Anti-hypertensive Medication Dosing Regimen in Effective Blood Pressure Control (HARMONY)

• Mean day-time ABPM systolic BP [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
• Mean day-time ABPM diastolic BP [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
• Μean night time ABPM systolic BP [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
• Μean night time ABPM diastolic BP [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
• Mean clinic - systolic BP [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
• Mean clinic - diastolic BP [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
• Concordance with taking drug treatment [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
• Self reported side effects [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
• Quality of Life [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
• Clinical events (extra GP or hospital visits and procedures and hospitalization) [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]

A randomised crossover trial of anti-hypertensive medication dosing regimen in effective blood pressure control.

To investigate whether there is a difference in 24 hour blood pressure (BP) control when antihypertensive medications are taken in the morning compared with the evening. The identification of any significant difference could lead to more effective therapeutic management of arterial hypertension, which in turn would result in a reduced cardiovascular burden, lower costs and a better quality of life for hypertensive patients.

• Active Comparator: Group B
  Anti hypertensive medication in the evening (between 18.00 and 23.00)
  Intervention: Drug: Anti-hypertensive Medication -
• Active Comparator: Group A
  Antihypertensive medication in the morning(between 06.00 and 11.00)
  Intervention: Drug: Anti-hypertensive Medication -

• Lemmer B. Clinical chronopharmacology: the importance of time in drug treatment. Ciba Found Symp. 1995;183:235-47; discussion 247-53. Review.
• Bruguerolle B. Chronopharmacokinetics. Current status. Clin Pharmacokinet. 1998 Aug;35(2):83-94. Review.
• Rothwell PM, Howard SC, Dolan E, O'Brien E, Dobson JE, Dahlöf B, Sever PS, Poulter NR. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet. 2010 Mar 13;375(9718):895-905.
• Smolensky MH, Hermida RC, Ayala DE, Tiseo R, Portaluppi F. Administration-time-dependent effects of blood pressure-lowering medications: basis for the chronotherapy of hypertension. Blood Press Monit. 2010 Aug;15(4):173-80. Review.
• Hermida RC, Ayala DE, Mojón A, Fernández JR. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int. 2010 Sep;27(8):1629-51.
• Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000 Jan 20;342(3):145-53. Erratum in: 2000 May 4;342(18):1376. N Engl J Med 2000 Mar 9;342(10):748.
• Mayet J, Chapman N, Li CK, Shahi M, Poulter NR, Sever PS, Foale RA, Thom SA. Ethnic differences in the hypertensive heart and 24-hour blood pressure profile. Hypertension. 1998 May;31(5):1190-4.

Inclusion Criteria:

• Caucasian patients aged 18-80 years;
• History of any grade of hypertension for at least 1 year, including at least 3 months of constant antihypertensive medication (consisting of ≥ 1 antihypertensive drugs, each administered in one dose daily), with reasonably controlled BP (≤150/90 mmHg and ≥ 115/75 mmHg on usual medication) based on previous clinic records, in the last 3 months.

Exclusion Criteria:

• BP levels > 150/90 mmHg or < 115/75 mmHg in the last 3 months.
• Postural hypotension, defined as symptoms resulting from a > 20 mm Hg drop of systolic BP or a > 10 mm Hg drop of diastolic BP or both between 1 and 3 min after standing from the sitting position.
• Known Extreme dippers at baseline (fall of mean night time SBP > 20% of mean day time SBP)
• Individuals with jobs which require night-time shift work.
• Pregnant women or those planning to become pregnant.