EBM: Therapy. Thunyarat Anothaisintawee, M.D., Ph.D. Department of Family Medicine, Ramathibodi Hospital, Mahidol University

Transcription

1 EBM: Therapy Thunyarat Anothaisintawee, M.D., Ph.D. Department of Family Medicine, Ramathibodi Hospital, Mahidol University How to appraise therapy literature Are the result valid? What are the result? How can I apply the result to patient care? 1

2 Are the result valid? Were patients randomized? Was randomization concealed? Were patients in the study groups similar with respect to known prognostic factors? To what extent was the study blinded? Was F/U complete? Were patients analyzed in the group to which they were randomized? 2

3 Was patient randomization? Assign exposure / intervention? yes no Experimental study Observational Comparison group? yes no Analytic Descriptive Start with Outcome or Exposure E O E O E/O Case-control Cohort Cross sectional 3

4 Population at risk Intervention Group Control Group Outcome Outcome Why randomize? 4

5 Selection Bias Clopidogrel + ASA ASA HRT & CHD NHS study Cohort study HRT have been routinely prescribed For prevention of CHD and osteoporosis 5

6 WHI study RCT Stopped 2002 HRT increased risk of stroke, CHD, breast cancer and venous throboembolism Why randomize? To Make 2 groups equal (same baseline characteristics) Similar prognosis at the beginning of the study Make sure different result due to Rx (Validity) not from selection bias 6

7 Randomization Tossing a coin to decide the assignment of a patient to study group Each subject has the same chance of being assigned to either intervention or control groups Unpredictability of the next assignment Simple randomization 7

8 Block randomization Stratifiedrandomization Example Gender: Male or female Male R A B Female R A B 8

9 2. Was randomization concealed? Open VS Laparoscopic Appendectomy Allocation concealment Generation of an unpredictable randomized allocation sequence. It represents the first crucial element of randomization in a RCT. Allocation concealment refers to the technique used to implement the sequence, not to generate it. 9

10 Was randomization concealed? Remote randomization 3 rd party Sealed envelope Were patients in the treatment and control groups similar with respect to known prognostic factors? 10

11 New treatment for heart failure: NYHC III &IV Trial A: enroll 8 patients Trial B: enroll 800 patients Which trials that randomization will be effective? 11

12 Were patients in the treatment and control groups similar with respect to known prognostic factors? Baseline characteristic Whether or not statistically significant Magnitude of the difference Sample size: large or small Statistical adjust To What Extent Was the Study Blinded? 12

13 Potential benefits of blinding Individuals Patients Clinicians Assessors Potential benefits -Less likely to have biased psychological or physical responses to intervention -More likely to comply with trial regimens -Less likely to seek additional adjunct interventions -Less likely to differentially administer co-interventions -Less likely to differentially adjust dose -Less likely to differentially withdraw participants -Less likely to differentially encourage or discourage participants to continue trial -Less likely to have biases affect their outcome assessments, especially with subjective outcomes of interest Placebo An inert medication or procedure. The placebo effect (usually but not necessarily beneficial) is attributable to the expectation that the regimen will have an effect. 13

14 Who have to be blinded? Patients Clinicians Data collectors Adjudicators of outcome Data analysts Was follow-up complete? 14

15 Was follow-up complete? Greater loss to follow up, lesser study s validity. Different prognoses Suffer adverse outcome or doing well CONSORT diagram showing participant flow and retention. Bleakley Copyright C BMJ M et Publishing al. Br J Group Sports Ltd Med & British 2006;40: Association of Sport and Exercise Medicine. All rights reserved. 15

16 Trial A Trial B Rx. Con Rx. Con No. of pt No. of loss F/U 30(3%) 30(3%) 30(3%) 30(3%) No. of death RRR ( )/0.4 ( )/0.06 = 0.50 =0.50 Worst case 0.17/0.4 = /0.06 = 0 Were patients analyzed in the group to which they were randomized? 16

17 Rosuvastatin: 1000 LSM: 1000 X 900: CAD CAD Intention-To-Treat (ITT) CAD Compliance Non-compliance Total Rosuvast atin 45/900 = 5% LSM 100/1000 = 10% 90/100 = 90% 0/0 = 0 % 135/1000 = 13.5% 100/1000 = 10% Ideal Can it work? Censored; Pre-protocol Drug company;researcher Real Does it work? Un-Censored; ITT MD 17

