Tolerability of Angiotensin Receptor Neprilysin Inhibitor (ARNI) with Two Classes of Beta-Blockers: A Real-world Retrospective Study in a Tertiary Hospital Volume 50- Issue 5

Razan Alqadi¹, Faisal Alqarni¹, Abdulaziz Alqadi¹*, Mohammed alsultan², Saleem Alanazi³, Abdullah Alzahrani¹, Ahmad Alharthi³, Abdulmajed Alshahrani¹, Khalid Almutairi³ and Sultan Alharbi³

• ¹Department of Pharmacy, Security Forces Hospital, Saudi Arabia
• ²Department of Pharmacy Practice, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Saudi Arabia
• ³Department of Cardiology, Security Forces Hospital, Saudi Arabia

Received: May 24, 2023;   Published: June 02, 2023

*Corresponding author: Abdulaziz Alqadi, Department of Pharmacy, Security Forces Hospital, Riyadh, Saudi Arabia

DOI: 10.26717/BJSTR.2023.50.008009

Abstract PDF

Objective: Our study compares the use of ARNI plus Carvedilol or ARNI plus Bisoprolol in real-world settings to assess suboptimal ARNI use due to hypotension.

Methods: A respective single-center study was performed in a tertiary hospital in the Riyadh region from 2017 to 2021. We studied individuals diagnosed with HFrEF who have started using ARNI drugs. First patients who were on ARNI plus Bisoprolol, while the second group included patients who were on ARNI plus Carvedilol. A descriptive analysis was conducted, and a chi-square test was used to assess the differences between categorical variables and outcomes. The statistically significant p-value was less than 0.05.

Results: Our study included 151 participants, of which 96 received the medication Bisoprolol and 55 received the medication Carvedilol. In the two groups, the average patient age is about 55 years old. In the two therapy groups, there were no significant differences in age or gender (p > 0.05). Also, both the bisoprolol and the carvedilol groups had mean systolic blood pressure values of about 126 mmHg. The suboptimal ARNI use confirmed that none of the beta-blockers was superior to the other in terms of suboptimal ARNI use due to hypotension, hyperkalemia, and elevated serum creatinine (p > 0.05). Finally, the difference between the bisoprolol and carvedilol groups regarding the discontinuation, the downtitration, and the maintenance of initial or medium doses of ARNI use was non-significant for all three events.

Conclusion: The utilization of either bisoprolol or carvedilol as the beta blocker of choice in therapeutic regimens of HFrEF with sacubitril/valsartan, as they provide the same level of ARNI tolerability.

Keywords: Heart Failure; ARNI; Beta-Blockers; Bisoprolol; Carvedilol

Abbreviations: HF: Heart Failure; ACEIs: Angiotensin-Converting Enzyme Inhibitors

Heart failure (HF) is a serious medical problem in Saudi Arabia, where people’s quality of life is still significantly impacted despite the use of advanced therapies [1]. Thirty years ago, angiotensinconverting enzyme inhibitors (ACEIs) had been demonstrated to reduce overall HF mortality by 16–40% [2,3]. Angiotensin-receptor blockers (ARBs) have similar effects as ACEIs but work by blocking the AT1 receptor and interfering with the action of angiotensin II. In 2001, the Val-HeFT trial established the use of ARB therapy for patients diagnosed with HF [4]. Three beta-blockers for HF, namely bisoprolol, carvedilol, and sustained-release metoprolol, can block adrenergic activation and lead to a substantial reduction in mortality [5-7]. The mineralocorticoid receptor antagonist (MRAs) spironolactone has been proven to reduce mortality by 30% among patients already receiving ACEIs in the RALES trial [8]. Also, the EMPHASIS-HF trial in 2011 justified and expanded the utilization of MRA eplerenone in patients with mildly symptomatic HF [9]. The cornerstones of modern HF therapy are these neurohumoral antagonists. As a result, after the PARADIGM-HF trial’s release in 2014, there was a significant paradigm change in HF therapy [10]. The trial showed that, compared to enalapril, a novel strategy to HF medication called angiotensinreceptor and neprilysin inhibition (ARNI) by the combination of sacubitril and valsartan resulted in a 20% reduction in cardiovascular mortality and a 16% reduction in all-cause mortality.

