Effectiveness and safety assessment of beta-blockers, calcium channel blockers, and angiotensin receptor blockers in hypertensive patients: a prospective study

Abstract

Background: Hypertension is most common prevailing cardiovascular disease worldwide. In this condition the effectiveness and safety of already available and many time-tested medications should be regularly reviewed. Methodology: Ethical approval of study was obtained from human research ethics committee of the hospital. 180 patients were enrolled with three groups of antihypertensive medication groups as calcium channel blocker (amlodipine), beta blocker (metoprolol) and angiotensin receptor blocker (telmisartan) over a span of eight months. The data was obtained from week zero to twelve (SBP: Systolic Blood Pressure and DBP: Diastolic Blood Pressure). Safety of Beta blocker, calcium channel blocker and angiotensin receptor blocker were investigated. Results: Comparison of efficacy between the beta blocker, calcium channel blocker and angiotensin blocker receptor blocker were shown to be non-significant. It indicated that all drug therapies have the same successful reduction of SBP (P-0.4819). No significant adverse reactions were observed in either class of the medicines. Conclusion: The study showed the efficacy of Calcium Channel Blocker, Beta Blocker and Angiotensin Receptor Blocker in reduction of SBP & DBP was same, while Calcium Channel Blockers were superior to other two medications.

Introduction

Hypertension is a common root of disease and mortality worldwide [4]. Systolic blood pressure above 140 mmHg and diastolic blood pressure beyond 90 mmHg is characterized as hypertension [18]. Approximately 50 million population in the USA and 1 billion all over the world are affected by hypertension [17]. Cardiac output and peripheral vascular resistance are circumstances of BP (Blood Pressure) [4]. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) in its 7th report of 2003 defined pre-hypertension as 120-139 mmHg systolic or 80-89 mmHg diastolic, whereas the European Society of Hypertension Guidelines (2007) [17]. British Hypertension Society (BHS) IV (2004) uses optimum, normal, and high normal categories to subdivide pressures lower than 140 mmHg systolic and 90 mmHg diastolic [8]. A joint guideline that updated the recommendations of the JNC7 report is published by the American Heart Association and the American College of Cardiology [9]. Cardiovascular risks can be decreased by monitoring and regulating BP in its normal range [2]. Hypertension is accompanied by cardiovascular complications, stroke, and renal diseases [1]. Hypertension can be classified as essential and secondary. 90-95% of hypertensive cases belong to the introductory class with no medical history of hypertension [4,24] and 5-10% cases of secondary hypertension due to endocrine and kidney disease [19,24]. A correlation was demonstrated through observational, epidemiological, and cohort studies between elevated systolic BP (SBP) and diastolic BP (DBP) with increased cardiovascular risks [6,16,25,25,31]. Pre-hypertension is an indicator of CVD. Lifestyle changes and medicaments can reduce CV complications [3]. Cardiovascular disease has been seen mostly in men rather than women for many years. The proportion of all deaths due to cardiovascular disease is lower among men (37%) than women (43%). Furthermore, the prevalence of this disease has seen to be decreased in men and uplifted in women in the last ten years [5]. CV risks can also be extrapolated with higher BMI as per epidemiological studies [22,23]. As per the WHO report, 62% of cerebrovascular disease and 49% of the ischemic heart disease result from sub-optimal BP (>115 mmHg) with minor deviations by gender [9].

Adults

People aged 18 years or more suffering from hypertension are prone to have more than 129 or 139 mmHg systolic, 89 mmHg diastolic pressure as per the guideline. Other approaches are used if measurements are obtained from home monitoring or 24 hours ambulatory (135 mmHg systolic or 85 mmHg diastolic) [5,6].

Children

Around 0.2 to 3.0% of newborns come up with hypertension; however, in healthy newborns, the BP is not measured routinely [11]. Hypertension is more common in newborns. Birth weight, Gestational age, postconceptional age are the variety of factors influencing BP [10]. Hypertension and pre-hypertension are identified and classified using similar criteria as in adults is proposed by BP [11].

