Surrogate marker

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In clinical studies, a surrogate marker (synonymous: surrogate parameter; from Latin surrogatum 'replacement' , and English marker 'indicator' ) is a measured value whose influence on the effect of an intervention , e.g. B. a therapy , on an overarching medical phenomenon , e.g. B. to indicate the occurrence of a disease or a symptom . The minimum requirement for a surrogate marker is that there is already a statistically significant relationship between it and the phenomenon . However, this requirement is not sufficient. The surrogate marker is usually easier and faster to determine than the phenomenon itself and is therefore often preferred for reasons of economy. It can also happen that the phenomenon of interest cannot be measured at all, but can only be recorded using surrogate markers (see examples). Both the phenomenon and the surrogate marker can be defined as so-called endpoints of the study, i.e. as target values ​​on the basis of which the study result is interpreted and assessed. Making biological (and other) phenomena measurable is called operationalization .

That of Prentice (1989) is regarded as a stringent definition of a surrogate marker. (In this context one speaks of the Prentice criteria .) The definition works with the concept of conditional stochastic independence . According to her, an intervention that is supposed to influence the endpoint of interest is conditionally independent of this endpoint, given the surrogate marker. In other words, the therapy that a patient has received does not provide any information beyond the surrogate marker for the prognosis of a patient. Measured against this criterion, the selected endpoints in the examples on antiarrhythmics and fluorides are not real surrogate markers.

It should be noted that the effect of a therapy on a surrogate marker can only be transferred to a very limited extent to the medical phenomenon that is actually of interest, because firstly, a statistical relationship does not necessarily prove causality , and secondly, the occurrence of diseases almost never depends on just one single pathologically changed parameter. Serious study presentations point out, dubious ones distract from it.

Since in medicine one therapy is ultimately only superior to another if it prevents or cures diseases and alleviates symptoms and not if it only influences laboratory values, a good study design defines as many clearly identifiable medical events as possible as endpoints (such as Death from heart attack) and as few surrogate markers as possible.

Examples

The fear a person feels in a situation cannot be measured directly. Instead, z. B. the increase in heart rate associated with a fearful situation is recorded.

Evidence of the effectiveness of thrombosis therapy in acute deep vein thrombosis is determined by an improvement in the radiological findings of the thrombus size (marker score).

Measuring blood lipid levels in a clinical study of lipid-lowering drugs instead of survival rate: the real goal of lipid-lowering drugs is to prolong life, not just to contribute to lowering lipid levels.

Surrogate markers are also used in the clinical trials of the effectiveness of the HPV vaccines . HPV 16 and HPV 18 associated precursors of cervical cancer - cervical intra epithelial neoplasia (CIN) and cervical adenocarcinoma in situ (AIS) - are used as primary endpoints in place of the cervical cancer itself.

Problems

Often there is only a statistical relationship between marker and disease activity, without a relationship between marker and clinical endpoint of actual interest, e.g. B. the survival rate. In this case one speaks of a correlation .

Examples of false surrogate markers

Class 1c antiarrhythmics and premature ventricular contractions

If premature ventricular contractions (a type of cardiac arrhythmia ) occur after a heart attack , the risk of sudden cardiac death is increased. Class 1c antiarrhythmics (drugs that interfere with the heart rhythm) are able to effectively suppress this arrhythmia. Class 1c antiarrhythmics have therefore been approved for the treatment of ventricular arrhythmias after myocardial infarction. A later placebo- controlled study ( CAST study ) then showed that class 1c antiarrhythmics increased the frequency of sudden cardiac death, despite effective inhibition of cardiac arrhythmias.

Fluoride and increased bone density

With reduced bone density , the risk of bone fractures is increased. Sodium fluoride increases bone density, but the likelihood of fractures increases. In contrast, the bisphosphonate class of substances is able to both increase bone density and reduce the frequency of bone fractures.

Postmenopausal hormone replacement therapy

After the menopause, there is an increase in strokes and heart attacks in women. This has been attributed to falling hormone levels. The administration of hormones after the menopause leads to an improvement in blood lipids in women. Estrogen and progesterone were therefore administered for decades until large randomized, controlled studies showed that coronary heart disease, strokes, pulmonary embolisms and breast cancer were significantly more common with hormone replacement therapy.

Rosiglitazone and HbA 1c

HbA 1c , the proportion of the red blood pigment hemoglobin to which glucose is bound, is a measure of the quality of the blood sugar control in patients with diabetes mellitus . In diabetics, the incidence of cardiovascular diseases is significantly higher than in non-diabetics. The drug rosiglitazone lowers the HbA 1c value in patients with type 2 diabetes better than comparable drugs such as metformin and sulfonylureas . Nevertheless, the frequency of cardiovascular complications is higher with rosiglitazone than with other blood sugar lowering preparations.

