic nervous system, is commonly reported in patients with hATTR amyloidosis. OI increases the risk that patients will experience clinically significant events, such as presyncope, syncope, and falls. In the Phase 3 APOLLO study, patisiran demonstrated improvement in OI. This analysis further describes the impact of patisiran on OI symptomatology. APOLLO was an international, randomized (2:1), double-blinded, placebo-controlled study of patisiran 0.3mg/kg or placebo IV q3W in patients with hATTR amyloidosis with polyneuropathy (NCT01960348). COMPASS-31 is a patient-reported autonomic symptoms questionnaire containing 31-items evaluating 6 autonomic domains. In the OI domain, patients were asked, “In the past year, have you ever felt faint, dizzy, ‘goofy’, or had difficulty thinking soon after standing up from a sitting or lying position.” Change in presence and severity of these OI symptoms collected from the OI domain of COMPASS-31 were evaluated descriptively. APOLLO enrolled 225 patients: median age 62 years, 74% male, 43% V30M, FAP Stage 1 (46%) and 2 (53%), 56% in the pre-defined cardiac subpopulation. At baseline, about two-thirds of patients reported mild to severe symptoms of OI in the past year. After 18 months, patisiran-treated patients were 3-fold more likely to report improvement in OI symptoms compared to placebo (30% vs 10%, respectively). Patisiran-treated patients were also less likely to worsen on these symptoms compared to placebo-treated patients after 18 months (14% vs 23%, respectively). Following 18 months of treatment, patients treated with patisiran were three times more likely to improve in their OI symptoms versus their own baseline compared to placebo. These data reinforce the clinical benefit of patisiran in addressing the debilitating autonomic symptoms of hATTR amyloidosis.
208 Withdrawal of Beta- Blockers and ACE Inhibitors after Left Ventricular Systolic Function Recovery in Patient with Dilated Cardiomyopathy Randomized Control Trial Abeer Bakhsh1, George Thanassoulis2, James C. Engert2, Eleanor Elstein2, Thao Huynh2, Nadia Giannetti2; 1Prince Sultan Cardiac Centre PSCC, Riyadh, Saudi Arabia; 2McGill University, Montreal, QC, Canada Introduction: Recovery of left ventricle (LV) systolic function with normalization of ejection fraction (LVEF) occurs in 10 - 27% of patients with 80% maintaining recovery. However, the need for medical therapy after recovery is often questioned. Previous randomized studies of treatment withdrawal were small, not selected for non-ischemic dilated cardiomyopathy (DCM) and had a reference of improved or recovered LVEF to > 40% or > 10% change from LVEF at time of diagnosis. Hypothesis: In patients with DCM with recovery of the LV systolic function to an EF (>50%), medical therapy withdrawal is possible without rebound LV systolic dysfunction. Method: This was a pilot randomized control open-label trial with 2:1 randomization for withdrawal of b-blockers and ACE inhibitors in patients with recovered LV systolic function. Patients’ medication discontinuation occurred in 2 phases with a six-month interval and patients were followed for one year. In phase 1, the b-blockers were withdrawn. In phase II, the ACE inhibitors were withdrawn. The primary endpoint was LVEF reduction (< 40%). Results: There were 22 patients (10 females) enrolled. The mean age was 60 § 12y. The mean LVEF at enrollment was 58 § 5% with no significant difference in the mean LVEF in both