Effect of Therapeutic Drug Monitoring on Adherence and Blood Pressure: A Multicenter Randomized Clinical Trial.

BACKGROUND: Drug concentration in blood or urine is an acknowledged method to detect nonadherence. Observational studies suggest that informing patients about low or absent serum drug levels improves blood pressure (BP). We performed a multicenter randomized clinical trial to test the hypothesis that therapeutic drug monitoring (TDM) could improve drug adherence and BP in patients with uncontrolled hypertension (HT). METHODS: Patients were ≥18 years on stable treatment with at least 2 antihypertensive agents. We planned to randomize 80 nonadherent patients with a systolic daytime ambulatory BP ≥135 mm Hg to TDM intervention or not. The control group and the study personnel who measured BP remained uninformed about serum drug measurements throughout. All patients and physicians were blinded for BPs. Lifestyle advice and detailed information on the disease process and the importance of BP treatment were given to both groups. RESULTS: From 2017 to 2022, we randomized 46 diagnosed nonadherent from a total of 606 patients with uncontrolled HT. The TDM group had a 6.7 (±14.5) mm Hg reduction from 147.9 (±10.3) to 141.1 (±14.1) mm Hg, and the control group experienced a 7.3 (±13.2) mm Hg reduction from 147.1 (±9.2) to 139.1 (±17.4) mm Hg, P = 0.9 between groups. Adherence improved in both groups, 73% in the TDM group and 59% in the control group became adherent at 3 months, P = 0.51. CONCLUSIONS: In our prospective multicenter clinical trial of uncontrolled and nonadherent hypertensive patients, we found no additional effect of TDM on BP and drug adherence compared with standard care. CLINICAL TRIALS REGISTRATION: Trial Number NCT03209154, www.clinicaltrials.gov.

Nonadherence by Serum Drug Analyses in Resistant Hypertension: 7-Year Follow-Up of Patients Considered Adherent by Directly Observed Therapy.

Background Measurement of serum concentrations of drugs is a novelty found useful in detecting poor drug adherence in patients taking ≥2 antihypertensive agents. Regarding patients with treatment-resistant hypertension, we previously based our assessment on directly observed therapy. The present study aimed to investigate whether serum drug measurements in patients with resistant hypertension offer additional information regarding drug adherence, beyond that of initial assessment with directly observed therapy. Methods and Results Nineteen patients assumed to have true treatment-resistant hypertension and adherence to antihypertensive drugs based on directly observed therapy were investigated repeatedly through 7 years. Serum concentrations of antihypertensive drugs were measured by ultra-high-performance liquid chromatography-tandem mass spectrometry from blood samples taken at baseline, 6-month, 3-year, and 7-year visits. Cytochrome P450 polymorphisms, self-reported adherence and beliefs about medicine were performed as supplement investigations. Seven patients (37%) were redefined as nonadherent based on their serum concentrations during follow-up. All patients reported high adherence to medications. Nonadherent patients expressed lower necessity and higher concerns regarding intake of antihypertensive medication (P=0.003). Cytochrome P450 polymorphisms affecting metabolism of antihypertensive drugs were found in 16 patients (84%), 21% were poor metabolizers, and none were ultra-rapid metabolizers. Six of 7 patients redefined as nonadherent had cytochrome P450 polymorphisms, however, not explaining the low serum drug concentrations measured in these patients. Conclusions Our data suggest that repeated measurements of serum concentrations of antihypertensive drugs revealed nonadherence in one-third of patients previously evaluated as adherent and treatment resistant by directly observed therapy, thereby improving the accuracy of adherence evaluation. Registration URL: https://www.clinicaltrials.gov; unique identifier: NCT01673516.

Establishing Serum Reference Ranges for Antihypertensive Drugs.

BACKGROUND: Therapeutic drug monitoring (TDM) involves the measurement of serum drug concentrations to optimize pharmacotherapy. Traditionally, blood pressure measurements alone, and not TDM, have been used to evaluate the antihypertensive drug response. However, approximately 50% of hypertensive patients treated with lifestyle changes and antihypertensive drugs fail to achieve blood pressure control. Serum drug concentration measurements could be useful to select the optimal drugs in adjusted doses and to identify nonadherence. Implementation of TDM in clinical routine for antihypertensive drugs depends on established serum reference ranges. METHODS: Commonly used antihypertensive drugs were identified based on prescription data. The authors performed a review of authoritative literature on reported serum drug concentrations and calculated expected concentrations from previously reported pharmacokinetic parameters with commonly prescribed daily doses. Finally, serum drug concentrations in samples from patients undergoing antihypertensive treatment were measured. RESULTS: Serum reference ranges for 24 frequently used antihypertensive drugs were established based on results from 3 approaches. CONCLUSIONS: Serum drug concentration measurements, interpreted in light of the established reference ranges, together with blood pressure measurements and other clinical data, may help identify nonadherent patients and tailor individual antihypertensive treatment when deviant drug responses appear in line with the concept of personalized medicine.