Dual antihypertensive strategies: A real-world comparative study of efficacy and safety of fixed-dose combinations in a tertiary care setting

Abstract

Aim:

The aim of this study was to evaluate the comparative efficacy and safety of fixed-dose combinations of amlodipine 5 mg + hydrochlorothiazide 12.5 mg (A+H) (Group 1), telmisartan 40 mg + hydrochlorothiazide 12.5 mg (T+H) (Group 2), and ramipril 5 mg + hydrochlorothiazide 12.5 mg (R+H) (Group 3) in patients of essential hypertension.

Materials and Methods:

A prospective, randomized, open-labeled study was conducted for a period of 12 months (April 2023–March 2024), at a single tertiary care center involving 327 patients that were newly diagnosed with essential hypertension without any comorbid conditions. Patients were assessed at baseline, 15 days, 1 month, and then followed up at monthly intervals up to 6 months.

Results:

In the study, significant reductions in systolic blood pressure (SBP) were noted for A+H with R+H at 3 and 4 months and for T+H with R+H from 3 to 6 months. Diastolic blood pressure (DBP) reductions were significant for A+H with R+H at 15 days and 1 month. T+H was significantly more effective than A+H and R+H in reducing SBP, while all groups showed comparable efficacy in reducing DBP over 6 months. Adverse drug reactions (ADRs) were highest in the A+H group at 29.4% and lowest in the T+H group at 19.8%.

Conclusion:

This real-world clinical study provided valuable insights into the comparative efficacy of different antihypertensive drug combinations, with T+H being most effective in reducing SBP; in terms of DBP, all the groups were equally efficacious.

INTRODUCTION

Hypertension is a significant health concern substantially raising the likelihood of conditions impacting the heart, brain, kidneys, and other vital organs. The World Health Organization (WHO) African Region shows prevalence at 27% which is the highest, while the WHO Region of the Americas shows 18% which is the lowest.[1] Worldwide, 1.28 billion individuals aged 30–79 years have hypertension, with about two-thirds residing in low- and middle-income countries. Over half also have additional cardiovascular risk factors.[2,3] National Family Health Survey-5 (NFHS-5), showed hypertension prevalence among individuals of age 15-49 years was 22.8% (with a sample of 172,532), out of these newly diagnosed cases were 52.06%.[4]

Hypertension management includes lifestyle changes and pharmacotherapy. Lifestyle modifications include quitting smoking, controlling blood glucose and lipid levels, and reducing alcohol and sodium intake. Pharmacotherapy includes diuretics, renin-angiotensin antagonists, sympatholytic drugs, calcium channel blockers, and vasodilators.[5]

While numerous antihypertensive drugs are available, achieving optimal blood pressure control is often difficult due to varying drug efficacy, ADR occurrence, and challenges with patients adhering to medication regimens.[6] WHO recommends combination therapy, especially single-pill combinations for effectively managing BP and improving adherence to medication. The FDCs of drugs used in hypertension should be from the following three classes: diuretics, angiotensin-converting enzyme inhibitors (ACEi) or angiotensin-receptor blockers (ARBs), and calcium channel blockers (CCBs). The European Society of Hypertension guidelines suggest that combining 2 drugs in a single pill is preferred, it address two significant obstacles, inadequate adherence to the prescribed regimen and therapeutic inertia.[7,8]

Antihypertensive drugs often lead to adverse effects that can diminish patients’ quality of life, adding strain on healthcare systems and increasing financial burdens. Elderly patients, typically on long-term polypharmacy, experience a higher incidence of these ADRs.[9] ADRs are a significant source of sickness and death. It is estimated that ADRs account for approximately 6% of hospitalizations, and severe ADRs affect between 6% and 15% of hospital patients.[10]

In our study, we compare hydrochlorothiazide, a diuretic in combination with amlodipine (CCB), telmisartan (ARB), and ramipril (ACEi), respectively, for their efficacy and safety profile.