groups. Sixteen patients were assigned to the withdrawalgroup and 6 assigned to the control group.The primary endpoint occurred in 44% of the withdrawal group compared to none of the control. Event free survival at 6 month and 1 year were 87.5% and 73% respectively, p-value 0.087. The mean LVEF at 1 year for the treatment withdrawal group was 46.8 § 12% and control 55 § 6%. The mean LVEF reduction was 10.6 § 11%. The difference in the mean LVEF between the groups at 1 year was 8% with 95% CI (-3.3,20) at p-value 0.1. The difference in the mean LVEF at enrollment and at 1 year follow up for the medication withdrawal group was 10.6 § 11% and 95% CI (4.6,16.49) with p-value 0.0017. Conclusions: In DCM patients with recovery of
206 Optimal Medical Therapy in Heart Failure: Reasons for Lack of Medication Titration in the GUIDE IT Trial Mona Fiuzat1, Wendimagegn Alemayehu2, Justin Ezekowitz2, Cindy Westerhout2, David Whellan3, Hillary Mulder1, Tariq Ahmad4, Kirkwood Adams5, Ileana Pina6, Kevin Anstrom1, Lawton Cooper7, Brooke Alhanti1, Marco Sbolli8, Daniel Mark1, Eric Leifer7, Michael Felker1, Christopher O’Connor8, James Januzzi9; 1Duke University, Durham, NC; 2Canadian VIGOUR Centre, Alberta, ON, Canada; 3Jefferson University, Philadelphia, PA; 4Yale University, New Haven, CT; 5UNC, Chapel Hill, NC; 6 Detroit Medical Center, Detroit, MI; 7NIH, Bethesda, MD; 8Inova Heart and Vascular Institute, Falls Church, VA; 9Massachusetts General Hospital, Boston, MA Background: The use of guideline directed medical therapy (GDMT) improves clinical outcomes in patients with heart failure (HF). Despite this, many patients are under-treated. This led to the hypothesis that serial measurements of natriuretic peptides may be useful to guide titration of medical therapy, and achieve better outcomes (the GUIDE-IT trial). We evaluated the reported reason for not following the protocol and increasing GDMT medications. Methods: GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDEIT) explored a ‘guided’ therapy with a goal to suppress NT-proBNP 1000 pg/mL on clinical outcomes of HF with reduced Ejection Fraction (HFrEF), utilizing a protocol of suggested medication titrations. For each clinical encounter, medication titrations were captured, along with a reason if a modification was not made. 894 patients were randomized to either the biomarker guided or GDMT group. Reasons were provided by the site in categorical and free-text reasons, and mapped to appropriate groupings. There were no differences between groups in rates and % of target doses achieved, but only about half achieved target doses of B-Blockers and ACE-I/ ARB, and only half were on an MRA by end of study. Results: This analysis included 6223 visits over a maximum of 24 months. In total, medication adjustments were made in 51% of the study visits representing 831(94%) of patients. The majority (74%) of adjustments occurred within the first 6 months, primarily within the first 6 weeks of enrollment (52%). Reasons for not titrating medications are shown in Figure 1. The primary reason for not adjusting medication was clinician decision, with the second top reason listed as already at maximally tolerated therapy. Conclusions: Despite a protocol-driven approach to titrating HF medications, many patients did not receive GDMT medication adjustments in GUIDE IT, particularly in the long term. There may be a gap in opportunities to titrate medications for maximal benefit in HF.
