title: Impact of number of prescribed medications on visit-to-visit variability of blood pressure: implications for design of future trials of renal denervation.
abstract: BACKGROUND
  Visit-to-visit blood pressure (BP) variability limits the ability to detect therapeutic effects in hypertension trials.
  
  
  METHODS
  To enable future renal denervation trials to detect smaller effect sizes and reliably identify technical improvements, we examined within-patient visit-to-visit BP variability, quantified as SD of change from baseline to final BP (SDΔ), in renal denervation (RDN) trials, trials of BP-lowering tablets, and the VOLTAGE study including 4151 patients.
  
  
  RESULTS
  The control arms of RDN trials had more visit-to-visit BP variability than tablet trials (SDΔ 23.6 versus 13.5 mmHg; P < 0.001). This might be explained by more prescribed antihypertensive patients in the RDN trials (5.19 ± 0.13 versus 0.11 ± 0.11; P < 0.001). In the VOLTAGE study, as the number of medications prescribed rose from 0 to 4, SDΔ rose: 11.9, 11.2, 12.9, 14.4 and 18.0 mmHg (P < 0.001 for trend). Neither baseline BP, nor demographics, nor diabetes independently affected variability. The sample size required for a trial rises proportionally to the square of the number of medications prescribed (rather than just linearly). The relationship between the number of background medications prescribed in a cohort and the excess test-retest variance closely fitted this quadratic formula (R = 0.98, P = 0.001).
  
  
  CONCLUSIONS
  Visit-to-visit variability in BP is dramatically larger in patients with more background medications prescribed. If this is due to variable adherence, then future RDN trials, needing to detect smaller effect sizes, would benefit from measures to guarantee adherence. Conceivable measures include enrolling patients on no background medication, preceding each BP measurement with a period off medication, or directly supervising medication intake.
authors.affiliation: aInternational Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London bNIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, UK cAP-HP, Hospital Avicenne, Paris 13 University, Bobigny dHospital Hotel-Dieu, Paris, France eKlinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Kirrberger Strasse 1, 66421 Homburg/Saar fHeart Centre Bad Krozingen, Bad Krozingen, Germany gState University of New York, Downstate College of Medicine, Brooklyn, New York, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Howard
authors.forename: Hitesh
authors.initials: H
authors.lastname: Patel
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Shun-Shin
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Mourad
authors.forename: Jacques
authors.initials: J
authors.lastname: Blacher
authors.forename: Felix
authors.initials: F
authors.lastname: Mahfoud
authors.forename: Thomas
authors.initials: T
authors.lastname: Zeller
authors.forename: Michael
authors.initials: M
authors.lastname: Weber
authors.forename: Darrel P
authors.initials: DP
authors.lastname: Francis
mesh_terms: D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D001795:Blood Pressure Determination; D018660:Blood Pressure Monitoring, Ambulatory; D002986:Clinical Trials as Topic; D003714:Denervation; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology / Q000601:surgery; D007668:Kidney / Q000294:innervation* / Q000503:physiopathology; D055553:Prescription Drugs; D012107:Research Design; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D055553:Prescription Drugs