Classification of hypertension

Classification based on etiology [14, 15]

Essential hypertension

The cause for hypertension is an idiosyncrasy in 90% of patients with elevated arterial BP. Genetic make-up, blood relatives, and indicating these are the effective factors for essential hypertension.

Secondary hypertension

Less than 1/10th% of patients suffer from secondary hypertension.

Remediable hypertension

Very negligible patients have a spirit to prevent the hypothesis, which is occurred by renal disease, adrenal disease, and so on. The most curable case of hypertension is renovascular hypertension which comprises 0.5% of cases.

Drug-induced hypertension

Twenty patients consuming oral contraceptives were associated with hypertension. Females were less prone to hypertension due to estrogen, but progestin can elevate the BP.

Classification as per WHO [12]

Staging of normal, high normal, stage-1 mild, stage-2 moderate and stage-3 severe SBP (mmHg) are 130, 130-139, 140-159, 160-179, greater than 180 respectively, while staging of Normal, high normal, stage-1 mild, stage-2 moderate and stage-3 severe DBP (mmHg) are less than 85, 85-89, 90-99, 100-109, greater than 110 respectively.

Classification as per JNC [13]

Staging of normal, pre-hypertension, stage-1 and stage-2 SBP (mmHg) are less than 120, 120-139, 140-159 and greater than 160 respectively; while staging of Normal, pre-hypertension, stage-1 and stage-2 DBP (mmHg) are less than 80, 80-89, 90-99 and greater than 100 respectively.

Diagnosis includes an overview of the medical history of individuals and family, physical examination, laboratory tests, and other co-morbidity associations [7].

Extreme high blood pressure is not curable because the cause is not identified. But if uncontrolled, several body vital organs such as the heart, brain, kidney, and retina can be affected. Blood pressure regulation is therefore important and must be maintained at normal or near-normal levels. Antihypertensive agents help to regulate and monitor BP [27,44], surpass the CV diseases [30] and reduce the rate of death and morbidity associated with CVD [32,33]. Since different groups have various pharmacodynamics and kinetics, they can also be combined.

Calcium channel blockers, beta-blockers, and ARBs are the three most used, time-tested types of antihypertensives. B-blockers were found to be partially cardio-selective membrane stabilizers, intrinsic sympathomimetic agents [29]. While there have long been in use for hypertension, in this age of newer and newer molecules that come on the market and are used, it’s also important to reassess and repeatedly compare the efficacy and protection of these old medicines. We, therefore, planned to carry out this future analysis.

Methodology

Study site

The study was conducted at the multi-specialty hospital, Ahmedabad. Hospital is fully equipped, excellent staffed, and with fully air-conditioned ICCU with 14 beds and an ICU of 6 beds, to cater to acute cardiac disorders and emergencies.

Study design

The prospective observational research has been performed in hypertensive patients. Adult Patients with outdoor as well as indoor hypertension were included in the study.

Study duration

The study was performed from the period of June 2018 and February 2019.

Number of participants

180 patients.

Selection criteria

Inclusion criteria

1. Patients were selected randomly having essential hypertension; 2. Age: Above 18-years; 3. Patients of both sexes were included after appropriate consent; 4. Systolic Blood pressure is more than 140 mmHg, and Diastolic Blood Pressure is more than 90 mmHg.

Exclusion criteria

1. Age <18 years; 2. Patients who were not treated with hypertension medications; 3. Females who are pregnant or breastfeeding or on the oral contraceptive pill; 4. Individuals with Diabetes Mellitus.

Ethical approval

Ethical approval was obtained from the institutional ethics committee from the Research Department at Shree Jivraj Mehta Smarak and Health Foundation (ECR/274/inst/GJ/2013/RR-19).

