Dissections INTERVENTIONAL

25 June 2009
Evidence-based Medicine for Surgeons

Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD
study): a prespecified analysis
Authors: Rajamani K, Colman PG, Li LP, et al
Journal: Lancet 2009; 373: 1780–88
Centre: National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Australia
Diabetes mellitus is the leading cause of non-traumatic lower-extremity amputations. Despite
rigorous management of reversible factors, around one in ten patients with diabetes will
BACKGROUND eventually need at least one amputation. Neither control of glycemia or blood pressure nor
lowering of cholesterol has prevented the risk of amputation. Any therapeutic option to prevent
amputation would be highly desirable.

RESEARCH QUESTION IN SUMMARY

Population Fenofibrate use and amputation
A cohort of patients in the Fenofi Fenofibrate Placebo
brate Intervention and Event
Lowering in Diabetes (FIELD) study Number 4895 4900
with Type II diabetes mellitus.
Non-traumatic amputations 45 70
Indicator variable Minor amputations 1
28 52
Long-term lipid lowering with Major amputations 2
24 26
fenofibrate.
Based on large vessel disease status
Outcome variable 3
No disease - minor amputation 18 34
Adverse microvascular and 4
With disease - minor & major amputation 34 42
macrovascular outcomes including
amputations. The number of patients needed to treat (NNT) with fenofibrate over 5 years
to prevent at least one amputation in one patient is 197
Comparison Key: Hazard ratio (95% CI) p value
Patients placed on placebo. 1 - Significant 0.54 (0.34 - 0.85) 0.007
2 - Not significant 0.93 (0.53 - 1.62) 0.79
3 - Significant 0.53 (0.30 - 0.94) 0.027
4 - Not significant 0.81 (0.52 - 1.28) 0.37
Authors' claim(s): “...Treatment with fenofibrate was associated with a lower risk of amputations, particularly minor
amputations without known large-vessel disease, probably through non-lipid mechanisms.”

THE TISSUE REPORT

A narrowly defined subgroup appears to benefit from fenofibrate therapy: those with Type II diabetes without major
vascular disease. Once macrovascular disease sets in, there is no protective effect. The number needed to treat (NNT) to
prevent one amputation is almost 200. Still, considering the large and growing prevalance of Type II diabetes, and the
socioeconomic impact of amputations, the benefits and cost savings could be considerable. The point of discomfort in the
study is the complete lack of data on the vascular status of the patients. On what basis, was the distinction made between
those with and without macrovascular disease? Considering that the end point is amputation and that the study seems to
have shown no benefit in those with major vascular disease, this is a a serious concern.

EBM-O-METER
Evidence level Overall rating Bias levels
Double blind RCT Sampling
Randomized controlled trial (RCT) Comparison
Trash Swiss Safe News-
Prospective cohort study - not randomized cheese worthy Measurement
Life's too Holds water
short for this Full of holes “Just do it”
Case controlled study
Interestingl | Novel l | Feasible l
Case series - retrospective  Ethical l | Resource saving l

The devil is in the details (more on the paper) ... 

© Dr Arjun Rajagopalan
 SAMPLING
Sample type Inclusion criteria Exclusion criteria Final score card
Simple random 50-75 yrs  Renal impairment  Fenofibrate Placebo
Type II diabetes Chronic liver
Stratified random Target ? ?
(WHO criteria)  disease 
Cluster T. cholesterol - 3.0 - Symptomatic Accessible 13,900
6.5 mmol/L  gallstones 
Consecutive Total:HDL ratio>4  Cardiovascular event Intended 4895 4900
Convenience Triglyceride - 1-5 within 3 months Drop outs 16 15
mmol/L  before recruitment 
Judgmental Study 4879 4885

 = Reasonable | ? = Arguable |  = Questionable

The study offered 80% power to detect an observed 22% reduction in cardiovascular events
Analysis of data was on an "intention to treat" basis

Sampling bias: All patients were recruited in Australia.

COMPARISON
Randomized Case-control Non-random Historical None

Controls - details
Allocation details A central telephone computer randomisation service was used to randomly assign patients to
the fenofibrate group or the control. 9795 patients were enrolled and randomly assigned to
receive once-daily micronised fenofibrate 200 mg (n=4895) or matching placebo (n=4900).
Comparability The two groups were comparable. There were no statistically significant differences between
treatment and control groups in terms of general characteristics, clinical history, laboratory
data and baseline medications.
Disparity -

Comparison bias: Baseline characteristics differed between patients who had on-study amputations, those who had
other cardiovascular events, and those who had neither event. However, randomisation ensured distribution of equal
numbers of each strata into each arm of the study.

MEASUREMENT
Measurement error
Device used Device error Observer error
Gold std.
Repetition

Protocols

Device suited to task

Training

Scoring

Blinding

Y ? N

1.Non-traumatic amputation Y - - - N N Y
2.Presence of major vascular disease - - - - - - - - -

All patients were followed up at 4–6-month intervals for a median follow-up of 5 years, and all study outcomes and
serious adverse events were recorded. The records of patients who underwent non-traumatic amputations were
reviewed separately by two clinicians who were masked to treatment allocation.
Vascular status was not routinely measured at baseline in this study, or obtained thereafter for those who did not have
an amputation.
Major amputations were defined as those above the ankle and minor amputations as those below the ankle.
Measurement bias: The glaring error in measurement is the complete lack of data on the vascular status of the
patients. On what basis, then, was the distinction made between those with and without macrovascular disease?
Considering that the end point is amputation and that the study seems to have shown no benefit in those with major
vascular disease, this is a a serious concern.

© Dr Arjun Rajagopalan