SURROGATE MEASURES FOR CLINICAL OUTCOME

J.R. Andersen (DK)

ESPEN Congress Copenhagen 2016BUILDING EVIDENCE IN CLINICAL NUTRITION- HOW TO DO WITHOUT RANDOMIZED CONTROLLED TRIALS

Jens Rikardt Andersen

Department of Nutrition, Exercise and

Sports

University of Copenhagen, Denmark

27/09/2016 1

A surrogate outcome measure is

A laboratory measurement

A physical sign

Another intermediate substitute, that is able to

predict an interventions effect on a clinically

meaningful outcome

A clinical outcome detects how a patient feels,

functions or survives

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We know surrogate measures from the area of

cardio-vascular diseases – plasma cholesterol

and blood pressure as well known examples

These measurements are correlated to

survival, risk of myocardial infarction, stroke

etc as the correspondent clinical outcome

The changes in the surrogate measure is much

faster than the correspondent clinical, and

much easier to use in practice

These surrogates have predictive value

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A surrogate outcome measure occurs

faster or more often,

is cheaper

and/or less invasively achieved than the clinicaloutcome

In practice validation of a surrogate outcome is surprisingly often overlooked, especially if a biological plausible rationale is proposed

Surrogate outcomes must be validated before usein the ideal world – but in clinical practice, we have to find ways until such validations are documented

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First step: correlation between surrogate and

clinical outcome?

Second step: do the interventions effect on the

surrogate outcome predict the interventions effect

on the clinical outcome?

Third step: is the surrogate meausure valid for

groups or individuals (to which extent can you use

the measure in the treatment of the individual

patient?

To my knowledge no surrogate measure fulfills all

these demands, so what do we do in clinical

practice?

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Traditionally weight (weight-loss) has been the dominating variable used to predict clinicaloutcomes as mortality, risk of infectiouscomplications, risk of thrombosis during hospital stay etc

Now we know that body-composition is veryimportant, so weight is often substituted with LBM (lean body mass)

On the other hand we know, that a lot of confounders emerge: hydration in the acutephase, deposition of fat in the long run

We have major problems in finding practical solutions for these problems

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3 l water and 154 mmol Na+ per day or

2 l water and 77 mmol Na+ per day

2 N = 20; 4th postoperative day

Lobo DN et al. The Lancet 2002; 359: 1812-1818

Restricted NaCl

Body weight, kg - 0.5 + 2.21)

P-albumin, % - 8 - 262)

Water balance, l 0.2 3.73)

Na+ balance, mmol 80 7504)

Gastric emptying T50, min 62 1255)

Peripheral oedema, N 0 76)

Length of stay, d 6 94)

1) P< 0.001 2) P = 0.01 3) P = 0.0001 4) P = 0.001 5) P = 0.028 6) P = 0.01

2 N = 141

Brandstrup et al. Ann Surg 2003; 238: 641-648

Restricted Usual

Fluid, operating day and 1. postop day, l 3.2 6.91)

Body weight, 2nd postop d, kg 0.9 3.82)

Major complications, N 8 183)

Minor complications, N 15 364)

Major: Anastomosis leakage, Sepsis, Bleeding, pulmonary edema

etc.

Minor: Wound infection, pulmonary congestion, pneumonia,

arrhytmia etc.1) P <0.0005 2) P < 0.001 3) P = 0.04 4) P = 0.0001

The hypothesis is that nutrients (glucose) feed

the mitochondrium and increase muscle cell

contraction (myosine shortness in the sarcomer)

Is that the only factor involved?

Perfusion of the muscle? Physical training

Motivation? Psychological fitnes, no concentration

Pain in the arm or hand?

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It is now well established, that p-albumine is not a good estimate of the nutritional state

P-albumine is affected by hydration

P-pre-albumine is used by some to get an estimateof albumine production

Albumine synthesis is decreased when the synthesis of acute phase reactants are increasedand gluconeogenesis is accellerating (i.e. stress-metabolism)

May be p-albumine is valuable in describingextreme malnutrition in refugee camps, but probably only in steady-state conditions (noinfection)

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Energy and protein intake in relation to estimatedneeds

N-balance

P-tranferrin

Anthropometric measurements

Skin test for delayed hypersensitivity

Lymphocyte count

An investigation of the concordance (allthoughbased on underpowered trials) between thesemeasurements and valid clinical outcomes (so-called ”hard endpoints”) – NO CONCORDANCE

(Koretz. Proc Nutr Soc 2005;64:277-84)

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ADL - Activities of Daily Living (multiple questionaires and

Time to ability to resume habitual activities (work, hobby)

Quality of life (multiple questionaires)

Muscle strenght (remember, that strenght without muscle

co-ordination is rarely usefull)

Estimates of LBM:

Frequent DXA-scans are probably not possible inless new

technologies are developed

BIA has its pitfalls, but the technology is under fast

improvement

Blood-tests: Hardly usefull in general, but may be in

selected patients

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Unless the nutritional problem is one of shortage

of micro- or macronutrients the clinical outcomes

depend on nutrition in combination with other

kinds of therapies (surgery, antibiotics, drugs etc)

We have to accept that and choose a combined

clinical outcome (and may be a suurogate for that

particular outcome)

Follow-up is therefore essential for nutritional

therapy as well as other kinds of therapy

Clinical Nutrition is a discipline for co-operation

with other disciplines – but also an important one

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Does the patient improve in a reasonable manner?

Is the improvement important for the patient´slife (or merely a measurement, that satisfies the therapeutic system)?

Is the improvement a real improvement or a slower development of expected problems?

Can problems in any way be related to metabolism(nutrients, the oxydation or excretion)?

Is the patient compliant to advices given? (If no –change the therapy instead of the patient)

At which time-point is follow-up not necessary anylonger?

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