CRCM

Introduction

Coronary artery disease (CAD) is a common heart condition that involves atherosclerotic plaque formation in the vessel lumen leading to impairment in blood flow and thus oxygen delivery to the myocardium [1]. It can progress to congestive heart failure (HF) [1]. In 2022, the age-standardized prevalence of CAD was 3605 (2892 to 4454) per 100000 [2]. Studies have shown that 50–60% of CAD patients had comorbid hypertension (HTN), and 13% HTN patients had comorbid CAD [3]. Epidemiological studies have established a strong association between HTN and CAD. HTN is a major independent risk factor for the development of CAD, stroke, and renal failure [4]. Pathophysiological mechanisms of blood pressure as a risk factor for CAD are complex and include the influence of blood pressure as a physical force on the development of atherosclerotic plaque, and the relationship between pulsatile hemodynamic/arterial stiffness and coronary perfusion [5]. A meta-analysis by Lewington S et al reported that at ages 40-69 years, each difference of 20 mmHg usual SBP (or 10 mmHg usual DBP) is associated with more than a twofold difference in the stroke death rate, and with twofold differences in the death rates from ischemic heart diseases (IHD) and from other vascular causes [6]. 2017 AHA/ACC guidelines for HTN management lowered the BP target to BP <130/80 mmHg in the population with CAD [7].

β-Blocker administration remains the standard of care in hypertensive patients with angina pectoris or prior MI, or LV dysfunction with or without symptoms of HF unless contraindicated. The β-blockers carvedilol, metoprolol, and bisoprolol have been shown to improve outcomes in patients with HF [8]. Bisoprolol is reported to be well-suited as the first-line treatment of angina in primary care [9]. Bisoprolol can effectively reduce resting heart rate in Asian CAD patients with comorbid HTN and hence, improve composite cardiac clinical outcome [10].

Several angiotensin receptor blockers (ARBs) have been shown to reduce the incidence or severity of IHD events, the progression of renal disease in type 2 diabetes mellitus, and cerebrovascular events [8]. Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) study reported that Telmisartan was well tolerated in patients unable to tolerate ACE inhibitors and modestly reduced the risk of the composite outcome of cardiovascular death, myocardial infarction, or stroke [11]. ARB is one of the five classes of antihypertensive drugs recommended as first-line treatment for stage 1–2 HTN by Indian guidelines on HTN-IV [12].

Combination antihypertensive drug therapy is typically needed to achieve and sustain effective long-term BP control [4]. Two neurohormonal systems, the sympathetic nervous system (SNS) and renin–angiotensin–aldosterone system (RAAS), are intricately involved in the progression of disease throughout the cardiovascular disease continuum [13]. Therefore, there is a considerable rationale for combining pharmacological therapies that target both neurohormonal pathways [13].

There is insufficient evidence on the efficacy and safety of the bisoprolol with telmisartan combination and its potential in treating CAD patients with uncontrolled HTN. To date, limited real-world evidence is available evaluating the effectiveness and safety of the telmisartan and bisoprolol combination in Indian patients with CAD and uncontrolled hypertension. Thus, the purpose of this study was to determine the effectiveness and safety of Telmisartan 40mg+ Bisoprolol 2.5/5mg for the management of HTN in Indian CAD patients.

Method

This was an investigator-initiated, multicenter, prospective, observational, population-based study conducted across 50 sites in India from July 2024 to Dec 2024 to understand the effectiveness and safety of Telmisartan 40mg+ Bisoprolol 2.5/5mg for the management of HTN in CAD patients with uncontrolled HTN.

The study was initiated after receiving approval from the Suraksha Ethics Committee. The study was conducted following ‘The Declaration of Helsinki’ principles (World Medical Association) and Good Clinical Practice (GCP) Guidelines issued by the ICMR & DCG(I), Govt. of India. The study was explained to the patients in detail, and they were recruited only after receiving voluntary written informed consent.

The inclusion criteria were adult patients of either sex aged ≥18 and ≤85 years; diagnosed with CAD with or without heart failure with normal cardiac function or with HFrEF (≤40% LVEF), and long-standing uncontrolled HTN (blood pressure (BP) > 140/90 mmHg) on existing therapy of ACE-I/ARB + BB; and patients who were switched from existing therapy to Telmisartan 40mg + Bisoprolol 2.5/5mg as per the prescription of treating physicians and at investigator discretion as part of routine clinical practice.

Exclusion criteria were pregnant or breastfeeding female patients; patients suspected of or known to have an intolerance to any of the drugs prescribed; presence of any other clinically significant disease or laboratory findings that in the Investigator’s opinion may affect the study outcomes or continued participation of the patient in the study; and the patients participating in another study concurrently or within 4 weeks before the Screening Visit.

Study medications were Telmisartan 40mg+ Bisoprolol 2.5/5mg as per the prescription of treating physicians, and the study duration was 12 weeks.

