Background: In PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure), heart failure treatment with sacubitril/valsartan reduced the primary composite outcome of cardiovascular death or heart failure hospitalization compared with enalapril but resulted in more symptomatic hypotension. Concern on hypotension may be limiting use of sacubitril/valsartan in appropriate patients. Methods and Results: We characterized patients in PARADIGM-HF by whether they reported hypotension during study run-in periods (enalapril, followed by sacubitril/valsartan) and after randomization and assessed whether hypotension modified the efficacy of sacubitril/valsartan. Of the 10 513 patients entering the enalapril run-in, 136 (1.3%) experienced hypotension and 93 (68%) were unable to continue to the next phase; of 9419 patients entering the sacubitril/valsartan run-in period, 228 (2.4%) patients experienced hypotension and 51% were unable to successfully complete the run-in. After randomization, 388 (9.2%) participants had 501 hypotensive events with enalapril, and 588 (14.0%) participants had 803 hypotensive events with sacubitril/valsartan ( P <0.001). There was no difference between randomized treatment groups in the number of participants who discontinued therapy because of hypotension. Individuals with a hypotensive event in either group were older, had lower blood pressure at randomization, and were more likely to have an implantable cardioverter defibrillator. Participants with hypotensive events during run-in who were ultimately randomized derived similar efficacy from sacubitril/valsartan compared with enalapril as those without hypotensive events ( P interaction>0.90). Conclusions: Hypotension was more common with sacubitril/valsartan relative to enalapril in PARADIGM-HF but did not differentially affect permanent discontinuations. Patients with hypotension during run-in derived similar benefit from sacubitril/valsartan compared with enalapril as those who did not experience hypotension.
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.TableHypotension events post-randomization & actions takenAction taken for hypotension AEEnalapril (N = 4212)Sacubitril/Valsartan (N = 4187)P-valueN = 1109 events, 775 patientsN = 1525 events, 1018 patientsNo Action484 Events (43.6%)646 events (42.4%).51Dose Adjustment / Temporary Interruption380 events (34.3%)594 events (39%).014Permanent Discontinuation29 events (2.6%)39 events (2.6%).93Change in Concomitant Medication141 events (12.7%)196 events (12.9%).92Non-drug Therapy23 events (2.1%)39 events (2.6%).42Hospitalization136 events (12.3%)115 events (7.5%)<.001 Open table in a new tab
BackgroundTransthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, often fatal disease. Nexiguran ziclumeran (nex-z) is an investigational therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) targeting the gene encoding transthyretin (TTR).MethodsIn this phase 1, open-label trial, we administered a single intravenous infusion of nex-z to patients with ATTR-CM. Primary objectives included assessment of the effect of nex-z on safety and pharmacodynamics, including the serum TTR level. Secondary end points included changes in N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, high-sensitivity cardiac troponin T levels, the 6-minute walk distance, and the New York Heart Association (NYHA) class.ResultsA total of 36 patients received nex-z and completed at least 12 months of follow-up. Of these patients, 50% were in NYHA class III and 31% had variant ATTR-CM. The mean percent change from baseline in the serum TTR level was −89% (95% confidence interval [CI], −92 to −87) at 28 days and −90% (95% CI, −93 to −87) at 12 months. Adverse events were reported in 34 patients. Five had transient infusion-related reactions, and two had transient liver-enzyme elevations that were assessed as treatment-related. Serious adverse events, most of which were consistent with ATTR-CM, were reported in 14 patients. The geometric mean factor change from baseline to month 12 was 1.02 (95% CI, 0.88 to 1.17) in the NT-proBNP level and 0.95 (95% CI, 0.89 to 1.01) in the high-sensitivity cardiac troponin T level. The median change from baseline to month 12 in the 6-minute walk distance was 5 m (interquartile range, −33 to 49). A total of 92% of the patients had either improvement or no change in their NYHA class.ConclusionsIn this phase 1 study involving patients with ATTR-CM, treatment with a single dose of nex-z was associated with transient infusion-related reactions and consistent, rapid, and durable reductions in serum TTR levels. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.)
Aims To assess differences in diuretic dose requirements in patients treated with sacubitril/valsartan compared with enalapril in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM‐HF) trial. Methods and results Overall, 8399 patients with New York Heart Association class II–IV heart failure and reduced LVEF were randomized to sacubitril/valsartan 200 mg bid or enalapril 10 mg twice daily. Loop diuretic doses were assessed at baseline, 6, 12, and 24 months, and furosemide dose equivalents were calculated via multiplication factors (2x for torsemide and 40x for bumetanide). Percentages of participants with reductions or increases in loop diuretic dose were determined. At baseline, 80.8% of participants were taking any diuretics ( n = 6290 for loop diuretics, n = 496 for other diuretics); of those, recorded dosage data for loop diuretics were available on 5487 participants. Mean baseline furosemide equivalent doses were 48.2 mg for sacubitril/valsartan and 49.6 mg for enalapril ( P = 0.25). Patients treated with sacubitril/valsartan were more likely to reduce diuretic dose and less likely to increase diuretic dose relative to those randomized to enalapril at 6, 12, 24 months post‐randomization, with an overall decreased diuretic use of 2.0% ( P = 0.02), 4.1% ( P < 0.001), and 6.1% ( P < 0.001) at 6, 12, and 24 months, respectively, with similar findings in an on‐treatment analysis. Conclusion Treatment with sacubitril/valsartan was associated with more loop diuretic dose reductions and fewer dose increases compared with enalapril, suggesting that treatment with sacubitril/valsartan may reduce the requirement for loop diuretics relative to enalapril in patients with heart failure with reduced ejection fraction.
Background: Diuretics are frequently used in patients with heart failure but can lead to neurohormonal activation, electrolyte abnormalities, and worsening renal function. Hypothesis: We hypothesiz...
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