23 May 2015 11:00 CEST (Paris)
23 May 2015 10:00 BST (London)
23 May 2015 05:00 EDT (New York)
Seville, Spain – 23 May 2015: The TITRATION study has confirmed that LCZ696 is safe and tolerated by patients with heart failure and reduced ejection fraction (HFrEF) in clinical practice, announced principal investigator Dr Michele Senni in a late breaking trials session today at Heart Failure 2015. More than 70% of patients achieved the target dose 200 mg BID over a 3- or 6-week up-titration regimen.
“At the end of the study patients asked us to continue LCZ696 because they felt better.”
Heart Failure 2015 is the main annual meeting of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). The scientific programme is here.
Dr Senni, who is head of the Cardiology, Heart Failure and Heart Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy, and national leader of PARADIGM-HF, said: “When you are treating patients you need to be confident with a new drug. The PARADIGM-HF trial demonstrated the superiority of LCZ696, an angiotensin receptor neprilysin inhibitor, over the ACE inhibitor enalapril in reducing the risk of cardiovascular mortality and heart failure hospitalisation.1 Moreover it prevented clinical progression in patients with HFrEF. The TITRATION study was designed to evaluate the practical application of LCZ696 in the clinic.”
TITRATION was a randomised, double blind study that assessed the safety and tolerability of initiating and up-titrating LCZ696 from 50mg BID to a target dose of 200mg BID in a 3-week (condensed) versus 6-week (conservative) regimen in patients with HFrEF (ejection fraction ≤35%). The study enrolled a broader range of patients than the PARADIGM-HF trial, including inpatients and patients naïve to ACE inhibitors or angiotensin receptor blockers (ARBs).
The study was conducted in two phases. The first was an open label run in period in which LCZ696 was tested for tolerability and safety at a dosage of 50 mg BID for 5 days. Patients were then randomised 1:1 to LCZ696 in a conservative up-titration over 6 weeks versus a condensed up-titration over 3 weeks. In both groups the target dose was 200 mg BID.
Primary endpoints were the proportion of patients experiencing pre-specified adverse events (symptomatic hypotension, hyperkalaemia, renal dysfunction, angioedema) and laboratory outcomes including systolic blood pressure <95 mmHg and a doubling of serum creatinine from baseline. Secondary endpoints included the number of patients achieving the target dose without any down-titration or interruption over 12 weeks (defined as treatment success).
Of the 540 patients enrolled in the run in, 498 (92%) were randomised and of those, 429 (86%) completed the study. There were no differences in the primary endpoints between groups. After excluding patients who discontinued LCZ696 because of non-adverse events or death, treatment success was achieved in 78% and 84% of patients in the condensed and conservative regimens, respectively (p=0.07).
Dr Senni said:
“At least 76% of randomised patients achieved and maintained the target dose of LCZ696 200mg BID, regardless of the up-titration regimen. The target dose was also achieved for at least 2 weeks leading to study completion in 80% of patients including those requiring a temporary down-titration or dose interruption during the study. Commonly reported adverse events in the TITRATION study were in line with the LCZ696 group in the PARADIGM-HF trial, confirming those findings in real life.”
“This study provides complementary data beyond PARADIGM-HF to support the use of LCZ696 in clinical practice in a broader range of patients such as inpatients and patients naïve to ACE inhibitors and ARBs, which largely mimics the real life situation. Both regimens reached a very high rate of treatment success and tolerability.”
Dr Senni concluded:
“We expect LCZ696 to be on the market in Europe and the US within the coming year which is good news. At the end of the study patients asked us to continue LCZ696 because they felt better. TITRATION was an open label study so we know patients were taking the drug. We have seen in real life that switching to LCZ696 is beneficial for patients.”