Data collection

Patients’ data were collected in preapproved CRF (case record form), consisting of patient history, prescribed drugs, presenting complaint, co-morbid condition, and adverse events, if any. The informed consent form was acquired from the patients. All patients were recorded with age, gender, body weight, and height. Blood pressure pre-therapy was reported, and patients were graded as per JNC 7 classification (Table 1).

Table 1.

Classification of hypertension according to JNC 7

	SBP	No. of Patients	DBP	No. of Patients
Normal	>120	0	>90	13
Pre hypertension	120-139	104	80-89	153
Stage-1 Hypertension	140-159	66	90-99	14
Stage-2 Hypertension	>160	10	>100	0
Total		180		180

Calcium blocker (Amlodipine), beta-blocker (Metoprolol), ARB (Telmisartan) was selected for either class. Blood pressure measurement was conducted on a weekly basis (SBP: Systolic Blood Pressure and DBP: Diastolic Blood Pressure), and data were reported in the case record form from week 0 to week 12. Patients were often interviewed during each appointment for any new symptoms or raised severity of symptoms. All complaints have been recorded in the CRF. A master diagram was prepared for patients, and all information was collected using a statistical approach (the t-testing of blood pressure values pre and post-treatment).

Evaluating parameters

1) Effectiveness of antihypertensive drugs was analyzed through Blood pressure measurement (SBP: Systolic Blood pressure and DBP: Diastolic Blood Pressure) was carried out by hospital staff, and data were collected from week 0 to week 12. 2) Safety of Beta-blocker, Calcium channel blocker, and Angiotensin receptors blockers were analysed.

Statistical analysis

● Blood Pressure (BP) data were illustrated as the mean ± SEM (Standard error of mean).

● Distribution of condition (Hypertension) was mentioned as mean ± SEM.

● The effectiveness of antihypertensive drugs was assessed by change in BP from the baseline by paired t-test and mentioned as mean ± SEM. P-value ≤0.05 was considered significant.

Results

Demographic and clinical parameters of hypertensive patients

Table 2 shows the distribution of hypertensive patients according to Age, Body mass index (BMI), Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP).

Table 2.

Distribution of hypertensive patients

	Gender	No. of patients	Mean ± SEM
Age (years)	Male	104	63.902 ± 7.621
	Female	76	64.671 ± 4.552
	Total	180	64.285 ± 6.086
BMI (kg/m2)	Male	104	27.815 ± 1.309
	Female	76	28.092 ± 1.343
	Total	180	27.953 ± 1.326
SBP (mm of Hg)	Male	104	154.40 ± 0.811
	Female	76	158.023 ± 0.913
	Total	180	156.2115 ± 0.862
DBP (mm of Hg)	Male	104	83.991 ± 0.708
	Female	76	85.384 ± 0.832
	Total	180	85.687 ± 0.77
Pulse (min)	Male	104	89.68 ± 5.37
	Female	76	90.80 ± 5.57
	Total	180	90.24 ± 5.47

Classification of hypertension according to JNC 7

Out of 180 patients, no patient was under the normal group (SBP>120). One hundred four patients were pre-hypertensive (120-139). Sixty-six patients were in Stage-1 Hypertension (140-159) and ten patients in Stage-2 hypertension (>160). In Diastolic Blood Pressure, out of 180 patients, 13 patients belonged to the Normal group (>90) and 153 patients in Pre-Hypertension (80-89). Fourteen patients were shown in Stage-1 Hypertension (140-159) and zero patients under Stage-2 Hypertension (>100).

Hypertensive patients with BMI rating

Most patients fall within a spectrum of overweight (39.44%). Many male patients displayed overweight and obesity compared to females (Table 3).

Table 3.