207 Impact of Patisiran, an RNAi Therapeutic, on Orthostatic Intolerance in Patients with Hereditary Transthyretin-Mediated Amyloidosis Daniel P. Judge1, Alejandra Gonzalez-Duarte2, Angela Dispenzieri3, Hollis Lin4, Madeline Merkel4, Yue Wang4, Michael Polydefkis5; 1Medical University of South Carolina, Charleston, SC; 2Instituto Nacional de Ciencias Medicas y Nutricion,
Salvador Zubiran, Mexico City, Mexico; 3Mayo Clinic, Rochester, MN; 4Alnylam Pharmaceuticals, Cambridge, MA; 5Johns Hopkins University, Baltimore, MD Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease which can impact numerous organs, including peripheral and autonomic nerves and heart. Orthostatic intolerance (OI), caused by amyloid deposition in the autonomic nervous system, is commonly reported in patients with hATTR amyloidosis. OI increases the risk that patients will experience clinically significant events, such as presyncope, syncope, and falls. In the Phase 3 APOLLO study, patisiran demonstrated improvement in OI. This analysis further describes the impact of patisiran on OI symptomatology. APOLLO was an international, randomized (2:1), double-blinded, placebo-controlled study of patisiran 0.3mg/kg or placebo IV q3W in patients with hATTR amyloidosis with polyneuropathy (NCT01960348). COMPASS-31 is a patient-reported autonomic symptoms questionnaire containing 31-items evaluating 6 autonomic domains. In the OI domain, patients were asked, “In the past year, have you ever felt faint, dizzy, ‘goofy’, or had difficulty thinking soon after standing up from a sitting or lying position.” Change in presence and severity of these OI symptoms collected from the OI domain of COMPASS-31 were evaluated descriptively. APOLLO enrolled 225 patients: median age 62 years, 74% male, 43% V30M, FAP Stage 1 (46%) and 2 (53%), 56% in the pre-defined cardiac subpopulation. At baseline, about two-thirds of patients reported mild to severe symptoms of OI in the past year. After 18 months, patisiran-treated patients were 3-fold more likely to report improvement in OI symptoms compared to placebo (30% vs 10%, respectively). Patisiran-treated patients were also less likely to worsen on these symptoms compared to placebo-treated patients after 18 months (14% vs 23%, respectively). Following 18 months of treatment, patients treated with patisiran were three times more likely to improve in their OI symptoms versus their own baseline compared to placebo. These data reinforce the clinical benefit of patisiran in addressing the debilitating autonomic symptoms of hATTR amyloidosis.
208 Withdrawal of Beta- Blockers and ACE Inhibitors after Left Ventricular Systolic Function Recovery in Patient with Dilated Cardiomyopathy Randomized Control Trial Abeer Bakhsh1, George Thanassoulis2, James C. Engert2, Eleanor Elstein2, Thao Huynh2, Nadia Giannetti2; 1Prince Sultan Cardiac Centre PSCC, Riyadh, Saudi Arabia; 2McGill University, Montreal, QC, Canada Introduction: Recovery of left ventricle (LV) systolic function with normalization of ejection fraction (LVEF) occurs in 10 - 27% of patients with 80% maintaining recovery. However, the need for medical therapy after recovery is often questioned. Previous randomized studies of treatment withdrawal were small, not selected for non-ischemic dilated cardiomyopathy (DCM) and had a reference of improved or recovered LVEF to > 40% or > 10% change from LVEF at time of diagnosis. Hypothesis: In patients with DCM with recovery of the LV systolic function to an EF (>50%), medical therapy withdrawal is possible without rebound LV systolic dysfunction. Method: This was a pilot randomized control open-label trial with 2:1 randomization for withdrawal of b-blockers and ACE inhibitors in patients with recovered LV systolic function. Patients’ medication discontinuation occurred in 2 phases with a six-month interval and patients were followed for one year. In phase 1, the b-blockers were withdrawn. In phase II, the ACE inhibitors were withdrawn. The primary endpoint was LVEF reduction (< 40%). Results: There were 22 patients (10 females) enrolled. The mean age was 60 § 12y. The mean LVEF at enrollment was 58 § 5% with no significant difference in the mean LVEF in both groups. Sixteen patients were assigned to the withdrawalgroup and 6 assigned to the control group.The primary endpoint occurred in 44% of the withdrawal group compared to none of the control. Event free survival at 6 month and 1 year were 87.5% and 73% respectively, p-value 0.087. The mean LVEF at 1 year for the treatment withdrawal group was 46.8 § 12% and control 55 § 6%. The mean LVEF reduction was 10.6 § 11%. The difference in the mean LVEF between the groups at 1 year was 8% with 95% CI (-3.3,20) at p-value 0.1. The difference in the mean LVEF at enrollment and at 1 year follow up for the medication withdrawal group was 10.6 § 11% and 95% CI (4.6,16.49) with p-value 0.0017. Conclusions: In DCM patients with recovery of