Anvendelse af Lægemiddelstatistikregistret til forskning: Fra opstart af evidensbaseret behandling til compliance og lægemiddelsikkerhed Gunnar H. Gislason overlæge, ph.d. Kardiologisk afdeling Gentofte Hospital
Evidensbaseret medicinsk behandling
Cumulative frequency of patients with first AMI who filled a first prescription of beta-blocker, ACE-inhibitor, or statin within 1 year after discharge 100 80 Proportion of patients (%) 60 40 20 0 ACE inhibitor Beta-blocker Statin 0 30 60 90 120 150 180 210 240 270 300 330 360 Days from discharge Gislason et al. Eur Heart J 2006 27:1153-1158
Which physician initiates treatment? 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 0-30 d 31-365 d 0-30 d 31-365 d 0-180 d 181-365 d Beta-blockers ACE inhibitors Statins General Practitioner Specialist (private) Hospital physician Gislason et al. Eur Heart J 2006 27:1153-1158
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Beta-blockers Dosages 100% ACE inhibitors 90% 80% 70% 60% 50% 40% 30% 50 5 75 20% 2 5 10 10% 37,5 0% Metoprolol Atenolol Bisoprolol Trandolapril Ramipril Captopril Enalapril Median dosis Anbefalet dosis 100% Statins Median dosis Anbefalet dosis 90% 80% 70% 60% 50% 40 40% 30% 20% 10% 0% 20 10 Simvastatin Atorvastatin Pravastatin Median dosis Anbefalet dosis Gislason et al. Eur Heart J 2006;27:1153-8
Drugs don t work in patients who don t take them C.E. Koop US Surgeon General
Duration of pharmacotherapy in patients after myocardial infarction Proportion of patients receiving treatment (%) 100 80 60 40 20 Statin ACE inhibitor Beta-blocker 0 0 1 2 3 4 5 Years from first prescription claim Gislason et al. Eur Heart J 2006 27:1153-1158
Duration of pharmacotherapy in patients after myocardial infarction and chronic heart failure Acute myocardial Infarction Chronic Heart Failure Proportion of patients receiving treatment (%) 100 80 60 40 20 Statin ACE inhibitor Proportion of Patients (%) Beta-blocker 100 80 60 40 20 Statins ACEi/ARBs Beta-blockers Spironolactone 0 0 1 2 3 4 5 Years from first prescription claim 0 0 1 2 3 4 5 Years from first dispensing Gislason et al. Eur Heart J 2006 27:1153-8 Gislason et al. Circulation 2007;116:737-44
Poor Compliance increases mortality in patients with chronic heart failure ACE inhibitors/arbs Beta-blockers Spironolactone Statins 1,0 1,2 1,4 1,6 1,8 2,0 Hazard Ratio Gislason et al, Circulation 2007;116:737-44
Using treatment as a proxy for disease Antidiabetic medication Specific treatment for specific disease Only patients with diabetes receive treatment Does not identify diabetics receiving non-pharmacologic intervention e.g. dietary modification Loop diuretics Proxy for heart failure Not as specific as antidiabetic medication Patients without heart failure receive loop diuretics - Oedemas, Renal failure, Hypertension Not all heart failure patients receive loop diuretics (80%) Loop diuretic dosage as a proxy for severity of heart failure - Related to prognosis
Event rates for cardiovascular mortality in men (A) and women (B) stratified by age and sex in relation to diabetes mellitus (DM) and a prior MI Schramm, T. K. et al. Circulation 2008;117:1945-54
PRIMUM NON NOCERE [First not to harm] Hippocrates and Galen
Fosbøl et al, Pharmacoepidemiol Drug Saf. 2008
Risk of Death associated with NSAID treatment in patients with Acute Myocardial Infarction Rofecoxib any use Rofecoxib <= 25 mg Rofecoxib > 25 mg Celecoxib any use Celecoxib <= 200 mg Celecoxib > 200 mg Ibuprofen any use Ibuprofen <= 1200 mg Ibuprofen > 1200 mg Diclofenac any use Diclofenac < 100 mg Diclofenac =>100 mg Other NSAIDs any use No use 0,5 0,6 0,7 0,8 0,9 1 1,5 2 2,5 3 4 5 6 7 8 9 10 Hazard Ratio (Horizontal bars symbolize 95% Confidence Intervals) Gislason et al, Circulation 2006;113:2906-13
Rofecoxib any dose <=25 mg/d >25 mg/d Celecoxib any dose <=200 mg/d >200 mg/d Diclofenac any dose <=100 mg/d >100 mg/d Ibuprofen any dose <=1200 mg/d >1200 mg/d Naproxen any dose <= 500 mg/d > 500 mg/d Other NSAID Risk of death associated with NSAID treatment in patients with Chronic Heart Failure 0,7 0,8 0,9 1 1,5 2 2,5 3 4 5 6 Hazard Ratio Horizontal bars symbolize 95% Confidence Intervals Gislason et al, Arch Int Med 2009;169:141-9
Risk of death associated with NSAID treatment in patients with CHF according to risk group (propensity score for death within 1 year) 2,5 Rofecoxib Celecoxib 2 Hazard Ratio 1,5 1 0,9 0,8 2,5 Ibuprofen Diclofenac 2 Hazard Ratio 1,5 1 0,9 0,8 2,5 Naproxen Other NSAID 2 Hazard Ratio 1,5 1 0,9 0,8 Low Intermediate High Risk group Low Intermediate High Risk group Gislason et al, Arch Int Med 2009; 169:141-9
