Shmeta-analysis.

Post-treatment discontinuation eGFR trajectory is somewhat reassuring. No?

I think it is a positive first step, but whether there is a convincing evidence of an additive effect of combination therapy requires proof in an outcome study.

For now, combination therapy has won the bragging rights, but I would not go so far as to proclaim this is a practice-changing trial.

Is there a dose-response or a threshold relationship with UACR reduction and clinical outcome benefit? In other words, will a >50% reduction translate into a greater kidney or CV benefit than >30% reduction?

Hyperkalemia on combo vs nsMRA: RR 0.82, 95% CI 0.50-1.36
No clearcut evidence that hyperkalemia risk is mitigated by combining sglt2i with nsMRA (? Inadequate power/Sample Size)

Pragmatic trials like comparative effectiveness studies require realistically ‘sober’ assumptions to account for the issues you stated.

Lipid hypothesis lingered on for several decades until LDL-C lowering was proven to reduce CV risk. Analogy applies to INOCA/ANOCA/MINOCA. Need novel targeted Rxs.

95% CI is compatible with a 6% benefit (clinically trivial) to 37% harm (clinically important). If CI contained a clinically important benefit, say HR of 0.80 or a more plausible HR of 0.85 to 0.90, but CI was wide spanning across HR of 1, then an inference of inconclusive result would be justified.

Trial powered for a HR of 0.80 which was excluded by the 95% CI.
Is it still a null outcome?

Who are the optimal candidates for acoramidis therapy?

When should it be considered first-line therapy?

Does the proposed cost provide value?

NI margin in EVEREST II trial of MitraClip vs MV surgery for MR was 31% absolute difference, a margin through which one could drive 3 buses lined side by side.
Trial met NI despite the fact that HR excluded 1.0, i.e., MitraClip was INFERIOR to surgery, yet NONINFERIOR!

www.nejm.org/doi/full/10....

Even though the observed rates were lower than assumed (22%), had NI margin been fixed as risk ratio of 1.18 ([22+4]/22), the overall results would still have met NI as RR was 0.90, 0.77-1.05. An excellent example of how a NI trial should be designed and executed. Congrats to trial investigators.

So you are suggesting you need longer f/u and greater LDL and Lp(a) reduction, both of which favor PREVAIL. So what is the probability of success?

4/
Key Qs
What is probability of success with obicetrapib?
Why should obicetrapib succeed when 2 other CETPi did not?
Is absolute or relative LDL reduction key driver of benefit?
Is duration of treatment important?
Is LDL lowering with CETPi different from other LDL lowering Rx?

3/
PREVAIL(Obicetrapib), N=9541, F/U: ~4y
Mean LDL 103; LDL⬇️35-40%, Lp(a)⬇️45% (based on BROOKLYN)
PEP (4-MACE): Powered for 15-20% RRR
Recruitment completed; event-driven trial
Targeting higher baseline LDL & higher risk patients

2/
REVEAL (Anacetrapib), N=30,449, F/U: 4.1y
Mean LDL 61; LDL⬇️41%, Lp(a)⬇️25%
PEP (3-MACE): 10.8% vs 11.8%, HR 0.91, 0.85-0.97
Development halted (long half-life, modest Rx effect)