Effective BP control: High dose ARB monotherapy or combination therapy of ARB and CCB for hypertension?

Unlike in a small number of cases that occur due to a specific cause, in most individuals, the etiology of Hypertension cannot be determined. It is assumed to be an interplay of genetic, environmental, and behavoural factors (2). The primary factor are sometimes pointed to the imbalance between sodium and kidney function whereas the other adjunctive factors like diet, obesity, diabetes, aging, emotional stress, sedentary lifestyle, and potassium intake are also known to play a role in the development of hypertension (3,4). Various studies in the past have shown that several pathophysiologic factors are involved in the development of high BP which in turn leads to cardiometabolic syndrome thus leading to cardiovascular diseases and chronic kidney diseases.

Growing evidence shows that increased activation of the Renin-angiotensin-aldosterone system (RAAS) as the key factor in the development of endothelial dysfunction and thus Hypertension. Inappropriate activation of RAAS, oxidative stress, inflammation, and other factors like impaired insulin-mediated vasodilatation, enhanced sympathetic nervous system (SNS) activation, and abnormal sodium handling by the kidney can all lead to the development of hypertension (5).

Diuretics, β-blockers (BB), α blockers, calcium channel blockers (CCBs), angiotensin- converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are the various classes of antihypertensive drugs that are prescribed as monotherapy or combination therapy for the treatment of hypertension (1).

Out of these multitudes of drugs, recent studies have shown that angiotensin receptor blockers (ARB) are important for treating hypertension as the RAAS plays an important role in the pathophysiology of hypertension. These have excellent efficacy, no negative metabolic effects, no accumulation of bradykinin and they also activate angiotensin II type 2 receptors which can cause vasodilatation in the small vessels leading to additional cardiac and renal protection. The latest guidelines show that ARBs are one of the preferred drugs of choice in patients with co-morbid microalbuminuria, chronic kidney disease, metabolic syndrome, and in any other cardiovascular disease (6).

CCBs are widely prescribed drugs used for treating Hypertenion. The two types of CCBs are Dihydropyridines (DHPs) which cause vasodilatation by binding to L type Calcium channels in vascular smooth muscles and non DHPs which by exerting equipotent effects on L type calcium channels bind at the sinoatrial and atrioventricular node. Some National guideline committees recommend these for initial therapy either as mono or combination therapy (7).

Various trials in the past compared ARBs and CCBs providing evidence that ARBs are as effective as CCBs in suppressing cardiovascular morbidity and mortality and treating hypertension. There is also evidence that ARBs prevent the onset of type 2 DM. Comparing the adverse effects of both the groups, the adverse effects with CCBs are dose-dependent hampering prescribing of higher doses while ARBs have placebo-like tolerability and reduce HTN with no increase of the incidence of adverse events at higher doses.

At the same time, ARBs and CCBs can both be used in conjunction with each other as a part of combination therapy for treatment of Hypertension where monotherapy fails to show desired results. The question before a practitioner then becomes, whether to use a higher dose of one class of drug or to go for a combination therapy.

As the higher doses of ARBs were found to be effective for treating HTN but the significance of using higher doses not defined, Hisao Ogawa et al conducted a study called the

Olmesartan and calcium antagonists Randomised study to compare ARBs and CCBs. The trial popularly known as the OSCAR trial was the first largest trial in Japan which compared the efficacy between high-dose ARB and the combination of ARB plus CCB in elderly Japanese patients with high-risk hypertension in terms of prevention of cardiovascular morbidity and mortality.

The inclusion criteria included patients between 65 to 85 years of age of both sex, and receiving treatment with a single antihypertensive drug, and showing a SBP >140 mmHg and DBP >90mmHg at two casual blood pressure measurements. They had at least one of the following cardiovascular risk factors - type 2 diabetes, cerebral disease (cerebral infarction, cerebral hemorrhage or Transient ischaemic attack), cardiac disease (MI, angina, heart failure, left ventricular hypertrophy), vascular disease (aortic aneurysm, aortic dissection, arteriosclerotic peripheral artery disease), and renal disease (serum creatinine of 1.2-2.5mg /100ml for men or 1-2.5mg /100ml for women, proteinuria ±1).

Patients with Secondary hypertension or malignant hypertension, Severe heart failure (NYHA Class III or IV), Malignancy requiring treatment, Serious hepatic or renal dysfunction, Difficulty in stopping previous drugs and switch to the study medication, History of a serious adverse drug reaction to an ARB or CCB, and Any other condition that makes a patient unsuitable for the study in the opinion of the investigator were excluded from the study.

After taking informed consent, the patients were prescribed olmesartan medoxomil as ARB and amlodipine besilate or Azelnidipine as CCB while with routine use of other drugs as taken by the patient. After the patients agreed to all the terms by understanding the procedure and gave the consent, the investigator sent the enrolment data to the OSCAR study data center for randomization.

All patients were switched to olmesartan at a dose of 20 mg/day in step 1. If blood pressure was not controlled and treatment was well tolerated the patients in the high-dose ARB group received the increased dose of olmesartan medoxomil at 40 mg/day in step 2. Those in the ARB plus CCB group received a CCB in addition to olmesartan medoxomil at 20 mg/day. If an additional drug was required another antihypertensive drug could be added, except that ARBs, angiotensin-converting enzyme inhibitors, and CCBs were excluded.