Classification of BMI in hypertensive patients

Classification	BMI (kg/m2)	Male (%)	Female (%)	Total (%)
Underweight	<18.50	0 (00)	2 (2.63)	2 (1.11)
Normal range	18.50-24.99	28 (26.92)	18 (23.68)	46 (25.55)
Overweight	25.00-29.99	41 (39.42)	30 (3.94)	71 (39.44)
Obese	≥30.00	35 (33.65)	27 (35.52)	62 (34.44)
Total		104 (100)	76 (100)	180 (100)

Related hypertension co-morbidity

In the current study, the majority of hypertensive patients between 50 and 79 years evidenced co-morbidities. Most common was diabetes Mellitus 65 (50%), followed by coronary artery disease 40 (30.79%), Hypothyroidism 4 (3.07%), and Hyperlipidemia 2 (1.53%), Chronic Kidney Failure & Ischemic Heart Disease 5 (3.84%) (Table 4).

Table 4.

Associated co-morbidity with hypertension

Co-morbidity	No. of patients	% Of patients
CAD	40	30.79
CKD	5	3.84
CV stroke	8	6.15
Diabetes	65	50
Heart disease	1	0.76
Hyperlipidaemia	2	1.53
Hyperthyroidism	4	3.07
IHD	5	3.84

Hypertensive patients’ age distribution

Table 5 represent age-wise patient distribution. In our sample, hypertension prevalence in the 20-29 year age group was 2.22%, rising from 50-79 years to 28.33%. In the elderly, 51.8% prevalence was found in 60-69 years.

Table 5.

Age distribution of hypertensive patients

Age	Male (%)	Female (%)	Total (%)
20-29	0 (00)	4 (5.26)	4 (2.22)
30-39	4 (3.84)	3 (3.94)	7 (3.88)
40-49	11 (10.57)	2 (2.63)	13 (7.22)
50-59	24 (23.07)	13 (17.10)	37 (20.55)
60-69	30 (28.84)	21 (27.63)	51(28.33)
79-79	19 (18.26)	24 (31.57)	43 (23.88)
80-89	14 (13.46)	7 (9.21)	21 (11.66)
90-99	2 (1.92)	2 (2.63)	4 (2.22)
Total	104 (100)	76 (100)	180 (100)

Side-effect profile based on gender

In beta-blocker, the male had more side effects than female whereas calcium channel blocker and ARB more side effects were observed in female than male (Table 6).

Table 6.

Side effects in gender group

Class of drug	Gender wise patients
	Male	Female
Beta blocker	14	10
Ca channel blocker	5	8
ARB	6	9

Efficacy of hypertensive patients treatment

Blood Pressure was successfully lowered by all three classes of medications. It was evidenced that one factor of effectiveness in systolic blood pressure was removed between the group analyzes of Beta Blocker, Calcium Channel Blocker, and Angiotensin Receptor Blockers by ANOVA (P-value-0.481856, F-value-0.73313). This research showed that the effectiveness of all three classes of antihypertensive drugs substantially decreased diastolic blood pressure. Beta-blocker, calcium canal blocker, and angiotensin receptor blocker by ANOVA were found to be a factor in the effectiveness of the diastolic blood pressure (P-value <0.00001, F-value-16.20) (Tables 7, 8).

Table 7.

Effectiveness of hypertensive patients (systolic BP)

Class of Drugs	Before ± SEM	After ± SEM	Difference	P value
Beta Blocker	157.43 ± 8.76	138.93 ± 2.66	18.5	0.0000069
Ca channel Blocker	160.77 ± 9.45	138.88 ± 3.58	21.89	0.0000014
ARB	153.78 ± 9.93	137.1 ± 2.33	16.68	0.0001670

Table 8.

Effectiveness of hypertensive patients (diastolic BP)

Class of Drugs	Before ± SEM	After ± SEM	Difference	P value
Beta blocker	89.91 ± 4.56	84.08 ± 1.43	5.83	0.00308069
Ca channel blocker	89.09 ± 4.61	82.03 ± 0.84	7.06	0.000403974
ARB	83.0 ± 3.87	80.58 ± 0.52	2.42	0.027018544

Safety assessment of antihypertensives

Mild to moderate degrees of side effects for all three medications were observed. Patients administering β-blockers had Cough (3.70%), dry mouth (33.33%), fatigue (7.40%), nausea (3.70%), stomach discomfort (7.40%), skin rashes (44.44%). Complaints about calcium channel blockers include Sedation (66.66%), vomiting (13.33%), stomach pain (6.66%), and swelling (13.33%). However, ARB induced cough (15.78%), headache (21.05%), nausea (31.57%), skin rashes (31.57%). All these side effects were mild and did not require drug dose monitoring because they confined themselves and needed no further care (Table 9).

