Resistant Hypertension and Adherence: Therapeutic Drug Monitoring Prof. Sverre E. Kjeldsen, MD, Dr. Med., FAHA, FESC Department of Cardiology Oslo University Hospital, Oslo, Norway, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan Past-President of European Society of Hypertension
THE BURDEN OF HT In 2010, HT was estimated to be the leading single risk factor for disease burden globally Murray CJL, et al. Lancet; 2012.
Patients (%) When Stringent Definitions are Used, 7.6% to 18% of Patients Have True Treatment-Resistant Hypertension Spanish ABPM Monitoring Registry definition: 1 Use of 3 antihypertensive drugs (with 1 diuretic) Clinic BP 140 and/or 90 mm Hg Daytime BP 130 and/or 80 mm Hg 18% Pierdomenico et al definition: 2 Use of triple therapy Clinic BP 140 or 90 mm Hg at 2 visits Daytime BP 135 or 85 mm Hg Both studies excluded patients at BP target being treated with 4 drugs 1,2 True prevalence of treatment-resistant hypertension may therefore be somewhat higher 7.6% US data suggest 5% (Calhoun D et al. 2015) Spanish ABPM Monitoring Registry 1 (N=8295) Italy: Pierdomenico et al 2 (N=742) ABPM=ambulatory blood pressure monitoring; BP=blood pressure. 1. de la Sierra A et al. Hypertension. 2011;57:898-902; 2. Pierdomenico SD et al. Am J Hypertens. 2005;18:1422-1428.
Ray W. Gifford: Hypertension 1988 Proceedings From Course at the Cleveland Clinic in October 1987:
Eskås et al, Blood Pressure, 2015
Drug Compliance or Adherence Electronic pill boxes Blood measurements of drugs Urine measurements of drugs Written patients reports Witnessed intake of drugs
Methods 3 Witnessed Intake of Antihypertensive Drugs Patients were asked to bring their prescribed medication to the clinical visit Medication was documented and administered by the investigator and swallowed by the patient under continuous observation Patients were then continuously under the observation by the investigator
Methods 2 Inclusion criteria Office SBP >140mmHg (measured per guidelines) Daytime ambulatory SBP >135mm/Hg (after witnessed intake of anti-hypertensiv drugs prior to ABPM) Age 18-80 years At minimum, 3 antihypertensive medications must meet one of them must be a diuretic. Exclusion criteria Hemodynamically or anatomically significant renal artery abnormalities or stenosis (>50%) or prior renal artery intervention egfr < 45 ml/min/1.73m² (MDRD formula) Alb/creat ratio > 50 mg/mmol Type 1 diabetes mellitus Known alcohol/drug abuse MI, unstable angina, or CVA in the prior 6 months Known secondary cause of hypertension Known chronic serious disease
Flow Chart of Oslo RND First Part Open Design Fadl Elmula F et al. Hypertension 2013;62:526-532 Copyright American Heart Association, Inc. All rights reserved.
F. Elmula et al. Hypertension 2014
Ambulatory Blood Pressure, mmhg Change in The Mean Ambulatory Daytime BP after Witnessed Intake of Antihypertensive Drugs (n=13) 180 160 164 Amb. daytime SBP Amb. daytime DBP 140 130 120 100 102 80 81 60 Referral BPs BPs after witnessed drugs intake
Control Methods: Integrated Non-Invasive Hemodynamic Management Using the HOTMAN System to guide improvement and adjustment of drug treatment F. Elmula et al. Hypertension 2014;63:991-999.