Enrolment was carried out from June 2005 to May 2007, and follow-up continued for 3 years by collecting data from patients every 6 months. The primary endpoints of measurement were a composite of fatal and non-fatal cardiovascular events which included cerebrovascular diseases, coronary artery diseases, heart failure, other arteriosclerotic diseases, diabetic complications, renal function deterioration by any cause and finally all-cause death. The secondary point of measurement was the incidence of any cardiovascular events or any other adverse events and assessment of blood pressure. Any alterations in the heart rate, glucose metabolism, laboratory analyses, and subgroup analyses were also measured. Statistical analyses for endpoints and intergroup comparison was done. For all analyses, the statistical significance was P= 0.05.

• A total of 1217 elderly patients diagnosed with high-risk hypertension were recruited and randomized between June 2005 and May 2007. After exclusions, Finally, 1164 patients were included in the analysis and of these, a total of 578 patients were randomly assigned to the high-dose ARB group and 586 patients to the ARB plus CCB group.

• The mean age of the patients was 73.6 years, and 509 (43.7%) patients were 75–84 years old.

• Systolic blood pressure and diastolic blood pressure of the patients were 157.7±12.0 and 84.9±9.9 mm Hg, respectively.

• Frequencies of mild and moderate hypertension were 60.5 and 34.8%, respectively.

• About 70% of the patients had a history of cardiovascular disease, including cerebrovascular disease (40.0%), cardiac disease (38.7%), and renal dysfunctions (17.3%).

• 54.0 and 45.0% of the patients had type 2 diabetes and hyperlipidemia, respectively.

At 3 years, the authors observed the following results

• At 3 years, both systolic BP and diastolic BP were reduced in both arms, but to a larger extent in the low-dose ARB + CCB arm than the high-dose ARB arm. Systolic BP and diastolic BP were 136 mm Hg/133.4 mm Hg, and 74.6 mm Hg/73.1 mm Hg in the high-dose ARB versus low-dose ARB + CCB arms, respectively

• The primary composite endpoint of fatal and nonfatal CV events and non-CV death was similar between the high-dose ARB and low-dose ARB + CCB arms.

• Similarly, fatal and nonfatal CV events, cerebrovascular disease, CHF, and diabetic complications were similar between the two arms.

• On subgroup analysis, the incidence of the primary composite outcome was higher in the high-dose ARB arm in patients with established CV disease

• In the subgroup with type 2 diabetes and no other comorbidities, there was a trend toward benefit for the primary endpoint in the high-dose ARB arm

• Serious adverse events were similar between the two arms

The authors thus observed that the results of this study provide a novel insight into the therapeutic strategy for hypertension in high-risk elderly patients.

They also mentioned the reason for selecting Olmesartan as the choice ARB. Since several studies in the past indicated that olmesartan exerts a dose-dependent reduction of systolic blood pressure and diastolic blood pressure and as olmesartan is as efficacious in elderly patients as in younger hypertensive patients. And olmesartan was found to be as efficacious as

amlodipine in treating elderly hypertensive patients.

The researchers also added that comparing the equihypotensive doses of azelnidipine and amlodipine on hypertensive rats has shown that azelnidipine exerts a lower heart rate, reduces cardiac hypertrophy and remodeling than does amlodipine, by a greater reduction of cardiac oxidative stress and inflammation. Azelnidipine in combination with ARB exerted additional renoprotective effects in hypertensive patients with diabetic nephropathy. Hence in the trial, not only amlodipine but also azelnidipine as CCB was used.

1. Tiwaskar, M., Langote, A., Kashyap, R., & Toppo, A. (2018). Amlodipine in the Era of New Generation Calcium Channel Blockers. Journal of The Association of Physicians of India, 66(March), 59–64.

2. Bolívar JJ. Essential hypertension: an approach to its etiology and neurogenic pathophysiology. Int J Hypertens. 2013;2013:547809. doi:10.1155/2013/547809.

3. Meneton P, Jeunemaitre X, de Wardener HE, Macgregor GA. Links between dietary salt intake, renal salt handling, blood pressure, and cardiovascular diseases. Physiological Reviews. 2005;85(2):679–715.

4. Takahashi H, Yoshika M, Komiyama Y, Nishimura M. The central mechanism underlying hypertension: a review of the roles of sodium ions, epithelial sodium channels, the renin-angiotensin-aldosterone system, oxidative stress and endogenous digitalis in the brain. Hypertension Research. 2011;34(11):1147–1160.

5. Med Clin North Am. 2009 May ; 93(3): 569–582. doi:10.1016/j.mcna.2009.02.014.

6. Am J Cardiovasc Drugs (2016) 16:255–266

7. The Role of Existing and Newer Calcium Channel Blockers in the Treatment of Hypertension, https://doi.org/10.1111/j.1524-6175.2004.03683.x

8. Ogawa, H., Kim-Mitsuyama, S., Jinnouchi, T. et al. Rationale, design and patient baseline characteristics of OlmeSartan and calcium antagonists randomized (OSCAR) study: a study comparing the incidence of cardiovascular events between high-dose angiotensin II receptor blocker (ARB) monotherapy and combination therapy of ARB with calcium channel blocker in Japanese elderly high-risk hypertensive patients (ClinicalTrials. gov no. NCT00134160). Hypertens Res 32, 575–580 (2009). https://doi.org/10.1038/hr.2009.60

9. Ogawa H. LBCT IV 3015. Presented at: ACC 60th Annual Scientific Sessions; April 2-5, 2011; New Orleans.