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Valsartan in Hospitalized Patients with Chronic Heart Failure
S34 Journal of Cardiac Failure Vol. 22 No. 8S August 2016 of TAC required to achieve therapeutic levels was approximately 2 fold higher than the starting dose, representing an opportunity to optimize initial dosing. Conclusions: Early, therapeutic TAC levels have been associated with improved outcomes in renal transplant recipients. In an analysis of 40 heart transplant recipients receiving only methylprednisolone induction, there was not an apparent impact on 12 month incidence of treated rejection with regards to time to therapeutic levels, CV, and therapeutic TAC dose. A high CV was observed in our population; a CV greater than 15% has been associated with increased risk of rejection and poor outcomes among renal transplant recipients, however outcomes were no different in our cohort.
Table. Hypotension events post-randomization & actions taken
Action taken for hypotension AE No Action Dose Adjustment / Temporary Interruption Permanent Discontinuation Change in Concomitant Medication Non-drug Therapy Hospitalization
Enalapril (N = 4212)
Sacubitril/Valsartan (N = 4187)
N = 1109 events, 775 patients
N = 1525 events, 1018 patients
P-value
484 Events (43.6%) 380 events (34.3%)
646 events (42.4%) 594 events (39%)
.51 .014
29 events (2.6%) 141 events (12.7%)
39 events (2.6%) 196 events (12.9%)
.93 .92
23 events (2.1%) 136 events (12.3%)
39 events (2.6%) 115 events (7.5%)
.42 <.001
089 Preliminary Observations of the Initiation and Tolerability of Sacubitril/Valsartan in Hospitalized Patients with Chronic Heart Failure Kathleen M.D. Faulkenberg, J. Bradley Williams, Michael Militello, Antonio L. Perez, Randall C. Starling, W.H. Wilson Tang; Cleveland Clinic, Cleveland, OH
088 Incidence, Predictors, and Outcomes Associated with Hypotensive Episodes among Patients Receiving Sacubitril/Valsartan or Enalapril: The PARADIGM-HF Trial Orly Vardeny1, Brian Claggett2, Jessica Kachadourian3, Scott M. Pearson1, Milton Packer4, Michael Zile5, Jean Rouleau6, Karl Swedberg7, John J.V. McMurray8, Scott D. Solomon2; 1University of Wisconsin, Madison, WI; 2Brigham and Women’s Hospital, Boston, MA; 3Novartis Pharmaceuticals Coorporation, East Hanover, NJ; 4Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX; 5Medical University of South Carolina and Ralph H. Johnston Veterans Administration Medical Center, Charleston, SC; 6Institut de Cardiologie de Montreal, Université de Montréal, Montreal, QC, Canada; 7University of Gothenburg, Gothenburg, Sweden; 8British Heart Foundation Cardiovascular Research Center, University of Glasgow, Glasgow, United Kingdom
Introduction: The angiotensin receptor/neprilysin inhibitor (ARNI) sacubitril/ valsartan was recently found to be superior to enalapril in the reduction of cardiovascular death and hospitalization in heart failure patients with a reduced ejection fraction (HFrEF). A run phase was required to assure tolerability of enalapril 20 mg daily and sacubitril/ valsartan 200 mg BID. Hypotension eliminated some candidates during the run in phase. Historical trials have also demonstrated a substantial decrease in systolic blood pressures (SBP) with dual angiotensin receptor/neprilysin blockade compared with either class used alone. The tolerability of initiating therapy with sacubitril/valsartan in hospitalized patients with heart failure is currently unknown. Hypothesis: Specific subsets of patients who are initiated on sacubitril/valsartan during hospitalization may be unable tolerate the medication for continuation on discharge due to hypotension. Methods: Medical records for all hospitalized patients who received sacubitril/valsartan during an inpatient admission from September 2015-March 2016 were identified and reviewed. Only patients who were newly initiated on therapy during admission were included in the cohort. The starting dose of sacubitril/valsartan, discharge dose (if applicable), incidence of hypotension, renal function and serum potassium were evaluated. Results: Twenty-eight patients were identified who had received sacubitril/valsartan during their admission and 32% (n = 9) were naïve to sacubitril/valsartan prior to hospitalization. Our cohort median age 67 (46–81) and 78% were male. Sacubitril/valsartan was continued in only four of nine patients (44%) upon discharge. Patients who were discharged on sacubitril/valsartan during had a higher mean baseline SBP (129 vs. 111 mmHg) and left ventricular ejection fraction (EF 40% vs. 19%) with lower mean serum creatinine (SCr 1.16 vs. 1.37). The most common reason for patients not to be discharged on sacubitril/valsartan was hypotension (SBP < 90 mmHg), which occurred in three of nine patients (33%). Other reasons for discontinuation of the medication included worsening renal function (11%) and transition to palliative care (11%). Conclusion: In our preliminary study, 44% of patients initiated on sacubitril/valsartan during hospitalization were prescribed this therapy at discharge. Hospitalized patients who tolerated sacubitril/ valsartan initiation tended to have higher baseline SBP and LVEF with a lower SCr. Although limited by a small sample size in this preliminary observation, we identified the most common reason for medication discontinuation was hypotension. More data is needed to assess the safety and efficacy of inpatient initiation of sacubitril/valsartan.