18 Patient who did not adhere to their treatment regimen have worse prognosis than those who adhere. Exclude noncompliant will destroy randomization Intention to treat analysis Are the study valid? Was patient randomized? Was randomization concealed? Were patient in the treatment and control groups similar with respect to known prognostic factors? 18

19 Are the study valid? Were patient aware of group allocation? Were clinician aware of group allocation? Are the study valid? Were outcome assessors aware of group allocation? Was follow-up complete? Were patient analyzed in the group to which they were randomized? 19

20 What Are The Result? How large was the treatment effect? 1. Dichotomous outcome Death rate 8 6% : Proportion (ARR,RR,RRR) 2. Continuous outcome BP Drop 80 60mmHg : Mean (Mean difference) 20

21 Population at risk Intervention Group Control Group Outcome Outcome Develop disease Not develop disease Incidence Rate Treatment a b a a+b Control c d c c+d 21

22 Relative risk The ratio of the incidence rate: = Incidence in treatment group Incidence in control group = a a+b c c+d Relative risk reduction = (1- RR) * 100 a a+b c c+d 1 - *

23 Relative risk reduction = (1- RR) * 100 c - c+d c c+d a a+b * 100 Absolute risk reduction Incidence in control group incidence in treatment group = c - a c+d a+b NNT = 1/ARR 23

24 ASA ASA+ ARR RR RRR Clo Death 9% 3% 6% % Allergy 4% 4% UGIB 6% 9% -3% % = C-T = T/C = [C-T] C Rx ARR RR RRR Benefit + < 1 + No conclusion Harm - > 1-24

25 Control Rx RR RRR ARR NNT 3% A: 1% % 2% 50 90% B: 30% % 60% % C: 5% % 10% 10 How precise of Rx effect? 25

26 sample conclusion What is P value? 26

27 RR = 50% RRR = 50% ARR = 20% P value = %CI 95% CI 27

28 95%CI of RRR B (95% CI = 2%-41%) (95% CI = ) A % CI of RRR A Risk B C Benefit No conclusion

29 Study A: 100 Study B: 1000 RRR = 25% How can I apply the result to patient care? 29

30 Were the study patients similar to the patient in my practice? Met all inclusion criteria and none of exclusion criteria Rx. Not uniformly effective!!! Expose some patients with cost and toxic without benefit Be careful!!!! Drug class effect Subgroup analysis: older, sicker Large effect size and very unlikely to occur by chance 30

31 Were all clinically important outcomes considered? MI A VS B LDL Surrogate outcome: LDL, CO Are the likely treatment benefits worth the potential harm and cost? 31

32 cardiovascular Benefit morbidity Lengthen life other Risk QOL cause mortality Drug toxicity or adverse effect Economic analysis Small sample size RCT: common SE Serious SE 32

33 Scenario A 59-yr-old Thai man with DM was sent to perform coronary angiography. His serum creatinine is 2.1 mg/dl (egfr 33 ml/min/1.73 m 2 ). Your extern asks you how to prevent acute renal failure from radiocontrast nephropathy. You hear something about N-acetyl cysteine (NAC). Would you prescribe NAC in this patient? Step 1: Ask answerable question Converting a clinical problem into a clinical question 1. Patient Among diabetes patients with CKD 2. Intervention Would prescribing with N-acetylcysteine 3. Comparison intervention compared with IV hydration 4. Outcome prevent radiocontrast nephropathy? 33

34 Step 1: Ask answerable question Converting a clinical problem into a clinical question 1. Patient Among diabetes patients with CKD 2. Intervention Would prescribing with N-acetylcysteine 3. Comparison intervention compared with IV hydration 4. Outcome prevent radiocontrast nephropathy? Underline the search concept in your question 1. Patient Among diabetes patients with CKD 2. Intervention Would prescribing with N-acetylcysteine 3. Comparison intervention compared with IV hydration 4. Outcome prevent radiocontrast nephropathy? 34

35 Coyle LC, et al. American Heart Journal 2006; 151: 1032 Thank you for your attention 35