Monday, 29 August 2011

Composite endpoints in RCTs: what are they worth?

Composite endpoints in Phase 3 trials – doncha just love them?  Well I don’t.  As has been pointed out elsewhere, in terms of proving value in an economic evaluation, the first thing I want to do is pick the composite apart because I want to convert each bit into QALYs and savings to understand how that compares against the added cost.

An article has just been published that goes some way to illustrating this point:
‘Weighting components of composite end points in clinical trials: an approach using disability-adjusted life-years’ K.-S. Hong, L. Ali, S. Selco, G. Fonarow and J. Saver  Stroke 2011; 42: 1722-1729.

You need to read the original article but in brief they have focused on vascular endpoints and converted the common components into DALYs left as follows:
7.63 DALYs lost per non-fatal stroke
5.14 DALYs lost per non-fatal MI
11.59 DALYs lost per vascular death
In DALY terms, therefore, if a non-fatal MI = 1 then a non-fatal stroke = 1.48 and vascular death = 2.25.

As a QALY-orientated economist my ideal would have been if they had used QALYs instead of DALYs, but I can understand the DALY disease weightings are more accessible than disutilities in QALY studies.  If you were intending to use these results you also need to understand the different assumptions made – events happen at age 60, US life expectancy data, 3% discount rate, and an assumption good health for older people is worth less than good health for younger people, and so on.  As I said, you have to read the article!

But with those gripes aside I think this is a fantastic illustration of the issue.  I’d like to take it one stage further because Hong and colleagues were thinking as clinicians and trying to produce a measure of health effect alone whereas I would be interested in savings as well.  Supposing I work in a system that is willing to pay £20,000 per QALY, and let’s assume for present purposes DALYs and QALYs are roughly equivalent.  Just to illustrate let’s assume that the lifetime discounted cost of managing events are as follows:
Non-fatal stroke £20,000
Non-fatal MI £4,000 without PCI, £10,000 with PCI
Vascular death £5,000
Then in QALY terms these are worth 1, 0.2 to 0.5, and 0.25 QALYs respectively.

Adding these back in to Hong et al’s figures, we get
Non-fatal stroke = 7.63 (health) + 1 (saving) = 8.63
Non-fatal MI = 5.14 (health) + either 0.2 or 0.5 (saving) = 5.34 to 5.64
Vascular death = 11.59 (health) + 0.25 (saving) = 11.84
Using the higher value of 5.64 for non-fatal MI and setting that to 1, the ratios are 1.53 (non-fatal MI) and 2.1 (vascular death).

I’m a little surprised as my intuition would be that there is a bigger gulf between non-fatal MI on the one hand and non-fatal stroke and vascular death on the other.  I don’t perceive the disability consequence of a non-fatal MI to be any where near that of a stroke.  Vascular death also seems to me a major loss of DALYs or QALYs, losing years of life at 0.6 or 0.7 quality, whereas an MI might be the difference between 70% and 60% over a decade.

But that is to lose sight of the main point of this article which is to put in the public domain something to get this sort of debate started.  Thank you to Hong and colleagues!

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