Table 9.

Side effects reported in angiotensin receptor blocker, beta blocker and Calcium channel blocker

Reported Side Effects	Reported in Angiotensin Receptor Blocker	Reported in Beta Blocker	Reported in Calcium channel Blocker
	No. of Patients (%) (N=19)	No. of Patients (%) (N=27)	No. of Patients (%) (N=15)
Cough	3 (15.78)	1 (3.70)	-
Headache	4 (21.05)	-	2 (13.33)
Nausea	6 (31.57)	1 (3.70)	-
Skin rashes	6 (31.57)	-	-
Dry mouth	-	9 (33.33)	-
Gastrointestinal Pain	-	2 (7.4)	1 (6.66)
Rashes on skin	-	12 (44.44)	-
Fatigue	-	2 (7.4)	-
Sedation	-	-	10 (66.6)
Swelling on legs	-	-	2 (13.33)

Discussion

The current study contains 180 patient’s enrollment, and data collection was done in Case record form consisting of 104 males and 76 females.

Age ranging from 20-99years was included. The majorly affected age group was 61-69 years, with a total of 51 (28.33) subjects having 30 (28.84) males and 21 (27.63) females. One drug utilization study showed that out of two hundred patients, 115 (57%) patients were females and 85 (43%) were males, which is slightly different from current study results [48]. The average age was found to be 53.36 years in an open-labeled study [20]. In one study, cardiovascular disease patients were observed of the age group 51-60 years (37.5%) followed by 61-70 years (20%), where Male patients (63%) had a higher prevalence of Cardiovascular disease than females (37%) [46].

As per JNC 7 classification, in the case of systolic BP 104 (120-139) patients were pre-hypertensive, followed by 66 patients under Stage-1 Hypertension (140-159). While for diastolic BP, 153 patients were observed in the Pre-Hypertension group (80-89), followed by 14 patients were shown in Stage-1 Hypertension (140-159).

BMI-based classification showed that prominent patients were included in the over-weight range (39.44%). The obese and overweight males showed higher BMI compared to females. In our study, most of the hypertensive patients fall under the age range of 50-79 years, along with other co-morbidities. A study observed that overweight criteria were linked with 2 to 6 fold increased risk of developing hypertension. The study suggested that 10% increases in the weight give increase of 6.5 mmHg in systolic pressure [29]. It was also noted that 78% of cases of hypertension in males and 65% in females are linked with obesity [21,29]. A recent study showed a causal relationship between BMI with hypertension [9,22]. However, these studies were done in the western population. The WHO showed that the occurrence of overweight (BMI≥30 kg/m²) was higher in the Americans 27% obese and 61% overweight or obese in both sexes. In contrast, the Korean community has a lower obese population (4.6% obese and 31% overweight or obese in both sexes). However, The United States and Korea have the same prevalence of hypertension (9.4% vs. 8.4% respectively) [23,33].

Diabetes 65 (50%) was the most common precipitating condition associated with hypertension in this study, followed by coronary artery disease 40 (30.79%), Cardiovascular Stroke 8 (6.15), Chronic Kidney Failure & Ischemic Heart Disease 5 (3.84%), Hyperthyroidism 4 (3.07), and Hyperlipidemia 2 (1.53%), heart disease 1 (0.76%). A clinical study observed that diabetes (13%) was the highest co-morbid condition along with hypertension, followed by hyperlipidemia (7.5%), Renal disorder, obesity (6.5%), peptic ulcer disease, and stroke (4% each), and congestive cardiac failure (3.5%) [24].