The American College of Cardiology (ACC), American Heart Association (AHA), and European Society of Cardiology (ESC) recently updated evidence-based recommendations for the management of HF, according to this study [11,12]. Both guidelines provided class I, level of evidence B recommendation to replace ACEIs by sacubitril/valsartan in patients with chronic symptomatic HF with reduced ejection fraction (HFrEF) despite optimal treatment [13]. In HFrEF, β-blockers have a well-known record of reducing mortality and hospitalization [14]. Carvedilol therapy is a multiple action non-selective β-adrenergic receptor blocker that also induces α1- adrenergic receptor blockade and has been shown to improve the state of HF patients in several large-scale trials [7]. However, the most common adverse clinical effects of carvedilol include dizziness and hypotension, which appear to be mainly related to an α1 blockade effect (vasodilation). On the other hand, bisoprolol, a highly selective β1-adrenergic receptor blocker, has also been found to be effective for HF patients in multiple studies [15]. Patients with heart failure and a lower ejection fraction (HFrEF) frequently have low blood pressure. Although spontaneous hypotension is a risk indicator for HFrEF, there is only weak evidence linking hypotension experienced during heart failure (HF) drug titration to prognosis. In clinical trials, around 10- 15% of patients with heart failure (HF) reported having low blood pressure (BP), even though this percentage is substantially greater in everyday clinical practice [2,7,10].

Low BP in HFrEF may have multiple origins, such as low cardiac function, hypovolemia, treatment-related vasodilatation, and altered vasoreactivity related to comorbidities. On the background of several landmark trials, a totally well-established arsenal of medications for the treatment of HFrEF exists. Therefore, clinical practice guidelines strongly articulate recommendations for the initiation and titration of these therapies to target doses. In daily clinical practice, dose adjustment of HFrEF drugs relies on signs and symptoms of HF, BP, and heart rate, biological parameters (mainly creatinine, serum potassium, hemoglobin, and natriuretic peptides), or imaging parameters [11,12,16-18]. Low blood pressure (90 mmHg) is the commonly used measure of low blood pressure in HF patients since it has been consistently highlighted as an indicator of a bad prognosis in cases of acute HF. Target dosages of medications for HFrEF may be difficult due to dose-related declines in BP since clinicians are reluctant to further titrate therapies [12]. Low BP has been observed to frequently restrict the usage and up-titration of some life-saving medications in HFrEF and can lead to stopping these medications [19,20]. Yet, when compared to patients with greater BP, HFrEF patients with low BP levels may potentially benefit from these medications [21,22]. The approved ARNI is available in three doses that include one that was not tested in the HF trial; the target dose of valsartan/sacubitril used in the trial was 97/103 mg twice daily [23].

Theoretically, the use of Carvedilol with ARNI makes the patient more susceptible to hypotension, which limits the successful titration of ARNI and increases the incidence of suboptimal ARNI use. To the best of our knowledge, the suboptimal due to hypotension with the use of two different classes of β-blocker has not been compared or studied yet. Therefore, the aim of our study is to assess suboptimal ARNI use due to hypotension between the use of ARNI plus Carvedilol or ARNI plus Bisoprolol in real world settings.

Study Design

A single-center, retrospective observational cohort study was conducted at the Security Forces Hospital Program in Riyadh from January 2017 to June 2021.

Study Population

Our target population is patients diagnosed with HFrEF who have started using ARNI drugs. To achieve our outcomes, we divided the patients into two groups in our study. The first group was made up of patients who were on ARNI plus Bisoprolol, while the second group included patients who were on ARNI plus Carvedilol.

Inclusion and Exclusion Criteria

In our study, we included patients ages 18 and older diagnosed with HF with a reported LVEF less than 40% by echocardiography test and using either carvedilol or bisoprolol and started on ARNI. On the other hand, patients who lost follow-up or were on any antihypertensive medication that was not one of the guidelines-directed medical therapies were excluded from our study [11].