090 Background: In PARADIGM-HF, sacubitril/valsartan reduced the composite of CV or HF hospitalization compared with enalapril, but resulted in more hypotensive episodes. Methods: We characterized patients in PARADIGM-HF by whether or not they experienced hypotension (reported as an AE) during study run-in (sequential phases of enalapril 10 mg BID, sacubitril/valsartan 49/51 mg BID, and sacubitril/valsartan 97/ 103 mg BID) and following randomization. We assessed whether hypotension during run-in modified the efficacy of sacubitril/valsartan for the primary outcome. Results: 174 patients had 180 hypotension events during enalapril run-in (64% were unable to continue to the next phase); 274 patients had 283 hypotension events during sacubitril/ valsartan run-in (48% were unable to continue to randomization). The likelihood of having a hypotensive episode during run-in was no greater in patients who were on sub-target doses of ACE inhibitors or ARBs prior to screening (P = .30). Following randomization, 542 patients had 702 hypotensive events with enalapril, and 799 patients had 1072 hypotensive events with sacubitril/valsartan. Those with a hypotensive event were older, had more renal dysfunction and lower LVEF. There were no differences between groups in permanent study medication discontinuations (Table). Patients with hypotensive events during run-in who continued on to randomization derived similar efficacy from sacubitril/valsartan compared with enalapril (HR 0.77, [95% CI 0.50– 1.19]) as those without hypotensive events (HR 0.80, [95% CI 0.73–0.88], p-interaction = 0.84). Conclusions: Hypotension was more common with sacubitril/ valsartan relative to enalapril in PARADIGM-HF, but did not differentially affect permanent discontinuations. Participants with hypotension during run-in derived similar benefit from sacubitril/valsartan compared with enalapril as those who did not experience hypotension.
