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 alJournal: Lancet 2009; 373: 1780–88 Centre: National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Australia

BACKGROUND

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 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.

IN SUMMARY Fenofibrate use and amputation

Fenofibrate Placebo

Number 4895 4900

Non-traumatic amputations 45 70

Minor amputations 1 28 52

Major amputations 2 24 26

Based on large vessel disease status

No disease - minor amputation 3 18 34

With disease - minor & major amputation 4 34 42The number of patients needed to treat (NNT) with fenofibrate over 5 years

to prevent at least one amputation in one patient is 197Key: Hazard ratio (95% CI) p value1 - Significant 0.54 (0.34 - 0.85) 0.0072 - Not significant 0.93 (0.53 - 1.62) 0.793 - Significant 0.53 (0.30 - 0.94) 0.0274 - 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.

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

© Dr Arjun Rajagopalan

EBM-O-METER

Evidence level Overall rating Bias levelsDouble blind RCT

TrashLife's too

short for this

Swiss cheese

Full of holes

SafeHolds water

News-worthy

“Just do it”

Sampling

Randomized controlled trial (RCT) Comparison

Prospective cohort study - not randomized Measurement

Case controlled study Interesting l | Novel l | Feasible l Ethical l | Resource saving lCase series - retrospective

RESEARCH QUESTION

Population

A cohort of patients in the Fenofi brate Intervention and Event Lowering in Diabetes (FIELD) study with Type II diabetes mellitus.

Indicator variable

Long-term lipid lowering with fenofibrate.

Outcome variable

Adverse microvascular and macrovascular outcomes including amputations.

Comparison

Patients placed on placebo.

INTERVENTIONAL

25 June 2009DissectionsDissectionsEvidence-based Medicine for Surgeons

SAMPLING Sample type Inclusion criteria Exclusion criteria Final score card

Simple random 50-75 yrs Type II diabetes (WHO criteria) T. cholesterol - 3.0 - 6.5 mmol/L Total:HDL ratio>4 Triglyceride - 1-5 mmol/L

Renal impairment Chronic liver disease Symptomatic gallstones Cardiovascular event within 3 months before recruitment

Fenofibrate Placebo

Stratified random Target ? ?

Cluster Accessible 13,900

Consecutive Intended 4895 4900

Convenience Drop outs 16 15

Judgmental Study 4879 4885

= Reasonable | ? = Arguable | = QuestionableThe 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.

© Dr Arjun Rajagopalan

COMPARISON Randomized Case-control Non-random Historical None

Controls - detailsAllocation 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

Device suited to task

Y ? N

Rep

etitio

n

Gol

d st

d.

Trai

ning

Prot

ocol

s

Sco

ring

Blin

ding

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.