Kari Laine, MD, PhD CEO, medbase Ltd medbase.fi

1. E-solutions for the safe & effective use of drugs Tallinn 2016 Kari Laine, MD, PhD CEO, medbase Ltd www.medbase.fi

2. Lazarou et al., JAMA 1998 (meta-analysis) 39 studies in hospitalized patients in the U.S. 6.7% of all patients (n=2 216 000) are exposed every year to a serious adverse drug reaction 106 000 die every year due to adverse drug reactions 4-6. leading cause of death in the U.S. Yearly cost to the hospitals 1.56 – 4 billion USD Several other studies indicate similar results in various health care setting in different countries Adverse drug reactions as a clinical problem

3. Bisoprolol 10 mg x1 Amlodipine 5 mg x1 Metformin 500 mg 2+3 Cholestyramine 1 bag x2 Low-dose ASA 50 mg x1 Arcoxia 120 mg x1 Tramadol dep 100 mg x3 Tizanidine 2 mg x2 Estradiol 2 mg x1 Nitrofurantoin C 75 mg x1 Pantoprazole 20 mg x1 Perfenazine 8 mg x2 Mianserine 25 mg x1 Sertraline 100 mg x1 Levomepromazine 50 mg x1 Stesolid 10 mg 1x1 Metronidazole vagit. 1x week Seretide Discus Multitabs 1x1 Polypharmacy 19 medicines in regular use, yearly cost 4000€

4. Effect of itraconazole on the exposure to various statins

5. Patient 2 • Male, 64 years of age, coronary heart disease, atrial fibrillation • Medication: isosorbide-mono-nitrate, bisoprolol, telmisartan, warfarin • Left abdominal pain, Fever 38.2 C, CRP 110 • Dg: Diverticulitis • Which antibiotic?

6. Warfarin, co-medication and bleeding

7. 1000 to 1500 new publications on drug interactions evidence-based information is poorly penetrated to clinical practice Warfarin - metronidazole Kazmier FJ. A significant interaction between metronidazole and warfarin.Mayo Clin Proc. 1976;51:782-4. O’Reilly RA. The stereoselective inter- action of warfarin and metronidazole in man. N Engl J Med. 1976;295:354-7

8. Holm et al. Eur J Clin Pharmacol 2014 The 15 most prevalent D-interactions • Register based study • Population: the whole Swedish population 9,340,682 inhabitants • 34% (n=3,243,419) dispensed more than one drug during 4-month period • Setting: analysis of level C and D interactions utilizing Sfinx • 94,267 D-interactions detected • 953,898 C-interactions detected • About 50% of all C and D interactions related to potential therapeutic failure • Top 15 interactions (Table) explained about 80% of D-interactions

9. 113682 treatment periods (65352 patients) between 1 July 1996 and 30 June 2002 internal medicine, oncology, pulmonary medicine, neurology wards 4472 on codeine 6281 on tramadol 953 (21%) on concomitant 1273 (20%) on concomitant CYP2D6 inhibitor CYP2D6 inhibitor Prodrug interactions in Turku University hospital

10. Retrospective chart review *p = 0.008 ns p=0.53 The prevalence of potentially serious drug-drug interactions decreased by 20 percent immediately when SFINX was integrated into EHR SFINX-group: RR 0.80, 95% CI: 0.68-0.94 Control: RR 0.88, 95% CI: 0.59-1.31

11. Alert fatigue Select carefully what you want to say Well-defined classification – thresholds for alerts Possibility for individual customisation - EHR

12. Penetration of & portal to public health care in Finland is 100%

13. Integration • EPRs • Tieto – Effica • Logica – Pegasos • Logica – Uranus • Acute FDS • MediConsult - Mediatri • Pharmacy IT-systems • Receptum • Pharmadata Gate 1 Cover 90% of the doctors - alert response 2%  15-20% Gate 2 – OTC! Cover more than 95% of pharmacies

14. Karolinska Institute: reasons for hospitalisation due to ADR (n=115; 96% of ADRs type A) 12% Odar-Cederlöf I et al. Läkartidnigen 2008;105:890-3.

