CME INDIA Presentation by Admin.
Now Sacubitril/valsartan and Spironolactone have been approved by the USFDA for HFpEF (Heart Failure Preserved Ejection Failure) and new hopes do radiates. Till now no drugs were approved for this very tedious and difficult to diagnose condition. As results of trials with SGLT2 Inhibitors will be out, rosier picture is expected to bloom.
An FDA advisory committee voted to make history
- In a 12-1 vote Dec. 15, the agency’s Cardiovascular and Renal Drugs Advisory Committee ruled that new evidence supports use of the heart failure drug sacubitril/valsartan to treat patients in heart failure with preserved ejection fraction.
- On Dec. 16, the committee recommended in an 8-4 vote that existing evidence from a controversial clinical trial supported the use of the blood pressure drug spironolactone to treat HFpEF.
- This is based on the phase 3 HFpEF study (PARAGON-HF).
- Sacubitril/valsartan reduced the rate of the primary composite endpoint of total HF hospitalization and CV death by 13% relative to the active comparator valsartan.
Worth to witness
- Sacubitril/Valsartan becomes the first drug to be approved for HFpEF.
- Spiranolactone became the second drug to be approved for the same indication later this week based on TOPCAT results, where it was better than placebo by 18%.
CME INDIA Discussion on 17/12/2020
Dr Awadhesh K Singh, DM Endo., Kolkata: Both ARNI and Spironolactone is under FDA hammer 🔨 for new indication in HFpEF based on PARAGON and TOPCAT study. Already ARNI leading by 12/1 and Spiro by 8/4/1 vote. What is take of our Cardiologist colleagues? Very much interested to hear their views!
Dr N K Singh:
- PARALLAX trial evaluated the impact of sacubitril/valsartan on biomarkers and functional outcomes in patients with heart failure and preserved ejection fraction.
- There were hints of benefit in post hoc and exploratory analyses.
- PARALLAX joined PARAGON-HF in failing to deliver a win for sacubitril/valsartan in HFpEF.
- HFpEF accounts for more than half of all heart failure cases.
- There are no proven, specific therapies.
- PARAGON-HF trial did not show a significant difference in the composite primary endpoint of hospitalization for heart failure or CV death, only exploratory secondary endpoints—including improvements in NYHA class and quality of life and reduced likelihood of worsening renal function—hinted at a benefit of sacubitril/valsartan.
Dr Prasun Dev, KIMS Hyderabad: SGLT2I probably will show the same….
- HFpEF remains a clinical diagnosis…only symptomatic patients with normal ejection fraction qualify.
- ARNi raises ANP levels, so that cannot be used for diagnosis or prognosis once you start this, I presume.
- Surprised that lack of statistical significance did not stop the current recommendations for HFpEF patients being prescribed ARNi, given that a molecule like ezetimibe was rejected after the ENHANCE study….
Dr Varun Kumar, DM, Card, Ranchi:
- HFpEF is really a big headache for cardiologists due to lack of effective treatment.
- Paragon HF & Parallax trials have shown some benefits in this group of patients. But the patients most benefitted were those with heart failure with mid-range EF.
- In Paragon, it was patient group with EF between 45-57% while those with more than 57% EF didn’t show any benefits.
- Similarly, in Parallax trial the mean EF was 56%. So, it is difficult to say in patients with absolutely normal EF this drug will be effective or not but after its approval in this group of patient, we have to see the real-life data that how effective these drugs would be.
- But at least now we can offer something to these patients.
Dr Sanjeev R Pathak, Diabetologist, Ahmedabad: Dr Nissen the only one to vote against ARNI!!
Dr Awadhesh K Singh, DM Endo., Kolkata: Yes, he also voted against Spironolactone
Dr Deepak Gupta, DM Card., Pulse Hospital Ranchi:
- It is overall true that both drugs just missed the level of significance by p value of 0.05 for primary endpoints.
- Although the approval is unusual if they become strict
- Previously they approved some drugs in spite of just non-achievement of significant p value. Examples are:
- Enalapril- SOLVED prevention trial
- Carvedilol in HFrEF -CAPRICON
- Digoxin in heart failure-DIG study
- Bivalirudin in PCI-BAT Study
- Subgroup analysis of both trials also showed benefits in some specified group and in female patients.
- Voting are in favour of both drugs.
- It is very true that HFp EF is not simple as HFrEF and we need to understand it more.
Dr Rajiv Kovil, Diabetologist, Mumbai: I am a little surprised-Paragon was a negative trial for HHF and CV death.
Dr Awadhesh K Singh, DM Endo., Kolkata: Not negative but neutral – missing by a flicker. HR 0.86 (0.75-1.01), p=0.06 in Paragon vs Valsartan.
Dr Rajiv Kovil, Mumbai: Agree. Another thing both paradigm and paragon were active comparator trials.
Dr Deepak Gupta, DM Card., Pulse Hospital Ranchi: We are still learning from the Biostatistician. They needed just seven more events in opposite group to achieve significant P value. It is number game 😊
CME INDIA Learning Points:
- Spironolactone failed the primary endpoint in the TOPCAT trial. It didn’t reduce death from cardiovascular causes, aborted cardiac arrest, or HF hospitalization in those with an EF of 45% or more compared with placebo (HR 0.89, P=0.14).
- The extenuating circumstances were different this time but worth to remember that FDA ‘s approval of other drugs remind us about other drugs that didn’t make the primary endpoint in their pivotal trials.
- For Sacubitril/Valsartan-PARAGON-HF really only missed its target by a little.
- FDA view point about Sacubtril/Valsartan
- For one thing, requiring events in the primary endpoint to be adjudicated cost some events that would have tipped the P-value under the 0.05 threshold but didn’t materially change the risk ratios.
- The “yes/no” determination of events also wasted some data. The negative adjudication of 562 events was often due to a lack of information or alternative practices that lessen, but don’t eliminate, the degree of confidence that they were real events.
- “We favour giving ‘partial credit’ to events based on the level of evidence provided, rather than a dichotomous ‘yes’ or ‘no.
- PARAGON-HF participants closer to the range for patients with heart failure with reduced ejection fraction (HFrEF, which is already an approved indication for sacubitril/valsartan) had better results.
- In the group with an EF of 57% or less, the primary endpoint was statistically significant (RR 0.78, 95% CI 0.64-0.95). “Retrospectively, that still seems relevant.”
- FDA view point for Spironolactone
- TOPCAT was sponsored by the National Institutes of Health, not by a drug company, and spironolactone is available from multiple manufacturers in generic form.
- So, the agency took the initiative to consider the HFpEF indication anyway, “to respond to an important, unmet medical need for treatments to improve clinical outcomes in patients with HFpEF, a serious and sometimes fatal condition for which there are presently no treatments approved to affect the course of the disease.”
- “If one were to conclude that the Americas results were an appropriate basis for a regulatory decision, approval based on a single study is supported by the reduction in death and HF hospitalization, either subjects with any HF hospitalization (part of the primary composite) or cumulative events.”
CME INDIA Tail Piece
- Ejection Fraction in Focus
- Diagnosing heart failure with preserved ejection fraction (HFpEF) is a Herculean Task-The H2FPF guides:
- HFA-PEFF Algorithm
- Future is Promising
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