MATERIALS AND METHODS

A randomized, prospective, real-world, single-center analysis study, focused on the comparative efficacy and safety of different antihypertensive fixed-dose combination (FDC) drugs in treating primary hypertension. Participants were randomly assigned to one of three groups: Group 1 received amlodipine 5 mg + hydrochlorothiazide 12.5 mg (A+H), Group 2 was administered telmisartan 40 mg + hydrochlorothiazide 12.5 mg (T+H), and Group 3 was treated with ramipril 5 mg + hydrochlorothiazide 12.5 mg (R+H). The total study duration was 12 months (including 6 months of follow-up). The follow-up included monitoring BP levels and the occurrence of any ADRs.

Ethical approval was secured, and written informed consent was obtained from each participant before their inclusion in the study. The study is registered with CTRI (CTRI/2023/09/057435).

The inclusion criteria targeted newly diagnosed hypertension patients of any sex, aged 18 years and older, and who had not previously been treated with antihypertensive agents. For diagnosis, JNC 8 guidelines were followed: individuals ≥60 started treatment when their SBP was ≥150 mmHg or DBP ≥90 mmHg. Those <60 began treatment at a DBP of ≥90 mmHg or SBP of ≥140 mmHg. Exclusion criteria included individuals under 18, those with any other comorbid conditions, patients previously diagnosed with hypertension and on any other hypertensive agent before, secondary hypertension, pregnancy, breastfeeding, active infections, or a history of significant cardiovascular events or carcinoma. Anyone not providing consent was also excluded from the study.

The sample size was computed by the formula: (n) = Z1−α/22 × p (1 − p)/d². Prevalence in India as quoted in previous studies is 29.8%.[11] The total sample size was 322, and considering the 10% loss of sample during the study, it was calculated to be = 354.

Data collection

Study design flowchart: Patient enrolment, randomization, and follow-up [Figure 1].

Figure 1.

Study design flowchart: Patient enrolment, randomization, and follow-up

Statistical analysis

Statistical significance was set at 95% (P < 0.05) with a study power of 80. Data were assessed as nonparametric via the Shapiro–Wilk test, underwent within-group comparisons using the Wilcoxon signed-rank test, and between-group analyses using the Kruskal–Wallis and Mann–Whitney U tests with Bonferroni correction, all performed on SPSS version 27.00 for Windows; SPSS Inc, Chicago, IL, USA.

RESULTS

Of all the enrolled 327 individuals, group analysis revealed that Group 1, Group 2, and Group 3 consisted of 109, 111, and 107 patients, respectively. Out of 327 cases, 172 were females and 155 were males. The mean age of presentation in years was 59 ± 13.4. Groupwise mean age of presentation in years was in Group 1 (56.11 ± 12.54, m = 53, f = 56), Group 2 (56.81 ± 12.94, m = 51, f = 60), and Group 3 (62.19 ± 12.91, m = 51, f = 56).

BP analysis of each group showed statistically significant changes at each follow-up period (15 days, 1 month, and then at monthly intervals till 6 months) (P < 0.001), showing that the changes in BP within each group across all time points were highly significant. Furthermore, negative Z-values were observed for each group at every time point, denoting a significant decrease in BP from the pretreatment values.

Intergroup comparisons revealed no considerable differences in SBP at 15 days, 1 month, then as followed up at monthly intervals up to 6 months, similarly for DBP considerable difference were present initially at 15 days and 1 month rest at all time period no differences were present [Table 1].

Table 1.

Intergroup comparison of blood pressure

Time interval	SBP (P)	DBP (P)
15 days	0.071	0.002
1 month	0.081	0.026
2 months	0.056	0.089
3 months	0.005	0.418
4 months	0.002	0.428
5 months	0.016	0.647
6 months	0.006	0.445

SBP=Systolic blood pressure, DBP=Diastolic blood pressure

In the analysis, pairwise comparisons among antihypertensive FDCs were made, using a Bonferroni correction to manage the increased risk of Type I errors from multiple tests. The alpha level was adjusted to 0.0167, recalculated by dividing the standard 0.05 by the three comparisons made.