Effect of RDN on 6 Months Office SBP FEM Fadl Elmula et al. Blood Press 2015; 24: 263-274
Effect of RDN on 6 Months 24-hour BP FEM Fadl Elmula et al. Blood Press 2015; 24: 263-274
How Many Patients Are Actually Adherent to Their Antihypertensive Medication? Reasons for non-eligibility in Oslo RDN Study¹ ². 83 referred patients to RDN were thoroughly worked-up in the outpatient clinic and following directly observed therapy (DOT) of antihypertensive drugs prior to ambulatory blood pressure monitoring (ABPM). 1. Fadl Elmula F et al. Hypertension 2013;62:526-532. 2. Fadl Elmula F et al. Hypertension 2014;63:991-999
Drug Compliance or Adherence Written patients reports Electronic pill boxes and pill counts Blood/urine measurements of drugs (TDM) Home BP monitoring Witnessed intake of drugs (DOT) Prescription registries
Patients (%) How Many Patients Are Actually Adherent to Their Antihypertensive Medication? A quantitative analysis based on serum drug levels in patients taking free combination multidrug therapy* Poor drug adherence in apparent treatment resistant hypertension makes renal denervation wide open for Hawthorne effect: Patients start taking their prescribed medication when getting attention with subsequent fall in BP N=84 Number of antihypertensives: 5.0±1.2 65.5% 34.5% 34.5% Fully Compliant With Treatment *All patients except 3 were taking agents as free combinations. Ceral J et al. Hypertens Res. 2011;34:87-90. Fulfilled Criteria for Nonadherence No Drugs Detectable in Serum
Fractions (%) of apparent treatment resistant HT patients detected to be non-adherent by therapeutic drug monitoring (TDM) or direct observed treatment (DOT) Ceral et al. 2011 N=84 TDM, blod 65.5 % Jung et al. 2013 N=76 TDM, urin 53.0 % Strauch et al. 2013 N=163 TDM, blod 47.0 % Strauch et al. 2013 N=176 TDM, blod 19.0 % Fadl Elmula et al. 2013 and 2014 N=83 DOT + 24t ABM 29.3 % Brinker et al. 2014 N=56 TDM, blod 54.0 % Tomaszewski et al. 2014 N=208 TDM, urin 25.0 % Florczak et al. 2015 N=36 TDM, blod 86.1 % Hameed et al 2015 N=50 DOT + 24t ABM 50.0 % Eskås PA, Heimark S et. al. Blood Press 2016; 25: in press.
Therapeutic Drug Monitoring Facilitates BP Control in Resistant Hypertension Brinker S, Kaplan NH et al. JACC 2014; 63: 834-5. 20
J Hypertens 2014; 32: 2411-2421.
J Hypertens 2014; 32: 2357-2358.
UPLC-MSMS analyse av antihypertensive medikamenter Analyse av serumkonsentrasjon av antihypertensiva med UPLC-MSMS metode, se vedlagte liste over aktuelle legemidler basert på bruk -og salgsstatistikk. Slike analyser er i dag ikke tilgjengelige for bruk i rutine og forskning i Norge. En UPLC-MSMS maskin koster ca 2,5 mill kroner pluss oppmontering med N 2 -tilgang og online tilkobling i støysikret og godt ventilert lokale. I følge OUS regler må innkjøp ut på anbud. Både kjøp og installering vil ta noe tid, samt utvikling av analysene. Analyserepertoaret kan utvikles trinnvis, først de mest aktuelle legemidler, deretter et bredere analyserun.
UHPLC-MSMS instrument Ultra High Pressure Liquid Chromatography Mass Spectrometry machine Kvantiterer/påviser legemidler i serum med høy sensitivitet og spesifisitet Kostnad varierer fra 2,71-3,75 mill avhengig av instrument og leverandør Serviceavtale koster ca 130 000 kr-287 500 kr 24
Analyseprinsipp Enkel prøveopparbeidelse fra serumprøve (felling) Kromatografisk separasjon av legemidlene Ionisering av stoffene Deteksjon ved massespektrometri Kort analysetid (ca 5-10 min) Kapasitet: 6 prøver/time, avlesning av resultat 25
Antihypertensiva ACE-hemmere Ramipril Enalapril Lisinopril Captopril Angiotensin II- blokkere Candesartan Losartan Valsartan Irbesartan Telmisartan Aktuelle antihypertensiva for terapikontroll som ledd i forskningsprosjekt Mulig forklarings variabel på endret respons Diuretika Furosemid Bumetanide Aldosterone antagonister Tiazider med kalium med aldosteronanatagonist Betablokkere Metoprolol Bisoprolol Alfa og beta-blokker labetolol karvedilol Atenolol Men, maskin med stor kapasitet til å kunne kjøre flere forskningsprosjekter, også med andre legemidler som for eksempel antikoagulasjon, antiarytmika, antibiotika Kalsiumblokkere Dihydropyridiner Amlodipine Nifedipin Lercandipine 26
Vitenskapelig Hva skal vi bruke TDM til «Oslo TDM» Se på BT-effekt av å informere pas om serumkonsentrasjonsmålinger Se på egenskaper/årsaker til at pasienter er non-adherente ( samarbeid med M. Rostrup prof i atferdsfag) Få lærdom om farmakogenetiske og farmakokinetiske årsaker til høye/lave serumkons, bivirkninger, interaksjoner mm Forskningsbiobank Tilby analyser i nasjonale og internasjonale blodtrykksstudier Eks BAT studien, måle serumkonsentrasjoner av antihypertensiva hos 100 pas med resistent HT, fra Norden Metoden er også planlagt benyttet i studier om epilepsi, immunterapi, antibiotikabeh hos intensivpasienter og metadonbehandling av stoffmisbrukere Klinisk Et nasjonalt tilbud til alle som behandler pas med høyt blodtrykk i primær- og spesialisthelsetjenesten 27
Screeming out for better BP control