Comparative effectiveness - and the case of diabetes therapy Tanker fra en simple-minded klinisk-epidemiologisk pragmatikermand Reimar W. Thomsen, MD,

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1 Comparative effectiveness - and the case of diabetes therapy Tanker fra en simple-minded klinisk-epidemiologisk pragmatikermand Reimar W. Thomsen, MD, PhD Associate professor, consultant physician Department of Clinical Epidemiology Aarhus University Hospital

2 Lone Frank

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4 Weekendavisen, februar 2017

5 Klask til Reimar Lone modtaget en læser-reaktion 22FEB17. ”Har han/hun ret?” ”Placebo? Det er sjældent, at man læser noget sludder i Weekendavisen. Det gør man dog på forsiden af Ideer # 06 (…) ‘Og så står man pludselig med syv medikamenter, som alle er bedre end placebo’. Dette er ikke rigtigt (…) I dag godkendes lægemidler ikke på baggrund af placeboforsøg. Man afprøver nye lægemidler op imod andre lægemidler, der findes på markedet. Hvis der allerede findes en effektiv behandling, så må der ikke gennemføres forsøg, hvor patienterne får en dårligere behandling.” ?

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8 Problemer med kliniske (indregistrerings-) trials / fase 3 studier
The 5 S - too: selected (patients) small (rare outcomes) short (no long term effects/side effects) simple (interactions) specific (outcomes) Oftest aktiv vs placebo trial (ex antidiabetika), i stedet for head-to-head trial Ofte surrogatendemål (ex. HbA1c)

9 The randomized controlled trial approach

10 The real-world evidence approach

11 Problem på antidiabetika området (jf. WA artikel):
Ingen ved hvilket drug har bedst effectiveness på hårde kliniske endepunkter, for store head-to-head trial results mangler! Ingen ved hvad præcis sker, når de nye drugs udbredes bredt real-life, uden for det sterile RCT miljø!

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15 CVOT: a game changer?

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17 We still need head-to-head effectiveness data, in broad type 2 diabetes populations!

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19 Efficacy, Effectiveness of Efficiency?
Does it works in clinical trials? Effectiveness Does it work in clinical practice? Efficiency Does it contribute to more efficient use of ressources?

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21 Definition of comparative effectiveness
“The conduct and synthesis of research comparing the benefits and harms of different interventions and strategies to prevent, diagnose, treat, and monitor health conditions in ‘real world’ settings.” Federal Coordinating Council for Comparative Effectiveness Research

22 Background, CER A sustainable health system requires health care that is guided by reliable information about which medical diagnostics and treatments work best, for whom, and in what situations Growing recognition that RCTs alone will not fill the information gaps. Challenge: nonrandomized studies may have inferior quality of evidence because of limited internal validity: Uncertain data quality Insufficient transparency in design and conduct Shortage of researchers with adequate methodologic training Real life studies are on the other hand a rich resource for information about Treatment and adherence Tolerance Use of concomitant therapies Decision-making processes and consequences of selecting or switching treatments. Real-world studies sometimes provide the only information about effectiveness in: Sensitive real-life populations Sustained therapeutic effectiveness and risks Health services–related issues

23 Typical CER studies (Pragmatic) randomized controlled trials
Observational real-life effectiveness/safety studies (Network) meta-analyses

24 Pragmatic RCTs Ref: N Engl J Med. 2016:375:454-63

25 Pragmatic RCTs Store, simple interventionsforsøg i heterogene settings (diverse patienter, diverse ko-behandlinger, flexibilitet i experimental og comparison arm) Skal derfor være store N, da dilution of effect Man følger folk via registre Ex TASTE trial: hjertepatienter randomiseres inden for almindelig klinisk praksis (”alle der kommer ind”), kliniske outcomes fra registre (genindlæggelse, død, nyt AMI etc).

26 Network Meta-analysis

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28 Observational real-life effectiveness/safety studies

29 The good one: null-effect for comparison of adverse drug events
Incretin-based therapy and pancreatitis (Thomsen et al, Diabetes Care 2015) Pancreatitis cases = 12,868 + Incretins no GLDs + other GLDs Population controls = 128,680 + Incretins no GLDs + other GLDs

30 Unadjusted and adjusted ORs - incretins
Exposure Pancreatitis cases (12,868) Population controls (128,680) Unadjusted RR (95% CI) Adjusted RR* Never use GLDs 11,777 (91.5%) 120,812 (93.9%) 1.00 (ref) Ever use any GLD 1,091 (8.5%) 7,868 (6.1%) 1.44 ( ) 1.05 ( ) Ever use incretins 89 (0.7%) 684 (0.5%) 1.36 ( ) 0.95 ( ) Ever use DPP4 inhibitors 68 (0.5%) 516 (0.4%) 1.38 ( ) 1.04 ( ) Ever use GLP-1 receptor analogues 30 (0.2%) 230 (0.2%) 1.35 ( ) 0.82 ( ) * Adjusted for previous diagnoses of gallstone disease, alcoholism-related conditions, obesity, inflammatory bowel disease, or any cancer; for 3 levels of the Charlson Comorbidity Index score; and for current use of oral glucocorticoids, azathioprine, lipid-lowering drugs, antiepileptics, or NSAIDs.

31 The problematic one: effectiveness on A1c reduction in 4,734 metformin users with first add-on therapy (Thomsen et al, Diabetologia 2015)

32 Adjusted RRs for attaining HbA1c targets of <7% (all patients, left panel) and <6.5% (patients <65 y with no comorbidities, right panel) HbA1c<7.0% HbA1c<6.5% Add-on to metformin Sulfonylurea DPP4 inhibitor GLP-1 receptor agonists Other non-insulin GLDs Insulin N 2,484 1,262 329 282 377 RR (95% CI) 1 (ref) 0.94 ( ) 1.10 ( ) 0.86 ( ) 0.88 ( ) 824 462 108 95 105 0.83 ( ) 1.05 ( ) 0.78 ( ) 0.74 ( ) Adjusted for age, gender, diabetes duration, macrovascular T2D complications, microvascular T2D complications, Charlson Comorbidity Index level, and baseline HbA1c.

33 The usual suspect: Uncontrolled confounding by indication…

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37 ”Insulin kills T2D patients (?)”
Observed for all T2D outcomes in multiple studies, even with meticulous attempts of good confounder adjustment In contrast with trial results, e.g. ORIGIN trial

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39 Adj. HR for CVD death with SGLT2i: 0. 53 (0. 40-0. 71) (Denmark: 0

40 Udfordringen Hvis den sande kliniske event reduktion for et stof vs. et andet svarer til fx RR = 0,85… Vil vi så nogen sinde lande lige dér i vores farmakoepi studier, og opleve at alle tror på resultatet?  Vil nye metoder (som vi skal høre om om lidt) løse udfordringen?

41 Conclusion (Pharmaco)epidemiology is not for amateurs…

42 THE END Aarhus University Hospital