Controlling Variability in Home Blood Pressure: Which Combination therapy is better?
Hypertension is one of the most preventable causes of death worldwide that accounts for more than 12.8% of all deaths annually. Elevated blood pressure is one of the major modifiable contributing risk factors to various cardiovascular diseases. Changes in physical and mental activities, sleep, autonomic, humoral, mechanical, myogenic, and environmental stimuli constantly fluctuate this variable.
Numerous studies in the past have shown that variation in Blood pressure has a significant cardiovascular impact and even add to death risk
Blood Pressure Variability
Blood pressure variability (BPV) is defined by a continuous dynamic and spontaneous fluctuations occurring over a lifetime (2). A growing number of clinical and observational studies have demonstrated an independent relationship between both short and long term BPV and the risk of CV events and death, regardless of mean blood pressure (BP) levels (3). Besides, changes in BPV have been associated with target organ damage such as arterial stiffness (4, 5), left ventricular hypertrophy (6), a decline in renal function (7) subclinical brain small vessel disease (8) and the risk of developing foot ulcers in diabetes (9)
Measuring BP and BPV
When it comes to the measurement of Blood Pressure, while there are many methodologies present, Clinic blood pressure (BP) is recognized as the gold standard for the screening, diagnosis, and management of hypertension. (1)
However, to measure accurate Clinic BP as well as its variations, several office visits are required over a period of time, which may be difficult for some patients. In this scenario, practitioners often initiate the treatment of a patient based on clinic measurements and then recommend home BP monitoring as a practical tool to assess the efficacy of antihypertensive drugs on BP as well as their impact on day-by-day BPV
BP and BPV management
Combination therapy is often recommended for management of blood pressure when monotherapy fails to reach the desired goals. Studies have shown that about 70% of hypertensive patients require the combination of at least two antihypertensive agents to reduce blood pressure levels below the recommended goals.
Combination therapy provides greater antihypertensive power than the use of high doses of monotherapy, adding several mechanisms of action that block various pathways of increased blood pressure, in addition to providing greater protection to target organs than monotherapy, and reduced potential for side effects.
While many studies have been done to understand the impact of combination therapy on Blood Pressure management, only a few studies have been undertaken to understand the impact of combination drugs on BPV.
In 2012, a study called J-Core Trial (Japan Combined Treatment With Olmesartan and a CCB Versus Olmesartan and Diuretics Randomized Efficacy Study) was conducted in to test the hypothesis that the angiotensin II receptor blocker (ARB) /calcium-channel blocker (CCB) combination decreases day-by-day BPV more than the angiotensin II receptor blocker (ARB) /diuretic combination does (2). The study evaluated the mechanism underlying the reduction in home BPV using data on aortic pulse wave velocity (aPWV) in each ARB /CCB and ARB / diuretic group.
The study was done between May 2006 to October 2007 using patients from the outpatient department of Internal Medicine at Mishima Clinic, Hagi, Japan. The study was a 24-week, prospective, randomized, open-label, blinded-end point study with 2 treatment arms. The subjects with an office BP ≥140 and/or 90 mm Hg were eligible for the study after a run period of a once-daily 20-mg dose of Olmesartan monotherapy. Eligible subjects were randomly assigned to receive either azelnidipine 16 mg or hydrochlorothiazide (HCTZ) 12.5 mg as an add-on to olmesartan 20.0 mg.
Office BP was recorded as the average of triplicate measurements taken at intervals of 1 minute using a validated oscillometric device. Home BP was measured in a sitting position 3 times each morning and 3 times each evening for 5 consecutive days before each office visit. The subjects were instructed to place the cuff on the nondominant arm, rest for 5 minutes before the first reading, and take a 15-second interval between readings. Morning BP was measured within 1 hour after waking, after urination, and before breakfast. Evening BP was measured just before going to bed and 60 minutes after taking a bath (based on Japanese home BP guidelines). aPWV was measured with a SphygmoCor device from sequentially recorded ECG-gated carotid and femoral artery waveforms. The day-by-day home BPV and HR variability (HRV) were defined as the SD of the daily BP/HR average (average of 6 readings) of 5 consecutive days. the day-by-day morning BPV/HRV and evening BPV/HRV were defined as the SD of the daily BP/HR average in the morning or the evening.
Results of the study:
From the study, it was found that
- The average number of home BP measurements per subject during the 5-day period was 29.8±0.7 at baseline, 29.6±1.4 at 1 month, 29.5±1.4 at 2 months, 29.3±1.7 at 3 months, 29.4±1.5 at 4 months, 29.4±1.5 at 5 months, and 29.2±1.8 at 6 months.