In beta-blockers, males were more prone to side effects than females, whereas, in calcium channel blockers and ARB, females had major side-effect profiles. A study consisting of 14644 patients treated with beta-blockers (65% female, 66.1 years) were like those of the 40676 patients who received other antihypertensive drugs (57% female, 65.9 years). It showed that beta-blocker might be associated with a higher cause of mortality and morbidity and other side effects in female as compared to the male [42]. Another study expressed higher incidences of stroke with β-blockers [34].

As a matter of efficacy, all three classes of antihypertensives showed an efficient reduction in BP. In a study consisting of 1797 patients, 760 (42.3%) were newly, and 1037 (57.7%) were previously diagnosed. Of these, 29.9% were classified as high-risk and 43.2% under very high-risk group. Amlodipine was administered for six months follow-up with the conclusion of high potency and safety [37,24]. A significant decrease in Blood pressure was noted in 87 patients at a daily dose of 5-10 mg Amlodipine were enrolled in the study [41]. It was found that calcium channel blockers have better efficacy compared to other classes of drugs for long-term treatment and even in combination [39,40,28]. 61-91% of patients achieved desired BP with the help of amlodipine [26]. In a previous study, it was shown that 696 patients were assigned, of which 85 patients met all inclusion criteria. Systolic Blood Pressure was calculated, which included that systolic Blood Pressure decreased by a mean of 17.5 mm Hg from baseline [38].

Cough (3.70%, n=1), Dry mouth (33.33%, n=9), Fatigue (7.40%, n=2), Nausea (3.70, n=1), Gastrointestinal pain (7.40, n=2), Rashes on the skin (44.44%, n=12) were the common side-effects observed for β-blockers. A study indicated that side-effects of β-blockers could be due to pharmacological or non-pharmacological consequences. Other Side effects like bronchospasm, heart failure, depression, Bradycardia, nightmares, heart block are associated [43]. They are inferior in terms of side effects compared to calcium channel blockers [35]. They elevated the risk of CV disease, stroke, and mortality than calcium channel blockers [36]. In one study, antiplatelet, Dyslipidemia agents, and Beta-blockers were prescribed as 34%, 19%, and 14%, respectively, while antianginals, ACE inhibitors, and diuretics were prescribed in 11%, 8%, 5%, respectively [46]. Another study showed out of 187 patients received monotherapy, which revealed that calcium channel blockers were the drugs of choice for hypertensive patients because it is prescribed to 54 (28.87%) patient of hypertension as single-drug therapy, followed by the fixed-dose combination (FDC) of β-blockers with amlodipine 42 (22.45%), β-blockers 37 (19.78), angiotensin two receptor blocker 23 (12.29%), diuretics 9 (4.81%), angiotensin-converting enzyme inhibitors 9 (4.81%) [47].

Side-effect profile of calcium channel blockers include Sedation (66.66%, n=10), Headache (13.33%, n=2), Gastrointestinal pain (6.66%, n=1), Swelling in the leg (13.33%, n=2). The study stated major side effects associated with calcium channel blockers such as headache, flushing, palpitations, peripheral Edema, and hypotension [44].

ARBs resulted in cough (15.78%, n=3), headache (21.05%, n=4), nausea (31.57%, n=6), skin rashes (31.57%, n=6). Headache, respiratory infection, dizziness and fatigue were reported with 2.1% on Telmisartan 40 mg, 4.5% on Telmisartan 80 mg [45].

Conclusion

In this study, we observed that diabetes is the most common co-morbid condition associated with hypertension in the effectiveness and protection of the anti-hypertension drug. The most prescribed antihypertensive was amlodipine (calcium channel blocker) followed by Metoprolol (β-blocker) and telmisartan (angiotensin receptor blocker). Three types of antihypertensive drugs were found to reduce systolic and diastolic blood pressure substantially in all patients. Mild to moderate side effects were observed with all three classes of drugs.

Disclosure of conflict of interest

None.