dr. Hari Yusti Laksono

FIELD Study merupakan studi uji klinis untuk menilai efek terapi fenofibrate jangka panjang pada angka kejadian Penyakit Jantung Koroner (Coronary Heart Disease (CHD) pada pasien dengan diabetes mellitus (tipe 2).

Jurnal ini merupakan bagian dari FIELD Study yang menganalisis dampak prognostik kejadian CVD(CardioVascular Disease; tidak hanya CHD) antara subgroup pasien DM2 dengan dan tanpa riwayat kejadian CVD sebelumnya yang mendapat terapi fenofibrate.

A. Critical appraisalB. Journal review

1. Jenis JurnalJurnal uji klinis (clinical trial) tipe prognosis, randomized, blind, controlled trial

2. Appraisal Jurnala. Is this evidence about prognosis valid?b. Is this valid evidence about prognosis important?c. Can we apply this valid, important evidence about prognosis to our patient?

Was a defined, representative sample of patients assembled at a common point in the course of their disease?Yes, DM2 patients aged 50-75yo with defined inclusion and exclusion criteria (p509 pgf2).

Was follow up of study patients sufficiently long and complete?Yes, follow up for median 5 years, but loss of study patients in the end of study not defined clearly, only total CVD events shown (p509 pgf2, p512 fig3).

III. Were objective outcome criteria applied in blind fashion?Yes, there was Outcomes Assessment Committee blindly adjudicate the CVD events outcome (p509 pgf5).IV. If subgroup of different prognoses are identifiedWas there adjustment for important prognostic factors?Yes, there was adjusment for patients whose needed statin and other medications to the treatment effect (p511 pgf3).

Was there validation in a independent group of test-set patient?Yes, there was comparations with results of fenofibrate effect on another studies (VA-HIT trial, Helsinki Heart Study, ACCORD trial) on discussion section (p512 pgf5)

How likely are the outcomes overtime?Total CVD events (hazard) rate reduction significantly favor fenofibrate compared placebo in patients without prior CVD (HR 0,81 p=0,004), but theres was no significant effect over placebo in patients with prior CVD (HR 1,02 p=0.9) (p511 pgf1)

How precise are the prognostic estimates?Quite precise as shown by narrow 95%CI of fenofibrate vs placebo on total CVD events in patients without prior CVD (95%CI 0,70-0,94 p=0,004), but again in patient with prior CVD even the 95%CI was narrow but the result was not significant (95%CI 0,86-1,20 p=0,9)(p511 pgf1)

Is our patient so different from those in the study that its result cannot apply?Not really, except from the demographic view, the inclusion and exclusion clinical criteria are quite familiar in the routine of outpatient and inpatients hospital/clinic settings.

Will this evidence make a clinically important impact on our conclusion about what to offer/tell our patient?Yes, from this evidence we can select fenofibrate to treat dislipidemia(especially high TG) in DM2 patient without CVD history, but on patient with CVD history we better select other treatment modalities such as statin.

1. Background2. Methods3. Result4. Discussion5. Conclusion

Fenofibrate as peroxisome proliferator-activated receptor(PPAR) alpha agonist have no spesific evidence of clinical trial on cardiovascular event rate changes in large number of diabetes mellitus type 2 (DM2) patients, as compared to the infamous statin.

Comparison of the effect of fenofibrate on prognoses of CVD events between DM type 2 patients subgroup with and without prior CVD.

Study Design- Multicenter (63 centers, 3 countries (Australia, NewZealand, Findland) )- Large sample (9795 patients, 2131(21,8%) with prior CVD, 7664 (78,2%) without)- Randomized (after categorized as those with and without prior CVD)- Blinded (independent Outcomes Assessment Committee blindly adjudicate outcomes)- Controlled (placebo)- Clinical trial (fenofibrate, on DM2 patients)- 5 years follow up

- Inclusion criteria- man/women- age 50-75- DM type 2 diagnosed- Specific Lipid profile criteria

Exclusion criteriaRenal impairmentChronic liver diseaseSymptomatic gallbladder diseaseCVD events within 3mo prior recruit

Prior CVD event defined reported history of: MI Stroke Angina (stable/unstable) Coronary revascularization Claudication Peripheral artery vascular disease Peripheral arterial revascularization

b. Statistical Methods- Baseline characteristic- Categorical comparison outcome: X2 (chi-square)- Continous/numerical comparison: t test/ Wilcoxon rank sum test(if distribution was nonnormal)- Change from baseline- linear model, standard log-rank (covariates)- Hazard Ratio, 95%CI, p values- Cox proportional hazard modelling- Penalizad Cox model (adjustment for nonstudy medication)

c. Funding and Ethical Approval

- Laboratories Fournier SA (Abbott)- National Health and Medical Research Council (NHMRC) Australia- Informed consent on all study patients- Ethics based on Declaration of Helsinki

A. Baseline characteristics

After categorized and randomized, the characteristic between with and without prior CVD well-matched, but differed substantially.

B. Lipids and the effect of fenofibrate treatments- At 12moHDL raise, LDL-TG lowering favor patients without prior CVD

- At 24moHDL raise, TG lowering seen on patients with prior CVD

- End of studyDifferences seen on LDL and TG, both

C. Compliance- Uptake of additional lipid lowering therapy(higher on placebo patients, prior CVD patients)- Discontinued fibrate therapy(higher on prior CVD patients-hospitalization; without prior CVD-adverse effect)

- Prior CVD patient more likely receiving other CVD medication- Adjusment of additional lipid lowering therapy surprisingly have little influence- Data from other monotherapy fibrate trial do not support(different) result of FIELD study (VA-HIT trial, Helsinki Heart Study, ACCORD trial)

Straus, Sharon E. Et al. 2005. Evidence-Based Medicine, Third Ed.. Philadelphia: Elsevier.

Dahlan, M. Sopiyudin. 2009. Statistik Untuk Kedokteran Kesehatan, Ed. 4. Jakarta: Salemba Medika.