Assessing antihypertensive adherence with therapeutic drug monitoring Erika SW JONES, Maia LESOSKY, Marc BLOCKMAN, Sandra CASTEL, Eric H DECLOEDT,

Assessing antihypertensive adherence with therapeutic drug monitoring Erika SW JONES, Maia LESOSKY, Marc BLOCKMAN, Sandra CASTEL, Eric H DECLOEDT, Sylva LU SCHWAGER, Edward D STURROCK, Lubbe WIESNER, Brian L RAYNER

1 year extra, but the good news it will seem like 15 years Doctor, if I take all these pills how long will I live?

Persistence, BP Control, and Events Data shows that people who drop out of treatment have: A 63% higher chance of death or first cardiovascular hospitalization A 74% increase in charges in annual medical care Patients who stop taking their medications end up with higher blood pressures and the attendant higher risk of cardiovascular events Elliott W. J Hypertens. 2000;18(suppl 4):S169.

Resistant hypertension? Assessment of adherence by toxicological urine analysis Jung, Oliver; Gechter, Janis L.; Wunder, Cora; Paulke, Alexander; Bartel, Christine; Geiger, Helmut; Toennes, Stefan W. Journal of Hypertension. 31(4):766-774, April 2013. doi: 10.1097/HJH.0b013e32835e2286 FIGURE 3. Percentage of prescribed drugs taken by nonadherent patients. Copyright 2014 Journal of Hypertension. Published by Lippincott Williams & Wilkins. 5

Renal Nerve Anatomy Allows a Catheter-Based Approach Spacing of e.g. 5 mm. Renal artery access via standard interventional technique 4-6 two-minute treatments per artery Proprietary RF generator Automated Low power Built-in safety algorithms 7

SBP at 6 mo Primary Efficacy Endpoint Office Systolic Blood Pressure at 6 Months, 5 mm Superiority Margin N = 353 N = 171 RDN Control P value Baseline SBP 179.7 180.2 0.765 6 mo SBP 165.6 168.4 0.260 Change -14.1 P < 0.001-11.7 P < 0.001 0.255 1-2.39 (-6.89, 2.12), P = 0.255 (Primary analysis with 5 mm Hg superiority margin) Did not meet primary efficacy endpoint

TOOLS OF ASSESSING/IMPROVING ADHERENCE Use of pillboxes Reminders/care givers Improved dosing schedule Single pill combinations Names of the medications, and dosage Self admitted non-adherence Medication possession ratios Electronic monitoring Therapeutic Drug Monitoring (TDM)

AIM To determine if TDM is valuable tool in the evaluation of patients referred for treatment of resistant hypertension

METHODS Patients attending a referral hypertension clinic for resistant hypertension that were prescribed enalapril and amlodipine (± other antihypertensives) were enrolled into the study After informed consent patients underwent BP monitoring, completed a questionnaire on adherence and blood samples were taken for amlodipine levels and ACE activity Patient demographics and medications were recorded Assessments were repeated at next follow up visit The study was approved by the University of Cape Town Human Research Ethics Committee.

METHODS 2 Amlodipine assay Plasma amlodipine concentrations were determined using a validated liquid chromatography-tandem mass spectrometry assay. A level of <2.5ng/ml for amlodipine was found to indicate nonadherence, 2.5 7 ng/ml indeterminate and > 7ng/ml adherent ACE activity assay ACE activity was measured by the hydrolysis of two synthetic substrates [Z-Phe-His-Leu (ZFHL) and Hippuryl-His-Leu (HHL)] in a sensitive fluorimetric assay as described previously (Schwager et al. 2006). A Z-FHL/HHL ratio <1.75 was considered non-adherent

RESULTS Data were collected on 100 patients and follow up data for 65 patients 54% were female, 20% were Black African and 80% were Mixed Ancestry Mean age (±SD) was 50±12y Patients were taking 2-8 antihypertensives and 2-10 medications in total All patients were taking an ACE inhibitor and amlodipine 80% of patients were on 10mg amlodipine daily, and 88% were on 10mg enalapril twice a day Dose did not affect serum levels

Measures of adherence 90% issued their own medications 24% used pillboxes 90% of patients knew the dosing schedule 52% knew the names of the medications 40% knew the dose 33% admitted to forgetting their medication regularly Adherence measures showed no association with amlodipine concentrations or ACE activity.

BASELINE and FOLLOW UP Baseline Baseline Follow up P value* (n = 100) (n = 63) (n = 63) SBP (mmhg) 146 (127, 163) 147 (128, 161) 154 (130, 169) 0.067 DBP (mmhg) 88 (74, 99) 88 (74, 100) 88.0 (77, 104) 0.55 Amlodipine level (ng/ml) 13.6 (5.1, 24.4) 16.1 (4.9, 25.3) 11.9 (3.1, 2.8) 0.34 Z-FHL/HHL ratio 2.61 (1.47, 3.12 2.6 (1.9, 3.1) 2.2 (1.3, 2.8) 0.029

AMLODIPINE Adherent Non-adherent Indeterminate p-value* Visit 1 (n=100) 62 (62%) 20 (20%) 18 (18%) SBP 140 (122, 149) 166 (160, 187) 159 (138, 161) < 0.0001 DBP 84 (73, 91) 104 (96, 117) 93 (72, 106) < 0.0001 Visit 2 (n=65) 36 (55%) 14 (22%) 15 (23%) SBP 137 (126, 153) 169 (164, 179) 161 (137, 173) 0.0005 DBP 81 (74, 90) 106 (99, 115) 92 (90, 111) < 0.0001

ACEi Adherent Non-adherent p-value* Visit 1 (n=97) 71 (73%) 26 (27%) SBP 142 (122, 156) 163 (143, 171) 0.0004 DBP 82 (72, 93) 102 (89, 114) <0.0001 Visit 2 (n=58) 37 (64%) 21 (36%) SBP 149 (128, 164) 167 (158, 178) 0.01 DBP 86 (76, 93) 104 (92, 114) 0.004

2 patients with therapeutic amlodipine levels 6 patients with unsuppressed ACE BPs > 160/100 mmhg at the first visit

IMPLICATIONS Our findings suggest that TDM is an essential tool in evaluating patients with resistant hypertension It will identify patients with true resistance Reduce the need for expensive tests looking for a secondary cause, reduce pill burden and the costs of medications associated with polypharmacy Furthermore, TDM will focus attention on barriers to good adherence (for instance fixed drug combinations or side effects) An early diagnosis of lack of adherence could decrease pill burden and side effects associated with polypharmacy.

CONCLUSIONS TDM of antihypertensive medication identifies patients with poor adherence and poorly controlled BP This should become a routine part of the evaluation of resistant hypertension The pharmaco-ecomomic implications need to be established

Current Practice Amlodipine has become a routine part of clinic practice A simplified and cheaper methodology has been implemented with ranges < 0.5, 0.5 2.5, 2.5 7, and > 7 ng/ml A point of care assay is being considered