Data Collection

Data collection from the patient’s medical records was used to gather baseline demographic data, including age, sex, LVEF, blood pressure, serum potassium, and creatinine. It also included administered beta-blocker dose and administered ARNI dose. Also, variables like BP, LVEF, beta blocker and ARNI doses, serum potassium, and serum creatinine levels were assessed after the start of ARNI and for up to six months after the start.

Outcomes

The primary outcome is to assess the suboptimal ARNI use due to hypotension between the use of ARNI with Carvedilol and ARNI plus Bisoprolol. On the other hand, the secondary outcome, compares the suboptimal ARNI use between the use of ARNI plus Carvedilol and ARNI plus Bisoprolol due to hyperkalemia or elevated serum creatinine. We also compared how these two groups differed in terms of heart failure with improved ejection fraction (HFimpEF) [24].

Definition of ARNI Use

In our study, the criteria of suboptimal ARNI use involves discontinuation of ARNI, down-titration of ARNI dose, or maintaining the initial or medium ARNI doses [25]. Also, the definition of reasons for suboptimal ARNI use is hypotension, determined as the systolic blood pressure being less than 100 mm Hg, hyperkalemia reported to be more than 5.5 mmol/liter for the potassium level, and elevated serum creatinine by more than 30% [10].

Statistical Analysis

A descriptive analysis of the baseline characteristics of the individuals was applied. The median and standard deviation were used for the continuous variables, while percentages and frequencies were used for the categorical variables. The chi-square test was used to assess the differences between categorical variables and outcomes. The cutoff values were p< 0.05, which indicate statistically significant results. The Statistical Package for Social Science (SPSS) version 25 was used to analyze the collected data.

In our study, 151 patients were included; 96 of them received the bisoprolol medication, and 55 received the carvedilol medication. In the bisoprolol group, the mean patient age was 56 years, and 74% of the patients were men, while the mean patient age in the carvedilol group was 54 years, and 63.6% of the patients were men. Age and gender did not significantly differ between the two treatment groups, according to our findings (p > 0.05). The mean systolic blood pressure in the bisoprolol group was 127.97 mmHg, whereas it was 125.31 mmHg in the carvedilol group, which did not statistically differ from one another (p = 0.317). There was no significant different between the bisoprolol group’s mean serum creatinine level of 89.61 mg/dl and the carvedilol group’s mean serum creatinine level of 91.29 mg/dl (p = 0.732). Furthermore, the mean potassium level was 4.31 mmol/liter in the bisoprolol group and 4.37 mmol/liter in the carvedilol group, with no significant difference between both groups (p = 0.490). Finally, there was no statistically significant difference between the bisoprolol group’s baseline LVEF of 28.11% and the carvedilol group’s baseline LVEF of 26.55% (p = 0.258). (Table 1) represented the characteristics of the patients in our study. The suboptimal ARNI use confirmed that none of the beta-blockers was superior to the other in terms of suboptimal ARNI use due to hypotension (p=0.515). In addition, the suboptimal ARNI use confirmed that none of the betablockers was superior to the other in terms of suboptimal ARNI use due to hyperkalemia (p=0.929) and elevated serum creatinine (p=0.914).

Table 1: Baseline Characteristics of the Patients.

Note: p-value < 0.05

There was no significant different between the bisoprolol and carvedilol groups regarding the improvement in EF being greater than 40% at a 6-month interval (p=0.527). Furthermore, the difference between the bisoprolol and carvedilol groups regarding the discontinuation, the down-titration, and the maintenance of initial or medium doses of ARNI use was non-significant for all three events (p> 0.05). Finally, the target dose of a beta blocker at the end of six months did not significantly differ between the two groups (p=0.767) which is shown in (Table 2).

Table 2: Outcomes of ARNI Plus either Bisoprolol or Carvedilol in Heart Failure Patients.

