Het Verbeteren van de Therapietrouw Meten is Weten Dr. E. M. van Maarseveen, PharmD, PhD Clinical pharmacist, clinical pharmacologist University Medical Center Utrecht NVIVG symposium, 7 september 2018
Conflicts of interest I have nothing to declare in relation to the content of this talk
Adherence in Hypertension
Dealing with and monitoring of Adherence Huffman et al., The Lancet 2017 DOI:https://doi.org/10.1016/S0140-6736(17)30553-6
Towards Measuring is Knowing The Mass Spectrometer
Clinical Mass Spectrometry Core Facility @ UMC Utrecht Pharmacy Department
Step 1: Qualification using mass spectrometry Found spectrum Library spectrum
First Results of “ Objective ” Monitoring of Adherence to Antihypertensive Agents from Sympathy No or less than half of the number of prescribed antihypertensive drugs could be detected in 13 (26%) and 17 (34%) patients, respectively. de Jager et al., Hypertension 2017 de jager et al., BJCP 2018
Impact on Blood Pressure? Sympathy trial: Intervention by Renal denervation • D elta sy stolic b loo d p ressu re (m m H g) 1 0 D a y tim e s y sto lic A B P M 5 2 4 -h o u r s y sto lic A B P M O ffic e S B P 0 -5 -1 0 -1 5 -2 0 -2 5 In ten tio n -to -trea t-p o p u la tio n S elected p o p u la tio n w ith sta b le a d h eren ce De Jager et al, Hypertension 2017
Adherence to Antihypertensive Treatment and the Blood Pressure – Lowering Effects of Renal Denervation in the Renal Denervation for Hypertension (DENERHTN) Trial Figure 2. Spaghetti plots of individual changes in daytime ambulatory systolic blood pressure (SBP) between baseline and 6 months in the renal denervation group (red lines) and control group (blue lines) in patients who were fully adherent and nonadherent (partially nonadherent plus completely nonadherent) Azizi et al., Adherence to Antihypertensive Treatment and the Blood Pressure – Lowering Effects of Renal Denervation in the Renal Denervation for Hypertension (DENERHTN) Trial, Volume: 134, Issue: 12, Pages: 847-857, DOI: (10.1161/CIRCULATIONAHA.116.022922)
Therapeutic drug monitoring-guided definition of adherence profiles in resistant hypertension and identification of predictors of poor adherence* Figure 2 Differences in office diastolic blood pressure (DBP) and office heart rate values among fully adherent (AD), partially adherent (PAD) and totally nonadherent (NAD) patients, according to Kruskal – Wallis test. TDM, therapeutic drug monitoring *Avataneo et al., Britisch Journal of clinical pharmacology, 2018 .
Step 2: Quantitation of antihypertensive agents in serum • Combined screening and (semi-)quantification of 52 antihypertensive agents using LC-MS/MS in serum • Why serum? – Quantitative option vs Qualitative urine screening – Direct exposure- effect relationship (PKPD) • Concentrations linked to blood pressure
Quantitative Reporting Samplenr 21711xxxx CONCENTRATION RATIO (CR) = Nefine Neg Metoprolol 0,05 Measured Concentration/Population Cmin Triamtereen 0,04 Perindoprilaat 0,33 Example Quinalapril: FARMACOLOGISCHE INTERPRETATIE Nefine niet teruggevonden. Triamtereen, perindoprilaat en metoprolol in zeer lage (waarschijnlijk CR= 20 (µg/L) /10 (µg/L) = 2 supratherapeutische) CR waarden teruggevonden. CR’s kunnen duiden op inconsistente /niet- consequente therapietrouw of op enkelvoudige inname voor polibezoek, waarbij de concentraties in bloed van o.a. nifedipine te laag zijn om te detecteren. CR*= concentratie ratio = ratio gevonden waarde gedeeld door populatie dalspiegel. .
Qualitative versus Quantitative Results? P<0.001 P<0.01 Nr. of patients . Punt et al., abstract @ IATDMCT Congress, Brisbane, september 16-20, 2018
But then…..the MS screening results…… R B Z P P X PATIENT Sample lijst 217113016601 217120420601 117120432601 117120443301 217120502501 217120504801 Used Medication Hydrochloorthiazide_204 5,77 15,93 Neg Lercanidipine_280 2,71 Metoprolol_103 0,42 Neg Telmisartan_276 5,15 Barnidipine_315 5,44 Irbesartan_207 114,96 Sotalol_255 1,04 Amlodipine_220 Neg Neg Chloorthiazide_213 Neg Doxazosin_247 Neg Neg 0,66 Neg Olmersartan_429 Neg Neg Neg Furosemide_204 Neg Canrenon_91 Neg Labetalol_311 Neg Nefidipine_284 Neg
Current Clinical Applications Adherence Screen for Routine Care Research • • – SYMPATHY (on/off meds) – CALM-START (on/off meds) – intervention – + antidiabetics + antiplatelets https://www.umcutrecht.nl/nl/Ziekenhuis/Profes sionals/Diagnostiek-aanvragen/Farmalab
Take Home Messages Screening and quantification of cardiovascular agents • using LC-MS/MS is a valuable tool for objective drug adherence assessment, • which deserves further exploration in clinical practice with the ultimate goal to improve treatment outcomes. • Objective assessment is only the beginning…..
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