JAMA offers this excellent commentary on the topic of diminishing returns in reducing mortality in the treatment of myocardial infarction by further therapeutic innovations.We have come a long way but to go much further in terms of mortality reduction becomes progressively more difficult and this can be expressed both in terms of cost of the clinical trial and the number needed to enroll in clinical trials.
How far have we come? Consider ISIS 2 and the subsequent innovations in the treatment of acute myocardial infarction.
ISIS2 was published in 1988 and demonstrated that the combination of aspirin and streptokinase decreased the 35 day mortality from acute myocardial infarction from 13.2 % ( in the control group) to 8 % in the treatment arm.This is a five percent absolute reduction and about a 20% decrease in relative risk.
Over the next decade or two we saw the introduction of TPA ,and angioplasty and then coronary artery stents and drugs to inhibit the platelets and the mortality rate dropped to around 4%.In some more recent trials the mortality rate of acute MI is actually closer to 2%.
The authors assert that ...it is a mathematical truism that , given the diminished control rate,future innovations can never match the benefits already realized (at least in terms of case fatality).
( by "control rate" the authors mean the rate of death in an control group as it would be constituted today with the current standard of care)
Why not? Is it simply the mathematics involved?
They explain that the mortality reduction by successive trials with a constant relative risk reduction can be characterized by a declining exponential function for mortality and an increasing exponential function for the sample size necessary to show the effect. (Their mathematical argument seems reasonable to me but I'll admit I am easy to fool with that type of thing)
The argument continues that if larger and larger sample sizes will be required then the use of surrogate measures and combined end points increasingly come into play.Also those planning clinical trials will turn to the use of control groups with higher rates of mortality as can be found in less developed countries and utilize non-inferiority trials.It does seem we have be seeing more and more of these type trials particularly trials with combined end points .