The Case-crossover design Day -120 Day -90 Day -60 Day -30 Day 0 Control Period Control Period Case period Event ± Exposure ± Exposure ± Exposure
Risk of Death associated NSAID use in patients with MI Cox regression analysis Case-crossover analysis Rofecoxib any use Rofecoxib <= 25 mg Rofecoxib > 25 mg Celecoxib any use Celecoxib <= 200 mg Celecoxib > 200 mg Ibuprofen any use Ibuprofen <= 1200 mg Ibuprofen > 1200 mg Diclofenac any use Diclofenac < 100 mg Diclofenac =>100 mg Other NSAIDs any use No use 0,50,60,70,80,91 1,5 2 3 4 5 6 7 8 910 Hazard Ratio 0,50,60,70,80,91 1,5 2 3 4 5 6 7 8 910 15 20 Odds Ratio Gislason et al, Circulation 2006;113:2906-13
Anne-Marie Scjerning Olsen et al, Circulation 2011
Anne-Marie Scjerning Olsen et al, Circulation 2011
Antithrombotic treatment in AF patients and bleeding rate Morten Lock Hansen, Arch Int Med 2010
Hazard ratios for the risk of hospitalization or death because of bleeding or anemia associated with the use of warfarin, aspirin, clopidogrel in patients with AF NNH 8 (6-11) NNH 9 (7-13) Morten Lock Hansen, Arch Int Med 2010
Risiko for blødning og død hos patienter behandlet med forskellige antitrombotiske regimer efter AMI Rikke Sørensen et al, Lancet 2009;374:1967-74
Risiko ved ophør med antikoagulations behandling med warfarin hos patienter med atrieflimren Jacob Raunsø et al, EHJ 2011
Risk of Tromboembolism after DC conversion of Atrial Fibrillation Morten Lock Hansen et al, unpublished
Risk of Tromboembolism after DC conversion of Atrial Fibrillation Morten Lock Hansen et al, unpublished
Blødningsrisiko ved antitrombotisk behandling hos patienter med AF og AMI Morten Lamberts, Unpublished
Benefit vs. Risiko ved antitrombotisk behandling efter AMI hos patienter med AF Morten Lamberts, Unpublished
Er signifikant interaktion mellem clopidogrel og protonpumpe hæmmere? Adverse outcome associated with use of PPI stratified according to clopidogrel use CV death, MI or stroke All Cause death 26,5 21,2 19 14,9 16,7 9,1 8,6 4 Without PPI With PPI Without PPI With PPI No Clopidogrel Clopidogrel Charlot et al, Annals of Internal Medicine 2010;153:378-86
Charlot et al, Annals of Internal Medicine 2010;153:378-86
Patients admitted with first-time MI 2000-2006 (n=71.987) Excluded (n=15.581) Alive 30 days after discharge (n=56.406) No clopidogrel (n=31.704) Clopidogrel (n=24.702) No PPI PPI No PPI PPI (n=22.815) (n=8.889) (n=17.949) (n=6.753) No PPI (n=8.437) PPI (n=8.437) No PPI (n=6.556) PPI (n=6.556) Charlot et al, Annals of Internal Medicine 2010;153:378-86
Charlot et al, Annals of Internal Medicine 2010;153:378-86
Clopidogrel / no PPI Clopidogrel / + PPI No Clopidogrel / No PPI No Clopidogrel / + PPI Charlot et al, Annals of Internal Medicine 2010;153:378-86
Risk of Cardiovascular death, recurrent MI or stroke associated with use of PPI in patients after first MI No PPI (ref) Whole cohort Cox regression Only PPI PPI and clopidogrel Hazard Rate Ratio (p for interaction 0.72) Propensity score matchet cohort Only PPI (PS) PPI and clopidogrel (PS) 0,9 1 1,5 2 Hazard Ratio Charlot et al, Annals of Internal Medicine 2010;153:378-86
Risiko for pludselig død (hjertestop) ved brug af antidepressiv medicin Peter Weeke et al, Clinical Pharmacology and Therapeutics 2012
The Case-time-control design Day -120 Day -90 Day -60 Day -30 Day 0 Control Period ± Exposure Control Period ± Exposure Case period ± Exposure Event Control Period ± Exposure Control Period ± Exposure Matched controls 4 controls : 1 case Case period ± Exposure No event
Case-time-control analyse af risikoen for hjertestop ved forskellige typer antidepressiva Peter Weeke et al, Clinical Pharmacology and Therapeutics 2012
Hold da op! Er ikke snart frokost? Gunnar H. Gislason PhD forsvar 40 30. maj 2012
Konklusion Lægemiddelstatistikregistret giver enestående muligheder for at undersøge forskellige farmakoepidemologiske problemstillinger Kvalitetsvurdering af behandling - Opstart af anbefalet behandling - Hensigtsmæssig anvendelse af medicin Compliance / adherence Drug-safety studier - Interaktioner mellem lægemidler - Kendte og ukendte bivirkninger Afprøvning af hypoteser som ikke vil være muligt andre steder Samkørsel med Landspatientregistret og kliniske registre Der er mange faldgrupper! Studiedesign Valg af analyser
The Good news is that statistical analysis is becoming easier and cheaper. The bad news is that statistical analysis is becoming easier and cheaper Hofacker 1983