On comparing the efficacy of drugs pairwise at 15 days, 1 month, then every month till 6 months, there was a statistically considerable difference in SBP reduction between Group 1 and Group 3 (P = 0.002) and between Group 2 and Group 3 (P = 0.010) at 3^rd month between Group 1 and Group 3 (P = 0.001) and between Group 2 and Group 3 (P = 0.004) at 4^th month. Another significant result was observed while comparing Groups 2 and 3 (P = 0.009) in the 5^th month and between Groups 2 and 3 in the 6^th month (P = 0.003). Apart from these, for other group comparisons, no significant changes were observed at all timelines [Table 2].

Table 2.

Comparative analysis of drugs used in hypertension at different time intervals (systolic blood pressure)

Drug group	SBP (P)
	SBP and P value at 3 months	SBP and P value at 4 months	SBP and P value at 5 months	SBP and P value at 6 months
A+H–T+H (Group 1–Group 2)	142.2±11.3–142.4±14.5 (0.763)	139.8±11.4–139.5±13.8 (0.703)	137.9±11.3–136.8±13 (0.312)	135.7±10.8–134.1±12.6 (0.220)
A+H–R+H (Group 1–Group 3)	142.2±11.3–146.5±10.7 (0.002)	139.8±11.4–144.1±10.4 (0.001)	137.9±11.3–140.7±10.1 (0.029)	135.7±10.81–138.3±9.7 (0.023)
T+H–R+H (Group 2–Group 3)	142.4±14.5–146.5±10.7 (0.010)	139.5±13.8–144.1±10.4 (0.004)	136.8±13–140.7±10.1 (0.009)	134.1±12.6–138.3±9.7 (0.003)

SBP=Systolic blood pressure

For DBP reductions, significant results were observed between Group 1 and Group 3 at 15 days (P ≤ 0.001) and between Group 1 and Group 3 at 1 month (P = 0.006). Rest all remained insignificant [Table 3].

Table 3.

Comparative analysis of drugs used in hypertension at different time intervals (diastolic blood pressure)

Drug groups	DBP (P)
	P value at 15 days	P value at 1 month
A+H–T+H (Group 1–Group 2)	90.7±8.4–89.1±8 (0.142)	87.2±8.3–86.3+8.4 (0.314)
A+H–R+H (Group 1–Group 3)	90.7±8.4–86.9±7.5 (<0.001)	87.2±8.3–84.7±7.7 (0.006)
T+H–R+H (Group 2–Group 3)	89.1±8–86.9±7.5 (0.027)	86.3+8.4–84.7±7.7 (0.109)

DBP=Diastolic blood pressure

The total number of ADRs reported was 78, assessed by the Naranjo Probability Scale;[12] percentage-wise distribution is shown in Table 4.

Table 4.

Percentage of adverse drug reactions for different groups of drugs used for the treatment of hypertension

Drug group	ADRs	Number of ADRs (%)
Amlodipine + hydrochlorothiazide	Pedal edema	7 (22)
	Dizziness	4 (13)
	Headache	4 (13)
	Palpitation	4 (13)
	Dyspnea	3 (9)
	Bradycardia	3 (9)
	Pruritus	3 (9)
	Skin rash	2 (6)
	Abdominal pain	1 (3)
	Ankle edema	1 (3)
	Total	32 (29.4)
Telmisartan + hydrochlorothiazide	Dizziness	5 (23)
	URTI	5 (23)
	Headache	4 (18)
	Diarrhea	3 (14)
	Nausea	3 (14)
	Abdominal pain	2 (9)
	Total	22 (19.8)
Ramipril + hydrochlorothiazide	Dry cough	6 (25)
	Headache	5 (21)
	Drowsiness	3 (13)
	Diarrhea	3 (13)
	Weakness	2 (8)
	Metallic taste	2 (8)
	Rash	2 (8)
	Dizziness	1 (4)
	Total	24 (22.4)

ADRs=Adverse drug reactions

The analysis of ADR across the three FDCs revealed varying incidence rates. The A+H combination recorded the highest at 29.4%, suggesting a higher frequency of adverse effects among patients using this combination. The R+H combination showed a slightly lower ADR incidence of 22.4%, which, while lower than the amlodipine combination, still constituted a considerable proportion. Conversely, the T+H combination demonstrated the lowest ADR rate at 19.8%, indicating better tolerability compared to the other combinations.