Primary outcome: Percentage of patients achieving the target blood pressure (Systolic BP (SBP):120-130 mmHg/ Diastolic BP (DBP):70-80 mmHg) at the end of the treatment after 12 weeks.

Secondary outcomes:

• Percentage of patients achieving the target blood pressure (SBP:120-130 mmHg/DBP: 70-80 mmHg) after 4 weeks and 8 weeks of treatment

• Mean reduction in seated SBP and DBP after 4, 8, and 12 weeks of treatment (Average of 3 BP readings measured using an Automated Office BP Machine)
• Mean reduction in SBP and DBP from supine to standing position after 4, 8, and 12 weeks of treatment (average of three BP readings measured using an automated office BP machine)
• Evaluation of echocardiography, ECG, HbA1c, random glucose, serum creatinine, lipid profile, and eGFR at baseline and 12 weeks of treatment; serum electrolytes/potassium (optional at 4 & 8 weeks), echocardiography, serum potassium & ECG

• Physician’s global assessment of treatment post-completion of the treatment regimen
• Safety and tolerability assessment of treatment postcompletion of the treatment regimen (Serious ADRs and any other ADRs )
• Mean Change in score of SF-36 Quality of Life Questionnaire after 4, 8, and 12 weeks of treatment

Eligible patients on enrollment in the study underwent diagnostic and laboratory tests at baseline and 12 weeks (ECG, ECHO, HbA1c, random glucose, serum creatinine, eGFR, serum electrolytes, lipid profile). Patients were requested to visit the site once every 4 weeks for follow-up. During the follow-up visit, the patient’s disease status (heart rate (HR) and BP) was evaluated. The physician’s global assessment of the treatment post-completion of the treatment regimen was done at 12 weeks. The detailed schedule of procedures is provided in Table 1.

Statistical Analysis

Demographic Characteristics: Continuous data such as age and weight were summarized with n, mean, SD, and range. Categorical data such as sex were depicted with count (%).

Efficacy Analysis: For continuous variables such as SBP & DBP at different clinical postures, heart rate, serum electrolytes, HbA1c, random glucose, eGFR, and serum creatinine, mean change from baseline was derived and paired t-test was applied to assess statistical significance. For categorical variables such as the percentage of patients achieving target blood pressure at 4, 8, and 12 weeks, heart rate & ECG, ECHO, other laboratory parameters, and safety & tolerability, results were summarized with count (%). If applicable, chi-square test was performed to assess statistical significance. A p-value of <0.05 was considered statistically significant.

Safety Analysis: Incidences of adverse events were summarized with count (%). Other safety measures such as physical examination and vital signs were summarized using descriptive statistics and change from baseline, if applicable.

Results

A total of 157 eligible subjects were enrolled in the study, of whom data were considered for final analysis. The CONSORT flowchart detailing patient enrolment is presented in Figure 1.

Figure 1: CONSORT Flowchart of Participant Recruitment

Patient Demographics

Out of 157, 82(52.2%) were male and 75 (47.8%) were female. The mean age of the study population was 56.58(11.34) years, and the mean weight was 72.43(8.92) kg. A total of 43 (27.2%) of the patients had diabetes mellitus, 34 (21.5%) had dyslipidaemia, and 25 (15.8%) patients had CAD.

The study population’s demographics, along with vitals at baseline and concomitant medical history, are presented in (Table 2).

Table 2: Summary Statistics of Demographics

Baseline prescribed dosage of FDC, Telmisartan (40mg) + Bisoprolol (2.5/5mg)

A total of 85 (54.14%) of the subjects were prescribed Telmisartan (40mg) + Bisoprolol (5mg), while 75 (45.85%) were prescribed Telmisartan (40mg) + Bisoprolol (2.5mg).

Effectiveness Parameters

No. of subjects achieving target BP

The primary objective of the study was to evaluate the percentage of patients achieving the target blood pressure (120-130 mmHg SBP/70-80 mmHg DBP) at the end of 12 weeks of the Telmisartan 40mg + Bisoprolol 2.5/5mg treatment.

 At the end of 12 weeks of study treatment, 37 (23.56%) of the subjects reached the target SBP <130 mmHg, and 108 (68.78%) of the subjects achieved the target DBP of 70-80 mmHg in the sitting position.

A total of 20 (12.74%) of the subjects attained the target SBP/DBP of <130 mmHg / 70-80 mmHg (sitting) at the end of 12 weeks.

A summary of the number (%) of study subjects achieving target SBP and DBP at each follow-up visit in sitting, supine, and standing positions is provided in Figure 2 (A and B).

Figure 2 (A and B): A summary of the % of subjects achieving target SBP and DBP at each follow-up visit.

The secondary objective was to understand the mean change in SBP and DBP from baseline to each follow-up visit in sitting, supine, and standing positions.

Changes in SBP: One of the effectiveness parameters recorded for this clinical study was the mean change in sitting, supine, and standing SBP (mmHg) for all patients during Baseline Visit, Follow-up Visit 1, 2 and 3 (Final Visit).

With study treatment, a statistically significant reduction (p < 0.001) was observed at each visit.

