Senni M, McMurray JJV, Wachter R, et al.
Eur J Heart Fail. 2016; published online ahead of print

Background
The PARADIGM-HF study assessed the safety and tolerability of 200 mg twice daily LCZ696 (sacubitril/valsartan) in ambulatory HFrEF patients. However, whereas PARADIGM-HF patients were pre-exposed to optimal ACE inhibitors (ACEi)/angiotensin receptor blockers (ARB) doses, it is accepted that during clinical practice many HFrEF patients are not at target dose  [1-3].
The aim of the present TITRATION study was to evaluate whether the tolerability was affected by the duration of initiating or up-titrating LCZ696 regimes, which is representative to routine practice. This study also included patients naïve to or on varying levels of pre-exposure to ACEi/ARBs, with and without elevated BNP or NT-proBNP, who were ambulant or hospitalised.
During an 11-week, double-blind randomised study period, two up-titration regimens were compared in 498 patients: the ‘condensed’ (3-weeks: 100 mg twice daily for 2 weeks, followed by 200 mg) protocol or ‘conservative’ (6-weeks: 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily) regimen, preceded by a 5-day open-label run-in period (50 mg sacubitril/valsartan). 429 (86.1% of randomised) completed the study. Patients were stratified according to pre-study dose of ACEI/ARB.

Main results

• Prespecified tolerability criteria for hypertension, renal failure, serum creatinine levels, hyperkalaemia, serum potassium levels and angioedema did not differ significantly between the two up-titration regimens. No interaction was observed between the ACEI/ARB dose stratum and uptitration regimen for any pre-defined adverse event.
• Treatment success: 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks. Specifically, 77.8% of people on the ‘condensed’ regimen and 84.3% on the ‘conservative’ regimen: (P for ‘condensed’ vs. ‘conservative’ = 0.078).

• Treatment success rates by ACEi/ARB pre-study dose stratification were:  82.6% vs. 83.8% (P =0.783) for high-dose/‘condensed’ vs. high-dose/‘conservative’, 84.9% vs. 73.6% (P =0.030) for low-dose/‘conservative’ vs. low-dose/‘condensed’.
• 19 out of 74 (25.7%) patients with down-titration or dose interruption during the post-randomisation period, were able to maintain a dose of LCZ696 200 mg twice daily for at least the final two weeks before completion of the study.

Conclusion

In a wide range of HFrEF patients, the initiation and up-titration regimens of LCZ696 resulted in tolerability similar to other HF treatments. A gradual up-titration was associated with increased attainment of the target doses in patients transitioning from lower pre-treatment doses of ACEi/ARBs.

Find this article online at Eur J Heart Failure

References

1. McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004.
2. McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail 2013;15:1062–1073.
3. Calvert MJ, Shankar A, McManus RJ, et al. Evaluation of the management of heart failure in primary care. Fam Pract 2009;26:145–153.