The data clearly indicate a variation in the safety profile. This could influence prescribing practices, particularly for patients who are more susceptible to side effects.

DISCUSSION

In our study on comparing the efficacy of FDCs of drugs in terms of their ability to reduce SBP, it was concluded that Group 2 was significantly more effective than Group 1 and Group 3 in reducing SBP over six months also at the end of 6 months all the Group were equally efficacious in reducing DBP. Conducted at a single center with a limited sample size, the study faces risks of statistical errors and limitations due to the lack of blinding, placebo controls, and short duration.

In our study, T+H was significantly better than A+H in controlling SBP. Neldam et al.[13] also showed that throughout the entire 24-h period, T+H was more effective (−19.3 mmHg compared to − 17.2 mmHg; P = 0.001) than A+H and achieved greater systolic control rates (65.9% vs. 58.3%; P = 0.0175). Similar to our study, Bhushan et al.[14] showed significant reductions in SBP and DBP compared to baseline values (P < 0.0001), but here intergroup comparisons revealed no statistically considerable differences in SBP and DBP decrease among the groups, which differed from our study.

In the present study, T+H showed a significant fall in SBP than its individual components, that is in conformity with the following studies.[15,16,17] Research indicates that the combination of T+H is more effective because hydrochlorothiazide activates the renin-angiotensin-aldosterone system (RAAS), enhancing the effects of RAAS-blocking drugs. Excess salt intake reduces these drugs’ effectiveness as BP becomes volume dependent, but adding a diuretic restores efficacy by increasing dependence on renin activity.[18]

Aligning with the findings of previous research[19] the group treated with A+H demonstrated a notable decrease in SBP than with hydrochlorothiazide alone.

In a number of studies, R+H combination has shown a decline in both SBP as well as DBP with their respective components.[20,21,22] The inclusion of ramipril helps counteract the side effects of hydrochlorothiazide, such as hypokalemia, hyperuricemia, hyperglycemia, and hypercholesterolemia, due to their complementary mechanisms of action.[18]

A total of 78 ADRs were observed in 327 hypertensive patients (155 male and 172 female) during 6 months of the study. On comparing ADRs between various groups, A+H showed maximum number of ADRs (29.4%) while T+H showed minimum (19.8%).

A higher percentage of ADRs occurred in males – 41 (53%) than females – 37 (47%). A similar study by Sharma et al. (2018)[23] and Chandra et al.[24] supported our findings. The presumed reason for a higher count of male patients could be the increased levels of androgens like testosterone, which are known to contribute to raised blood pressure.[24] Conversely, Khurshid et al.[25] found that female experienced more ADRs, which contrasted with our results.

Comparable to my study where there was lesser incidence of ADRs in T+H group than A+H group, Neldam et al.[13] also showed that ADRs (41.2% for telmisartan and 53.7% for amlodipine) and cessation (5.0% for telmisartan and 11.3% for amlodipine) were significantly less with telmisartan compared to amlodipine (P < 0.0001). In this study, T+H has lesser number of adverse events than R+H, similarly in a study conducted by Bhushan et al.[14] Group I (R+H) experienced a higher total number of ADR events compared to Group II (T+H), with dry cough being the most frequent ADR in Group I.

CONCLUSION

This real-world study assesses the efficacy and safety of different antihypertensive FDC drugs in a real-world clinical setting. The T+H combination was most effective in lowering SBP, with all combinations showing similar efficacy in managing DBP. The T+H group also had the lowest incidence of adverse drug reactions. Future multicentric, larger-scale studies with extended follow-ups are recommended to confirm these findings and improve treatment strategies.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.