Aspirin Does Not Have a Significant Impact on Loop Diuretic Response or Renin Release in Heart Failure Patients J. Samuel Broughton, Jennifer S. Hanberg, Mahlet Assefa, Veena S. Rao, Jeffrey M. Testani; Yale University, New Haven, CT Introduction: Through inhibition of cyclooxygenase activity, nonsteroidal antiinflammatory drugs (NSAIDs) prevent synthesis of renal prostaglandins which have important cardio-renal effects such as regulating renal filtration, solute transport, and renin release. Although traditional NSAID use is relatively uncommon in heart failure, aspirin use is common. Notably, the cardio-renal effects of even low dose aspirin may be clinically relevant, as several studies have found that aspirin use decreases the effects of angiotensin converting enzyme inhibition in heart failure. Previous studies have suggested that NSAIDs worsen the response to loop diuretics but paradoxically can reduce renin release. Our objective was to determine if a clinically meaningful effect of aspirin on loop diuretic response and renin release occurs in a real world heart failure population undergoing loop diuretic treatment. Hypothesis: We hypothesized that aspirin use would not be associated with meaningful effects on diuretic response or renin release. Methods: Heart failure patients receiving treatment with loop diuretics at the Yale Transition Care Center were prospectively enrolled. Spot urine samples were collected before diuretic administration, and one hour after. All urine produced after diuretic administration was collected cumulatively. Diuretic response and renin release were compared between patients taking aspirin, and those who were not. We define diuretic efficiency as the increase in sodium output per doubling of diuretic dose. Results: Among
Table. Hypotension events post-randomization & actions taken
Action taken for hypotension AE No Action Dose Adjustment / Temporary Interruption Permanent Discontinuation Change in Concomitant Medication Non-drug Therapy Hospitalization
Enalapril (N = 4212)
Sacubitril/Valsartan (N = 4187)
N = 1109 events, 775 patients
N = 1525 events, 1018 patients
P-value
484 Events (43.6%) 380 events (34.3%)
646 events (42.4%) 594 events (39%)
.51 .014
29 events (2.6%) 141 events (12.7%)
39 events (2.6%) 196 events (12.9%)
.93 .92
23 events (2.1%) 136 events (12.3%)
39 events (2.6%) 115 events (7.5%)
.42 <.001
089 Preliminary Observations of the Initiation and Tolerability of Sacubitril/Valsartan in Hospitalized Patients with Chronic Heart Failure Kathleen M.D. Faulkenberg, J. Bradley Williams, Michael Militello, Antonio L. Perez, Randall C. Starling, W.H. Wilson Tang; Cleveland Clinic, Cleveland, OH
088 Incidence, Predictors, and Outcomes Associated with Hypotensive Episodes among Patients Receiving Sacubitril/Valsartan or Enalapril: The PARADIGM-HF Trial Orly Vardeny1, Brian Claggett2, Jessica Kachadourian3, Scott M. Pearson1, Milton Packer4, Michael Zile5, Jean Rouleau6, Karl Swedberg7, John J.V. McMurray8, Scott D. Solomon2; 1University of Wisconsin, Madison, WI; 2Brigham and Women’s Hospital, Boston, MA; 3Novartis Pharmaceuticals Coorporation, East Hanover, NJ; 4Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX; 5Medical University of South Carolina and Ralph H. Johnston Veterans Administration Medical Center, Charleston, SC; 6Institut de Cardiologie de Montreal, Université de Montréal, Montreal, QC, Canada; 7University of Gothenburg, Gothenburg, Sweden; 8British Heart Foundation Cardiovascular Research Center, University of Glasgow, Glasgow, United Kingdom
Introduction: The angiotensin receptor/neprilysin inhibitor (ARNI) sacubitril/ valsartan was recently found to be superior to enalapril in the reduction of cardiovascular death and hospitalization in heart failure patients with a reduced ejection fraction (HFrEF). A run phase was required to assure tolerability of enalapril 20 mg daily and sacubitril/ valsartan 200 mg BID. Hypotension eliminated some candidates during the run in phase. Historical trials have also demonstrated a substantial decrease in systolic blood pressures (SBP) with dual angiotensin receptor/neprilysin blockade compared with either class used alone. The tolerability of initiating therapy with sacubitril/valsartan in hospitalized patients with heart failure is currently unknown. Hypothesis: Specific subsets of patients who are initiated on sacubitril/valsartan during hospitalization may be unable tolerate the medication for continuation on discharge due to hypotension. Methods: Medical records for all hospitalized patients who received sacubitril/valsartan during an inpatient admission from September 2015-March 2016 were identified and reviewed. Only patients who were newly initiated on therapy during admission were included in the cohort. The starting dose of sacubitril/valsartan, discharge dose (if applicable), incidence of hypotension, renal function and serum potassium were evaluated. Results: Twenty-eight patients were identified who had received sacubitril/valsartan during their admission and 32% (n = 9) were naïve to sacubitril/valsartan prior to hospitalization. Our cohort median age 67 (46–81) and 78% were male. Sacubitril/valsartan was continued in only four of nine patients (44%) upon discharge. Patients who were discharged on sacubitril/valsartan during had a higher mean baseline SBP (129 vs. 111 mmHg) and left ventricular ejection fraction (EF 40% vs. 19%) with lower mean serum creatinine (SCr 1.16 vs. 1.37). The most common reason for patients not to be discharged on sacubitril/valsartan was hypotension (SBP < 90 mmHg), which occurred in three of nine patients (33%). Other reasons for discontinuation of the medication included worsening renal function (11%) and transition to palliative care (11%). Conclusion: In our preliminary study, 44% of patients initiated on sacubitril/valsartan during hospitalization were prescribed this therapy at discharge. Hospitalized patients who tolerated sacubitril/ valsartan initiation tended to have higher baseline SBP and LVEF with a lower SCr. Although limited by a small sample size in this preliminary observation, we identified the most common reason for medication discontinuation was hypotension. More data is needed to assess the safety and efficacy of inpatient initiation of sacubitril/valsartan.
