Claims / C-DCFNXMCTT2

EmpiricalRequires evidence

Surrogate-endpoint failure has a third mode that neither "the proxy was never causally sufficient" nor "the proxy was valid until it was targeted" covers: the intervention moves the proxy in the intended direction and moves the outcome in the opposite direction, through a channel that does not pass through the proxy. CAST (1986-1989, over 1700 patients, 27 centres) suppressed premature ventricular complexes with encainide and flecainide as intended and raised total mortality, the excess attributed to proarrhythmic effects of the agents. Torcetrapib raised HDL and lowered LDL as intended and its phase III programme was halted in December 2006 after an imbalance of mortality and cardiovascular events, reported as about a 60% increase in deaths in the torcetrapib plus atorvastatin arm. Neither case involves gaming: the proxy was honestly optimised and the optimisation succeeded. This mode is detectable only by a trial that measures the outcome itself under the intervention, not by validating the proxy-outcome correlation and not by removing the incentive to target the proxy.

Health and flourishing

Evidence 6 passages

  • groundsUntitled source

    The excess mortality was attributed to proarrhythmic effects of the agents.

  • groundsUntitled source

    The drugs used (encainide, flecainide, and moracizine) successfully reduced the amount of PVCs, but led to more arrhythmia-related deaths. Total mortality was significantly higher with both encainide and flecainide at a mean follow-up period of 10 months.

  • groundsUntitled source

    One of the completed studies found it raised systolic blood pressure and concluded "Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further."

  • groundsUntitled source

    In the terminated trial, a 60% increase in deaths was observed among patients taking torcetrapib and atorvastatin versus taking atorvastatin alone.

  • groundsUntitled source

    On December 2, 2006, Pfizer cut off torcetrapib's phase III trial because of "an imbalance of mortality and cardiovascular events" associated with its use.

  • groundsUntitled source

    Inhibition of this process results in higher HDL cholesterol levels and reduces LDL cholesterol levels.

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