Sitting SBP: The mean baseline sitting SBP decreased from 158.11(12.43) mmHg to 134.43(6.85) mmHg at follow-up visit 3, i.e., at the end of the 12-week study treatment.

Supine SBP: The mean supine SBP at baseline was 157.86(12.83) mmHg. It reduced to 134.11(8.06) mmHg at final visit.

Standing SBP: The mean standing SBP at baseline was 155.82(12.75) mmHg, which decreased to 133.03(7.044) mmHg with 12 weeks of Telmisartan 40mg+ Bisoprolol 2.5/5mg treatment.

A comparison of mean SBP (sitting, supine, and standing) at each visit is presented in Table 3. A comparison of mean reductions at each visit is presented in Figure 3 (A-C).

Table 3: Comparison of changes in mean SBP (sitting, supine, and standing) at each visit

Figure 3 (A-C): A Comparison of mean reductions in SBP (sitting, supine, and standing) at each visit from baseline

Changes in the mean DBP (mmHg):

Other effectiveness parameters included the change in mean DBP. The study observed statistically significant reductions in mean sitting, supine, and standing DBP from baseline to consecutive follow-up visits at weeks 4, 8, and 12. Statistically significant (p < 0.001) reductions were observed across all follow-up visits in sitting, supine, and standing DBP.

Sitting DBP: The mean baseline sitting DBP was 93.41(3.74) mmHg. It reduced by 12.01 mmHg to 77.44(7.13) mmHg at week 12.

Supine DBP: The mean supine DBP at baseline was 92.36 (5.06) mmHg and decreased by 15.31 mmHg to 77.05 (7.51) mmHg at final visit.

Standing DBP: The mean standing DBP at baseline was 91.38 (3.82) mmHg. It decreased by 14.3 mmHg to 77.08 (6.81) mmHg at final visit.

A comparison of mean DBP (sitting, supine, and standing) at each visit is presented in Table 4. A comparison of mean reductions at each visit is presented in Figure 4 (A-C).

Table 4: Comparison of changes in mean DBP (sitting, supine, and standing) at each visit

Figure 4(A-C): A comparison of mean reductions at each visit in sitting, supine, and standing DBP at each visit from baseline

Figure 4A: A comparison of mean reductions in sitting DBP from baseline

Figure 4B: A comparison of mean reductions in Supine DBP from baseline

Figure 4C: A comparison of mean reductions in Standing DBP from baseline

One of the secondary objectives was to assess the changes in available ECG, echocardiograph, and laboratory parameters (HbA1c, random glucose, serum creatinine, lipid profile, and eGFR) from baseline to final visit.

Analysis of Summary Statistics of ECG and Echocardiograph

ECG: One of the safety parameters recorded for this clinical study was ECG at baseline and final visit. At baseline, out of 157 patients, ECG details of 128 patients were available. For the final visit, ECG details of 44 subjects were available. At final visit, none of the patients’ ECGs recorded atrioventricular block. The summary statistics of ECG results of the baseline and final visits are presented in Table 5.

Table 5: Summary of ECG results

The summary statistics of the available echocardiograph reports from the baseline and final visits are presented in (Table 6).

Table 6: Summary of Echocardiography Results

Analysis of available Laboratory and Diagnostic Assessments:

The summary statistics of the mean change from baseline to the final visit (Visit-3) for HbA1c, Random Blood Glucose, eGFR, and Serum Creatinine are presented in Table 7.

The mean difference at the final visit from baseline in HbA1c was -0.19%, random blood glucose was -0.68 mmol/L, eGFR was 0.6 ml/ min/1.73m2, and serum creatinine was -0.02 mg/dL.

The difference in mean HbA1c was statistically significant.

Table 7: Summary Statistics of Laboratory and Diagnostic Assessments

Mean changes in serum potassium and serum cholesterol from baseline to week 12 (final visit) are presented in Table 8. Both parameters reported statistically significant reductions in mean values from baseline by 3.19 and 5.99, respectively.

Table 8: Summary of changes in mean serum potassium and cholesterol

Physician’s global assessment of treatment post-completion of the treatment regimen:

One of the efficacy parameters recorded for this clinical study was Physician’s global assessment of treatment.

A total of 77.3% of the physicians were satisfied with the improvement in the patient’s ability to perform daily activities following Bisoprolol + Telmisartan administration.

Figure 5: Graphical Representation of Physician’s global assessment of treatment: “How Satisfied are you with the improvement in the patient’s ability to perform daily activities following Bisoprolol + Telmisartan administration?”

“How likely would you recommend the usage of Bisoprolol + Telmisartan in existing coronary artery disease (CAD) patients with uncontrolled HTN?”

One of the efficacy parameters recorded for this clinical study was Physician’s global assessment of treatment: “How likely would you recommend the usage of Bisoprolol + Telmisartan in existing coronary artery disease (CAD) patients with uncontrolled HTN?” Summary statistics are presented in Table 9 and Figure 6 below.