090 Background: In PARADIGM-HF, sacubitril/valsartan reduced the composite of CV or HF hospitalization compared with enalapril, but resulted in more hypotensive episodes. Methods: We characterized patients in PARADIGM-HF by whether or not they experienced hypotension (reported as an AE) during study run-in (sequential phases of enalapril 10 mg BID, sacubitril/valsartan 49/51 mg BID, and sacubitril/valsartan 97/ 103 mg BID) and following randomization. We assessed whether hypotension during run-in modified the efficacy of sacubitril/valsartan for the primary outcome. Results: 174 patients had 180 hypotension events during enalapril run-in (64% were unable to continue to the next phase); 274 patients had 283 hypotension events during sacubitril/ valsartan run-in (48% were unable to continue to randomization). The likelihood of having a hypotensive episode during run-in was no greater in patients who were on sub-target doses of ACE inhibitors or ARBs prior to screening (P = .30). Following randomization, 542 patients had 702 hypotensive events with enalapril, and 799 patients had 1072 hypotensive events with sacubitril/valsartan. Those with a hypotensive event were older, had more renal dysfunction and lower LVEF. There were no differences between groups in permanent study medication discontinuations (Table). Patients with hypotensive events during run-in who continued on to randomization derived similar efficacy from sacubitril/valsartan compared with enalapril (HR 0.77, [95% CI 0.50– 1.19]) as those without hypotensive events (HR 0.80, [95% CI 0.73–0.88], p-interaction = 0.84). Conclusions: Hypotension was more common with sacubitril/ valsartan relative to enalapril in PARADIGM-HF, but did not differentially affect permanent discontinuations. Participants with hypotension during run-in derived similar benefit from sacubitril/valsartan compared with enalapril as those who did not experience hypotension.
Aspirin Does Not Have a Significant Impact on Loop Diuretic Response or Renin Release in Heart Failure Patients J. Samuel Broughton, Jennifer S. Hanberg, Mahlet Assefa, Veena S. Rao, Jeffrey M. Testani; Yale University, New Haven, CT Introduction: Through inhibition of cyclooxygenase activity, nonsteroidal antiinflammatory drugs (NSAIDs) prevent synthesis of renal prostaglandins which have important cardio-renal effects such as regulating renal filtration, solute transport, and renin release. Although traditional NSAID use is relatively uncommon in heart failure, aspirin use is common. Notably, the cardio-renal effects of even low dose aspirin may be clinically relevant, as several studies have found that aspirin use decreases the effects of angiotensin converting enzyme inhibition in heart failure. Previous studies have suggested that NSAIDs worsen the response to loop diuretics but paradoxically can reduce renin release. Our objective was to determine if a clinically meaningful effect of aspirin on loop diuretic response and renin release occurs in a real world heart failure population undergoing loop diuretic treatment. Hypothesis: We hypothesized that aspirin use would not be associated with meaningful effects on diuretic response or renin release. Methods: Heart failure patients receiving treatment with loop diuretics at the Yale Transition Care Center were prospectively enrolled. Spot urine samples were collected before diuretic administration, and one hour after. All urine produced after diuretic administration was collected cumulatively. Diuretic response and renin release were compared between patients taking aspirin, and those who were not. We define diuretic efficiency as the increase in sodium output per doubling of diuretic dose. Results: Among