Homocysteine ​​and cardiovascular risk

Elevated homocysteine levels are associated with a significantly increased risk of heart attacks and strokes, especially in patients with chronic kidney disease . The administration of vitamin B combination preparations can effectively reduce increased homocysteine ​​levels. However, this does not reduce the risk of cardiovascular disease.

LDL cholesterol, simvastatin, ezetimibe, and intima-media thickness of the external carotid artery

Treatment with statin leads to a reduction in LDL cholesterol and a significant decrease in cardiovascular endpoints such as death from myocardial infarction. The combination of the cholesterol synthesis inhibitor simvastatin with the cholesterol absorption inhibitor ezetimibe leads to a significantly better reduction in LDL cholesterol, but not to a greater decrease in the thickness of the intima media in the external carotid artery and the carotid artery communis , which are associated with a reduction in cardiovascular risk.

HDL and cardiovascular risk

A decreased level of high density lipoprotein (HDL) is also associated with an increased cardiovascular risk. Protection against heart attack and stroke is attributed to an increased HDL level. The drug torcetrapib causes a significant increase in HDL levels; however, cardiovascular complications and mortality increase with torcetrapib .

Conclusion

In some cases the use of surrogate markers is useful or even unavoidable. Findings that result from their use, however, must always be viewed with the necessary skepticism, since the indirect measurement can lead to an unnoticed falsification of the result.

See also

literature

Individual evidence

  1. ↑ RL Prentice: Surrogate endpoints in clinical trials: definition and operational criteria. In: Statistics in Medicine. 8 (4), Apr 1989, pp. 431-440.
  2. ↑ John O'Quigley, Philippe Flandre: Quantification of the Prentice Criteria for Surrogate endpoints . In: Biometrics . tape 62 , no. 1 , March 2006, p. 297-300 , doi : 10.1111 / j.1541-0420.2006.00538.x ( wiley.com [accessed May 15, 2019]).
  3. ↑ B. Manns et al. a .: Surrogate Markers in Clinical Studies: Problems Solved or Created? In: American Journal of Kidney Diseases . No. 48 , 2006, p. 159-166 ( full text ).
  4. ^ The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report (Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction). In: N Engl J Med . 321, 1989, pp. 406-412. content.nejm.org
  5. ↑ BL Riggs, SF Hodgson, WM O'Fallon u. a .: Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. In: N Engl J Med. 322, 1990, pp. 802-809. content.nejm.org
  6. ↑ S. Hulley, D. Grady, T. Bush et al. a .: Heart and Estrogen / progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. In: JAMA . 280, 1998, pp. 605-613. jama.ama-assn.org
  7. ^ JE Rossouw, GL Anderson, RL Prentice u. a .: Risks and benefits of estrogen plus progestin in healthy postmenopausal women (Principal results from the Women's Health Initiative randomized controlled trial). In: JAMA. 288, 2002, pp. 321-333 jama.ama-assn.org
  8. ^ CJ Rosen: The Rosiglitazone Story - Lessons from an FDA Advisory Committee Meeting . In: N Engl J Med . No. 357 , 2007, p. 844-846 ( abstract ).
  9. ↑ KH Bonaa u. a .: Homocysteine ​​Lowering and Cardiovascular Events after Acute Myocardial Infarction . In: N Engl J Med . No. 354 , 2006, pp. 1578-1588 ( abstract ).
  10. ↑ J. Kastelein u. a .: Comparison of ezetimibe plus simvastatin versus simvastatin monotherapy on atherosclerosis progression in familial hypercholesterolemia. Design and rationale of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial . In: American Heart Journal . No. 149 , 2005, pp. 234-239 , PMID 15846260 .
  11. ↑ John JP Kastelein et al. a .: Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia . In: N Engl J Med . No. 358 , 2008, p. 1431-1443 ( Article ).
  12. ^ B. Greg Brown, Allen J. Taylor: Does ENHANCE Diminish Confidence in Lowering LDL or in Ezetimibe? In: N Engl J Med . No. 358 , 2008, p. 1504-1507 ( Article ).
  13. ↑ Jeffrey M. Drazen et al. a .: Cholesterol Lowering and Ezetimibe . In: N Engl J Med . No. 358 , 2008, p. 1507-1508 ( Article ).
  14. ↑ Barter u. a .: Effects of Torcetrapib in Patients at High Risk for Coronary Events . In: N Engl J Med . No. 357 , 2007, p. 2109-2122 ( Article ).