Note: p-value < 0.05

According to our study, individuals with HFrEF who started using ARNI after taking Bisoprolol or Carvedilol experienced similar suboptimal ARNI use due to hypotension and other reasons. Patients with HFrEF who are in NYHA functional classes II to III have showed a decrease in mortality and hospitalization rates in several randomized trials of particular beta blockers, such as carvedilol, metoprolol succinate, and bisoprolol [5,26-29]. A meta-analysis has shown that beta blockers are beneficial for reducing mortality after one and two years [30]. A randomized double-blind experiment (PARADIGM-HF) also demonstrated sacubitril/superiority valsartan’s to enalapril in the treatment of HFrEF [10]. A study has reported that patients who receive beta blockers and ARNI at 50% to 99% of their target dose (TD) have a better prognosis than those who only receive one of these medications at more than 100% of the TD [31]. It has also been shown in another study that the use of beta-blockers, reninangiotensin system inhibitors, and angiotensin receptor neprilysin inhibitors is related with a lower risk of mortality and morbidity in patients with heart failure [32]. Nevertheless, hypotension is one of the major preventive measures in achieving optimal pharmacologic therapy doses for HFrEF and may be exacerbated or induced by concomitant ARNI and beta-blocker therapy. Additionally, compared to enalapril, sacubitril/valsartan has been seen to have a greater risk of symptomatic hypotension [10].

In our study, among the three main causes of suboptimal ARNI use identified in the current research, hypotension was the most frequent reason, with an average of 42.1% between the two study groups. Although 43.8% of the patients in the bisoprolol group and 40.4% of those in the carvedilol group received suboptimal ARNI use due to hypotension, the difference between the beta-blocker arms was negligible. Our results suggest that neither of the two beta blockers investigated is statistically inferior to the other in terms of the incidence of suboptimal ARNI use due to hypotension. The result is in accordance with other studies comparing bisoprolol and carvedilol in patients with heart failure [33-35]. The HEAAL trial, has pointed out that the clinical benefit of a high-dose ARB comes with an increased risk of kidney impairment, hyperkalemia, and hypotension [36]. However, lower rates of hyperkalemia and renal impairment have been reported with ARNIs [10]. In our study, elevated serum creatinine and hyperkalemia accounted for an average of 15% and 7.5% of suboptimal ARNI use, respectively. However, the results suggest that none of the two beta blockers investigated is inferior to the other in terms of the incidence of suboptimal ARNI use due to hyperkalemia or elevation in serum creatinine. After six months, 14.5% of patients in the carvedilol group and 19.8% of patients receiving bisoprolol had improved ejection fraction (EF > 40%), however this difference was not statistically significant.

The result of the current work is in line with a network metaanalysis of 21 trials with a focus on atenolol, bisoprolol, bucindolol, carvedilol, metoprolol, and nebivolol, where β-blockers illustrated obvious mortality benefits in comparison with standard treatment or placebo after 12 months, which showed the improvements in left ventricular ejection fraction were similar irrespective of the individual study drug [37]. Moreover, we concluded that regarding discontinuation, down-titration, or maintained initial or medium doses of ARNI, both beta blocker classes indicated unremarkable differences. Overall, our results comparing the two different beta blockers depict that there is no class superiority between bisoprolol and carvedilol concerning our primary outcomes. Conversely investigators have opined that due to carvedilol’s vasodilatory effect, it could exert more clinically vigorous outcomes in HFrEF in contrast to selective beta inhibitors, including bisoprolol and metoprolol. The COMET (Carvedilol or Metoprolol European Trial) study, a large randomized controlled trial comparing carvedilol and metoprolol, found that carvedilol extended survival compared to metoprolol in patients with chronic heart failure [38]. Meanwhile, this study had two major limitations. First, metoprolol tartrate, which has not been proven to reduce mortality in HF and is not advised by guidelines, was compared to carvedilol. Second, lower than recommended doses of metoprolol were provided compared to the full indicated dose of carvedilol. The mortality benefits of carvedilol and bisoprolol were comparable in a multicenter cohort study carried out in Korea, which supports our interpretation [39].

It is important to understand this study in light of its limitations. First, the small number of patients that were enrolled in the study is its primary limitation. Second, during the trial period, only 20.8% of the patients were on the target dose of beta blockers. Finally, most of the sample was made up of men, which might make it difficult to generalize the findings to include both genders. Therefore, it is essential that a bigger, randomized clinical trial be performed with a larger sample size.

Our findings support the use of either bisoprolol or carvedilol as the beta blocker of choice in therapeutic regimens of HFrEF with sacubitril/valsartan, as they provide the same level of ARNI tolerability.

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