15. Prevalence of renal failure • In the U.S. 35.000.000 people are estimated to suffer from chronic renal failure • 13% of the population • Measured GFR<60 ml/min or demonstrated renal injury • A recent meta-analysis estimated that in the Western population 23%-36% of people >64years of age has GFR<60 ml/min

16. Blix HS et al. Nephrol Dial Transplant 2006;21:3164-71. • Prospective study in general hospitals • 201 patients (GFR<60 ml/min; 25% of the whole population) used an average of 10 drugs • Approximately 40% of drugs were harmful to the kidneys or required modification of the dose; 5% fully contraindicated • Almost all patients were co-administered a minimum of two harmful drugs • Typical risk drug toxicity in 62% of exposed patients • 26% of risk drug exposures caused toxicity • Beta-lactam antibiotics, ciprofloxacin, aminoglycosides • antithrombotic agents and anticoagulants • anti-inflammatory drugs, codeine, tramadol • ACE-inhibitors/sartans, spironolactone/potassium • Allopurinol, metformin, sulphonylureas

17. Hepatic impairment and AEs Eur J Clin Pharmacol. 2013;69:1565-73. • Retrospectivechartstudy in 400 patients with cirrhosis at hospitaladmission (Child-Pugh: A 18%; B 39%; C 43%) • Altogether 1653 prescriptions (0-15 / patient) • Everyfifth (336) prescription with an error (184 patients) • 36 contraindicated; 300 toohighdose (no adjustment) • 69 adverseeventsrelated to non-adjustment of the dose in relation to the hepaticfunction • 68% preventable • Flaws in prescribing led to 94 extrain-hospitaldays • Problemsdrugs: • NSAIDs (g-i bleeding), benzodiazepines

22. PRIMA-eDS project partners • EU-funded study • Start: 11/2012 • Duration: 4 years • Witten/Herdecke University (Germany) • Rostock University Medical Center (Germany) • Paracelsus Medical University (Austria) • Duodecim Medical Publications & Medbase Ltd (Finland) • South Tirolean Academy of General Practice (Italy) • University of Manchester (UK)

23. PRIMA-eDS -DDI (SFINX) -renal dosing (renbase) -hepatic dosing (heparbase) -cross allergies -contraindications -adverse events (Pharao) -Indications and dosing

24. Virtual health check Communityhealth / medication data in EHR (Sipoo 16.000 patients) VirtualhealthcheckbyEBMeDS (renbase) of the wholepopulation Identification of 1164 cases of inappropriatedosing and 28 prescriptions with contraindicateddrugs in patients with GFR < 50 ml/min

25. Why decision support? • Adverse drug reactions and inappropriate prescribing constitute a major health hazard and increased cost to health care • Most adverse drug reactions could be avoided by right choice of medication/dose/ monitoring • Information overflow – evidence is not penetrated to clinical practice and does not benefit doctor/patient • Reduced need for consultation within organisations

26. What are the tools? • Frequently updated decision support portals with functional search methods, which warn and solve problem • On-line warnings from EHRs & pharmacy dispensing software (decision support systems) • Garbage in – garbage out • Comprehensive medication review tools • Tools exit – now we just have to use them • Virtual health checks – what’s wrong? • Ward, hospital, city, health region, nation-wide

27. What are the challenges? • Misconceptions – fear for IT & attitude problems • Lack of proper healthcare infrastructure • Lack of proper national drug registry (things in right order) • Need for databanks at national level • Fragmented HISs and lack of communication among them • Primary care  specialist care • Who’s holistically taking care of the patient? • Poor functionality and localization • Local trade names, dosage forms – control of false alarms • Correct current medication list in the EHR!!!! • Alert fatigue • Can alerts be customized at the level of single user of the EHR? • Expert analysis of clinical relevance of the alerts – classification & threshold • Respect for potential risks that prescribing can lead to

28. Primum non nocere – first of all do no harm