- Baseline characters were similar between the groups.
- Percentage of subjects with white coat hypertension was 25% in the HCTZ group and 23% in the azelnidipine group.
- BPs were similar between the groups, except for office diastolic BP
- Home Heart rates (HRs) decreased significantly from baseline only in the azelnidipine group, and the follow-up means of home HRs were significantly smaller in the azelnidipine group than in the HCTZ group.
- The Standard deviation (SD) of home SBPs/diastolic BPs were significantly smaller in the azelnidipine group than in the HCTZ group. the follow-up means of the SD of home HRs were similar between the groups.
- After 6 months of treatment, the reductions in the SD of home BP and the SD of home HR were greater in the azelnidipine group than in the HCTZ group.
- The change in aPWV was significantly correlated with the change in the SD of home SBP in the azelnidipine group, whereas this significant correlation was not observed in the HCTZ group
From the trial, the authors concluded that the addition of CCB to ARB decreased the day-by-day home BPV more effectively than the addition of a diuretic to ARB, while the reductions in home BP level were similar in both regimens. The researchers noted that in the CCB group the arterial stiffness reduction was independently associated with the reduction in home BPV
The authors noted that the greater reduction in BPV among subjects treated with CCB was probably because of the profound effects on the relaxation of peripheral muscular arteries. As BPV is controlled by baroreflex sensitivity (BRS), it was speculated that the effect of CCB on BPV was by improving BRS.
Also, the study provided evidence that the aPWV reduction is an independent determinant of the reduction in home BPV in the ARB/CCB group. Thus, the authors noted that destiffening of the large arteries by ARB/ CCB treatment might be a common underlying mechanism of the significant reductions in central SBP and home BPV, each of which was reported to be an independent predictor of cardiovascular events.
The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Azelnidipine, click here
1. Chadachan VM, Ye MT, Tay JC, Subramaniam K, Setia S. Understanding short-term blood-pressure-variability phenotypes: from concept to clinical practice. Int J Gen Med. 2018;11:241-254. Published 2018 Jun 22. doi:10.2147/IJGM.S164903
2. Nardin C, Rattazzi M, Pauletto P. Blood Pressure Variability and Therapeutic Implications in Hypertension and Cardiovascular Diseases. High Blood Press Cardiovasc Prev. 2019;26(5):353-359.
3. Mehlum MH, Liestøl K, Kjeldsen SE, Julius S, Hua TA, Rothwell PM, et al. Blood pressure variability and risk of cardiovascular events and death in patients with hypertension and different baseline risks. Eur Heart J. 2018;39(C):2243–2251. doi: 10.1093/eurheartj/ehx760.
4. Zhou TL, Henry RMA, Stehouwer CDA, Van Sloten TT, Reesink KD, Kroon AA. Blood pressure variability, arterial stiffness, and arterial remodeling: the Maastricht Study. Hypertension. 2018;72:1002–1010. doi: 10.1161/HYPERTENSIONAHA.118.11325.
5. Kim J, Park S, Yan P, Jeffers BW. Effect of inter-individual blood pressure variability on the progression of atherosclerosis in carotid and coronary arteries: a post hoc analysis of the NORMALISE and PREVENT studies. Eur Heart J Cardiovasc Pharmacother. 2017;3:82–89
6. Mustafa EM, Strătoaie OI, Ușetescu ROM. Blood pressure variability and left ventricular mass in hypertensive patients. Curr Health Sci J. 2016;42(1):47–50
7. Wang X. Twenty-four-hour systolic blood pressure variability and renal function decline in elderly male hypertensive patients with well-controlled blood pressure. Clin Interv Aging. 2018;13:533–540. doi: 10.2147/CIA.S161752.
8. Filomena J, Riba-Llena I, Vinyoles E, Tovar JL, Mundet X, Castañé X, et al. Short-term blood pressure variability relates to the presence of subclinical brain small vessel disease in primary hypertension. Hypertension. 2015;66(3):634–640. doi: 10.1161/HYPERTENSIONAHA.115.05440
9. Palatini P. Risk of developing foot ulcers in diabetes. J Hypertens. 2018;36(11):2132–2134. doi: 10.1097/HJH.0000000000001815.
10. Guerrero-García C, Rubio-Guerra AF. Combination therapy in the treatment of hypertension. Drugs Context. 2018;7:212531. Published 2018 Jun 6. doi:10.7573/dic.212531